Ketoconazole 65277-42-1

History

Ketoconazole was discovered in 1976 and released in 1981. It followed griseofulvin as one of the first available oral treatments for fungal infections.

Usage

Ketoconazole is usually prescribed for topical infections such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), and jock itch. The over-the-counter shampoo version can also be used as a body wash for the treatment of tinea versicolor. Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma. The side-effects of ketoconazole are sometimes used to treat non-fungal problems. The decrease in testosterone caused by the drug makes it useful for treating prostate cancer and for preventing post-operative erectionsfollowing penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease. These side effects have also been studied for use in reducing depressive symptoms and drug addiction; however, it has not succeeded in either of these roles. Ketoconazole can be prescribed as a 200 mg pill, a 2% cream, a 2% gel,a 2% foam,or 2% shampoo for the treatment of dandruff or seborrhoeic dermatitis, or as a 1% over-the-counter shampoo (Perkhotal) & (Nizoral). However, 2% shampoo is sold over-the-counter in many countries as well. Ketoconazole is also available as a topical mousse marketed under the brand name Ketomousse. In clinical studies, this preparation proved to be a superior mechanism of delivery to the shampoo. Currently it is only available in Europe. The anti-dandruff shampoo is designed for people who have a more serious case of dandruff where symptoms include, but are not limited to constant non-stop flaking, and severe itchiness. It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis in high dosages. Until recently, there were two human test cases on record (both during the treatment of Cushing's syndrome) and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole. This medication is also sometimes prescribed by veterinarians for use on pets, often as 200 mg unflavored tablets that may need to be cut to smaller size for correct dosage.

Mechanism of action

As an antifungal, ketoconazole is structurally similar to imidazole and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole and itraconazole are required to kill fungi, compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes. As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e. g. 400 mg 3x/day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. Ketoconazole produces this effect through inhibition of cytochrome P450 and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used as a treatment for androgen-dependent prostate cancer. Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and DHT for androgen receptor binding. This effect is thought to be quite weak, even with high oral doses of ketoconazole.

Sensitive fungi

Ketoconazole inhibits growth of dermatophytes and yeast species such as Candida albicans. The rise in the number of HIV/AIDS immune compromised patients has led to an increase in the frequency and significance of opportunistic fungal infections. Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including C. albicans. Experimentally resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-Resistance Genes (MDR) can also play a role in reducing cellular levels of the drug. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family.

Hair loss benefits

A study in mice indicated that ketoconazole may have a stimulatory effect on hair growth. Nizoral shampoo has shown to be beneficial in men suffering from androgenic alopecia. One 1998 study showed that Nizoral 2% worked just as well as minoxidil 2% (brand name Rogaine) in men with androgenic alopecia. Both medicines increased hair thickness and increased the number of anagen-phase hair follicles on the scalp. Researchers were guarded about the meaning of these results, saying that more rigorous studies on larger groups of men should be done to confirm the findings, both to evaluate the ideal dosage and formulation, and to assess the desirability of routine treatment in this condition. Nizoral Shampoo is only FDA approved for the treatment of dandruff and seborrheic dermatitis of the scalp, so although Nizoral may be useful as a hair loss remedy, it cannot be endorsed or marketed as one to the general public. As dihydrotestosterone (DHT) has been found to be the trigger and ongoing factor of male pattern baldness (MPB), ketoconazole's androgen receptor antagonist activity against this hormone in the hair follicles of the scalp is likely to be the major contributor. Results so far indicate that both the 1% and 2% dosages have hair loss benefits; however, the more potent 2% formulation could have better results. Excessive usage of either formulation has not been shown to produce better results. The results produced in these studies are based on usage once every third day and leaving the shampoo on the scalp for 3–5 minutes before rinsing, as with the treatment of dandruff and seborrheic dermatitis. It has been stated that medications capable of maintaining the existing hair population should be regarded as effective treatments for androgenic alopecia. The present data suggest that ketoconazole should enter this group of drugs.

Synthesis

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