Ketoconazole and reduction of follicular dermatophyte-mediated alopecia.

[blowdry]

Ketoconazole and reduction of follicular dermatophyte-mediated alopecia.

 

There is one mode of action of topical Ketoconazole—it kills dermatophytes such as malassezia that play a pathogenic role in various skin conditions including folliculitis, pityriasis verslccolor and seborrhoeic dermatitis (1), and trichomycoses—diseases of the hair (2), among others.

 

Based on scientific observations malassezia resides on the skin and in upper part of the follicle, called the follicular infundibulum and are unique among the fungus as the only species to form part of the normal, human cutaneous microbial flora.(3), (4).

 

Dermatophytes, such as malassezia, have an affinity to hair and this can be witnessed in the laboratory. For example when isolating fungal cultures from soil to conduct research, scientists use what is called the hair-bait technique, whereby they place sterile hair in soil and observe as dermatophytes in the soil start invading the hair, producing colonies using hair as the substrate.(5).

 

For many people malassezia can exist on the skin and follicles as commensals, (living on or within another organism, and deriving benefit without harming or benefiting the host) with minimum immune system stimulation. For others however, malassezia is either able to cause or exacerbate various skin conditions.(6)

 

Malassezia's influence on IL-4 and TNF-α in the pathogenisis of alopecia

 

Exosomes, or nano-vesicles, are small 30-90 nanometer vesicles that are released from cells.(7) They play a key role in cell communication and signaling but are significantly elevated in a number of diseases.(8)

 

Just recently (2011) it has been scientifically demonstrated and published that malassezia, which resides in the follicle infundibulum, releases exosomes that carry allergens that induce Interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α) (9). TNF-α specifically can induce inflammation and cell apptosis.

 

TNF-α and loss of follicular immune privileges.

 

As far as the connection between malassezia to TNF-α induced inflammation is concerned, the slow, subtle process of micro-inflammation is highly regarded as the cause. Since there is little or no pain associated with micro-inflammation, in contrast to scarring alopecias,(10) it is very easy to disassociate the possibility of micro-inflammation in the pathogenesis of hair loss. Reports of dermatological studies have noted that follicular micro-inflammation plays an integral role in the pathogenesis of androgenic alopecia (11).

 

The hair follicle is known to possess immune privileges by producing immunosuppressive cytokines.(12) Active, healthy follicle stem cells maintain this type of immunosuppressive mechanism that appears to restrict immune system injury. It is written that micro-inflammation may cause damage to follicle stem cells and the follicles loose their "no danger" immunosuppressive attributes and are no longer protected from immune-mediated attack, which can lead to permanent loss of follicles (13) (14) as seen in common baldness.(15)

 

IL-4 Interlinking cascade & tissue damage.

 

IL-4 is an immunomodulatory cytokine that produces various biological effects. Traditionally, IL-4 was regarded mainly as a protective, anti-inflammatory cytokine.(16) However early studies have shown that serum levels of IL-4 are notably elevated in those with localized alopecia areata.(17) Recent research has demonstrated the dual roles of IL-4 as both a suppressive and pro-inflammatory cytokine.(18) Most interestingly through a variety of mechanisms, IL-4 expression has been shown to increase TNF-α.(19)

 

Eosinophils are a type of white blood cell produced by bone marrow and circulate at relatively low levels (1-3%) in the blood and their job is to protect the body by killing microogranisms. They can excessively accumulate in tissues in response to antigenic stimulation or tissue damage.(20) Eosinophils are also considered to play an important role in allergic disease by causing tissue damage through the release of toxic proteases, lipid mediators, cytokines and oxygen free radicals.(21)

 

Human eotaxin is an amino acid residue polypeptide that is produced by a number of normal cells and cell lines. Eotaxin has been shown to directly prime and direct the migration of eosinophils.(22)

 

TNF-α & IL-4 and the eotaxin relationship

 

What is interesting to note here is that when both TNF-α and IL-4 are expressed together there is a dramatic increase in eotaxin production, e.g. In a culture medium experiment when keratocytes were incubated with TNF-α or IL-4 alone there was only a small effect on eotaxin release. However exposure to the cells with TNF-α in combination with IL-4 resulted in a marked increase in eotaxin production.(23)

 

Immunoglobulin E (IgE) - antibodies that fight malassezia

 

The following question begs to be answered: Since malassezia is common in human skin and hair why do only certain people experience the associated diseases?

