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CLINICAL TRIAL OF NAILCARE CAPSULE AND CREAMS IN TOENAIL TINEA UNGUIUM INFECTION
SV INDRA KUMAR*, KALA KULKARNI**
*Professor and Head, Department of Dermatology, Bangalore Medical College, Bangalore. **Medical Advisor, R and D Centre, The Himalaya Drug Company, Makali, Bangalore 562 123.
A randomised double blind clinical study was undertaken to evaluate the efficacy and tolerability of a herbal formulation, NailCare capsule and cream in Tinea unguium infection. One hundred and two patients with clinically suspected infection of tinea or dermatophytes in the nail in baseline culture were selected for the study. The patients were randomly administered NailCare capsule at a dose of 2 capsules twice daily and local of NailCare cream application twice daily or an identical placebo capsule and cream at the same dosage of 12 weeks. Ninety two patients completed the study period, of which 46 were in the treated group and 46 in the placebo group, the remaining patients being excluded due to non compliance. Mycological care (negative results on microscopy and culture) and clinical improvement (length and area of affected nail) at week 12 were considered for evaluation. At the end of the study, mycological cure rates were 80.92% (17 out of 21 who had previously tested positive for culture) in the treated group and 13.63% (2 out of 22 who had previously tested positive for culture) in the placebo group. Length of the affected nail was 9.4 mm in the treated group and 3.9 mm in the placebo group. There were no adverse effects in any of the patients.
INTRODUCTION
Dermatophyte infection is a common fungal infection occurring in onychomycosis. Topical antifungal treatment for onychomycosis have been unsatisfactory, [1] although the more recently developed antifungal nail lacquers may be effective in mild to moderate cases. [2,3] Systemic treatment is imperative when the fungus spreads to the nail matrix. [4] Until recently, only 2 systemic drugs were available to treat Tinea unguium - namely, griseofulvin and ketoconazole. With griseofulvin, the therapeutic results were unsatisfactory in toe nail infection [5] and ketoconazole is associated with the risk of hepatotoxicity and produce drug interactions. [6] In recent times, many herbal preparations have been used to treat various nail infections. Therefore, a clinical study was planned for the herbal preparations, NailCare capsules and cream in treating toenail infections. NailCare cream contains multiple herbs such as Ocimum basilicum and Vetiveria zizanoides. Vetiveria zizanoides is a potent antifungal agent when used topically. It is reported to possess fungicidal activity against many known fungi especially the trichophyton group. [7] Ocimum basilicum also has antifungal activity against various species. [9] NailCare capsules contain herbs that have anti-inflammatory, immunomodulatory, antifungal and antimicrobial properties. Commiphora mukul present in the capsules have shown anti-inflammatory activity when used in arthritis. [10] It reduces inflammation of nail infection, the action similar to NSAIDs phenylbutazone and ibuprofen. [11] Fungal infections are known to occur in individuals with compromised immune functions. Withania somnifera present in NailCare has immunomodulatory properties. [12,13] Terminalia arjuna is well known for its antifungal and antimicrobial properties.
MATERIAL AND METHODS
The clinical trial was carried out in 102 patients of either sex 21 to 70 years with clinical diagnosis of distal subungual or proximal onychomycosis or the presence of dermatophytes in mycological culture. Pregnant or lactating women those withpre-existing renal, hepatic or gastrointestinal disease, bacterial or yeast infections of the nails or the periungual area, psoriasis and psoriatic changes of the toenail were excluded from the study. All patients withdraw their systemic antifungal treatment and topical treatment one month prior to taking samples for baseline mycological culture.
Patients were screened before starting the trial treatment and those within clinically suspected toenail infection were included. Samples were taken for analysis of mycological growth of dermatophytes before admission to the trial. Nail clippings taken at fortnightly follow-up visit were sent to a central laboratory for mycological investigation. This consisted of direct microscopy in 20% potassium hydroxide and culture on sabourauddextrose-agar (with chlorampheniol 0.05% and actidione 0.5%) at room temperature for upto 4 weeks. To exclude any possible of previous treatment with antimycotic agents, it was mandatory that dermatophytes be present and proliferating in the screening culture before a patient could be included in the study, especially for those patients who were on antifungal therapies. Clinical response to treatment was monitored by observing the movement of a scratch at the border between infected and normal areas on the most affected nail excluding the little toe. In addition, the affected nails were examined for onycholysis, hyperkeratosis, brittleness and paronychial inflammation by means of a 4-point scale (0=absent, 1=mild, 2=moderate, 3=severe). The area of the affected nail was assessed as 0%, < 30%, 30-60% and > 60%. Adverse effects were evaluated using a standardised questionnaire at each visit. The following haematological and biochemical investigations were evaluated before and after treatment : packed cell volume, haemoglobin concentration, erythrocyte and leucocyte counts of creatinine, cholesterol, triglyceride, g-glutamyltransferase, glutamic-oxaloacetic transaminase, glutamic-pyruvic transminase, alkaline phosphatase and bilirubin.
The distribution of age, sex, height and weight were identical in both treatment groups, the percentage of males being 64%. The mean age was 49 years (range 21-70), mean height 174 cm (range 153-193 cms), and mean weight 69 kg (range 48-90 kg). Most patients were diagnosed as severe onychomycosis since 30% of the toenail was affected (Table). Sixteen of them had been treated systemically, mainly griseofulvin. However, response to treatment was poor and few of them suffered from griseofulvin reactions.
After obtaining the informed consent, the patients were randomly assigned to treatment with either NailCare capsule and cream or an identical placebo, according to a computer generated randomisation schedule. NailCare capsules and cream were administered for 3 months at a dose of 2 capsules and daily application of the cream, twice daily. Patients were assessed every fortnightly during the 3 months’ treatment period.
