EP0942725A1 - Use of cis-hydroxyitraconazole in order to avoid side-effects of itraconazole and hydroxyintraconazole - Google Patents
Use of cis-hydroxyitraconazole in order to avoid side-effects of itraconazole and hydroxyintraconazoleInfo
- Publication number
- EP0942725A1 EP0942725A1 EP97946574A EP97946574A EP0942725A1 EP 0942725 A1 EP0942725 A1 EP 0942725A1 EP 97946574 A EP97946574 A EP 97946574A EP 97946574 A EP97946574 A EP 97946574A EP 0942725 A1 EP0942725 A1 EP 0942725A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cis
- hydroxyitraconazole
- infection
- pharmaceutically acceptable
- human
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Definitions
- the invention relates to methods of treatment using cis- hydroxyitraconazole, a metabolic derivative of cis- itraconazole and derivatives thereof for the treatment of bacterial, microbial, and fungal infection and other disorders, while avoiding the concomitant liability of adverse side effects associated with the administration of itraconazole.
- Hydroxyitraconazole has the chemical formula 4- (4- (4- (4- ( (2 , 4-dichlorophenyl) -2- (1H-1 , 2 , 4-triazol-l- ylmethyl) -1, 3-dioxolan-4-yl)methoxy)phenyl) -1- piperazinyl) phenyl) -2 , 4-dihydro-2- (2-hydroxy-l-methylpropyl) - 3H-l,2,4-triazol-3-one. (CAS Registry Number 112559-91-8).
- the invention further relates to methods of treatment and pharmaceutical compositions employing compounds of the structure:
- R is a hydrogen, -P(O) (OH) 2 or -S0 3 H. 0
- Itraconazole a compound having the formula C 35 H 38 Cl 2 Ng ⁇ 4 , 5 is a synthetic antifungal agent sold commercially as
- Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs) , each possessing three chiral * centers. Itraconazole is an orally active; broad- spectrum anti-fungal agent and is structurally related to miconazole and clotrimazole.
- Itraconazole is extensively distributed into lipophilic tissues, causing concentrations of 2-20 times the corresponding plasma concentrations. In vitro studies have shown that itraconazole inhibits the cytochrome P450- dependent synthesis of ergosterol, which is a key component in fungal cell membranes. This generally results in an increased permeability and leakage of intracellular content.
- Itraconazole exhibits in vitro activity against Blastomyces dermatitidis , Histoplasma capsulatum, Histoplasma duboisii , Aspergillus flavus , Aspergillus fumigatus , and Cryptococcus neo for mans , as well as sporadic activity against other fungal species.
- Itraconazole is also a potent inhibitor of CYP3A4, which is responsible for the metabolism of many drugs including ijovastatin. It has recently been reported-that' itraconazole” significantly increases the plasma concentration of this cholesterol-lowering drug which leads to toxicity, i.e., skeletal muscle toxicity or myopathy. Neuvonen and Jalava, Clin . Pharmacol . Ther . , 60(1): 54-61 (1996).
- Itraconazole in humans, is metabolized by the liver into a variety of metabolites. Specifically, itraconazole is hydroxylated on the sec-butyl side-chain by CYP3A4 to form a 3-hydroxy-2-butyl moiety, yielding the active metabolite hydroxyitraconazole.
- CYP3A4 hydroxylated on the sec-butyl side-chain by CYP3A4 to form a 3-hydroxy-2-butyl moiety, yielding the active metabolite hydroxyitraconazole.
- 4,791,111 discloses a plethora of compounds, including hydroxyitraconazole, and describes these as being useful against fungi and bacteria in warm-blooded animals.
- Itraconazole has three stereogenic centers, while hydroxyitraconazole has four stereogenic centers, affording sixteen stereomeric forms — eight cis-isomers and eight trans-isomers .
- the antifungal activity of hydroxyitraconazole has been shown to be comparable to itraconazole against certain fungal species. (See Physician's Desk Reference®, pp. 1305-1307, 50th Ed. Medical Economics Data Production Co., N. J. , 1996). It has also been reported that itraconazole is generally more potent than hydroxyitraconazole against fungal infection.
