Ethnopharmacological approaches to wound healing—Exploring medicinal plants of India

Ethnopharmacological approaches to wound healing—Exploring medicinal plants of India

Available online at www.sciencedirect.com Journal of Ethnopharmacology 114 (2007) 103–113 Review Ethnopharmacological approaches to wound healing—E...

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Available online at www.sciencedirect.com

Journal of Ethnopharmacology 114 (2007) 103–113

Review

Ethnopharmacological approaches to wound healing—Exploring medicinal plants of India B. Kumar a , M. Vijayakumar a , R. Govindarajan a,∗ , P. Pushpangadan b a

b

National Botanical Research Institute, Rana Pratap Marg, Lucknow 226001, India Amity Institute for Herbal and Biotech Products Development, Thrivananthapuram 695014, India Received 12 November 2006; received in revised form 1 August 2007; accepted 2 August 2007 Available online 12 August 2007

Abstract India has a rich tradition of plant-based knowledge on healthcare. A large number of plants/plant extracts/decoctions or pastes are equally used by tribals and folklore traditions in India for treatment of cuts, wounds, and burns. The present review thus attempts to analyze the ethnobotanical knowledge base for treatment of cuts and wounds which includes a usage of plants, methods employed by tribals and folklore practices prevailing in India. Pharmacological reports available on Indian medicinal plants employing various wound healing models and its underlying molecular mechanism, wherever available, has also been briefly reviewed. This pharmacological validation on Indian medicinal plants is very limited and a large number of plants used in tribal and folklore with enormous potential have not been validated for their wound healing activity. This review therefore attempts to bridge the lacunae in the existing literature and offers immense scope for researchers engaged in validation of the traditional claims and development of safe and effective and globally accepted herbal drugs for cuts and wounds. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Wound healing; Cuts; Wounds; Burns; Indian medicinal plants; Ayurveda

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology of wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ayurvedic remedies for healing of wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnobotanical approaches/leads to wound healing —Indian perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnopharmacological validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The concept of developing drugs from plants used in indigenous medical system is much older, while in some cases direct links between a local and biomedical use exists, in other cases the relationship is much more complex (Heinrich and Gibbons, 2001). Wounds and particularly chronic wounds are major concerns for the patient and clinician alike; chronic wounds affect a large number of patients and seriously reduce their quality of ∗

Corresponding author. Tel.: +91 522 2205831. E-mail address: [email protected] (R. Govindarajan).

0378-8741/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2007.08.010

103 104 104 105 108 109 110

life. Current estimates indicate that nearly 6 million people suffer from chronic wounds worldwide. There are very few Indian studies on the epidemiology of chronic wounds. The prevalence of chronic wounds in the community was reported as 4.5 per 1000 population whereas that of acute wounds was nearly doubled at 10.5 per 1000 population (Gupta et al., 2004). Balick and Cox (1996) reported that only 1–3% of drugs listed in Western pharmacopoeia are intended for use in the skin and for wounds; by comparison, at least one third of herbal remedies are for such use. It has been estimated in America that 3–5% of all hospitalized patients suffer from ulcers and if the patient has spinal cord injuries, the percentage of ulcer in patients is

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between 25 and 85%. In America the cost of institutional care on the same is supposed to be US$ 1000 per day while no such estimates are available for Indian institutions, the same demographic study has projected market expenditure of over US$ 7 billion world wide for provisions of wound healing properties (Shefali and Bhaduri, 1999). Both traditional and Western systems of medicine for wound healing suffer from lack of resources and awareness. These need advocacy and wider publication for relevant research to be pursued. In broad terms, the relevant headings for consideration are utilization, safety and efficacy. Research on wound healing agents is one of the developing areas in modern biomedical sciences. Many traditional practitioners across the world particularly in countries like India and China with age old traditional practices have valuable information of many lesser-known hitherto unknown wild plants used by the traditional healers for treating wounds and burns. Several drugs of plant, mineral and animal origin are described in the traditional texts of Indian systems of medicine like Ayurveda for their healing properties under the term ‘Vranaropaka’. Besides the classical systems of Indian Medicine, the folk and the tribal medicine also employ a number of plants and animal products for treatment of cuts, wounds and burns. Some of these plants have been screened scientifically for the evaluation of their wound healing activity in different pharmacological models and human subjects, but the potential of most of the plants remain unexplored.

wounds is another major problem due to the high cost of therapy and the presence of unwanted side effects (Porras-Reyes et al., 1993; Suh et al., 1998). It is consented that reactive oxygen species (ROS) are deleterious to wound healing process due to the harmful effects on cells and tissues. Absorbable synthetic biomaterials are considered to be degraded via ROS (Aliyeva et al., 2004). Free-radical-scavenging enzymes (FRSE) are a cytoprotective enzymatic group that has an essential role in the reduction, de-activation and removal of ROS as well as regulating wound healing process. Inflammation, which constitutes a part of the acute response, results in a coordinated influx of neutrophils at the wound site. These cells, through their characteristic “respiratory burst” activity, produce free radicals (Baboir, 1978). Wound related non-phagocytic cells also generate free radicals by involving non-phagocytic NAD(P)H oxidase mechanism (Griendling, 2000). Thus, the wound site is rich in both oxygen and nitrogen centered reactive species along with their derivatives. The presence of these radicals will result in oxidative stress leading to lipid peroxidation, DNA breakage, and enzyme inactivation, including free-radical scavenger enzymes. Evidence for the role of oxidants in the pathogenesis of many diseases suggests that antioxidants may be of therapeutic use in these conditions. Topical applications of compounds with free-radical-scavenging properties in patients have shown to improve significantly wound healing and protect tissues from oxidative damage (Thiem and Grosslinka, 2003).

2. Pathology of wounds 3. Ayurvedic remedies for healing of wounds Wounds are physical injuries that result in an opening or break of the skin. Proper healing of wounds is essential for the restoration of disrupted anatomical continuity and disturbed functional status of the skin. Healing is a complex and intricate process initiated in response to an injury that restores the function and integrity of damaged tissues. Wound healing involves continuous cell–cell and cell–matrix interactions that allow the process to proceed in three overlapping phases viz. inflammation (0–3 days), cellular proliferation (3–12 days) and remodeling (3–6 months) (Glynn, 1981; Clark, 1996; Martin, 1996). Healing requires the collaborative efforts of many different tissues and cell lineages (Martin, 1997). It involves platelet aggregation and blood clotting, formation of fibrin, an inflammatory response to injury, alteration in the ground substances, angiogenesis and re-epithelialization. Healing is not complete until the disrupted surfaces are firmly knit by collagen (Buffoni et al., 1993). The basic principle of optimal wound healing is to minimize tissue damage and provide adequate tissue perfusion and oxygenation, proper nutrition and moist wound healing environment to restore the anatomical continuity and function of the affected part (Pierce and Mustoe, 1995). Cutaneous wound repair is accompanied by an ordered and definable sequence of biological events starting with wound closure and progressing to the repair and remodeling of damaged tissue (Phillips et al., 1991). In spite of tremendous advances in the pharmaceutical drug industry, the availability of drugs capable of stimulating the process of wound repair is still limited (Udupa et al., 1995). Moreover, the management of chronic

Ayurveda, the Indian traditional system of medicine, is based on empirical knowledge of the observations and the experience over millennia. More than 1200 diseases are mentioned in different classical Ayurvedic texts. Management in various forms of these diseases is made with more than 1000 medicinal plants (89.93%); 58 minerals, metals, or ores (5.24%); and 54 animal and marine products (4.86%) (Biswas and Mukherjee, 2003). Healing of wounds is one of the important areas of clinical medicines explained in many Ayurvedic texts under the heading “Vranaropaka”. The wound as a medical problem was first discussed by Maharshi Agnibesha in Agnibesha Samhita (later known as Charaka Samhita) as “Vrana” Maharshi Sushruta in Sushruta Samhita elaborated on the same and also gave some more details about wound and its healing. According to the Ayurveda, Vrana (wounds or ulcers) is the discontinuation of lining membrane that after healing leaves a scar for life closely resembling the modern definition. Similarly, inflammation is considered to be an early phase in the pathogenesis of wounds termed Vranashotha. Different types of wounds as mentioned in Ayurveda may be endogenous in origin due to a defect in human functional units, such as Vata (nerve impulses), Pitta (enzymes and hormones), and Kapha (body fluids), or exogenous due to trauma, such as Chinna (cut wound), Bhinna (perforated wound), Viddha (punctured wound), Kshata (lacerated wound), Picchita (contusion), and Ghrista (abrasion wound) (Biswas and Mukherjee, 2003). These steps have striking similarities with wounds described in modern medicine (Fig. 1). Classical man-

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Fig. 1. Comparative representation of etiopathogenesis of wound in Ayurvedic and modern medicine.

