Medicinal plants as snake venom antidotes

Journal of Experimental and Applied Animal Science Volume 1, Number 1, pp. 156-181, 2013 Print ISSN 2314-5684 | Online ISSN 2314-5692

REVIEW ARTICLE

Medicinal plants as snake venom antidotes Payel Bhattacharjee and Debasish Bhattacharyya Division of Structural Biology and Bioinformatics; CSIR-Indian Institute of Chemical Biology; 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032 – India

ABSTRACT The conflict between man and snake arises primarily from their overlapping habitats. Neutralization of snake venom toxicity by the application of serum antivenom is a development of the last century. Traditionally people treated snake bite victims by medicinal plants alone or in combination with processed edible items and various rituals. In spite of the success of antivenom treatment, the drug is still not available to a large number of people worldwide who are vulnerable to snake bites. Thus the use of plants as snake venom antidotes will be continued in future. It is also hypothesized that components isolated from plants together with antiserum may yield better results in the neutralization of venom toxins. In this article, we have visited continents to note the severity of snake bites and compiled various plants used as antidotes. These plants warrant establishment of their anti-venom potential leading to a good possibility of discovering new drugs or templates to design better drugs for various diseases. KEYWORDS: Anti-snake venom, medicinal plants, snakebite, herbal therapy.

INTRODUCTION There are over 3000 species of snakes found worldwide including the sea and at high altitudes like Himalayan range of Asia, Arctic Circle in Scandinavia and extreme south of Australia, although, snakes are absent in Antarctica, Ireland, New Zealand and many small islands of the Atlantic and central Pacific region (Bauchot 1994). Amongst the 600 species of venomous snakes, about 410 are considered medically important (Pinho and Pereira 2001). World Health Organization (WHO) assessed the relative risk of each species and divided them into two major categories, one of highest medical importance and other of sec-

ondary medical importance (Warrel, 2010). There are about 5 million snakebite cases per year worldwide, among which 1,00,000 – 2,00,000 deaths are reported. Chippaux (1998) has summarized the scenario of snake envenomation in different parts of the world. Many people, who survive, however suffer from snakebite related amputations or permanent tissue damage leading to disability. Children have both higher incidence of snakebites and suffering than do adults, since they are exposed to a larger amount of venom per unit area of body surface and body weight. Snakebite cases are higher in rural areas and show seasonal variation, with the peak incidences ob156

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Journal of Experimental and Applied Animal Sciences. 1, 1:156-181

11 species, Duke (1993) enlisted 470 species, Gomes (2010) and Dey and De (2012) enlisted several flowering plants that are active against snake venoms. Hashimoto (2002) in an ethnobotanical database enlisted 66 species of plants belonging to 31 families which are used in the Brazilian folk medicine as antidotes against snake venoms (Website 1). Amui et al. (2011) have developed a plant-antivenom database that contains information regarding anti-venom medicinal plants, amino acid sequences of venom toxins and related publications. Continent wise details of the application of the antivenom plants will follow in the later sections.

served in the rainy and harvesting seasons (WHO, 2008). Table 1 summarizes the names of most relevant venomous snakes of the world, their major toxic compounds, mechanism of action of the toxins and their clinical manifestations. From ancient times indigenous communities depended on herbal medicines to cure variety of ailments including cases of snakebites (Samy et al. 2008). There are ample evidences of practice of herbal treatments by aboriginal people from various sources like written documents on parchment papers and preserved stone monuments and even the original medicines themselves. Since 5000 B.C. Indians, Chinese, Babylonians, Hebrews, Egyptians and Assyrians (an ethnic group whose origin lies in ancient Mesopotamia) were acquainted with medicinal plants. The Greeks were familiar with many of the modern drugs as evidenced from the works of Hippocrates, Theophrastus, Aristotle and Pythagoras. In spite of the relative geographical isolation, however, there is a remarkable degree of similarity in healing practices, founding principles and beliefs when compared among varied cultures. In India, specific plants were used for the treatment of victims bitten by specific snakes in ‘Ayurvedic’ system of medicine. There is a complete description of Capparis deciduas in Brooklyn Papyrus, which is a medicinal plant used against snakebite by Egyptians (Vinel and Pialoux 2005). ‘Cherokees’ - the native of America, followed a general therapy for treatment of snakebites. It consisted of both internal and external applications of decoction of medicinal plants (Cozzo 2007). Houghton and Osibogun (1993) compiled a list of flowering plants used for the treatment of snakebite. They also reviewed the methods of testing the activity of the whole plant or parts thereof and discussed the modes of action of the phytochemicals. Many authors have mentioned the versatility of antivenom plants. Rizzini et al. (1988) enlisted 83 species, Mors (1991) compiled 578 species; Martz et al. (1992) enlisted