- itraconazole in the treatment of fungal infections in humans has demonstrated certain adverse side effects including, but not limited to, abnormal hepatic function and toxicity; cardiac dysrhythmia; decreased libido; dizziness; edema; fatigue; fever; gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and anorexia; headache; hypertension; hypokalemia; impotence; malaise; pruritus; rash; and somnolence.
- U.S. Patent No. 5,474,997 discloses methods and compositions using optically pure (2R,4S) -itraconazole. The methods are directed to the treatment of local and systemic fungal, yeast and dermatophyte infections, while avoiding the concomitant liability of adverse effects associated with racemic itraconazole.
- Itraconazole is known to have certain adverse effects, including, but not limited to, those described above.
- One such adverse effect is that cis-itraconazole interferes or inhibits the oxidative metabolism of several drugs.
- the biochemical basis for this inhibition involves the drug interaction of cis-itraconazole with cytochrome P450.
- This cytochrome P450 system is involved in the metabolism of numerous drugs including, but not limited to, tricyclic antidepressants, non-sedating antihistamines, antiarrhythmics and beta adrenergic blocking agents. Stevens and righton, J. Pharm . Exp. Therap . 266 (2) :964-971 (1993).
- Systemic fungal diseases are usually chronic, very slowly developing conditions induced by opportunistic causative fungi which may not normally be pathogenic. However, when they enter a host compromised by HIV, ionizing irradiation, corticosteroids, cancer, immunosuppressives, and the like, or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like, they may become pathogenic. Symptoms in such fungal diseases are generally not intense, and may include fever, chills, anorexia and weight loss, malaise, and depression.
- Fungal diseases are often confined to typical anatomic distributions, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections when the fungus disseminates from a primary focus.
- coccidioidomycosis occurs in a primary form as an acute, benign, self-limiting respiratory disease, with progressive disease developing from the primary form as a chronic, often fatal infection of the skin, lymph glands, spleen and liver.
- blastomycosis primarily involves the lungs, and occasionally spreads to the skin.
- infectious diseases such as paracoccidioidomycosis and candidiasis offer a different course, and depending on the etiology may exhibit several forms involving the skin, mucous membranes, lymph nodes, and internal organs.
- the diagnosis of specific fungal diseases may be made- by isolation of the causative fungus from sputum, urine, blood, or the bone marrow, or with prevalent fungus types by evidence of tissue invasion.
- Superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, hair or nails. The infections may result in a mild inflammation, and cause intermittent remissions and exacerbations of a gradually extending, scaling, raised lesion.
- Yeast infections including candidiasis, and oral candidiasis (thrush) are usually restricted to the skin, and mucous membranes, and the symptoms vary with the site of infection. Commonly, infections appear as erythematous, often itchy, exudative patches in the axillas, umbilicus, groin, between toes, and on fingerwebs. Oral thrush involves an inflamed tongue, or buccal ucosa and presents as white patches of exudate, while chronic mucocutaneous candidiasis is characterized by red, pustular, crusted, thickened lesions on the forehead or nose. Many of the "conazole” antifungal agents, including itraconazole, share the same adverse effects.
- itraconazole interacts with cytochrome P-450 (liver metabolism) and since fungal and bacterial infections for which these compounds may be useful are often found in the CNS, particularly the brain, there are limitations associated with the use of these drugs. Similarly, since itraconazole is often administered to patients being treated concurrently or in conjunction with antivirals, antibiotics, antihistamines, antidepressants, antiarrhythmics , antitumor agents, beta blockers and hypocholesteremic agents or combinations thereof, drug interactions are a major concern.
- compositions and methods for treating the above-mentioned bacterial, fungal or other microbial infections while reducing inhibition of drug metabolism, reducing adverse drug interactions, reducing hepatotoxicity, and improving selectivity, CNS penetration and overall efficacy.
