METHODS AND PHARMACEUTICAL PREPARATIONS TO CONTRIBUTE TO THE TREATMENT OF INDUCED NEUROPATHY
FOR CHEMOTHERAPY
Field of the Invention The present invention relates to methods and pharmaceutical preparations for contributing to the treatment of neuropathy induced by chemotherapy (eg, induced by cisplatin). Background of the Invention Although chemotherapeutic agents are vital for cancer treatment, their use can be limited by side effects such as neuropathy, which can result in at least partial loss of body sensation. An example of such a chemotherapeutic agent is cisplatin, which is used extensively in the treatment of various types of cancers including bladder, testicular and ovarian tumors (Williams et al., (1979) Br. MED. J. 1: 1689- 1691). While cisplatin may provide beneficial effects in the treatment of cancers, the total dose that can be administered is limited by its toxic effects on the peripheral nervous system (Mollman, (1990) N. Engl. J. Med 322: 126-127 ). Specifically, the pathological examination of patients treated with cisplatin reveals damage or selective loss of large sensory nerve fibers, which can result in loss of sensation in various parts of the body.
body (Thompson et al., (1984) Cancer 54: 1269-1275). The recovery of this damage to the nerves is variable and many cancer survivors treated with cisplatin suffer persistent damage to the nerves and sensory loss. (Cavaletti et al., (1994) Anticancer Res 14: 1287-1292). A variety of agents have demonstrated potential activity as protectors to nerves against cisplatin-induced damage to nerves in clinical trials. Some of these agents include a fragment of ACTH 4-9 with the activity of the growth factor (ORG2766) (Gerritsen et al., (1990) N. Engl. J. Med. 322: 89-94), and the thiols amifostine (Kemp et al., (1996) J. Clin. Oncol. 14: 2101-2112) and glutathione (Pirovano et al., (1992) Tumori 78: 253-257). In preclinical studies, compounds such as nerve growth factor (Apfel et al., (1992) Ann Neurol., 31: 76-80), neurotrophin-3 (Gao et al., (1995) Ann. Neurol. 38 (1): 30-37) and glutamate (Boyle et al, (1999) J. Neuro Oncol. 41: 107-116) have demonstrated an ability to help prevent nerve damage caused by cisplatin. While all of these agents have demonstrated a potential to assist in the prevention of nerve damage induced by cisplatin, there remains a need for additional agents that can perform this function. The present invention provides such an agent. Brief Description of the Invention The present invention is directed to compositions containing leteprinim (in any of its various forms)
including the salts and acids of leteprinim) and their use to contribute to the prevention of damage induced by chemotherapy (for example, induced by cisplatin) to the nerves in cancer patients. The present invention also provides methods for administering leteprinim and leteprinim formulations to help attenuate neuropathy induced by chemotherapy. Thus, the present invention includes the methods and pharmaceutical preparations that can be used to contribute to the prevention of damage induced by chemotherapy (eg, induced by cisplatin) to the nerves. Specifically, an embodiment according to the present invention includes a method that consists of administering leteprinim (SPI-082) to a patient thus contributing to the treatment of neuropathy induced by chemotherapy. Another embodiment according to the present invention includes a method consisting of administering leteprinim (SPI-082) to a patient thus contributing to the treatment of cisplatin-induced neuropathy. Another method according to the present invention includes the administration of a chemotherapeutic (eg, cisplatin) to contribute to the treatment of a cancer and the administration of leteprinim thereby contributing to the treatment of neuropathy induced by the chemotherapeutic (eg, induced by cisplatin). Another method according to the present invention includes the administration of cisplatin to contribute to the treatment of a cancer and the administration of leteprinim thereby contributing to the treatment of the
neuropathy induced by cisplatin. In accordance with the present invention, the administration of leteprinim may precede the initiation of treatment with a chemotherapeutic (e.g., cisplatin) or the administration of leteprinim may begin after the initiation of treatment with a chemotherapeutic (e.g., cisplatin). In certain embodiments, leteprinim can be administered, without limitation, less than once a day on a weekly basis (ie, up to six times a week for seven days), preferably twice weekly (ie, twice a week for seven days) ). A chemotherapeutic can be administered, without limitation, of any effective amount up to its toxic amount. For example, cisplatin can be administered twice weekly. Leteprinim and chemotherapeutic administration (eg, cisplatin) can also occur substantially simultaneously. When the administration occurs substantially simultaneously, leteprim and the chemotherapeutic (eg, cisplatin) may be part of different or part of the same pharmaceutical preparations. Appropriate doses of leteprinim may include, without limitation, from about 25 mg / kg to about 100 mg / kg, eg, about 50 mg / kg. In one embodiment, leteprinim and, optionally, other active agents may be formulated as a suspension, optionally, a buffered suspension. The embodiments of the present invention also include those