Even today the traditional healers are the first line of defense against illnesses in rural areas due to poor communication and lack of emergency medical facilities in primary health care centres. They serve more snake bite victims as compared to the registered medical practitioners. Direct testimonies from victims confirm success of their treatment. However, medical science ignores their practice partly due to unknown materials they use and mystical nature of their practices (Chippaux 1998). Application of the plant or its sap onto the bite area, chewing leaves and bark, drinking plant extracts or decoctions are some procedures intended to counteract snake venom toxicity (Samy et al. 2008).

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Herbal medicines are in great demand in both developed and developing countries as a source of primary health care due to their wide biological and medicinal activities, high safety margins, availabilities and cost considerations. WHO estimated that, more than 80% of the world’s population relies on traditional healing practices and herbal medicines for primary health care. In United States, about 25% of all prescribed drugs are derived from herbal sources and most of them were discovered owing to their prior use by traditional healers (Rawat 2006). The demand of herbal medicine in global market is increasing day by day. Near the turn of the century, there was a



layan pit vipers (Calloselasma rhodostoma) per year with 22% fatality, was recorded. In Mynamar, 14,000 bites with 1,000 deaths were recorded in 1991 (Cruz et al. 2009). Warrell (2010) and Eriksson (2011) have compiled the reports on snake bite cases in South-East Asian countries. In Japan, the majority of venomous bites are inflicted by the Asian pit vipers. The Palestine viper (Vipera palaestinae) and Lebetine viper (Macrovipera lebetina) are the most important species in Western and South East Asia (Warrell 2010). However, existing epidemiological data remain fragmented and the factual impact of snake bites is possibly underestimated. Moreover, total area and the size of the whole population of a country should be considered, otherwise the true epidemiological picture of snakebite in different regions would not be reflected.

rise of spending on herbal medicines by 4.6 billion US dollar in a decade; 19.6 in 1992 to 24.2 in 2002 (Vasisht and Kumar 2002). Euromonitor International has reported the latest market trends and sources of future market growth for the industry of herbal/traditional products in 80 countries (Website 1). Balick and Cox (1996) have noted that even with the advent of modern or allopathic medicines, a number of essential drugs have been derived from plants that are used by indigenous people. At this stand point it is crucial to evaluate antivenom plants to gather an overall idea for future research and drug development. In this review, we survey snake bite incidents continentwise and describe the variety of plants used to save the snakebite victims. As the trend shows, the use will be continued in near future demanding their rational evaluation. Epidemiology of snakebite and traditional herbal treatment Asia: People of South Asia are most affected by snake bites. India has the highest number of snake bite related deaths in the world; 35,000–50,000 people dye per year (David, 2005). In Pakistan, 40,000 bites are reported annually, resulting in 8,200 fatalities (Ali 1990; Kasturiratne et al. 2008). In Nepal, 1,000 recorded deaths occur among 20,000 cases of envenomation annually (Alirol et al. 2010). In Sri Lanka, around 33,000 cases of envenomation are reported annually from government hospitals (Kularatne 2003; Kasturiratne et al. 2008). In Bangladesh, the annual incidence of snake bite is 4.3 per 1,00,000 population, where 20% are fatal (Sarker et al. 1999). In Iran, 5,000-7,000 snake bite cases with 7 deaths were recorded annually between 2001-2009 (Kohli and Sakhuja 2003). In Sayyed Dakhil district of Iraq, there are 150 cases of snake bites leading to the death of more than 40 people since 2003. In 2011, local Government admitted for the first time that saw-scaled viper is responsible for the majority of the death cases (Website 2). In Vietnam, between 1992-1998, 3,00,000 bites by Ma-