agement of wounds according to Sushruta Samhita follows 60 therapeutic steps, starting with an aseptic dressing of the affected part and ending with the rehabilitation of the normal structure and function. These therapeutic measures were aimed not only to accelerate the healing process but also to maintain the quality and aesthetics of the healing. As described in different Ayurvedic classics like Charaka Samhita (ca. 5000 b.c.), Sushruta Samhita (ca. 1000 b.c.), Astamga Hridaya (ca. a.d. 600), Bhavaprakash Nighantu (ca. a.d. 1500), Dhanwantari Nighantu (ca. a.d. 1800), and Ayurveda Siksha (a.d. 20th century), it has been estimated that 70% of the wound healing Ayurvedic drugs are of plant origin, 20% of mineral origin, and the remaining 10% consisting of animal products. These drugs are stated to be effective in different conditions such as Vrana (wounds or ulcers), Nadivrana (sinuses), Vidradhi (abscess), Visarpa (erysipelas), Upadamsha (syphilitic ulcers), Vranajakrimi (maggots in wounds), Dustavrana (septic wounds), Vranashotha (inflammatory changes of wounds), Vranavisha (cellulitis), Ugravrana (purulative ulcer), Netravrana (hordeolum or stye sepsis), Pramehapidaka (diabetic carbuncle), and Bhagandara (fistula-in-ano) (Biswas and

Mukherjee, 2003). Scientific investigations have been carried out to assess the wound healing properties of some these drugs. 4. Ethnobotanical approaches/leads to wound healing —Indian perspective The classical systems of Indian Medicine especially Ayurveda, Siddha and Unani employed a large number of medicinal plants for treatment of skin diseases which includes cuts, wounds and burns. Medicinal plants have been used since time immemorial for treatment of various ailments of skin and dermatological disorders especially cuts, wounds and burns. A classical application of plant-based medicine in treatment of injuries is described in the Indian epic Ramayana, when Lord Rama’s brother Lakshman lay mortally wounded on the battlefield in Lanka, medicinal plants from Himalayas were used for treatment to restore Lakshman to fighting strength. Historically, Alexander the Great was reputed to have stopped at the island of Socotra, which was abundant in Aloe plants; these were subsequently used to provide post-battle care to the wounded. In

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Table 1 Ethnobotanical information on lesser-known Indian plants used in treatment of cuts, wounds and burns Plant name

Family

Habit

Plant part used

Ailment treated

References

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51

Abrus precatorius L. Agave cantala Roxb. Ageratina adenophora (Spreng) King and H.E. Robins Annona squamosa L. Aporusa lindleyana (Wight) Baill Ardisia solanacea Roxb. Aristolochia bracteolate Lam. Artemesia roxburghiana Wall, ex. Boisser Bergenia ciliata (Haw.) Sternb Bidens biternata (Lour.) Merr. & Sherff Blumea lacera (Burm. f.) DC Calatropis gigantea (L.) R. Br. Callicarpa arborea Roxb. ex. CB Clarke Calycopteris floribunda Lam. Chloroxylon swietenia DC Clematis gouriana Roxb. Cleome viscose L. Colebrookea oppositifolia J.E. Sm. Commelina benghalensis L. Crotalaria prostrata Rottl. ex Willd. Dactylorhiza hatagirea D. Don Dillenia pentagyna Roxb. Diospyros melanoxylon Roxb. Drymaria cordata (L.) Willd. Roem and Schultes Elephantopus scaber L. Erythrina variegata L. Euphorbia hirta L. Ficus racemosa L. Galium aparine L. Haldinia cordifolia (Roxb.) Ridsd. Holarrhena antidysentrica (Roxb. ex. Flem.) Wall Impatiens balsamina L. Jatropha gossypifolia L. Leonotis nepetifolia (L.) Br. Litsea glutinosa (Lour.) Robinson Lygodium flexulosum (L.) Sw. Melastoma malabathricum L. Moringa oleifera Lam. Pergularia daemia (Forsk) Chiov Piper betel L. Pogostemon benghalensis (Burm. f.) O. Kuntze. Potentilla nepalensis W.J. Hooker Rheum emodi Wall Saussurea obvallata Wall Schima wallichii Chois Sida cordata (Burm. F.) Borss. Stachytarpheta jamaicensis (L.) Vahl Stephania japonica (Thunb.) Miers Syzygium cumini (L.) Skeels Tagetes patula L. Zizyphus oenoplias (L.) Miller

Fabaceae Agavaceae Asteraceae Annonaceae Euphorbiaceae Myrsinaceae Aristolochaceae Asteraceae Saxifragaceae Asteraceae Asteraceae Asclepiadaceae Verbenaceae Combretaceae Rutaceae Ranunculaceae Capparidaceae Lamiaceae Commelinaceae Fabaceae Orchidaceae Dilleniaceae Ebenaceae Caryophyllaceae Asteraceae Fabaceae Euphorbiaceae Moraceae Rubiaceae Rubiaceae Apocyanaceae Balsaminaceae Euphorbiaceae Lamiaceae Lauraceae Lycopodiaceae Melastomataceae Moringaceae Asclepiadaceae Piperaceae Lamiaceae Rosaceae Polygonaceae Asteraceae Terestroemiaceae Malvaceae Verbenaceae Menispermaceae Myrtaceae Asteraceae Rhamnaceae

Shrub Herb Under shrub Shrub Herb Shrub Herb Herb Herb Herb Herb Shrub Tree Shrub Tree Climber Herb Shrub Herb Herb Herb Tree Tree Herb Herb Tree Herb Tree Climber Tree Shrub Herb Shrub Shrub Shrub Climber fern Shrub Tree Climber Climber Shrub Herb Herb Herb Tree Herb Herb Climber Tree Herb Shrub

LF LF WP LF, SD LF RT, BK LF, WP LF RT/RH LF LF LA BK LF LF LF LF LF LF LF TU BK FR LF, ST RT, LF LF WP BK, FR WP, AP LF BK, LA FL WP, LA FL ST, BK RT LF, BK, RT LF LF, RT PE, LF SH, WP RT RT FL, BD BK, LF, FR LF LF LF, RT BK, LF LF RT, BK

Cuts and wounds Cuts, wounds and burns Cuts and wounds Cuts and wounds, animal wounds Burns Cuts and wounds Wounds Cuts and wounds Wounds Cuts and wounds Cuts and wounds Cuts and wounds Cuts and wounds Cuts and wounds Cuts, cattle wounds Cuts and wounds, burns Cuts and wounds Cuts, Wounds Wounds Cuts Cuts and wounds Cuts and burns Wounds Cuts, burns and wounds Cuts, bruises and wounds Burns, wounds Wounds Cuts, wounds and ulcers Cuts Wounds and boils Deep cuts, wounds Wounds, burns and scalds Cuts and wounds Scalds and burns Wounds Cuts and wounds Cuts and wounds Cuts, wounds, snake and dogbite wounds Wounds, leprotic wounds Cuts, burns Wounds Burns Cuts and wounds Cuts, bruises and cattle wounds Cuts and wounds Cuts and wounds Cuts and wounds Cuts and wounds Burns Cuts and boils Wounds

Bhatt et al. (2002), Katewa et al. (2004) Jain (1991), Upadhyaya et al. (1998) Augustine and Sivadasan (2004), Uniyal and Shiva (2005) Dash and Misra (1999), Nayak et al. (2004) Bhandary and Chandrasekhar (2002), Kshirsagar et al. (2003) Girach and Aminuddin (1995), Rawat (2001) Ramadas et al. (2000), Kothari and Moorthy (1996) Jain and Puri (1994), Singh (1997) Punjani (2002), Sindhi et al. (2003) Begum and Nath (2000), Harsha et al. (2002) Upadhyaya et al. (1998), Rajendran et al. (2001) Begum and Nath (2000), Reddy et al. (2003) Begum and Nath (2000), Sharma et al. (2001) Bhandary and Chandrasekhar (2002), Kshirsagar et al. (2003) Girach and Ahmed (1998), Panda and Das (1999) Hosagouder and Henry (1996a,b), Kshirsagar and Singh (2001) Girach et al. (1999), Ganesan and Kesaven (2003) Upadhyaya et al. (1998), Ramadas et al. (2000) Lal et al. (1996), Begum and Nath (2000) Girach and Aminuddin (1995), Jha and Varma (1996) Singh (1999b), Nautiyal et al. (2001) Sharma et al. (2001), Rao et al. (2003) Kothari and Rao (1999), Punjani (2002) Hosagouder and Henry (1996a), Begum and Nath (2000) Singh (1999a), Tripathi (2000) Pal and Jain (1997), Thomas and John De Britto (2003) Upadhyaya et al. (1998), Girach et al. (1999) Punjani (2002), Sen and Behara (2003) Singh (1997), Natarajan et al. (2000) Panda and Das (1999), Bhandary and Chandrasekhar (2003) Girach et al. (1999), Parinatha et al. (2004) Paliwal and Badani (1990), Goud and Pulliah (1996) Pal and Jain (1997), Girach et al. (1999) Upadhyaya et al. (1998), Dash and Misra (1999) Parhar and Biswas (1998), Ramadas et al. (2000) Lalramnghinglova (1996), Upadhyaya et al. (1998) Begum and Nath (2000), Bharadwaj and Gakhar (2005) Das (1997), Begum and Nath (2000) Ramadas et al. (2000), Kshirsagar et al. (2003) Sarma et al. (2002), Thomas and John De Britto (2003) Dutt (1996), Mokat and Deokule (2004) Kapur (1990), Paliwal and Badani (1990) Aswal (1996), Nautiyal et al. (2001) Chaurasia et al. (1999) Begum and Nath (2000), Sharma et al. (2001) Ravi Kumar and Vijaya Sankar (2003), Purkayastha et al. (2005) Jain (1991), Dagar and Dagar (1996) Girach et al. (1999), Srivastava et al. (2003) Hosagouder and Henry (1996b), Mishra et al. (1996) Girach et al. (1999), Sarma et al. (2001) Singh et al. (2002), Maya et al. (2003)

BD: Bud; BK: bark; FL: flower; FR: fruit; INF: inflorescence; LA: latex; LF: leaf; PE: petiole; RH: rhizome; RT: root; SH: shoot; TU: tuber; WP: whole plant.

