WO2011046454A1

WO2011046454A1 - Treatment of molluscum contagiosum using honey

Info

Publication number: WO2011046454A1
Application number: PCT/NZ2010/000204
Authority: WO
Inventors: Laurence Greig; Shaun Holt
Original assignee: Laurence Greig Limited
Priority date: 2009-10-14
Filing date: 2010-10-14
Publication date: 2011-04-21

Abstract

Provided is the use of honey for the treatment of molluscum contagiosum, the use of honey in pharmaceutical compositions for the treatment of molluscum contagiosum, and the use of honey in the manufacture of medicaments for the treatment of molluscum contagiosum.

Description

TREATMENT OF MOLLUSCUM CONTAGIOSUM USING HONEY

FIELD OF THE INVENTION

The present invention relates to a treatment for Molluscum Contagiosum using honey. More particularly but not exclusively the present invention relates to the use of honey for the treatment of Molluscum Contagiosum lesions.

BACKGROUND TO THE INVENTION

Molluscum contagiosum (MC) is a skin condition resulting from epidermal skin viral infections that cause characteristic epidermal lesions. The causative agent is the molluscum contagiosum virus (MCV), which is a DNA virus in the Poxviridae family.

The epidermal lesions of MC are generally in the form of raised, pearl-like papules or nodules on the skin. The papules are typically 2-5 millimetres in diameter. They are frequently seen on the face, neck, armpit, arms, and hands but may occur anywhere on the body, except the palms and soles. In children, molluscum contagiosum is most prevalent on the face, torso and the extremities.

The virus can spread through skin-to-skin contact, and contact with contaminated objects, such as towels, clothing, or toys. The estimated incubation period varies from 14 days to 6 months.

About one in six children are infected at some time with MC. Infection is most common in children aged from one to ten. In people with a normal immune system, the disorder is a self-limiting disease and usually resolves itself over a period of 6 months to 5 years. In immunocompromised individuals, the infection is generally not self-limiting and can be much more severe.

Although the lesions are generally self-resolving without scarring, treatment is often sought for various reasons, including: alleviating discomfort, including itching;

cosmetic reasons; social stigma from visible lesions; limiting spread to other parts of the body; preventing scarring or secondary infection; and preventing trauma or bleeding of lesions.

There are many prior art treatments for molluscum contagiosum, which may be categorised as physical destruction of the lesions, topical agents, and systemic treatments. Physical destruction of individual lesions includes surgical removal, scraping, de-coring, freezing, or though needle electrosurgery. Generally these physical treatments are not very effective, are painful and can result in scarring. Topical treatment includes application of preparations such as podophyllotoxin, liquefied phenol, tretinoin, cantharidin, potassium hydroxide, and Australian lemon myrtle oil. Suggested systemic treatments have included cimetidine, griseofulvin and methisazone. Many of these known treatments can not be applied at home by the patient, and require multiple trips to a doctor for repeat treatments. According to a review by the Cochrane Collaboration, no single intervention has been shown to be convincingly effective in treating molluscum contagiosum (van der Wouden JC, Koning S, van Suijlekom-Smit LWA, Berger M, Butler C, Menke J, Gajadin S, Tasche MJA. Interventions for cutaneous molluscum contagiosum.

Cochrane Database of Systematic Reviews ΐ 2006, Issue 2. Art. No.: CD004767. DOI: 10.1002/14651858.CD004767.pub2). The United Kingdom National Health Service (NHS) recommends watchful waiting and reassurance as first-line management. Accordingly there is a need for new, effective, and simple treatments for this condition.

OBJECT OF THE INVENTION

It is an object of the invention to provide a treatment for molluscum contagiosum, and/or a composition for treating molluscum contagiosum, and/or the manufacture of a medicament for treating molluscum contagiosum and/or to at least provide the public with a useful choice. SUMMARY OF THE INVENTION

In one aspect the invention broadly consists in a pharmaceutical composition comprising honey for use in the treatment of molluscum contagiosum.

Preferably the pharmaceutical composition is for the treatment of a molluscum contagiosum lesion.

Preferably the pharmaceutical composition comprises 50% to 100% honey; more preferably the composition comprises substantially 100% honey.

In another aspect the composition further comprises a pharmaceutically acceptable excipient. Preferably the composition is formulated as a dermatologically-acceptable cream, gell, ointment, salve, lotion, cerate, balm, solution or the like.

