WO2004112819A1 - Compositions and methods of treatment comprising plant extracts - Google Patents

Abstract

Methods of treating a disease associated with prolonged or excessive activation of NF-kB are provided, comprising administering a composition comprising at least one plant extract from a plant that is a source of sesquiterpene lactone, or a composition comprising a sesquiterpene lactone in an effective amount to a patient in need thereof. In a preferred embodiment, the plant extract is extracted from feverfew, and the sesquiterpene lactone is parthenolide. In a preferred embodiment of the invention, the composition is administered via a route that bypasses the GI tract. In another preferred embodiment of the invention, the composition is administered in an amount of active ingredient that is surprisingly low.

Description

Compositions and Methods of Treatment Comprising Plant Extracts

FIELD OF THE INVENTION

The present invention relates to compositions and methods of treatment. It more particularly relates to a means of benefiting an animal by the effective administration of compositions comprised of a sesquiterpene lactone, or a plant extract from a plant that is a source of sesquiterpene lactone. The present invention more particularly relates to a practical and advantageous means of treating various specific and types of maladies and conditions, especially those known or thought to involve the NF-kB pathway, its components, modulators, products and effects. BACKGROUND OF THE INVENTION Without intending to be bound, limited or reliant on any particular theory, it appears evident that the NF-kB (Nuclear Factor-kB) pathway is a very important regulatory pathway, that it is present in nearly all mammalian cells, and that its regulation or dysregulation can and often does have a significant impact on the health and well being of the organism. Therefore effective, previously unknown compositions and methods of potentially modifying the activity of this regulatory pathway are of great value and tremendous usefulness, especially when such compositions and methods are economical, convenient, and might be employed in such a manner as to be relatively free from serious side effects.

A transcription factor, NF-kB regulates gene expression, especially of those genes coding for inflammation and immune response. To date there are more than 150 genes found to be regulated by NF-kB (Pahl, 1999). The components of the NF- kB pathway are intimately involved in many important signaling pathways. NF-kB is a family of transcription factors that was originally identified in B cells (in 1986) but was then found to be ubiquitously expressed and also phylogenetically conserved down to Drosophila. Under basal conditions, NF-kB is sequestered within the cytoplasm by the Ik

B family of inhibitory proteins. In response to various stimuli, especially pro- inflammatory stimuli, IkB is phosphorylated by the IkB Kinase Complex (IKK). Phosphorylation of two Ser residues on IkB triggers its ubiquination and rapid degradation, thereby releasing NF-kB for translocation into the nucleus and subsequent stimulation of gene expression. The IKK Complex is composed of two catalytic subunits, IKKA, IKKB and a third, non-catalytic subunit, IKKC (also known as NEMO). IKKA is important in early embryonic development of the skin and skeletal system. IKKB and NEMO are indispensable for cytokine signaling. For example, cells lacking IKKB are entirely unresponsive to tumor necrosis factor-a (TNFa) or interleukin-1 (IL-1) stimulation. As another example, while the mechanism and pathway of iNOS and COX-2 induction is complex and still incompletely understood, it presently appears that the inhibition of NF-kB (especially, in the case of COX-2, and then especially with the simultaneous inhibition of NF-AT) results in the reduction or elimination of COX-2 and iNOS activity.

NF-kB family members include RelA (p65), RelB, c-Rel, NF-kB 1 (p50), and NF-kB2 (p52), the latter two being synthesized from the inactive precursor molecules p 105 and p 100 respectively. NF-kB subunits form homo- and heterodimers, the most prominent one being the p65/p50 heterodimer, and bind to the decameric consensus sequence GGGRNNTTCC (R=G or A, Y=C or T, Nis any nucleotide). Under basal conditions this dimer remains sequestered in the cytoplasm, in an inactive state, by means of its interaction with IkB. ΝF-kB is rapidly activated in response to a variety of inflammatory and other stimuli that lead to degradation of IkB. Fig. 1 is a schematic representation of ΝF-kB activation via the IKKB subunit of the IKK Complex.

IKKB, an active catalytic subunit of the IKK Complex, is of central importance in regulating ΝF-kB, especially its activation, and the resulting transcription of genes, especially those related to inflammation. In fact, activation of ΝF-kB via IKKB appears to be a conserved mechanism across species and is a convergence point of many upstream signaling pathways (including cytokines and other agents which ultimately up-regulate ΝF-kB expression, all or nearly all acting via IKKB.) In practical terms, the IKKB subunit regulates (by regulating ΝF-kB) much of the immunologic and inflammatory response in cells and in humans generally. The mechanism appears to be conserved down to Drosophila and probably of similar great importance in all species wherein it is conserved, especially mammals. IKKB can be 'turned on' and thus stimulate (result in) NF-kB activation in response to stimuli as diverse as fluid sheer stress in arteries, heat, cold, mechanical trauma, hypoxia, antibodies, exposure to radiation, microorganisms (viral, bacterial, fungal) and various biologic mediators such as complement and cytokines. These stimuli and genes regulated by NF-kB are shown in Table 1, below.

Table 1

Inducers of NF-kB

Interleukins, growth factors, IL-1, TNF-er, lymphotoxin, LFN-7, phorbol esters, mitogens lectins, PDGF, VEGF

Viruses, microorganisms, LPS, Chlamydia pneumoniae, Vaccinia virus, and their products Borrelia burgdorferi, Shigella dysenteriae,

Plasmodium falciparum

Physical factors UV, T-irradiation, shear stress (?), heat shock, cold shock

Others Ox-LDL, AGEs, thrombin, double-standard RNA, homocysteine, hypoxia/reperfusion, leptin, heavy metals (Ni, Co), complement, xenoreactive natural antibodies

Genes regulated by NF-kB¹

Interleukins and growth IL-1, IL-6, IL-8, TNF-α, G-CSF, M-CSF, GM-CSF, factors MCP-1, RANTES, MGSA/gro-α-

Cytokine and cell adhesion E-selectin, IC AM- 1 , VC AM- 1 , MAdC AM- 1 , Lox- 1 , receptors RAGE

Apoptosis related A20, A 1 , XIAP, c-IAP 1 , C-IAP2

Immunomodulatory MHC-I, MHC-II, IRF-1

Others iNOS, COX-2, tissue factor, PAI-1 , I«Bα, MnSOD,

MMP-2, MMP-9, PTX3

^SF indicates colony-stimulating factor; GM, granulocyte/macrophage;

RANTES, regulated upon activation normal T lymphocyte expressed and secreted; MGSA, melanoma growth-stimulating activity; MAd, mucosal addressin; XIAP, X- linked inhibitor of apoptosis; IRF, interferon regulatory factor; SOD, superoxide dismutase; and PTX, pertussis toxin. (De Martin R The transcription factor NF- kappa B and the regulation of vascular cell function. Arterioscler Thromb Vase Biol 2000 Nov;20(l l):E83-8).

The NF-kB pathway was discovered in 1986 and soon thereafter came to be recognized as a key component in the immune response as well as certain other biologic processes. The scope of knowledge relating to NF-kB and its role is expanding rapidly. It is at present believed to be involved in numerous disease states and may be central to many, including without limitation: those of chronic inflammation (e.g. arthritis, atherosclerosis, arteriosclerosis, inflammatory bowel disease, multiple sclerosis, etc.); those of acute, intermittent inflammation (e.g. migraine, asthma, etc.); those wherein auto-immune processes figure prominently (e.g. lupus, fibromyalgia, autoimmune myocarditis, etc.); those of dysfunctional immune response (e.g. cancer, AIDS, etc.); those associated with infectious agents and parasites (e.g. Hepatitis B&C, H. pylori infection, malaria, tuberculosis, etc.); those associated with endocrine function (e.g. diabetes, pancreatitis, etc.); those associated with degenerative processes (e.g. aging, Alzheimer's, Parkinson's, etc.); those genetically mediated (e.g. muscular dystrophy, etc.), and; those associated with various forms of trauma (e.g. heat shock, post-perfusion injury, restenosis after angioplasty, etc.) among many others. With few exceptions (e.g. the prophylactic treatment of migraine by specific doses and administration routes of feverfew), neither the herb feverfew, which naturally contains parthenolide and other sesquiterpene lactones, nor parthenolide itself, nor any other sesquiterpene lactone has been used to prevent or treat any of the above specific conditions or diseases, nor any of the above types of conditions or diseases.

SUMMARY OF THE INVENTION The present invention provides a method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising administering a composition comprising at least one plant extract from a plant that is a source of sesquiterpene lactone, or a composition comprising a sesquiterpene lactone in an effective amount to a patient in need thereof. In a preferred embodiment, the plant extract is extracted from feverfew, and the sesquiterpene lactone is parthenolide. As used herein, "feverfew" is understood to include the herb as well as any portion or preparation thereof, including without limitation various extracts thereof. The present invention more particularly relates to a practical and advantageous means of treating various specific and types of maladies and conditions, especially those known or thought to involve the NF-kB pathway, its components, modulators, products and effects. It has been found that various maladies and conditions, especially maladies and conditions known to be associated with the activation of NF-kB, may be treated by the appropriate administration of an effective amount of a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew. Said effective amount is often found to be a surprisingly small amount. In the few select instances (especially migraine) where compositions comprising sesquiterpene lactones have been previously employed, most particularly the naturally occurring herb feverfew, the use of the specific doses and administration routes previously employed has proven to be generally ineffective. Namely, oral administration by means of ingesting tablets, pills and the like is ineffective. The administration of the surprisingly small amount of the composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is most effective, and surprisingly is remarkably more effective, when administered by alternate routes as disclosed herein, namely, administration which bypasses the gastrointestinal tract. Parenteral, topical or topical mucosal administration has been found to be required to achieve the most efficacious treatment.

For purposes of the present invention, an amount of one or more of the compositions disclosed hereby is considered to be effective to treat the disease if the disease either is observed to have a reduced likelihood of occurrence or a reduced rate of symptom or exacerbation occurrence or a reduced rate of increase in severity or to reduce in severity upon treatment as described herein. Thus, for example, an amount of one or more of the compositions disclosed hereby is considered to be effective in treatment of migraine, MS, asthma, or similar maladies characterized by episodes of symptoms or exacerbations if the rate of occurrence of such episodes is reduced. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic representation of NF-kB activation via the IKKB subunit of the IKK Complex.

FIG. 2 is a schematic representation of NF-kB inhibition by aspirin and parthenolide.

FIG. 3 is a schematic representation of basic signaling pathways leading to activation of NF-kB.

DETAILED DESCRIPTION Some of the specific genes known to be regulated by NF-kB and implicated in disease include: Cyclin Dl (cancer); IL-8 (asthma); MCP1 (atherosclerosis);

MMP9 (cancer, arthritis); c-Myc (cancer); 5'deiodinase (euthyroid sick syndrome); HIV LTR (AIDS); Bcl-xL (cancer); C-IAP2 (cancer); iNOS (septic shock, migraine); COX-2 (inflammation generally, colorectal cancer).

A peculiarity of NF-kB is that it may be induced very rapidly and (with few non-pathological exceptions) is only transiently activated, which makes it well suited for the expression of many immune and "stress"-response genes, because these often need to be up-regulated only on demand and then only for a relatively brief period of time before being turned off (down-regulated.) There are several mechanisms whereby activated NF-kB is thought to be deactivated (down- regulated). This down-regulation is necessary if the effects of NF-kB activation (inflammation, generally) are to remain transient. Prolonged activation of NF-kB may occur in many ways, including via persistence of the stimulating agent(s) and/or through impairment of down-regulation mechanisms. Prolonged activation of NF-kB (extreme to mild overactivation) is, for example, a hallmark of many chronic inflammatory, vascular and autoimmune diseases. It is also noted in and associated with many other pathological conditions. That is, based on evidence accumulated to date, the transient activation of NF-kB appears as though it is often protective or beneficial while its chronic activation appears as though it is often harmful or pathological. Of the many products regulated by NF-kB, either in whole or in part, (all or any one of which may be of importance or particular importance in respect of a specific effect, circumstance, condition or ailment), iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) have received a great deal of recent attention. The activation of NF-kB is thought potentially to be of substantial importance in regard to both of these inflammation associated agents.

NF-kB and the activation thereof is thought to play a pivotal role in iNOS (inducible nitric oxide synthase) induction and also in the transcription of many acute phase proteins, including cytokines, adhesion molecules, and antioxidant enzymes, among others It is informative to look at the theoretical relationship between NF-kB activation and iNOS. Under basal (non-inflammation) conditions, NF-kB is sequestered within the cytoplasm by the IkB inhibitory proteins. Phosphorylation of two Ser residues on IkB, mediated by IKKB of the IKK

Complex, triggers the ubiquination and rapid degradation of IkB, thereby releasing NF-kB which may then translocate to the nucleus and initiate (in the case of the present example) iNOS gene expression. (Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF -kappa B/Rel in induction of nitric oxide synthase. JBiol Chem 1994; 269: 4705-4708.) Additional recent data seems to confirm the role of NF-kB in human iNOS gene expression (Taylor BS, de Vera ME, Ganster RW, et al. Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. JBiol Chem 1998; 273: 15148-15156.) iNOS is believed to be associated with many aspects of inflammation generally, and is believed to be closely associated with certain diseases in particular (migraine, post- cerebral infarct injury, septic shock, etc.). As but one example, in tissue macrophages, iNOS synthesis can be triggered by and result from cellular exposure to a variety of stimuli, such as bacterial lipopolysaccharide (LPS), cytokines (e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6), and interferon- (IFN-), as well as by oxidative stress. In examining the pathophysiology of migraine, for example, Reuter and colleagues recently demonstrated that brief exposure to GTN (known to induce migraine in susceptible individuals) increased iNOS expression in rat meninges and generated NO within resident macrophages 6 hours after drug administration (Reuter, U., Chiarugi A., Bolay H., et. al. Nuclear factor-B as a molecular target for migraine therapy. Ann Neural 2002;51 (4):507-516.) and (Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001; 124: 2490-2502.) Edema and mast cell degranulation, considered fundamental aspects of inflammation (including possibly that associated with migraine pathogenesis), were detected over a similar time course. In addition, levels of the cytokines interleukin (IL)-l and IL-6 were demonstrated to have increased. Importantly, parthenolide, (a sesquiterpene lactone component of the medicinal herb feverfew) has been shown to suppress iNOS and interleukin expression, presumably by blocking NF-kB activity and related transcriptional events. (Reuter, U., Chiarugi A., Bolay H., et. al. Nuclear factor-B as a molecular target for migraine therapy. Ann Neurol 2002;51(4):507-516.) As used hereinafter, the terms "NF-kB" and "NF-kB pathway" should each be understood to include the pathway, its components, modulators, products and effects. Other mediators known to be of central importance and shown to be effected or regulated by NF-kB include, without limitation, interleukins and growth factors, cytokine and cell adhesion receptors, apoptosis related mediators, immunomodulatory mediators and others, including iNOS, COX-2, IL-6 and TNF. (Figure 2) With few exceptions, neither the herb feverfew, which naturally contains parthenolide as the most abundant sesquiterpene lactone, nor parthenolide itself, nor feverfew extract has been used to prevent or treat conditions associated with NF-kB, including iNOS. In those few cases where historical use of specific doses and administration routes is known (e.g. feverfew for migraine) the treatment has always been prophylactic, never acute, and of questionable value in its supposed prophylactic role. Without wishing to be bound or limited by the present theory, the present invention may provide an effective, novel means of selectively inhibiting iNOS expression by means of its effect on the components, modulators, products and effects of the NF-kB pathway, especially the inhibition thereof.

COX-2 is of particular interest and importance, especially considering the relatively recent arrival, popularity and commercial success of selective COX-2 inhibiting NSAIDs (non-steroidal anti-inflammatory drugs). Inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunologically-based diseases has been dramatically altered. One example of this relates to the discovery of an inducible form of the cyclooxygenase enzyme. Constitutive cyclooxygenase (COX), first purified in 1976 and cloned in 1988, functions in the synthesis of prostaglandins (PGs) from arachidonic acid (AA). Three years after its purification, an inducible enzyme with COX activity was identified and given the name COX-2, while constitutive COX was termed COX- 1.

The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These selective COX-2 inhibitors may not only be anti-inflammatory, but may also act in ways that are ultimately beneficial in the prevention and treatment of colon cancer and Alzheimer's disease.

COX-2 gene expression is under the control of pro-inflammatory cytokines and growth factors. One theory holds that freed NF-kB dimers translocate to the nucleus and induce target genes, including the one for cyclooxygenase 2 (COX-2), which then catalyses the synthesis of pro-inflammatory prostaglandins,- in particular PGE. Thus, the inference is that COX-2 functions in both inflammation and control of cell growth. While COX-2 is inducible in many tissues, it is present constitutively in the brain and spinal cord, where it may function in nerve transmission for pain and fever. The two isoforms of COX are nearly identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX- 1. On the other hand, PGs synthesized by COX-2 in immune cells are central to the inflammatory process.

An ideal formulation for the treatment of inflammation via inhibition of COX would inhibit the induction and activity of COX-2 without affecting the activity of COX-1. Historically, the non-steroidal and steroidal anti-inflammatory drugs used for treatment of inflammation are not specific and lack the ability to inhibit COX-2 without affecting COX-1. Therefore, most anti-inflammatory drugs damage the gastrointestinal system when used for extended periods. Thus, these new treatments for inflammation and inflammation-based diseases, those that selectively inhibit COX-2, have been of substantial benefit. Yet there remains a need for additional such selective inhibitors of COX-2 that may be more selective, more effective (either in general or for a specific user), have fewer side effects, greater convenience or lower cost. Without wishing to be bound or limited by the present theory, the present invention may provide an effective, novel and advantageous means of selectively inhibiting COX-2 expression, especially by means of its effect on the components, modulators, products and effects of the NF-kB pathway, especially the inhibition thereof.

Since the identification and cloning of COX-2 (Kujubu et al., 1991), accumulating evidence from epidemiological investigations, clinical trials, animal models, and various in vitro experiments supports the critical role of COX-2 in carcinogenesis (Prescott and Fitzpatrick, 2000; Williams et al., 1999; Dubois et al., 1998; Taketo, 1998a; 1998b). For instance, upregulation of COX-2 expression and PG production are commonly found in many cancer cells such as colorectal cancer and a number of COX-2 inhibitors (selective or non-selective) such as nonsteroidal anti-inflammatory drugs (NSAIDs) are able to selectively induce apoptotic cell death in cancer cells (Sano et al., 1995; Shiff et al., 1995; Kutchera et al., 1996;

Sheng et al., 1997; Chinery et al., 1998). COX-2 is involved not only in the onset of inflammation, but also with mitogenic responses (Dubois et al., 1998; Williams et al., 1999). Most probably, COX-2 promotes cell proliferation and inhibits apoptosis in cancer cells through a dual-mechanism: (i) enhanced synthesis of PGs, which favor the growth of malignant cells by increasing cell proliferation (Sheng et al., 1997; 1998), and (ii) reduced level of arachidonic acid, which has recently been found to promote apoptosis in cancer cells (Chan et al., 1998; Cao et al., 2000). Aspirin is known to be a very weak inhibitor of NF-kB, but nonetheless has been noted to exert an anti-carcinogenic effect. Without wishing to be bound or limited by the present theory, the surprising efficacy and substantial benefit of the invention disclosed herein may result from or be largely attributable to its being a much more potent and better inhibitor of NF-kB.

Several preliminary in vitro studies have shown that parthenolide is capable of inhibiting DNA synthesis and cell proliferation in a number of different types of cancer cells, but the mechanism of action is not known (Woynarowski and Konopa, 1981; Hall et al., 1988; Ross et al., 1999). A more recent study demonstrated that parthenolide is capable of increasing the sensitivity of human breast cancer cells to paclitaxel, a chemotherapeutical drug (Patel et al., 2000). However, neither the herb feverfew, nor parthenolide or other sesquiterpene lactone has been effectively used to prevent or treat cancer. The present invention provides an effective, novel means of preventing and treating cancer, either as a sole agent or in combination with generally known chemotherapeutic agents.

Among its many other known effects, high dose administration of aspirin has been found to exert a beneficial effect in diabetic patients through a mechanism generally believed not directly related to COX, iNOS or other mediators known to be potentially affected by the NF-kB pathway, but still believed intimately related to that pathway. Fatty acid activation of NF-kB (via IKKB in particular) is believed to interfere somehow with the insulin signaling pathway. This presumably aberrant activation of NF-kB may play a central role in the pathogenesis and continuation of insulin resistance. Aspirin has been shown to inhibit IKKB at high doses (preventing or diminishing the activation of NF-kB), thus Hundal et al postulated that high dose aspirin might ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. (Hundal et al Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002 May;109(10):1321-6.) They found high-dose aspirin treatment resulted in an approximate 25% reduction in fasting plasma glucose, associated with an approximately 15% reduction in total cholesterol and C-reactive protein, an approximately 50% reduction in triglycerides, and an approximately 30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by approximately 20% and approximately 50%), respectively. Aspirin treatment also resulted in approximately a 20% reduction in basal rates of hepatic glucose production and approximately a 20% improvement in insulin-stimulated peripheral glucose uptake. The implication is that type 2 diabetes may be successfully treated by inhibition of the NF-kB pathway, in this case by administration of aspirin at high doses. More specifically, by blocking the IKKB component of the IKK Complex, clinical improvement may be substantial. Again, aspirin is regarded as but a weak inhibitor of NF-kB. The potential value of a more potent such inhibitor might be substantial, especially one found to be economical, convenient, and relatively free from serious side effects. Neither the herb feverfew, which contains sesquiterpene lactones, primarily parthenolide, nor parthenolide itself has previously been used to prevent or treat diabetes or its sequelae. The present invention as disclosed herein might therefore provide an effective, novel and uniquely advantageous means by which to treat or preventing Type II diabetes and its sequelae.

