Review Article

Stem cell therapy: A novel treatment approach for oral mucosal lesions

G. N. Suma, Madhu Pruthi Arora, Manisha Lakhanpal

Department of Oral ABSTRACT Medicine and Radiology, Stem cells have enormous potential to alleviate sufferings of many diseases that currently have no effective ITS CDSR, Dental therapy. The research in this field is growing at an exponential rate. Stem cells are master cells that have College and Hospital, Muradnagar, Ghaziabad, specialized capability for self‑renewal, potency and capability to differentiate to many cell types. At present, the Uttar Pradesh, India adult mesenchymal stem cells are being used in the head and neck region for orofacial regeneration (including enamel, dentin, pulp and alveolar bone) in lieu of their proliferative and regenerative properties, their use in Address for correspondence: the treatment of oral mucosal lesions is still in budding stages. Moreover, there is scanty literature available Dr. Madhu Pruthi Arora, regarding role of stem cell therapy in the treatment of commonly seen oral mucosal lesions like oral submucous E‑mail: aroramadhu21@ gmail.com fibrosis, oral lichen planus, oral ulcers and oral mucositis. The present review will focus on the current knowledge about the role of stem cell therapies in oral mucosal lesions and could facilitate new advancements in this area (articles were obtained from electronic media like PubMed, EBSCO, Cochrane and Medline etc., from year 2000 to 2014 to review the role of stem cell therapy in oral mucosal lesions).

Received : 02‑06‑14 Review completed : 09‑09‑14 KEY WORDS: Leukoplakia, lichen planus, mucositis, oral carcinoma, oral mucosal lesions, oral submucous Accepted : 01‑10‑14 fibrosis, oral ulcers, pemphigus, stem cell therapy

n the modern era, where biology and biotechnology Present day treatment modalities for oral mucosal lesions I have replaced the chemistry, we are exploring “biological like ulcerative lesions, premalignancies and malignancies solutions to biological problems.” Stem cell therapy is a part of mainly consist of steroids and antioxidants (which provide regenerative medicine that involves the use of undifferentiated only a short term and symptomatic relief) and surgery with cells in order to cure the disease. It is believed that stem cell or without chemo/radiotherapy (which leave the patient treatments have the potential to change the face of human with certain amount of morbidity). Advances in stem cell disease and reduce the suffering.[1] technology have opened new vistas for treatment of these lesions. Various studies have shown the successful role of stem Stem cell‑based therapies are being investigated for the cell therapies in the treatment of precancerous conditions, treatment of many conditions, including neurodegenerative oral ulcers, wounds and mucositis.[3] The recent concept of conditions such as Parkinson’s disease, cardiovascular disease, cancer stem cells (CSCs) has directed scientific communities liver disease, diabetes, autoimmune diseases and for nerve toward a new area of research and possible potential treatment [2] regeneration. In orofacial region these therapies are being used modalities for oral cancer.[4] The present article will discuss for tooth and periodontal regeneration, temporomandibular the role of stem cell applications in oral mucosal lesions. joint reconstruction, alveolar bone regeneration. Craniofacial stem cells including dental pulp derived stem cells have the Basic Concepts of Stem Cells potential to cure a number of diseases.

Access this article online Stem cells and it’s types Quick Response Code: Website: Stem cells are the precursors of the body tissue. They are www.jpbsonline.org defined as immature or undifferentiated cells that are capable of generating daughter cells identical to themselves or of DOI: differentiating into diverse cellular phenotypes.[5] There are 10.4103/0975-7406.149809 various types of stem cells. Embryonic stem cells, harvested from fertilized egg or blastocyst, have an extraordinary ability to form

How to cite this article: Suma GN, Arora MP, Lakhanpal M. Stem cell therapy: A novel treatment approach for oral mucosal lesions. J Pharm Bioall Sci 2015;7:2-8.