- cis-hydroxyitraconazole is an effective agent for the treatment of local and systemic infections in humans while significantly reducing or avoiding adverse side effects including but not limited to hepatotoxicity, inhibition of drug metabolism, drug interactions, and cardiac side effects associated with prolonged Qt intervals. Further, cis-hydroxyitraconazole has been found to be a potent agent for the treatment of secondary opportunistic infections localized in the brain or other parts of the CNS. Cis-hydroxyitraconazole can penetrate the blood brain barrier and selectively interact with the fungal cytochrome P450 in order to eradicate the fungal disease with minimal hepatotoxicity and CNS toxicity.
- cis-hydroxyitraconazole provides an effective method of treating local and systemic fungal, yeast and other dermatophyte infections while reducing adverse effects.
- the methods of the present invention provide a treatment of a variety of infections and inflammation, in a human, while avoiding adverse side effects normally associated with the administration of compounds such as itraconazole.
- adverse side effects include, but are not limited to, abnormal hepatic function; cardiac dysrhythmias ; decreased libido; dizziness; edema; fatigue; fever; gastrointestinal disorders, such as nausea, vomiting, diarrhea, abdominal pain, and anorexia; headache; hypertension; hypokalemia; impotence; malaise; prolonged QT interval; pruritus; rash; and somnolence.
- the invention also encompasses methods for treating local or systemic microbial infection while avoiding the concomitant liability of adverse side effects associated with the administration of itraconazole, by administering to said human a therapeutically effective amount of cis- hydroxyitraconazole, a phosphate derivative, a sulfate derivative, or a pharmaceutically acceptable salt thereof.
- the invention further encompasses methods of treating local or systemic microbial infection, bacterial infection, fungal infections, yeast infections, dermatophyte infections, or inflammation; each method can be achieved while avoiding the concomitant liability of adverse side effects associated with the administration of cis-itraconazole, by administering to said human a therapeutically effective amount of cis- hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
- the methods of the present invention are achieved while substantially avoiding inhibition of the metabolism of other drugs by the cytochrome P450 pathway.
- a therapeutically effective amount of cis-hydroxyitraconazole is typically from about 1.0 mg to about 1000 mg per day, more preferably from about 10 mg to about 500 mg per day.
- the amount of said cis- hydroxyitraconazole, phosphate derivative, sulfate derivative, or a pharmaceutically acceptable salt thereof may be administered together with a pharmaceutically acceptable carrier.
- the methods of the present invention include the treatment of bacterial infection including, but not limited to, Erysipelotric insidiosa, a Staphylococci such as Staphylococcus hemolyticus, or a Streptococci such as Streptococcus pyogenes ; and fungal, yeast, and dermatophyte infections including, but not limited to, Aspergillosis , Aspergillus fumigatus , Bla ⁇ tomycosis, Blastomyces dermatitides , Candidasi ⁇ and Oral Candidasis (thrush) , Candida albicans , Candida tropicalis , Coccidioidomycosi ⁇ , Cryptococcosis, Cryptococcus neo for mans , Ctenomyces mentagrophy
- the amount of cis-hydroxyitraconazole in a composition is typically from about 50 mg to about 1200 mg, but in a preferred embodiment is from about 100 mg to about 1000 mg.
- the composition can be adapted for oral, parenteral (intravenous) or topical administration.
- the aforementioned compositions may optionally contain one or more other active components including an anti-fungal agent.
- the present invention further encompasses an improved method of treating bacterial or fungal infection, both systemic and local, using compounds having enhanced potency, improved solubility, enhanced bioavailability, ability to penetrate the CNS, selectivity for inhibition of fungal cytochrome P450 and decreased cardiac side effects or adverse drug interactions. These compounds have the formula:
- R is selected from the group consisting of hydrogen, -P(O) (OH) 2 , -S0 3 H, or a salt thereof.
- R is selected from the group consisting of hydrogen, -P(O) (OH) 2 , -S0 3 H, or a salt thereof.
- R is selected from the group consisting of hydrogen, -P(O) (OH) 2 , -S0 3 H, or a salt thereof.
- R is selected from the group consisting of hydrogen, -P(O) (OH) 2 , -S0 3 H, or a salt thereof.
- asterisks two on the sec-butyl side- chain on the triazolone and two on the dioxolane ring.
- these compounds are beneficial in treating fungal infections of the brain in immunocompromised patients, particularly HIV infected patients.
