4- Ketoconazole

Trade Name Manufacturer Country Year Introducad 

A solution of 0.7 g of 2-(2-amino-N-methylacetamido)-5-chlorobenzophenone in 10 ml of a 50% solution (by weight) of diketene in acetone is refluxed for 3 hours and then evaporated to give a brown oil. The oil Is chromatographed on 200 g of silica gel using a 1 1 (by volume) mixture of ethyl acetate cyclohexane 25 ml fractions are collected. Fractions 11-14 are combined, mixed with chloroform, evaporated and triturated with ether to give 0.337 g of 11-chloro-8,12b-dihydro-2,8-dimethy 1-12b-phenyl-4H-[ 1,3]oxazino[3,2-dl [1,4] benzodiazepine-4,7 (6H)-dione as a pale yellow solid, MP 174°C to 176°C. 

Chemical Name 1 -Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(1 H-imidazol-1 -ylmethyl)-1,3-di-oxolan-4-yl 1 methoxy] phenyl ] piperazine 

Heeres, J., Backx, L.J.J.and Mostmans, J.H. U.S. Patent 4,144346 March 13,1979 assigned to Janssen Pharmaceutics N.V. (Belgium) 

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Ketoconazole. Initial observations indicating that oral administration of ketocona2ole (10) produced good results in seborrheic ec2ema and dandruff, led to the development of a 2% cream and a 2% shampoo (scalp gel) of this antimycotic (17,18). Naturally, these two topical forms of ketocona2ole [65277-42-1] are highly active against superficial mycoses. 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Ketoconazole is active against dermatophytes (Microsporum, Trichophyton Tpidermophyton) yeasts Candida species, Cyptococcus) and the dimorphous... 

Itraconazole. Itraconazole (18) is a highly lipophilic compound with a triazole stmcture. Compared to ketoconazole, itraconazole has a broader spectmm (including yispergillus spp.) (29,30) and an in vitro activity that is 10 times higher than ketoconazole for most species. 

Because of the outbreak of antimony-resistant leishmania sis and the need to develop an oraky-adrninistered therapy, the use of many other compounds has been considered. Those that appear to have clinical utility ate aHoputinol (62), ketoconazole (63), and both systemicaHy and topically applied paromomycin (8) (see Antiparasitic agents, antimycotics). 

Adrenal endocrine disrupters Aniline dyes Ketoconazole fungicides PCBs... 

Insertion of a triazole ring in place of an imidazole ring is consistent in some cases with retention of antifungal activity. The synthesis of one such agent, azoconazole (64), proceeds simply by displacement of halide with 1,2,4-triazole. The route to terconazole (65) is rather like that to ketoconazole (34). ... 

The imidazoles and triazole ( azoles) (for example, ketoconazole, itraconazole (ITRA), fluconazole (FLU), voriconazole) interfere with cytochrome P45o-dependent lanosterol C14 demethylase, leading to dqDletion of ergosterol and accumulation of lanosterol in the... 

Asternizole, terfenadine Ketoconazole, erythromycin, etc. CYP3A4 Ventricular, arrhythmia... 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Ketoconazole is contraindicated in patients with known hypersensitivity to the drug. Ketoconazole is used cautiously in patients with hepatic impairment, those who are pregnant (Category C), and during lactation. The absorption of ketoconazole is impaired when the drug... 

KETOCONAZOLE This drug is given with food to minimize gastrointestinal irritation. Tablets may be crushed. Ketoconazole is absorbed best in an acid environment. Do not administer antacids, anticholinergics, or histamine blockers until at least 2 hours after ketoconazole is given. 

Ketoconazole Complete die full course of dierapy as prescribed by die primary healdi care provider. 

There is a decreased absorption of lansoprazole when it is administered with sucralfate Lansoprazole may decrease tiie effects of ketoconazole, iron salts, and digoxin. When lansoprazole is administered with theophylline, there is an... 

Oral administration of bicarbonate may decrease the absorption of ketoconazole. Increased blood levels of quinidine, flecainide, or sympatiiomimetics may occur when these agents are administered with bicarbonate There is an increased risk of crystalluria when bicarbonate is administered with the fluoroquinolones. Fbssible decreased effects of lithium, methotrexate, chlorpropamide, salicylates, and tetracyclines may occur when these drag s are administered with sodium bicarbonate. Sodium bicarbonate is not administered within 2 hours of enteric-coated drugs the protective enteric coating may disintegrate before the drug reaches the intestine. 

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