AU715999B2 - 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 hydroxyintraconazole Download PDFInfo
- Publication number
- AU715999B2 AU715999B2 AU51720/98A AU5172098A AU715999B2 AU 715999 B2 AU715999 B2 AU 715999B2 AU 51720/98 A AU51720/98 A AU 51720/98A AU 5172098 A AU5172098 A AU 5172098A AU 715999 B2 AU715999 B2 AU 715999B2
- Authority
- AU
- Australia
- Prior art keywords
- hydroxyitraconazole
- cis
- infection
- pharmaceutically acceptable
- amount
- 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.)
- Ceased
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- A—HUMAN NECESSITIES
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Description
WO 98/20876 PCT/US97/20290 USE OF CIS-HYDROXYITRACONAZOLE IN ORDER TO AVOID SIDE-EFFECTS OF ITRACONAZOLE AND
HYDROXYINTRACONAZOLE
1. TECHNICAL FIELD The invention relates to methods of treatment using cishydroxyitraconazole, a metabolic derivative of cisitraconazole 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-1ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-lpiperazinyl)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: NN
OR
N
wherein R is a hydrogen, or -SO 3
H.
2. BACKGROUND OF THE INVENTION 2.1 Itraconazole And Hydroxyitraconazole Itraconazole, a compound having the formula C 35
H
38 gC 2
N
8 0 4 is a synthetic antifungal agent sold commercially as SPORANOX®. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three WO 98/20876 PCT/US97/20290 chiral centers. Itraconazole is an orally active5 broadspectrum anti-fungal agent and is structurally related to miconazole and clotrimazole.
Following oral administration, itraconazole is slowly absorbed. Peak plasma levels are attained after 15 days of daily administration, and the pharmacokinetic behavior of itraconazole is non-linear. The compound is eventually metabolized through the biologically active hydroxyitraconazole to several inactive metabolites.
Metabolism is apparently through hepatitic mechanisms, and in most subjects no metabolites are excreted through the urine.
See Hardin et al., Antimicro. Agents and Chemotherapy, 32:1310-1313 (1988).
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 P450dependent synthesis of ergosterol, which is a key component in fungal cell membranes. This generally results in an increased permeability and leakage of intracellular content.
At high concentration, cellular internal organelles involute, peroxisomes increase, and necrotic changes may occur.
Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Cryptococcus neoformans, as well as sporadic activity against other fungal species.
The co-administration of itraconazole with cisapride, terfenadine or astemizole, is contraindicated. Possible contraindications of the administration of itraconazole include: idiosyncratic hepatitis, cardiac dysrhythmia, and, in one instance, death. As oral midazolam or triazolam have also resulted in increased plasma concentrations when administered with itraconazole, those agents should not be used in conjunction with itraconazole.
Itraconazole is also a potent inhibitor of CYP3A4, which is responsible for the metabolism of many drugs including 2 WO 98/20876 PCT/US97/20290 Lovastatin. It has recently been reported-that'itraconazold 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. (See, for example, Mikami et al., "In Vitro Antifungal Activities of Hydroxy-Itraconazole, An Active Metabolite of Itraconazole," Chemotherapy, 42:290-296 (1994)). U.S. Patent No. 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, Ed. Medical Economics Data Production Co., 1996).
It has also been reported that itraconazole is generally more potent than hydroxyitraconazole against fungal infection.
(See, for example, Mikami et al., "In Vitro Antifungal Activities of Hydroxy-Itraconazole, An Active Metabolite of Itraconazole," Chemotherapy, 42:290-296 (1994)). No correlation between in vitro minimum inhibitory concentrations and clinical data, however, has been established for azole antifungal agents. Both hydroxyitraconazole and itraconazole are inhibitors of the cytochrome P450 3A4 enzyme system. Thus, co-administration of either with drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations that could increase or prolong both therapeutic and adverse effects, such as arrhythmias.
3 _1 WO 98/20876 PCT/US97/20290 (Neuvoneb and Jalava, "Itraconazole Drastically increases Plasma Concentrations of Lovastatin and Lovastatin Acid," Clin. Pharmaco. Ther., 60(1):54-61 (July, 1996) (lovastatin); Honig et al., J. Clin. Pharmacol., 33:1201-1206 (1993) (interaction with terfenadine)).
The use of 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.
In an effort to circumvent the shortcomings of itraconazole, 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.