pharmaceutical preparations including leteprinim wherein the pharmaceutical preparation is sold with instructions indicating the administration of the pharmaceutical preparation to contribute to the treatment of a neuropathy induced by the chemotherapeutic (eg, induced by cisplatin). In certain embodiments, the instructions will indicate the administration of leteprinim in the form of one or more of the methods described above. The pharmaceutical preparations accompanied by such instructions may include leteprinim as the sole active ingredient or may further include at least one other active agent (eg, a chemotherapeutic such as cisplatin). These pharmaceutical preparations can also include other active or inactive ingredients. The pharmaceutical preparations according to the present invention may also include chemotherapeutics (eg, cisplatin) and leteprim in which the chemotherapeutic agent in the pharmaceutical preparation is intended to contribute to the treatment of a cancer and leteprinim is intended to contribute to the treatment of cisplatin-induced neuropathy. . Brief Description of the Drawings Figure 1 shows the effect of leteprinim on changes induced by cisplatin in body weight. Figure 2 shows the effect of leteprinim on changes induced by cisplatin in sensory perception as measured in a hot plate paradigm. Figures 3 and 4 show the effect of leteprinim on the
changes induced by cisplatin in the amplitude and latency of the H wave respectively. Figure 5 shows the effect of leteprinim on cisplatin-induced changes in nerve conduction velocity (SNCV). Figure 6 shows the effect of leteprinim on the changes induced by cisplatin in the diameter of the axon. Figure 7 shows the effect of leteprinim on changes induced by cisplatin in the ratio g. Figure 8 shows the effect of leteprinim on changes in the ratio of degeneration to non-degenerated fibers after administration of cisplatin. Detailed Description of the Invention I. Definitions Instructions: As used herein the term "instructions" shall mean the material that accompanies a pharmaceutical product that provides a description of how to administer the product, together with the safety and efficacy data required to allow that the doctor, the pharmacist, and the patient make an informed decision regarding the use of the product. These Instructions are generally considered to be the "label" for a pharmaceutical product. The Instructions can come in many forms including, without limitation, a paper insert, a CD-ROM or the address to an internet site that contains information regarding the pharmaceutical product.
Prodrug: As used herein the term "prodrug" will mean compounds that are rapidly transformed in vivo to a compound useful in the invention, for example, by hydrolysis. A careful discussion of prodrugs is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, of the A.C.S.D. Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. Substantially Simultaneously: As used herein, the term "substantially simultaneously" means that two pharmaceutical preparations ( ie leteprinim and cisplatin) are administered at the same time. According to this definition, "at the same time" should be interpreted as including in exactly the same way as in approximately ten minutes. Treat, treat or contribute to the treatment of: as the terms are used here; "treat", "treatment" and "contribute to the treatment of" shall mean prevention, retardation of the progression or growth of, contraction, or elimination of a cancer including a solid tumor. As such, these terms include medical therapeutic and / or prophylactic administration, as appropriate. As used herein, the term "twice a week" means that a pharmaceutical preparation is administered twice within a period of seven days. Generally, you are
administrations will be evenly spaced during the course of the seven-day period but this feature is not required and the two administrations can occur with any separation from each other during the course of the seven-day period. As used herein, the term "leteprinim" refers to propanamide of N-4-carboxyphenyl-3- (6-oxohydropurin-9-yl) and its various forms (forms for example, leteprim in the form of acid and salt). ). Leteprinim is also known as AIT-082, SPI-082, and SPI-205. The leteprinim compositions and methods of the present invention can be used to treat peripheral neuropathy associated at least in part with the administration of any chemotherapeutic agent. Exemplary chemotherapeutic classes include, but are not limited to, podofillotoxins, terpenoids (e.g., taxanes and vinca alkaloids), antimetabolites, anthracyclines, alkylating agents (e.g., platinum), and other antitumor agents. Vinca alkaloids include, among others, vinblastine, vincristine, vinorelbine, and vindesine. Other exemplary chemotherapeutic agents include, but are not limited to, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, suramin, altretamine, chlorambucil, cytarabine, dacarbazine, docetaxel, etoposide, fludarabine, ifosfamide with mesna, non-tamoxifen, teniposide , and thioguanine. Peripheral neuropathy associated with the administration of oncolytic drugs is described by C.M. Haskell, "Cancer Treatment"