In another aspect the pharmaceutical composition further comprises a second agent suitable for treating molluscum contagiosum.

In another aspect, the invention broadly consists in a kit for treating molluscum contagiosum, the kit comprising a pharmaceutical composition comprising honey, and a dressing. In another aspect the invention broadly consists in a use of honey in the manufacture of a medicament for the treatment of molluscum contagiosum.

Preferably the medicament is for the treatment of a viral-induced lesion of molluscum contagiosum.

Preferably the medicament comprises from 50 to 100% honey; more preferably the medicament comprises substantially 100% honey.

In another aspect the medicament is in the form of a dressing that incorporates the honey. In another aspect, the invention broadly consists in a method of treating molluscum contagiosum in a subject, the method comprising administering to the subject a therapeutically effective amount of honey. Preferably the honey is administered topically; more preferably directly to a molluscum contagiosum lesion.

The subjects treatable by the methods and medicaments of the inventive are humans and non-humans. Preferably the subjects suitable for treatment by the methods and medicaments of the invention are humans. In certain embodiments the subjects are children. In certain other embodiments the subjects are immunocompromised individuals.

In another aspect the honey administered to the subject is in the form of a medicament.

Preferably the medicament is administered topically; more preferably the

medicament is administered to a molluscum contagiosum lesion. Preferably the medicament comprises medical-grade honey.

Preferably the medicament comprises from 50 to 100% honey; more preferably the medicament comprises substantially 100% honey. In another aspect the treatment is administered in combination with a second therapy for treating molluscum contagiosum.

In one embodiment the treatment is co-administered (that is at a similar time) with said second therapy.

In another embodiment the treatment is administered before said second therapy.

In another embodiment the treatment is administered after said second therapy. In one embodiment, the second therapy relates to physical destruction of a lesion, by means including but not limited to surgical removal, scraping, de-coring, freezing, needle electrosurgery, or combinations thereof. In another embodiment, the second therapy relates to a topical treatment, including but not limited to the administration of podophyllotoxin, liquefied phenol, tretinoin, cantharidin, potassium hydroxide, Australian lemon myrtle oil, or combinations thereof.

In another embodiment, the second therapy relates to a systemic treatment, such as a therapy that boosts or strengthens the immune system or response, including but not limited to the administration of cimetidine, griseofulvin, methisazone or combinations thereof.

BRIEF DESCRIPTION OF THE FIGURES

Preferred forms of the invention will now be described with reference to the accompanying figures in which:

Figure 1A shows an area of molluscum contagiosum on subject 01 on day 1 of treatment.

Figure 1B shows an area of molluscum contagiosum on subject 01 on day 29 of treatment. Figure 2A shows an area of molluscum contagiosum on subject 06 on day 1 of treatment.

Figure 2B shows an area of molluscum contagiosum on subject 06 on day 29 of treatment.

Figure 3A shows an area of molluscum contagiosum on subject 07 on day 1 of treatment.

Figure 3B shows an area of molluscum contagiosum on subject 07 on day 29 of treatment.

Figure 4A shows an area of molluscum contagiosum on subject 08 on day 1 of treatment. Figure 4B shows an area of molluscum contagiosum on subject 08 on day 28 of treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In reference to the figures, the preferred embodiments of the invention will be illustrated by way of non-limiting example.

Although it is anticipated that the general invention as described has other uses, the preferred use of the invention is a medicament and treatment of molluscum contagiosum.

The inventors have surprisingly discovered that honey can be used for the treatment of molluscum contagiosum. More particularly, honey can be used to treat molluscum contagiosum skin lesions. As used herein, the term 'honey' refers to a sweet and viscous fluid produced by honeybees and other insects from the nectar of flowers.

As used herein, the term 'dermatologically-acceptable' means that the described compositions and components thereof, are suitable for use in contact with skin without undue toxicity, incompatibility, instability, and the like.

As used herein, the terms 'lesion' and 'lesions' are used interchangeably to both refer to either a single lesion or multiple lesions. As used herein the term 'medical-grade honey' refers to a honey that is sterile, or has a sufficiently low microorganism content to be considered suitable for medical use.