In theory, NF-kB activation affects and is involved in many diverse processes and many diverse conditions and diseases, not all of which are presently known, but even the number known being so extensive as to preclude exhaustive discussion or entire inclusion herein. Nonetheless, while not wishing to be bound or limited by any particular theory, the present invention relates to each such diverse disease and condition and provides a novel means for the treatment or prevention of any and each each such diverse disease and/or condition.

Given the present body of evidence suggesting the the role NF-kB and its importance in many diverse conditions and ailments, it is certain that the well established and well funded pharmaceutical industry has devoted and continues to devote substantial resources to the development of effective inhibitors and other modulators of NF-kB. Noted are recent discovery efforts and the development of several novel, low-molecular- weight inhibitors of NF-kB that are reported to offer potential therapeutic benefit. However, the fact that NF-kB is involved in a wide variety of cellular functions raises concerns about possible side effects of inhibitory drugs and suggests that such side effects might be severe. It may be argued that NF- kB is a "stress response" factor that is needed during certain pathological "defense" situations and is dispensable only during the unchallenged physiological state. That said, historic use of such NF-kB inhibiting drugs as aspirin and glucocorticoids suggests that inhibition of NF-kB might be reasonably well tolerated and extremely beneficial.

One estimate holds that 70-80% of all diseases now under study are significantly related to the NF-kB pathway and its dysregulation, which dysregulation is generally manifested as overactivation. In recognition of that assessment, massive amounts of time and money have been spent trying to better understand and modify this pathway. There has been and continues an intense search by pharmaceutical companies for an effective and safe way to interact with and regulate (generally turn off, down-regulate or block the activation of) the NF-kB pathway. The ability to affect the NF-kB pathway represents the potential ability to alter the outcome of many diverse diseases and conditions. As such, the discovery of an effective, practical and safe means to modify (and especially suppress) the NF-kB pathway, as disclosed herein, is of great value. The significance of the present invention is magnified by the fact that it is of relatively low cost, has a favorable side effect profile, and is easy to administer in a variety of circumstances and, as appropriate, for a variety of conditions.

Without wishing to be bound, limited or reliant on the following theory, it is noted that in 2001 a proposed mechanism of action of parthenolide (a sesquiterpene lactone and the purported active ingredient in feverfew) was defined and specifically elaborated. Parthenolide was shown to bind to and inactivate the IKK Complex by specifically binding with and inactivating its beta subunit, IKKB. This binding to and inactivation of IKKB prevents the activation (up regulation) of NF-kB (Kwok BH, Koh B, Ndubuisi MI, et al. Tlie anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IB kinase. Chem Biol 2001; 8: 759-756). By binding to and inhibiting IKKB, the generation of mediators, including those of inflammation, might be prevented or suppressed (in whole or in part). In fact, parthenolide has been shown to reduce the DNA binding activity of NF-kB even when administered after IKKB activation. It is believed parthenolide and perhaps other sesquiterpene lactones may also inhibit NF-kB- driven transcription by alkylating p65, thereby preventing its transactivation through the inhibition of binding (figure 3). Despite the accumulation of evidence pointing to parthenolide' s potential role in preventing the activation of NF-kB and its mediation of effect thereby, Pozarowski et al recently demonstrated parthenolide' s capacity to induce cell cycle arrest, apoptosis and necrosis in tumor cells with entirely non-functional NF-kB, presumably by targeting the plasma membrane and causing its destruction (Pozarowski P. Cell Cycle 2003 Jul-Aug;2(40:377-83.)) Thus parthenolide, as well as other sesquiterpene lactones, may act by mechanisms independent of NF-kB, including cell membrane destruction as well as by other, even entirely unknown mechanisms. Note that the above actions were reported to have been observed in vitro. The transcription factor nuclear factor of activated T-cells (NF-AT) may also play an important or essential role in the activation of many early immune response genes, and this transcription factor is also shown to be blocked (inactivated) by a sesquiterpene lactone present in Arnica montana (Klaas, CA Studies on the anti- inflammatory activity of phytopharmaceuticals prepared from Arnica flowers. Planta Med. 2002 May;68(5):385-91.) Since many sesquiterpene lactones studied thus far have been shown to exert similar effects, it is likely that parthenolide acts like the sesquiterpene lactone of Arnica in regard to the inactivation of NF-AT. Nonetheless, parthenolide has been shown to inhibit NF-kB activation in vitro, and thus represents a potential means to achieve NF-kB inhibition, and thus affect some or all of the disease states and conditions in which the NF-kB pathway plays a role.

For some of these diseases and conditions the effect of NF-kB inhibition may be an effective treatment or even a "cure," while in others merely a mitigation or limitation of symptoms or the provision of a specific beneficial effect other than a "cure". As but one example, a composition comprising a sesquiterpene lactone, or more specifically parthenolide, or yet more specifically of feverfew, may possibly be used in combination with other therapies to augment said other therapies and the beneficial effects thereof. Such augmentation use might be employed with another NF-kB inhibitor (e.g. aspirin, steroids) or by augmentation of the effects of a drug or therapy seemingly unrelated to inhibition of NF-kB (e.g. blocking the activation of NF-kB as a means of preserving or enhancing the tumor killing (cytotoxic) activity of radiation therapy or cancer chemotherapeutic agents.) As noted, individual members of the sesquiterpene lactone class have been noted to exert similar effects in biologic systems. Some other common sesquiterpene lactones are artemisinin, encelin, leucanthin B, enhydrin, melapodin A, tenulin, confertiflorin, bilobalide, burrodin, psilostachyin A, costunolide, strigol, helenalin, 5-.alpha.-hydroxy- dehydrocosruslactone, chlorochrymorin, chrysandiol, chrysartemin A, chrysartemin B, cinerenin, curcolone, cynaropicrin, dehydrocostus lactone, dehydroleucodin, dehydrozaluzanin C, deoxylatucin, eremanthine, eupaformonin, eupaformosanin, eupatolide, furanodienone, heterogorgiolide, lactucin, magnolialide, michelenolide, repin, spirafolide, and zaluzanin C. Some drugs now in use, and whose use precedes discovery of the NF-kB pathway, are at present believed to function, at least in part, via inhibition of NF-kB. The potent anti-inflammatory glucocorticoids such as prednisone have been shown to block NF-kb activation, albeit different mechanisms are proposed in respect of different cell types. Glucocorticoids have been reported to directly bind to the RelA and NF-kB 1 subunits of NF-kB, thereby preventing DNA binding and transactivation. Another mechanism involves the induction of IkB at the transcriptional level (more inhibitor thus preventing the activation of NF-kB by keeping a greater percentage sequestered in the cytoplasm). Aspirin and other NSAIDS have been reported to inhibit NF-kB activation. In particular, salicylates (e.g. aspirin, sodium salicylate) are reported to inhibit NF-kB via binding to Ik2 and also through inhibition of RSk2 and decreased activity of IKKB (perhaps by direct binding thereto). Direct inhibition of NF-kB has been demonstrated with sulfasalazine, a sulfa medicine, which is especially used to prevent and treat inflammatory bowel disease (for example ulcerative colitis) and rheumatoid arthritis in patients who have not been helped by or who cannot tolerate other medicines for rheumatoid arthritis. Interestingly, gold compounds have been found to exert their therapeutic effect at least in part via inhibition of NF-kB. Other known inhibiters of NF-kB include many natural and synthetic antioxidants (e.g. vitamins A, C & E, polyphenols of green tea, etc.), immunosuppressants, and natural plant compounds, suggesting that the ability to inhibit NF-kB at least partially accounts for their purported mild therapeutic effects (e.g. reducing incidence rates of cancer and atherosclerosis with prolonged usage). In addition, trans-resveratol (found in red wine) has been found to exert anti-inflammatory and anti-cancer properties, purportedly through its inhibition of NF-kB activation, the proposed mechanism of which is inhibition of IKKB. Atorvastatin, a synthetic 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor that lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis, has been shown to prevent activation of NF-kB in SMCs (smooth muscle cells) by interfering with IKKB. (De Martin R The transcription factor NF-kappa B and the regulation of vascular cell function. Arterioscler Thromb Vase Biol 2000 Nov;20(l l):E83-8) Nonetheless, with the possible exception of some glucocorticoids, none of these are believed to be potent inhibitors of NF-kB.

Thus, presently existing NF-kB inhibitors are proposed to act at several different points in the signaling pathway, including by means of scavenging of oxygen radicals, inhibition of the IKK Complex, inhibition of (subsets of) the proteasome, binding to the transcription factor, interference with transactivation, and interference with the degradation of IkB as well ashy the induction of IkB. Many of the presently known inhibitors (e.g., antioxidants) lack specificity and potency (inhibit NF-kB only weakly). Others are associated with severe and limiting side effects, as is generally the case for what might be the single potent inhibitor

(glucocorticoids), and as is also the case with high dose aspirin. The association with often severe side effects greatly limits the usefulness of corticosteroids (glucocorticoids) in particular and might be expected to severely limit the practical utility of high dose aspirin as well. Therefore the present invention is of great benefit as potentially offering a novel means by which one might effectively inhibit NF-kB activity without incurring the severe side effects sometimes encountered with other such inhibitors, especially in that the compositions and methods revealed hereby are practical, relatively inexpensive and clinically effective in the treatment of various diverse ailments and conditions. As noted, parthenolide has been shown in vitro to bind to and inactivate

IKKB. The scientific literature currently suggests approximately 25 separate biological effects associated with parthenolide. The potential pharmacological activities range from the inhibition of isolated bovine prostaglandin synthetase (Pugh and Sambo (1988) J. Pharm. Pharmacol. 40:743-745) to the prevention of ethanol-induced gastric ulcers in the rat (Toumier et al. (1999) J. Pharm. Pharmacol. 51 :215-219). Research at the molecular level has also described parthenolide inhibition of nuclear factor kappa B (NF-kB) activation in several cell-based systems (Hehner et al. (1999) J. Immunol. 163:5617-5623; Bork et al. (1997) FEBS Letters 402:85-90) and inhibition of inducible nitric oxide gene expression in cultured rat aortic smooth muscle cells (Wong and Menendez (1999) Biochem. Biophys. Res. Commun. 262:375-380). Parthenolide naturally occurs in feverfew and is generally found therein. Feverfew has been noted as a folk remedy for the relief of arthritis and the prevention of migraine headaches. No clinical trial has demonstrated that feverfew is effective in the treatment of arthritis. In the case of migraine headaches, both a reduction in frequency and a reduction in associated symptoms have been reported by some users after prolonged use of specific doses and administration routes, though clinical trials of feverfew in migraine have failed to conclusively demonstrate its efficacy as a migraine prophylactic. Previous investigations using feverfew extracts have suggested interference with arachidonate metabolism as one possible mechanism behind these reported pharmacological effects. In one study (Sumner et al. (1992) Biochem. Pharmacol. 43:2313-2320), crude chloroform extracts of fresh feverfew leaves produced dose-dependent inhibition of the generation of thromboxane B2 and leukotriene B4 by ionophore-and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Commercially available powdered leaves also produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Sumner, et al concluded that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb. Williams noted feverfew's 6-hydroxyflavonols as inhibitors of cyclo-oxygenase and 5-lipoxygenase (Williams, CA, The flavonoids ofTanacetumparthenium and T. vulgar e and their anti-inflammatory properties Phytochemistry 1999

Nov;52(6):l 181-2.) Other research has suggested inhibition of 5-HT as a mechanism of reduced platelet aggregation and the platelet release reaction by feverfew extracts (Groenewegen et al. (1986) J. Pharm. Pharmacol. 38:709-712). It has been suggested that the anti-aggregation effect exerted on platelets may suggest feverfew's potential use as an anti-thrombotic drug (Loesch et al, Feverfew— an antithrombotic drug?

Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115(1-2): 181-4.) It has also been suggested that monocyte adherence is diminished by feverfew. Krause noted that incubation with an extract of the plant feverfew, which contains materials that neutralize cellular sulfhydryl groups, diminished monocyte adherence (Krause et al Influence of substances affecting cell sulfliydryl/disulfide status on adherence of human monocytes. Arzneimittelforschung. 1990 Jun;40(6):689-92.) Pretreatment of synovial fibroblasts with either feverfew extracts or purified parthenolide has been shown to inhibit the expression of intercellular adhesion molecule- 1 (ICAM-1) induced by the cytokines IL-1 (up to 95% suppression), TNF-alpha (up to 93% suppression), and, less strongly, interferon-gamma (up to 39% suppression). The decrease in ICAM-1 expression was accompanied by a decrease in T-cell adhesion to the treated fibroblasts. The modulation of adhesion molecule expression has been proposed as an additional mechanism by which feverfew mediates anti- inflammatory effects. (Piela-Smith TH, Feverfew extracts and the sesquiterpene lactone parthenolide inhibit intercellular adhesion molecule-1 expression in human synovial fibroblasts. Cell Immunol. 2001 May l;209(2):89-96.) Numerous other potential activities of feverfew and the components thereof, including parthenolide, have been noted, including parthenolide' s suggested action as a novel type of mast cell inhibitor (Hoffmann et al Cytotoxic agents from Michelia champaca and Talauma ovata: parthenolide and costunolide. J Pharm Sci. 1977 Jun;66(6):883-4.), inhibition of MAP kinases (Hwang et al Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases. Biochem Biophys Res Commun. 1996 Sep 24;226(3):810-8.), inhibition of phospholipase- A2 hydrolysis of phosphatidylcholines (Jain et al Action of phospholipase A2 on bϊlayers. Effect of inhibitors. Biochim Biophys Acta. 1985 Apr 11;814(2):319-26.), inhibition of DNA biosynthesis in cancer cells (Woynarowski et al Inhibition of DNA biosynthesis in HeLa cells by cytotoxic and antitumor sesquiterpene lactones. Mol Pharmacol. 1981 Jan;19(l):97-102.) and inhibition of prostaglandin synthetase (Pugh et al Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol. 1988 Oct;40(10):743-5.) among others. Recent research has suggested that parthenolide may suppress Interleukin-4 (IL-4) expression at the mRNA and protein levels in a dose dependent manner (Li- Weber M. European Journal of Immunology 2002 ;32(12):3587-97). IL-4 is a key cytokine that influences the development of T-helper 2 cells and plays an important role in the pathogenesis of allergic diseases. While not wishing to be bound or limited by any particular theory, it may be that certain of the various findings result from or are closely associated with the action of parthenolide and other sesquiterpene lactones, or even other co-occurring pharmacologically active compounds, as inhibitors of the NF-kB pathway. There may also be effects, either by the sesquiterpene lactones or the other pharmacologically active agents, which, though acting by means of a different mechanism, are synergistic with, or augment these NF-kB effects. Similarly, active components of feverfew, in this case, may act by mechanisms significant but as yet unknown. Numerous publications suggest that the active components of feverfew are sesquiterpene lactones, parthenolide being the most abundant. Nonetheless, parthenolide is almost certainly not the sole pharmacologically active constituent of feverfew (Brown et al Pharmacological activity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in-vitro. J Pharm Pharmacol. 1997 May;49(5):558-61.)

Noteworthy is that despite many published articles disclosing certain in vitro effects (and very occasional in vivo experiments, such as that conducted to demonstrate the prevention of ethanol-induced gastric ulcers in the rat (Toumier et al. (1999) J. Pharm. Pharmacol. 51:215-219)) and wherein are called out potential or theoretical mechanisms of action, the practical, clinical application of feverfew and its constituents (especially parthenolide and other sesquiterpene lactones) outside of the laboratory setting and for the in vivo treatment of diseases and conditions has not been pursued, but has in fact been all but entirely neglected. Feverfew and its constituents (especially parthenolide and other sesquiterpene lactones) are generally regarded as being useful only as in vitro research tools and items of investigational curiosity. With but only several isolated exceptions, they not been employed for the treatment of conditions presently believed to involve the NF-kB pathway. One possible exception (unproven as to efficacy, and at best marginally effective) is the prophylactic (preventative) treatment of migraine headaches using specific doses and administration routes. Established medicine has in fact rejected this prior known use of feverfew in migraine prophylaxis using specific doses and administration routes as being an ineffective means of migraine prophylaxis, or has at best adopted a neutral and skeptical stance in regard to its application.

Neglect by medicine and science of feverfew, parthenolide and sesquiterpene lactones for the clinical treatment and/or prevention of various ailments and conditions is not due to lack of knowledge concerning the many proposed in vitro activities of feverfew and parthenolide (or other sesquiterpene lactones), but rather stems from what are believed to be practical considerations concerning what are believed to be limitations or obstructions to its effective in vivo use and practical clinical application. Parthenolide, as feverfew, is believed to be only a weak inhibitor of NF-kB and thus of no greater clinical utility than other supposed weak inhibitors such as naturally occurring antioxidants like vitamins C and E, it not being thought possible to employ these in vivo in an effective and practical manner, namely in clinical medicine, specifically in the effective treatment or prevention of pathology, especially in the acute treatment thereof. Prior to the present invention disclosed herein, there has been no evidence to suggest that feverfew or its constituents, including parthenolide, or other sesquiterpene lactones, are anything other than very weak inhibitors of NF-kB, or that effective application to the in vivo treatment of various diseases and conditions is possible, and in fact may be achieved by a practical, convenient, economical and effective means that is also clinically advantageous when employed in the treatment of human pathology, especially the acute treatment thereof. The present invention therefore discloses and constitutes a novel and exceptionally useful tool in clinical medicine which is surprisingly effective in the treatment of many diverse maladies and conditions.

The conditions and concentrations of parthenolide and/or feverfew required to be employed in the laboratory setting to evidence the in vitro effects noted (for example, the use of relatively high concentrations as often employed and the use of relatively long incubation times as often employed, these often in combination) has lead investigators to conclude that parthenolide and/or sesquiterpene lactones and/or feverfew cannot be practically employed in the treatment of various diverse maladies and conditions because such concentrations and/or times of exposure could not practically be achieved in a living organism, especially not in a general setting. This and the lack of clinical efficacy observed with traditional use of feverfew by specific doses and administration routes, have combined to suggest that there are but extremely limited or even no practical clinical applications for feverfew and/or its constituents, including parthenolide, or other sesquiterpene lactones. The use of these for the in vivo treatment of diseases and conditions as might otherwise be thought to have been suggested by in vitro laboratory observations and theoretical mechanisms has therefore been judged to be neither possible nor practical, and has thus been neither pursued nor applied. The present invention provides an easy, practical and inexpensive means to apply an effective dose in an effective way and thus reveals both the possible and practical application of feverfew and/or its constituents, including parthenolide and other sesquiterpene lactones for use in the treatment of diseases and conditions as described herein.

No published study has conclusively demonstrated the efficacy of feverfew or parthenolide in vivo for the treatment of any condition. Migraine is the most studied among all ailments for which these compositions have been employed in certain specific doses and by certain specific administration routes. Several published studies (Murphy, JJ Lancet 1988 Jul 23;2(8604): 189-92), and (Johnson, ES British Medical Journal 1985 Aug 31;291(6495):569-73), have suggested a potential role for feverfew in reducing the incidence and/or severity of migraines. These early trials did in fact find that patients reported a reduction in the number and/or severity of migraine attacks with the use of feverfew and suggested the efficacy thereof. More recently however, several systemic reviews of feverfew use in the prevention of migraine have been published (Vogler BK, "Feverfew as a preventive treatment for migraine: a systematic review." Cephalalgia 1998 Dec;18(10):704-8) and (Pittler MH, "Feverfew for preventing migraine." Cochrane Database Syst Rev 2000;(3):CD002286) both of which reviews concluded that the efficacy of feverfew for the prevention of migraine "has not been established beyond reasonable doubt." Pittler also noted that "the trial with the highest methodological quality, which was also among the largest, found no significant difference between feverfew and placebo." Most clinicians in the United States do not consider feverfew an effective prophylactic treatment for migraine and as such do not endorse its use. Feverfew has not been effectively used for the acute relief of migraine attacks. Each of the referenced studies investigated only its prophylactic (preventing migraine) use. There is no evidence that feverfew, sesquiterpene lactones in general, or parthenolide specifically, are appropriate or beneficial agents for use where acute relief is desired. There is little to no evidence of prophylactic efficacy, and that only with regard to this one specific condition (migraine). No published clinical trial has shown any therapeutic effecacy for feverfew and/or parthenolide and/or sesquiterpene lactones with regard to any of the host of potential applications suggested by in vitro laboratory studies in which is observed the inhibition of NF-kB by parthenolide. One controlled trial is known to have been conducted on the use of feverfew in the treatment of arthritis, another of its historical uses and certainly a condition known to be associated with the activation of NF-kB. The published results of that study failed to demonstrate any benefit from from the use of orally ingested feverfew when employed in the treatment of arthritis. (Heptinstall et al Feverfew in rheumatoid arthritis: a double blind, placebo controlled study. Ann Rheum Dis. 1989 Jul;48(7): 547-9.) . Parthenolide is viewed as an investigational tool, and is employed (as are any other number of known NF-kB suppressors) in vitro in laboratory settings, especially for use in further elaborating the mechanism and role of NF-kB through its in vitro blockade thereof (at relatively high doses and under specific conditions, which specific conditions generally include the exposure of the cells or other system under study to parthenolide at a relatively high concentration and for an extended period of time).