- R is hydrogen, -P(O) (OH) 2 , -S0 3 H, or a pharmaceutically acceptable salt thereof.
- the infection to be treated is found in the brain.
- interaction between cis- hydroxyitraconazole and a drug that inhibits cytochrome P450 is avoided.
- the amount of cis-hydroxyitraconazole administered is typically from about 1 mg to about 1000 mg per day.
- the present invention encompasses a method of treating or preventing an infection selected from the group consisting of bacterial, fungal, yeast or dermatophyte infection in a human while avoiding the concomitant liability of adverse side effects associated with the administration of itraconazole, which comprises administering to said human a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
- the present invention further encompasses the treatment or prevention of bacterial, fungal, yeast or dermatophyte infection of the central nervous system including, but not limited to, the brain, which comprises administering to a human in need of such therapy an effective amount of cis- hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
- the invention encompasses the use of a compound of the formula:
- R is -PO(OH) 2 , -S0 3 H, or a salt thereof.
- the present invention further includes pharmaceutical compositions for the treatment or prevention of the above- mentioned infections in normal or in an immunocompromised or immunosuppressed patient, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of cis-hydroxyitraconazole, or a phosphate derivative, a sulfate derivative, or a pharmaceutically acceptable salt thereof.
- hydroxyitraconazole contains four (4) asymmetric carbons, which gives rise to sixteen (16) stereogenic isomers—eight cis and eight trans .
- This invention includes only cis-hydroxyitraconazole, and includes racemic cis-hydroxyitraconazole, as well as the eight (8) optically pure isomers of the cis-hydroxyitraconazole and any combination thereof that may be isolated or otherwise prepared.
- the invention should also be understood by those skilled in the art to specifically include the methods of using compositions containing these isomers, or mixtures thereof, for the claimed methods of treatment.
- cis- hydroxyitraconazole in the present methods of treatment permits the treating physician to more readily use other therapeutics concurrently with or sequentially with cis- hydroxyitraconazole therapy. This allows a better overall and continuous treatment plan. Such is not readily accomplished with cis-itraconazole because the physician must take into consideration adverse drug interactions, short half-life, and tissue distribution, that may result from the inhibitory effects of itraconazole, the co-administered drug or both.
- this invention permit the treating physician to intervene sooner with the sequential administration of another drug following cis- hydroxyitraconazole treatment, but other drugs can be used in combination or in parallel with cis-hydroxyitraconazole since the latter is not believed to interfere with the metabolism of the former. This is a significant advantage of cis- hydroxyitraconazole over cis-itraconazole.
- Cis-hydroxyitraconazole is not equally inhibitory of the cytochrome P450 system in therapeutic doses and therefore allows for safer and more rapid sequential or concurrent co- therapy.
- other drugs such as antidepressants, anti- arrhythmics, antihistamines, antibiotics, antifungal agents, and others described herein can be used sequentially or in combination with cis-hydroxyitraconazole.
- this invention also encompasses a method of avoiding drug interaction with the cytochrome P450 system, while treating microbial infection (e.g., bacterial, fungal, dermatophyte) in a human, wherein said human is administered cis-hydroxyitraconazole, or a phosphate derivative, sulfate derivative, or a pharmaceutically acceptable salt thereof.
- microbial infection e.g., bacterial, fungal, dermatophyte
- abnormal hepatic function includes, but is not limited to, abnormal hepatic function; hepatotoxicity; cardiac dysrhythmias; cardiac side effects associated with prolonged Qt intervals such ⁇ as- cardiac- arrhythmias; adverse drug interactions; decreased libido; dizziness; edema; fatigue; fever; gastrointestinal disorders; headache; hypertension; hypokalemia; impotence; malaise; pruritus; rash; and somnolence; or combinations thereof.
- gastrointestinal disorders includes, but is not limited to, nausea, vomiting, diarrhea, abdominal pain, and anorexia, and combinations thereof. It has been reported that the administration of certain conazoles may be associated with an increased risk of cardiac arrhythmia.