It is also known that certain drugs, such as ketoconazole and/or erythromycin, interfere with cytochrome P450, and thereby inhibit the metabolism of anti-infectious or anti-inflammatory compounds, such as itraconazole. There exists a greater potential for adverse interaction between itraconazole or other anti-infectious or anti-inflammatory drugs known to inhibit cytochrome P450, because of the interference with the itraconazole metabolism.
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 4 f WO 98/20876 PCT/US97/20290 and beta adrenergic blocking agents. Stevens and Wrighton, J. Pharm. Exp. Therap. 266(2):964-971 (1993). The inhibition of drug metabolism by itraconazole presents an important limitation to its clinical use because it has a potential to alter the metabolism and pharmacokinetics of sequentially administered or co-administered drugs. As a result, this drug interaction limits the safe use of itraconazole and certain other drugs when given sequentially or concurrently administered with itraconazole. (See Physician's Desk Reference®, pp. 1305-1307, 50th Ed. Medical Economics Data Production Co., 1996).
2.2 Secondary Infections And Fungal Diseases Systemic fungal diseases (systemic mycoses) 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. For example, 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. Similarly, blastomycosis primarily involves the lungs, and occasionally spreads to the skin.
Other 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 5 WO 98/20876 PCT/US97/20290 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 mucosa 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. These adverse effects include, but are not limited to, nausea, vomiting, anemia, thrombocytosis, hypersensitivity reactions, hepatotoxicity and some central nervous system toxicity. The racemic mixture of itraconazole has been found to cause nausea and vomiting, anorexia, headache, and dizziness.
Hepatotoxicity and hypersensitivity reactions including urticaria and elevations in serum liver enzymes are also associated with the administration of the drug.
Hepatotoxicity is a less common but more serious adverse effect. Indeed, the use of oral conazoles as a first line antifungals is usually discouraged because of the potentially serious consequences of the low incidence of hepatotoxicity.
(See, for example, Lavrijsen et al., Lancet 340:251-252 (1992)).
6 WO 98/20876 PCT/US97/20290 2.3 Secondary Infections Of The CNS Often in immunocompromised patients, particularly
HIV
infected patients, secondary infections take root in the brain or other parts of the central nervous system These types of infections are quite difficult to treat because of the inability of active agents to cross the blood brain barrier and to penetrate the CNS. Further, drugs that can effectively or ineffectively penetrate the blood brain barrier often lead to CNS toxicity. Clearly, there is a need for an active agent having significant antimicrobial or antifungal activity and the ability to cross the blood brain barrier without causing significant toxicity.
Although some predictions have been made concerning the ability of molecules to pass through the blood brain barrier, these predictions are at best speculative. The rate and extent of entry of a compound into the brain are generally considered to be determined primarily by partition coefficient, ionization constant(s) and molecular size. No single partition solvent system has emerged as a universally applicable model for brain penetration, although the octanol water system has received particular attention, and Hansch and coworkers have suggested that a partition coefficient in this system of about 100 is optimal for entry into the CNS.
(Glave and Hansch, J. Pharm. Sci. 61:589 (1972); Hansch et al., J. Pharm. Sci., 76:663 (1987)). However, optimizing the structure of a compound to improve brain penetration may lead to reduced efficacy. Thus, it is fundamentally difficult to optimize both blood brain barrier permeability and function of a compound.
Many factors must be taken into consideration in developing a pharmaceutical, particularly an antifungal agent that will often be used in a therapeutic regimen with other therapies. For example, physical properties for formulating the drug, bioavailability, potency, drug interaction, drug metabolism, toxicity and the like. The relative polarity and insolubility of itraconazole renders it difficult to prepare in a parenteral solution. Additionally, since itraconazole 7 WO 98/20876 PCT/US97/20290 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.
It is particularly desirable to develop 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.
3. SUMMARY OF THE INVENTION It has now been discovered that 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.
The use of 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 8 WO 98/20876 PCT/US97/20290 the administration of'compounds such as itraconazole. Such 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 cishydroxyitraconazole, 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 cishydroxyitraconazole, 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 cishydroxyitraconazole, 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 9 WO 98/20876 PCT/US97/20290 Staphylococcus hemolyticus, or a Streptococci such as Streptococcus pyogenes; and Tungal, yeast, and dermatophyte infections including, but not limited to, Aspergillosis, Aspergillus fumigatus, Blastomycosis, Blastomyces dermatitides, Candidasis and Oral Candidasis (thrush), Candida albicans, Candida tropicalis, Coccidioidomycosis, Cryptococcosis, Cryptococcus neoformans, Ctenomyces mentagrophytes, Histoplasmosis, Microsporum canis, Mucor species, Onychomycosis, Paracoccidioides brasiliensis, Phialophora verrucosa, Pityrosporum ovale, Saprolegnia species, Sporotricum schenckii, Sporothrix schenckii, Trichophyton mentagrophytes, and Trichophyton rubrum.