Aspirin is but one 'traditional' product which is believed to exert at least some small portion of its effect, at least at high dosages, through the inhibition of NF-kB (believed most likely to act, at least in part, via the same general site of action as that proposed for parthenolide; Fig. 2). Aspirin, as noted, may exert effects by means of its effect on the NF-kB pathway, such as a long-term reduction in the risk of developing certain cancers and perhaps provides its noted cardio-protective effect in the same manner (e.g. reduction in heart attack risk). However, the dose having been noted to be generally required to achieve a clinically significant acute effect by means of NF-kB suppression (for example, in the treatment of type 2 diabetes) is believed to be on the order of 7-9 grams of aspirin per day, somewhat more than 20 standard 325 mg tablets per day. Aspirin use even at 'normal' doses is already associated with significant side effects. The administration of such high doses is very inconvenient, and more importantly would be expected to result in substantial stomach upset as well as additional, more serious side effects. Such a large dose may be genuinely dangerous with regard to short-term toxicity as well as long-term sequelae (e.g. stomach ulcers, kidney failure). While aspirin might, in theory, be used to acutely modify the NF-kB pathway, it has no known practical utility in this regard and is not employed clinically to do so. Likewise feverfew, parthenolide and other sesquiterpene lactones are not presently employed in the modification (suppression) of the NF-kB pathway where they have no known practical utility and are not employed for such purposes.

Parthenolide as a biological agent is not entirely unique, as it is but one example of a large class of "sesquiterpene lactones" (albeit parthenolide is probably the best known and most studied of this class). It appears that all or many sesquiterpene lactones may exhibit similar effects through their common α- methylene γ-lactone moiety. Thus other sesquiterpene lactones, though not having been in every case so thoroughly investigated as parthenolide, are often found to behave in a similar manner in vitro. Generally, other sesquiterpene lactones have been shown to exhibit an identical or a very similar mechanism of action as parthenolide. As but one example, a sesquiterpene lactone from the Korean traditional medicinal herb Carpesium divaricatum has recently been shown, in vitro, to inhibit NF-kB activation (Kim EJ, Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation Biochem Pharmacol 2001 Apr 1;61(7):903-10) The sesquiterpene lactones may nonetheless vary somewhat in their actions and effects, especially in relation to specific medical conditions. It has been suggested that the mode of action of helenalin and bis (helenalinyl) malonate (sesquiterpene lactones shown to be cytotoxic against the growth of P-388 lymphocytic leukemia cells in culture) is different and not similar to that of the parthenolide-type sesquiterpene lactones which contain an epoxide moiety (Hall et al Inhibition of nucleic acid synthesis in P-388 lymphocytic leukemia cells in culture by sesquiterpene lactones. Anticancer Res. 1988 Jan-Feb;8(l):33-42.) Nonetheless, despite what must certainly be some exceptions, the weight of presently available research suggests that sesquiterpene lactones often act in similar ways and may exert their respective effects by the same general mechanism as has been proposed for parthenolide. As such, all or nearly all sesquiterpene lactones might potentially be in vitro inhibitors ofNF-kB. One important activity proposed to be in part regulated by NF-kB relates to apoptotic cell death (Barkett and Gilmore, 1999). Although there is present uncertainty whether NF-kB promotes or inhibits apoptosis, this appears to depend on the specific cell type under study and perhaps the nature of stimuli otherwise influencing apoptosis. Under most circumstances, up-regulation of NF-kB appears to act as an apoptosis blocker, especially in TNF-. alpha. -induced apoptotic cell death (Barkett and Gilmore, 1999; Aggarwal, 2000). Such a finding might well explain the finding that in most cell types TNF-.alpha. is not cytotoxic unless the cells are simultaneously treated with RNA or protein synthesis inhibitors that block the expression of NF-kB dependent anti-apoptotic genes (Baichwal and Baeuerle, 1997). The list of such anti-apoptotic genes includes Bcl-2 family proteins, inhibitors of apoptosis proteins, Mn-superoxide dismutase and COX-2 (Barkett and Gilmore, 1999).

Many cancer cells are found to have high levels of activated NF-kB. Cancer cells might normally be eliminated by the body's own defense system, but the activation of NF-kB seems, at least in part, to account for their continued survival. Indeed, NF-kB activation in cancer cells may confer not only protection against the body's natural defenses, but also protection against what might otherwise be effective therapeutic interventions. NF-kB activation is increased markedly in certain cancers after exposure to anti-cancer radiation treatments of ionizing radiation (Jung et al NF-kappa B signaling pathway as a target for human tumor radiosensitization. Semin Radiat Oncol. 2001 Oct;l l(4):346-51.) and anti-cancer chemotherapeutic agents, (Wang et al Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition ofNF- kappaB. Nat Med. 1999 Apr;5(4):412-7.) in each case said activation apparently conferring protection on the cancer cells. NF-kB activation can be an adaptive response of cells to short term stress, in which case it may be either beneficial or detrimental to the organism. Increased NF-kB activation found in association with (and purportedly resulting from) both radiation therapy and chemotherapy for neoplastic disorders is clearly disadvantageous. In this case, (cancer) cell survival is obviously not what is desired. Pre-treatment or concurrent treatment with a sesquiterpene lactone has been shown in vitro to sensitize cells to the anti-cancer agent, or to prevent their becoming desensitized to the anti-cancer agent. Regardless of which sesquiterpene lactone (of the several reported to have been investigated) employed in combination with these therapies, the anti-cancer effect appears to be consistent, further supporting the idea that sesquiterpene lactones, as a class, most often exhibit similar effects. These similar effects are most likely due to a similar mechanism of action.

The potential utility of various sesquiterpene lactones in the treatment and prevention of various cancers is but one such noteworthy similarity. Sesquiterpene lactones in general, especially those containing an . alpha. -methylene-.gamma.- lactone group, have been shown to possess activity against tumor growth and general inflammation. Hall discloses that sesquiterpene lactones possess activity against general inflammatory reactions (Hall I. et al., "Anti-Inflammatory Activity of Sesquiterpene Lactones and Related Compounds," J. Pharm. Sci., vol. 68, pp. 537-542 (1979)). See also (Hall et al., "Mode of Action of Sesquiterpene Lactones as Anti-Inflammatory Agents," J. Pharm. Sci., vol. 69, pp. 537-543 (1980)). The mechanism of action of other sesquiterpene lactones has been shown in several cases to be identical, or nearly so, to the proposed mechanism of action of parthenolide (Garcia-Pineres AJ, Castro V, Mora G, et al. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. JBiol Chem 2001; 276: 39713-39720.) (Lee K. "Antitumor Agents. 32. Synthesis and Antitumor Activity of

Cyclopentenone Derivatives Related to Helenalin," J. Med. Chem., vol. 21, pp. 819- 822 (1978)) discloses that the sesquiterpene lactone helenalin and certain related compounds had some antitumor activity. See also (Lee K. et al., "Cytotoxicity of Sesquiterpene Lactones," Cancer Research, vol. 31, pp. 1649-1654 (1971). (Cassady J. "Potential Antitumor Agents. Synthesis, Reactivity, and

Cytotoxicity of .alpha.-Methylene Carbonyl Compounds," J. Med. Chem., vol. 21, pp. 815-819 (1978)) reports antitumor activity of certain sesquiterpene lactones and related compounds. See also (Howie G. et al., "Potential Antitumor Agents. Synthesis of Bifunctional . alpha. -Methylene-.gamma.-butyrolactones," J. Med. Chem., vol. 19, pp. 309-313 (1976).)

(Kupchan S. "Tumor Inhibitors. 69. Structure-Cytotoxicity Relationships among the Sesquiterpene Lactones," J. Med. Chem., vol. 14, pp. 1147-1152 (1971)) discloses the structures of several cytotoxic sesquiterpene lactones, reports that an .alpha.-methylene-.gamma. -lactone group was found to be essential for significant cytotoxic activity, and discloses other features associated with increased activity among those compounds. Waddell discloses antitumor activity of the group (Waddell T. et al., "Antitumor Agents: Structure-Activity Relationships in Tenulin Series," J. Pharm. Sci., vol. 68, pp. 715-718 (1979)).

Many other proposed effects of sesquiterpene lactones, besides the anti- neoplastic effects, are suggested to be relatively or entirely consistent among the entire class of sesquiterpene lactones. Sesquiterpene lactones include (without limitation) (+)-Isovelleral; (+)-Isovelleral isomer 2; (+)-Juvabione; (+)-T-Cadinol; (- )-Isovelleral; (1)10-Aristolen-2-one; (5-Hydroxymethyl-5,8a-dimethyl-2-methylene- decahydro-naphthalen-1 -ylmethoxy)-(2-oxo-tetrahydro-furan-3-yl)-acetic acid; (5- Hydroxymethyl-5 , 8 a-dimethyl-2-methylene-decahydro-naphthalen- 1 -ylmethoxy)- (2-oxo-tetrahydro-furan-3-yl)-acetic acid, methyl ester; (6E)-2,3-Dihydrofarnesol; 1,10-Epoxy-l lbetaH,13-dihydrocostunolide; 1,10-Epoxy-l lbetaH,13- dihydroparthenolide; 1 , 10-Epoxycostunolide; 1 ,2,3a,6-Tetramethyl-decahydro- cyclopenta[c]pentalen-2-ol; l-Hydroxy-6,9a-dimethyl-l,3,5,5a,6,7,8,9,9a,9b- decahydro-naphtho[l ,2-c]furan-6-carboxylic acid; 1 -Hydroxymethylene-5,5,8a- trimethyl-octahydro-naphthalen-2-one; 1 -Methoxy-6,6,9a-trimethyl-decahydro- naphtho[l,2-c]furan-3,3a-diol; l-Methoxy-6,6,9a-trimethyl-dodecahydro- naphtho[ 1 ,2-c]furan; 10-Hydroxy-2-isopropyl-5-methyl- 11,12-dioxa- tricyclo[5.3.2.0-l,5]-8-dodecene-8-carboxylic acid, methyl ester; 11,13- Dihydrohelenalin acetate; 11,13-Dihydroreynosin triol derivative; ll-Dihydro-9- epipolygodial; 11 -Dihydro-polygodial; 11 -Dihydroxy-drim-8-ene- 12,13 -dioic acid 13-methyl ester 11 12-lactone; llbetaH, 13-Dihydrocostunolide; llbetaH, 13- Dihydroparthenolide; llbetaH, 13-Dihydroreynosin; l lbetaH, 13- Dihydrosantamarine; 14-o-Hydroxycinnamoyl-dauc-4,8-diene; 2,3-Dimethyl- oxirane-2-carboxylic acid, 1 -acetoxy-7-(l -hydroxy- 1 -methyl-ethyl)- 1 ,4a-dimethyl- 6-oxo-l,2,3 ,4,4a,5,6,8a-octahydro-naphthalen-2-yl ester; 2,3-Dimethyl-oxirane-2- carboxylic acid, l-acetoxy-7-isopropyl-l,4a-dimethyl-6-oxo-l,2,3,4,4a,5,6,8a- octahydro-naphthalen-2-yl ester; 2,3-Dimethyl-oxirane-2-carboxylic acid, 1- acetoxy-7-isopropylidene- 1 ,4a-dimethyl-6-oxo-decahydro-naphthalen-2-yl ester; 2,3 -Dimethyl-oxirane-2-carboxylic acid, 1 -hydroxy-7-(l -hydroxy- 1 -methyl-ethyl)- 1 ,4a-dimethyl-6-oxo-l ,2,3,4,4a,5,6,8a-octahydro-naphthalen-2-yl ester; 2,3- Dimethyl-oxirane-2-carboxylic acid, 1 -hydroxy-7-isopropyl- 1 ,4a-dimethyl-6-oxo- l,2,3,4,4a,5,6,8a-octahydro-naphthalen-2-yl ester; 2,3-Dimethyl-oxirane-2- carboxylic acid, 1 -hydroxy-7-isopropylidene- 1 ,4a-dimethyl-6-oxo-decahydro- naphthalen-2-yl ester; 2-alpha-Hydroxymethyl-2,4alpha,8,8-tetramethyl-delta8a- octalin; 2-cis-6-cis-Famesol; 2-cis-6-trans-Farnesol; 2-Methyl-6-p-tolyl-hept-2-en-4- ol; 2-Methyl-6-p-tolyl-hept-3-en-2-ol; 2-Methyl-but-2-enoic acid, l-hydroxy-7-(l- hydroxy-l-methyl-ethyl)-l,4a-dimethyl-6-oxo-l,2,3,4,4a,5,6,8a-octahydro- naphthalen-2-yl ester; 2-Methyl-but-2-enoic acid, l-hydroxy-7-isopropyl-l,4a- dimethyl-6-oxo-l ,2,3,4,4a,5,6,8a-octahydro-naphthalen-2-yl ester; 2-trans-6-cis- Farnesol; 2-trans-6-trans-Farnesol; 2beta-Acetoxy-4alpha-chloro-lbeta,8- diangeloyloxy-3beta, 10-dihydroxy- 11 -methoxy-bisabol-7(l 4)-ene; 3 ,6-Epoxydioxy- bisabola-l,10-diene; 3,7,8-Trimethyl-4a,5,9,9a-tetrahydro-4h,8h-azuleno[6,5- b]furan-2,6-dione; 3,7,8-Trimethyl-9,9a-dihydro-5h,8h-azuleno[6,5-b]furan-2,6- dione; 3-(l-Hydroxy-4,8,8-trimethyl-spiro[2.5]oct-4-yl)-propionic acid; 3-Acetoxy- thujopsene; 3-Isopropyl-6,10-dimethyl-ll-oxa-bicyclo[8.1.0]undec-6-ene-2,8-diol; 3-Methyl-but-2-enoic acid, 4a,8-dimethyl-3-methylene-2,5-dioxo- 2,3,3a,4,4a,5,7a,8,9,9a-decahydro-azuleno[6,5-b]furan-4-yl ester; 3 -Methyl-butyric acid, 4a,8-dimethyl-3-methylene-2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydro- azuleno[6,5-b]furan-4-yl ester; 3-O-Deacetyl-9-O-acetylsavigraviolide A; 3beta,8beta-Dihydroxy-l lalphaH-guaia-4(15),10(14)-diene-12,6alpha-olide; 4,9- Dihydroxy-6,10-dimethyl-3-methylene-3a,4,5, 8,9,1 la-hexahydro-3h- cyclodeca[b]furan-2-one; 4-(l ,5-Dimethyl-hexa-l ,3-dienyl)-l -methyl-cyclohexene; 4-Hydroxy-2-methyl-but-2-enoic acid, 9-acetoxy-3 ,6, 10-trimethyl-2-oxo- 2,3,3a,4,5,8,9,l la-octahydro-cyclodeca[b]furan-4-yl ester; 4-Hydroxy-3,4a,8- trimethyl-decahydro-azuleno[6,5-b]furan-2,5-dione; 4-Hydroxy-4a,8-dimethyl-3- methylene-decahydro-azuleno[6,5-b]furan-2,5-dione; 4-Isopropyl- 1 ,6-dimethyl- 1 ,2,3 ,4,4a,7,8,8a-octahydro-naphthalene-l -thiol; 4-Isopropyl-5-isothiocyanato- 1,5- dimethyl-l,2,3,4,4a,5,6,7-octahydro-naphthalene; 4a,8-Dimethyl-4,7-oxo-3- methylene-decahydro-azuleno[6,5-b]furan-2,5-dione; 4beta,5alpha-Epoxy-7alphaH- germacr-10(14)-ene-lbeta,6beta-diol; 5,6-Diformyl-l,4a-dimethyl-l,2,3,4,4a,5,8,8a- octahydro-naphthalene-1 -carboxylic Acid; 5-(l-Hydroxy-l-methyl-ethyl)-2-methyl- 8-methylene-cyclodecane-l ,6-diol; 5-epi-Homoisospongiaquinone; 5-epi- Isospongiaquinone; 5a,6-Dihydroxy-4,4,6a-trimethyl-3,4,5,5a,6,6a-hexahydro-lh- cyclopropa[f]indene-la,2-dicarbaldehyde; 6,6,9a-Trimethyl-decahydro-naphtho[l,2- c] furan- 1 -one; 6-(2-Hydroxy-4-methyl-phenyl)-2-methyl-hept-2-en-4-one; 6-(3 - Hydroxy-4-methyl-phenyl)-2-methyl-hept-2-en-4-one; 6-O-Angeloylplenolin; 6-O- Isobutyroylplenolin; 6-O-Methacrylplenolin; 6beta-Hydroxyaplysistatin; 7-(l- Hydroxy- 1 -methyl-ethyl)- 1 ,4a-dimethyl-decahydro-naphthalene- 1 ,8-diol; 7- Deacetoxyolepupuane; 7-Hydroxy-2,6,7a-trimethyl-decahydro- 1 ,4-dioxa- cyclopenta[fJcyclopropa[a]azulene-5,8-dione; 7-Hydroxy-3,4-dihydro-cadalin; 7- Hydroxy-6,1 l-cyclofames-3(15)-en-2-one; 7-Hydroxy-cadalin; 7-Isopropenyl-4- methyl-6,7-dihydro-azulen- 1 -yl Octadecanoate; 8,12,12-Trimethyl-4-oxa- tricyclo[6.4.0.01,3]dodecan-5-one; 8-Acetoxy-elemol; 8-Hydroxy-elemol; 8- Ketocopaenal; 8-Ketocopaenol; 8-Ketoylangenal; 8-Ketoylangenol; 9-alpha-

Hydroxy-merulidial; 9-alpha-Hydroxyacetylmerulidial; 9-Hydroxy-Isoisovelleral; 9- Hydroxyisovelleral; 9-Hydroxymarasmic acid; 9-O-Acetylsavigraviolide A; Acetic acid 4-acetoxy-6,10-dimethyl-3-methylene-2 -oxo-2,3 ,3 a,4,5, 8,9,1 la-octahydro- cyclodeca[b]furan-9-yl ester; Acetic acid, l-acetoxymethyl-5,5,8a-trimethyl- decahydro-naphthalen-2-yl ester; Acetic acid, l-acetoxymethyl-5,5,8a-trimethyl- decahydro-naphthalen-2-ylmethyl ester; Acetic acid, 4a,8-dimethyl-3-methylene- 2,5-dioxo-2,3,3a,4,4a,5,7a,8,9,9a-decahydro-azuleno[6,5-b]furan-4-yl ester; Acetic acid, 6,6,9a-trimethyl-3-oxo-l,3,4,5,5a,6,7,8,9,9a-decahydro-naphtho[l,2-c]furan-l- yl ester; Acetic acid, 6,6,9a-trimethyl-3-oxo-l,3,5,5a,6,7,8,9,9a,9b-decahydro- naphtho[l,2-c]furan-l-yl ester; Acetyl-isomerulidial; Acetyl-merulidial;

Acetylcedren; Acoradiene (also known as Acoradin); Alloaromadendran- < 7alpha,l lbeta-diol; Alloaromadendran-7beta,l lbeta-diol; Alloaromadendrene; Allolaurinterol; Allospathulenol; alpha- and beta-Santalol; alpha-Arteether; alpha- Bisabolol; alpha-Bisabolol oxide (A-form); alpha-Cadinol; alpha-Eudesmol; alpha- Guaiene; Aplysistatin; ar-5-Hydroxyturmerone; ar-Turmerone; Aromadendral (also known as Aromadendrene); Aromadendrane-7-alpha,l lbeta-diol; Aromadendrane- 7beta,l lbeta-diol; Aromadendrene; Avarol; Axisonitrile-3; Bazzanene; Bazzanenol; beta-Arteether; beta-Bisabolene; beta-Caryophyllene; beta-Elemene; beta- Humulene; Carolenalin monoacetate; Caryophyllene oxide; Caryophyllodienol; Cedral; Cedramber; Cedrene (alpha-isomer); Cedrenol; Cedrenyl acetate; Cedrol; Cedryl acetate; Chamazulene; Chromolaenide; Chromolaenide acetate; cis- Dihydronerolidol; Collybial; Costunolide; Davanone; Deacetoxymatricarin;

Debneyol; Debromolaurinterol; delta-Cadinene; delta-Cadinol; Deoxyelephantopin; Dermatolactone; Deferral; Dihydrolinderazulene; Dihydromicanolide; Dihydrothujopsene; Drimane-7,9(ll)-diene; Elemol; Encelin; Epicubenol; Epiglobulol; Epipolygodial; Eupatolide; Exomerulidal; Exovelleral A; Exovelleral B; Farinosin; Farnesal; Farnesol; Farnesyl acetate; Famesyl methyl ether;

Florilenalin diacetate; Germacrene D; Globulol; Guaiazulene; Guaiyl acetate; Helenalin; Helenalin acetate; Hexahydrofarnesol; Hexahydronerolidol; Hinokiic acid; Humulene; Humulene-2,3-epoxide; Hymenovin; Isoisovelleral; Isolongifolene; Isovellerol; Judeol; Lactardial; Lactaroviolin; Ledol; Leptospermone; Lettucenin A; Linderazulene; Longifolene; Marasmic acid; Merulidial; Methyl 2-oxo-3,5a,8- trimethylperhydromdeno[4,5-b]furan-7-carboxylate; Methyl marasmate; Mexicanin A 1,2-alpha-epoxide; Mexicanin A 2,3-epoxide deriv.; Mexicanin E; Micanolide; Michelenolide; Mukadial; Muurolene; Muzigadial; Neopentyl acetate; Nerolidol; O- Methylmelleolide; Palustrol; Partheniol; Parthenolide; Patchouli alcohol; Pentamethyloctalin; Piconia; Pilatin; Plenolin; Plumericin; Polygodial;

Prostantherol; PSF-A; PSF-B; PSF-D; Radulactone; Radulol; Radulone A; Reynosin; Reynosin triol derivative; Ridentin; Rosa rugosa aldehyde; Santalene (alpha-); Santamarine; Santamarine triol derivative; Savigraviolide A; Sclerocarpic acid; Selinene (alpha-isomer); Sesquiterpene lactone I; Sesquiterpene lactone II; Sesquiterpene lactone III; Sesquiterpene lactone IV; Shiromool; Sinensal (unknown isomer); Spathulenol; Sponge sesquiterpene; T-Muurolol; Tamaulipin A angelate; Taurin; Tayunin; Tenulin; Tetrahydronerolidol; Thujopsan-3-ol; Thujopsenal; Thujopsene; Thujopsenol; trans-Dihydronerolidol; trans-Nerolidol; Velleral;

Vellerdiol; Vellerol; Vetiverol; Vetiveryl acetate; Viridiflorol; Vulgarin;

Warburganal; Widdrol; Ylangene; Ylangenol; and Yomogin.