- Arrhythmia has been reported as a side effect of systemic racemic itraconazole, and a particular subtype of arrhythmia, Torsades de Pointes, has been reported when racemic itraconazole was administered concurrently with terfenadine.
- the lack of many clinical reports of arrhythmia or QT anomalies may simply be a reflection of the fact that there is to date a relatively small subject population.
- terapéuticaally effective amount means that amount of cis-hydroxyitraconazole that provides a therapeutic benefit in the treatment or management of infection and other disorders .
- anti-infective includes, but is not limited to, anti-bacterial, anti-microbial, anti-fungal, anti-yeast, and anti-dermatophyte, or combinations thereof.
- infection includes bacterial infection, microbial infection, fungal infection, yeast infection, and dermatophyte infection, or combinations thereof.
- a prophylactic or therapeutic dose of cis-hydroxyitraconazole in the acute or chronic management of disease will vary with the severity of the condition to be treated and the route of administration.
- the dose, and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient.
- the total daily dose range for the conditions described herein, is from about 0.1 mg to less than about 10 mg administered in single or divided doses orally, topically, transdermally, or locally by inhalation.
- a preferred oral daily dose range should be from about 0.1 mg to about 5 mg, more preferably about 0.2 mg to about 1 mg.
- cis-hydroxyitraconazole or a pharmaceutically acceptable salt or stereoisomer thereof and “therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof” are encompassed by the above-described frequency and dosage amounts.
- Any suitable route of administration may be employed for providing the patient with an effective dosage of cis- hydroxyitraconazole according to the methods of the present invention.
- oral, rectal, parenteral, intravenous, topical, transdermal, subcutaneous, intramuscular, and like forms of administration may be employed.
- Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
- compositions used in the methods of the present invention include cis-hydroxyitraconazole, the metabolic derivative of cis-itraconazole, as active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
- pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric.
- Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic) , methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
- aliphatic, aromatic, carboxylic and sulfonic classes of organic acids examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic) , me
- inorganic bases for potential salt formation with the sulfate or phosphate compounds of the invention, include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
- Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N- methylglucamine) , lysine and procaine.
- compositions for use in the methods of the present invention include compositions such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being preferred over the oral liquid preparations.
- oral solid preparations such as powders, capsules, and tablets
- the most preferred oral solid preparations are tablets.
- tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques .
- the compound for use in the methods of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the disclosures of which are hereby incorporated by reference.
- compositions for use in the methods of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non- aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
- Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
- a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
- Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- each tablet contains from about 0.1 mg to less than about 10 mg of the active ingredient
- each cachet or capsule contains from about 0.1 mg to about less than 10 mg of the active ingredient, i.e., cis- hydroxyitraconazole.
- Microbiological and pharmacologic studies can be used to determine the relative potency and the profile of specificity of the optically pure enantiomers and the racemic mixture of hydroxyitraconazole as antimycotic agents with a broad spectrum of activity against many fungi, yeast, and dermatophytes .
- antimicrobial activity of the aforementioned compounds selected experiments are illustrated to profile useful antimicrobial activity, and not to limit this invention in any way, including the scope of susceptible microorganisms.
- Antifungal conazoles may be evaluated in vitro at several concentrations (in ⁇ g/ml) against a number of fungi and bacteria. (See Van Cutsem, Chemotherapy 38 Suppl .
- the fungistatic assay is carried out in Sabouraud's liquid (1 g of neopeptone Difco and 2 g of glucose Difco per 100 m of distilled water) in 16x160 mm test tubes, each containing 4.5 L of liquid medium which has been autoclaved at 120°C for 5 min.
- the compounds to be tested are dissolved in 50% alcohol at initial concentration of 20 mg/mL.
- the solutions are subsequently diluted with sterile distilled water to give a concentration of 10 mg/mL. Successive decimal dilutions are made in distilled water.
- Control tubes are prepared by adding 0.5 mL of distilled water to 4.5 of L medium, alcohol being added to give concentrations identical with the tubes containing 1000 and 500 ⁇ g of the drug.
- the filamentous fungi are incubated in Sabouraud's agar at 25 °C for 2-3 weeks. A block of 2x2x2 mm is then inoculated into the medium. All cultures are made in duplicate and are incubated at 25 °C for 14 days.