The invention further relates to pharmaceutical compositions for the treatment of a human which comprise a pharmaceutically acceptable carrier and a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
The amount of cis-hydroxyitraconazole in a composition is typically from about 50 mg to about 1200 mg, but in a 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: 10 WO 98/20876 PCT/US97/20290 W N/ I\ SN
N
oOR
N
wherein R is selected from the group consisting of hydrogen,
(OH)
2
-SO
3 H, or a salt thereof. There are four asymmetric carbons in the chemical structure of these compounds (denoted by asterisks): two on the sec-butyl sidechain on the triazolone and two on the dioxolane ring. In particular, these compounds are beneficial in treating fungal infections of the brain in immunocompromised patients, particularly HIV infected patients.
The invention further includes methods of treating candidiasis infection of the central nervous system in a human by administering to a human a therapeutically effective amount of a compound of the formula:
CI
0 N N /N 'I "N o S--N OR
N
wherein R is hydrogen,
(OH)
2 -SO3H, or a pharmaceutically acceptable salt thereof. In one embodiment, the infection to be treated is found in the brain. In a 11 WO 98/20876 PCT/US97/20290 preferred embodiment, interaction between cishydroxyitraconazole 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.
4. DETAILED DESCRIPTION OF THE INVENTION 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 in need of such therapy an effective amount of cishydroxyitraconazole, or a pharmaceutically acceptable salt thereof. In particular, the invention encompasses the use of a compound of the formula: CI
/N
wherein R is -PO(OH) 2 -S0 3 H, or a salt thereof. These derivatives of cis-hydroxyitraconazole are particularly advantageous for their ability to penetrate the CNS, or to 12 WO 98/20876 PCTIUS97/20290 cross the blood brain barrier and inhibit-fungal infection by selectively inhibiting fungal CP450 interactions over human CP450 interactions.
The present invention further includes pharmaceutical compositions for the treatment or prevention of the abovementioned 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.
As stated above, 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 compositions containing these isomers, or mixtures thereof, for the claimed methods of treatment.
It has been found that when cis-hydroxyitraconazole, or a pharmaceutically acceptable salt or stereoisomer thereof, as compared to itraconazole, is administered to a human in need of anti-infectious or anti-inflammatory therapy, it advantageously: avoids the concomitant liability of cardiac side effects associated with prolonged QT interval, imparts increased potency, increased bioavailability, improved transport across the blood brain barrier, decreased cytochrome P450 based drug-enzyme interactions, decreased hepatotoxicity, and stronger interactions with fungal cytochrome P450 than with human cytochrome P450.
It is believed that administering cishydroxyitraconazole in the present methods of treatment permits the treating physician to more readily use other therapeutics concurrently with or sequentially with cishydroxyitraconazole therapy. This allows a better overall 13 WO 98/20876 PCT/US97/20290 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. Not only does this invention permit the treating physician to intervene sooner with the sequential administration of another drug following cishydroxyitraconazole 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 clshydroxyitraconazole 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 cotherapy. Thus, other drugs, such as antidepressants, antiarrhythmics, antihistamines, antibiotics, antifungal agents, and others described herein can be used sequentially or in with cis-hydroxyitraconazole.
It has, thus, been found that when cishydroxyitraconazole is concurrently administered with a drug that inhibits or is metabolized by cytochrome P450 including, but not limited to, ketoconazole, cisapride, lovastatin, terfenadine, fluoxetine, astemizole, loratadine, midazolam, triazolam, and others known by those skilled in the art, the interaction with said drug is decreased in comparison to the concurrent administration of cis-itraconazole with said drug.
Therefore, this invention also encompasses a method of avoiding drug interaction with the cytochrome P450 system, while treating microbial infection 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.
The term "adverse effects" or "adverse side effects" includes, but is not limited to, abnormal hepatic function; hepatotoxicity; cardiac dysrhythmias; cardiac side effects 14 WO 98/20876 PCT/US97/20290 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. The term "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.
