Introduction

A Triple combination of

CLOBETASOL PROPIONATE (superpotent steroid)

NEOMYCIN (anti bacterial) CLOTRIMAZOLE (antifungal)

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Why triple combination??

The secondarily infected skin dermatoses -difficult to treat and hence would require the combination therapy in view of frequent mixed infections. Topical therapy with a broad spectrum formulation combining an antibiotic, antifungal and steroid preparation is very useful in such complicated dermatoses. This is of particular advantage when a specific diagnosis of the source of infection is not possible. The corticosteroids are mainly used in such preparations for their anti-inflammatory and anti-allergic properties. Anti-microbial agents take care of a broad spectrum of infective etiologies.

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Why triple combination??

Secondary bacterial and fungal infections are common in steroid responsive dermatoses Combination therapy with antibiotic and anti-inflammatory agents or antifungal and anti-inflammatory agents has been proved to be effective in treatment of primary infected skin lesions and secondary infected dermatoses in number of clinical studies. Combination of corticosteroids with antibacterial and/or antifungal agents have been shown to be very effective in secondarily bacterial and fungal infections occurring in steroid responsive dermatoses.
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Why triple combination??

Secondary bacterial and fungal infections in patients requiring long term steroids or short term potent steroids for the primary SRD have always been the cause of concern among dermatologists.
Elevated rates of accompanying bacteria were detected with Candida species colonizing skin. These secondary bacterial and fungal infections become difficult to treat if not treated in initial stages.

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Steroid responsive dermatoses

Psoriasis contact dermatitis Atopic dermatitis

Chronic eczemas
Lichen sclerosis Lichen simplex chronicus Lichen planus

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Effect on action of steroid

Clinical trials show that antibacterial (neomycin) and / or antifungal (miconazole, clotrimazole) agents in combination with steroid do not alter the pharmacodynamic response of the steroid.
Rather eradication of Staphylococcus aureus prevents the exacerbation of steroid responsive dermatoses may lead to a steroid-saving effect.

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Host factors
Lack of expression of antimicrobial peptides on skin in SRD

Increased adherence of staph aureus to skin in atopic dermatitis

Compromised skin barrier function

Reduced epidermal hydration and skin surface lipids increased colonization with pathogens
Risk for secondary infections may also be increased by hard scratching that abrade the skin and opens it to bacterial invasion Hyperkeratotic skin favors fungal infections

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Neomycin sulphate
Aminoglycoside family of agents Neomycin interferes with bacterial protein synthesis. Used to treat infections caused by gram-negative and aerobic gram-positive bacilli (mainly staphylococci) Active against nearly all gram negative organisms, with the exception of Pseudomonas and anaerobic organisms, such as bacteroides. Of the gram positive organisms, staphylococci are highly sensitive. (staphylococci are responsible for 80% of the secondary bacterial infections occuring in SRD) Formulated alone or in combination with other antibiotics (bacitracin, polymyxin B, gramicidin) Most often combined with steroids.

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Neomycin sulphate MOA

binds to a specific protein on the 30S of the microbial ribosome faulty alignment or recognition wrt m-RNA & t-RNA during initiation m-RNA misread on the recognition region of the ribosome wrong amino acid inserted into the peptide affected ribosomes released, re-initiate and repeat the process increased proportions of nonfunctional peptide chains
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USES
First aid to help prevent infection in minor cuts, scraps, and burns
Eczema - topical neomycin + steroid is effective for the treatment of infected or potentially infected eczema

Establishing viable skin grafts in burn patients

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Allergic Contact Dermatitis and Neomycin

Despite its widespread use, the actual prevalence of contact allergy with neomycin in the general population is negligible. Actual incidence of allergic contact dermatitis to neomycin in general population to be 1% or less -- though some studies have reported - drug allergy upto 10% .

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Other Adverse Effects

Ototoxicity and nephrotoxicity have been reported. Hence should not be used over wide surface area. Topical application of the drug, resistant staphylococci have been reported.

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Clotrimazole
1st topical imidazole broad spectrum antifungal

Spectrum of Activity Candida species Dermatophytes (Trichophyton, Microsporum, Epidermophyton) Malassezia furfur Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum

Interrupts synthesis of ergosterol permiability of cell membrane.

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Uses Topical Candidiasis Complicated tinea infections Secondary fungal infections in SRD

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Clinical Studies
Comparable safety and efficacy with miconazole and econazole in superficial mycoses.
In combination with steroids ,Clotrimazole cream demonstrated better clinical results in patients of tinea infections than either agent alone did during the first 3 to 5 days. Cure rates were at least as good or better than compared to clotrimazole alone.

Patients with tinea cruris or tinea corporis better symptomatic improvement with clotrimazole combined with topical steroid than either agent used individually
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Clotrimazole Vs Miconazole
In superficial skin infections with candida and in candidal vaginitis miconazole and clotrimazole produced comparable results.

Clotrimazole has more potent invitro MIC levels as compared to miconazole against candida albicans
MIC of clotrimazole = 1to 2 mcg/ml MIC of miconazole = 1to 4 mcg/ml

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Clobetasol Propionate
Clobetasol is an analog of prednisolone. Class I- superpotent steroid. Chemically, clobetasol propionate is related to halobetasol.