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S. No.

Table 2 Indian plants with wound healing activity and their model reported Model studied

Author

Acalypha indica Aegle marmelos Allmanda cathartica Anogeissus latifolia Aristolochia bracteolata Areca catechu Argemone mexicana Azadirachta indica Bryophyllum pinnatum Butea monosperma Calotropis procera Canthium parviflorum Cassia fistula Celosia argentea Centella asiatica Cinnamomum zeylanicum Coronopus didynamous Cyperus rotundus Datura alba Desmodium triquetrum Elephantopus scaber Eucalyptus globulus Euphorbia neriifolia Flaveria trinerva Gentiana lutea Glycyrrhiza glabra Gmelina arborea Heliotropium indicum Hemigraphis colorata Hippophae rhamnoides Hypericum hookerianum Hypericum mysorense Hypericum patulatum Thumb Hyptis suaveolens Indigofera enneaphylla Ixora coccinea Lantana camara Laura noblis Lawsonia alba Leucas hirta Leucas lavandulaefolia Moringa oleifera Nelumbo nucifera Ocimum sanctum Oxalis corniculata Pentas lanceolata Phyllanthus emblica Plagiochasma appendiculatum

Whole plant ethanolic extract Methanolic extract of plant Aqueous extract Ethanolic extract of bark Ethanol extract Betel nut extract and its two consitutents arecholine and polyphenols Ethanolic extract Pure neem oil and neem ointment Leaf, alcoholic and water extracts Alcoholic bark extract Latex Aqueous and ethanolic extract Alcoholic leaf extract Alcoholic extract Ethanolic extract Ethanol extract of bark Ethanol and aqueous extracts of whole plant Extract of tuber Alcoholic leaf extract Ethanolic leaf extract Aqueous ethanol extracts isolated compound deoxyelephantopin Ethanolic extract of leaf Aqueous extract of latex Methanol extract Alcohol and petroleum ether extract of rhizomes Ethanolic extract of root Alcoholic extract of leaf Whole plant ethanolic extract Crude leaf paste Aqueous extract of leaf Methanolic extracts of leaf Methanol extract of leaf Methanolic extract of leaf Ethanolic extract of leaf Alcoholic extract of aerial parts Alcoholic extract of flowers Leaf juice and hydroalcoholic extract Aqueous extracts Difference extracts of leaf Aqueous and methanolic leaf extracts Methanol extract Ethyl acetate extract of dried leaf Methanol extract of rhizomes Ethanolic extract of leaves Alcohol and petroleum ether extracts of whole plant Ethanolic extract of flowers Plant extract Alcohol and ethanolic extract

Excision and incision Excision and incision Excision and incision Excision and incision Excision, incision and dead space Excision, Incision and dead space Excision, incision and dead space wounds Incised and gap wounds in bovine calves Excision, incision and dead space Excision Excision Excision Excision Rat burn wound Incision, excision, and dead space Excision, incision and dead space Incision Excision, incision and dead space Burn rat wound Excision, incision and dead space Excision, incision and dead space Excision, incision and dead space Excision Excision and incision Excision, incision and dead space models Excision Excision, incision and dead space Excision and incision Excision Excision Incision and excision Excision and incision Excision and incision Excision, incision and dead space Excision and incision Dead space Excision Excision and incision Excision and incision Excision, incision and dead space Excision and incision Excision, incision and dead space Excision, incision and dead space Excision, incision and dead space Excision, incision and dead space Excision Excision Excision and incision

Reddy et al. (2002) Jaswanth et al. (2001) Nayak et al. (2006) Govindarajan et al. (2004) Shirwaikar et al. (2003a,b) Padmaja et al. (1994) Patil et al. (2001) Bhardwaj and Sharma (1997) Khan et al. (2004) Sumitra et al. (2005) Rajesh et al. (2005) Mohideen et al. (2003) Senthil Kumar et al. (2006) Priya et al. (2004) Suguna et al. (1996), Shetty et al. (2006) Kamath et al. (2003) Prabhakar et al. (2002) Puratchikody et al. (2006) Priya et al. (2002) Shirwaikar et al. (2004) Singh et al. (2005) Hukkeri et al. (2002) Rasik et al. (1996) Umadevi et al. (2006) Mathew et al. (2004) Kishore et al. (2001) Shirwaikar et al. (2002) Reddy et al. (2002) Subramoniam et al. (2001) Gupta et al. (2005) Mukherjee and Suresh (2000a) Mukherjee and Suresh (2000b) Mukherjee et al. (2000a) Shirwaikar et al. (2003a,b) Hemalatha et al. (2001) Nayak et al. (1999) Dash et al. (2001) Nayak et al. (2006) Patil and Mandewgade (2003) Manjunatha et al. (2006) Saha et al. (1997) Udupa et al. (1994a,b), Hukkeri et al. (2006) Mukherjee et al. (2000b) Udupa et al. (2006) Taranalli et al. (2004) Nayak et al. (2005a,b) Suguna et al. (2000) Singh et al. (2006)

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Extract used

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Plant name

Excision and incision Excision, incision and dead space Excision Excision, incision and dead space Excision, incision and dead space Excision and incision Incision and In vitro Incision and excision Excision and incision Excision Dead space Excision, incision and dead space Excision Excision, incision and dead space Excision, incision and dead space Incision and excision Whole plant ethanolic extract Leaf saponin extract Methanolic extract of peels Crude aqueous extract of galls Ethanolic extract 50% ethanolic extract of bark and tannins Alcoholic extract of leaf Aqueous extract of fruit Ethanol, petroleum ether, chloroform, acetone extracts Methanol extract Whole plant, aqueous extract, Aqueous extract of seed Extract of whole plant Aqueous and methanol leaf extracts Crude aqueous extract of plant Aqueous extract 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

Plumbago zeylanicum Polyscias scuttellaria Punica granatum Quercus infectoria Tephrosia purpurea Terminalia arjuna Terminalia chebula Thespesia populnea Toddalia asiatica Tragia involucrata Tridax procumbens Trigonella foenum graecum Vanda roxburghii Vernonia arborea Vitex leucoxylon Wedelia calendulaceae

Model studied Extract used Plant name

Table 2 (Continued )

Reddy et al. (2002) Divakar et al. (2001) Murthy et al. (2004) Jalalpure et al. (2002) Lodhi et al. (2006) Chaudhari and Mengi (2006) Suguna et al. (2002) Nagappa and Cheriyan (2001) Kar et al. (2005) Perumal Samy et al. (2006) Diwan et al. (1982), Udupa et al. (1995) Taranalli and Kuppast (1996) Nayak et al. (2005a,b) Manjunatha et al. (2005) Sidhartha et al. (1990) Hedge et al. (1994)

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developed countries too, people are seeking alternative to modern therapies of wound healing like antibiotics, corticosteroids, etc. obviously due to its side effects. Greater understanding is required in case of pathogenesis of chronic wounds, which fails to heal. Two inseparable aspects, pathogenesis and failure to heal, have guarded and intensified the use of herbal drugs as wound healing agents. Ethnobotanical information on plants used in India for treatment of cuts, wounds and burns is widely scattered with reports in leading journals devoted to ethnobotany and traditional medicine. A few papers have reported ethnomedicinal uses of plants for skin diseases, with a particular focus on cuts, wounds and burns. In the current review, we have presented such plants which are extensively used in both traditional and folk systems of medicine of India and have been reported in ethnobotanical literature for use in the healing of wounds, classifying these plants according to their use in cuts, wounds or burns as well. We have also indicated the same along with the part that have been reported to be used in the healing of the wound. The part used becomes all the more important because of the fact that while providing the ethnopharmacological evidence towards these plants, researchers must ensure that they use that particular part mentioned in traditional medicines rather than random screening. Some lesser-known plants indigenous to India but extensively used in traditional medicine have been tabulated in Table 1, which details the plants, its habit, part used along with the details of ailment for which it is being treated. 5. Ethnopharmacological validation Research into traditional wound healing remedies fall into several categories: (1) herbal remedies; (2) the use of animal/insect products as wound healing agents; (3) the use of organisms to effect wound healing. In rural areas of developing countries wounds and dermatological conditions constitute one of the five most common reasons for people seeking medical care (Ryan, 1992). Rural people sustain injuries working in the fields, burns from cooking and sleeping near fires, leg ulcers resulting from treated wounds, injuries incurred in conflicts and increasing injuries resulting from traffic accidents. The use of traditional medicines to treat many of these conditions has received little research or policy attention. Although traditional medicines offer a safe, inexpensive approach to treatment of wounds and burns, it has not received adequate attention. One of the reasons to neglect this area is that if falls outside WHO’s priority disease areas. Another reason is that there is a prevailing view that traditional systems of health care are most suited for use with chronic, low-level conditions rather than treatment of acute conditions. A third possible reason is that injuries and chronic wounds tend to be treated locally rather than being presented at clinics under the most advanced stage of pathology (Bodeker, 1995; Bodeker and Hughes, 1998). There are a number of plants which have been reported for their wound healing activity. Most of these studies involve random screening of plant or extracts for wound healing activity. We have tabulated (Table 2 ) some of the plants, which have been pharmacologically validated for their wound healing activity.

