Tinea+Versicolor

**Motivation and Background** :
==== Tinea versicolor, otherwise known as //pityriasis versicolor//, is a fungal skin infection [1]. The primary cause for this infection emerges from overgrowth of a yeast species known as Malassezia, which emerges from the pores of the epidermis [1]. About 200,000 individuals are affected by tinea versicolor every year just in the United States [2]. Worldwide, there are about 2.9 million cases annually [2]. Teens and younger children are most susceptible to this infection since this type of yeast typically grows faster in individuals with a weakened immune system [1]. Other risk factors include oily skin, hormonal changes, sweating, and hot weather [1]. Due to this last condition, several people living in tropical regions such as South America, Mexico, and Africa, develop tinea versicolor at a greater rate [2]. Heat causes branching of the yeast cells into a form known as hyphae [3]. Symptoms include small circular patches to appear on the skin in the neck, upper chest, shoulders, armpits and arms, usually yellow or pink in color; they could appear as either hypo or hyperpigmented lesions depending on the individual’s skin tone [3]. This discoloration is due to production of azelaic acid in the skin cells [2]. The acid acts as a tyrosinase inhibitor and prevents synthesis of melanin in the skin [2]. The patches tend to be scaly and cause itchiness since they become very dry [1]. Yeast grows over the skin when exposed to heat and slowly increases the size of the patches under these conditions [2]. Conversely, when the temperature drops, the patches could disappear [2]. While the infection does not have any chronic effects, there is a lot of social stigma associated with effect on physical appearance [4]. This cosmetic change has effects on psychological stability of the patients, which is a primary reason why it should be a frontrunner in research [4]. Tina versicolor often gets confused for vitiligo, which is an autoimmune skin depigmentation disorder caused by destruction of melanocytes in the epidermis. ==== Figure 1. //Masassezia// Yeast cells as seen under scanning electron microscope

** Location ** : Ergosterol is a vital component of the yeast cytoplasmic membrane in the epidermis.
====** Function in a normal cell ** : Ergosterol plays a vital role in maintaining the dynamic permeability of the plasma membrane in fungi and is necessary in all cells; it plays a similar role to cholesterol in humans. Theories suggest that fungi have developed ergosterol as an evolutionary advantage to maintain the cell membrane structure. ====

[[image:schematic.png]]
Figure 2. Schematic of cytochrome P-40 (indicated in pink) interacting with Clotrimazole. Source: PubChem. [|https://pubchem.ncbi.nlm.nih.gov/compound/clotrimazole#section=Top] database, (accessed Feb 4, 2017).

__**Drug Information**** : **__
Clotrimazole is an azole, which specifically acts as an inhibitor to alter the activity of lanosterol 14-alpha demethylase in order to reduce production of ergosterol [5]. In turn, the permeability of the plasma membrane is increased [5]. In the case of tinea versicolor, Clotrimazole reduces the activity of ergosterol to alter the rigidity of the membrane and causes azelaic acid to spill out of the cells and targeted by other enzymes to be destroyed in the body [6]. The yeast cells carrying azelaic acid die off, returning original pigmentation by allowing tyrosine to function properly [6].

[[image:cytochrome P450.jpg width="560" height="339"]]
Figure 3. Schematic of lanosterol 14-alpha demethylase enzyme-substrate binding site. Source: Wang, M.; Roberts, D. L.; Paschke, R.; Shea, T. M.; Masters, B. S. S.; Kim, J. J. P., Three-dimensional structure of NADPH–cytochrome P450 reductase: Prototype for FMN- and FAD-containing enzymes. PNAS 1997, 94 (16), 8411-16.

** Side effects ** :
==== Side effects are rare, but include the following: itching, burning, irritation, redness, swelling, stomach pain, fever, foul-smelling discharge if using the vaginal product, upset stomach or vomiting with consumption of the edible tablets. ====

** Clinical Trials: **
==== There are not many clinical trials currently taking place with Clotrimazole and tinea versicolor since the effectiveness of Clotrimazole has encouraged extensive use of the drug to treat this antifungal infection. However, one trial is taking place to increase effectiveness of Clotrimazole in treating tinea versicolor. This is being tested by increasing solubility of the ointment through combining honey with its ingredients [15]. The problem with all topical treatments is that they tend to only be effective for a short period of time. This is why more funding is needed to provide affordable, effective treatments for Tinea Versicolor. ====

** Alternatives to this drug ** :
==== Popular OTC medications are miconazole, selenium sulfide, and terbinafine. They are less effective at targeting the cytochrome P-450 enzyme, so they are not as popular for tinea versicolor treatment. Oral medications are the less effective in comparison to ointments since they are not soluble for an effective amount of time, but fluconazole and itraconazole are alternatives used to treat this temporary condition. ====

** Other uses ** :
==== Clotrimazole treats other skin infections (candidiasis), athlete’s foot, jock itch, vaginal fungal infections, and ringworm [7]. It is being investigated to treat sickle cell disease by inhibiting Gardos channel [8].The drug’s ability to alter rigidity of the cell membrane has been investigated in other disease- especially cancer [9]. By halting cell growth in the G1 phase, it has been found to kill cancer cells [9]. This works by inhibiting mitochondrial-bound glycolytic enzymes and calmodulin, which reduce metabolism in cancer cells [9]. ====

** References: **
[1] // NIH //. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0076676/ // database //, (accessed Feb 1, 2017).

[2] Heidrich, D.; Daboit, T. C.; Stopiglia, C. D.; Magagnin, C. M.; Vetoratto, G.; Amaro, T. G.; Scroferneker, M. L., Sixteen Years of Pityriasis Versicolor in Metropolitan area of Porto Alegre, Southern Brazil. // Rev Inst Med Trop Sao Paulo //** 2015 **, 57 (4), 277-80.

[3] Rosen, T., Mycological Considerations in the Topical Treatment of Superficial Fungal Infections. //  J Drugs Dermatol   //** 2016 **, 15 (2), 49-55.

[4] Burke, R. C., Tinea versicolor: susceptibility factors and experimental infection in human beings. // J Invest Dermatol   //** 1961 **, 36, 389-402.
[5] Warrilow, A. G.; Martel, C. M.; Parker, J. E.; Melo, N.; Lamb, D. C.; Nes, W. D.; Kelly, D. E.; Kelly, S. L., Azole binding properties of Candida albicans sterol 14-alpha demethylase (CaCYP51). // Antimicrob Agents Chemother //** 2010 **, 54 (10), 4235-45.

[6] Sawyer, P. R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, Clotrimazole: A review of its antifungal activity and therapeutic efficacy. // Drugs //** 1975 **, 9 (6), 424-47.

[7] // NIH //. [] // database //, (accessed Feb 4, 2017).

[8] Brugnara, C.; Gee, B.; Armsby, C. C.; Kurth, S.; Sakamoto, M.; Rifai, N.; Alper, S. L.; Platt, O. S., Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease. // J Clin Invest //** 1996 **, 97 (5), 1227-34.

[9] Kadavkollu, S.; Stailey, C.; Kunapareddy, C.S.; White, S., Clotrimazole as a Cancer Drug: A Short Review. // Med Chem (Los Angeles // //)// **2014**, 4 (11), 722-724.