 2 Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 Suma, et al.: Stem cell therapy in oral mucosal lesions many cell types. Adult stem cell, found deep within organs and biomaterials (like polyglycolic acid, polytetrafluoroethylene), tissues, spread diffusely throughout and have restricted ability fibrin sealant and certain growth factors, which act as temporary to proliferate. Induced pluripotent stem cells (iPSCs) are adult matrix during the regeneration of tissue.[10,11] cells that have been genetically reprogrammed to an embryonic stem cell‑like state by being forced to express genes and factors Applications of Stem Cell in Orofacial Region important for maintaining the defining properties of embryonic stem cells. They express stem cell markers also and are capable Mesenchymal stem cells derived from dental and nondental of generating cells characteristic of all three germ layers. iPSCs sources have been effectively used for regeneration in may prove to be useful tools for drug development and modeling maxillofacial region like regeneration of tooth, pulp, of diseases and in transplantation medicine.[6,7] periodontal ligament, production of enamel and dentin, regeneration of salivary gland, repair of cleft lip and palate The stem cells are also divided into totipotent stem and craniofacial regeneration.[12‑14] However, the use of stem cells (e.g., fertilized egg cell or zygote), that can generate all cell cell treatment for oral mucosal lesions is a new concept, and tissue types present in an organism; Pluripotent stem which needs to be reviewed to promote the research further cells (like embryonic stem cells) can generate the majority in the area. of cell and tissue types present in an organism; multipotent stem cells (like mesenchymal stem cells [MSC]) can generate Stem Cell Therapy in Oral Mucosal Lesions a limited number of cell and tissue types, usually dependent on their germ layer of origin.[7] Among oral mucosal lesions, stem cell research is presently focused on the treatment of certain lesions only. These oral Properties of stem cells mucosal lesions are:

The main properties of stem cell, which make it different from • Ulcerative lesions: Like oral ulcers and wounds, oral any other specialized cells in the body are: Self‑renewal, that is mucositis, pemphigus vulgaris the ability to go through numerous cycles of cell division while • Premalignant disorders: Oral submucous fibrosis (OSMF), maintaining their undifferentiated state; differentiation, that is the oral lichen planus (OLP) ability to differentiate into a specialized cell type and the ability • Malignant lesions: Like oral carcinomas. to grow in vitro, in a laboratory, under a given environment.[7] The main mechanism behind the use of stem cells in these Extraction of stem cells lesions is discussed underneath.

Stem cells can be derived from the following sources Ulcerative lesions like embryonic stem cells sources and adult stem cells sources[7,8] [Figure 1]. The tissue samples containing stem Oral ulcers and wound healing cells are placed under specific conditions in laboratories/stem cell banks. The extraction of these stem cells is possible due Optimum healing of a cutaneous wound requires a good to unique receptors like Oct4, TRA‑1‑60 (called as stem cell integration of the complex biological and molecular events markers) present on the stem cell surface.[9] The extracted of cell migration and proliferation and extracellular matrix stem cells are grown on an appropriate scaffold made of deposition, angiogenesis and remodeling. Large wounds

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Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 3  Suma, et al.: Stem cell therapy in oral mucosal lesions take a long time to heal, and defective healing leaves behind Zhang et al. injected spheroid gingiva‑derived mesenchymal unacceptable scars and strictures. stem cells (GMSCs) in mice with chemotherapy‑induced oral mucositis and found that treatment with GMSCs Bone marrow‑derived MSCs (BM‑MSCs) are self‑renewing, decreased the severity and incidence of ulceration and expandable stem cells and are able to differentiate into restored the papillae structure, the lining, and thickness adipocytes, osteoblasts, and chondrocytes. These cells of the epithelial layer as compared with those of untreated possess the ability to engraft at the site of injury and promote disease group. The improved therapeutic benefits of tissue regeneration and wound healing through synergistic spheroid‑derived GMSCs may be attributed to their increased downregulation of proinflammatory cytokines and increased capabilities for engraftment and survival at the injury sites, production of soluble factors with antioxidant, antiapoptotic, trans‑differentiation into epithelial cells, and preconditioning and proangiogenic properties.[15] In oral wounds, they exhibit to hypoxic and oxidative challenges. Hence, GMSCs could increased re‑epithelialization, cellularity, intracellular matrix prove a sure shot therapy in oral mucositis following the formation and neoangiogenesis, thereby accelerate wound cancer therapies.[15] healing.[16] Hence, MSC therapy can be a promising therapeutic modality for oral ulcers and wounds [Figure 2]. Pemphigus vulgaris