As used herein, the term 'therapeutically effective amount' refers to an amount of substance or composition that is sufficient to treat, i.e. reduce, ameliorate or eradicate, at least one symptom associated with the indicated condition.

As used herein, the term 'treatment' or 'treating' refers to any means of control of a condition or disorder, including prevention or prophylaxis, cure and relief, or arrestation or relief of development of the condition or disorder. As used herein, the term 'subject' refers to a warm-blooded mammal, and includes humans and any mammal that is capable of developing a molluscum contagiosum lesion. As used herein, the term 'subject in need thereof refers to a subject that has at least one molluscum contagiosum lesion.

Honey Honey has been used for medicinal purposes for thousands of years, particularly in wound healing and for its antibacterial activity. However, the healing properties of honey have not yet been fully assessed, despite extensive research.

Honey is a naturally occurring and complex mixture of components. Bees collect nectar from flowers and process the nectar at the hive, introducing further

substances, such as enzymes, into the processed nectar. The water content of the processed nectar is slowly evaporated down from about 70 to 80% by weight, to about 17 to 18% by weight, eventually resulting in ripe honey. Consequently, ripe honey has a low water activity, and high osmotic effect, which contributes to its antibacterial activity. It is known that the antibacterial activity of honey is based on at least two

mechanisms, one being the hyperosmality of honey and the other being the intrinsic antibacterial activity of the honey. The hyperosmality results in the honey drawing water out of tissues, producing a low water vapour pressure, or a_w value. The very low value of a_w for honey (0.45 - 0.70) effectively inhibits the growth of bacteria and fungi. Honey also generally has a pH of 3 to 4. This level of acidity inhibits the growth of bacteria.

The intrinsic antibacterial activity of honey is at least in part attributable to the presence of an amount of hydrogen peroxide in the honey, which is referred to as 'peroxide activity'. The peroxide activity results from the enzyme glucose oxidase that in diluted honey, converts glucose into gluconic acid and hydrogen peroxide. The resulting low concentration of hydrogen peroxide is seemingly sufficient to kill bacteria.

The various properties of honey have led to its use in the treatment of MRSA infections, burns and other wounds. Studies have indicated that honey may accelerate the healing of wounds. Suggested means for the wound healing effect include the release of hydrogen peroxide, the acidification of the wound, the provision of a moist environment and nutrition for cell growth, or a combination thereof. The debriding action of honey in wound healing has also been noted in studies. The medicinal properties of honey may be dependent on the variety of honey. In particular some monofloral honey varieties (honey produced predominantly from the nectar of one plant species) have been recognised as having distinct medicinal properties.

A significant characteristic of honey, particularly when used for medicinal purposes, is its microbial content. Honey in its raw state generally contains a variety of fungus, yeast and bacteria, and may include pathogenic bacteria such as Clostridium botulinum strains. Accordingly, it is preferred that the honey used in the

compositions, treatments, and medicaments of the invention is medical-grade honey.

Although multiple studies have investigated the use of honey for use in the treatment of many conditions, particularly the use of honey as an antibacterial agent, no studies have previously assessed the efficacy of honey for treating molluscum contagiosum.

One of the inventors made the surprising discovery that honey was effective in treating the molluscum contagiosum lesions on his 7 year old son. These

observations led the inventors to undertake a pilot study on the use of honey to treat molluscum contagiosum.

It is known to one skilled in the art that various genetic variants of molluscum contagiosum virus exist. In embodiments relating to the treatment of molluscum lesions, no limitation is placed as to the particular variant of molluscum contagiosum virus associated with the lesion. Furthermore, no limitation is placed on the type or physical characteristics of a particular lesion to be treated (e.g. size, pattern, shape, thickness, location on the body, hardness or softness, colour, etc.).

A preferred variety of honey to be used in the invention is kanuka honey, produced predominantly from nectar from kanuka (Kunzea ericoides) also known as white tea tree. The composition and activity of kanuka honey are especially suitable for medicinal applications. In particular, compared to manuka honey (which is a variety often mentioned for medicinal uses), kanuka honey has higher levels of peroxide, a lower pH, high levels of abscisic acid, and has low levels of methylglyoxal which has been indicated in glucose intolerance and diabetes complications. Other compounds of note identified in kanuka honey include the antimicrobial 4-methoxyphenyllactic acid, the antioxidant 4-methoxybenzoic acid, and the antimicrobial and fungicidal syringic acid.

