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Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 60-65

Drug Treatments in Development for Pemphigus Vulgaris (Pv) - A Review

Alekhya P*1, Subash vijayakumar1, Ramchandra dharak2
1

Department of Pharmacy Practice, Vaagdevi College of Pharmacy, MGM Hospital, Warangal.2 Department of Dermatology, MGM Hospital, KMC, Warangal.

ABSTRACT: New therapies are needed to combat the symptomatic underlying disease processes in the pemphigus vulgaris (PV). The author examine the rapid increase in the management of disease by using systemic corticosteroid have dramatically reduce complication of the disease, current therapeutic options are limited by toxicity profiles. In this review, potentially new symptomatic and disease modifying therapies will be described. We undertook a review of observational study of intervention which could reduce the burden of PV, particularly in low income and middle income countries. So we identified several interventions which sufficient evidence to recommend implementation in health system, including calcium supplementation with the corticosteroid. The most promising novel treatment includes KC706, a p38 mitogen active proteinkinase (p38 MAPK) inhibitor. The pharmacological treatments for disease continue to change, with many exciting possibilities for the future.

Introduction
The term pemphigus refers to a group of autoimmune blistering diseases of the skin and mucous membranes. The three primary sub-sets of pemphigus are: pemphigus vulgaris (PV), pemphigus foliaceus and paraneoplastic pemphigus. Each type of pemphigus has distinct clinical and Immuno-pathological features. PV accounts for approximately 70% of pemphigus cases. Common symptoms include blisters in the mouth and on the skin, with the skin lesions forming erosions which tend to develop excessive granulation and crusting. Genetic factors, old age and the presence of autoimmune disorders are risk factors for this condition. GOALS The goal of managing pemphigus is to induce and maintain remission with the lowest possible doses of medication and to minimize the risk of serious and potentially fatal adverse effects [1] Treatments: It includes/involves 1. Topical therapy 2.Systemictherapy Adjuvant therapy Conventional therapy 3. Biological therapy 4. Emerging therapy.

1. Topical therapy The topical therapy is mainly used if the mucosal surface is involved huilgol and black have reviewed topical therapy for pemphigus and pemphigoid in detail [2, 3] show in table no1: Topical therapy of pemphigus vulgaris and its various formulation.
Formulation Topical analgesic or anaesthetics Antiseptic mouthwashes Mouthwashes Drug name Benzydamine hcl (difflam oral rinse) Chlorhexidine gluconate (corsodyl) Hexetidine (Oral dene) Soluble betamethasone sodium phosphate 0.5mg tablet dissolved in 10ml water (QID) Triamanolone acetonide 0.1% in adhesive paste (Adcortyl in orabase) Dose 0.15% Oral hygiene 0.1% Category

0.5mg

For multiple oral erosions

Topical agent

0.1%

For isolated oral erosion

For oral pemphigus measures such as soft diets and soft Key words: Corticosteroid, Immunoglobulins, KC706, toothbrushes help minimize local trauma . Others : 2.5mg hydrocortisone lozenges or sprayed directly with Pemphigus vulgaris an asthma aerosol inhaler. Eg: Beclomethasone Received 7 April 2012; accepted 28 April 2012; dipropionate 50-200g or budenoside 50-200g. Topi*Corresponding Author: Alekhya cal cyclosporine 100mg/ml oral pemphigus [4]. Department of Pharmacy Practice, Vaagdevi College of 2. Conventional therapy It includes both the systemic therapy and the adjuvant Pharmacy, MGM Hospital, Warangal. therapy. It has been depict in table no :2. Systemic E-mail: alekhyapabba@gmail.com therapy of pemphigus vulgaris and its mechanism of action. Copyright 2011 Published by IJPSL. All rights reserved

Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 59-64 Systemic agent Prednisolone Mechanism of action Directly inhibit pemphigus serainduced acantholysis 26 Route of administration Oral Dose and frequency 1-2mg/kg/d Advantage Effective rapid onset Inexpensive Rapid onset inexpensive Disadvantage Osteoporosis

