Antifungals, azole

The Corey-Chaykovsky reaction incited some applications in medicinal chemistry. During the synthesis of analogs of fluconazole, an azole antifungal agent, treatment of 49 with 1 led to the corresponding epoxide, which was subsequently... 

Aqueous Diels-Alder reaction has also been applied at the industrial level. 2,2,5-Trisubstituted tetrahydrofurans 21 are a class of active azole antifungals. Workers at Schering-Plough [21] developed a synthetic approach based on a Diels-Alder reaction between 2-arylfurans 22 and ethyl acetylenedicarboxylate (Scheme 6.9). Under thermal conditions the reaction gave a low yield of... 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Perea S, JL Lopez-Ribot, WR Kirkpatrick, RK McAtee, RA Santillan, M Martinez, D Calabrese, D Sanglard, TP Patterson (2001) Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antibicrob Agents Chemother 45 2676-2684. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

All azole antifungals carry the potential for rash, photosensitivity, and hepatotoxicity. In general, hepatotoxicity is mild and reversible, presenting as asymptomatic increases in liver transaminases. However, fulminant hepatic failure has been reported with itraconazole. Therefore, serial monitoring of liver function... 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

In the synthesis of 2,2,5-trisubstituted tetrahydrofurans, a novel class of orally active azole antifungal compounds, Saksena95 reported that the key step of Diels-Alder reaction in water led to the desired substrate virtually in quantitative yields (Eq. 12.34), while the same reaction in organic solvent resulted in a complicated mixture with only less than 10% of the desired product being isolated. This success made the target compounds readily accessible. 

Jurima-Romet, M., Crawford, K. et al. (1994). Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab. Dispos., 22(6), 849-57. 

Raab [123] presented a discussion on the topical clinical pharmacology of miconazole and two other azole antifungal agents. 

HIV-infected patients should receive induction therapy with amphotericin B and chronic suppressive therapy with an oral azole antifungal. Itraconazole is the drug of choice for non-life-threatening histoplasmosis. 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

One tab qd on an empty stomach. QT prolongation not reported with azole antifungals or macrolide antibiotics. 

Azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole)... 

Drugs that may affect sulfonylureas include androgens, anticoagulants, azole antifungals, barbiturates, beta blockers, calcium channel blockers, charcoal, chloramphenicol, cholestyramine, ciprofloxacin, clofibrate, corticosteroids, diazoxide, estrogens, ethanol, fluconazole, gemfibrozil, histamine H2 antagonists, hydantoins,... 

Drugs that may affect HMG-CoA reductase inhibitors include alcohol, amiodarone, antacids, azole antifungals, bile acid sequestrants, cimetidine, cyclosporine, diltiazem, erythromycin, gemfibrozil, isradipine, nefazodone, niacin, nicotinic acid, omeprazole, phenytoin, propranolol, protease inhibitors, ranitidine, rifampin, St. John s wort, and verapamil. 

Hepatic metabolism of citalopram and escitalopram occurs primarily through cytochrome P450 3A4 and 2C19 isoenzymes. Inhibitors of 3A4 (eg, azole antifungals, macrolide antibiotics) and 2C19 (eg, omeprazole) would be expected to increase plasma citalopram levels. Inducters of 3A4 (eg, carbamazepine) would be expected to decrease citalopram and escitalopram levels. 

Drugs that may affect SSRIs Drugs that may affect SSRIs include azole antifungals, barbiturates, carbamazepine, cimetidine, cyproheptadine, lithium, macrolides,... 

Drugs that may interact with halopehdol include anticholinergic agents, azole antifungal agents, carbamazepine, lithium, rifamycins, and fluoxetine. 

Ramelteon is affected by alcohol, azole antifungals, fluvoxamine, and rifampin. Drug/Food interactions Ramelteon should not be taken with or immediately after a high-fat meal. 

Drugs that may be affected by proton pump inhibitors include azole antifungal agents (eg, itraconazole, ketoconazole), benzodiazepines, cilostazol, clarithromycin, digoxin, phenytoin, salicylates, sulfonylureas, and warfarin. Drugs that may affect proton pump inhibitors include sucralfate and clarithromycin. 

Hypersensitivity to fluconazole or to any excipients in the product. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents use with caution in patients with hypersensitivity to other azoles. P.986... 

Drugs that may interact with rifabutin include the following Anticoagulants, azole antifungal agents, benzodiazepines, beta blockers, buspirone, corticosteroids, cyclosporine, delavirdine, doxycycline, hydantoins, indinavir, rifamycins, losartan, macrolide antibiotics, methadone, morphine, nelfinavir, quinine, quinidine, theophylline, aminophylline, tricyclic antidepressants, and zolpidem. 

Drugs that may affect ritonavir include clarithromycin, didanosine, azole antifungals, nevirapine, SSRIs, St. John s wort, and rifamycins. 

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