A large number of sesquiterpene lactones and their sources are described in N. Fischer et al., "The Biogenesis and Chemistry of Sesquiterpene Lactones," in W.

Herz et al. (eds.), Prog. Chem. Org. Nat. Prod. Springer- Verlag, vol. 38, pp 47-390

(1979).

Fig. 3 shows basic signaling pathways leading to activation of NF-kB.

Binding of soluble mediators, e.g., inflammatory cytokines, to their receptors triggers the assembly of cytoplasmic receptor-specific adapter molecules (e.g.,

TRAFs) that activate members of the MAP3 (NIK, MEKK1) and other kinases. The latter further activate IKK that phosphorylates IkB on amino-terminal serine residues, leading to its proteasome-mediated degradation. Thereby NF-kB is liberated from its cytoplasmic complex and translocates to the nucleus. (De Martin R The transcription factor NF-kappa B and the regulation of vascular cell function.

Arterioscler Thromb Vase Biol 2000 Nov;20(l l):E83-8).

NF-kB has been specifically shown to be of importance in

Ischemia/reperfusion (Toledo-Pereyra & Lopez-Neblina, 2002); Pulmonary Disease

(Christman et al., 2000); Chronic Obstructive Pulmonary Disease (COPD) (Barnes, 2002); Renal Disease (Guijarro & Egido, 2001); Leptospiriosis renal disease (Yang et al., 2001); Gut Diseases (Neurath et al., 1998); Skin Diseaes (Bell et al., 2003);

Incontinentia pigmenti (Courtois & Israel A, 2000); Asthma (Pahl & Szelenyi,

2002); Arthritis (Roshak et al, 2002); Crohns Disease (Pena & Penate, 2002);

Ocular Allergy (Bielory et al., 2003); Pancreatitis (Weber & Adler, 2001); Periodonitis (Nichols et al., 2001); rnflammatory Bowel Sybdromes (Dijkstra et al.,

2002); Sepsis (Wratten et al., 2001); Silica-induced inflammation (Chen & Shi,

2002); Sleep apnoea (Lavie, 2003); AIDS (HIV-1) (Hiscott et al, 2001);

Autoimmunity (Hayashi & Faustman, 2000); Lupus (Kammer & Tsokos, 2002);

Neuropathological Diseases (Cechetto, 2001; Mattson & Camandola, 2001); Alzheimer's Disease (Mattson & Camandola, 2001); and Cancer (Gilmore et al.,

2002; Karin et al., 2002) (see Table 2, below). Table 2: Constitutive activation of NF-kB in human cancer cells

Cancer type Reference

Primary Tumors and Cell Lines

Breast Nakshatri et al., 1997; Sovak et al., 1997 Cervix Nair et al, 2003

Ovary Dejardin et al., 1999; Huang et al., 2000

Vulva Seppanen & Vihko, 2000

Prostate Huang et al., 2001b; Palayoor et al., 1999

Kidney Oya et al, 2001 Liver Tai et al, 2000

Pancreas Wang et al., 1999

Stomach Sasaki et al., 2001

Colon Lind et al, 2001

Thyroid Visconti et al., 1997 Melanoma Yang & Richmond, 2001

Head and neck Ondrey et al, 1999

Cylindromatosis R Bernards, G Mosialos, pers. commun.

Oral carcinoma Nakayama et al., 2001

Astrocytoma/glioblastoma Hayahsi et al, 2001 Neuroblastoma Bian et al., 2002

Hodgkin's lymphoma Bargou et al., 1996, 1997; Staudt, 2001

Acute lymphoblastic leukemia Kordes et al., 2000

Acute myelogenous leukemia Guzman et al., 2001

Acute T-cell leukemia (HTLV-1) Arima & Tei, 2001 Chronic lymphocytic leukemia Furman et al., 2000 Burkitts Lymphoma (EBV) Knecht et al., 2001 Multiple myeloma Berenson et al., 2001 Diffuse large B-cell lymphoma Davis et al., 2001; Shaffer et al., 2002 In vitro transformation of cells BCR-ABL Reuther et al., 1999 DBL/DBS Whitehead et al., 1999

RAF Baumann et al., 2000 RAS Finco et al., 1997 TEL-JAK2 Santos et al, 2001

TEL-PDGFR Besancon et al., 1998

All parenteral routes are contemplated hereby, though for most applications the treatment is most preferably administered mucosally or transdermally. Parenteral administration includes intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, transepithelial (for example in the form of a slow-release subcutaneous implant), nasally, infrapulmonary, transdermal (for example, by means of an external patch or application as described further herein), and all mucosal and transmucosal modes of administration such as sublingual mucosal, buccal mucosal, oral mucosal, nasal mucosal, pulmonary mucosal, vaginal mucosal and rectal mucosal. Parenteral administration may also be by oral or nasal inhalation with the intention of delivering to any combination of oral mucosa, nasal mucosa, any of the branches of the airways (especially pulmonary mucosa), and any of the portions of the digestive tract, where various portions of the digestive tract benefit from local and, as it were, topical administration, versus serving as a route to systemic administration. Formulations for mucosal delivery may be employed for primarily local action at the mucosal site of administration, as well as for systemic delivery thereby, or any combination thereof; Topical mucosal application includes application to the mucosal areas of the rectum, vagina, eye, nose, mouth and both the gastrointestinal tract and respiratory tract generally. In addition to topical application for systemic delivery, topical (e.g. dermal) application primarily for local action and non-systemic delivery is also contemplated hereby. When administered mucosally or topically, at least a portion of the administered dosage composition is preferably retained in contact or approximation with the mucosal membrane or topical surface for a time sufficient to allow additional or sufficient absorption by those mucosal tissues or topical surfaces. Parenteral administration may be by discrete dosing or by continuous infusion or administration by any means over a selected period of time. Suitable pharmaceutically acceptable carriers and diluents known in the art may therefore be combined in the preparation of suitable dosage forms comprised of one or more sesquiterpene lactones (including especially parthenolide), preferably comprised of feverfew, or derivatives of one or more sesquiterpene lactones and/or feverfew. A particularly preferred embodiment of the present invention utilizes a feverfew extract comprising a composition extracted from the feverfew plant that contains one or more of the various constituents initially isolatable from the feverfew plant and degradation products thereof. While not being bound by theory, it is believed that subjecting said particularly preferred feverfew extract to an acidic pH, especially in an aqueous solution (one comprised of greater than 50% water), results in the formation of certain specific degradation products, including degradation products of parthenolide. Compositions comprising these degradation products have been found to provide the desired benefits of the present invention. As used herein the term "sesquiterpene lactones" includes not only those components initially present but also their degradation products as disclosed above and, likewise, the term "parthenolide" includes the degradation products thereof as disclosed above. The present invention has been found to be effective both as a treatment, as a preventative, and in other applications for the health of an animal, preferably a mammal and most preferably a human.

For purposes of the present invention, a local route of administration is one in which the primary objective is to deliver actives to the tissue with which the composition comes in direct contact and the immediately adjacent tissues, not withstanding the fact that some minority amount of actives may at any particular time generally be absorbed and distributed systemically. Likewise, the location to be affected by such local administration includes the tissue with which the composition comes in direct contact and the immediately adjacent tissues.

In one aspect of the present invention, it has been found that a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is effective, and often extremely effective, in treating or preventing maladies, especially maladies associated with NF-kB, when administered by any means which results in delivery of actives to the bloodstream without substantial reliance on ingestion and subsequent absorption through the gastrointestinal tract, specifically the gastrointestinal tract distal to the pharynx

("distal gastrointestinal tract") as typically and previously employed. It further has been found that often a surprisingly small amount of that a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is effective when administered in this manner. The most preferable such means is, generally, through mucosal absorption or transdermal absorption.

However, other means resulting in delivery of actives directly to the bloodstream without substantial reliance on ingestion and subsequent absorption through the distal gastrointestinal tract may be employed as well, and may in fact be at times preferred, especially given the diversity of ailments potentially treated hereby and not surprising in light thereof. In addition, such alternate delivery of actives may be especially preferred when the desired action is local, for which systemic administration is neither desired nor required. In each case, however, substantial reliance on ingestion and subsequent absorption through the distal gastrointestinal tract is avoided. This substantial reliance on ingestion and subsequent absorption through the distal gastrointestinal tract is the means typically and previously employed whereby compositions comprised of sesquiterpene lactones, including parthenolide and feverfew, have at times been administered in specific doses and by specific administration routes, in the few select instances in which they have been administered at all with respect to any of the ailments described herein (e.g. migraine). By avoiding substantial reliance on the typical and previously employed ingestion and subsequent absorption through the distal gastrointestinal tract, and by providing an alternate, unique and surprisingly beneficial means of delivering actives, the present invention provides an effective, practical, convenient means of treating or preventing maladies by the administration of compositions comprising relatively small doses of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew. Namely, compositions comprised of surprisingly small amounts of sesquiterpene lactones can be employed as effective treatments for a variety of conditions when administered so as to avoid substantial reliance on typical and previously employed ingestion and subsequent absorption through the distal gastrointestinal tract, the most preferably means of such avoidance being by use of mucosal or transdermal administration, most preferably said compositions being comprised of feverfew, an extract of feverfew being generally preferred. This has been neither known nor taught, either in general or with regard to specific ailments and conditions called out herein. Those potential and theoretical effects of NF-kB inhibition and other effects of compositions comprising one or more sesquiterpene lactones, including parthenolide, and especially feverfew, which are suggested by the scientific literature to have been observed in vitro, previously known only in theory and by way of speculation, but not available for practical, clinical application in the treatment of ailments and conditions, and not useful in the treatment of an animal, particularly a mammal and most particularly a human, become by means of the present invention a clinical and practical reality which may be of great use and tremendous value to a great many individuals in the treatment or prevention of many diverse ailments. By means of the present invention, compositions comprised of sesquiterpene lactones, preferably parthenolide and most preferably feverfew, are made available in a useful, convenient, generally inexpensive and effective form for treatment of patients, who may thus benefit very substantially in regard to any number of diseases and conditions, especially those wherein NF-kB is known to or does play a role. That the invention is useful and of great benefit will be readily appreciated. That it has been heretofore unknown and has not previously been employed as specified herein for the treatment and prevention of ailments is readily apparent. More specifically, the present invention provides in one aspect a method of treating or preventing maladies comprising administering parenterally, especially and preferably mucosally and/or transdermally, a composition comprising one or more sesquiterpene lactones, especially parthenolide, to a patient in need thereof, especially in one or more doses in a total (cumulative) amount of less than about 200 mg, and preferably from about 0.025 mg. to about 100 mg. in a two hour period. For purposes of the present invention, a "dose" is a predetermined aliquot of composition having a predetermined amount of active ingredient contained therein. Multiple doses may be administered to a patient at about the same time, with each aliquot being administered considered a separate dose.

In another embodiment of the present invention, administration may be continuous by any appropriate means of achieving same (slow release salts, transdermal patch, etc.). In another embodiment of the present invention, a plurality of doses of sesquiterpene lactone are administered to a mucus membrane over a 24 hour period, preferably the total amount of sesquiterpene lactone being about 0.025 mg. to about 500 mg. In this embodiment, preferably the individual doses of sesquiterpene lactone each do not exceed about 100 mg. except possibly in the case of transdermal administration, where the dose is adjusted to provide delivery at the preferred rate as set forth herein according to the specific transdennal delivery system employed. Preferably, the sesquiterpene lactone may be administered in one to six doses in a 24 hour period. In another embodiment of the present invention, a multiplicity of both doses and routes may be employed so as to maintain a low but still therapeutic blood level of the active constituents ("Actives" or "Active").

For purposes of the present invention, "Actives" or "Active" refers to one or more active constituents derived from a source of sesquiterpene lactones. A preferred example of actives includes the active constituents derived from feverfew, especially sesquiterpene lactones and especially parthenolide and the compositions comprised thereof. As but one example, an immediate sublingual dose may be applied to a patient in need thereof, followed or preceded in a short amount of time (e.g., within approximately two hours) or immediately or nearly immediately by the administration of a transdermal dose. The sublingual (in this example) dose is absorbed rapidly and quickly establishes a therapeutic blood level, while the transdermal (in this example) administration delivers Actives to a therapeutic concentration in a less immediate but more prolonged and sustained manner. Other combinations of fast acting but unsustained administration combined with more sustained administration of Actives are possible as alternate embodiments of the present invention.

In a preferred embodiment of the present invention, maladies and/or their associated symptoms are treated by administering a composition comprising feverfew, especially feverfew extract, parenterally, preferably to a mucous membrane or transdermally, to a patient in need thereof, preferably in a total administered amount of from about 2.0 mg. to about 1000 mg. of feverfew extract in a two hour period. In another embodiment of the present invention, a plurality of doses of feverfew extract are administered parenterally, preferably to a mucus membrane or transdennally, over a 24 hour period, the total amount of feverfew extract preferably not exceeding about 5000 mg. Preferably, the individual doses of feverfew extract each does not exceed about 1000 mg. except possibly in the case of transdermal administration where the dose is adjusted to provide delivery at the preferred rate as set forth herein according to the specific transdermal delivery system employed. In a preferred embodiment, the feverfew extract is administered parenterally, most preferably to a mucous membrane or transdermally, in one to six doses in a 24 hour period, preferably either mucosally or transdermally.

It has also been found that the efficacy of the composition is enhanced, especially when administered via the oral or nasal mucosal route, when the composition is of an acidic pH, preferably at a pH of from about 2.5 to about 6.0. It has additionally been found that the efficacy of the composition is enhanced, especially for oral or nasal mucosal application, when the composition, if a liquid, has a viscosity greater than water, and more preferably when said composition has a viscosity greater than about 100 cP. Liquid compositions having higher viscosity have been found to enable the patient to better establish and maintain contact of the composition with the mucosal membrane, including the nasal or oral mucosa and most particularly the sublingual area. It has also been surprisingly found that such composition and treatment is effective in providing very rapid relief from a number of ailments and their associated symptoms. In another embodiment of the present invention, the carrier liquid includes a mucosal permeation enhancer. In a particularly preferred aspect of the present invention, the treatment may also be used daily or occasionally as a prophylactic treatment, or as needed as a prophylactic treatment, or for the maintenance of health.

In one aspect of the present invention, convenient systems for administration of sesquiterpene lactones, and as another embodiment, parthenolide, and as yet another embodiment, feverfew, preferably feverfew extract, are provided wherein compositions are provided in a unit dose applicator for oral mucosal or nasal mucosal administration, preferably sublingual administration. More particularly, a unit dose applicator and composition for oral mucosal administration to patients is provided comprising a dispenser for dispensing liquids having a reservoir and a delivery spout. The dispenser has a liquid capacity of about 0.1 to about 10 mis. This dispenser is provided with a liquid composition disposed therein. The composition comprises a sesquiterpene lactone, preferably parthenolide, in an amount not exceeding about 100 mg. In another embodiment, the liquid composition in the unit dose dispenser comprises feverfew, preferably feverfew extract, in an amount not exceeding about 1000 mg. Alternately, the dosage may be administered in any convenient and appropriate form for mucosal or transdermal administration, or any form appropriate for the parenteral route of administration employed, or any form appropriate for the local administration thereof. An active sesquiterpene lactone may be administered to a patient by any suitable means. Pharmaceutically acceptable carrier preparations for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. The Active therapeutic ingredient may be mixed with excipients that are pharmaceutically acceptable and are compatible with the Active ingredient. Suitable excipients include water, saline, dextrose, glycerol and ethanol, or combinations thereof. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.

The form may vary depending upon the route of administration. For example, compositions for injection may be provided in the form of an ampule, each containing a unit dose amount, or in the form of a container containing multiple doses. Compositions for treatment of and by application to the eye may be provided in a dropper bottle or similar which is suitable to the intended purpose.

Compositions for use by application to the nasal mucosa may be provided in a nasal spray squeeze bottle, etc.

Active sesquiterpene lactone may be formulated into therapeutic compositions as pharmaceutically acceptable salts. These salts include the acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, or tartaric acid, and the like. Salts also include those formed from inorganic bases such as, for example, sodium, potassium, arnmonium, calcium or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like. Controlled delivery may be achieved by admixing the Active with appropriate macromolecules, for example, polyesters, polyamino acids, polyvinyl pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, prolamine sulfate, or lactide/glycolide copolymers. The rate of release of the Active may be controlled by altering the concentration of the macromolecule. Another method for controlling the duration of action comprises incorporating the Active into particles of a polymeric substance such as a polyester, peptide, hydrogel, polylactide/glycolide copolymer, or ethylenevinylacetate copolymers. Alternatively, an Active may be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrylate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.

Various compositions are also provided, wherein the composition comprises a sesquiterpene lactone, preferably parthenolide, in an amount of from about 0.01 mg/ml to about 100 mg/ml, and more preferably from about 0.01 mg/ml to about 10 mg/ml. and yet more preferably in an amount from 0.01 mg/ml to about 5 mg/ml. In another embodiment, the composition comprises feverfew, preferably feverfew extract, in an amount of from about 1 mg/ml to about 500 mg/ml. Alternative vehicles appropriate for administration, especially mucosal and transdermal administration, are also contemplated. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.

It has surprisingly been found that systemic administration of a composition comprised of a relatively small amount of sesquiterpene lactone, and more preferably, parthenolide, and yet more preferably feverfew, to mucosal membranes, transdermally, or by an alternate, appropriate parenteral route, either alone or in combination with other treatments, provides excellent treatment for various maladies and conditions, including at times the prevention thereof. As appropriate, local, non- systemic administration of Actives is also contemplated hereby as an alternate embodiment of the present invention. The ability to effectively treat maladies using such low yet rapidly effective doses of Active ingredient (Actives) provides substantial benefits, including not only effective relief from maladies, but also the drastic reduction in side effects which might otherwise be associated with said Active ingredient or alternative treatments. The methods and compositions of the present invention thus may provide an improved safety profile that may make the present invention most suitable to the average user, and particularly suitable for those with whom additional caution need be exercised, such as those who are sensitive to various medications or in the case of pediatric use, where additional cautions are generally warranted. In another aspect of the present invention, sesquiterpene lactones may be administered via the G.I. tract in a manner effective to provide either acute benefit or prophylactic benefit for the diseases described herein. In one embodiment, one or more Actives, especially sesquiterpene lactones, are administered at a higher dose to account for the amount of Actives destroyed or eliminated by first-pass metabolism. In this embodiment, the amount of G.I. administration dose is determined such that the amount of Actives that are actually delivered to the affected cells of the patient is sufficient to suppress the activity of NF-kB or otherwise be effective. For example, in certain embodiments it may be determined that 95% of Actives are destroyed by first-pass metabolism. In this example, a tablet that contains 20x the amount of Actives is administered to achieve the desired treatment result. This approach of administration is particularly practical in the present invention, in light of the relatively inexpensive nature of the Actives. This aspect of the present invention is particularly desirable where long term administration of Actives, especially sesquiterpene lactone is contemplated for prophylactic treatment due to the convenience and low cost for the patient. A specifically preferred example of such a treatment course is the use of feverfew in a daily administered tablet, which would in one particular example be taken for years as prophylaxis for Alzheimer's disease by patients in the early stages of the disease or who have been identified as having a high risk of developing this disease. Prophylactic treatment by administration of a high dose to account for the amount of Active that is destroyed or eliminated by first-pass metabolism is specifically contemplated for each disease listed herein.