(5.sup.th Ed., W.B. Saunders, Philadelphia, 2001), chapter 10, p. 104-214. In one embodiment, the present invention is directed to treating peripheral neuropathy induced by the drug associated with the administration of vinca alkaloids (e.g., vincristine), of taxanes (e.g., paclitaxel / Taxol®) , or to alkylating agents (for example, cisplatin). In another embodiment, the present invention is directed to treating peripheral neuropathy induced by the drug associated with the administration of cisplatin. Cisplatin is an antitumor agent widely used in the treatment of many common tumors refractory to therapy. Cisplatin is useful as an anticancer agent due to its effects as an inhibitor of DNA synthesis that hinders cell division. Currently, neuropathy (ie, nerve damage) is recognized as dose-limiting toxicity, with symptoms developing after a cumulative dose greater than about 300 mg / m2. Cisplatin neuropathy predominantly affects the sensory neurons of large fibers and is generally associated with a reduction in sensory nerve signal amplitude, resulting in a sensory ataxia of profound disability. This neuropathy may continue to progress after cessation of cisplatin treatment. The present invention shows that leteprim can contribute to the treatment or prevention of cisplatin-induced damage to the nerves. Depending on the individual needs of the individual
involved, the leteprinim compositions of the present invention can be administered in various doses and regimens to provide effective treatments. What constitutes an effective amount of the selected composition of leteprinim will vary based on factors including, but not limited to, the activity of the chemotherapeutic compound, the physiology of the patient, the disease or condition of the patient, and the method / frequency / mode of administration of leteprinim and / or chemotherapeutic agents. Initially, the dosage and dosage regimen can be modulated to determine the optimal dosage for a particular patient. The minimum concentrations of the dosage of leteprinim (weight of the drug to the patient weight) effective in the attenuation of neuropathy induced by the chemotherapeutic are approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, or approximately 45 mg / kg. The maximum concentrations of the effective dosage in the attenuation of the neuropathy induced by the chemotherapeutic are approximately 100 mg / kg, 75 mg / kg, approximately 65 mg / kg, approximately 60 mg / kg, or approximately 55 mg / kg. A concentration of the effective dosage in the attenuation induced by the chemotherapeutic (eg, cisplatin) induced neuropathy is approximately 50 mg / kg. The leteprinim compositions can be administered less than once a week based on a week of seven
days (for example, three to six times a week), or twice a week. Regardless of the regime, the time interval between administrations does not need, but can, be the same. The leteprinim compositions can be administered using a number of diverse routes including oral, topical, transdermal, intraperitoneal, subcutaneous, or intravenous. Effective amounts of the compounds can also be administered through injection into the cerebrospinal fluid or infusion directly into the brain. In one embodiment, the mode of administration is subcutaneous administration. The methods of the present invention can be performed using leteprinim administered to a patient (e.g., mammals in need of treatment) alone or as a pharmaceutical formulation. In addition, leteprinim can be combined with excipients and pharmaceutically accepted carrier materials such as inert solid diluents, aqueous solutions or non-toxic organic solvents. If desired, these pharmaceutical formulations may also contain preservatives and stabilizing agents and the like, as well as minor amounts of auxiliary substances such as wetting agents or emulsifiers, as well as pH buffering agents and the like which improve the efficacy of the active ingredient. The pharmaceutically acceptable carrier can be chosen from those generally known in the art, including, but not limited to, human serum albumin, exchangers of
ions, dextrose, alumina, lecithin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, propylene glycol, polyethylene glycol, and salts or electrolytes such as protamine sulfate chloride, sodium chloride or potassium. Other carriers can be used. The liquid compositions may also contain liquid phases either in addition to water or excluding water. Examples of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions. In one embodiment, the leteprinim formulation may be an optionally protected hydrophobic suspension, in another embodiment, the leteprinim formulation may be an optionally lipid-protected suspension. The formulations can be protected with conventional buffers (eg acids or salts). In another modality, the formulation is protected with, for example, a salt or an acid form of leteprinim (for example, form of the potassium salt of leteprinim). In another embodiment, the leteprinim formulation is a lipid suspension buffered in the form of the potassium salt of leteprinim. Materials and methods 1. Animals Dark Agouti female rats (Janvier, Le Genest-St-lsle, France) of ten weeks of age were randomly distributed into 5 experimental groups: (a) to the control group (n = 17) receiving the placebo treatment of acid suspension