RESULTS
Out of a total of 102 patients who were recruited for the trial, 92 patients completed the trial. Ten patients were excluded from the evaluation of drug efficacy, as they did not adhere to their allotted appointments during the trial. The data of 46 patients in the NailCare treated group and the same number in the placebo group were available for analysis. Patients treated with NailCare capsules and cream were identified as Group A and those patients treated with placebo as group B.
The main measure of efficacy was mycological cure, which was defined as negative results on microscopic examination and no growth of dermatophytes in culture. The treatment groups were compared by means of Fisher’s exact test for differences in mycological cure rates and in percentages of negative cultures. Secondary measures of efficacy were changes in the area of the affected nail, length of the unaffected nail and drug tolerance.
In Group A, Trichophyton rubrum was identified as the pathogen in thirteen patients (28.26%), and T. mentagrophytes in eight (17.39%). Mycological cultures gave negative results after treatment in seventeen (80.92%) patients. In Group B, Trichophyton rubrum was identified as the pathogen in fifteen patients (32.60%), and T. mentagrophytes was observed in seven (15.21%). After treatment, mycological cultures showed negative growth of fungi in 3 (13.63) patients in this group. The length of the affected nail increased in Group A from 1.3 mm to 9.4 mm in Group B from 1.2 mm to 3.9 mm. The clinical response was also reflected by the decrease of the affected area of the nail plate (Table). Fifty per cent in the patients of the treated group were completely cured with clear nail while 32.60% had less than 30% of their nail surface affected. Seven out of forty six patients had 30-60% nail discoloration and only one patient did not respond to the treatment. None of the patients in the placebo group were cured completely, eight patients had 30% of the nail infection in spite of 12 weeks of treatment. Eighty two per cent had more than 30% of their nails affected and 43.47% had more than 60% infection. This showed that the area of affected nail plate decreased in the treated group while it increased or not changed in the placebo group.
The mean global symptom score proved to be less sensitive in differentiating between the two groups than the variables related to the area and decreased from 5.8 to 1.9 in the treated group and from 5.5 to 4.2 in the placebo group. NailCare capsule and cream proved to be significantly more effective in terms of clinical improvement and eradication of fungal pathogens.
Biochemical tests showed a slight effect of NailCare capsule and cream on g-glutamyltransferase, but the median change was only 1 U/l and other related variable either remained unchanged or were significantly decreased. These findings suggest that there is no risk of hepatotoxicity with NailCare capsule and cream.
TABLE
Area of nail plate clinically affected by dermatophyte infection.Area of affected nail plate (%) Treated group (n=46) Placebo group (n=46) Before treatment No. of patients
Percentage
No. of patients
Percentage
< 30 1 2.17 4 8.69 30-60 15 34.78 15 32.60 > 60 30 65.21 27 58.69 0 23 50 0 0 < 30 15 32.60 8 17.39 30-60 7 15.21 18 39.13 After treatment > 60 1 2.17 20 43.47
DISCUSSION
Nails and hair grow from the matrix. As older cells grow out and are replaced by newer ones, they are compacted and take on a flattened, hardened form. The average growth rate for nails is 0.1 mm each day; individual rates depend on age, time of year, activity level and heredity. Fingernails grow faster than toenails. Nails also grow more rapidly in the summer than in the winter. Nails on a person’s dominant hand (right vs. left) grow faster and men’s nails grow more quickly than women’s except possibly during pregnancy and old age. Disease, hormonal imbalance and the ageing process affect nail growth. Fungal infections make up approximately 50 per cent of all nail disorders and can be difficult to treat. More common in toenails than fingernails, they often cause the end of the nail to separate from the nail bed. Additionally, debris consisting of white, green, yellow or black colour may build up under the nail plate and discolour the nail bed. The top of the nail orthe skin at the base of the nail can also be affected. Toenails are more susceptible to fungal infections because the feet are confined in a warm, moisture bearing environment.
Onychomycosis is a common fungal disease infecting upto 20% of the population over the age of 40. Uncontrolled infection may eventually lead to penetration of the newly forming nail plate. In spite of the encouraging cure rate with recent antifungal agents such as terbinafine, itraconazole and fluconazole, in some patients this therapy is ineffective. [14] Often, the daily use of cosmetic significantly contributes to the diseases of the nails. A study carried out on operation theatre nurses has shown that chipped fingernail polish or fingernail polish worn longer than 4 days fosters increased bacteria on the fingernails of nurses after surgical hand scrubs. [15] Herbal drugs of late have been emerging as an alternative therapy for many diseases. In a randomised, double blind, placebo-controlled clinical study, 2% butenafine hydrochloride and 5% Melaleuca alternifolia oil incorporated in a cream to manage toenail onychomycosis was carried out. After 16 weeks, 80% patients using the medicated cream were cured as opposed to now on the placebo group. [16]
In this trial, 2 capsules of NailCare with topical application of the cream were found effective against Tinea unguium infections. Even though the fungus could be isolated in only 43 patients out of 102 patients. NailCare capsules and cream helped the nails to grow faster, stronger, harder and more flexible. The treatment could rejuvenate the cuticles, make it healthy and allow for normal nail growth.
CONCLUSION
Treatment of nail onychomycosis with alternative medicine is a rapidly evolving field. The high rate of mycological and clinical success of NailCare capsule and cream observed here make them a safe and effective alternative medication especially for those patients where conventional treatment is contraindicated. This medication was accepted by all the patient with no side effects in any of them. In this trial, it is seen that herbs can be used in patients with nail onychomycosis. However, further biochemical and clinical research has to be done to confirm the activity against other fungal pathogens that affect the nail.
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