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Also shown in Table 2 are the model in which these plants have been reported for activity and the extract which showed activity. This information becomes valuable when one thinks of coming out with a drug or a formulation in line with a modern medicine using the traditional wisdom. Incidentally almost all the plants which have been reported pharmacologically are being used traditionally as well. Some very common plants like Aloe vera (Heggers et al., 1996; Davis et al., 1989), Azadirachta indica (Bhardwaj and Sharma, 1997), Carica papaya (Mikhalchik et al., 2004), Celosia argentea (Priya et al., 2004), Centella asiatica (Shetty et al., 2006), Cinnamomum zeylanicum (Kamath et al., 2003), Curcuma longa (Mehra et al., 1984), Nelumbo nucifera (Mukherjee et al., 2000b), Ocimum sanctum (Udupa et al., 2006), Phyllanthus emblica (Suguna et al., 2000), Plumbago zeylanica (Reddy et al., 2002), Pterocarpus santalinus (Biswas et al., 2004), Terminalia arjuna (Chaudhari and Mengi, 2006) and Terminalia chebula (Suguna et al., 2002) have been extensively reported in Ayurveda, Siddha and Unani systems of medicines for their wound healing potential. A number of secondary metabolites/active compounds isolated from plants have been demonstrated in animal models (in vivo) as active principles responsible for facilitating healing of wounds. Some of the most important ones include tannins from Terminalia arjuna (Chaudhari and Mengi, 2006), oleanolic acid from Anredra diffusa (Letts et al., 2006), polysaccharides from Opuntia ficus-indica (Trombetta et al., 2006), gentiopicroside, sweroside and swertiamarine from Gentiana lutea (Ozturk et al., 2006), shikonin derivatives (deoxyshikonin, acetyl shikonin, 3-hydroxy-isovaleryl shikonin and 5,8-Odimethyl acetyl shikonin) from Onosma argentatum (Ozgen et al., 2006), asiaticoside, asiatic acid, and madecassic acid from Centalla asiatica (Maquart et al., 1999; Shukla et al., 1999a,b; Hong et al., 2005), quercetin, isorhamnetin and kaempferol from Hippophae rhamnoides (Fu et al., 2005), curcumin from Curcuma longa (Jagetia and Rajanikant, 2004), oleo-resin from Copaifera langsdorffi (Paiva et al., 2002), proanthocyanidins and reseveratrol from grapes (Brakenhielm et al., 2001; Khanna et al., 2002), acylated iridoid glycosides from Scrophularia nodosa (Stevenson et al., 2002), phenolic acids (protocatechuic, p-hydroxybenzoic, p-coumaric, ferulic and vanillic acids) from Chromolaena odorata (Phan et al., 2001), glycoprotein fraction from Aloe vera (Choi et al., 2001), (+)-epi-alpha-bisabolol from Peperomia galioides (Villegas et al., 2001), fukinolic acid and cimicifugic acids from Cimicifuga sps. (Kusano et al., 2001) and xyloglucan from Tamarindus indicus (Burgalassi et al., 2000). 6. Conclusion In the field of wound healing, there are several unknowns; this includes the wound itself. Such agents available to traditional systems of medicine (TSM) should not disappear from use before they can be fully assessed. There are a number of plants which are used traditionally and by the tribal people which have not been validated or not been evaluated keeping the traditional claim in mind. Most of the pharmacological reports of plant/plant extracts screens the organic soluble extracts of the

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dried plant for their ability to heal wounds in rats and mice, but what is the major concern is that the most traditional claims of the plants as wound healing agents involves application of fresh plants as pastes in water. This is a major problem when it comes to the wound healing agents as what is being validated is the organic solvent extract of dry plant material and what is being used is the fresh plants aqueous extract, the chemical constituents in both cases will be very different. In this review, we have shown that leaf is mainly used in treatment of wounds by the traditional and tribal medicine (42%), while bark and root come the distance second at 13% followed by flowers and reproductive parts at around 10% (Table 1). Over the last 20 years, ethnopharmacological studies have increasingly included in vitro bioassays as a replacement for experiments using tissues or whole animals. This is partly due to the ethical and commercial problems of using animals but also the unsuitability of such practices for bioassay-guided fractionation of the compounds responsible for any activity observed (Houghton, 2000). In spite of the widespread use of in vitro assays, it is important to point out the deficiencies of such an approach. It is very unusual for one in vitro assay alone to represent a disease state and the use of a battery of relevant tests is preferred, since most disease states are complex and several mechanisms are involved, all of which may offer targets for compounds which effect amelioration of the condition. However, even with a variety of relevant tests, it is generally acknowledged that in vitro tests are too reductionist to extrapolate their results to provide evidence for clinical efficacy, and that eventually animal testing and clinical trials have to be performed (Houghton et al., 2005). The process of wound healing involves a variety of processes such as inflammation, cell proliferation and contraction of the collagen lattice formed (Bodeker and Hughes, 1998). In addition, the healing process may be hampered by the presence of oxygen free radicals or microbial infection. Over the last 15 years, the in vitro tests developed have exploited all of these processes as targets. The different phases of the wound healing process overlap and ideally a plant-based remedy should affect at least two different processes before it can be said to have some scientific support for its traditional use. Another major problem with pharmacological validation is that the exact mechanism of the healing process of wound is not clearly understood; hence most of the researchers restrict the screening of plants to simple healing of wounds and do not go into the details. One has to remember that there are a number of parameters which are involved in the healing of wound including epithelization, antioxidant defense and biochemical changes (hydroxyproline). Thus, this review will help pharmacologists to understand the exact part of the plant and its exact use (cuts, burns or wounds) in the traditional system of medicine, thereby strengthening the ethnopharmacological claims and building the global acceptance of the wound healing agents of plant origin. Table 1 clearly indicates that almost 31% of the plants have been used for treating wounds, while 29% for cuts and 10% for burns while 22% have been used for cuts and wounds. Also there is a lack of concerted effort on the part of researchers to study the concept of synergism in wound healing. Synergism combination of the potential plants highlighted in the

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current review may be combined judiciously in the development of a globally acceptable wound healing formulation, which if validated properly and proven scientifically can act as substitute or may even replace the modern wound healing agents. Thus, the major aim of the current review is to identify and project the plants especially of Indian origin which have the potential to become the modern drug substitute.

