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Ketoconazole
Systematic (IUPAC) name
1-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-
2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-
4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one
Identifiers
CAS number 65277-42-1
ATC code J02AB02 D01AC08 G01AF11
PubChem 47576
DrugBank APRD00401
ChemSpider 401695
Chemical data
Formula C 26H28Cl2N4O4  
Mol. mass 531.431 g/mol
Pharmacokinetic data
Bioavailability Variable
Protein binding 84 to 99%
Metabolism Hepatic
Half life Biphasic:
  • Initial phase: 2 hours
  • Terminal phase: 8 hours
Excretion Biliary and renal
Therapeutic considerations
Pregnancy cat. B3 (Au), C (U.S.)
Legal status OTC (US) POM (UK, oral formulation)
Routes Oral, topical
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Ketoconazole (pronounced /ˌkiːtəʊˈkoʊnəzol/) 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, topical cream, and oral tablet, under the trademark name Nizoral by Johnson & Johnson.

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.

Contents

History

Ketoconazole was discovered in 1976 and released in 1981.[1] 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.[2][3]

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[4] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's disease.[5] These side effects have also been studied for use in reducing depressive symptoms[6] and drug addiction;[7] however, it has not succeeded in either of these roles.[8][9]

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, 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)[10][11] 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. [12]

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.[13]

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.

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)[14] 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

Nizoral 2% shampoo (AU)

A study in mice indicated that ketoconazole may have a stimulatory effect on hair growth.[15] 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 has U.S. Food and Drug Administration (FDA) approval for the treatment of dandruff and seborrheic dermatitis of the scalp only, so although Nizoral may be useful as a hair loss remedy, it cannot be endorsed or marketed as one to the general public.[16]

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 suggest that ketoconazole should enter this group of drugs.[17]

References

  1. ^ ketoconazole (Nizoral, Extina, Xolegel, Kuric) - MedicineNet.com
  2. ^ MedlinePlus Medical Encyclopedia: Tinea versicolor
  3. ^ Tinea Versicolor
  4. ^ 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:10.1038/sj.ijir.3901160. PMID 14973533. http://www.nature.com/ijir/journal/v16/n4/full/3901160a.html.  
  5. ^ 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. doi:10.1210/jcem-63-6-1365. PMID 3023421.  
  6. ^ Wolkowitz, Owen M.; Victor I. Reus (September 1999). "Treatment of depression with antiglucocorticoid drugs". Psychosomatic Medicine 61 (5): 698–711. PMID 10511017. http://www.psychosomaticmedicine.org/cgi/content/full/61/5/698.  
  7. ^ 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:10.1016/S0376-8716(98)00108-2. PMID 10933341.  
  8. ^ 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. doi:10.1097/00004714-199910000-00011. PMID 10505589.  
  9. ^ 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. doi:10.1097/00008877-199811000-00013. PMID 9862083.  
  10. ^ 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. doi:10.1136/pgmj.66.773.221. PMID 2362890.  
  11. ^ 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. doi:10.3109/09513599909167552 (inactive 2009-11-21). PMID 10451809.  
  12. ^ 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:10.1111/j.1741-4520.2005.00053.x. PMID 15737124.  
  13. ^ Ketoconazole for Your Pet at Petscriptions
  14. ^ MDR Gene: on Medical Dictionary Online
  15. ^ Jiang J, Tsuboi R, Kojima Y, Ogawa H (April 2005). "Topical application of ketoconazole stimulates hair growth in C3H/HeN mice". J. Dermatol. 32 (4): 243–7. PMID 15863844. http://www.dermatol.or.jp/Journal/JD/2005/032040243.html.  
  16. ^ Nizoral Shampoo as a Hair Loss Remedy? http://www.dermadoctor.com/pages/newsletter198.asp
  17. ^ Ketoconazole Shampoo: Effect of Long-Term Use in Androgenic Alopecia http://www.hairlosstalk.com/hair-loss-pdf/nizoral-study.pdf

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