subcutaneous leteprinim (s.c); (b) to the control group (n = 17) receiving the s.c. with placebo with leteprinim salt (0.9% NaCl); (c) the group treated only with cisplatin (n = 17) (d) a group treated with cisplatin (n = 17) receiving a treatment with acid suspension of leteprinim 50 mg / kg / d s.c; and (e) the group treated with cisplatin (n = 17) receiving a s.c. with the K salt solution of leteprinim 50 mg / kg / d. The animals were housed 2 per cage and kept in a room with controlled temperature (21-22 ° C) and an inverted light-dark cycle (12h / 12h) with food available ad libitum and water. All the experiments were performed according to institutional guidelines. 2. Induction of neuropathy by cisplatin, pharmacological treatment and schedule of supervision and testing Neuropathy was induced by intraperitoneal (ip) injection of 0.1 mg / ml cisplatin solution (sigma, L 'Isle d' Abeau Chesnes, France) two times per week for 4 weeks in a dose of 2 mg / kg per injection. The leteprinim treatments were performed on a daily basis from the first day of cisplatin administration until the end of the study (week 7). Cisplatin and K salt of leteprinim were dissolved in sterile 0.9% NaCl solutions (salines). The Leteprinim acid suspension and its placebo form were prepared in a 5% glucose solution. The acid suspension of Leteprinim and its solution of K salt of leteprinim and of placebo were prepared daily. Body weight and survival rate were
registered daily. The hot plate and electromyography (EMG) test were performed once a week. The sciatic nerves of 5 animals in each group were collected in week 5 for histological analysis. 3. Sensory test: hot plate The rats were individually placed inside a glass cylinder (height: 17 cm, diameter: 21 cm) on a hot plate heated to 52 ° C (Medite OTS 40, Microm, Francheville, Rhone, France ). Animal behavior was observed and recorded, particularly foot licking and tight jumping (jumping to escape heat). The time needed to feel the thermal pain (as evidenced by licking and jumping) is related to thermal sensitivity and tends to increase when thermal sensitivity decreases. 4. Electromyography Electrophysiological recordings were performed using an electromyograph of Neuromatic 2000M (EMG) (Dantec, Les Ulis, France). The rats were anesthetized by i.p. injection. 60 mg / kg of ketamine hydrochloride (Imalgene 500, Rhone Merieux, Lyon, France) and 4 mg / kg hyaline (Rompum 2%, Bayer Pharma, Kiel, Germany). The normal body temperature was maintained at 30 ° C with a heating lamp and controlled by a contact thermometer (Quick, Bioblock Scientific, Illkirch, France) placed on the surface of the tail. The H wave reflex was recorded in the thigh muscle
back after stimulation to the sciatic nerves. A reference electrode and a ground needle were placed on the lower back of the rat. The sciatic nerve was stimulated with pulses of 0.2 ms with supramaximal intensity. The amplitude (mV) and the latency of the H waves were recorded. The conduction velocity of nerve sensitivity (SNCV) was also recorded. The skin electrodes of the tail were placed as follows: a reference needle inserted at the base of the tail and an anode needle was placed 30 mm from the reference needle towards the end of the tail. A ground electrode of the needle was inserted between the anode and the reference needles. The caudal nerve was stimulated with a series of 20 pulses (during 0.2 ms) with an intensity of 12.8 mA. The speed was expressed in m / s. 5. Morphometric analysis At the end of the study, five animals per group were assigned for the histological analysis to evaluate the effect of 50 mg / kg of leteprinim on the pathological changes induced by cisplatin. These animals were anesthetized with an i.p. of 100 mg / kg of Imalgene 500. A 5mm segment of sciatic nerve was excised for histology. The tissue was fixed overnight with 4% glutaraldehyde solution (Sigma, L'lsle d 'Abeau-Chesnes, France) in phosphate buffer solution (pH = 7.4) and maintained in 30% sucrose at + 4 ° C until use. The samples of the nerves were subsequently fixed in 1% osmium tetroxide (Sigma,
L'lsle d'Abeau-Chesnes, France) in the phosphate buffer solution for 2 h, dehydrated in the serial alcohol solution, and encapsulated in Epon. The encapsulated tissues were then placed at + 70 ° C for 3 days to allow polymerization of the tissue wax. Transverse sections of 1.5 μm were cut with a microtome, stained with a blue solution of 1% toluidine (Sigma, L'lsle d'Abeau-Chesnes, France) for 2 minutes, dehydrated and mounted in Eukitt. A section of each sample of the sciatic nerves was examined using an optical microscope (Nikon, Tokyo, Japan). The analysis was performed on the entire surface of the section using a semi-automatic digital image analysis software (Biocom, France). For each fiber, the axonal and myelin sizes were calculated and reported automatically in the surface area (pm2). These two parameters were used to calculate the area equivalent to the quotient g (axonal diameter / fiber diameter) of each fiber (ie, [A / (A + M)] 0.5, A = axonal area, M = myelin area ), which indicates the thickness relative to the myelin sheath. The thickness of the myelin is inversely proportional to the quotient g. The number of degenerated fibers was then counted manually by an operator. The myelinated fibers without axons, the redundant myelin, and fibers that showed envelopes with a thickness too large compared to their axonal diameter were considered as the fibers that underwent the processes of degeneration.