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Properties
Anti-inflammatory

Induction of inhibitory proteins (lipocortins)

Inhibit release arachidonic acid from membrane phospholipids by phospholipase A2. PG & LT (potent mediators of inflammation) Vasoconstrictive actions: access of inflammatory cells . extravasation, swelling.

Antipruritic

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Mechanism of action
Membrane phospholipids Phospholipase A2

Inhibition

Lipocortins

Arachidonic acid

Prostaglandins and leukotrienes

Topical steroids Inflammation

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USES
Relief of inflammatory and pruritic manifestations of hyperkeratotic dermatoses (moderate to severe) such as resistant atopic dermatitis, contact dermatitis, chronic eczema, and psoriasis
Short term (2 weeks or less) Conc: 0.05 percent cream, gel and ointment

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Place in therapy
Can be used for treating chronic, hyperkeratotic or lichenified lesions More efficacious than fluocinonide, betamathasone and halcinonide in treatment of psoriasis, eczema and other refractory SRD. Palms and soles have a thick stratum corneum, hence can be used at these sites Ointment bases are preferred as they enhance the penetration for extremely dry, thick, hyperkeratotic lichenified skin lesions and creams for acute and subacute dermatoses Class 1 steroid: appropriate for plaque in regions excluding face, axilla, groin and genitals
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Indication

For the treatment of corticosteroid-responsive dermatoses with secondary infection caused by organisms susceptible to neomycin and clotrimazole. For the treatment of complicated tinea infection by organisms susceptible to neomycin and clotrimazole.
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DOSAGE : Thin layer of Gracederm cream to the affected skin areas twice daily Therapy should be discontinued when control has been achieved or up to a maximum of 2 weeks

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Precautions: Gracederm cream is not for ophthalmic use. Not to be used in children less than 12 years age. Not to be large surface areas, prolonged use, and occlusive dressings Not for application on face & intertriginous areas like groin or axillae Failure to heal; may be evidence of allergic contact dermatitis Not for herpes, scabies, tubercular and viral skin disease, rosacea, perioral dermatitis, uncontrolled infection. Dosage should not exceed 50 g per week Not used > 2 weeks continuously, drug holiday of at least 1 week is required after 14 days of continuous use If no improvement is seen within 2 weeks, reassessment of the diagnosis may be necessary. Due to the concern of nephrotoxicity and ototoxicity associated with neomycin, this combination should not be used over wide surface area.
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ADVERSE EFFECTS
Common: burning, stinging, or itching. skin atrophy, erythema, fissuring, folliculitis, paresthesia, numbness & telangiectasia. striae, acne, urticaria, hypopigmentation, secondary infection, miliaria. Ointment for 16 days - (12% skin thickness) Rarely hypersensitivity - allergic contact dermatitis Pustular psoriasis -withdrawal of clobetasol for plaque psoriasis used in higher doses >2 weeks.

Neomycin can cause allergic Contact dermatitis, Ototoxicity and nephrotoxicity .

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Contraindications
Gracederm Cream is contraindicated in those patients with a history of sensitivity reactions to any of its components.
Not for use in the eyes or in the external ear canal if the eardrum is perforated.

It is contraindicated in viral and tuberculous lesions of the skin

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Contraindications

Carcinogenesis and mutagenesis-Though well controlled animal or human studies have not done with the triple combination. There is not much cause for concern as all these three molecules have been used safely for many years and there are no reported cases.

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Patient Profile
Pregnancy: not recommended
Lactation : not recommended Children <12 yrs: not recommended Geriatric : caution in patients with history of preexisting skin atrophy.

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FAQs
1.
What benefit will patient get with Gracederm? Ans- Gracederm contain clobetasol propionate which is a super potent steroid, clotrimazole a time tested antifungal and neomycin sulphate which is a broad spectrum antibacterial. It gives 3600coverage and quick relief from all directions in complicated tinea.

2. Why the price is Rs 45/- for 15 gm pack? Ans- All the products from Gracewell are known for its quality. We never compromise with the quality of the products. So we are buying the bulk drugs at a higher rate from developed countries. Also your patients quick relief is our concern and it will only come when Gracederm quality is good 3. Can Gracederm be used with other drugs? Ans-Yes it can be used with other drugs but it is advisable to use it for a short period of time (not more than 2 weeks)
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FAQs
4.
Why have you used the combination of Clobetasol propionate, neomycin sulphate and clotrimazole? Ans We have added adequate amount of constituents to deliver the adequate therapeutic quantities in infections.Also,with the right concentration of triple combination your patients will have better patient compliance and have cost convenience. 5. Can Gracederm be used for infection caused by both dermatophytes and Candida species? Ans-Yes doctor,Gracederm is effective in control of both dermatophytes and Candida species as it give 3600 resolution to your patients. 6. Can Gracederm be prescribed to the pediatric patients? Ans- It is recommended only to the patients above 12 yrs.
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FAQs
7. Why have you combined with a high potent steroid Clobetasol propionate? Ans- Clobetasol propionate is a high potent steroid which gives quick relief from inflammation. When combined with antibiotic and anti-fungal agents,clobetasol proved to be very effective in treatment of complicated tinea infections and secondary infected dermatoses 8. Can it be used in all types of tinea infections? Ans-Gracederm cream is recommended only for the treatment for tinea corporis(ringworm),tinea pedis,tinea unguium,tinea barbae and tinea manuum.It should not be on face and intertrigenious areas like groin and axilla region.

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