Enhancement of the oral G.I. efficacy (bioavailabiUty) is contemplated by selection of oral administration formats or content to increase the amount of Active that is delivered after first pass metabolism. Examples of such enhancements include providing a protective coating, modification of tablet dissolution rates, addition of stabilizers or other such chemical components that counteract the destructive activity of the G.I. tract, or other such measures as may be appropriate to enhance administration of sesquiterpene lactones.

It is specifically contemplated that Actives, especially sesquiterpene lactones may be administered in combination with other active ingredients for treatment of the same or a different malady. Such combination of active ingredients may be desirable for treatment of acute diseases, and is contemplated to be particularly advantageous for long term administration of prophylactic treatments. For example, sesquiterpene lactones may be combined in administration forms with another agent to be taken daily (such as a cholesterol lowering drug), so that the patient need only administer one medication/dose vs. multiple medications and doses.

One substantial advantage of the present invention is its safety. But one example of which is the lack of mutagenicity of the Actives. Thirty migraine patients who had taken the leaves, tablets or capsules of feverfew daily for more than 11 consecutive months were compared to 30 feverfew non-user migraine patients who had been individually age- and sex-matched. The frequency of chromosomal aberrations and sister chromatid exchanges (SCE) were determined from lymphocyte cultures established from blood samples taken over a period of several months. Matched pairs were sampled on the same date for two-thirds of the cases, and the greatest difference in sampling time of the remainder was 20 days. Also, the mutagenicity of urine samples from 10 feverfew user migraine patients was compared to that from 10 matched non-user migraine patients using the Ames Salmonella mutagenicity test system. Paired samples were given on the same date. The mean frequency of chromosomal aberrations in the feverfew user group was lower than that in the non-user group both in terms of cells with breaks (2.13% vs. 2.76%) and in terms of cells with all aberrations (4.34% vs. 5.11%). However, this difference was small and not significant (Johnson et al Investigation of possible genetoxic effects of feverfew in migraine patients Hum Toxicol. 1987 Nov;6(6):533-

4.)

By far the most commonly reported side effect of feverfew use is the occurrence of mouth sores, primarily associated with chewing feverfew leaves, wherein it has at times been reportedly observed in up to 11% of such users. Mouth sores are occasionally accompanied by general inflammation of tissues in the mouth. Infrequently reported side effects of feverfew use include gastrointestinal side effects such as abdominal pain, indigestion, flatulence, diarrhea, nausea, and vomiting. Another advantage of the present invention is the likely avoidance of these oral and gastrointestinal side effects. Some users have reported that when daily use is stopped suddenly after long periods of use, rebound headaches may occur, along with anxiety, sleep disturbances, and muscle stiffness or pain (collectively referred to as "post-feverfew syndrome," reported to occur in up to 10% of migraine patients who abruptly stop taking feverfew after a long history of daily use). Another advantage of the present invention is the likely avoidance of such side effects, as the use of feverfew as envisioned hereby is generally not daily, and even when employed daily will generally be in an amount substantially less than those orally ingested amounts reported to have caused these side effects. While most side effects are mild, it is nonetheless advantageous to avoid or reduce their occurrence to the greatest extent possible while still employing an effective dose.

Certainly these side effects are mild and offer an improved side effect profile when compared to certain known and commonly employed inhibitors of NF-kB or other treatments of diseases and conditions involving NF-kB. Considering aspirin for example (which is a weak and generally ineffective inhibitor of NF-kB), it is observed that use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, account for an estimated 7600 deaths and 76,000 hospitalizations in the United States each year (Fries JF. Assessing and understanding patient risk. Scand J Rheumatol Suppl. 1992;92:21-4.). Glucocorticoids are believed to be more effective inhibitors of NF-kB. Glucocorticoid associated side effects may be serious and can include osteoporosis, susceptibility to bruising, infections, diabetes, cataracts, glaucoma, high blood pressure and weight gain. An additional side effect that may be caused by treatment with glucocorticoids is osteonecrosis, which involves serious damage to the bones. Osteonecrosis may begin to develop even after the short-term use of glucocorticoids to treat rheumatoid arthritis. Thus there is a notable advantage to the invention of the alternate inhibitor of NF-kB disclosed hereby including that it may have a substantially more advantageous side effect profile. The invention is particularly beneficial to those patients concerned about using large amounts of medication for treatment of ailments. The low total administered amount of Actives and relatively small amount of total composition that may be applied to the mucosal membranes, transdermally, or otherwise in one aspect of the present invention may additionally be of particular benefit to those treating ailments. As a naturally occurring substance, the present invention provides substantial benefits to patients, not least of which may be the cost savings associated with a decreased reliance on expensive pharmaceuticals.

For some maladies, presently known treatments are generally slow in providing relief, or provide only partial relief, or are unable to provide any substantial relief, in each case often while exhibiting undesired side effects. Surprisingly, the present invention often provides rapid relief of symptoms. Depending on the condition treated or the use for which it is employed, beneficial effects of the treatment may be felt within minutes of administration. Alternate existing treatments may be effective for some patients, but not for others, necessitating a lengthy and sometimes costly search by each person for the treatment that will be effective for that particular individual. Surprisingly, the present invention is for many ailments effective for a large percentage of people who try this treatment. Thus, the present invention provides additional substantial benefit to the practitioner or individual who may discover conveniently and without delay those for whom this treatment is effective, searching amongst other alternatives only in those cases where this medication proves insufficiently effective.

Additionally, there is a growing desire to use naturally generated ingredients to provide treatments for disorders. Therefore, a particularly preferred embodiment of the present invention comprises administration of feverfew, most preferably feverfew extract. More specifically, a preferred method of treating maladies comprises administering a liquid composition comprising feverfew extract via a mucous membrane, most preferably sublingually, to a patient in need thereof. Feverfew extract is derived from the feverfew plant (Tanaecetum parthenium), which is also known, for example, as Chrysanthemum parthenium, Chrisanthemum parthenium, Pyrethrum parthenium, Tanacete parthenii herba or folium, Matricaria parthenoides, Matricaria parthenium, Leucanthemum parthenium, Matricaria parthenium, Spanish pellitory, Featherfew, Featherfoil, feather-fully, and by a number of common names, various of which are used throughout the world (Midsummer daisy, Bachelor's buttons, Altamisa, nosebleed, flirtwort, ague plant, devil daisy, feddygen fenyw (Welsh), maid's weed, Missouri snakeroot, mutterkaut (German), prairie-dock, vetter-voo, wild chamomile, grande camomille (French), Santa Maria (Spain), febrifuge plant.) The extract may be obtained by techniques known in the art using solvents such as petroleum spirits or polar organic solvents. See U.S. Patent No. 5,384,121 to Rhodes, and also WO 94 06800; EP 0 553 658; WO 92 11857; GB 2,166,952; EP 98 041; WO 98 39018. The extract of the feverfew plant generally contains parthenolide, and may additionally contain other components such as Polyynes, Flavonoids and Volatile oils including camphor, bomeol and others, each of which may contribute to the therapeutic effect of the preparation disclosed herein. Feverfew also naturally contains relatively large quantities of sesquiterpene lactones, primarily parthenolide. In addition to parthenolide, feverfew extracts, and feverfew itself, is known to contain many components, including the following non-ubiquitous chemicals: 1- Beta-hydroxyarbusculin, 10-Epicanin, 8-Beta-reynosin, Apigenin-7-glucuronide, Apigenin-7-glucoside, Chrysanthernolide, Chrysanthemonin, Chrysartemin-A, Chrysartemin-B, Cosmosiin, L-Borneol, L-camphor, Mangoliolide, Reynosin, Santamarin, chrysanthernolide, chrysanthemomin, chrysarten-A, chrsyarten-c, chrysoeriol-7-glucuronide, cobalt, cosmosiin, epoxyartemorin, luteolin-7-glucoside, luteolin-7-glucuronide, Tanaparthin, Tanaparthin-1 -alpha, 4-alpha-epoxide, Tanaparthin- 1 -beta,4-beta-epoxide, quercetagentin-3 ,7,3 '-trimethylether, quercetagetin-3'7-dimethylether, reynosin, tenetin 3-b-hydroxyparthenolide, seco- tanaparthenolide A, l-.beta.-hydroxyarbusculin, 6-hydroxykaempferol-3,7-4'- trimethylether (Tanetin), 6-hydroxykaempferol-3,7-dimethyl ether, 8-.beta.- reynosin, 10-eρicanin, ascorbic acid, canin, artecanin, beta-carotene, calcium, chromium and balchanin. Although not all components have been isolated and characterized, the known components of an extract of feverfew contain a significant number of biologically active components. The specific role that each of these component compounds plays in the biological activity of feverfew is to date not well known. However, some information is known about the allergic reactions to the extract. It is believed that approximately 2% of the population may experience an allergic reaction to feverfew, especially the topical application thereof, and that many of these allergic reactions are caused by the .alpha. -unsaturated .gamma. - lactones such as parthenolide. (See, Arch. Dermatol. Forsch. 1975, 251 (3):235-44; Arch. Dermatol. Forsch 1976, 255 (2):111-21; Contact Dermatitis, 1988, 38 (4):207- 8; Am. J. Contact Dermatol. 1998-9 (l):49-50; Br. J. Dermatol, 1995, 132 (4): 543- 47).

Because feverfew extract may contain additional beneficial components, compositions comprising the extract of feverfew are generally preferred for use in the present invention as compared to compositions comprising a highly purified parthenolide or other sesquiterpene lactone that has been isolated from the additional components naturally occurring in feverfew extract. For example, the ability of parthenolide deprived feverfew to affect the inflammatory responses by reducing the production of lymphocyte function has been demonstrated, along with a decrease in nitric oxide activity.

The use of other forms of feverfew preparations is also contemplated hereby, including fresh feverfew, dried feverfew, feverfew powder, and dried leaf bits in solution, among a number of other such possible preparations.

Preferred embodiments of the present invention use feverfew extract that has been standardized to initially contain a predetermined standardized parthenolide concentration of preferably not less than about 1.0%, and more preferably 4.0% and higher. While the source of sesquiterpene lactone, especially parthenolide, in compositions of the present invention is preferably feverfew as discussed above, it may alternatively be obtained from any number of other plant species. Such plant species include especially other members of the Compositae family, which include especially the many species of chrysanthemums, daisies, marigolds, chamomile, yarrow and aster. Parthenolide and other sesquiterpene lactones can also be obtained from tansy and a very large number of other woody and herbaceous plants. Alternatively, sesquiterpene lactones, including parthenolide, may be made by any appropriate synthetic route.

The composition to be used in the present invention may optionally comprise additional active ingredients. These active ingredients may also be provided as a treatment of maladies or may provide other physical benefits, provided that the treatment benefit of sesquiterpene lactones such as parthenolide and/or the feverfew extract is not adversely affected. In one aspect, preferably additional amounts of already present sesquiterpene lactones or additional sesquiterpene lactones are incorporated in the compositions of the present invention. Preferred such sesquiterpene lactones include especially those which are known to be contained in (naturally occur in) feverfew, such as 3-Beta-hydroxyparthenolide, seco- tanaparthenolide A, canin, artecanin, chrysanthemonin, chrysartemin A and B, santamarin and balchanin, as well as those occurring in other plant species such as encelin, leucanthin B, enhydrin, melampodin A, tenulin, confertiflorin, burrodin, psilostachyin A, costunolide, guaianolide, cinerenin, artemisinin, aristolactone, lactarorufin A, bilobalide, helenalin, furandiol. Sesquiterpene lactones in addition to parthenolide may be isolated from plants such as dandelion, burdock, butterburr, mugwort and sunflower plants, among very many others. Compositions to be used in the present invention may optionally additionally comprise other naturally occurring components and extracts, including those identified in the Homeopathic Pharmacopoeia of the United States (HPUS).

Preferred additional components include the extracts of bay leaf and/or ginger and/or green tea, and/or turmeric or the isolated components thereof. A particularly preferred isolated component of green tea is L-theanine and a particularly preferred isolated component of turmeric is cucumin.

Particularly preferred compositions of the present invention contain substantially no active ingredients other than those that are extractable from herbal sources. In a particularly preferred embodiment of the present invention, the compositions contain substantially no active ingredients other than those that are extractable from feverfew, bay leaf, ginger, turmeric and green tea sources. In another particularly preferred embodiment, the compositions contain substantially no active ingredients other than those that are extractable from feverfew, ginger and turmeric. In another particularly preferred embodiment, the compositions contain substantially no active ingredients other than those that are extractable from feverfew and ginger, or from feverfew alone. Such compositions additionally may comprise non-pharmacologically active ingredients, such as thickeners, carrier liquids and flavorants. Compositions may additionally contain one or more members selected from the group consisting of antioxidants, vitamins, minerals, proteins, fats, carbohydrates, glucosamine, chondrotin sulfate and aminosugars. It has surprisingly been discovered that the use of only active ingredients that are extracted from herbs provide particular benefit to the user in being both effective and also providing natural healing conditions particularly suited to the well being of patients. Such compositions contain parthenolide in the amounts as discussed earlier, and preferably contain less than about 500 mg of any given natural active ingredient per dose. The compositions as described herein are formulated using a carrier appropriate for administration to the topical region or mucosal membrane employed, the most preferable mucosal membrane being the sublingual region of the mouth, when such administration is employed these are selected from the group consisting of jelly, creme, gel, solid, semi-solid, rapidly dissolving tablet or pill, liquid, droplet, aerosol, powder, microsome, liposome, emulsion, sol-gel, foam, gum (e.g. chewing gum), sustained release, degradable polymer, impregnated film, impregnated fiber, impregnated patch, coated film, coated fiber, coated patch, flexible solid, semisolid carrier, polymeric matrix, suspended microspheres, and thermoreversible gel. The carrier liquid preferably is selected from water, alcohol, oils (such as synthetic mono or digylcerides), fat, polyethylene glycols, glycerin, propylene glycol, and mixtures thereof. Most preferably the carrier comprises water.

Thickening agents are preferably incorporated in liquid compositions of the present invention. When employed mucosally, the thickening agent preferably assists in retention of the liquid composition on or in close proximity with the surface of the mucosal region for a time sufficient to allow absorption of the active ingredients by the patient. Thickening agents are particularly desirable in sublingual and nasal applications, as a more viscous agent is more easily retained in the proper area. In the case of sublingual administration, a more viscous agent further reduces the user's involuntary impulse to swallow, in this case perhaps prematurely. Thus, the thickening agent may assist in providing sublingual liquid retention or nasal mucosal retention for a time appropriate for proper absorption of the active ingredient by the patient, and also thereby may improve the clinical efficacy of the composition. Any appropriate thickening agent may be used in the composition of the present invention. Preferred such thickening agents include agar, alginate, carrageenan, carboxymethylcellulose, cellulose, chitosan, com starch, Danish agar, dextrin, furcelleran, galactomannans, gelatin, gellan gum, guar gum, gum acacia, gum arabic, gum ghatti, gum tragacanth, hydroxypropyl methylcellulose, karaya gum, methylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, hyaluronic acid and salts thereof, modified starches, mucilage, pectin, potato starch, rice starch, starch, tara gum, vegetable starch, wheat starch, and xanthan gum and combinations thereof. Most preferably, the compositions of the present invention when employed in liquid form for sublingual administration have a viscosity that is from about 100 cP (somewhat lower than the viscosity of Olive Oil) to about 50,000 (i.e. the viscosity of molasses), and more preferably from about 500 cP (the viscosity of SAE #10 motor oil) to about 5000 cP (approximately the viscosity of Com Syrup), all measured at 25 °C.

The compositions as described herein may further comprise suitable adjuvants, such as preservatives (for example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid), stabilizers, antibacterial agents (such as benzyl alcohol or methyl paraben), antioxidants (such as ascorbic acid or sodium bisulfite), chelating agents (such as ethylenediaminetetraacetic acid), buffers (such as acetates, citrates or phosphates), agents for the adjustment of tonicity (such as sodium chloride or dextrose), dyes, colorants, thickening agents, flavorants, sweetening agents, and suspending agents.

In a particularly preferred embodiment of the present invention, the compositions of the present invention are provided in combination with a mucosal permeation enhancer appropriate for enhancing the mucosal absorption of the composition employed. Such permeation enhancer is particularly desirable for applications to nasal mucosal tissue, and is most desirable for applications to oral mucosal tissue, such as buccal and sublingual tissue. Permeation enhancers additionally may be particularly desirable for use in applications to nasal mucosal tissue. Mucosal permeation enhancers may in such cases increase the absorption of Actives and thereby may improve the clinical efficacy of the composition. Preferred mucosal permeation enhancers include azone, sodium glycholate, sodium cholate, sodium tauracholate, sodium taurocholate plus EDTA, deoxycholate, sodium lauryl sulfate, lauric acid, ethanol, lysophosphatidyl choline, polysorbate 80, cyclodextrin, cetylpyridinium chloride, cetyltrimethylammonium bromide, benzalkonium chloride, sodium salicylate, sodium EDTA, aprotinin, dextran sulfate, linoleic acid, labrafil, transcutol, urea, methoxysalicylate, POE 23 lauryl ether, various surfactants and other mucosal permeation enhancers and combinations thereof. Most preferably, the mucosal permeation enhancer comprises sodium lauryl sulfate. In a particularly preferred embodiment of the present invention, the compositions of the present invention are provided at a pH of from about 2.0 to about 6.5, more preferably at a pH of from about 2.5 to about 6.0, and more preferably at a pH of from about 3 to about 5. Various pH adjusters may be used to adjust the pH of the composition to the desired level. Examples of suitable pH adjusters include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, boric acid, sodium borate, and the like. Preferably, the pH of the composition is adjusted to be acidic using ascorbic acid.

Preferably, the composition is buffered by a pharmaceutically acceptable buffer. Examples of buffering agents include borate buffers, citrate buffers, phosphate buffers, tartarate buffers, acetate buffers, carbonate buffers, and amino acid salts, etc. Most preferably, the buffer is sodium citrate. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein. When used for oral mucosal administration, such as sublingually, compositions as described herein may be administered using any appropriate technique, such as by use of a medicine dropper, syringe, vial, or the like. Preferably, the composition is administered using a unit dose applicator that is a dispenser having a reservoir and a delivery spout and having a liquid capacity of about 0.1 to about 10 mis. In a preferred embodiment, the unit dose applicator is provided as a dispenser having parthenolide in an amount not exceeding about 100 mg, or other limited quantities as discussed above. As an alternative preferred embodiment, the unit dose applicator is provided as a dispenser having feverfew extract in an amount not exceeding about 1000 mg, or other limited quantities as discussed above. A particularly preferred dispenser is the MicroDose™ dispenser commercially available from Unicep Packaging, Inc., Sandpoint, ID. Alternatively, the dispenser may be an ampule designed to mate with a plunger of a syringe to facilitate controlled delivery of the composition, such as described in U.S. Patent No. 6,328,715.

This invention also includes a method of treating inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient.

In addition to the extracts of feverfew, other substances, such as biologically active agents, pharmaceutical excipients, and cosmetic agents may be included in the topical compositions of this invention.

Biologically active agents to be employed in topical compositions may include, but are not limited to, flavanoid/flavone compounds which include but are not limited to tanetin, 3,7,3'-trimethoxyquercetagetin, apigenin and its derivatives. When flavanoid/flavone compounds are present, they are present at a concentration of between about 0.001% to about 0.5% preferably, between about 0.005% and 0.2% based on the weight of the topical composition. Additional biologically active agents for use in topical applications include but are not limited to sunscreens, anti-wrinkling/antiaging agents, antifungal agents, antibiotic agents, anti-acne and antipsoriatic agents, depigmentating agents, where such agents may be utilized so long as they are physically and chemically compatible with the other components of the topical composition. The compositions of this invention when employed topically may include additional skin actives. Actives can be but not limited to vitamin compounds. Skin lightening agents (kojic acid, ascorbic acid and derivatives such as ascorbyl pamiltate, and the like); anti-oxidant agents such as tocopherol and esters; metal chelators, retinoids and derivatives, moisturizing agents, hydroxy acids such as salicylic acid, sun screen such as octyl methoxycinnamate, oxybenzone, avobenzone, and the like, sun blocks such as titanium oxide and zinc oxide, and skin protectants. Mixtures of above skin actives may be used.

Sunscreens which may be used in the compositions of this invention intended for topical use and may include but are not limited to organic or inorganic sunscreens, such as, octylmethoxycinnamate and other cinnamate compounds, titanium dioxide, zinc oxide and the like. Anti-wrinkling/anti-aging agents used in the compositions of this invention intended for topical use may include but are not limited to retinoids (for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate) alpha hydroxy acids, galactose sugars (for example, melibiose and lactose), antioxidants, including but not limited to water soluble antioxidants such as sulfhydryl compounds and their derivatives (for example, sodium metabisulfite and N-acetyl-cysteine, acetyl- cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferin, ascorbic acid and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide). Oil soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to tocopherols (for example, tocopheryl acetate, . alpha. -tocopherol), tocotrienols and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of this invention, include, but not limited to extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavonoids, mono, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark and propolis extracts and legume extracts and the like.

Antifungal agents used in the compositions of this invention intended for topical use include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts.

Antibiotic (or antiseptic agents) used in the compositions of this invention intended for topical use include but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetrachcycline hydrochoride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts. Acne ingredients used in the compositions of this invention intended for topical use include but are not limited to agents that normalize epidermal differentiation (e.g. retinoids), keratolytic agents (e.g. salicylic acid and alpha hydroxy acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum.