6. Data analysis Body weight was compared during the course of the experiment through the analysis of two-way variation (ANOVA). Behavioral, electrophysiological and histological data were analyzed for each individual time point by ANOVA, followed by Fischer's less significant difference tests as post-hoc tests (PLSD). The level of significance was set at p < 0.05. The results are expressed as mean ± standard error (s.e.m,). RESULTS 1. Body weight In contrast to the control rats that show a progressive weight gain throughout the study, all the animals that received cisplatin showed marked weight loss from the day following the administration of cisplatin (p <0.001, ANOVA two-way) (see figure 1). The most severe weight loss was observed during the 3rd and 4th week of cisplatin administration. After withdrawal of the cisplatin treatment, the rats showed a progressive weight gain but remained below (approximately 20%) of the control level. These results show that leteprinim acid treatment or leteprinim K salt did not prevent the appearance of growth arrest but was associated with an improved growth profile with respect to the cisplatin only treatment group (approximately 10% on the treatment group only with cisplatin).
2. Sensory test: hot plate Figure 2 shows that from week 2 onwards, the rats in the cisplatin-only treatment group showed a significant increase in threshold latency ratings with respect to the control groups (p < 0.05, Fisher's PLSD Test). The most severe dysfunction was observed in week 4 (the week of cisplatin administration) with a time rating of the control groups of approximately 30%. Even at the end of the study, the animals in the cisplatin-only treatment group did not recover to the performance level of the control animals. As also observed in Figure 2, the treatment with the leteprinim acid or with the K salt of leteprinim significantly improved the performance in the hot plate of the rats treated with cisplatin (p = 0.05, Fisher's PLSD test). Significant effects were observed from week 3 to week 7. In week 4, where the most severe dysfunction of cisplatin was observed, the rats under cisplatin and treated with the leteprinim acid or with the K salt of leteprinim showed a time rating of only about 15% over the previous control values. At the end of the study (week 7), the performance of the cisplatin-treated rats receiving the leteprinim acid or the K salt of leteprinim was comparable to that of the control rats. These results show that leteprinim can contribute to the prevention of pathologies associated with cisplatin treatment.