Pharmaceutical Composition

In a preferred embodiment the invention provides a pharmaceutical composition comprising honey, for use in the treatment of a molluscum contagiosum. In particular the invention provides a pharmaceutical composition comprising honey for use in the treatment of a molluscum contagiosum lesion. Preferably the pharmaceutical composition comprises from 50 to 100% honey. Preferably the honey used in the composition is medical grade honey. In one preferred embodiment, the composition is 100% medical grade honey. In other embodiments, the composition may also include one or more pharmaceutically acceptable excipients.

In another aspect of the embodiment, the pharmaceutical composition comprising honey is formulated as a dermatologically-acceptable cream, gel), ointment, salve, lotion, cerate, balm, solution or the like. Medicament

In one embodiment, honey is used in the manufacture of a medicament for use the treatment of a molluscum contagiosum lesion. Preferably the medicament uses a composition comprising 100% honey. Preferably the honey is medical grade honey. Preferably the honey is medical grade kanuka honey. In other embodiments, further components such as pharmaceutically acceptable excipients may be added to the medicament, as may be considered appropriate by one skilled in the art. The medicament may also comprise a dressing, such as gauze, which the honey containing composition is applied to, or incorporated with. In one embodiment the medicament comprises a self-adhesive bandage, in which is incorporated a honey composition. The honey composition may be incorporated in various ways, for example it may be applied to a surface of the bandage, or the honey may be incorporated with an absorbent core, or enclosed within an

encapsulation means. Preferably the bandage will include adhesive portions that may be used to adhere the bandage to the skin of the treatment subject. The medicament may be packaged in a sealed wrapper to prevent contamination of the medicament, and/or to retain the honey composition within the medicament.

Instructions may also be provided, with directions on using the honey to treat molluscum contagiosum. The treatment regime may depend on the needs of the subject and the advice of a medical practitioner. In one embodiment, the honey is administered at a frequency of at least once per week, preferably at least once every two days, more preferably at least once per day. Kitset

A kitset may be provided comprising a medicament comprising honey, and a dressing or multiple dressings suitable for use in treating molluscum contagiosum with honey.

Treatment Method

In one embodiment, the invention is directed to a method of treating molluscum contagiosum lesions by administering a therapeutically effective amount of honey to the subject in need thereof. Preferably the honey is directly administered to the lesions under treatment. Direct administration can include any suitable application known in the art, particularly topical application. The form of the administered honey can be any composition or medicament as described above. The frequency of administration of the honey may vary depending on various factors, as determined by one skilled in the art. Examples of various factors include the age of the patient, the severity of the lesions, the locations of the lesions on the body, and the progress of the treatment. In one embodiment, the honey is administered at a frequency of at least once per week, preferably at least once every two days, more preferably at least once per day.

In another embodiment, the invention relates to administering the honey in combination with a second therapy that is intended for treating molluscum

contagiosum. The second therapy can be any known method that may be useful in ameliorating, reducing, or eradicating the molluscum contagiosum lesions. A particular second therapy is physical destruction of a lesion, by means including but not limited to surgical removal, scraping, de-coring, freezing, needle electrosurgery, or combinations thereof.

Other second therapies may relate methods for inhibiting or eradicating the underlying viral infection, such as a topical treatment, including but not limited to the administration of podophyllotoxin, liquefied phenol, tretinoin, cantharidin, potassium hydroxide, Australian lemon myrtle oil, or combinations thereof; or a systemic treatment, such as a therapy that boosts or strengthens the immune system or response, including but not limited to the administration of cimetidine, griseofulvin, methisazone or combinations thereof. The frequency and time of administration of the second therapy can be determined by one skilled in the art. For example, the second therapy may be administered more or less frequently than the administration of honey, and may be at time before, after or similar to the administration of the honey.

Example 1

A clinical trial was performed to determine if honey is an effective treatment for - molluscum cohtagiosum. The study participants consisted of 15 children diagnosed with molluscum contagiosum, aged 3 to 16 years old. The participants were enrolled in the study following referral by their general practitioner or in response to public advertisements. The inclusion criteria included children aged from 3 to 16 years, diagnosed with MC, and with lesions in at least two discrete sites of similar appearance. Immuncompromised children were excluded from the study.