 

For one, there are many species of malassezia, and each or a combination of them may be specific to certain skin diseases. (24)

 

Secondly, the immune system plays a protective role. It was demonstrated when comparing healthy subject to those affected by atopic dermatitis, a more common disease associated with malassezia, healthy subjects had specific serum immunoglobulin E (IgE) antibodies against malassezia.(25)

 

Dietary and lifestyle habits play an import part in health and disease. Interventions that strengthen the immune system may be a logical adjunct therapy. It has been demonstrated that Vitamin D strengthens the human immune system,(26) and that vitamin D deficiency is associated with the severity of atopic dermatitis.(27)

 

An underdeveloped or compromised immune system might cause or increase cutaneous and follicular dermatophyte activity and could explain one reason why young children (27) and older adults (28) and AIDS patients experience immune-mediated dermatophyte-associated diseases such as dermatitis.(29)

 

Conclusion - Connecting the dots

 

What can be extrapolated from my research is that dermatophytes do in fact have an affinity to hair, and malassezia specifically can be found the the human hair follicle residing as a commensal or an allergenic. Malasseza induces the pro-inflammatory cytokines TNF-α and IL-4. IL4 also induces TNF-a, creating an even greater expression of TNF-a. Both together increase eotaxin significantly which in turn primes and directs the migration of eosinophils (white blood cells) to the follicles where malasseza resides. Micro-inflammation induced by TNF-a damages follicle stem cells which in turn loose their immunosuppressive attributes being left open to attack and tissue damage by eosinophils of the innate immune system.

 

The clearance of malassezia via topical anti-fungal agents such as ketoconazole would in-turn eliminate the associated release of exosomes and resulting inflammation, restoring normal, follicle stem cell activity, follicular immune privileges and immune reactions. Hair loss from malassezias' cascade of events could be reduced or thwarted.

 

I present this very probable mode of action of malassezia and one reason why topical anti-fungal agents like ketoconazole has become an effective adjunct therapy for attenuating or reversing the associated, cutaneous and follicular diseases.

 

___________________________________________

References:

 

(1) Recenti Prog Med. 2011 Mar;102(3):126-33.

(2) Int J Trichology. 2009 Jul;1(2):100-7.

(3) Br J Dermatol. 2011 Oct;165 Suppl 2:2-8.

(4) Clin Microbiol Rev. 2002 January; 15(1): 21–57.

(5) Mycoses. 2011 Nov;54(6):e789-94.

(6) The Yeast Handbook, 2010; Chapter 10: Malassezia - H. Ruth Ashbee and Annika Scheynius

(7) Commun Integr Biol. 2010 Sep-Oct; 3(5): 447–450.

(8) Immunol Lett. 2006 Nov 15;107(2):102-8.

(9) PLoS One. 2011;6(7):e21480 - Ulf Gehrmann, et al. Clinical Allergy Research Unit, Stockholm, Sweden.

(10) Int J Dermatol. 2000 Aug;39(8):576-84.

(11) J Cosmet Dermatol. 2009 Jun;8(2):83-91.

(12) J Investig Dermatol Symp Proc. 2003 Oct;8(2):168-72.

(13) Autoimmun Rev. 2009 May;8(6):474-7.

(14) Clin Exp Dermatol. 2010 Aug;35(6):637-44.

(15) Nature biotechnology 2004, R.J Morris, et al.