3. Electrophysiological measurements a. Amplitude of the H wave As shown in Figure 3, a significant reduction in the H wave amplitude was observed in the cisplatin-only treatment group from 1a. week after the start of cisplatin administration. The most severe reduction in the amplitude of the H wave occurred in week 4, where the loss exceeded 45% of the control levels. Recovery began after withdrawal of cisplatin treatment (post-cisplatin time points) and was completed by week 7 (end of study). The rats under cisplatin treated with the leteprinim acid or the K salt of leteprinim showed a better performance of the H wave when compared with the group of treatment alone with cisplatin. These differences were evident from week 2, in week 4, where the loss of the H wave amplitude was highest in the treatment group with cisplatin alone, the rats under cisplatin that received leteprinim showed only about 20% H wave amplitudes below the control values. By week 5, rats under cisplatin treated with leteprinim recovered the H-wave rating of the control rats. These results also demonstrate that leteprinim can help prevent or alleviate the physiological changes associated with the administration of cisplatin. b. H wave latency Figure 4 shows a significant extension of latency
of wave H in the treatment group only with cisplatin starting at week 2 with respect to that of the control rats (p <0.05, Fisher's test). The most severe alteration was observed in week 4 with a latency rating extended by approximately 12%. Rats treated only with cisplatin were completely recovered with this measurement by week 7. Treatment with leteprinim acid or K salt of leteprinim significantly attenuated the alteration of the latency of the H wave induced with cisplatin (p = 0.05 , Fisher's Test). In week 4, where the alteration in the treatment group with cisplatin alone was maximum, only an extension of approximately 4% of the latency score (with respect to the control value) was observed in the cisplatin groups receiving the treatment of leteprinim. c. Velocity of sensory conduction to the nerves A progressive decrease of SNCV was observed in the cisplatin group starting from week 1 (p = 0.05, Fisher's test) (figure 5). The most severe dysfunction was observed in week 4 with a rating of approximately 15% below control. Recovery began in week 5 but performance did not return to control levels. Treatment with leteprinim significantly improved the SNCV performance of rats treated with cisplatin. In week 4, where SNCV dysfunction was highest in the treatment group with cisplatin only, the dysfunction associated with rats under cisplatin
receiving leteprin was at most 7% below control value. At week 7, the performance of the rats under cisplatin treated with leteprinim was comparable to that of the control rats. 4. Morphometric analysis a. Axon diameter There was no statistical difference between the groups (p> 0.05, ANOVA) (Figure 6), although the axon diameters of the nerve fibers harvested from the rats treated with cisplatin alone were slightly higher than those of the other groups . Treatment with leteprinim did not significantly modify the axon size of rats treated with cisplatin. b. Ielin thickness There were no statistical differences between the groups with respect to the thickness of the myelin sheath of the nerve fibers (p> 0.05, ANOVA) (FIGURE 7). c. Percentage of degenerated fibers According to the indications in figure 8, the proportion of fibers degenerated in the sciatic nerves of the group treated with cisplatin alone was significantly higher than that of the control rats (p = 0.05, Fisher's test). In addition, treatment with leteprinim significantly reduced the proportion of degenerated fibers in the sciatic nerves of rats treated with cisplatin. The results described show that the administration of the chemotherapeutic (in this case, cisplatin) induces the dysfunction
marked by the nerves indicated by the alteration of the H wave signal (reduced amplitude and latency understood) and SNCV as well as by the delayed reactivity to heat. These samples of sensory neuropathy were supported by histological results that showed a significant increase in the proportion of sciatic nerve fibers that showed axonal degeneration characteristics, although the nature of these affected fibers (sensory or motor) was not identified. The results described also showed that treatment with leteprinim can markedly attenuate the nervous dysfunction induced by the chemotherapeutic (in this case, induced by cisplatin) and can accelerate the recovery of this disorder. These improvements were evident in most of the studied parameters (amplitude and latency of the H wave, SNCV and axonal degeneration) and seemed to be in good correlation with the improvements observed in the hot plate test. The histological results showed that the axon diameter of the group treated with cisplatin only slightly increased. This may represent axonal degeneration, a phenomenon observed as a consequence of the administration of cisplatin in the brain of the developing rat (Rzeski et al., (2004) Ann Neurol 56: 351-360). The treatment of Leteprinim seems to completely prevent this axonal swelling. In summary, the results described show that daily treatment with leteprinim can improve sensory neuropathy related to cisplatin.
A method of the present invention can be carried out using the active ingredients described above, or as a physiologically acceptable salt, derivative, prodrug, or solvate thereof. The active ingredients may be administered as a pure compound, or as a pharmaceutical composition containing one or both entities. The pharmaceutical compositions include those wherein the active ingredients are administered in an effective amount to achieve their intended purpose. More specifically, a "therapeutically effective amount" means an amount effective to prevent the development of, eliminate it, retard the progression of, or reduce the size of, a solid tumor. The determination of a therapeutically effective amount may be made by those skilled in the art, especially in light of the detailed description provided herein. A "therapeutically effective dose" refers to the amount of the active ingredients that result in obtaining the desired effect. The toxicity and therapeutic efficacy of such active ingredients can be determined by standard pharmaceutical procedures in experimental cell or animal cultures, for example by determining the LD50 (the lethal dose for up to 50% of the population) and the ED50 (the therapeutically dose effective for 50% of the population). The proportion of the dose between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
A high therapeutic index is preferred. The data obtained can be used to formulate a dosage range for use in humans. The dosage of the active ingredients is preferably within a range of circulation concentrations that include ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form used, and the route of administration used. The exact formulation and dosage are determined by an individual physician based on the patient's condition. The amount and range of the dosage can be adjusted individually to provide the levels of the active ingredients that are sufficient to maintain the therapeutic or prophylactic effects. The amount of pharmaceutical composition administered may depend on the patient treated, their weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The active ingredients can be administered alone, or with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention can thus be formulated in a conventional manner using one or more acceptable physiological carriers that include the excipients and auxiliaries that facilitate the processing of the active ingredients in the preparations that can be used.