In the Indian subcontinent, almost all snakebite deaths are attributed to the ‘big five’, consisting of the Russell's viper (Daboia russelli), Indian cobra (Naja naja), saw-scaled viper (Echis carinatus), common krait (Bungarus caeruleus) and king cobra (Ophiophagus hannah). However, hump-nosed viper (Hypnale hypnale), banded krait (Bungarus fasciatus), monocled cobra (Naja kaouthia) and Asian pir viper (Trimeresurus sp.) are capable of delivering fatal bites. The tribal and rural people of Asia have preserved a huge traditional knowledge regarding the application of medicinal plants growing around their habitat. More than 100 species of Indian plants have been reported as snake venom antidotes (Chopra et al. 1956; Usher 1974; Nadkarni 1976; Lewis and ElvinLewis 1977; Alam and Gomes 2003). Plants are used either as single or in combination (Kirtikar and Basu 1975). Indian plants that are most effective as antivenom are Aristolochia sp., Cissus assamica, Echinacea sp., Excoecaria agallocha, Gloriosa superba, Guiera senegalensis, Hemidesmus indicus, Nerium oleander, Parkia biglobosa, Sarsapa-

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rilla hemidesmus, Securidaca longipedunculata, Tamarindus indica, Thea sinensis, Trianosperma tayuya, Withania somnifera etc (Das 2009). The traditional healers first tie a piece of cloth with a knot immediately above the bitten area to minimize spread of poison into the entire body with flow of blood. The place of wound is properly cut to ooze out the infested blood from the victim’s body and then the paste prepared from the herbal plant is applied over the wound for a time period for healing. Such pastes are generally prepared from rhizomes, stems, roots or leaves of plants, e.g. the paste from rhizome of Acorus calamus, stem and bark of Buchnania lanzan, shoot and leaves of Bombax ceiba and Moringa oleifera are applied on wounds as antidote of snake-bite. The seed oil of Madhuca indica is applied on the wounds due to snakebite and scorpion sting for instant healing. Rhapidophora pertusa has analgesic and antiinflammatory effects that help to reduce pain caused by snake bite (Rai and Nath 2003). Rauvolfia serpentina grows in the foothills of Himalaya. Local people use the root of this plant to treat snake bite victims. They claim that the practice has been evolved through generations after observing that mongoose (Helogale parvula) feed on this plant before combating with snakes (Balick and Cox 1996). The Kani tribes of the state of Kerala, India use Aristolochia indica and Aristolochia tagala to treat krait and cobra bites. Paste of fresh leaves or roots of the plants are applied externally over the bitten area and 10 – 15 ml of fresh juice from leaves or roots with a pinch of black pepper is administered orally 6 times a day to recover from the pain and coma. Aristolochia tagala is more potent than Aristolochia indica as a snake venom antidote. The Malapandaram tribe of Kerala uses leaves of Cipadessa baccifera mixed with pepper and administer orally against snake bite (Latha et al. 2008). The Sugali tribes of Yerramalais area, Tamil Nadu, India use 23 species of ethnomedicinal plants in the form of paste, powder,

juice, decoction, infusion and also in crude form to treat snake bite victims. Some of them claim that there is no death due to snake bites till date (Basha and Sudarsanam 2012). Kunjam et al. (2013) described the application of herbal medicines by the Cherwa and Pando tribes of Chattisgarh, India. They prepare paste, pills, powder, decoction, infusion and aqueous extracts of medicinal plants, either separately or in combination with other plants and minerals. The main tribal communities of Rajasthan, India viz., Bhil, Meena, Garasia, Damor, Sahariya and Kathodia etc use nearly 44 plants for the treatment of snake bite, among which 5 are monocotyledonous and 39 are dicotyledonous (Jain et al. 2011). Tribal people of Kalahandi, Orissa, India use the term ‘Gada’ for antivenom plants. Similar terms like ‘Sarpairi’ or ‘Sapabisha-jhadagada’ literally means ‘snake medicine’ and is used by the people in coastal districts of Orissa. Mund and Sathpathy (2011) compiled the widely used antivenom plant species used by these ethnic people. Sometimes the snake teeth were mixed with roots of Aristolochia indica to treat victims. Herbal therapy of the tribals also involved oral consumption of leaf powder of Ocimum sanctum or rhizome powder of Curcuma longa before treatment (Mund and Satapathy 2011). In North East India, the leaves and flowers of Mesua ferrea are used against snake bite (Sahni 1998). Some species are grown around houses or their extracts are sprinkled on the floor to repel snakes. e.g., Allium sativum (garlic) and Pseudocalyma alliceaum (garlic vine). Aristolochia indica root has a strong aromatic smell which is believed to repel snakes (Latha et al. 2008). Figure 1 shows the demand for medicinal plants in West Bengal, India. Aristolochia indica, Azadirachta indica, Ocimum sanctum and Andrographis paniculata are some of the plants widely used as a snake venom antidote. In rural areas of West Bengal, people tie small piece of roots of Aristolochia indica with a thread on upper arm and use as amulet to protect them from Russell’s vipers (information