(16) Immunol Today. 1996 May;17(5):225-3.

(17) Acta Derm Venereol. 1996 Nov;76(6):421-3.

(18) Expert Opin Drug Metab Toxicol. 2010 May;6(5):519-31.

(19) J Immunol. 2002 Mar 1;168(5):2456-63.

(20) American Partnership for Eosinophilic Disorders / apfed.org / accessed:10/30/2011

(21) Gac Med Mex. 2006 Mar-Apr;142(2):139-44.

(22) J Exp Med. 1994 Mar 1;179(3):881-7.

(23) Invest Ophthalmol Vis Sci. 2000 May;41(6):1448-53.

(24) J Clin Aesthet Dermatol. 2009 November; 2(11): 14–17.

(25) J Clin Microbiol. 2001 October; 39(10): 3486–3490.

(26) Clin Endocrinol (Oxf). 2011 Oct 13.

(27) Br J Dermatol. 2011 May;164(5):1078-82.

(28) Inflamm Allergy Drug Targets. 2009 Dec;8(5):398-404.

(29) J Immunotoxicol. 2008 Apr;5(2):159-62.

[Sean]

This is very interesting.

I guess the following info from the study proves how valuable ketoconazole is:

 

"The clearance of malassezia via topical anti-fungal agents such as ketoconazole would in-turn eliminate the associated release of exosomes and resulting inflammation, restoring normal, follicle stem cell activity, follicular immune privileges and immune reactions. Hair loss from malassezias' cascade of events could be reduced or thwarted. "

 

 

I guess ketoconazole can really help preserve hairs/protect them from certain fungal scalp infections. I didn't know that some inflammed follicles may loose their immune response and can be permanently destroyed. Realizing malassezia is a very common condition, it may be a very good idea to be on nizoral (ketoconazole) shampoo. Just to make sure the bad bacteria doesn't invade the scalp and put follicles in jeopardy.

[SugarHighs]

Is there a recommended alternative to Nizoral that is also 1% Ketoconazole? There has been an ongoing Nizoral shortage for almost 6 months, and prices on what few bottles are available are ridiculous.

[SugarHighs]

There is a 1% keto shampoo on amazon called perfect image solutions hair-regrowth shampoo.

 

Anyone tried it? I'd prefer to hear from fellow consumers, and not anyone with a business interest in the company.

[Sean]

Is there a recommended alternative to Nizoral that is also 1% Ketoconazole? There has been an ongoing Nizoral shortage for almost 6 months, and prices on what few bottles are available are ridiculous.

 

 

I looked at Ebay. They have a couple of various shampoos with ketoconazole. There is one called ketozal and I believe it is 1%. The item number is 110692444531 and you can read a description about it there. I have never used that particular version, but considering the price/availability, it may be worth looking into since the price of actual Nizoral is higher. Ebay has a lot of ketoconazole stuff but I agree the prices are really high for Nizoral as it seems to be either low on stock or out of stock in most places.

 

When I used Ketoconazole, I used a prescription version 2% by Perrigo Pharm Clay Park Rx USA. I think i'll start using it again after another month or two because these shampoos are very strong for your transplanted grafts. When you get a transplant, it is recommended that when you stop using the post op baby shampoo, you switch to another softer shampoo such as dove or pantene pro v, and then wait a couple of months until you can use nizoral or any other ketoconazole shampoo. Another shampoo you may want to look into is Revita. It has 1% ketoconazole in it, but also has a bunch of other things. I did use Revita before, but I felt it kind of made my scalp oily. This is because I had oily skin, and the Revita also had a bunch of other things including EMU oil, so it kind of made my hair feel flat. I think it's a good shampoo for those that may have dry hair. When I used the regular 1% or 2% version of ketoconazole shampoo, I didn't get the flat hair/oily feeling.

[blowdry]

In addition to Revita shampoo, I would think that the 2% zinc shampoo would be beneficial due to its anti inflammatory properties.