Articles

NIZRAL® - A Time Tested Globally Accepted Therapy For Seborrheic Dermatitis

Author: Dr. A. K. Jha

M.B.B.S (Hons.); PG Dip. Hosp. Management (Distinction); MD (SKIN); Ph.D. (Derm); FIAMS (Skin); Fellow, Indian Academy of Dermatology; Fellow, Asian Academy of Dermatology; Professor of Dermatology (Retd.); Neelam Skin City, Patna

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Abstract

Seborrheic dermatitis is a common inflammatory condition mainly affecting scalp, face, chest, back, axilla, and groin, characterized by a chronic relapsing course. Treatment with antifungal agents such as topical ketoconazole is the mainstay of therapy for seborrheic dermatitis. Nizral 2% formulated with micronized ketoconazole, a NHS-recommended ingredient for anti-dandruff shampoos, effectively relieves and prevents the symptoms of seborrheic dermatitis. Nizral 2% micronized ketoconazole shampoo solution is effective in the treatment of moderate to severe dandruff; and ketoconazole 2% shampoo appears to be well tolerated. Various antidandruff shampoos simply wash the dandruff away, but Nizral 2% addresses the root of the problem by helping treat the underlying cause of the condition and restoring the scalp to its normal healthy state. Yeast Malassezia is responsible for dandruff/seborrheic dermatitis and using a treatment such as Nizral 2% helps to control it. Nizral 2% is a global brand of Ketoconazole shampoo solution, mentioned in many medical textbooks, with clinical legacy of 35 years.

Keywords: Seborrheic dermatitis, Antifungal, Ketoconazole

 

Introduction

Seborrheic dermatitis (SD) is a chronic inflammatory dermatologic condition that usually appears on areas of the body with a large density of sebaceous glands, such as the scalp, face, chest, back, axilla and groin. Although it can be associated with human immunodeficiency virus infection and neurologic disease (e.g. cerebrovascular event, Parkinson disease) [1], seborrheic dermatitis typically occurs in healthy persons. Its prevalence is 1-3% in the general population and 34-83% in immunocompromised persons [2]. It has a bimodal distribution, with peaks at 2-12 months of age and in adolescence and early adulthood [2]. It is more common in men and is typically more severe in cold and dry climates and during periods of increased stress [3].

Seborrheic dermatitis (SD) is a multifactorial disease that requires several predisposing factors for its progress. Presence of these factors leads to reproduction of opportunistic yeast Malassezia spp. [4]. The fungus uses lipids from the skin surface to produce unsaturated and saturated fatty acids which, when left in the individual’s skin milieu, induce an inflammatory response. The sebum in the skin aids the growth of P. ovale (i.e. Malassezia) and hence the development of SD.

Dandruff and SD are considered the same basic condition differing only in magnitude [5]. The development of effective drugs for treating dandruff/SD requires appropriate outcome assessment measures like presence and level of skin flakes for the quantification of the condition of the scalp and assessment of therapeutic resolution [6]. Other such outcome assessment measures employed by various studies establishing the efficacy of a drug in SD mainly include total clearance of lesions at the end of treatment phase/maintenance phase, mean change in symptom scores, i.e. erythema score, scaling score and pruritus score and patient assessment methods (usually visual analogue score method) [7].

 

Diagnosis

Seborrheic dermatitis is a clinical diagnosis that is based on appearance of lesions and their location. In infants, it may present as thick white or yellow greasy scales on the scalp; it is usually benign and resolves spontaneously. In adolescents and adults, seborrheic dermatitis typically presents as flaky, greasy, erythematous patches on the scalp (Fig 1a), nasolabial folds (Fig. 1b), ears, eyebrows (Fig. 1c and 1d), anterior chest, or upper back [3]. The differential diagnosis is lengthy but the correct diagnosis can usually be made clinically by the characteristic distribution of lesions and varying course of the disease [8]. If the diagnosis is uncertain, a biopsy demonstrating parakeratosis in the epidermis, plugged follicular ostia and spongiosis can confirm the presence of seborrheic dermatitis.