Antipsoriatic agents used in the compositions of this invention intended for topical use include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), Vitamin D and its analogues (e.g. calcipotriene), retinoids (e.g. Tazarotene) and anthraline.

Cosmetic agents which may be used in the compositions of this invention when intended for topical use may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera). Further, the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, flavors, fragrances, surface active agents, and the like. Examples of humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3 -butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.

Cosmetic agents may also include substances which mask the symptoms of inflammatory disorders and related conditions; such substances include but are not limited to pigments, dyes, and other additives (e.g., silica, talk, zinc oxide, titanium oxide, clay powders). The pharmaceutical excipients include but are not limited to pH modifying agents such as pH-modifying agents, organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium gluconate, oils (e.g., mineral oil), ceteareth-20, ceteth-2, surfactants and emulsifiers, thickener (or binders), perfume, antioxidants, preservatives, and water. When intended for topical use, binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions. Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions.

Examples of preservatives which may be used in the compositions of this invention intended for topical use include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para- hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl parahydroxybenzoate and the like.

Examples of flavors and fragrances which may be used in the compositions of this invention intended for topical use include menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citranellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like.

The compositions of the present invention may be prepared in a number of forms for topical application to a patient. For example, the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioner, liquid, spray liquid, paint-/brush-on preparation, aerosol, powder or adhesive bandage. In addition the composition may be impregnated on bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes. The compositions of this invention when intended for topical use may be in the form of emulsions, such as creams, lotions and the like. Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.

Examples of surface active agents which may be used in the compositions of this invention intended for topical use include sodium alkyl sufates, e.g., sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodium dioctylsulfosuccinate; N-alkylaminoglycerols, e.g., N-lauryldiaminoethylglyecerol and N-myristyldiaminoethylglycerol, N-alkyl- N-carboxymethylammonium betaine and sodium 2-alkyl-l -hydroxy ethylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerol ester, sorbitan aliphatic acid ester, Pluronic type surface active agent, and polyoxyethylenesorbitan aliphatic acid esters such as polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan monolaurate. Emulsifier-type surfactants know to those of skill in the art should be used in the compositions of this invention.

Another important ingredient of the present invention when intended for topical use is a dermatologically acceptable carrier. Such a suitable carrier is adequate for topical use. It is not only compatible with the active ingredients described herein, but will not introduce any toxicity and safety issues. An effective and safe carrier varies from about 50% to about 99% by weight of the compositions of this invention and more preferably from about 75% to about 99% of the compositions.

The choice of which pharmaceutical excipient or biological agent, or cosmetic agent to use in the compositions of this invention intended for topical use is often controlled or affected by the type of inflammatory disorder or related condition which is being treated. For example, if the compositions of this invention were used to treat a skin inflammation associated with athlete's foot, jock itch or diaper rash, talc would be a preferred pharmaceutical excipient and an antifungal agent would be preferred biological agent. If the compositions of this invention were to be used to treat eczema of the scalp, emulsifiers and oils would be preferred pharmaceutical excipients. The condition of contact dermatitis may be treated by applying a topical composition comprising a sesquiterpene lactone, preferably parthenolide and most preferably feverfew extract.

Transdermal administration is also contemplated. In one aspect of the present invention, convenient systems for administration of sesquiterpene lactones, and as another embodiment parthenolide, and as another embodiment, feverfew extract, are provided wherein compositions are provided as a transdermal patch for transdermal administration. US Patent No. 5,503,843 to Santus discloses a transdermal patch for the delivery of a specific Compound to the skin of a patient. The patch comprises a backing layer, a drug depot comprising the compound and a permeation enhancer composition.

US Patent No. 5,837,289 to Grasela, et al. discloses a composition and procedures for its formation and administration to provide a convenient, efficacious and simple transdermal administration of medications from a topically applied cream. The composition incorporates at least two separate penetration enhancers which function synergistically to provide for rapid but controllable transport of the medication from the cream into the skin. The use of a plurality of penetration enhancers, at least one of which facilitates the separation of medication from the cream and at least a second of which alters the structure of the outer layers of skin, particularly the stratum corneum, enhances migration of the drug through the stratum comeum.

US Patent No. 6,410,062 to Callaghan, et al. describes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition comprising an effective amount of an extract of feverfew, where the extract is substantially free of α-unsaturated γ-lactone, and particularly substantially free of parthenolide.

US Patent 5,905,089 to Hwang, et al. describes the use of sesquiterpene lactones for treatment of severe inflammatory disorders; possible route of administration is transdermal. The term "transdermal" in this patent is described in a very specific manner that does not contemplate topical application of a composition or a patch, stating that the composition may be "administered transdermally, for example in the form of a slow-release subcutaneous implant." See column 6, line 26.

When an Active agent is administered intravenously, intramuscularly, orally or mucosally, the initial level of the active agent in the blood rapidly rises to a maximum, which is generally much higher than the therapeutically effective level of the active agent. Sometimes initial levels of actives administered orally may reach toxic concentrations resulting in undesirable side-effects. This is known as

"overdosing." After the maximum level in the blood is reached, the concentration then falls slowly as the active is distributed, metabolized, excreted, or degraded. Eventually, the blood concentration of the active agent falls below the therapeutically effective level (i.e., there is "underdosing"). At this point, the active agent needs to be re-administered to achieve effectiveness. Maintaining the blood concentration of the active agent between the minimum therapeutically effective level and toxic levels is important. One way to achieve this is to administer lower active agent doses to the patient more frequently. This, however, is an unacceptable alternative in many instances, due to problems with patient compliance. Transdermal delivery of sesquiterpene lactones offers a means of circumventing the problems of overdosing and underdosing that may sometimes be associated with conventional delivery methods. The transdermal delivery of parthenolide or other Actives as disclosed herein can be designed so that the rate of delivery of the parthenolide or other actives as disclosed herein closely follows the rate of the clearance of the particular active(s) from the environment, thus keeping constant or near constant levels of said active(s) in the blood, and reducing waste of active(s) and overdosing problems.

The term "pharmaceutically acceptable" or "therapeutically acceptable" refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host or patient. The term "patient" refers to a mammal that is being treated. Preferably the patient is a human. In situations where very rapid onset of action is desired along with a sustained blood level, an initial dose may be provided by means of, for example, sublingual administration of parthenolide, which provides an immediate and rapid rise in blood levels of the desired composition. Transdermal delivery as presently described may then be employed in combination with the rapid sublingual delivery mechanism, thereby maintaining blood levels of the active agents in the therapeutic range. The amount of time required for onset of absorption of a representative active (e.g. nitro glycerin) when an active ingredient is delivered via a sublingual administration route is very short (about 2 minutes), while the time required for onset of absorption when the active is delivered via transdermal delivery is much longer (about 11 minutes). The amount of time required to achieve peak plasma concentration when a representative active ingredient (e.g. nitro glycerin) is delivered via a sublingual administration route is also very short (about 5 minutes), while the time required to achieve peak plasma concentration when the active is delivered via transdermal delivery is much longer, generally about 90 minutes, though as another advantage of transdermal dosing, the time required to achieve peak plasma concentration via transdermal dosing can be modified based on the specifics of the transdermal system employed. Thus, a particularly preferred embodiment of the present invention is a combination of mucosal, preferably sublingual, and transdermal administration as taught herein, so that one may achieve rapid active ingredient levels that are then sustained over many hours.

In a particularly preferred aspect of the present invention, the transdermal delivery system may be designed to deliver actives, especially a sesquiterpene lactone, at the indicated rate for an extended period. Thus, preferably the transdermal delivery system will administer actives at the indicated rates for periods of 24 hours, or from about 1 to about 3 days, or about 3 to about 7 days, or from about 1 week to about 4 weeks. Longer rates of delivery of actives are also contemplated. The extended controlled dose delivery of these as described herein provide particular benefit to the user in prophylactic uses, or where the ailment to be treated is one of long and continuous duration (e.g. arthritis, migraine associated with a menstrual period). In addition to the advantage of being able to control the delivery rate, transdermal delivery also provides a comfortable, convenient and non-invasive method of administering Actives, especially sesquiterpene lactones, especially parthenolide. Gastrointestinal irritation and other side-effects associated with oral ingestion of actives, including parthenolide or other sesquiterpene lactones, may be reduced or eliminated, and patient anxiety regarding invasive delivery methods, such as needles, is also eliminated.

Further, transdermal administration (as mucosal and other administration routes contemplated hereby) avoids the "first pass effect," which often results when a medication is administered orally and thus has to pass through various organs, including the stomach and then, once in the bloodstream, the liver, before reaching the affected area of the body. These organs can absorb or chemically alter significant quantities of the passing medication, thus sometimes making effective administration of actives by this route impossible, or requiring that large excess quantities of the medication be administered initially to insure that an effective quantity of the medication will ultimately reach the affected area of the body.

In one embodiment of the present invention, compositions are provided in the form of a lotion cream or other spreadable or moldable material. Using these formulations, actives including parthenolide may be effectively topically administered by application of the cream to many bodily areas where a patch either will not fit or cannot be shaped to conform to the skin contours. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein. For example, an appropriate cream composition may be formulated by forming an organogel from lecithin and isopropyl palmitate, as disclosed in U.S. Patent No. 5,837,289. Suitable gel structures thus may be formed and used as the base for a cream composition. Parthenolide is preferably solubilized with a solvent, such as water, alcohol or other appropriate solvent, and mixed into the matrix to formulate an appropriate composition for application to the dermis of a patient, for transdermal systemic delivery of parthenolide to the patient. Additional components, such as cosmetic agents, binders, thickeners, preservatives and fragrances may be present in the topically applied cream or other moldable or spreadable material when intended for transdermal systemic delivery. Cosmetic agents which may be used in the compositions of this invention when intended for transdermal systemic delivery may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera). Further, the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, surface active agents, and the like. Examples of humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3 -butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.

Binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions. Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions. Examples of preservatives which may be used in the compositions of this invention include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para- hydroxybenzoate, propyl para-hydroxybenzoate, butyl parahydroxybenzoate and the like.

Examples of fragrances which may be used in the compositions of this invention include menthol, anethole, carvone, eugenol, limonene, ocimene, n- decylalcohol, cifronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like. The compositions of the present invention may be prepared in a number of forms for topical application to a patient. For example, the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioners, liquid, spray liquid, paint-/brush-on preparation or aerosol. In addition the composition may be impregnated on a bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes.

The compositions of this invention may be in the form of emulsions, such as creams, lotions and the like. Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.

Optionally, a cover sheet may be applied over the applied cream or spreadable material containing parthenolide, and further the cover sheet may be secured with an adhesive sheet or strip to protect against undesired exposure of the applied cream to the elements.

Preferably, transdermal application of Actives is carried out by use of a transdermal composite, commonly referred to as a "patch." In this embodiment, the transdermal composite is a preconstructed composite capable of adhering to the dermis of a patient, having an effective amount of Actives that can be delivered from the transdermal composite, and a protective overlay material that substantially prevents undesired loss of Actives to the air or to surfaces that may contact the outer portion of the transdermal composite. As used herein, transdermal refers to systemic delivery, that is, delivery of Actives to regions in addition to the topical area of application and immediately surrounding tissues.

The transdermal composite may be provided in a number of configurations, as described herein and as may be readily carried out by the routineer in the drug delivery art.

In one embodiment of the invention, the transdermal patch for the delivery of Active is a simple adhesive patch. The patch comprises an impermeable backing layer, a release liner, and an Active/adhesive containing matrix. The impermeable backing layer defines the top of the delivery device, i.e., the side furthest away from the skin when the device is in use. The backing forms an occlusive layer that prevents the loss of Active and/or enhancers to the environment and protects the patch from contamination from the environment. The backing layer may be opaque so as to protect the Active from light. The backing layer can be made from standard commercially available films for medical use, such as those supplied by 3M Corporation, St. Paul, MN; Dow Chemical, Midland, MI; or AF Packaging, Winston-Salem, N.C. Suitable materials which can be used to form the backing layer include films or sheets of polyolefin, polyester, polyurethane, polyvinyl alcohol, polyvinylidene, polyamide, ethylene- vinylacetate copolymer, ethylene-ethylacrylate copolymer, and the like, metal- apor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, unwoven fabrics, fabrics, knitted fabrics, paper, and foils. These materials can be used individually or as laminates. These films can be pigmented or metalized. In some aspects of the invention, the patch may include a peel strip or release liner to cover the surface of the pressure-sensitive adhesive during storage, and prevent evaporative loss of the Active or enhancer(s). The release liner may be formed with dimples for decreasing contacting surface with the adhesive layer, and it may also be formed with a pull-tab for making it easier for removing it from the device.

The peel strip may be made from any impermeable film, such as is specified for the backing layer. Additionally it may be made from metal foil, Mylar™ film, polyethylene terephthalate, or any material normally used for this purpose in the art that is compatible with the Active and the chosen adhesive. Examples of suitable compositions for the release liner include siliconized polyester, poly (1,1- dihydroperfluoroctylmethacrylate), fumed silica in silicone rubber, end-capped siliconized polyethylene terephthalate, polytefrafluoroethylene, cellophane, a film of polyvinyl chloride having titanium dioxide dispersed therein, and the like.

In the simple adhesive matrix patch, the Active source layer is comprised of the Active and an adhesive, the layer attaching directly to the skin of the patient after the peel strip or release liner is removed. In the preferred embodiments of the invention, the Active source layer also comprises one or more enhancers. Generally, the selection of the adhesive is important to the proper functioning of the transdermal delivery device. This is particularly true if a plasticizer-type enhancer is placed in the adhesive layer. Specifically, the adhesive layer must retain its functioning properties in the presence of the plasticizer-type and solvent-type enhancers, as well as upon exposure to the Active.

Alternatively, the adhesive may comprise matrix regions interspersed throughout the adhesive, wherein the matrix regions comprise Active. These matrix regions act as small reservoirs from which Active is released.

An alternative embodiment of the transdermal patch of the invention is a matrix patch. Such a patch comprises an impermeable backing layer, a release liner, a matrix layer comprising a matrix in which Active is dispersed, and a peripheral adhesive layer. The matrix may be a polymer matrix, or a gel or cream in which the Active resides. In some embodiments, the patch may also include an optional porous membrane layer. In yet other embodiments, the patch may have an adhesive layer that is co-extensive with the skin facing surface of the patch. The matrix layer comprises the Active, and one or more enhancers dispersed in a polymeric matrix.

The matrix layer may also comprise additional components such as diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like. A preferred embodiment of the matrix patch is a matrix patch with a peripheral adhesive annular ring and an Active source having a hydrogel matrix or a foam matrix.

A further embodiment of the invention is the reservoir type patch which allows a higher loading level of active material, and usually, a higher loading level of enhancer. Such a patch is comprised of an impermeable backing layer which is sealed at its periphery to an inert membrane, thereby defining between these two layers an Active source. An adhesive layer is affixed to the skin facing side of the patch. The patch also comprises a release liner. The Active source contains the Active, and optionally one or more enhancers or gelling components. Thus, in the reservoir type patches, a membrane separates the Active reservoir from the adhesive layer. In some embodiments the membrane is a non-rate controlling membrane. According to the present invention, a non-rate controlling membrane is one in which the rate of permeation of the enhancer(s) and Active through the membrane is greater than their permeation rate through the skin or any other portion of the device (typically two to five times greater or more). Thus, a non-rate controlling membrane is extremely permeable to the enhancer(s) and the Active contained in the reservoir.

In other embodiments, the membrane may be a rate-controlling membrane. As used herein, a rate-controlling membrane is one in which the rate of permeation of the enhancer(s) and the Active through the membrane is less than or equal to their permeation rate through the skin or any other portion of the device. Rate-controlling membranes are described, for example, in U.S. Pat. Nos. 4,460,372 and 4,379,454. The membrane may comprise a microporous or porous material. Microporous membranes have a distinct pore structure with pores ranging in diameter from approximately 0.08 to 0.5 microns, preferably from about 0.1 and 0.4 microns, and more preferably from about 0.2 and 0.4 microns. Examples of suitable microporous membranes include polyethylene and polypropylene films, nylon, and nitrocellulose film.

In the reservoir type patches, the membrane and the backing layer are sealed at their peripheral edges to form the Active reservoir. This seal should be substantially fluid-tight to prevent Active leakage from the reservoir through the seal between the backing layer and the membrane. As used herein, the term "peripheral edges" of the membrane and backing layers refer to the areas that are sealed together to define the Active reservoir. Therefore, extraneous membrane and backing layer material may extend outwardly from the Active reservoir and peripheral edge.

The Active reservoir contains a solution, suspension, or gel of the Active and the permeation enhancers, as well as diluents, such as water, and vehicles or other additives. The Active can be dispersed in the solution, suspension, or gel in either a dissolved or undissolved state. A gelling agent may be incorporated into the reservoir or matrix to increase the viscosity and rheological characteristics of the Active and enhancers. The gelling agent comprises a pharmaceutically-acceptable material that is capable of increasing viscosity of the reservoir solution. Typically, the Active delivery devices described herein will employ cellulosic materials as the gelling agent. Examples of suitable cellulosic materials include cellulose, cellulose derivatives, alkylcellulose, hydroxy- (lower alkyl) cellulose derivatives where the alkyl group contains one to six carbons, carboxyalkylcellulose and the like. Other gelling agents include PVP, CMC, Klucel, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, carboxy polymethylene, ethylene maleic anhydride, polyacrylamide, and poly (methyl vinyl ether maleic anhydride.)

The reservoir or matrix layer also may include diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like. For example, water is frequently utilized as a diluent in the reservoir type patches. Typically water will be present in the reservoir in an amount not greater than about 50 wt %, based on the reservoir fill solution; preferably, not greater than 40 wt %. Other diluents which will frequently find use in the Active delivery devices described herein include glycerine and propylene glycol .

A pressure-sensitive adhesive layer is affixed to the membrane opposite to the backing layer. In one embodiment, the adhesive layer should interact minimally with the Active. In another embodiment, the adhesive may comprise Active for additional delivery of Active to the user. The adhesive should adhere firmly to the membrane, but removably to the release liner. The device should stick securely to the wearer for extended periods, yet be removed at the desired time with minimum discomfort. The device should not give rise to undue skin irritation, allergic reactions or other dermatological problems. These properties must be maintained from the time of patch manufacture, throughout storage, and up to and throughout the time of application.

An alternative embodiment of the reservoir patch has a peripheral adhesive, wherein the area of the adhesive layer is not co-extensive with the active releasing area of the patch, but rather forms an annular ring around the active releasing area of the patch. The delivery of the Active thus is not primarily through the adhesive layer of the patch, although some lateral diffusion may occur within the patch, resulting in delivery of active substance through the adhesive at the periphery of the patch. The shape of the peripheral adhesive region will vary with the shape of the patch, but will generally comprise the outer perimeter of the patch, in order that an adequate adhesive seal is maintained between the skin and the patch to prevent the patch from falling off. The percentage of the patch that comprises the peripheral adhesive portion depends on the type of adhesive, the type of backing layer, the length of time the patch will be worn, and the weight and loading of Active in the patch. Such determinations will be apparent to the skilled artisan.

Prior to use, the patches typically are stored in laminate foil pouches, both to prevent contamination and to avoid Active and/or enhancer(s) loss. Such pouches are standard in the industry, and therefore may be selected by the routineer in this art.

The patch may be assembled by any of the techniques known in the art for producing transdermal patches. The patches may be of various shapes, but the round shape is preferred as it contains no comers and thus is less easily detached from the skin.

For adequate skin penetration of most Actives, a chemical permeation enhancer may be desired. As used herein, the term "enhancer" is meant to encompass any enhancer or combination of enhancers that increases the flux of a substance across a mammalian stratum comeum. There are numerous possible permeation enhancers that can be used and they are typically categorized into two groups, solvent-type enhancers and plasticizing-type enhancers.

Plasticizer-type enhancers refers to fatty acids, fatty acid esters, fatty alcohols and similar hydrophobic compounds that are capable of increasing the permeability of Actives to the stratum corneum. Without limiting the scope of the present invention, the following is proposed as the mechanism of action of the plasticizer-type enhancers. It is believed that the function of the plasticizer-type enhancers is to migrate into the upper stratum corneum layers of the skin and disrupt the lipids which occupy the extracellular spaces of the stratum comeum. The stratum comeum layer, although only 25-50 microns thick, is the principal barrier to transdermal permeation. The plasticizer-type enhancers that migrate into the skin serve to increase the mobility and diffusion of the Active into the skin.