The phrase "therapeutically effective amount" means that amount of cis-hydroxyitraconazole that provides a therapeutic benefit in the treatment or management of infection and other disorders.
The term "anti-infective" includes, but is not limited to, anti-bacterial, anti-microbial, anti-fungal, anti-yeast, and anti-dermatophyte, or combinations thereof. The term "infection" includes bacterial infection, microbial infection, fungal infection, yeast infection, and dermatophyte infection, or combinations thereof.
The magnitude of 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. In general, the total daily dose range, for the conditions described herein, is from about 0.1 mg to less than about mg administered in single or divided doses orally, topically, transdermally, or locally by inhalation. For 15 WO 98/20876 PCT/US97/20290 example, 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.
It is further recommended that children, patients aged over 65 years, and those with impaired renal or hepatic function initially receive low doses, and that they then be titrated based on individual response(s) or blood level(s).
It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those of ordinary skill in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The terms "therapeutically effective amount of cishydroxyitraconazole 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 cishydroxyitraconazole according to the methods of the present invention. For example, 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.
The pharmaceutical 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.
The term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids.
16 WO 98/20876 PCT/US97/20290 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. Examples of such 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.
The 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. The most preferred oral solid preparations are tablets.
Because of their ease of administration, 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.
In addition to the common dosage forms set out above, 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, 17 WO 98/20876 PCTIUS9720290 the disclosures of which are hereby incorporated by reference.
Pharmaceutical 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 nonaqueous 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.
In general, 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.
For example, a tablet may be prepared by compression or 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. Desirably, each tablet contains from about 0.1 mg to less than about 10 mg of the active ingredient, and each cachet or capsule contains from about 0.1 mg to about less than 10 mg of the active ingredient, cishydroxyitraconazole.
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.
18 WO 98/20876 PCT/US97/20290 With respect to 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 gg/ml) against a number of fungi and bacteria. (See Van Cutsem, Chemotherapy 38 Suppl. 1:3-11 (1992) and Van Cutsem et al., Rev. Infect. Dis. 9 Suppl. 1:S15-S32 (1987)). The fungistatic assay is carried out in Sabouraud's liquid (1 g of neopeptone Difco and 2 g of glucose Difco per 100 mL of distilled water) in 16x160 mm test tubes, each containing mL of liquid medium which has been autoclaved at 120 0 C for 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. To tubes containing 4.5 mL of Sabouraud's liquid medium 0.5 mL of the solution of the drug is added, thereby obtaining concentrations of 1000, 500, 100, and 1 gg/mL of medium. Control tubes are prepared by adding 0.5 mL of distilled water to 4.5 of mL medium, alcohol being added to give concentrations identical with the tubes containing 1000 and 500 ig of the drug. The filamentous fungi are incubated in Sabouraud's agar at 25 0 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 0 C for 14 days. Hydroxyitraconazole antifungal activity is enhanced in vitro in Sabouraud broth containing 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 canis, Trichophyton mentagrophytes, Candida albicans, Sporothrix schenckii, Paracoccidioides brasiliensis, Blastomyces dermatitides, Histoplasma spp., Aspergillus spp. and other fungi and bacteria.
Concentration/response curves may be compared for 19 WO 98/20876 PCT/US97/20290 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 ug 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. In similar studies, the activity against cutaneous candidosis in guinea pigs (Van Cutsem et al., Chemotherapy, 17:392 (1972)) provides the basis of testing compounds of the invention.
The potential for promoting arrhythmia is evaluated by examining the effects of hydroxyitraconazole on cardiac action potential and contractility in human, rabbit and canine hearts.
Torsades de Pointes is a well known side effect of antiarrhythmic 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 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; 20 WO 98/20876 PCT/US97/20290 10.0 or 30'.0 gM of racemic itraconazole. QT duration and action potential duration (APD) are measured from cardiac electrodes. In separate experiments, the hearts are divided into 3 subgroups receiving either itraconazole or hydroxyitraconazole to determine the respective effects on QT duration and APD.
To observe the effects in vivo, 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 gg/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.
The potential for promoting hepatotoxicity is assessed in vitro in human hepatic microsomes, human lymphocytes, and cell culture systems. 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 0 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. The samples are centrifuged, and lymphocytes are then removed from the aqueous-Ficoll interface and suspended in 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-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide (MTT) to a purple formazan. 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 21 -22a concentration range from 1 to 400 pM 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. After the incubation, 125 pg of MTT is added to each well.