 (a)                             (b)

   (c)                    (d)

Figure 1: Seborrheic dermatitis of different regions: (a) scalp; (b) nasolabial; (c,d) eyebrows

 

Treatment Considerations for Seborrheic Dermatitis

Ketoconazole - A Topical Antifungal for Seborrheic Dermatitis Treatment

Seborrheic dermatitis (SD) is caused by yeast belonging to Malassezia species, which comes under fungal based classification. This mainly affects the skin surface producing excessive sebum (oily textured secretion) by sebaceous gland. In response to which formation of dead skin cells spreads up, which further flourishes fungal colony at the site of infection. Hence leading to characteristic symptoms, such as inflammation, flaky, greasy, erythemous patches with dandruff on oily skin surfaces [9].

Fungal infections can be tough to fight. There are many antifungal medicines which can be used for the treatment, such as selenium sulfide, zinc pyrithione, bifonazole.  Steroids are also used for topical application. They are used to treat fungal infections, but total eradication does not occur and the site of infection on skin is prone for reinfection. Ketoconazole is an antifungal agent belonging to azole group of antifungal which is highly effective in treating such type of fungal infections either alone or as an adjunct to other treatments [10].

 

Ketoconazole - Mechanism of Action

Fungal cell consists of outer cell wall and cell membrane.  Ergosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in fungi. It is a component of yeast and other fungal cell membranes, functions as maintaining the membrane integrity, where it regulates permeability and fluidity [11]. Fungus cannot survive without ergosterol, and the enzymes that synthesize it have become important targets for drug discovery. As ergosterol is the main sterol of fungal membrane and yet is absent in animal cells, hence, a useful target for antifungal drugs [12].

Ketoconazole belongs to the azole group of antifungals. It is a fungistatic agent which causes growth arrest in fungal cells thereby preventing growth and spread of the fungus throughout the body. Ketoconazole inhibit the synthesis of ergosterol (the main fungal sterol) [13].

Ketoconazole targets the enzyme used for synthesis of ergosterol (Fig. 2). The mechanism of action is believed to be based on the inhibition of fungal cytochrome P450 enzyme. This in turn impairs the biosynthesis of ergosterol. Ergosterol is a vital component of fungal cell membranes and changes the composition of other lipid components in the membrane. Impaired synthesis of ergosterol eventually leads to cell death and elimination of the fungus [14].

Figure 2: Ketoconazole inhibiting the synthesis of ergosterol (the main fungal sterol)

 

Research Studies on Ketoconazole for Seborrheic Dermatitis Treatment

Efficacy Study

For treatment of seborrheic dermatitis, topical solutions containing ketoconazole are found to improve the symptoms.

When severity of symptom is considered, many studies on ketoconazole shampoo compared with placebo are done. They showed ketoconazole shampoo is more effective than placebo at improving scalp symptoms such as scaling, itching, redness, and dandruff at 4 weeks in people with seborrhoeic dermatitis of the scalp [9, 15]. As per the Cochrane database of systematic reviews, the treatment with ketoconazole showed fewer side effects when compared with steroidal treatments [10].

A multicentre study performed to investigate the efficacy of ketoconazole 2% shampoo in the treatment and prophylaxis of seborrhoeic dermatitis, observed that medication was well tolerated in all patients. Further, the study concludes the therapy to be highly effective, not only in clearing scalp seborrhoeic dermatitis and dandruff, but also in preventing relapse of the disease when used prophylactically once weekly [16]. These results were supported by another study, in addition also mentioned the use of ketoconazole shampoo reduces hair greasiness significantly [17].

 

Comparative Analysis Study

Beside Ketoconazole there are other antifungals that are active against Malassezia species yeast infections, and are believed to play an effective role in dandruff and seborrheic dermatitis treatment. But the efficacy of therapy varies and depends on the type of antifungal used.

A study was based on randomized, double-blind, placebo-controlled trial of ketoconazole 2% shampoo and selenium sulfide 2.5% shampoo for the treatment of moderate to severe dandruff. Results showed a decline in mean total adherent dandruff score throughout the treatment period with both ketoconazole 2% and selenium sulfide 2.5% shampoos significantly better than placebo, with overall reduction in irritation and itching. Data suggested ketoconazole was statistically superior to selenium sulfide at day 8 (p = 0.0026). However, there were a few adverse experiences during treatment phase were observed with selenium sulfide 2.5% shampoo; but not with ketoconazole. Henceforth, ketoconazole 2% shampoo appears to be better tolerated [18].