Plasticizer-type enhancers generally will have a molecular weight of greater than 150 but less than 1000. In addition, the plasticizer-type enhancers should also be relatively water insoluble or they will leach into the subcutaneous tissue layers below the stratum comeum. Thus, plasticizer-type enhancers with water solubility of less than 0.5 wt % are preferred, and more preferably 0.2 wt % or less. A preferred group of plasticizer-type enhancers includes lower alkyl and alkoxy esters of pharmaceutically acceptable fatty acids, fatty acid esters, fatty alcohols, and similar hydrophobic compounds. As used herein, the term lower alkyl and lower alkoxy" refers to alkyl and alkoxy groups having up to and including 7 carbon atoms and preferably, up to and including 4 carbon atoms. Some examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and heptyl. Some examples of alkoxy groups include the oxides corresponding to the above alkyl groups. Examples of suitable fatty acid esters include saturated or unsaturated fatty acid esters, including isopropyl myristate, isopropyl palmitate, and the methyl and ethyl esters of oleic and lauric acid. Suitable fatty alcohols include stearyl alcohol and oleyl alcohol. Examples of suitable fatty acids include saturated and unsaturated fatty acids, including oleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, and palmitoleic acid. In addition, many other compounds can also serve as plasticizer-type enhancers, such as diethyl hexyl phthalate, octyldocecyl myristate, isostearyl isostearate, caprylic/capric triglycerides including polyethylene glycol esters of caprylic/capric acids, propylene glycol laurate (Lauroglycol), Miglyol (propylene glycol diester caproic, caprylic, capric, lauric acid), Lexol PG-865 (propylene glycol diester decanoic, octanoic acid), propylene glycol myristate (mirpyl), com oil polyethylene glycol-6 esters (Labrafil M2124CS), polyethylene glycol-8 caprylic capric glycerides (Labrasol), caprylic/capric triglycerides (Labrafac Lipophile WL 1349), caprylic/capric triglyceride polyethylene glycol-4 esters (Labrafac Hydro WL1219 available from Gattefosse, Westwood N.J.), glyceryl oleate, hexamethyldisiloxane, m dimethicone, cyclomethicone, squalene, mineral oil, macrocyclic ketones/lactones, plant extracts such as Chradarom

Calendula O or Chradarom Chamomile O, and various oils including wintergreen, jojoba oil, or eucalyptol (cineole). A preferred plasticizer-type enhancer for use with the mesylate salt of Rec 15/2739 include caprylic/capric acids triglyceride PEG-4 esters, available as Labrafac Hydro WL 1219, (Gattefosse, Westwood, N.J.) which contains a mixture of saturated polygly colyzed glycerides consisting of glycerides and polyethylene glycol esters of caprylic and capric acids. One of skill in the art would appreciate that the plasticizer-type enhancers may be used alone or in combination. A particularly preferred enhancer combination including the caprylic/capric triglycerides for use with the mesylate salt of Rec 15/2739 is an enhancer vehicle consisting essentially of ethanol: caprylic/capric triglycerides polyethylene glycol-4 ester:propylene glycohisopropyl myristate in a 1:1:1:1 ratio. As used herein, "solvent-type enhancer" generally refers to relatively hydrophilic compounds having molecular weights of less than about 200 that are capable of increasing the permeability of Actives to the stratum comeum. Solvent- type enhancers typically exhibit solubility parameters between about 10 and 24, and preferably between about 10 and 18. Solvent-type enhancers are often better enhancers because they generally provide higher flux rates for a given permeant than plasticizer-type enhancers. Typically, the solvent type enhancers will comprise a pharmaceutically-acceptable lower alkyl alcohol, aryl alcohol, or polyol, for example, ethanol, propanol, butanol, benzyl alcohol, glycerin, or propylene glycol. In some embodiments, the solvent-type enhancer is a 2-pyrrolidone or alkyl derivative thereof, such as N-methyl-2-pyrrolidone, 3-hydroxy-N-methyl-2- pyrrolidone, and pyroglutamic acid esters.

Other embodiments may employ an alkyl ether, such as ethylene, polyethylene or propylene glycol ether, as the solvent type enhancer. Preferred examples of ethylene glycol ethers include, but are not limited to, ethylene glycol monoalkyl ethers, such as ethylene glycol monomethyl ether (also known as methyl cellosolve), ethylene glycol dialkyl ethers, such as ethylene glycol dimethyl ether (also known as dimethyl cellosolve), and ethylene glycol monoalkyl ether esters, such as ethylene glycol monoethyl ether acetate (also known as cellosolve acetate). Preferred examples of polyethylene glycol ethers include, but are not limited to, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether (also known as butyl ethyl Cellosolve or butyl carbitol), diethylene glycol dialkyl ethers; and diethylene glycol monoalkyl ether esters, such as diethylene glycol monoethyl ether acetate (also known as Carbitol acetate), and transcutol (diethylene glycol monoethyl ether). Preferred solvent type enhancers have a molecular weight of less than about

150. They are also relatively hydrophilic, generally being greater than 2 wt % soluble in water, and are preferably greater than 10 wt % soluble in water. Most preferred solvent type enhancers are completely water miscible. One of skill in the art would appreciate that the solvent type enhancers may be used alone or in combination.

The percentage by weight of the Active in the solution, hydrogel or matrix may be varied according to the desired loading of the finished patch.

Alternative vehicles are also contemplated. For example, sublingual administration may be achieved by use of solid or semisolid formulations suitable for application under the tongue, such as dissolving tablets and powders. Alternatively, solid or semisolid formulations that may be retained in the mouth and that will effectively deliver total administered amounts as described herein to the mucosal membranes of the mouth, including the sublingual regions and buccal regions, may be used. Examples of such solid or semisolid formulations include chewable tablets, chewing gum, lozenges, pastes (including formulation as or in combination with a toothpaste), gels, gelatinous wafers and the like. Toothpaste is a particularly preferred vehicle for administration of the present compositions, because it provides the desired administration through exposure of the mucus membranes of the mouth to the active ingredient, and because it is a medium that is routinely used by the person in need of treatment every day. Incorporation of the Active in toothpaste provides exceptional convenience for administration of active to be administered on a daily basis over a long period of time. Vehicles suitable for rectal or vaginal administration, such as suppositories, liquids and gels, are also contemplated. Vehicles suitable for administration to nasal tissues, such as liquids, gels, semisolids, and solids, are also contemplated. Vehicles suitable for administration to lung tissues, such as aerosols, powders, liquids, gels, semisolids, and solids, are also contemplated. Formulation of these various delivery vehicles with the components and total administered amounts as described herein may be readily carried out by the routineer in the drug delivery art.

In use of a composition of the present invention, a person in need of treatment administers the composition as described herein mucosally or transdermally in an amount as described above. Preferably, the composition is administered as a plurality of applications in order to maximize effective uptake of the active ingredient by the patient, for example, for those whose malady or condition may require more composition than can be conveniently administered in one application for its effective or entire relief.

Most preferably, when administered as a liquid to the sublingual area (as but one example) the composition is administered as a first sublingual application which first application is held in place under the tongue for a predetermined time, preferably about 30 seconds, or more preferably about 60 seconds or more, after which the composition is swallowed. Most preferably, the composition is circulated or "swished" around the mouth by the patient prior to swallowing. Surprisingly, this apparently minor addition to the procedure noticeably increases the effect of the composition in the treatment. A second composition is then applied and held under the tongue for a predetermined time, preferably about 30 seconds, or more preferably about 60 seconds or more, after which the second composition also is swallowed. Again, preferably the composition is circulated or "swished" around the mouth by the patient prior to swallowing. In each embodiment hereof the advantageousness of maintaining some prolonged contact with the mucosal membrane or dermal area is considered. This divided dosage administration technique of course may be utilized in the alternative modes of administration to mucosal membranes as described herein.

As an alternative to the unit dose applicator preferentially utilized as described above, a bottle designed so as to dispense only a certain, measured dose may be used. Alternatively, the composition may be provided in a conventional bottle with instructions to measure a dose, with or without a dedicated appliance for so doing (e.g. cup, syringe). Alternative delivery vessels that do not deliver premeasured quantities of liquid lack the advantages of convenience and higher probability of administration of the correct amount of the composition, but may be more economical than delivery of the composition using a unit dose system.

The invention has particularly been described in the preferred administration mode of sublingual and transdermal administration. Alternatively, any appropriate mucosal administration route, such as buccal, nasal, rectal, vaginal, or by inhalation may be used for effective administration of the compositions as described herein. Similarly, any parenteral administration may be employed. Similarly, as appropriate to the condition treated, any topical may be employed as a means of non-systemic administration. According to the present invention, the animal may be a member selected from the group consisting of humans, non-human primates, such as dogs, cats, birds, horses, ruminants, other warm blooded animals or other animals. The invention is directed primarily to the treatment of human beings. Administration can be by any method available to the skilled artisan, for example, by oral, topical, transdermal, transmucosal, or any parenteral route.

The invention will further be described by reference to the following non- limiting representative of some of the examples. The following examples are illustrative, but do not serve to limit the scope of the invention described herein. They are meant only to suggest a method of practicing the invention. Those knowledgeable in the treatment and prevention of inflammatory and other disorders and related conditions as well as other specialties may find other methods of practicing the invention. However, those methods are deemed to be within the scope of this invention. While not wishing to be bound by the following proposed mechanisms, the results observed to date, both anecdotally and in clinical trials, demonstrate that the composition and invention disclosed hereby is an effective inhibitor of NF-kB. Efficacy in the treatment of migraine supports the conclusion that the invention is an effective inhibitor of NF-kB, and is consistent with certain present theories of migraine pathogenesis. In addition, the invention's observed efficacy in the treatment of other diverse ailments further supports inhibition of NF-kB as a mechanism of action. Thus, the compositions and methods of the present invention provide a surprising efficacy in the treatment of various conditions, optionally using a surprisingly small amount of the composition required to exhibit such efficacy. Additionally a surprisingly rapid time course of relief often is witnessed, and surprising benefits resulting from the use of certain routes of administration are observed as disclosed herein.

The effectiveness of the present invention in moderating or eliminating activation of the pro-inflammatory pathways which play a crucial role in the pathogenesis of migraine is believed to be primarily by means of parthenolide mediated IKKB inhibition, subsequent NF-kB down-regulation and resultant iNOS suppression. This understanding, especially in regard to IKKB inhibition and subsequent NF-kB down-regulation is supported by numerous observations of other effects (as partly related above) when using the composition. The role of iNOS in migraine remains more speculative, but is a presently emerging theory with substantial scientific support, as discussed below. The other, anecdotal effects are consistent with general inhibition of NF-kB and cannot be readily accounted for except by this mechanism.

Pathophysiological mechanisms underlying migraine remain poorly understood. Nitric oxide (NO), formed in many cells and tissues by three different isoforms of NO synthase (NOS), plays a key role in cell signaling and has been implicated in migraine based largely on pharmacological evidence in experimental animals and humans. For example, glyceryl trinitrate (GTN), an NO prodrug, stimulates neuropeptide release from trigeminal fibers innervating feline cerebral blood vessels, augmenting vasodilation, which is closely associated with migraine pain in some theories of migraine pathogenesis (Wei EP, Moskowitz MA, Boccalini P, Kontos HA. Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 1992; 70: 1313-1319.) In addition, NO is generated within cerebral blood vessels by activation of 5-hydroxytryptamine (5-HT)_2B receptors, and receptor blockers are given to patients to suppress attacks prophylactically. (Fozard JR. The 5-hydroxytryptamine- nitric oxide connection: the key link in the initiation of migraine? Arch Int

Pharmacodyn Ther 1995; 329: 111-119.) and (Mylecharane EJ. 5-HT2 receptor antagonists and migraine therapy. JNeurol 1991; 238(Suppl 1): S45-S52.) Typical migraine headaches are provoked 4 to 6 hours after GTN infusion in two-thirds of migraineurs, and migraine-like headaches have been described in workers exposed to GTN in explosives factories. (Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 1993; 4: 1027-1030.) Finally, the administration of an NOS inhibitor significantly improves the migraine headache and other attack-related symptoms in two-thirds of subjects during an acute attack. (Lassen LH, Ashina M, Christiansen I, et al. Nitric oxide synthase inhibition in migraine. Lancet 1997; 349: 401-402.) Recent evidence suggests that specific cytosolic transcription factors which lead to an upregulation of genes encoding for inflammatory cytokines may explain the headache latency of 4 to 6 hours after the administration of GTN.

The transcription factor nuclear factor-kappaB (NF-kB) plays a pivotal role in iNOS induction and controls transcription of acute phase proteins, including cytokines, adhesion molecules, and antioxidant enzymes, among others. (Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. JBiol Chem 1994; 269: 4705-4708.) NF-kB is ubiquitously expressed and consists of homo- and heterodimers (e.g., p65-p50) of Rel family proteins. Under basal conditions, NF-kB is sequestered within the cytoplasm by the IkB family of inhibitory proteins. Phosphorylation of two Ser residues on IkB triggers its ubiquination and rapid degradation, thereby releasing NF-kB to initiate iNOS gene expression after translocation to the nucleus. Recent data also implicate NF-kB in human iNOS gene expression (Taylor BS, de Vera ME, Ganster RW, et al. Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. JBiol Chem 1998; 273: 15148-15156.) In tissue macrophages, iNOS can be synthesized by a variety of stimuli, such as bacterial lipopolysaccharide (LPS), cytokines (e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6), and interferon- (IFN-), as well as by oxidative stress. Reuter and colleagues recently demonstrated that brief exposure to GTN increased iNOS expression in rat meninges and generated NO within resident macrophages 6 hours after drug administration. (Reuter,U., Chiarugi A., Bolay H., et. al. Nuclear factor-B as a molecular target for migraine therapy. Ann Neural 2002;51(4):507-516.) and (Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 2001; 124: 2490-2502.) Edema and mast cell degranulation, considered fundamental to inflammation and migraine pathogenesis, were detected with a similar time course; in addition, levels of the cytokines interleukin (IL)-l and IL-6 increased. Importantly, parthenolide suppressed iNOS and interleukin expression by blocking NF-kB activity and related transcriptional events in vitro. Parthenolide, an abundant sesquiterpene lactone found in the medical herb feverfew (Tanacetum parthenium), has been used historically by specific doses and administration routes in the treatment of migraine. (Palevitch D, Earon G, Carasso R. Feverfew as a prophylactic treatment for migraine: a double blind placebo controlled study. Phytother Res 1997; 11 : 506-511.) and (Groenewegen WA, Knight DW, Heptinstall S. Compounds extracted from feverfew that have anti-secretory activity contain an alpha-rnethylene butyrolactone unit. J Pharm Pharmacol 1986; 38: 709-712.) Feverfew's ability to inhibit the NF-kB complex (via primarily parthenolide) to block transcription of inflammatory proteins is now documented under certain specific conditions, including time of exposure and concentrations, in vitro. (Kwok BH, Koh B, Ndubuisi MI, et al. The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IB kinase. Chem Biol 2001 ; 8: 759-756.) and (Garcia-Pineres AJ, Castro V, Mora G, et al. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. JBiol Chem 2001; 276: 39713-39720.) Parthenolide reportedly inhibits the activity of IKK or the p65 binding activity of NF-kB. Parthenolide can also inhibit NF-kB-driven transcription by alkylating p65, thereby preventing its transactivation. In fact, parthenolide reduced the DNA binding activity of NF-kB even when administered after IKK activation and IkB degradation. Parthenolide's ability to block IkB degradation demonstrates at least one potential inhibitory mechanism within rodent meninges.

Targeting the inflammatory response by selectively inhibiting NF-kB-driven transcription or downstream pro-inflammatory gene expression has thus offered a promising therapeutic approach to the treatment of headache, though without known practical and effective application, said practical and effective application being the subject of the invention disclosed herein. Indeed, GTN infusion causes a prototypical induction of migraine headache in susceptible humans, and the cellular and molecular features of this response in rodents resemble what has been found in other experimental migraine models, i.e., delayed plasma protein extravasation, mast cell degranulation, and cytokine release. In addition, GTN increases electrophysiologically recorded neuronal responses to facial cutaneous stimuli within the trigeminal nucleus caudalis and increases early immediate gene response within this nucleus, although the relation of these events to the occurrence of delayed headache requires further examination. Consistent with a critical role of inflammation in migraine pathophysiology, the anti-inflammatory agents parthenolide and aspirin reduce the frequency and intensity of migraine attacks. It is worth noting that aspirin, probably the most widely used drug for the treatment of headache, also blocks IKK activity in addition to cyclooxygenase activity. (Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.) However, unlike aspirin, which causes gastrointestinal side effects, drugs such as parthenolide that selectively inhibit NF-kB activation appear to protect from experimental gastric ulcer. (Toumier H, Schinella G, de Balsa EM, et al. Effect of the chloroform extract of Tanacetum vulgare and one of its active principles, parthenolide, on experimental gastric ulcer in rats. J Pharm Pharmacol 1999; 51: 215-219.)

The cellular and molecular mechanisms generating many types of headaches remain poorly understood, but headaches develop commonly during infections and fever, following ingestion of certain foods, or with allergies. Because NF-kB is the target of diverse pathological and inflammatory stimuli, such as oxidative stress, cytokines, and bacterial and viral products, its activation may provide the substrate within resident meningeal macrophages that contributes to local inflammation and headaches in response to exogenous agents in susceptible individuals. Conversely, NF-kB and the activation thereof is not associated exclusively with disease or a pathological state. Rather, effective NF-kB function is an essential component of general cellular regulation, homeostasis and effective immune functioning (Baldwin, A The Transcription Factor NF-kB and Human Disease, The Journal of Clinical Investigation, Jan. 2001, 107: pp. 3-6.) Thus higher doses of parthenolide might be associated with an 'overdose', this observation perhaps accounting in part for prior belief that parthenolide treatment might not be a practical method of treatment. The present invention solves this problem by demonstrating the surprisingly small amounts of parthenolide required when administered as provided for herein. Whereas the goal is to reduce NF-kB activation where it's overactivation may have led to a pathological state, such as dysregulated inflammation (e.g. migraine), the most appropriate therapy would suppress NF-kB activation without overwhelming the body. Thus excessive doses of parthenolide may be ineffective or less effective, and might themselves be associated with significantly greater side effects. As in all pharmacologic interventions, the ideal is to achieve the maximum desired clinical outcome with the smallest effective amount of composition. It now appears that feverfew delivered by way of the distal gastrointestinal tract does not result in the delivery of any effective amount of parthenolide. Whether parthenolide is destroyed by the acidity of the stomach, broken down by the liver ("first pass metabolism") or simply passes out of the body without having been absorbed, the relative lack of effect when feverfew is delivered by specific doses and administration routes as previously employed (e.g. in migraine prophylaxis), that is, by means involving substantial reliance on ingestion and subsequent absorption through the gastrointestinal tract, specifically the gastrointestinal tract distal to the pharynx ("distal gastrointestinal tract"), suggests that only very modest amounts of parthenolide, if any, are being delivered by means of these historical administration methods. Further, while laboratory data suggests the need for substantially greater amounts of parthenolide than are delivered by means of the present invention, and that said concentrations must remain at the point of action for a more substantial amount of time than appears to be achieved by means of the present invention, we have clearly demonstrated the efficacy of these surprisingly small doses when administered as provided for herein (parenterally, specifically mucosally, most specifically sublingually). The speed of action that has been observed is as suφrising as the efficacy. It appears that NF-kB is truly an acute phase responder, perhaps capable of being turned off as quickly as it is turned on, and that it may in fact be turned on and exert its effects in a much shorter time course than has previously been known or taught.

The invention will further be described by reference to the following non- limiting representative sample of some of the possible applications and the theory and means of application. The following examples are illustrative, but do not serve to limit the scope of the invention described herein. They are meant only to suggest a method of practicing the invention. Those knowledgeable in the treatment and prevention of inflammatory and other disorders and related conditions as well as other specialties may find other methods of practicing the invention and many other applications for the invention. However, those methods and applications are deemed to be within the scope of this invention. Pain and Inflammation

The use of sesquiterpene lactones, especially parthenolide, and compositions comprising sesquiterpene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens disclosed herein has not been previously taught for relief of pain and inflammation generally. In this embodiment the present invention serves much like a typical over-the-counter analgesic and anti-inflammatory (e.g. like aspirin) with an equal diversity of preparations and applications. As contemplated hereby, the present invention may be employed for relief of pain and inflammation either singly (pain or inflammation) or jointly (both pain and inflammation). As discussed, NF-kB is intimately involved with many aspects of inflammation. It is also closely linked to many aspects of pain generation and sensation. As can be readily appreciated, the preferred route and means of administration of the invention will vary according the condition treated. For example, a topical cream might preferably be employed in the treatment of pain and inflammation limited to one specific area of the body, or sublingual administration might be employed to deliver relief systemically. Autoimmune Disease

Autoimmune disease includes, without limitation: Alopecia Areata, Lupus, Anklosing Spondylitis, Meniere's Disease, Antiphospholipid Syndrome, Mixed Connective Tissue Disease, Autoimmune Addison's Disease, Multiple Sclerosis, Autoimmune Hemolytic Anemia, Myasthenia Gravis, Autoimmune Hepatitis, Pemphigus Vulgaris, Behcet's Disease, Pernicious Anemia, Bullous Pemphigoid, Polyarteritis Nodosa, Cardiomyopathy, Polychondritis, Celiac Sprue-Dermatitis, Polyglancular Syndromes, Chronic Fatigue Syndrome (CFIDS), Polymyalgia Rheumatica, Chronic Inflammation leading to Demyelinating conditions, Polymyositis and Dermatomyositis, Chronic Inflammation leading to Polyneuropathy, Primary Agammaglobulinemia, Churg-Strauss Syndrome, Primary Biliary Cirrhosis, Cicatricial Pemphigoid Psoriasis, CREST Syndrome, Raynaud's Phenomenon, Cold Agglutinin Disease, Reiter's Syndrome, Crohn's Disease, Rheumatic Fever, Discoid Lupus, Rheumatoid Arthritis, Essential Mixed Cryoglobulinemia, Sarcoidosis, Fibromyalgia, Scleroderma, Grave's Disease, Sjogren's Syndrome, Guillain-Barre, Stiff-Man Syndrome, Hashimoto's Thyroiditis, Takayasu Arteritis, Idiopathic Pulmonary Fibrosis, Temporal Arteritis/Giant Cell Arteritis, Idiopathic Thrombocytopenia Puφura (ITP), Ulcerative Colitis, IgA Nephropathy, Uveitis, Insulin Dependent Diabetes (Type I), Vasculitis, Lichen Planus, and Vitiligo.