Dexamethasone

Oral or IV pulse

50-200mg/d for 33-5day

IV administration

(b) Conventional adjuvant therapy [1,5,6] It includes Immunosuppressive agents: Azathiprine, Mycophenolate mofetil, Methotrexate, Cyclophosphamide, Chlorambucil, and Cyclosporine respectively. Anti-inflammatory agents: Gold, Dapsone, Colchicine Antibiotics: Tetracycline, Erythromycin, Minocycline.It has been shown in Table no : 3 conventional adjuvant therapy of pemphigus vulgaris, mechanism of action and its advantages and disadvantage. 3.Biological therapy ; It includes Tumour Necrosis Factor-alpha antagonists : Eternacept, Infliximab Intravenous Immunoglobulins IgG1 anti-CD20 monoclonal antibody : Rituximab It has been depict in the table no. 4 Biological therapy of pemphigus vulgaris and its characteristic of drug. Drug Mechanism of action Route of administration SC injection IV infusion IV infusion Dose and frequency Side effects Advantage Disadvantage

Etanercept [12,13]

Infliximab [14,15] Intravenous Immunoglobulin (IvIg) [20]

Tumor necrosis factor- alpha (TNF-) Antagonists- role in acantholytic process [10,11] Rapid & selective decline in the serum levels of pathogenic PV auto antibodies Chimeric murine/Human IgG1 anti-CD 20 monoclonal antibody targets pre- & mature Blymphocytes results complement & antibody dependent cytotoxicity and apoptosis

50mg weekly

Under clinical trial

5mg/kg/ cycle 2g/kg/ cycle During infusion chills, HTN, Tachycardia, Pyrexia, Nausea & headache Rapid action IV administration expensive, risk of bloodborne virus infection Expensive

Rituximab [21]

IV infusion

375mg/ M2 weekly for 4 weeks; or 1,000mg on days 1&15

Systemic infections

Rapid action

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Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 59-64
Table no : 3
Drug type Systematic agent Azathioprine Mechanism of action Mode of administration Oral Dose and frequency 3-4mg/ kg/d Side effects Advantages Disadvantages Slow onset side effects profiles

Immunosuppresive agents I

Block DNA replication (inhibits lymphocyte proliferation and activation by interfering with several enzymes required for nucleotide replication Inhibits the proliferation of lymphocytes by interfering with DNA replication abrogate -cell proliferation [7,8] Folate antagonist

Myelosuppression & nausea

Inexpensive

Mycophenolate

Oral

30-45mg/ kg/d

Arterial Hypertension, GI disturbances Myelosuppression hepatotoxicity pneumonitis Neutropenia, alopecia, GI disturbances raised transaminases

Well tolerated & relatively less toxic

Expensive

Methotrexate

Oral

12mg/ weekly

Oral administration, inexpensive

Slow onset

Cyclophosphamide

It has pronounced effect on lymphocytes, and can also used as immunosuppresant

Oral IV pulse immunoablati ve highdose (IV)

2-3mg/ kg/d 0.5-1g/m (2Monthl y) 50mg/kg/ d for 4 days 0.050.2mg/ kg/d 2-5mg/ kg/d

Inexpensive

Potential risk of haemorrhagic cystitis & carcinoma of bladder Minimal data Side effect profile expensive

Chlorambucil

Steroid sparing effect

Oral

Myelosuppression Hypertension, renal impairment, hypertrophic gingivitis Rashes; Nephrotic syndrome, Myelosuppression Haemolysis: Methaemoglobinemia, Hypersensitivity reactions Anorexia Flushing & headache due to vasodilator with nicotinamide GI upset discolouration of teeth Headache Hyper pigmentation particularly at the sites of blistering