- Hydroxyitraconazole antifungal activity is enhanced in vitro in Sabouraud broth containing 10% inactivated bovine serum, and depends on the test medium used. Complete or marked inhibition of growth in Sabouraud broth after 14 days of incubation may be observed with Microsporum cani ⁇ , Trichophyton mentagrophytes, Candida albican ⁇ , Sporothrix schenckii, Paracoccidioide ⁇ bra ⁇ ilien ⁇ i ⁇ , Bla ⁇ tomyce ⁇ dermatitide ⁇ , Histoplasma ⁇ pp. , Aspergillu ⁇ ⁇ pp . and other fungi and bacteria. Concentration/response curves may be compared for hydroxyitraconazole, its derivatives, and such standard agents as miconazole, as regards scope, and potency.
- In vivo activity of hydroxyitraconazole may be compared against experimental cutaneous candidosis in guinea pigs, and vaginal candidosis in rats.
- the in vivo activity of the compounds in vaginal candidosis is evaluated by inducing vaginal infection with C. albicans in ovariectomized and hysterectomized Wistar rats (100 g) which are treated weekly with 100 ⁇ g of estradiol undecanoate in sesame oil, subcutaneously. Animals in pseudooestrus arc infected intravaginally with a fixed concentration of C. albicans in saline. Control of infection or cure is estimated by taking vaginal smears at fixed days after infection.
- Drugs to be evaluated, and compared on a mg/kg basis may be given prophylactically, or therapeutically and their efficacy judged by comparison the ratio of negative animals to the total number in each drug group.
- the activity against cutaneous candidosis in guinea pigs provides the basis of testing compounds of the invention.
- Torsades de Pointes is a well known side effect of anti- arrhythmic drugs, such as quinidine, sotalol and acetylprocainamide, which cause a prolongation of cardiac repolarization. All of these drugs have in common the ability to block a cellular potassium channel called the delayed rectifier (I ⁇ ) , and it is generally assumed that this is mechanistically linked to their ability to induce the syndrome of Torsades de Pointes. (See Zehender et al., Cardiovascular Drugs Ther . 515-530 (1991)).
- Increases in QT duration and action potential duration in isolated guinea pig or rabbit hearts can be used to indicate an arrhythmogenic effect.
- Hearts are perfused with an oxygenated Tyrode ' s solution, containing 0.0; 1.0; 5.0; 10.0 or 30.0 ⁇ M of racemic itraconazole.
- QT duration and action potential duration are measured from cardiac electrodes.
- the hearts are divided into 3 subgroups receiving either itraconazole or hydroxyitraconazole to determine the respective effects on QT duration and APD.
- mongrel dogs of either sex weighing 5-20 kg are anesthetized and instrumented by standard techniques for blood pressure and EKG.
- a solid state transducer for dP/dT is placed in the left cardiac ventricle, and an epicardial electrode is put into place.
- the test compound is infused at progressively higher doses, beginning at 2 ⁇ g/kg/min for 15 minutes and increased incrementally until a cardiovascular collapse ensues.
- Parameters measured are: blood pressure, heart rate, dP/dT, and the QT-interval. Measurements of hemodynamics and electrical activity are made in response to the test compound.
- Hepatic microsomes are prepared from human liver. Tissue is thawed and then homogenized in 0.15M KC1 in a Polytron homogenizer. The homogenate is centrifuged and the pellet is resuspended and homogenized in 0.15M KC1. Aliquots are frozen and stored at -70°C.
- Human lymphocytes are aseptically isolated from fresh, heparinized human blood. Blood is diluted with Eagle's minimal essential medium and layered on Ficoll-Paque.
- lymphocytes are then removed from the aqueous-Ficoll interface and suspended in medium (15 Mm HEPES, pH, 7.4).
- medium 15 Mm HEPES, pH, 7.4
- the cells are then centrifuged, washed once in the HEPES medium, and resuspended.
- Cytotoxicity is assessed by the conversion of 3- (4, 5- dimethylthiazol-2-yl) -2 , 5-diphenyltetrazolim bromide (MTT) to a purple formazan.