pharmaceutically When a therapeutically effective amount of the active ingredients is administered, the composition may be in the form of a parenterally acceptable, pyrogen-free aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the ordinary skill in the art. A preferred composition for intravenous injection will typically contain an isotonic vehicle although this feature is not required. For veterinary use, the active ingredients are administered as a suitably acceptable formulation according to normal veterinary practice. The veterinarian can easily determine the dosage regimen that is most appropriate for a particular animal. Various adaptations and modifications to the modalities may be made and used without departing from the scope and spirit of the present invention which may be related in a different manner to that specifically described herein. The above description is intended to be illustrative, and not restrictive. The scope of the present invention should be determined only by the claims. The terms and expressions that have been used herein are used as terms of description and not limitation, and there is no intent in the use of such terms and expressions to exclude equivalents of the characteristics shown and
described, or portions thereof, recognizing that various modifications are possible within the scope of the present invention. On the other hand, one or more features of any embodiment of the present invention can be combined with any one or more features of any other embodiment of the present invention, without departing from the scope of the present invention. Unless otherwise indicated, all numbers expressing quantities of ingredients, characteristics such as molecular weight, reaction conditions, and so forth used in the specification and claims shall be understood as modified in all cases by the manufacturer. term "approximately". Accordingly, unless otherwise indicated, the numerical parameters indicated in the following description and the appended claims are approximations that may vary depending on the desired characteristics intended to be obtained by the present invention. At least, and not as an attempt to limit the use of the doctrine of equivalents to the scope of the claims, each numerical parameter must at least be interpreted in light of the number of significant digits presented and applying ordinary rounding techniques. Although the ranges and numerical parameters which provide for the broad scope of the present invention are approximations, the numerical values set forth in the specific examples are indicated as exactly as possible. Any numerical value, however, intrinsically contains certain errors that result
necessarily of the standard deviation found in their respective measurements of the test. The terms "a" and "an" and "the" and the like used in the context of the description of the invention (especially in the context of the following claims) should be interpreted to cover the singular and the plural, unless I will indicate otherwise here or clearly by context. The indication of ranges of values here is intended to simply serve as a quick method to refer individually to each separate value that is within the range. Unless otherwise indicated here, each individual value is incorporated into the specification as if it were individually described here. All methods described herein may be performed in any convenient order unless otherwise indicated herein or otherwise clearly by context. The use of any and all examples, or exemplary language (for example "such as") provided herein is intended to further clarify the invention and not to raise a limitation on the scope of the present invention claimed otherwise. No language in the description should be construed as indicating any unclaimed element essential to the practice of the present invention. The groupings of alternative elements or embodiments of the present invention described herein should not be construed as limitations. Each member of the group can be referred and claimed individually or in any combination with others
members of the group or of other elements found here. It is anticipated that one or more members of a group may be included, or removed from, a group for reasons of convenience and / or patentability. When any inclusion or cancellation of that type occurs, the description is considered to contain the group as modified thus satisfying the written description of all the Markush groups used in the appended claims. Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations in these modalities will become apparent to those with ordinary skill in the art after reading the foregoing description. The inventor expects the skilled artisans to employ the variations as appropriate, and the inventors claim that the invention is practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the appended claims to this as permitted by applicable law. On the other hand, any combination of the elements described above in all possible variations is included in the invention unless otherwise indicated herein or otherwise clearly indicated by context. In addition, the numerical references that have been made to patents and printed publications in this description. Each of the references cited above and the publications printed here
they are incorporated individually as a reference. Concluding, it should be understood that the embodiments of the present invention described herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the present invention. Thus, by way of example, but not limitation, alternative configurations of the present invention may be used in accordance with the present teachings. Accordingly, the present invention is not limited exactly to what is shown and described.