Inexpensive

Cyclosporine

Steroid sparing effect

Oral

Inexpensive

Gold Antiinflammatory agents Dapsone

Steroid sparing agent

Intramuscular Oral

25-50mg/ biweekly 6-9mg/d 50200mg/d

Inexpensive

IM administration slow onset

Steroid Sparing action

Oral

Inexpensive

Minimal data Inexpensive Inexpensive

Colchicine Tetracycline Nicotinamide

Steroid sparing diuretic

Oral Oral

1.21.8mg/d 1-2g/d 15002000mg/ d

Antibiotics

It is acts as an adjuvant

Erythromycin Minocycline

Oral Oral

1,200mg/ d 100200mg/d

Inexpensive Inexpensive

Intake of pills more than required quantity

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Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 59-64 4. Emerging therapy It includes Plasmapheresis Immunoadsorption Extracorporeal photochemotherapy (ECP) Cholinergic agonists Other experimental therapies such as desmoglein 3 peptides & KC706. It has been shown in Table no: 5 Emerging therapy of pemphigus vulgaris. Table no:5 Drug Plasmapheresis Mechanism of action It is the process by which plasma is removed in the removal of the pathogenic PV antibodies [16] It is the process by which plasma is passed through an absorber column (ie Protein A) to remove circulating immune complexes & IgG [17] Process by which white blood cells are collected (Leukaphresis) exposed to 8methoxypsoralen irradiated with UV- light. It involve inhibition of pathogenic autoantibody production by lymphocytes [6] Acantholytic process of pemphigus . [1,18,19,26] eg: Pyridastigmine bromide (Mestinon@, valent pharmaceuticals) Side effects Septicemia; fluids &Electrolyte imbalance Advantages Direct & immediate removal of IgG & therefore removal of PV antibodies Rapid decline in desmogleinspecific IgG auto antibodies Disadvantages Central venous access; Specialist equipment; trained staff; expensive rebound production of PV antibodies Specialist equipment; trained staff; expensive venous access can be problem

Immunoadsorption (IA)

No side effects safe & well tolerated

Extracorporeal Photochemotherapy (ECP/ Photopheresis)

No side effects were noted

Used for refractory PV can be performed via peripheral venous access

Specialist equipment trained staff expensive venous access can be problem limited availability

Cholinergic agonists

Only 2 clinical studies have been performed

Other experimental therapy Selective therapy using intravenous desmoglein 3 peptides suppress the production of anti-desmoglein 3 antibodies through inactivation and/or deletion of disease associated CD4 +T lymphocytes [22] Novel therapy KC 706 (Kernia Inc) is an oral allosteric p38 mitogen- activated protein (P 38 MAPK) inhibitor. P38 MAPK Inhibition Prevents blister formation [23], under clinical trial to determine the safety and efficacy of KC 706 in the management of PV.

Combination Therapy Dexamethasone- Cyclophosphamide pulse therap. [9]/ The pulse consisted of 136 mg dexamethasone dissolved in 5% dextrose given in a drip over a period of 12 hours on 3 consecutive days. In addition, 500 mg cyclophosphamide was added in the drip on the first day. Such pulses were given at monthly intervals. In between the pulses patients were given 50 mg cyclophosphamide orally each day. The results were encouraging, the chief advantage being freedom from side effects of corticosteroid therapy. The lesions healed in 34 days and the patients were able to resume their work within one week.

Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 59-64 AYURVEDIC TREATMENT [24] The Ayurvedic treatment of PV is aimed at reducing blister formation, promoting healing of blisters and erosions, and boosting the immune system of the body. Medicines like Arogya-Vardhini, Panch-TiktaGhrut-Guggulu, Punarnavdi-Guggulu, GokshuradiGuggulu, Mahamanjishthadi-Qadha, Saarivasav, Usheerasav and Chandanadi-Qadha are used to treat blister formation. Herbal medicines like Punarnava (Boerhaavia diffusa), Manjishtha (Rubia cordifolia), Saariva (Hemidesmus indicus), Chandan (Santalum album), Haridra (Curcuma longa), Daruharidra (Berberis aristata), Yashtimadhuk (Glycerrhiza glabra), Gokshur (Tribulus terrestris), Kutki (Picrorrhiza kurroa) and Mandukparni (Centella asiatica) can also be used to treat the blisters. In order to promote healing of the blisters and erosions, local application of Chandanadi oil, Chandan- Bala-Laxadi oil, Jatyadi oil, Yashtimadhuk-Ghrut, Panch-TiktaGhrut and Shatadhout-Ghrut can be used. An ointment containing Manjishtha, Saariva, Chandan, Haridra and Mandukparni can also be used for this purpose. In order to improve the immune status of the body, medicines like Suvarna-Malini-Vasant, SuvarnaParpati, Tulsi (Ocimum sanctum), Bhrungraj (Eclipta alba), Ashwagandha (Withania somnifera), Shatavari (Asparagus racemosus), Bala (Sida cordifolia) and Naagbala (Grewia hirsuta) are used. All medicines need to be given long term in order to have a good therapeutic effect. Ayurvedic medicines can be given in combination with modern medicines to both improve the therapeutic response and to reduce the dose of steroids. HERBAL TREATMENT [25] As a herbal remedy, try tea tree oil, lavender, calendula and thyme. First cleanse with mild soap and then apply the mixture directly to the skin, covering with a sterile bandage. Speak to your doctor before starting anything new. Acupuncture can be used to ease nausea in those who suffer with pemphigus vulgaris. Acupuncture can also help with pain and side effects of treatment. It may be necessary to use electro-acupressure, a process in which nothing penetrates the skin. Homeopathy can also be used as a natural method of treatment for pemphigus vulgaris. It is important that the patient find a certified homeopath practitioner in order for treatment to be effective. According to ayurvedic medicine, herbal applications of chandanadi oil, jatyadi oil, yashtimadhuk-ghrut, panch-tikta-ghrut and shatadhout-ghrut can be used. An ointment containing manjishtha, saariva, chandan, haridra and mandukparni can also be used for treatment. Massage can help with circulation and can be used in the treatment of pemphigus vulgaris. It can be relaxing -and help in managing sleeplessness. Find an experienced massage therapist to give you the right massage. Apples Eating three apples a day are reported to be effective in treating the symptoms of pemphigus vulgaris. Some who are afflicted drink two glasses of apple juice a day instead of eating three apples. Applesauce and fruit leather are other sources for apple therapy. One healthy treat is to pour applesauce in a food dehydrator and run the machine. This makes homemade fruit leather. No dietary restrictions are needed, but patients with oral disease may benefit from avoiding certain foods (eg, spicy foods, tomatoes, orange juice) and hard foods that may traumatize the oral epithelium mechanically (eg, nuts, chips, hard vegetables and fruit). CONCLUSION Pemphigus vulgaris is a life threatening disease, it can be treated with the various type of therapies. Corticosteroid therapy remains the mainstay of treatment for PV, the number of side effects with its use is to be monitored. Conventional immunosuppressive and anti-inflammatory therapies are further associated with serious and potentially life-threatening adverse effects. Today, a number of novel therapies have been developed and these therapies appear promising, randomized controlled trials are needed to establish their safety and efficacy in the management of PV. This review reported the treatment modalities in Ayurvedic and Herbal system of medicine.

REFERENCE:
[2] Huilgol SC, Black MM. Management of the immunobullous disorders. II. Pemphigus. Clin Exp Dermatol 1995; 20: 28393. [3] Huilgol SC, Black MM. Management of the immunobullous disorders. I. Pemphigoid. Clin Exp Dermatol 1995; 20: 189201. [4] Goopta C, Staughton RCD. Use of topical cyclosporin in oral pemphigus. J Am Acad Dermatol 1998; 38: 8601. [5] Mydlarski PR, Ho V, Shear NH. Canadian consensus statement on the use of intravenous immunoglobulin therapy in dermatology. J Cutan Med Surg 2006; 10:205-21.. [6] Yeh SW, Sami N, Ahmed AR. Treatment of pemphigus vulgaris: current and emerging options. Am J Clin Dermatol200; 6:327-42. [7] Enk AH, Knop J. Mycophenolate is effective in the treatment of pemphigus vulgaris. Arch Dermatol. 1999; 135:54-56. [8] Lipsky JJ. Mycophenolate mofetil. Lancet. 1996; 348:1357-1359.