At the commencement of the study period, each participant was reviewed by a physician and an area of lesions to be treated was defined. The treatment involved parents/caregivers applying honey the specific lesions then covering with a dressing, either an Opsite™ dressing or gauze. The treatment was applied every second night. The honey used in the study was manuka honey, which is honey produced by honey bees predominantly from the manuka tree nectar (leptospermum scoparium), also known as tea tree. The subjects were reviewed by a physician after two weeks of treatment then a final review at the end of the four week study period. Table 1: clinical trial notes

The treatment notes of the first eight participants in the study are provided in Table 1. Photographs were taken of selected areas of lesions on these participants before treatment commenced, and then after the selected areas of molluscum contagiosum lesions were treated in accordance with the study.

Fig. 1A shows an area of molluscum contagiosum lesions on the right upper quadrant of subject 01 on day 1 of treatment, and Fig. 1B shows the same area after day 29. Fig. 2A shows an area of molluscum contagiosum lesions on the right upper quadrant of subject 06 on day 1 , and Fig. 2B shows the same area after day 29 (B). Fig. 3A shows an area of molluscum contagiosum lesions on the left arm of subject 07 on day 1 , and Fig. 3B shows the same area after day 29 (B). Fig. 4A shows an area of molluscum contagiosum lesions within the left axilla of subject 08 on day 1 of treatment (A), and Fig. 4B shows the same area after day 28. All 5 children completed the study, and at the end of the four week study period three assessments were made; firstly the effectiveness of the treatment for each participant was assessed by a physician; secondly a parent of each participant provided an indication of whether they agreed that the treatment was effective; and thirdly an opinion was provided by a parent of each child on their likelihood of using the treatment again. The assessments are shown in Table 2, with the legend and assessment criteria provided in Table 3.

The median parental assessment of the effectiveness of treatment was 4 (agree moderately). The median physician assessment of effectiveness was 1 (partial improvement, at least one lesion resolved). The median parental treatment option was 5 (definitely would use this treatment again). The physician assessment identified that in around half of the participants there was either partial improvement with at least one lesion resolved or substantive improvement with the majority of lesions resolved.

Irritation caused by either the honey or the dressings was noted in some of the participants. Two of the participants were deemed to be allergic to the Opsite™ dressing, but continued with the treatment using gauze as the dressing. Table 2: The effect of honey treatment on molluscum contagiosum lesions

Table 3: Assessment criteria

The honey used in this study was not medical grade honey, which may have contributed to skin irritation. Accordingly it is recommended to use medical grade honey to potentially avoid similar issues. To prevent skin irritation caused by the ₃ dressings, alternative dressings may be used that do not cause irritation. This may be factor that is dependent on the tolerance or sensitivity of the subject undergoing treatment.

This is the first study to show the efficacy of honey in the treatment of molluscum contagiosum, which is a common viral illness. A significant proportion of the participants showed a positive result to the treatment. Feedback from the parents of the child participants indicated that most appreciated that a natural product was being.used, and that it was relatively easy to apply. There was also reported evidence of clearance of lesions that did not had honey applied to them, suggesting a general immunological response initiated by the treatment. Example 2

A suitable honey for use in treating molluscum contagiosum is medical grade kanuka honey, sourced according to the following standards:

1. Kanuka honey is sourced from kanuka (Kunzea ericoides)

2. processed to medical grade as follows:

a. Harvest protocols

i. Hives to be located minimum of 10 km from any intensive horticulture

ii. Hives have GPS location recorded

iii. All batches can be traced to site origin

iv. All hives have been inspected by a certified apiarist v. All bees removed prior to extraction

vi. All frames have top/bottom bars scrapped and removed vii. All frames have wax cappings pierced to eliminate wax

contamination

viii. All frames inspected to ensure absence of pollen cells ix. All frames inspected to ensure absence of brood cells x. Risk assessment of harvesting and extraction process b. Assay protocol

i. Floral purity <90% ii. Foreign matter < 50 microns

iii. Crystallization < 200 microns

iv. Heavy metals < 20 ppm

v. Microbiology < 50 colony-forming units/g

vi. Hydroxymethylfurfural <10 mg/kg

vii. PDCB: zero tolerance

viii. Antibiotic contamination: zero tolerance

ix. Broad-spectrum screening for insecticides: zero tolerance x. Non-contamination level confidence 99%

c. All honey must be sterilized using gamma irradiation to a minimum level of 25 kiloGray