El‑Menoufy et al. submucosally injected autologous BM‑MSCs Pemphigus vulgaris is a potentially life‑threatening disease, suspended in phosphate buffered saline around formocresol primarily affects the mucous membranes of patients over the induced oral ulcers in dogs. There was increased expression of age of 50 years characterised by formation of autoantibodies, both collagen and VEGF (vascular endothelial growth factor) directed against desmosomal glycoproteins (dsg1, dsg3) present genes in MSCs‑treated ulcers compared with controls.[17] Similar on the cell surface of the keratinocyte, resulting in the formation results were seen by Aziz Aly et al. in a study on formocresol of intraepithelial bullae and mucosal ulceration. induced oral ulcers in dogs using BM and adipose‑derived stem cells. Hence concluded MSCs transplantation may help The effective treatment of pemphigus vulgaris is accelerate the healing of oral ulcers.[18] long‑term use of corticosteroids that itself has detrimental systemic complications.[19] The immunomodulatory Oral mucositis and antiinflammatory properties of stem cells can be utilized in the treatment of the condition. In a research Oral mucositis is one of the most debilitating side effects which Vanikar et al.(2007) performed allogenic hematopoietic stem occur with chemo or radiotherapy. Management of mucositis is cell transplant (HSCT) with nonmyeloablative low‑intensity fairly symptomatic as yet. Presently MSCs have been explored conditioning in nine patients of Pemphigus vulgaris and found in its management by virtue of their immunomodulatory, that the existing skin lesions started to regress within 24 h of antiinflammatory functions as well as regenerative properties. stem cell treatment.[20] Their therapeutic efficacy can further be increased by transgenic approach or preconditioning them with certain factors like In a similar study consisted of clinical trial on patients with pro‑inflammatory cytokines.[15] pemphigus vulgaris to evaluate the effects of allogenic HSCT

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Figure 2: Role of mesenchymal stem cells in wound healing

 4 Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 Suma, et al.: Stem cell therapy in oral mucosal lesions into thymus, BM and peripheral circulation on central and Stem cell therapy may help to stimulate resident tissue stem peripheral arms of self‑tolerance; it was found that the recovery cells to transform into new fibroblasts, which may help in the began within 24 h of HSCT and new lesions stopped after removal of disintegrated biochemically and morphologically 6 months.[21] Stem cell therapy in pemphigus not only has shown altered collagen fibers[23,24] [Figure 4]. promises in treatment but also brings about a shift towards nonsteroidal approach in autoimmune diseases. However, Sankaranarayanan et al. have demonstrated the effectiveness the use of stem cell therapy for oral pemphigus is yet to be of stem cell treatment in OSMF patients by injecting 0.5–1 ml ascertained and needs clinical trials [Figure 3]. of marrow‑derived stem cell concentrate into labial and buccal mucosa and tongue under local anesthesia. They found reduction Premalignant disorders in blanching, improved suppleness of the mucosa, decrease in the burning sensation while consuming spicy food, significant Oral submucous fibrosis increase in the mouth opening and the results were found to be sustained in the follow‑up period from 6 months to 5 years.[24] Oral submucous fibrosis is a chronic, insidious disease associated with both significant morbidity (including pain, reduced oral Oral lichen planus opening) and an increased risk of malignancy. Various agents like Areca nut, gutkha, spices etc., are known to cause insult to oral Oral lichen planus is a chronic mucocutaneous disease mucosa by increasing cytokine production and release of reactive with uncertain etiopathogenesis. Various factors like stress, oxygen species; which in turn results in increased synthesis genetics, systemic diseases, drugs, dental restorative materials of collagen, decreased collagen breakdown, compromised and viruses are known to cause the disease either by an vascularity and increased tissue oxidative stress, ultimately antigen‑specific mechanisms like activating cytotoxic T‑cells resulting in clinical OSMF.[22] and nonspecific mechanisms like mast cell degranulation and matrix metalloproteinase activation. Both of these cause the Various medicinal, as well as surgical treatment modalities, have disruption of the basement membrane, which in turn triggers been tried to intervene the disease process at different levels, apoptosis of basal epithelial cells.[25,26] but with limited success. Stem cell‑based therapy is evolving as a promising new approach in this direction. Satisfactory therapy results are not, usually, achieved with conventional treatment (mainly consists of topical or Stem cell therapy is primarily aimed at neoangiogenesis by systemic steroids). A new therapy employing T‑cell immune releasing cytokines and growth factors (paracrine effect). modulation using MSCs have been proposed to treat OLP. MSCs can be easily isolated and expanded in vitro and in vivo • This may result in increased free radical scavenging by and can be utilized via systemic infusion or local application antioxidants (either naturally occurring or extraneous) to the lesion site. In addition to their regenerative capacities, • Neoangiogenesis may also facilitate the removal of senescent culture‑expanded MSCs possess the unique ability to modulate cells from the lesions by supplying more number of scavenging immune responses (both in vitro and in vivo) and may function defense cells and reversal of hypoxia in the diseased tissue. as immunomodulators in the maintenance of peripheral