The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of autoimmune disease. At least 50 million Americans, over 20 percent of the adult population or one in five adults, suffer from an autoimmune disease. Women are more likely than men to be affected; some estimates say that 75 percent of those affected (approximately 30 million people) are women.

As noted, NF-kB is intimately associated with many various aspects of inflammation and immunity. Autoimmune diseases are those wherein a substantial component of the disease process is believed to be related to or caused by the body's own natural defense system attacking the tissues of the body. This 'overactivation' of the immune system can be lessened by the use of compositions comprised of sesquiteφene lactones, as described herein, to decrease the activation of certain aspects of the immune system which may be critical in certain autoimmune diseases, or to decrease immune reactivity generally and thus reduce disease or symptom severity. As can be readily appreciated, the preferred route and means of administration of the invention will vary according the condition treated. For example, eyedrops might preferably be employed in the treatment of the ocular symptoms of Sjogren's Syndrome, while sublingual administration might be employed to deliver relief for the systemic manifestations of that same disease. Arthritis

The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of arthritis. Both osteoarthritis and rheumatoid arthritis are diseases associated with chronic inflammation. Other various forms of arthritis may also be treated by the present invention. The present invention provides a means whereby to treat chronic inflammation such as in the case of arthritis. - Gastric Maladies Gastric maladies include gastritis, peptic ulcers, duodenal ulcers, acid reflux,

Barrett's esophagus, reflux esophagitis, H. pylori infection and functional dydpepsia. The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of gastric maladies.

The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.) However, unlike aspirin, which causes gastrointestinal side effects, d gs such as parthenolide that selectively inhibit NF-kB activation appear to protect from experimental gastric ulcer. (Toumier H, Schinella G, de Balsa EM, et al. Effect of the chloroform extract of Tanacetum vulgare and one of its active principles, parthenolide, on experimental gastric ulcer in rats. J Pharm Pharmacol 1999; 51: 215-219.) Diabetes, Types I and II

The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of diabetes. As noted above, inhibition of Nf-kB by means of high dose aspirin administration has been shown to be potentially beneficial in the treatment of Type II diabetes. Type I diabetes often evolves from Type II, therefore an effective treatment of Type II might delay or eliminate the onset of Type I in certain instances. As an effective inhibitor of NF- kB, the invention disclosed herein may be used to treat Type II diabetes, another of its many novel applications.

In addition, many of the sequelae of diabetes Types I and II can be effectively treated by means of the present invention, as NF-kB activation is associated with these sequelae, sometimes manifesting as an inflammatory component thereof. Sequelae which may be treated or prevented include diabetic retinopathy, peripheral neuropathy and peripheral vascular disease. Cystic Fibrosis

Cystic Fibrosis (CF) affects approximately 30,000 people in the United States. In CF, lung inflammation (as but one manifestation of the disease) leads to severe tissue destruction and ultimately organ failure. The transcription factor nuclear NF-kB regulates expression of many pro-inflammatory mediators believed crucial in the pathogenesis of CF. Recent evidence suggests that the manifestation of CF in the lungs is primarily an inflammatory disorder resulting from dysregulation of NF-kB (Blackwell T. Editorial Focus: Dysregulated NF-kB activation in cystic fibrosis: evidence for a primary inflammatory disorder. Am J Physiol Lung Cell Mol Physiol 281 : L69-L70, July 1, 2001.) The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of CF. As can be readily appreciated, the preferred route and means of administration of the invention will vary according the desired effect. For example, an aerosolized mist might be effectively employed for inhalation into the lungs and the treatment thereof locally, or sublingual administration might be employed to deliver relief systemically . Demyelinating Disease

Demyelinating Disease includes Multiple Sclerosis (the most common member of this group), Guillain-Barre Syndrome, Encephalomyelitis & Neuritis, Acute disseminated encephalomyelitis (postinfectious encephalomyelitis), HTLV- associated myelopathy, X-adrenoleukodystrophy, Adrenolekodystrophy,

Amyotrophic lateral sclerosis, central pontine myelinolysis, Schilder disease, Binswanger Disease, disseminated necrotizing leukoencephalopathy, and progressive supranuclear palsy as well as Progressive Multifocal Leukoencephalopathy such as is associated with slow viruses and Leber's hereditary optic atrophy. These are generally acquired inflammatory diseases that attack the myelin sheath. At times some may also be classified as autoimmune disease. As noted, NF-kB activation is central to many inflammatory processes. In addition, Nitric oxide (NO) has been implicated in the etiopathology of central nervous system (CNS) diseases such as multiple sclerosis (MS). Inhibition of NO synthesis has recently been proposed to be a possible mechanism of action of relevance in the treatment of multiple sclerosis and migraine, parthenolide was found to be an inhibitor of iNOS/NO synthesis, suggesting that parthenolide might have a potential in the treatment of CNS diseases, especially where NO is part of the pathophysiology (Fiebich BL. Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol. 2002 Nov; 132(1-2): 18-24.) The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of demyelinating diseases. Neurodegenerative Disorders Neurodegenerative diseases include Parkinson's disease, Alzheimers and

AIDS Dementia, among others. An estimated 4.5 million Americans have Alzheimer's disease and 1.2 million have Parkinson's. NF-kB is known to play a central role in neuronal cell survival, it's excess activation thought to be an important aspect of each disease. The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of neurodegenerative disorders. Hvpercholesterolemia and Hyperlipidemia High Cholesterol is a substantial problem in the United states and many other developed countries. The primary untoward manifestation of each being damage to vasculature. Hypercholesterolemia (HC), a pro-oxidant condition, activates NF-kB and is associated with coronary endothelial dysfunction. It may be that inhibition of NF-kB results in an actual decrease in cholesterol and triglycerides, as in studies referenced prior with inhibition of NF-kB by high dose aspirin. Alternately, inhibition of NF-kB may simply attenuate the harmful effects of high cholesterol, as has been demonstrated in a recent study of hypercholesterolemic pigs (Rodriguez- Porcel M. Chronic antioxidant supplementation attenuates nuclear factor-kappa B activation and preserves endothelial function in hypercholesterolemic pigs. Cardiovasc Res. 2002 Mar;53(4):1010-8.) Or some combination of these effects may work together for mutual benefit of the patient. The use of sesquiteφene lactones, especially parthenolide, and compositions comprising sesquiteφene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of hypercholesterolemia and hyperlipidemia and the sequelae thereof. Some examples of conditions or diseases that may be treated include, without limitation: pain; fever; inflammation; malaria; chagas disease;

Glucocorticoid resistance; heavy metal poisoning; allergies; suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease (IBD) and autoimmune diseases; any autoimmune disease, including: Alopecia Areata, Lupus, Anklosing Spondylitis, Meniere's Disease, Antiphospholipid Syndrome, Mixed Connective Tissue Disease,

Autoimmune Addison's Disease, Multiple Sclerosis, Autoimmune Hemolytic Anemia, Myasthenia Gravis, Autoimmune Hepatitis, Pemphigus Vulgaris, Behcet's Disease, Pernicious Anemia, Bullous Pemphigoid, Polyarteritis Nodosa, Cardiomyopathy, Polychondritis, Celiac Spme-Dermatitis, Polyglancular Syndromes, Chronic Fatigue Syndrome (CFIDS), Polymyalgia Rheumatica, Chronic Inflammation leading to Demyelinating conditions, Polymyositis and Dermatomyositis, Chronic Inflammation leading to Polyneuropathy, Primary Agammaglobulinemia, Churg-Strauss Syndrome, Primary Biliary Cirrhosis, Cicatricial Pemphigoid Psoriasis, CREST Syndrome, Raynaud's Phenomenon, Cold Agglutinin Disease, Reiter's Syndrome, Crohn's Disease, Rheumatic Fever, Discoid Lupus, Rheumatoid Arthritis, Essential Mixed Cryoglobulinemia, Sarcoidosis, Fibromyalgia, Scleroderma, Grave's Disease, Sjogren's Syndrome, Guillain-Barre, Stiff-Man Syndrome, Hashimoto's Thyroiditis, Takayasu Arteritis, Idiopathic Pulmonary Fibrosis, Temporal Arteritis/Giant Cell Arteritis, Idiopathic Thrombocytopenia Puφura (ITP), Ulcerative Colitis, IgA Nephropathy, Uveitis, Insulin Dependent Diabetes (Type I), Vasculitis, Lichen Planus, Vitiligo; Thyroid Disorders such as Hashimotos Thyroiditis, Grave's Disease and other autoimmune endocrine disorders; Autoimmune myocarditis; Immune Allergic airway inflammation; Allergic rhinitis; Neoplastic disorders (including all cancers); Immune or chemotherapeutic resistance of cancers; Solid Tumors such as Colon, Lung, Breast, Pancreatic, Neuroblastoma, Laryngeal, Prostate, Esophageal; other cancers such as Lymphoma, Hodgkin's Disease, T and B cell lymphomas and Leukemia; Gastric disease such as H. pylori (chronic gastritis), peptic ulcers, duodenal ulcers, acid reflux; rheumatic diseases such as spondyloarthropathies like Ankylosing spondylitis, Juvenile ankylosing spondylitis, Late onset spondyloarthropathy, Psoriatic arthritis, Reiter's syndrome/reactive arthropathy, Enteropathic spondylitis and Undifferentiated spondyloarthropathy; Rheumatoid arthritis; Osteoarthritis; Aseptic arthritis; inflammatory bowel disease such as

Crohn's and Ulcerative colitis; adult respiratory distress syndrome; cystic fibrosis; reactive airway disease such as Asthma; Panbronchiolitis; sinusitis; chronic sinusitis; colitis; Diabetes, especially type-2 diabetes; Parkinson's disease; Alzheimers; AIDS Dementia; Demyelinating Disease, including Multiple Sclerosis, Guillain-Barre Syndrome, Encephalomyelitis & Neuritis, Acute disseminated encephalomyelitis (postinfectious encephalomyelitis), HTLV-associated myelopathy, X-adrenoleukodystrophy, Adrenolekodystrophy, Amyotrophic lateral sclerosis, and progressive supranuclear palsy as well as Progressive Multifocal Leukoencephalopathy such as is associated with slow viruses and Leber's hereditary optic atrophy; myasthenia gravis; sepsis (liver failure); traumatic CNS injury (brain and spinal cord); migraine; cerebrovascular accident (CVA, Stroke); Trauma (including iatragenic, such as surgery or procedurally induced or caused); After spinal cord injury; subarachnoid hemorrhage; encephalitis; meningitis; and especially Cerebral angiopathy (vessel narrowing), such as that seen after or associated with subarachnoid hemorrhage, encephalitis, meningitis, and autoimmune diseases; Proteinuric nephropathies; use in association with the class of drugs called angiotensin-converting-enzyme (ACE) inhibitors; Glomemlonephritis (and immune glomeralonephritis); Conditions affecting the heart and circulatory system such as Repurfusion injury (ischemia reperfusion), Hemorrhagic shock, Cold/reperfusion injury, Whole body inflammation (shock), Coronary artery stenosis (restenosis, especially after invasive procedures such as balloon angioplasty), Atherosclerosis, Arteriosclerosis, Post-injury intimal hypeφlasia, Congestive heart failure (including that associated with congenital heart defects), Giant Cell Arteritis, Unstable angina, Hyperlipidemia, hypercholesterolemia, Endotoxemia and septic shock, Post-trauma cardiac function/cardiac inflammation (general cardioprotection), Cardiovascular damage in hypertension, Open heart surgery, Graft coronary artery disease; Lung and airway disease including silica induced damage, tobacco smoke induced damage, Pulmonary hypertension, Emphysema, chronic obstructive pulmonary disease (COPD), Bronchitis, Nasal polyps, Acute lung injury, Adult respiratory distress syndrome, Pulmonary tuberculosis, Acute lung injury after hepatic cryoablation; Pancreatitis (acute and chronic); Conditions of the stomach and esophagus including prevention of Barrett's esophagus, Reflux esophagitis, Treatment of H. pylori, Functional dydpepsia, Gastric Ulcer; Colitis; Choroidal Neovascularization in Patients With Age-Related Macular Degeneration; Diabetic Retinopathy; Intraocular neovascularization; Periodontitis; viral diseases including SARS (Severe Acute Respiratory Disease), Common Cold (rhinovims), Hepatitis B and Hepatitis C; Intestinal worms and parasites; leishmaniasis; Malaria; other parasitic infections; Organ Rejection; Neuropathic pain following nerve injury; dental pain; thermal hyperalgesia; Conception (use as birth control); Aging; Muscle regeneration after traumatic injury (including normal muscle breakdown injury resulting from strenuous workout); Polymyositis; Dermatomyositis; Duchenne muscular dystrophy; Pseudomonas aeruginosa infection and sequelae; Psoriasis; dermatitis (especially allergic contact dermatitis); eczema; Fibromyalgia; ageing; obesity; headaches.

The use of sesquiteφene lactones and compositions comprising sesquiteφene lactones, especially feverfew, in the amounts and by the delivery- routes, mechanisms and regimens described herein to treat or prevent any disease or condition associated with the NF-kB pathway in an animal, in combination with other therapies and/or prescription dmgs and/or nonprescription dmgs to treat any condition associated with the NF-kB pathway in an animal. As but several examples of other such therapies: NSAIDS; Acetaminophin; Celecoxib (COX-2 inhibitor; NSAID); other COX-2 inhibitors; Anti-malarial dmgs; Lactacystin, a proteasome inhibitor; Glucocorticoids; Diethyldithiocarbamate (Ditiocarb, DDTC) for heavy metal poisoning; Cetirizine (HI antihistamine); ionizing radiation as employed in the treatment of cancer and other proliferative disorders; cancer chemotherapeutic drugs; analgesics; drags intended for the treatment of type 2 diabetes; angiotensin converting enzyme inhibitors (ACE inhibitors); and any other drag or therapy against any disease or condition associated with the NF-kB pathway in an animal or in which the effect of the other drag or therapy can be enhanced or improved by the supression of NF-kB activation.

A particularly preferred embodiment of the present invention is the near simultaneous use of both a long acting and a short acting method of administering the composition, as discussed herein, primarily consisting of the administration of a dose sublingually or by other mucous membrane with the near simultaneous or appropriately timed administration of a transdermal dose. The result intended to be achieved and achieved thereby is both rapid onset of action and also the maintenance of a therapeutic concentration over time. Other means of achieving the same effect through the combination of various formats and compositions are envisioned, whereby a long therapeutic blood concentration is obtained along with a rapid rise in blood concentration to an effective amount is achieved.

In another aspect of the present invention, a sesquiteφene lactone, especially parthenolide, preferably as feverfew, is added to toothpaste as a convenient means of achieving daily dosing. Said toothpaste may also comprise other known beneficial agents including, without limitation, trans-resveratrol (lyophilized red wine) or other antioxidants such as vitamins C and E. The toothpaste may be an existing formulation, or a specifically prepared formulation as may be created by the routines in the formulary art by reference to known fonnulations, modifying the same as taught herein.

In another aspect of the present invention, a sesquiteφene lactone, especially parthenolide, preferably as feverfew, is added to food or beverage which is commonly ingested, the intention being to achieve contact with the mucosal areas of the mouth such that mucosal absoφtion was sufficient to result in the effective dosing of Actives by way of repeated contact with numerous bites and during mastication if a solid food or repeated swallows and residue liquid if a liquid food. In another aspect of the present invention, a sesquiteφene lactone, especially parthenolide, preferably as feverfew, is employed as a supplement meant to aid particularly athletes and others who, as a result of vigorous exercise or exertion, suffer substantial wear and tear to their muscles and wish to accelerate the healing thereof, thus lessening recovery time and increasing subsequent performance, especially performance which is required or opted for prior to that time at which they would otherwise be fully recovered. A particularly useful form of the present invention for such puφoses might be a chewing gum or similar presentation.

It can be readily appreciated that the present invention, bringing some degree of relief to the many millions of people who suffer from the above described conditions, will be of great benefit, especially as these conditions may often be severely debilitating and are often presently without effective treatment, those treatments known being often associated with significant and harmful side effects, among other disadvantages compared to treatment by the present invention. In another aspect of the present invention, a method of treating a disease associated with prolonged or excessive activation of NF-kB is provided comprising first a) identifying a disease associated with prolonged or excessive activation of NF-kB. The location of administration of a composition in a patient in need of treatment for the disease identified in step is then determined, and the amount of plant extract from a plant that is a source of sesquiteφene lactone that is effective to inhibit NF-kB at the desired location of administration determined in step b) to a degree sufficient to treat the disease determined in step a) is also determined. Using the information determined in step c) to formulate a treatment regimen for treating the disease including use of a local, rather than systemic, route of administration of the plant extract in a patient in need of treatment for the disease identified in step a). This method may be carried out for compositions comprising sesquiteφene lactones as described herein as well. This method may be carried out specifically for all diseases and all modes of administration discussed herein.

All patents, patent documents, and publications cited herein are incoφorated by reference as if individually incoφorated. Unless otherwise indicated, all parts and percentages are by weight. The foregoing detailed description has been given for clarity of understanding only. It will be appreciated that numerous modifications and variations of the invention are possible in light of the above teachings, and therefore the invention may be practiced otherwise than as particularly described.

Claims

Claims What is claimed:

1. A method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising administering a composition comprising at least one plant extract from a plant that is a source of sesquiteφene lactone in an effective amount to a patient in need thereof.

2. A method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising administering a composition comprising a sesquiteφene lactone in an effective amount to a patient in need thereof.

3. The method of claim 1, wherein the composition is administered in a route whereby the composition bypasses the GI tract.

4. The method of claim 1, wherein the composition is administered via a mucosal membrane.

5. The method of claim 1, wherein the composition is administered sublingually.

6. The method of claim 1, wherein the composition is administered transdermally.

7. The method of claim 1, wherein the composition comprises feverfew extract.

8. The method of claim 2, wherein the composition comprises parthenolide.

9. The method of claim 1 or 2, wherein the disease to be treated is a condition related to pain and inflammation.

10. The method of claim 1 or 2, wherein the disease to be treated is an autoimmune disease.

11. The method of claim 1 or 2, wherein the disease to be treated is arthritis.

12. The method of claim 1 or 2, wherein the disease to be treated is a gastric malady.

13. The method of claim 1 or 2, wherein the disease to be treated is diabetes.

14. The method of claim 1 or 2, wherein the disease to be treated is cystic fibrosis.

15. The method of claim 1 or 2, wherein the disease to be treated is a demyelinating disease.

16. The method of claim 1 or 2, wherein the disease to be treated is a neurodegenerative disorder.

17. The method of claim 1 or 2, wherein the disease to be treated is hypercholesterolemia.

18. The method of claim 1 or 2, wherein the disease to be treated is sinusitis.

19. The method of claim 1 or 2, wherein the disease to be treated is asthma

20. The method of claim 1 or 2, wherein the disease to be treated is a dermatologic condition.

21. The method of claim 1 or 2, wherein the composition is administered via a toothpaste composition.

22. A method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising a) identifying a disease associated with prolonged or excessive activation of

NF-kB; b) determining location of administration of a composition in a patient in need of treatment for the disease identified in step a); c) determining the amount of plant extract from a plant that is a source of sesquiteφene lactone that is effective to inhibit NF-kB at the desired location of administration determined in step b) to a degree sufficient to treat the disease determined in step a); and d) using the information determined in step c) to formulate a treatment regimen for treating the disease including use of a local, rather than systemic, route of administration of the plant extract in a patient in need of treatment for the disease identified in step a).

23. A method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising a) identifying a disease associated with prolonged or excessive activation of NF-kB; b) determining location of administration of a composition in a patient in need of treatment for the disease identified in step a); c) determining the amount of sesquiteφene lactone that is effective to inhibit NF-kB at the desired location of administration determined in step b) to a degree sufficient to treat the disease determined in step a); and d) using the information determined in step c) to formulate a treatment regimen for treating the disease including use of a local, rather than systemic, route of administration of the sesquiteφene lactone in a patient in need of treatment for the disease identified in step a).

24. The method of one of claims lor 2, wherein the administration of the composition is used to augment other therapies being used to treat the disease.

25. The method of claims 2, wherein the treatment comprises administering less than 500 mg of any given sesquiteφene lactone per hour.

26. The method of claim 1 , wherein the composition is administered orally via the G.I. tract, and the amount of plant extract is provided, taking into account the amount of plant extract lactone that is destroyed or eliminated via this route of administration

27. The method of claim 1, wherein the composition is administered orally via the G.I. tract, and the plant extract is enhanced through one or more enhancement techniques selected from the group consisting of providing a protective coating, modification of tablet dissolution rates, addition of stabilizer, or addition of a chemical components that counteracts the destractive activity of the G.I. tract.