Example 3

An analysis of kanuka honey suitable for use in treating molluscum contagiosum has identified that the honey comprises naturally occurring: a. Minimum level of 1.5 mg/kg abscisic acid

b. Minimum level of 50 mg/kg 4-methoxyphenyllactic acid

c. Minimum level of 2.0 mg/kg 4-methoxybenzoic acid

d. Minimum level of 1.0 mg/kg syringic acid

e. Maximum level of 50 mg/kg methylglyoxal

. f. Maximum level of 5.0 mg/kg 2-methoxybenzoic acid

g. Maximum level of 900 mg/kg phenyllactic acid

Example 4

A medicament for treating molluscum contagiosum comprises 50g of medical grade kanuka honey packaged in a sterile tube suitable for medicaments. This form of medicament has been registered as a Class I la Medical Device with Medsafe (New Zealand Medicines and Medical Devices Safety Authority) in accordance with the EU Directive 93/42/EEC specifications regarding medical devices. Example 5

A method of treating molluscum contagiosum comprises topically applying approximately a 1.5 ml dose of medical grade kanuka honey to each molluscum contagiosum lesion site or sites. The site of application is then covered by a hypoallergenic dressing. The topical application of the honey is repeated daily for a period of two weeks or more.

Claims

Claims:

1. A pharmaceutical composition comprising honey for use in the treatment of molluscum contagiosum.

2. The pharmaceutical composition as claimed in claim 1 for the treatment of a molluscum contagiosum lesion.

3. The pharmaceutical composition as claimed in any one of claims 1 and 2 wherein the composition further comprises a pharmaceutically acceptable excipient.

4. The pharmaceutical composition as claimed in any one of claims 1 to 3 wherein the composition is formulated as a dermatologically-acceptable cream, gell, ointment, salve, lotion, cerate, balm, solution or the like.

5. The pharmaceutical composition as claimed in any one of claims 1 to 4 further comprising a second agent suitable for treating molluscum contagiosum.

6. The pharmaceutical composition as claimed in any one of claims 1 and 2,

wherein the composition comprises 50 to 100% honey.

7. A kit for treating molluscum contagiosum, comprising a pharmaceutical

composition comprising honey and a dressing.

8. The use of honey in the manufacture of a medicament for the treatment of

molluscum contagiosum.

9. The use as claimed in claim 8 wherein the medicament is for the treatment of a viral-induced lesion of molluscum contagiosum.

10. The use as claimed in any one of claims 8 and 9 wherein the medicament

comprises 50 to 100% honey.

11. The use as claimed in any one of claims 8 and 9 wherein the medicament is in the form of a dressing incorporating the honey.

12. A method of treating molluscum contagiosum in a subject, comprising

administering to the subject a therapeutically effective amount of honey.

13. A method as claimed in claims 12, wherein the honey is administered topically.

14. A method as claimed in any one of claims 12 and 13, wherein the honey is

administered to a molluscum contagiosum lesion.

15. A method as claimed in any one of claims 12 to 14 wherein the honey comprises medical-grade honey.

16. A method of treating molluscum contagiosum in a subject, comprising

administering to the subject a medicament comprising honey.

17. A method as claimed in claim 16, wherein the medicament comprises from 50 to 100% honey.

18. A method as claimed in any one of claims 12 to 17, wherein said treatment is administered in combination with a second therapy for treating molluscum contagiosum.

19. A method as claimed in any one of claims 12 to 18, wherein said treatment is coadministered with said second therapy.

20. A method as claimed in any one of claims 12 to 18, wherein said treatment is administered before said second therapy.

21. A method as claimed in any one of claims 12 to 18, wherein said treatment is administered after said second therapy.

22. A method as claim in any one of claims 12 to 21 , wherein said second therapy is selected from the list consisting of surgical removal, scraping, de-coring, freezing, needle electrosurgery, or combinations thereof.

23. A method as claim in any one of claims 12 to 21 , wherein said second therapy is selected from the list consisting of the administration of podophyllotoxin, liquefied

24. A method as claim in any one of claims 12 to 21 , wherein said second therapy is selected from the list consisting of the administration of cimetidine, griseofulvin, methisazone or combinations thereof.