A 12-week long randomized parallel single center clinical trial was conducted on patients who presented moderate to severe dandruff. This comparative study was based on the prolonged antifungal effect of three proprietary shampoos containing either 2% ketoconazole, 1.5% zinc pyrithione or 2.5% selenium sulfide. The fact that ketoconazole 2% binds to keratinized structures of hair and skin; therefore, high concentrations remained on hair keratin (i.e. on hair shaft) up to 3 days after shampoo application. After following a 6‐week antifungal shampoo treatment, data showed the increased duration of yeast reduction for the ketoconazole shampoo over the two other formulations [19].

Comparing the efficacy and safety of ketoconazole 2% and zinc pyrithione 1% in shampoo formulations for the alleviation of severe dandruff and seborrheic dermatitis, an open multicentre randomized parallel-group trial was conducted. Clinical assessments showed that beneficial effects were evidenced for both medicated shampoos, but the effect was significantly better for ketoconazole 2%, and recurrence rate of the disease was also significantly lower. The results of the study complied with previous finding; and were noticeable and consistent. This concluded that after a 4-week treatment, ketoconazole 2% shampoo was significantly superior to zinc pyrithione 1% shampoo for treating severe dandruff or seborrheic dermatitis of the scalp [20].

 

Guidelines for Ketoconazole

International – WHO 2014 guidelines [21]

• “Topical ketoconazole has an excellent benefit v/s side effect profile.”
• “Topical ketoconazole 2% was graded as a strong recommendation for mild seborrheic dermatitis, and topical corticosteroids graded as a strong recommendation for severe seborrheic dermatitis.”
• “Ketoconazole is the most studied and has the strongest evidence for its effectiveness.”

Asia

• Cheong 2015 [22]: “Treatment of Seborrheic Dermatitis in Asia: A Consensus Guide.”
• Ketoconazole recommended for treatment of mild-moderate SD of scalp and non-scalp SD.

Danish Dermatology Society Guidelines [23]

• Give highest strength recommendation for use of ketoconazole 2% in SD based on highest quality available evidence.

United Kingdom

• British Association of Dermatologists [24]: recommends the use of ketoconazole shampoo for scalp and body SD.

 

Product Features

1. Micronized Ketoconazole: Nizral is manufactured using micronized technology. No particle of ketoconazole observed above 50 microns. This unique formulation/technology leads to better penetration. Micronized Ketoconazole gets uniformly distributed in the affected dermis/epidermis resulting in greater degree of efficacy.

 

1. Potent Antifungal: Effectively kills the fungus that causes dandruff. Nizral contains ketoconazole which belongs to the “azole” group of antifungals. Ketoconazole acts by intervening ergosterol (the main component of Malassezia cell membrane) biosynthesis. By inhibiting ergosterol synthesis, the cell membrane function is disrupted, increasing permeability of the cell, leading to cell death.

 

1. Anti-inflammatory and Anti-proliferative:  Relieves itching associated with seborrheic dermatitis and dandruff. Also reduces flaking, scaling and ensures higher treatment with lower recurrence rates.

 

1. High Keratinophilicity: Nizral exhibits a strong activity against the yeast Malassezia ovalis and is shown to have prolonged antidandruff effects. Persists in hair up to 72 hours.

 

1. Low viscosity: Nizral‘s molecular makeup results in very little friction when it is in motion which allows easy spreadability on the scalp.

 

1. Convenient dosage: One application per wash.

                                   

How to Use Nizral 2%

1. Apply Nizral to wet hair and massage gently to loosen flakes from scalp.
2. Leave Nizral on your scalp for 3 – 5 minutes.
3. Rinse thoroughly with water.

 

Dosage and Administration

 

As a shampoo for seborrheic dermatitis and dandruff	For children over 12 years of age and adults
Treatment	Apply twice weekly for 2–4 weeks, Leave preparation on for 3–5 minutes before  rinsing
Prophylaxis	Apply every 1–2 weeks, Leave preparation on for 3–5 minutes before  rinsing

 

How to Use Nizral 2%

                     

References

 

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