References Aliyeva, E., Umur, S., Zafer, E., Acigoz, G., 2004. The effect of polylactide membranes on the levels of reactive oxygen species in periodontal flaps during wound healing. Biomaterials 25, 4633–4637. Aswal, B.S., 1996. Conservation of medicinal plant diversity of Garhwal Himalaya in India. In: Jain, S.K. (Ed.), Ethnobiology in Human Welfare. Deep Publications, New Delhi, pp. 133–135. Augustine, T., Sivadasan, M., 2004. Ethnomedicinal plants of Periyar Tiger Reserve, Kerala, India. Ethnobotany 16, 40–43. Baboir, B.M., 1978. Oxygen dependent microbial killing by phagocytes (first of two parts). New England Journal of Medicine 298, 629–668. Balick, M., Cox, P.A., 1996. Plants, People and Culture: the Science of Ethnobotany. Scientific American Library, W.H. Freeman and Company, New York. Begum, D., Nath, S.C., 2000. Ethnobotanical review of medicinal plants used for skin diseases and related problems in Northeastern India, Journal of Herbs. Spices and Medicinal Plants 7, 55–93. Bhandary, M.J., Chandrasekhar, K.R., 2002. Glimpses of ethnic herbal medicine of coastal Karnataka. Ethnobotany 14, 1–12. Bhandary, M.J., Chandrasekhar, K.R., 2003. Herbal treatments for veterinary diseases from the coastal districts of Karnataka, India. Journal of Economic and Taxonomic Botany 27, 648–655. Bharadwaj, S., Gakhar, S.K., 2005. Ethnomedicinal plants used by tribals of Mizorum to use cuts and wounds. Indian Journal of Traditional Knowledge 4, 75–80. Bhardwaj, R.L., Sharma, D.N., 1997. Evaluation of neem (Azadirachta indica Juss) oil as a potent wound healer. Histomorphological and histochemical study. Indian Veterinary Medical Journal 21, 187–190. Bhatt, D.C., Mitaliya, K.D., Mehta, S.K., Joshi, P.N., 2002. Notes on some ethnomedicinal plants of Paccham Hills of Kachh district. Gujarat Ethnobotany 14, 34–35. Biswas, T.K., Maity, L.N., Mukherjee, B., 2004. Wound healing potential of Pterocarpus santalinus Linn: a pharmacological evaluation. International Journal of Low Extreme Wounds 3, 143–150. Biswas, T.K., Mukherjee, B., 2003. Plant medicines of Indian origin for wound healing activity. Lower Extremity Wounds 2, 25–39. Bodeker, G., 1995. In: Micozzi, M. (Ed.), Global Health Traditions, Fundamentals of Alternative and Complementary Medicine. Churchill-Livingstone, New York, pp. 279–290. Bodeker, G., Hughes, M.A., 1998. Wound healing, traditional treatments and research policy. In: Prendergast, H.D.V., Etkin, N.L., Harris, D.R., Houghton, P.J. (Eds.), Plants for Food and Medicine. Royal Botanic Gardens, Kew, pp. 345–359. Brakenhielm, E., Cao, R., Cao, Y., 2001. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB Journal 15, 1798–1800. Buffoni, F., Bancheli, G., Cambi, S., Ignesti, G., Irisind, R., Raimondi, L., Vannelli, G., 1993. Skin wound healing: some biochemical parameters in Guinea pig. Journal of Pharmaceutics and Pharmacology 45, 784–790. Burgalassi, S., Raimondi, L., Pirisino, R., Banchelli, G., Boldrini, E., Saettone, M.F., 2000. Effect of xyloglucan (tamarind seed polysaccharide) on conjunctival cell adhesion to laminin and on corneal epithelium wound healing. European Journal of Ophthalmology 10, 71–76. Chaudhari, M., Mengi, S., 2006. Evaluation of phytoconstituents of Terminalia arjuna for wound healing activity in rats. Phytotherapy Research 20, 799–805.

Chaurasia, O.P., Singh, B., Sareen, S.K., 1999. Ethnomedicinal plants of Artic Desert, Ladakh used in vertinary practices. Journal of Economic and Taxonomic Botany 23, 161–166. Choi, S.W., Son, B.W., Son, Y.S., Park, Y.I., Lee, S.K., Chung, M.H., 2001. The woundhealing effect of a glycoprotein fraction isolated from Aloe vera. British Journal of Dermatology 145, 535–545. Clark, R.A.F., 1996. Wound repair: overview and general consideration. In: Clark, R.A., Henson, P.M. (Eds.), Molecular and Cellular Biology of Wound Repair. The Plenum Press, New York. Dagar, H.S., Dagar, J.C., 1996. Some folklore medicinal claims on Plants of Car Nicobar Island. Bulletin of Medico-Ethno-Botanical Research 17, 8–17. Das, S.N., 1997. A study on the Ethnobotany of Karauli & Sawai, Madhapur Districts, Rajasthan. Journal of Economic and Taxonomic Botany 21, 587–605. Dash, G.K., Suresh, P., Ganapathy, S., 2001. Studies on hypoglycaemic and wound healing activities of Lantana camara Linn. Journal of Natural Remedies 1, 105–110. Dash, S.S., Misra, M.K., 1999. Taxonomic survey and systematic census of economic plants of Narayana Patna Hills of Koraput Dist., Orissa. Journal of Economic and Taxonomic Botany 23, 473–498. Davis, R.H., Leitner, M.G., Russo, J.M., Byrne, M.E., 1989. Wound healing. Oral and topical activity of Aloe vera. Journal American Podiatric Medical Association 79, 559–562. Divakar, M.C., Devi, S.L., Kumar, P.S., Rao, S.B., 2001. Studies of wound healing property of Polyscias scuttellaria leaf saponins. Indian Journal of Natural Products 17, 37–42. Diwan, P.V., Tillo, L.D., Kulkarni, D.R., 1982. Influence of Tridax procumbens on wound healing. Indian Journal of Medical Research 75, 460–464. Dutt, B., 1996. Ethnobotanical resources of Chattarpur dist. (M.P.). In: Jain, S.K. (Ed.), Ethnobiology in Human Welfare. Deep Publications, New Delhi, pp. 400–402. Fu, S.C., Hui, C.W., Li, L.C., Cheuk, Y.C., Qin, L., Gao, J., Chan, K.M., 2005. Total flavones of Hippophae rhamnoides promotes early restoration of ultimate stress of healing patellar tendon in a rat model. Medical Engineering Physics 27, 313–321. Ganesan, S., Kesaven, L., 2003. Ethnomedicinal plants used by the ethnic group of Valaiyans of Vellimalai Hills (Reserved forest) Tamil Nadu, India. Journal of Economic and Taxonomic Botany 27, 754–760. Girach, R.D., Singh, S., Brahmam, M., Misra, M.K., 1999. Traditional treatment of skin diseases in Bhadrak District, Orissa. Journal of Economic and Taxonomic Botany 23, 499–504. Girach, R.D., Ahmed, A., 1998. Medical ethnobotany of Sundargarh, Orissa, India. Pharmaceutical Biology 36, 20–24. Girach, R.D., Aminuddin, 1995. Ethnomedicinal uses of plants among tribals of Singhbhum district, Bihar, India. Ethnobotany 7, 103–107. Glynn, L.E., 1981. The pathology of scar tissue formation. In: Glynn, L.E. (Ed.), Handbook of Inflammation, vol. 3. Tissue Repair and Regeneration. Elsevier/North Holland Biomedical Press, Amsterdam. Goud, S.P., Pulliah, T., 1996. Ethnobotany of Kurnool Dist., Andhra Pradesh. Journal of Economic and Taxonomic Botany Additional Series 12, 410–412. Govindarajan, R., Vijayakumar, M., Rao, C.V., Shirwaikar, A., Mehrotra, S., Pushpangadan, P., 2004. Healing potential of Anogeissus latifolia for dermal wounds in rats. Acta Pharmaceutica 54, 331–338. Griendling, K.K., 2000. NADPH oxidase: role in cardiovascular biology and diseases. Circulation Research 86, 494–501. Gupta, A., Kumar, R., Pal, K., Banerjee, P.K., Sawhney, R.C., 2005. A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats. Journal of Lower Extremity Wounds 4, 88–92. Gupta, N., Gupta, S.K., Shukla, V.K., Singh, S.P., 2004. An Indian communitybased epidemiological study of wounds. Journal of Wound Care 13, 323–325. Harsha, V.H., Hebbar, S.S., Hedge, G.R., Shripati, V., 2002. Ethnomedical knowledge of plants used by Kunabi Tribe of Karnataka in India. Fitoterapia 73, 281–287. Hedge, D.A., Khosa, R.L., Chansouria, J.P.N., 1994. A study of the effect of Wedelia calendulacea Less on wound healing in rats. Phytotherapy Research 8, 439.