- MTT 5-diphenyltetrazolim bromide
- the conversion of MTT to dye is done in multiwell plates. After preparation, hepatic microsomes or lymphocytes are incubated alone or with the test compound in a concentration range from 1 to 400 ⁇ M at 37 °C. in a humidified incubator. After incubation, the microsomes/cells are washed with 5% albumin in HEPES-buffered medium and resuspended. The microsomes/cells are then incubated at 37 °C. in a humidified incubator.
- Itraconazole can by synthesized by the methods disclosed in an article by Heeres, J. , et al., J " . Med . Chem . 27:894-900 (1984), while (2R, 4S) -itraconazole can be synthesized by methods disclosed in U.S. patent No. 5,474,997, the disclosures of both of which are expressly incorporated herein by reference thereto for preparation of itraconazole. Hydroxyitraconazole is prepared similarly, by reaction steps conventional in the art. The preparation of hydroxyitraconazole is described, for example, in U.S. patent No. 4,791,111, the disclosure of which is expressly incorporated herein by reference thereto for preparation of hydroxyitraconazole .
- a dioxolane DTTT is prepared by a literature method from either R-3-toxyloxy-l, 2-propanediol or S-3-tosyloxy-l, 2- propanediol by acid-catalyzed ketalization to provide DTTT.
- a dioxothiolane is prepared from a butanediol of appropriate configuration by treatment with thionyl chloride, followed by in ⁇ itu oxidation of the resulting cyclic sulfite with sodium periodate in the presence of ruthenium 5 trichloride.
- the methoxy- sulfate salt may be partially hydrolyzed with 48% HBr at 45-
- protecting groups are cleaved by hydrogenolysis in the presence of a palladium catalyst and the product carried through described above.
- Data represent zones of in i ition in mm; A & B are hydroxyitraconazole samples.
- In vivo activity of hydroxyitraconazole and derivatives may be compared against experimental cutaneous candidosis in guinea pigs, and vaginal candidosis in rats.
- the in vivo activity of the compounds in vaginal candidosis is evaluated by inducing vaginal infection with C. albicans in ovariectomized and hysterectomized Wistar rats (lOOg), which are treated weekly with 100 ⁇ g of estradiol undecanoate in sesame oil, subcutaneously. Animals in pseudooestrus are infected intravaginally with a fixed concentration of C. albicans in saline. Control of infection or cure is estimated by taking vaginal smears at fixed days after infection.
- Drugs to be evaluated, and compared on a mg/kg basis may be given prophylactically or therapeutically and their efficacy judged by comparison of the ratio of negative animals to the total number in each drug group.
- the activity against cutaneous candidosis in guinea pigs provides the basis of comparison. (Van Cutsem et al., Chemotherapy 17:392 (1972)).
- cytochrome P4503A4 human cytochrome P4503A4
- CYP3A4 is involved in many drug-drug interactions and quantitation of inhibition of CYP3A4 by cis-itraconazole and cis-hydroxyitraconazole indicates the potential of such drug-drug interactions.
- Inhibition is measured using the model substrate testosterone and cDNA-derived CYP3A4 in microsomes prepared from a human lymphoblastoid cell line designated h3A4v3.
- the inhibition study consists of the determination of the 50% inhibitory concentration (IC 50 ) for the test substance.
- IC 50 50% inhibitory concentration
- a single testosterone concentration 120 ⁇ M, approximately twice the apparent K. and ten test substance concentrations, separated by approximately 1/2 log, are tested in duplicate.
- Testosterone metabolism is assayed by the production of the 6 (/_») -hydroxytestosterone metabolite. This metabolite is readily quantitated via HPLC separation with absorbance detection.
- test substances will be stored at room temperature.
- the test substances will be dissolved in ethanol for addition to the incubations.
- the solvent concentration will be constant for all concentrations of the test substance.
- test substance concentrations will be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0 ⁇ M. Each test concentration will be tested in duplicate incubations in accordance with the method below:
- a 0.5 ml reaction mixture containing 0.7 mg/ml protein, 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4 U/ml glucose-6- phosphate dehydrogenase, 3.3 mM magnesium chloride and 120 ⁇ M testosterone in 100 mM potassium phosphate (pH 7.4) will be incubated at 37 °C for 30 min.