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Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 5  Suma, et al.: Stem cell therapy in oral mucosal lesions tolerance, transplantation tolerance and autoimmunity. function of a broad range of immune cells, including T‑cells Making use of multiple pathways, MSCs suppress the and B‑cells[27] [Figure 5].

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Figure 4: Role of stem cell therapy in oral submucous fibrosis at various levels. (a) Removal of pathologically altered collagen and stimulation of healthy collagen. (b) Promoting neoangiogenesis. (c) Promoting antioxidant action

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 6 Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 Suma, et al.: Stem cell therapy in oral mucosal lesions

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Figure 6: Role of stem cells in cancer therapy Figure 7: Summarization of biology of stem cells in oral mucosal lesions

Malignant lesions gene expression and immunomodulation, thereby making it noninterventional and innovative treatment modality [Figure 7]. Oral carcinomas Conclusion Surgery and external beam radiation has been the mainstay of treatment for head and neck squamous cell carcinomas. Remedies in the medical field have always resulted from Despite the recent improvement in treatment modalities, the human inquisitiveness to know the nature and duplicate it. cancer recurrence and treatment failures continue to occur in The conservative treatment of life‑threatening and disfiguring a significant percentage of patients. Studies in a wide variety of defects and diseases is becoming the treatment of choice. The malignancies have demonstrated that a distinct subpopulation ability to treat currently incurable diseases has become a reality of tumor cells, termed CSCs, contain the ability to undergo with the evolution of stem cell therapy. Though certain studies self‑renewal and differentiation and hence have the ability to have confirmed the effectiveness of stem cell therapy in oral initiate tumorigenesis and support ongoing tumor growth.[28,29] mucosal disorders like OSMF, for diseases like oral ulcers and mucositis, the research is mainly confined to animal models and Stem cells here play a dual role‑in carcinogenesis and in the more human research trials are needed to ascertain the role of development of possible new cancer treatment options in stem cells in their management. There lies the need of extensive future. For past so many years stem cells have been used in the research by team of professionals including stem cell biologists, replenishment of blood and immune system damage during molecular biologists, geneticists, biomaterial scientists, treatment of cancer by chemotherapy or radiotherapy.[30] mechanical engineers and clinicians with knowledge of oral and maxillofacial disorders to make stem cell therapy a promising Apart from their use in the immuno‑reconstitution, the tool in such conditions. The evolution of more methods of stem stem cells have been reported to contribute in the tissue cell therapy in the future will give more simple, definitive and regeneration as they have extraordinary capacity to regenerate effective treatment of most of the oral mucosal diseases. and differentiate. The MSCs have been used in the cell‑based bone reconstruction following chemotherapy and surgery in References malignancies like osteosarcoma and Ewing sarcoma.[31] 1. Nadig RR. Stem cell therapy - Hype or hope? A review. J Conserv Another important aspect of their use in cancer therapy is the Dent 2009;12:131‑8. use as delivery vehicles.[32] Systematic delivery of drug or gene 2. Kim RH, Mehrazarin S, Kang MK. Therapeutic potential of mesenchymal stem cells for oral and systemic diseases. Dent Clin therapy has promising future but is currently limited by various North Am 2012;56:651‑75. factors such as immune detection, nonspecific accumulation 3. Devi P, Thimmarasa VB, Jayadev S, Mehrotra V, Arora P. Stem cells: in normal tissues and poor permeation. Stem cells can act as Treading the unexplored path. J Oral Sign 2010;2:41‑453. cell‑based carriers that may target the desired site. The recent 4. Sagar J, Chaib B, Sales K, Winslet M, Seifalian A. Role of stem cells in cancer therapy and cancer stem cells: A review. Cancer Cell Int concept of use of stem cells as delivery vehicles came from the 2007;7:9. fact that the tumors send out chemo‑attractants such as VEGF 5. Robey PG. Stem cells near the century mark. J Clin Invest to recruit MSC to form the supporting stroma of the tumor.[33] 2000;105:1489‑91. However, further work is required to understand the role of stem 6. Stem Cell Basics. In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of cells in cancer therapies, with the eventual goal of eliminating Health and Human Services, 2009. Available from: http://stemcells. the residual disease and recurrence [Figure 6]. nih.gov/info/basics/Pages/Default.aspx. [Last cited on 2013 Nov 12]. To summarize, the pivotal role of stem cell therapy in oral 7. Chotkowski G. Stem Cells: Emerging Medical and Dental Therapies and the Dental Professional. Friends of hu‑friedy academy. Available mucosal lesions is primarily aimed at neoangiogenesis, tissue from: http://www.friendsofhu‑friedy.com. [Last accessed on 2013 regeneration, increased cellularity, modulation of collagen Jun 28] Released 10/10/2008. [Reviewed on 2010 Oct 12].

Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 7  Suma, et al.: Stem cell therapy in oral mucosal lesions

8. Understanding Stem Cells. A Overview of the Science and Issues from 21. Vanikar AV, Trivedi HL, Patel RD, Kanodia KV, Modi PR, Shah VR. National Academies. National Academies Press. Available from:http:// Allogenic hematopoietic stem cell transplantation in pemphigus dels.nas.edu/resources/static‑assets/materials‑based‑on‑reports/ vulgaris: A single‑center experience. Indian J Dermatol 2012;57:9‑11. booklets/Understanding_Stem_Cells.pdf 22. Sudarshan R, Annigeri R, Vijayabala G. Pathogenesis of oral 9. Nagano K, Yoshida Y, Isobe T. Cell surface biomarkers of embryonic submucous fibrosis: The past and current concepts. Int J Oral stem cells. Proteomics 2008;8:4025‑35. Maxillofac Pathol 2012;3:27‑36. 10. Horst OV, Chavez MG, Jheon AH, Desai T, Klein OD. Stem cell and 23. Sankaranarayanan S, Ramachandran C, Padmanabhan J, Manjunath S, biomaterials research in dental tissue engineering and regeneration. Baskar S, Senthil Kumar R, et al. Novel approach in the management Dent Clin North Am 2012;56:495‑520. of an oral premalignant condition – A case report. J Stem Cells Regen 11. Gasparotto VP, Landim‑Alvarenga FC, Oliveira AL, Simões GF, Med 2007;3:21. Lima‑Neto JF, Barraviera B, et al. A new fibrin sealant as a 24. Sankaranarayanan S, Kailasam S, Elangovan S, Ravi VR, Sarkar S. three‑dimensional scaffold candidate for mesenchymal stem cells. Autologous bone marrow concentrate (Mononuclear Stem Cell) Stem Cell Res Ther 2014;5:78. therapy in the treatment of oral submucous fibrosis. J Indian Acad 12. Wu SM, Chiu HC, Chin YT, Lin HY, Chiang CY, Tu HP, et al. Effects Oral Med Radiol 2013;25:1‑4. of enamel matrix derivative on the proliferation and osteogenic 25. Srinivas K, Aravinda K, Ratnakar P, Nigam N, Gupta S. Oral lichen differentiation of human gingival mesenchymal stem cells. Stem planus - Review on etiopathogenesis. Natl J Maxillofac Surg Cell Res Ther 2014;5:52. 2011;2:15‑6. 13. Janebodin K, Reyes M. Neural crest‑derived dental pulp stem cells 26. Scully C, Carrozzo M. Oral mucosal disease: Lichen planus. Br J Oral function as ectomesenchyme to support salivary gland tissue Maxillofac Surg 2008;46:15‑21. formation. Dentistry S13:001. doi: 10.4172/2161‑1122.S13‑001 27. Ding G, Wang W, Liu Y, Zhang C, Wang S. Mesenchymal stem cell 14. Bueno DF, Sunaga DY, Kobayashi GS, Aguena M, Raposo‑Amaral CE, transplantation: A potential therapy for oral lichen planus. Med Masotti C, et al. Human stem cell cultures from cleft lip/palate Hypotheses 2011;76:322‑4. patients show enrichment of transcripts involved in extracellular 28. Rastogi P. Emergence of cancer stem cells in head and neck matrix modeling by comparison to controls. Stem Cell Rev squamous cell carcinoma: A therapeutic insight with literature review. 