B. Kumar et al. / Journal of Ethnopharmacology 114 (2007) 103–113 Heggers, J.P., Kucukcelibi, A., Listengarten, D., Stabenau, C.J., Ko, F., Broemeling, L.D., Robson, M.C., Winters, W.D., 1996. Beneficial effect of Aloe on wound healing in an excision wound model. Journal of Alternative and Complementary Medicine 2, 271–277. Heinrich, M., Gibbons, S., 2001. Ethnopharmacology in drug discovery: an analysis of its role and potential contribution. Journal of Pharmacy and Pharmacology 53, 425–432. Hemalatha, S., Subramanian, N., Ravichandran, V., Chinnaswamy, K., 2001. Wound healing activity of Indigofera enneaphylla Linn. Indian Journal of Pharmaceutical Sciences 63, 331–333. Hong, S.S., Kim, J.H., Li, H., Shim, C.K., 2005. Advanced formulation and pharmacological activity of hydrogel of the titrated extract of Centella asiatica. Archives of Pharmacological Research 28, 502–508. Hosagouder, V.B., Henry, A.N., 1996a. Ethnobotany of Kadars, Malasars and Muthuvums of Annamalais in Coimbatore Dist., Tamil Nadu, India. Journal of Economic and Taxonomic Botany Additional Series 12, 82–91. Hosagouder, V.B., Henry, A.N., 1996b. Ethnobotany of Soligas in Siliguir, Rangana betta, Karnataka, Southern India. Journal of Economic and Taxonomic Botany Additional Series 12, 82–91. Houghton, P.J., Hylands, P.J., Mensah, A.Y., Hensel, A., Deters, A.M., 2005. In vitro tests and ethnopharmacological investigations: wound healing as an example. Journal of Ethnopharmacology 100, 100–107. Houghton, P.J., 2000. Use of small scale bioassays in the discovery of novel drugs from natural sources. Phytotherapy Research 14, 419–423. Hukkeri, V.I., Nagathan, C.V., Karadi, R.V., Patil, B.S., 2006. Antipyretic and wound healing activities of Moringa oleifera Lam. in rats. Indian Journal of Pharmaceutical Sciences 68, 124–126. Hukkeri, V.T., Karadi, R.V., Akki, K.S., Savadi, R.V., Jaiprakash, B., Kuppast, J., Patil, M.B., 2002. Wound healing property of Eucalyptus globulus leaf extract. Indian Drugs 39, 481–483. Jagetia, G.C., Rajanikant, G.K., 2004. Role of curcumin, a naturally occurring phenolic compound of turmeric in accelerating the repair of excision wound, in mice wholebody exposed to various doses of gamma-radiation. Journal of Surgical Research 120, 127–138. Jain, S.K., 1991. Dictionary of Indian folk medicine and ethnobotany—a reference manual of man–plant relationships. In: Jain, S.K. (Ed.), Ethnic Groups and Ethnobotanists in India. Deep Publications, New Delhi, p. 311. Jain, S.P., Puri, H.S., 1994. An ethno-medico-botanical survey of Parbati Valley in Himachal Pradesh (India). Journal of Economic and Taxonomic Botany 8, 321–327. Jalalpure, S.S., Patil, M.B., Alagawadi, K.R., 2002. Wound healing activity of the galls of Quercus infectoria Oliver. Journal of Natural Remedies 2, 1. Jaswanth, A., Akilandeswari, Loganathan, V., Manimaran, S., Rukmani, S., 2001. Wound healing activity of Aegle marmelos. Indian Journal of Pharmaceutical Sciences 63, 41–44. Jha, R.R., Varma, S.K., 1996. Ethnobotany of Sauria Paharias of Santhal Pargana, Bihar 1. Medicinal Plants Ethnobotany 8, 31–35. Kamath, J.V., Rana, A.C., Chowdhury, A.R., 2003. Pro-healing effect of Cinnamomum zeylanicum bark. Phytotheraphy Research 17, 970–972. Kapur, S.K., 1990. Economically useful plants of Majauri-kirchi Forest Tract (Jammu & Kashmir). II: Verbenaceae to Bambusaceae & Gymnosperms. Journal of Economic and Taxonomic Botany 14, 523–534. Kar, D.M., Mohanty, A., Sethi, R.K., Dash, G.K., 2005. Antimicrobial and wound healing properties of stem bark of Toddalia asiatica Linn. Indian Journal of Pharmaceutical Sciences 67, 220–223. Katewa, S.S., Chaudhary, B.L., Jain, A., 2004. Folk herbal medicines from tribal area of Rajasthan India. Journal of Ethnopharmacology 92, 41–46. Khan, M., Patil, P.A., Shobha, J.C., 2004. Influence of Bryophyllum pinnatum (Lam.) leaf extract on wound healing in albino rats. Journal of Natural Remedies 4, 41–46. Khanna, S., Venojarvi, M., Roy, S., Sharma, N., Trikha, P., Bagchi, D., Bagchi, M., Sen, C.K., 2002. Dermal wound healing properties of redox-active grape seed proanthocyanidins. Free Radical Biology and Medicine 15, 1089– 1096. Kishore, G.S., Kumar, B.S., Ramachandran, S., Saravanan, M., Sridhar, S.K., 2001. Antioxidant and wound healing properties of Glycyrrhiza glabra root extract. Indian Drugs 38, 355–357.

111

Kothari, M.J., Moorthy, S., 1996. Ethnobotany in human welfare of Raigarh in Maharastra State, India. Journal of Economic and Taxonomic Botany 12, 82–91. Kothari, M.J., Rao, K.M., 1999. Ethnobotanical studies of Thane District, Maharashtra. Ethnobotany 12, 100–112. Kshirsagar, R.D., Singh, N.P., 2001. Some lesser-known ethnomedicinal uses from Mysore and Coorg districts, Karnataka State, India. Journal of Ethnopharmacology 75, 231–238. Kshirsagar, S.R., Parabia, M.H., Reddy, M.N., 2003. Ethnobotany of coastal areas in South Gujarat. Ethnobotany 15, 60–63. Kusano, A., Seyama, Y., Nagai, M., Shibano, M., Kusano, G., 2001. Effects of fukinolic acid and cimicifugic acids from Cimicifuga species on collagenolytic activity. Biological Pharmaceutical Bulletin 24, 1198–1201. Lal, B., Vats, S.K., Singh, R.D., Gupta, A.K., 1996. Plants used as ethnomedicine and supplementary food by Gaddis of Himachal Pradesh, India. In: Jain, S.K. (Ed.), Ethnobiology in Human Welfare. Deep Publications, New Delhi, pp. 384–387. Lalramnghinglova, J.H., 1996. Ethnobotany of Mizoram—A preliminary survey. Journal of Economic and Taxonomic Botany 12, 82–91. Letts, M.G., Villegas, L.F., Marcalo, A., Vaisberg, A.J., Hammond, G.B., 2006. In vivo wound healing activity of olanolic acid derived from the acid hydrolysis of Andredera diffusa. Journal of Natural Products 69, 978–979. Lodhi, S., Pawar, R.S., Jain, A.P., Singhai, A.K., 2006. Wound healing potential of Tephrosia purpurea (Linn.) Pers. in rats. Journal of Ethnopharmacology 108, 204–210. Manjunatha, B.K., Vidya, S.M., Krishna, V., Mankani, K.L., 2006. Wound healing activity of Leucas hirta. Indian Journal of Pharmaceutical Sciences 68, 380–384. Manjunatha, B.K., Vidya, S.M., Rashmi, K.V., Mankani, K.L., Shilpa, H.J., Singh, S.D.J., 2005. Evaluation of wound-healing potency of Vernonia arborea Hk. Indian Journal of Pharmacology 37, 223–226. Martin, A.A., 1996. The use of antioxidants in healing. Dermatological Surgery 22, 156–160. Martin, P., 1997. Wound healing aiming for perfect skin degeneration. Science 276, 75–81. Mathew, A.D., Taranalli, A.D., Torgal, S.S., 2004. Evaluation of antiinflammatory and wound healing activity of Gentiana lutea rhizome extracts in animals. Pharmaceutical Biology 42, 8–12. Maquart, F.X., Chastang, F., Simeon, A., Birembaut, P., Gillery, P., Wegrowski, Y., 1999. Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds. European Journal of Dermatology 9, 289–296. Maya, S., Kumari, S., Prameela, Menon, S.V., 2003. Ethnobotanical notes on the flora of sacred tanks of Kerala. Ethnobotany 15, 55–59. Mehra, K.S., Mikuni, I., Gupta, U., Gode, K.D., 1984. Curcuma longa (Linn) drops in corneal wound healing Tokai. Journal Experimental Clinical Medicine 9, 27–31. Mikhalchik, E.V., Ivanova, A.V., Anurov, M.V., Titkova, S.M., Penkov, L.Y., Kharaeva, Z.F., Korkina, L.G., 2004. Wound-healing effect of papaya-based preparation in experimental thermal trauma. Bulletin of Experimental Biology and Medicine 137, 560–562. Mishra, D.K., Samanta, C., Mishra, T.K., 1996. Ethnomedicine of the Tribe Khasia of Midnapore District, West Bengal. Journal of Economic and Taxonomic Botany Additional Series 12, 82–91. Mohideen, S., Illavarasan, R., Hemalatha, S., Anitha, N., Sasikala, E., 2003. Wound healing and diuretic activity of Canthium parviflorum Lam. Natural Product Sciences 4, 102–104. Mokat, D.N., Deokule, S.S., 2004. Plants used as veterinary medicine in Ratnagiri District of Maharastra. Ethnobotany 16, 131–135. Mukherjee, P.K., Mukherjee, K., Pal, M., Saha, B.P., 2000b. Wound healing potential of Nelumbo nucifera (Nymphaceae) rhizome extract. Phytomedicine 7, 66. Mukherjee, P.K., Suresh, B., 2000a. Studies on in vivo wound healing activity of leaf extract of Hypericum mysorense with different wound models in rats. Natural Product Sciences 6, 73–78. Mukherjee, P.K., Suresh, B., 2000b. The evaluation of wound healing potential of Hypericum hookerianum leaf and stem extracts. Journal of Alternative and Complementary Medicine 6, 61–69.