- a known quantity of 11 ( ⁇ ) - hydroxytestosterone will be added as an internal standard to correct for recovery during extraction.
- the reaction mixture will be extracted with 1 ml methylene chloride. The extract will be dried over anhydrous magnesium sulfate and evaporated under vacuum.
- the sample will be dissolved in methanol and injected into a 4.6 x 250 mm 5u C18 HPLC column and separated at 50°C with a mobile phase ethanol/water at a flow rate of 1 ml per min.
- the retention times are approximately 6 min for the 6 ( ⁇ ) -hydroxy, 8 min for 11 ( ⁇ ) -hydroxy and 12 min for testosterone.
- the product and internal standard are detected by their absorbance at 254 nm and quantitated by correcting for the extraction efficiency using the absorbance of the 11 ( ⁇ ) -hydroxy peak and comparing to the absorbance of a standard curve for 6 ( ⁇ ) -hydroxytestosterone.
- the concentration of 6 ( ⁇ ) - hydroxytestosterone metabolite in each replicate incubation is determined and the percentage inhibition relative to solvent control is calculated.
- the ic 50 is calculated by linear interpolation.
- a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1 to 100 5 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
- a mixture of active ingredient in a digestible oil such as soybean oil, lecithin, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 1 15 to 100 milligrams of the active ingredient.
- the capsules are washed and dried.
- Tablets 20 A large number of tablets are prepared by conventional procedures so that the dosage unit was 1 to 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 25 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2974096P | 1996-11-12 | 1996-11-12 | |
US29740P | 1996-11-12 | ||
PCT/US1997/020290 WO1998020876A1 (en) | 1996-11-12 | 1997-11-11 | Use of cis-hydroxyitraconazole in order to avoid side-effects of itraconazole and hydroxyintraconazole |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0942725A1 true EP0942725A1 (en) | 1999-09-22 |
Family
ID=21850627
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97946574A Withdrawn EP0942725A1 (en) | 1996-11-12 | 1997-11-11 | Use of cis-hydroxyitraconazole in order to avoid side-effects of itraconazole and hydroxyintraconazole |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0942725A1 (en) |
JP (1) | JP2001504119A (en) |
CN (1) | CN1244125A (en) |
AU (1) | AU715999B2 (en) |
CA (1) | CA2271849A1 (en) |
WO (1) | WO1998020876A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6147077A (en) * | 1999-04-29 | 2000-11-14 | Sepracor Inc. | 2R,4S-hydroxyitraconazole isomers |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ249494A (en) * | 1992-03-18 | 1996-04-26 | Janssen Pharmaceutica Nv | Itraconazole and saperconazole stereoisomers; pharmaceutical compositions |
WO1994016701A1 (en) * | 1993-01-27 | 1994-08-04 | Sepracor, Inc. | Methods and compositions of (2s,4r) itraconazole for treating fungal yeast and dermatophyte infections |
CA2154777A1 (en) * | 1993-01-27 | 1994-08-04 | Nancy M. Gray | Method and composition employing (2r,4s) itraconazole |
-
1997
- 1997-11-11 WO PCT/US1997/020290 patent/WO1998020876A1/en not_active Application Discontinuation
- 1997-11-11 CN CN 97181244 patent/CN1244125A/en active Pending
- 1997-11-11 JP JP52268598A patent/JP2001504119A/en active Pending
- 1997-11-11 AU AU51720/98A patent/AU715999B2/en not_active Ceased
- 1997-11-11 EP EP97946574A patent/EP0942725A1/en not_active Withdrawn
- 1997-11-11 CA CA002271849A patent/CA2271849A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9820876A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2271849A1 (en) | 1998-05-22 |
AU5172098A (en) | 1998-06-03 |
JP2001504119A (en) | 2001-03-27 |
WO1998020876A1 (en) | 1998-05-22 |
AU715999B2 (en) | 2000-02-17 |
CN1244125A (en) | 2000-02-09 |
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