Itraconazole

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P270：Bei Gebrauch nicht essen, trinken oder rauchen.

  P301+P312：BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM/Arzt/... (geeignete Stelle für medizinische Notfallversorgung vom Hersteller/Lieferanten anzugeben) anrufen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Itraconazole Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
  R36/38:Reizt die Augen und die Haut.
  R22:Gesundheitsschädlich beim Verschlucken.

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  Itraconazole is an orally-active triazole antifungal indicated for use in the treatment of dermal, vaginal and systemic mycoses. In immunocompromised and AIDS patients, itraconazole has been shown to significantly reduce the incidence of relapses of cryptococcal meningitis.

• Chemische Eigenschaften

  Off-White Crystalline Solid

• Originator

  Janssen (Belgium)

• Verwenden

  A traizole antifungal agent

• Verwenden

  For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.

• Verwenden

  vitamin, enzyme cofactor

• Verwenden

  Anti-infective

• Verwenden

  An orally active antimycotic structurally related to Ketoconazole. Antifungal

• Verwenden

  Anti Fungal. Used in the treatment of stomach upset/ indigestion and other gastrointestinal conditions

• Verwenden

  Itraconazole is a triazole antifungal agent. It is used to inhibit cytochrome P-450-dependent enzymes and ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. It?s different formulations are used to study Candida strains in murine invasive infections. It has been used to study proliferative changes of the forestomach mucosa in alloxan-induced diabetic rats..

• Indications

  Itraconazole (Sporanox) is effective in the treatment of histoplasmosis, blastomycosis, candidiasis, and dermatophyte infection. Its efficacy in the treatment of tinea capitis in children is equal to griseofulvin, and it is usually better tolerated (21). It is metabolized by the cytochrome P-450 system and may increase the levels ofwarfarin, cyclosporine, and digoxin among others. Its use is contraindicated with certain medications.
  Itraconazole (Sporanox) is a triazole antifungal that is related to the imidazole ketoconazole. Similar to ketoconazole, it interferes with ergosterol synthesis and cell membrane integrity. It is clinically active against dimorphic fungi, yeast, dermatophytes, Blastomycetes, histoplasmosis, sporotrichosis, and Aspergillus. Itraconazole is a potent inhibitor of the cytochrome P450 3A enzyme system, which may elevate blood levels of other drugs metabolized by this system if taken concomitantly. Itraconazole levels may decrease in patients who are concurrently taking rifampin, phenobarbital, or phenytoin. Cyclosporine, felodipine, digoxin, warfarin, and oral hypoglycemic levels may increase when given in conjunction with itraconazole. Itraconazole, like ketoconazole, is contraindicated in patients taking cisapride. Itraconazole may induce torsades de pointes, ventricular arrhythmias, and congestive heart failure.

• Definition

  ChEBI: Itraconazole is an N-arylpiperazine that is cis-ketoconazole in which the imidazol-1-yl group is replaced by a 1,2,4-triazol-1-yl group and in which the actyl group attached to the piperazine moiety is replaced by a p-[(+-)1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl group. A potent P-glycoprotein and CYP3A4 inhibitor, it is used as an antifungal drug for the treatment of various fungal infections, including aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and sporotrichosis. It has a role as a P450 inhibitor, an EC 3.6.3.44 (xenobiotic-transporting ATPase) inhibitor and a Hedgehog signaling pathway inhibitor. It is a member of triazoles, a dioxolane, a N-arylpiperazine, a dichlorobenzene, a cyclic ketal, a conazole antifungal drug, a triazole antifungal drug and an aromatic ether.

• Manufacturing Process

  Synthesis of cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4- dihydro-2-(methylpropyl)-3H-1,2,4-triazol-3-one is showed by the same procedure as for cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1- ylmethyl)-1,3- dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one described in the patent.
  A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with trichloromethane. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; melting point 195.1°C.
  A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at 20°C with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N,N-dimethylacetamide. Product is filtered off and crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4- methoxyphenyl)-1-piperazinyl]benzenamine; melting point 191.8°C.
  A mixture of 30 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and 300 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 10 days. The reaction mixture is evaporated and the residue is alkalized with sodium hydroxide. The mixture is filtered and the filtrate is acidified with acetic acid. The precipitated product is filtered off and crystallized from 1,4-dioxane, yielding 12 parts (44%) of 2,4-dihydro-4-{4-[4- (4-hydroxyphenyl)-1-piperazinyl]phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol- 3-one.
  To a stirred solution of 2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl] phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one in 100 parts of dimethyl sulfoxide are added 0.3 parts of sodium hydride dispersion 78% and the whole is stirred at 50°C till foaming has ceased. Then there are added 3.7 parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3- dioxolan-4-ylmethyl]methanesulfonate and stirring is continued for 3 hours at 100°C. The reaction mixture is cooled and poured onto water. The product is extracted with dichloromethane. The extracts are washed with a diluted sodium hydroxide solution and filtered. The residue is crystallized from 1- butanol. The product yield 4.3 parts (75%) of cis-4-{4-[4-{4-[2-(2,4- dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy] phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-(methylpropyl)-3H-1,2,4-triazol- 3-one.

• Trademarks

  Sporanox (Janssen).

• Therapeutic Function

  Antifungal

• Antimicrobial activity

  The spectrum includes dermatophytes, dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Penicillium marneffei and Spor. schenckii), molds (including Aspergillus spp.), dematiaceous fungi and yeasts (Candida spp. and Cryptococcus spp.).

• Acquired resistance

  This is uncommon, but fluconazole-resistant C. albicans and C. glabrata are often cross-resistant to itraconazole. There are reports of itraconazole-resistant strains of A. fumigatus.