112

B. Kumar et al. / Journal of Ethnopharmacology 114 (2007) 103–113

Mukherjee, P.K., Verpoorte, R., Suresh, B., 2000a. Evaluation of in vivo wound healing activity of Hypericum patulum (Family: Hypericaceae) leaf extract on different wound models in rats. Journal of Ethnopharmacology 70, 315–321. Murthy, K.N., Reddy, V.K., Veigas, J.M., Murthy, U.D., 2004. Study on wound healing activity of Punica granatum peel. Journal of Medicinal Herbs, Foods and Spices 7, 256–259. Nagappa, A.N., Cheriyan, B., 2001. Wound healing activity of the aqueous extract of Thespesia populnea fruit. Fitoterapia 72, 503–506. Natarajan, B., Paulsen, S.P., Komeleussen, V., 2000. An ethnopharmacological study from Kulu district Himachal Pradesh, India—traditional knowledge compared with modern biological science. Pharmaceutical Biology 38, 129–138. Nautiyal, S., Maikhuri, R.K., Rao, K.S., Saxena, K.G., 2001. Medicinal plant resources in Nanda Devi Biosphere Reserve in Central Himalayas. Journal of Herbs, Spices and Medicinal Plants 8, 47–64. Nayak, B.S., Suresh, R., Rao, A.V., Pillai, G.K., Davis, E.M., Ramkissoon, V., McRae, A., 2005a. Evaluation of wound healing activity of Vanda roxburghii R. Br (Orchidaceae): a preclinical study in a rat model. Journal of Lower Extremity Wounds 4, 200–204. Nayak, B.S., Udupa, A.L., Udupa, S.L., 1999. Effect of Ixora coccinea flowers on dead space wound healing in rats. Fitoterapia 70, 233–236. Nayak, B.S., Vinutha, B., Geetha, B., Sudha, B., 2005b. Experimental evaluation of Pentas lanceolata flowers for wound healing activity in rats. Fitoterapia 76, 671–675. Nayak, S., Behera, S.K., Nishha, M., 2004. Ethnomedico botanical survey of Kalahandi district of Orissa. Indian Journal of Traditional Knowledge 3, 72–79. Nayak, S., Nalabothu, P., Sandiford, S., Bhogadi, V., Adogwa, A., 2006. Evaluation of wound healing activity of Allamanda cathartica. L. and Laurus nobilis. L. extracts on rats. BMC Complementary and Alternative Medicine 5, 6–12. Ozgen, U., Ikbal, M., Hacimuftuoglu, A., Houghton, P.J., Gocer, F., Dogan, H., Coskun, M., 2006. Fibroblast growth stimulation by extracts and compounds of Onosma argentatum roots. Journal of Ethnopharmacology 104, 100–103. Ozturk, N., Korkmaz, S., Ozturk, Y., Baser, K.H., 2006. Effects of gentiopicroside, sweroside and swertiamarine, secoiridoids from gentian (Gentiana lutea ssp. symphyandra), on cultured chicken embryonic fibroblasts. Planta Medica 72, 289–294. Padmaja, P.N., Bairy, K.L., Kulkarni, D.R., 1994. Pro-healing effect of betel nut and its polyphenols. Fitoterapia 65, 298–300. Paiva, L.A., de-Alencar-Cunha, K.M., Santos, F.A., Gramosa, N.V., Silveira, E.R., Rao, V.S., 2002. Investigation on the wound healing activity of oleoresin from Copaifera langsdorffi in rats. Phytotherapy Research 16, 737–739. Pal, D.C., Jain, S.K., 1997. Tribal Medicine. Naya Prakash Publishers, Calcutta6. Paliwal, G.S., Badani, A.K., 1990. Ethnobotany of the Hill tribes of Uttar Kashi. Journal of Economic and Taxonomic Botany 14, 593–604. Panda, D.C., Das, P., 1999. Medicinal plant-lore of the tribals of Baliguda subdivision, Phulbain, District, Orissa. Journal of Economic and Taxonomic Botany 23, 515–521. Parhar, K., Biswas, S., 1998. Medicinal Plant Resources of Doon valley and adjacent Siwaliks—I. Journal of Non-Timber Forest Products 5, 29–33. Parinatha, M., Harish, G.U., Vivek, N.C., Mahesh, T., Shivanna, M.B., 2004. Ethnobotanical wealth of Bhadra Wildlife Sanctuary in Karnataka. Indian Journal of Traditional Knowledge 3, 37–50. Patil, K.S., Mandewgade, S.D., 2003. Wound healing activity of leaves of Lawsonia alba. Journal of Natural Remedies 3, 129–133. Patil, M.D., Jalalpure, S.S., Ali, A., 2001. Preliminary phytochemical investigation and wound healing activity of the leaves of Argemone mexicana Linn. (Papavaraceae). Indian Drugs 38, 288–293. Perumal Samy, R., Gopalakrishnakone, P., Sarumathi, M., Ignacimuthu, S., 2006. Wound healing potential of Tragia involucrata extract in rats. Fitoterapia 77, 300–302. Phan, T.T., Wang, L., See, P., Grayer, R.J., Chan, S.Y., Lee, S.T., 2001. Phenolic compounds of Chromolaena odorata protect cultured skin cells from oxidative damage: implication for cutaneous. Biological and Pharmaceutical Bulletin 24, 1373–1379.

Phillips, G.D., Whitehe, R.A., Kinghton, R., 1991. Initiation and pattern of angiogenesis in wound healing in the rat. American Journal of Anatomy 192, 257–262. Pierce, G.F., Mustoe, T.A., 1995. Pharmacologic enhancement of wound healing. Annual Review of Medicine 46, 467–481. Porras-Reyes, B.H., Lewis, W.H., Roman, J., Simchowitz, L., Mustoe, T.A., 1993. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Society of Experimental Biology and Medicine 203, 18–25. Prabhakar, K.R., Srinivasan, K.K., Rao, P.G.M., 2002. Chemical investigations, antiinflammatory and wound healing properties of Coronopus didynamous. Pharmaceutical Biology 40, 490–493. Priya, K.S., Arumugam, G., Bhuvaneswari, R., Wells, A., Mary, B., 2004. Celosia argentea Linn. leaf extract improves wound healing in a rat burn wound model. Wound Repair and Regeneration 12, 618. Priya, K.S., Gnanamani, A., Radhakrishnan, N., Babu, M., 2002. Healing potential of Datura alba on burn wounds in albino rats. Journal of Ethnopharmacology 83, 193–199. Punjani, B.L., 2002. Ethnobotanical aspects of some plants of Aravali Hills in North Gujarat. Ancient Science of Life 21, 268–280. Puratchikody, A., Devi, C.N., Nagalakshmi, G., 2006. Wound healing activity of Cyperus rotundus Linn. Indian Journal of Pharmaceutical Sciences 68, 97–101. Purkayastha, J., Nath, S.C., Islam, M., 2005. Ethnobotany of medicinal plants from Dibru-Saikhowa Biosphere Reserve of North east India. Fitoterapia 76, 121–127. Rajendran, S.M., Chandrasekar, K., Sundaresan, V., 2001. Ethnomedicinal lore of Seithur Hills—Southern Western Ghats, Tamil Nadu. Ethnobotany 13, 101–109. Rajesh, R., Raghavendra, G.C.D., Nataraju, A., Dhananjaya, B.L., Kemparaju, K., Vishwanath, B.S., 2005. Procoagulant activity of Calotropis gigantea latex associated with fibrin(ogen)olytic activity. Toxicon 46, 84–92. Ramadas, S.R., Ghotge, N.S., Ashalata, S., Mathur, N.P., Gour, V., Rao, S., 2000. Ethnoveterinary remedies used in common surgical conditions in some districts of Andhra Pradesh and Maharashtra, India. Ethnobotany 12, 100–112. Rao, V., Krishna, J., Rajagopal, Badrinath, K.V.S., 2003. Notes on economic importance of wild plants of Rampa agency—East Godavari district, A.P., India. Journal of Economic and Taxonomic Botany 27, 603–612. Rasik, A.M., Shukla, A., Patnaik, G.K., Dhawan, B.N., Kulshrestha, D.K., Srivastava, S., 1996. Wound healing activity of latex of Euphorbia neriifolia Linn. Indian Journal of Pharmacology 28, 107–109. Ravi Kumar, K., Vijaya Sankar, R., 2003. Ethnobotany of Malyali tribes in Malpattu Village, Javvadhu hills of Eastern Ghats, Thiruvannamalai Hills, Tamil Nadu. Journal of Economic and Taxonomic Botany 27, 715–726. Rawat, R.S., 2001. Some medicinal plants in Garhwal Himalaya. Journal of Non-Timber Forest Products 8, 207–218. Reddy, J.S., Rao, P.R., Reddy, M.S., 2002. Wound healing effects of Heliotropium indicum, Plumbago zeylanicum and Acalypha indica in rats. Journal of Ethnopharmacology 79, 249–251. Reddy, P.R., Rao, P.P., Prabhakar, M., 2003. Ethnomedicinal practices amongst Chenchus of Nagarjunasagar Srisailam Tiger Reserve (NSTR), Andhra Pradesh—plant remedies for cuts, wounds and boils. Ethnobotany 15, 67–70. Ryan, T.J., 1992. International Foundation for Dermatology – solving the problems of skin disease in the developing world. Tropical Doctor 22, 42–43. Saha, K., Mukherjee, P.K., Das, J., Pal, M., Saha, B.P., 1997. Wound healing activity of Leucas lavandulaefolia Rees. Journal of Ethnopharmacology 56, 139–144. Sarma, S.K., Bhattacharya, B.K., Devi, B., 2002. Traditional use of herbal medicine by Modahi tribe of Nalabari district of Assam. Ethnobotany 14, 103–111. Sarma, S.K., Bhattacharya, D.K., Devi, B., 2001. Medicinal plants used by Bodo tribe of Nalbari district in Assam. Ethnobotany 13, 135–139. Sen, S.K., Behara, L.M., 2003. Ethnomedicinal plants used against skin diseases in Bargat district of Orissa. Ethnobotany 15, 90–96. Senthil Kumar, M., Sripriya, R., Vijaya Raghavan, H., Sehgal, P.K., 2006. Wound healing potential of Cassia fistula on infected albino rat model. Journal of Surgical Research 131, 283–289.