[1] Dick SE, Werth VP. Pemphigus: a treatment update. Autoimmunity 2006; 39:591-9..

Alekhya et al /International Journal of Pharmaceutical Sciences Letters 2012 Vol. 2 (3)| 59-64 [9] Pasricha JS, Khaitan BK, Raman RS, Chandra M. Dexamethasonecyclophosphamide pulse therapy for pemphigus. Int JDermatol 1995; 34: 87582. [10] Feliciani C, Toto P, Amerio P, et al. In vitro and in vivo expression of interleukin-1alpha and tumor necrosis factor-alpha mRNA in pemphigus vulgaris: interleukin-1alpha and tumor necrosis factor-alpha are involved in acantholysis. J Invest Dermatol 2000; 114(1):71-7. Lopez-Robles E, Avalos-Diaz E, Vega-Memije E, [11] et al. TNFalpha and IL-6 are mediators in the blistering process of pemphigus. Int J Dermatol 2001; 40:185-8. Pardo J, Mercader P, Mahiques L, et al. Infliximab [12] in the management of severe pemphigus vulgaris. Br J Dermatol 2005; 153:222-3. Jacobi A, Shuler G, Hertl M. Rapid control of ther[13] apy-refractory pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol 2005; 153:448-9.. Berookhim B, Fischer HD, Weinberg JM. Treat[14] ment of recalcitrant pemphigus vulgaris with tumor necrosis factor alpha antagonist etanercept. Cutis 2004;74:245-7.. Lin MH, Hsu CK, Lee JY. Successful treatment of [15] the recalcitrant pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol2005;141:680-2. Guillaume JC, Roujeau JC, Morel P, et al. Con[16] trolled study of plasma exchange in pemphigus. Arch Dermatol1988;124:1659-63. Eming R, Hertl M. Immunoadsorption in pemphi[17] gus. Autoimmunity 2006; 39:609-16..

[18] Grando SA, Dahl MV. Activation of keratinocyte muscarinic acetylcholine receptors reverses pemphigus acantholysis. J Eur Acad Dermatol Venereol 1993;2:72-86. Iraji F, Yoosefi A. Healing effect of pilocarpine [19] gel 4% on skin lesions of pemphigus vulgaris. Int J Dermatol. 2006; 45(6):743-6. Bystryn JC, Jiao D. IVIg selectively and rapidly [20] decreases circulating pathogenic autoantibodies in pemphigus vulgaris. Autoimmunity 2006;39:601-7.. Schmidt E, Hunzelmann N, Zillikens D, et al. [21] Rituximab in refractory autoimmune bullous diseases. Clin Exp Dermatol 2006; 31:503-8 . Anhalt G, Werth V, Strober B, et al. An open[22] label phase I clinical study to assess the safety of PI-0824 in patients with pemphigus vulgaris. J Invest Dermatol2005; 125:1088. Berkowitz P, Hu P, Warren S, et al. p38 MAPK [23] inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci 2006; 103:12855-60. Abdulmubeen M. Pemphigus Vulgaris- Ay[24] urvedic Herbal Treatment. Ezine 2008;1-6 [25] Cited on : 16.04.2012. www.ehow.com/way5241770-natural-cures-pemphigus-vulgaris [26] Vijayakumar S, Alekhya P, Sasikala, Dharak RC. Pemphigus vulgaris A Short Review. IJPPR 2012; 3:64-72.
Cite this article as: Alekhya P, Subash vijayakumar, Ramchandra dharak. Drug Treatments in Development for Pemphigus Vulgaris (Pv) - A Review. Int. J. Pharm. Sci. Lett. 2012 : 2: (3) 60-65
Source of Support: Nil. Conflict of interest: None declared.

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