• Allgemeine Beschreibung

  Itraconazole is an antifungal drug prescribed for oral or intravenous treatment of fungal infections. The drug is sold under trade names such as Sporanoxor Onmel^?. This Certified Spiking Solution^? is suitable as starting material for calibrators, controls, or linearity standards for clinical and diagnostic testing or therapeutic drug monitoring of itraconazole in patient blood, serum, or plasma samples by LC-MS/MS or HPLC.

• Pharmazeutische Anwendungen

  A synthetic dioxolane triazole available for oral or parenteral administration.

• Biochem/physiol Actions

  Itraconazole inhibits cytochrome P-450-dependent enzymes which results in the inhibition of ergosterol synthesis. It does so by interacting with 14-α demethylase, which is a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. Ergosterol is a crucial compenent of fungal cell membranes. Therefore, it′s inhibition results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and phospholipid biosynthesis.

• Pharmakokinetik

  Oral absorption: 30% (capsules); 55% (solution)
  C_max 100 mg oral: 0.1–0.2 mg/L after 2–4 h
  Plasma half-life: 20–30 h
  Volume of distribution: 11 L/kg
  Plasma protein binding: >99%
  Absorption
  Absorption is improved if the drug is given with food or an acidic beverage. In contrast, absorption is reduced if it is given together with compounds that reduce gastric acid secretion. Higher concentrations are obtained with repeated dosing, but there is much individual variation. Incorporation into a solution of hydroxypropyl-β-cyclodextrin enhances bioavailability and leads to much higher blood levels in neutropenic individuals and persons with AIDS. This formulation is better absorbed if given without food. Increases in dosage produce disproportionate changes in blood concentrations.
  Distribution
  Levels in the CSF are low, but concentrations in lung, liver and bone are 2–3 times higher than in serum, and concentrations in the genital tract are 3–10 times higher. High concentrations are also found in the stratum corneum, as a result of drug secretion in sebum. The drug persists in the skin and nails for weeks to months after treatment is discontinued.
  Metabolism and excretion
  It is degraded by the liver into a large number of (mostly inactive) metabolites which are excreted with the bile and urine. Itraconazole is unusual because the major metabolite, hydroxyitraconazole, is bioactive and has a similar spectrum of activity as the parent compound. In the steady state, this metabolite is found at serum concentrations about two-fold higher than those of the parent drug. About 80–90% of the intravenous carrier, hydroxypropyl-β-cyclodextrin, is excreted unchanged in the urine. No adjustment of dosage is required in hepatic or renal failure, or during hemodialysis or peritoneal dialysis.

• Clinical Use

  Aspergillosis
  Systemic mycoses with dimorphic fungi (blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, penicilliosis) Subcutaneous mycoses (chromoblastomycosis, sporotrichosis)
  Mucosal and cutaneous candidosis.
  Dermatophytosis
  Phaeohyphomycosis
  Pityriasis versicolor

• Nebenwirkungen

  Unwanted effects are more common with oral solution than with capsules, and are more severe. They include nausea, abdominal discomfort, dyspepsia, diarrhea, headache, pruritus and skin rash. Rare side effects include Stevens–Johnson syndrome, transient abnormalities of liver enzymes, reversible idiosyncratic hepatitis and hypokalemia.
  Intravenous itraconazole has been associated with congestive heart failure. Neither intravenous nor oral itraconazole should be used to treat infections in patients with evidence of ventricular dysfunction unless the expected benefit clearly exceeds the risk. Patients with risk factors for congestive heart failure should be treated with caution and their condition monitored.

• Veterinary Drugs and Treatments

  Itraconazole may have use in veterinary medicine in the treatment of systemic mycoses, including aspergillosis, cryptococcal meningitis, blastomycosis, and histoplasmosis. Itraconazole is probably more effective than ketoconazole, but is significantly more expensive. It may also be useful for superficial candidiasis or dermatophytosis，Itraconazole does not have appreciable effects (unlike ketoconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals.
  It is considered by many to be the drug of choice for treating blastomycosis, unless moderate or severe hypoxemia is present (than amphotericin B).
  In horses, itraconazole may be useful in the treatment of sporotrichosis and Coccidioides immitis osteomyelitis.

• in vitro

  itraconazole was metabolized into hydroxy-itraconazole (oh-itz), a known in vivo metabolite of itz, and two new metabolites: keto-itraconazole (keto-itz) and n-desalkyl-itraconazole (nd-itz). itraconazole was a substrate for cyp3a and to characterize the metabolites generated. itraconazole exhibited an unbound km of 3.9 nm for cyp3a. itraconazole metabolites are as potent as or more potent cyp3a4 inhibitors than itz itself [1]. itraconazole was pharmacologically distinct from other azole antifungal agents. itraconazole has been shown to inhibit both the hedgehog signaling pathway and angiogenesis [2] itraconazole was active against 60 clinical isolates of aspergillus spp. with geometric mean (gm) mics of 0.25 mg/ml [3]. itraconazoleshowed an affinity for mammalian cytochrome p-450 enzymes as well as for fungal p-450-dependent enzyme, and thus has the potential for clinically important interactions [4].

• in vivo

  oral administration of itraconazole (200 mg) once daily for 4 days increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase [5].

• Lager

  Store at -20°C

• Einzelnachweise

  1) Vanden Bossche?et al.?(1993),?Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans; Antimicrob. Agents Chemother.,?37?2101 2) Liu?et al.?(2014),?Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking; Autophagy,?10?1241 3) Kim?et al. (2010),?Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth; Cancer Cell,?17?388 4) Nacev?et al. (2011),?The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells; J. Biol. Chem.,?286?44045

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