B. Kumar et al. / Journal of Ethnopharmacology 114 (2007) 103–113 Sharma, H.K., Chhangte, L., Dolui, A.K., 2001. Traditional medicinal plants in Mizoram, India. Fitoterapia 72, 146–161. Shefali, K.R., Bhaduri, A.P., 1999. Wound Healing: An Overview. Current R&D Highlights. CDRI, Lucknow, India. Shetty, B.S., Udupa, S.L., Udupa, A.L., Somayaji, S.N., 2006. Effect of Centella asiatica L. (Umbelliferae) on normal and dexamethasone-suppressed wound healing in Wistar Albino rats. Journal of Lower Extremity Wounds 5, 137–143. Shirwaikar, A., Ghosh, S., Rao, P.G.M., 2002. Effect of Gmelina arborea Roxb. leaves on wound healing in rats. Journal of Natural Remedies 3, 45–48. Shirwaikar, A., Jahangirdas, S., Udupa, L., 2004. Wound healing activity of Desmodium triquetrum leaves. Indian Journal of Pharmaceutical Sciences 65, 461–464. Shirwaikar, A., Shenoy, R., Udupa, A.L., Udupa, S.L., Shetty, S., 2003b. Wound healing property of ethanolic extract of leaves of Hyptis suaveolens with supportive role of antioxidant enzymes. Indian Journal of Experimental Biology 41, 238–241. Shirwaikar, A., Somashekar, A.P., Udupa, A.L., Udupa, S.L., Somashekar, S., 2003a. Wound healing studies of Aristolochia bracteolate Lam. with supportive action of antioxidant enzymes. Phytomedicine 10, 558–562. Shukla, A., Rasik, A.M., Dhawan, B.N., 1999a. Asiaticoside-induced elevation of antioxidant levels in healing wounds. Phytotherapy Research 13, 50–54. Shukla, A., Rasik, A.M., Jain, G.K., Shankar, R., Kulshrestha, D.K., Dhawan, B.N., 1999b. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica. Journal of Ethnopharmacology 65, 1–11. Sidhartha, P., Sarma, K., Srinivasa, A., Srinivasan, K.K., Udupa, A.L., Kumar, V., Kulkarni, D.R., Rajagopal, P.K., 1990. Anti-inflammatory and wound healing activities of the crude alcoholic extract and flavonoids of Vitex leucoxylon. Fitoterapia 61, 263–265. Sindhi, S., Chauhan, N.S., Choudhury, P.R., 2003. Ethnobotanical studies in villages around Dr. Y.S. Paramar University of Horticulture and Forestry, Solan, Himachal Pradesh. Journal of Non-Timber Forest Products 10, 90–96. Singh, A.K., 1999a. A contribution to the ethnobotany of sub Himalaya region of Eastern U.P. Journal of Economic and Taxonomic Botany 23, 237–246. Singh, A.K., Raghubansi, A.S., Singh, J.S., 2002. Medical ethnobotany of the tribals of Sonaghati of Sonbhadra district, Uttar Pradesh, India. Journal of Ethnopharmacology 81, 31–41. Singh, G.S., 1999b. Ethnobotanical study of useful plants of Kulu district in N.W. Himalaya, India. Journal of Economic and Taxonomic Botany 23, 185–198. Singh, K.K., 1997. Studies of native medicine of Jaunsari tribe of Dehradun District, U.P. India. International Journal of Pharmacognosy 35, 105–110. Singh, M., Govindarajan, R., Nath, V., Rawat, A.K., Mehrotra, S., 2006. Antimicrobial, wound healing and antioxidant activity of Plagiochasma appendiculatum Lehm. et Lind. Journal of Ethnopharmacology 107, 67–72. Singh, S.D.J., Krishna, V., Mankani, K.L., Manjunatha, B.K., Vidya, S.M., Manohara, Y.N., 2005. Wound healing activity of the leaf extracts and deoxyelephantopin isolated from Elephantopus scaber Linn. Indian Journal of Pharmacology 37, 238–242. Srivastava, S.C., Mitra, S., Bandopadhyay, S., 2003. Some plants of ethnomedicinal importance from Darjeeling District, West Bengal. Journal of Economic and Taxonomic Botany 27, 972–977. Stevenson, P.C., Simmonds, M.S., Sampson, J., Houghton, P.J., Grice, P., 2002. Wound healing activity of acylated iridoid glycosides from Scrophularia nodosa. Phytotherapy Research 16, 33–35. Subramoniam, A., Evans, D.A., Rajasekharan, S., Nair, G.S., 2001. Effect of Hemigraphis colorata (Blume) H.G. Hallier leaf on wound healing and inflammation in mice. Indian Journal of Pharmacology 33, 283–285.

113

Suguna, L., Singh, S., Sivakumar, P., Sampath, P., Chandrakasan, G., 2002. Influence of Terminalia chebula on dermal wound healing in rats. Phytotherapy Research 16, 227–231. Suguna, L., Sivakumar, P., Chandrakasan, G., 1996. Effects of Centella asiatica extract on dermal wound healing in rats. Indian Journal of Experimental Biology 34, 1208–1211. Suguna, L., Sumitra, M., Chandrakasan, G., 2000. Influence of Phyllanthus emblica extract on dermal wound healing in rats. Journal of Medicinal and Aromatic Plants 32, 2–3. Suh, D.D., Schwartz, I.P., Canning, D.A., Snyder, H.M., Zderic, S.A., Kirsch, A.J., 1998. Comparison of dermal and epithelial approaches to laser tissue soldering for skin flap closure. Lasers Surgery Medicine 22, 268–274. Sumitra, M., Manikandan, P., Suguna, L., 2005. Efficacy of Butea monosperma on dermal wound healing in rats. Journal of Biochemistry and Cell Biology 37, 566–573. Taranalli, A.D., Kuppast, I.J., 1996. Study of wound healing activity of seeds of Trigonella foenum-graecum in rats. Indian Journal of Pharmaceutical Sciences 58, 117–119. Taranalli, A.D., Tipare, S.V., Kumar, S., Torgal, S.S., 2004. Wound healing activity of Oxalis corniculata whole plant extract in rats. Indian Journal of Pharmaceutical Sciences 66, 444–446. Thiem, B., Grosslinka, O., 2003. Antimicrobial activity of Rubus chamaemorus leaves. Fitoterapia 75, 93–95. Thomas, J., John De Britto, A., 2003. Ethnobotanical study in Wyanad District of Kerala. Journal of Economic and Taxonomic Botany 27, pp. 915–824. Tripathi, Y.C., 2000. Ethnomedicinal treasure of tribal Rajasthan. Journal of Non-Timber Forest Products 7, 77–89. Trombetta, D., Puglia, C., Perri, D., Licata, A., Perogolizzi, S., Lairiano, E.R., De Pasquale, A., Saija, A., Bonina, F.P., 2006. Effect of polysaccharides from Opunta ficus-indica cladodes on the healing of dermal wounds in the rat. Phytomedicine 13, 289–294. Udupa, A.L., Kulkarni, D.R., Udupa, S.L., 1995. Effect of Tridax procumbens extracts on wound healing. International Journal of Pharmacognosy 33, 37–40. Udupa, S.L., Shetty, S., Udupa, A.L., Somayaji, S.N., 2006. Effect of Ocimum sanctum Linn. on normal and dexamethasone suppressed wound healing. Indian Journal of Experimental Biology 44, 49–54. Udupa, S.L., Udupa, A.L., Kulkarni, D.R., 1994a. Anti-inflammatory and wound healing properties of Aloe vera. Fitoterapia 65, 144–145. Udupa, S.L., Udupa, A.L., Kulkarni, D.R., 1994b. Studies on antiinflammatory and wound healing properties of Moringa oleifera and Aegle marmelos. Fitoterapia 65, 119–123. Umadevi, S., Mohanta, G.P., Kalaichelvan, V.K., Manavalan, R., 2006. Studies on wound healing effect of Flaveria trinervia leaf in mice. Indian Journal of Pharmaceutical Sciences 68, 106–108. Uniyal, B., Shiva, V., 2005. Traditional knowledge of medicinal plants among rural women of the Garhwal Himalaya, Uttaranchal. Indian Journal of Traditional Knowledge 4, 259–266. Upadhyaya, O.P., Kumar, K., Tiwari, R.K., 1998. Skin treatments of Bihar plants. Pharmaceutical Biology 36, 20–24. Villegas, L.F., Marcalo, A., Martin, J., Fernandez, I.D., Maldonado, H., Vaisberg, A.J., Hammond, G.B., 2001. (+)-epi-Alpha-bisabolol [correction of bisbolol] is the woundhealing principle of Peperomia galioides: investigation of the in vivo wound-healing activity of related terpenoids. Natural Products 64, 1357–1359.