2011;7:446‑57. Dent Res J (Isfahan) 2012;9:239‑44. 15. Zhang Q, Nguyen AL, Shi S, Hill C, Wilder‑Smith P, Krasieva TB, 29. Routray S, Mohanty N. Cancer stem cells accountability in progression et al. Three‑dimensional spheroid culture of human of head and neck squamous cell carcinoma: The most recent trends! gingiva‑derived mesenchymal stem cells enhances mitigation Mol Biol Int 2014;2014:375325. of chemotherapy‑induced oral mucositis. Stem Cells Dev 30. Beccheroni A, Lucarelli E, Donati D, Sangiorgi L, Capponcelli S, 2012;21:937‑47. Gorini M, et al. Recovery of stromal stem cells in bone sarcoma 16. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells patients after chemotherapy: Implication for cell‑based therapy in enhance wound healing through differentiation and angiogenesis. bone defect reconstruction. Oncol Rep 2003;10:891‑6. Stem Cells 2007;25:2648‑59. 31. Edwards RG. Stem cells today: B1. Bone marrow stem cells. Reprod 17. El‑Menoufy H, Aly LA, Aziz MT, Atta HM, Roshdy NK, Rashed LA, Biomed Online 2004;9:541‑83. et al. The role of bone marrow‑derived mesenchymal stem cells in 32. Gao Z, Zhang L, Hu J, Sun Y. Mesenchymal stem cells: A potential treating formocresol induced oral ulcers in dogs. J Oral Pathol Med targeted‑delivery vehicle for anti‑cancer drug, loaded nanoparticles. 2010;39:281‑9. Nanomedicine 2013;9:174‑84. 18. Aziz Aly LA, Menoufy HE, Ragae A, Rashed LA, Sabry D. Adipose 33. Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira‑Hansen M, stem cells as alternatives for bone marrow mesenchymal stem cells Bekele BN, et al. Mesenchymal stem cells: Potential precursors for in oral ulcer healing. Int J Stem Cells 2012;5:104‑14. tumor stroma and targeted‑delivery vehicles for anticancer agents. 19. Kanwar AJ, De D. Pemphigus in India. Indian J Dermatol Venereol J Natl Cancer Inst 2004;96:1593‑603. Leprol 2011;77:439‑49. 20. Vanikar AV, Modi PR, Patel RD, Kanodia KV, Shah VR, Trivedi VB, et al. Hematopoietic stem cell transplantation in autoimmune diseases: Source of Support: Nil, Conflict of Interest: None declared. The Ahmedabad experience. Transplant Proc 2007;39:703‑8.

 8 Journal of Pharmacy and Bioallied Sciences January-March 2015 Vol 7 Issue 1 Copyright of Journal of Pharmacy & Bioallied Sciences is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.