The plates are incubated at 370C. and centrifuged. After centrifugation, 100pL of isopropanol is added and, after incubation, the optical density is determined using an automated plate-reader.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions used in the methods of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced which are within the scope of this invention.
Throughout the description and claims of the specification the word 5. "comprise" and variations of the word, such as "comprising" and "comprises", is 15 not intended to exclude other additives, components, integers or steps.
5. EXAMPLES 0 5.1 Example 1 Preparation of cis-itraconazole and itraconazole metabolites Itraconazole can be synthesized by the methods disclosed in an article by Heeres, et al., J. Med. Chem. 27:894-900 (1984), while (2R,4S)-itraconazole oo°o 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-3toxyloxy-1,2-propanediol or S-3-toxyloxy-l,2-propanediol by acid-catalyzed ketalization to provide DTTT.
C:\My Docuentllona\Spd ciel\51720.doc WO 98/20876 PCT/US97/20290 A dioxothiolane is prepared from a butanediol of appropriate configuration by treatment with thionyl chloride, followed by in situ oxidation of the resulting cyclic sulfite with sodium periodate in the presence of ruthenium trichloride.
2,4-dihydro-4-[4-[4-(4-methoxyphenyl)piperazinyl]phenyl]-3H-1,2,4-triazol-3-one, prepared by the method of example XVII in U.S. Patent 4,267,179, is reacted with the dioxothiolane by a modification of the procedure of Gao and Sharpless, J. Am. Chem. Soc. 110:7538 (1988) using potassium hydride in DMF in the presence of crown ether. The resulting methoxy-sulfate salt is cleaved to the phenolalcohol by heating with 48% HBr at 100-110 0
C.
The tosyl ester and the phenol-alcohol are reacted in the presence of potassium hydroxide in DMF to provide the product.
When it is desired that R be sulfate, the order of steps can be rearranged so that the methoxyl of 2,4-dihydro-4-[4- [4-(4-methoxyphenyl)-piperanzinyl]phenyl]-3H-1,2,4-triazol-3one is cleaved before the addition of the residue of the secbutyl side-chain, and instead, the dioxolane DTTT is added first, then the dioxothiolane.
When it is desired that R be phosphate, the methoxysulfate salt may be partially hydrolyzed with 48% HBr at 50 0 C to provide the analog of the phenol-alcohol in which the phenol remains methylated. This is then treated with dibenzyl diisopropylphosphoramidite and t-butylhydroperoxide according to the procedure of PCT application WO 94/17407, which is incorporated herein by reference. The benzyl protecting groups are cleaved by hydrogenolysis in the presence of a palladium catalyst and the product carried through described above.
23 WO 98/20876 PCTS97/20290 5.2 Example 2 Antifunqal Activity Kirbv-Bauer Testing Actively growing cultures of Candida albicans, Cryptococcus neoformens, and Sacchromyces cerevisiae are prepared as described above in the discussion of Van Cutsem, and in U.S. Patent No. 5,474,997. The cultures are diluted to a 0.5 McFarland standard and swabbed onto 150 mm Sabouraud Dextrose agar plates. Paper disks (7 mm) are placed onto the agar plates using a disk dispenser. Next, 10 AL of 10 mg/mL solutions of each sample hydroxyitraconazole are pipetted onto separate paper disks. The plates are then incubated at 300C for 16 hours. Zones of inhibition are then measured in mm as summarized by the following: Compound Candida Cryptococcus Sacchromyces albicans neoformens cerevisae A 22 28 22 B 25 25 2- ±Itraconazole 17 22 Data represent zones of inhibition 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 (100g), which are treated weekly with 100 pg 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. In similar 24 WO 98/20876 PCT/US97/20290 studies, the activity against cutaneous candidosis in guinea pigs provides the basis of comparison. (Van Cutsem et al., Chemotherapy 17:392 (1972)).
5.3 Example 3 Inhibition of cvtochrome P450 This study is conducted to determine the extent that cis-itraconazole and cis-hydroxyitraconazole inhibit human cytochrome P4503A4 (CYP3A4). 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.
