Ketoconazole
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Ketoconazole
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| Systematic (IUPAC) name | |
| 1-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)- 2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy] phenyl]piperazin-1-yl]ethanone |
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| Identifiers | |
| CAS number | |
| ATC code | J02 D01AC08 G01AF11 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C26H28Cl2N4O4 |
| Mol. mass | 531.43 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Variable |
| Protein binding | 84 to 99% |
| Metabolism | Hepatic |
| Half life | Biphasic:
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| Excretion | Biliary and renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral, topical |
Ketoconazole is a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immunocompromised patients such as those with AIDS. Ketoconazole is sold commercially as an anti-dandruff shampoo, branded Nizoral, by Janssen Pharmaceutica.
Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole have largely replaced ketoconazole for internal use. Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption when taken orally.
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[edit] History
Ketoconazole was discovered in 1976 and released in the early 1980s, and was one of the first available oral treatments for fungal infections (griseofulvin was available before ketoconazole).
[edit] Usage
Ketoconazole is usually prescribed for 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[1][2].
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 erections[3] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease.[4] These side effects have also been studied for use in reducing depressive symptoms[5] and drug addiction;[6] however, it has not succeeded in either of these roles.[7][8]
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 (Nizoral). However, 2% shampoo is sold over-the-counter in many countries as well.
Ketocanazole is also available as a topical mousse, using patented Versafoam technology, marketed under the brand name Ketomousse. In clinical studies, the Versafoam 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)[9][10] and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. To remedy this, Drs Kazy, Puhó and Czeizel of the Foundation for the Community Control of Hereditary Diseases in Budapest, Hungary decided to go through the Hungarian Case–Control Surveillance of Congenital Abnormalities, specifically the years 1980 through 1996; that was 22,843 cases and 38,151 controls. There were six infants with congenital abnormalities and twelve infants without whose mothers received ketoconazole. No group of birth defects was preferentially associated with use of ketoconazole.[11]
This medication is also sometimes prescribed by veterinarians for use on pets, often as 200mg unflavored tablets that may need to be cut to smaller size for correct dosage.[12]
[edit] Mechanism of action
Ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as the equivalent mammalian pathway, leading to the biosynthesis of cholesterol, is not sensitive to ketoconazole. However, other mammalian cytochrome P450 enzymes can be sensitive to ketoconazole, and inhibition of steroid hormone synthesis is a possible side effect of ketoconazole treatment.
As with all azole antifungal agents, ketoconazole works principally by inhibition of an enzyme, cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme is in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Fluconazole and itraconazole have been found to have a greater affinity for fungal cell membrane than ketoconazole, and thus lower doses of these azoles are required to kill fungi.
[edit] 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 Candida 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. MDR or multidrug resistance genes 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.
[edit] Hair loss benefits
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.[13]
Results so far indicate that both the 1% and 2% dosages have positive hair loss benefits; however the more potent 2% formulation could have better results. Optimal usage is speculated at every third day, leaving the shampoo on the scalp for 3-5 minutes before rinsing. 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 suggests that ketoconazole should enter this group of drugs.[14]
[edit] References
- ^ http://www.nlm.nih.gov/medlineplus/ency/article/001465.htm#Treatment
- ^ http://www.aad.org/public/publications/pamphlets/common_tinea.html
- ^ Evans, K. C.; A. C. Peterson, H. E. Ruiz and R. A. Costabile (August 2004). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research 16 (4): 346–349. doi:. PMID 14973533.
- ^ Loli, Paola; Maria Elisa Berselli and Mariantonella Tagliaferri (1986). "Use of ketoconazole in the treatment of Cushing's syndrome.". Journal of Clinical Endocrinology & Metabolism 63 (6): 1365-71. PMID 3023421.
- ^ Wolkowitz, Owen M.; Victor I. Reus (1999). "Treatment of Depression With Antiglucocorticoid Drugs". Psychosomatic Medicine 61 (5): 698-711. PMID 10511017.
- ^ Goeders, Nick E.; Rachel L. Peltiera and Glenn F. Guerin (December 1998). "Ketoconazole reduces low dose cocaine self-administration in rats.". Drug and Alcohol Dependence 53 (1): 67-77. doi:. PMID 10933341.
- ^ Malison, Robert T.; Amit Anand, Gregory H. Pelton, Paul Kirwin, Linda Carpenter, Christopher J. McDougle, George R. Heninger and Lawrence H. Price (October 1999). "Limited Efficacy of Ketoconazole in Treatment-Refractory Major Depression.". Journal of Clinical Psychopharmacology 19 (5): 466-470. PMID 10505589.
- ^ Ward, Amie S.; Eric D. Collins, Margaret Haney, Richard W. Foltin and Marian W Fischman (November 1998). "Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.". Behavioural Pharmacology 9 (7): 577-86. PMID 9862083.
- ^ Amado, José Antonio; Carlos Pesquera, Eva M. Gonzalez, Macarena Otero, Julio Freijanes, and Angel Alvarez (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy.". Postgraduate Medical Journal 66 (773): 221-3. PMID 2362890.
- ^ Berwaerts, Joris; Johan Verhelst, Charles Mahler and Roger Abs (June 1999). "Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature.". Gynecological Endocrinology 13 (3): 175-82. PMID 10451809.
- ^ Kazy, Zoltán; Erzsébet Puhó and Andrew E. Czeizel (March 2005). "Population-based case–control study of oral ketoconazole treatment for birth outcomes". Congenital Anomalies 45 (1): 5-8. doi:. PMID 15737124.
- ^ Ketoconazole for Your Pet at Petscriptions
- ^ Nizoral Shampoo for Hair Loss
- ^ http://www.hairlosstalk.com/download/nizoral.pdf
[edit] Brand names
- Nizoral
- Xolegel
[edit] External links
- Janssen Pharmaceutica fungal infections page
- Doctor Fungus ketoconazole page
- Nizoral (manufacturer's website)
- Ketoconazole (patient information)
- Ketoconazole (Up to date product information)
- Study comparing the efficacy of ketoconazole (Nizoral) versus zinc pyrithione (Head & Shoulders)
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