Study Design: The inhibition study consists of the determination of the 50% inhibitory concentration (IC0) for the test substance. A single testosterone concentration (120 gM, approximately twice the apparent Km) 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 (f)-hydroxytestosterone metabolite.
This metabolite is readily quantitated via HPLC separation with absorbance detection.
Storage/Preparation of the test substances and addition to the incubations: The 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.
ICC Determination: Final test substance concentrations will be 100, 30, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0 M. Each test 25 WO 98/20876 PCT/US97/20290 concentration will be tested in duplicate incubations in accordance with the method below: Method: 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-6phosphate dehydrogenase, 3.3 mM magnesium chloride and 120 MM testosterone in 100 mM potassium phosphate (pH 7.4) will be incubated at 37 0 C for 30 min. A known quantity of 11(f)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 0 C with a mobile phase methanol/water at a flow rate of 1 ml per min. The retention times are approximately 6 min for the 6(f)-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(0)-hydroxy peak and comparing to the absorbance of a standard curve for Data reporting: For each test substance, the concentration of 6(1)hydroxytestosterone metabolite in each replicate incubation is determined and the percentage inhibition relative to solvent control is calculated. The ICs 5 is calculated by linear interpolation.
Useful pharmaceutical dosage forms for administration of the compounds used in the methods of the present invention can be illustrated as follows: 26 WO 98/20876 PCT/US97/20290 5.4. Example 4 Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1 to 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Example soft Gelatin Capsules 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 to 100 milligrams of the active ingredient. The capsules are washed and dried.
5.6 Example 6 Tablets 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 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. The foregoing disclosure includes all the information deemed essential to enable those skilled in the art to practice the claimed invention. Because the cited patents or publications may provide further useful information these cited materials are hereby incorporated by reference in their entireties.
27
Claims (34)
1. A method of treating or preventing systemic or local bacterial infection in a human while avoiding the concomitant liability of adverse side effects associated with the administration of racemic itraconazole, which comprises administering to said human a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein said adverse side effect is prolonged QT interval, hepatotoxicity or inhibition drug metabolism by the cytochrome P450 pathway.
3. The method of claim 1, wherein the amount of cis- hydroxyitraconazole administered is from about 10 mg to about 500 mg per day.
4. The method of claim 1, wherein the bacterial infection to be treated is Erysipelotric insidiosa, a Staphylococci, or a Streptococci. The method of claim 1, wherein the amount of said cis-hydroxyitraconazole or a pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.
6. The method of claim 1, wherein the infection is found in the central nervous system.
7. The method of claim 6, wherein the infection is found in the brain.
8. A method of treating or preventing systemic or local microbial infection in a human while avoiding the concomitant liability of adverse side effects associated with 28 WO 98/20876 PCT/US97/20290 the administration of itraconazole, which comprises administering to said human a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 wherein, said adverse side effect is prolonged QT interval, hepatotoxicity, or inhibition of drug metabolism by the cytochrome P450 pathway.
10. The method of claim 8, wherein the amount of cis- hydroxyitraconazole administered is from about 1 mg to about 1000 mg per day.
11. The method of claim 10, wherein the amount of cis- hydroxyitraconazole administered is from about 10 mg to about 500 mg per day.
12. The method of claim 8, wherein the amount of said cis-hydroxyitraconazole or a pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.
13. The method of claim 8, wherein the infection is found in the central nervous system.
14. The method of claim 13, wherein the infection is found in the brain. A method of treating or preventing local or systemic fungal, yeast, and dermatophyte infections 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. 29 WO 98/20876 PCT/US97/20290
16. The method of claim 15 wherein, said adverse side effect is prolonged QT interval, hepatotoxicity, or inhibition of'drug metabolism by the cytochrome P450 pathway.
17. The method of claim 15, wherein the amount of cis- hydroxyitraconazole administered is from about 1 mg to about 1000 mg per day.
18. The method of claim 17, wherein the amount of cis- hydroxyitraconazole administered is from about 10 mg to about 500 mg per day.
19. The method of claim 15, wherein the fungal infection is caused by Aspergillosis, Aspergillus fumigatus, Blastomycosis, Blastomyces dermatitides, Candidasis, Candida albicans, Candida tropicalis, Coccidioidomycosis, Cryptococcosis, Cryptococcus neoformans, Ctenomyces mentagrophytes, Histoplasmosis, Microsporum canis, Mucor species, Onychomycosis, Paracoccidioides brasiliensis, Phialophora verrucosa, Pityrosporum ovale, Saprolegnia species, Sporotricum schenckii, Sporothrix schenckii, Trichophyton mentagrophytes, and Trichophyton rubrum. The method of claim 15, wherein the amount of said cis-hydroxyitraconazole or pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.
21. The method of claim 15, wherein the infection is found in the central nervous system.
22. The method of claim 21, wherein the infection is found in the brain.
23. A method of treating or preventing inflammation in a human while avoiding the concomitant liability of adverse side effects associated with the administration of 30 WO 98/20876 PCT/US97/20290 itraconazole, which comprises administering to said human a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
24. The method of claim 23, wherein the amount of cis- hydroxyitraconazole administered is from about 1 mg to about 1000 mg per day. The method of claim 24, wherein the amount of cis- hydroxyitraconazole administered is from about 10 mg to about 500 mg per day.
26. The method of claim 23, wherein the amount of said cis-hydroxyitraconazole or a pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.
27. A pharmaceutical composition for the treatment of a human in need of anti-infective therapy which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of cis-hydroxyitraconazole, or a pharmaceutically acceptable salt thereof.
28. The composition of claim 27, wherein the amount of cis-hydroxyitraconazole is from about 50 mg to about 1200 mg.
29. The composition of claim 27, wherein the amount of cis-hydroxyitraconazole is from about 100 mg to about 1000 mg. The composition of claim 27, wherein the composition is adapted for oral, parenteral or topical administration.
31. A method of treating or preventing infection in the central nervous system which comprises administering to a 31 WO 98/20876 PCT/US97/20290 human a therapeutically effective amount of a compound of the formula: wherein R is selected from the group consisting of hydrogen, -P(O)(OH) 2 or -SO 3 H; or a pharmaceutically acceptable salt thereof.
32. The method claim 31 wherein said infection is a secondary opportunistic microbial infection selected from the group consisting of bacterial, fungal, yeast or dermatophyte infection.
33. The method of claim 32 wherein said infection is found in the brain.
34. A method of treating or preventing infection in a human while avoiding adverse drug interactions which comprises administering a therapeutically effective amount of a compound of the formula: 32 WO 98/20876 PCT/US97/20290 wherein R is selected from the group consisting of hydrogen, (OH)2 or -S03H; or a pharmaceutically acceptable salt thereof. infection comprises effective A method of treating or preventing candidiasis of the central nervous system in a human which administering to a human a therapeutically amount of a compound of the formula: 30 wherein R is selected from the group consisting of hydrogen, -P(0)(OH) 2 or -SO3H; or a pharmaceutically acceptable salt thereof.
36. The method of claim 35 wherein said infection is d in the brain. found in the brain. 33 -34-
37. The method of claim 35, wherein interaction between cis- hydroxyitraconazole and a drug that inhibits cytochrome P450 is avoided.
38. The method of claim 35, wherein the amount of cis- hydroxyitraconazole administered is from about 1 mg to about 1000 mg per day.
39. A method according to any one of claims 1 to 26, or claims 31 to 38, substantially as hereinbefore described with reference to any of the examples.
40. A composition according to any one of claims 27 to 30, substantially as hereinbefore described with reference to any of the examples. DATED: 28 September, 1999 PHILLIPS ORMONDE FITZPATRICK Attorneys for: SEPRACOR INC. 0* •0 **o 0 o C:\My Docmalon aSpiSda\S120doc
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US2974096P | 1996-11-12 | 1996-11-12 | |
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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 |
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AU14775/02A Division AU773405B2 (en) | 1996-11-12 | 2002-02-01 | Hydroxyitraconazole enantiomer mixtures |
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AU (1) | AU715999B2 (en) |
CA (1) | CA2271849A1 (en) |
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JPH08509464A (en) * | 1993-01-27 | 1996-10-08 | セプラコア,インコーポレイテッド | Methods and compositions using (2R, 4S) itraconazole |
AU6098094A (en) * | 1993-01-27 | 1994-08-15 | Georgetown University | Methods and compositions of (2s,4r) itraconazole for treating fungal yeast and dermatophyte infections |
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1997
- 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 JP JP52268598A patent/JP2001504119A/en active Pending
- 1997-11-11 CN CN 97181244 patent/CN1244125A/en active Pending
- 1997-11-11 WO PCT/US1997/020290 patent/WO1998020876A1/en not_active Application Discontinuation
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