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obtained from interviewing a local medicinal herbs seller). Asad et al. (2011) enlisted 35 plants having application as folklore (ethnobotanical) antidotes in Pakistan. The traditional use of leaves (35%) is higher than roots (25%), whole plant (21%), flower (7%), wood (5%), fruit (5%) and milky juice (2%) as a snake venom antidote. The herbs (55%) are mostly used as snake bite remedy than shrubs (31%) and trees (14%). Achranthes aspera, Albizia lebek, Cassia occidentalis and Verbena officinalis are used against snakebites in Pakistan (Ahmed 2007). Glycine max, Hedyotis diffusa and Ruta graveolens are used in traditional Chinese medicine as snake bite antidote. Ash of leaves and stem of Launea acanthodes is used as herbal antidote for snake bites and insect sting in Iran (Rajaeia and Mohamadi 2012). Africa: Africa is the habitat of four venomous snake families- Atractaspididae, Colubridae, Elapidae and Viperidae. Vipers alone cause approximately 60% of all bites. In drier regions of the continent, 90% of bites are inflicted by the saw-scaled vipers. Snakebites are most common in the sub-Saharan regions with approximately 1 million reports annually, resulting 5,00,000 envenomations and 25,000 deaths (Chippaux 1998). The annual incidence of snake bites in the Benue Valley of NorthEastern Nigeria is 500 per 1,00,000 population with 12.2% fatality (Cruz et al. 2009). In Kenya, up to 80% of snakebite victims take help from traditional practitioners before visiting a medical center (Snow et al. 1994). For treatment, plants belonging to Asteraceae family are used extensively followed by Annonaceae, Fabaceae, Combretaceae and Tiliaceae families. Among the Baka community, nearly all remedies are from Apocynaceae and Annonaceae. The Luo and Kamba ethnic groups of Kenya are highly exposed to snake bites, especially Bitis sp., Dendroaspis polylepis and Naja melanoleuca. The

traditional healers make an incision around the bite and herbal remedies applied on the wound site. Antidotes are administered within half an hour after the bite. Owuor and Kisangau (2006) have reported use of several indigenous plants by these communities. Both communities had two exotic species. Allium cepa and Tagetes minuta are used by Kambas and Senna siamea and Tithonia diversifolia are used by Luos of South Western Kenya. Only Combretum sp. is shared by these two ethnic groups. Similar practice of using Combretum sp. is reported in Tanzania. In some cases, the snake teeth were mixed with Opilia amentecea, a woody vine for the treatment of poisoning. Despite this difference, there are significant similarities among the Luo and Kamba beliefs of snake bite perception and etiology (Owuor and Kisangau 2006). Combretum collinum, Sebaea hymenosepala, Solanum incanum, Steganotaenia araliacea and 3 species of Grewia (G. bicolor, G. fallax and G. truncata) are used by the native people in East Africa. In addition, application of plants like Erythrina abyssinica, Sansevieria kirkii and Vernonia sp. are recorded (Reis and Lipp 1982). In South Nigeria, an infusion of the leaves of Clerodendron polycephalum and Sansevieria liberica are applied on the bitten area (Dalziel 1948; Gill 1992; Osabohien and Egboh 2008; Adeyemi et al. 2009). In South Africa and tropical America, Sansevieria trifasciata is used for the treatment of inflammatory conditions and sold as a crude drug in the market to treat victims of snakebite (Morton 1981). ‘Vemkill’ is a standardized ethanolic extract of a combination of three plants, which has been used successfully to abolish or reduce lethality of snake bites in Ghana (Naomesi et al. 1996). Hoodo, a traditional African-American community treats victims by applying a boiled mixture of Argentina anserine, Musa sp. and milk to the site of snake bite (Yonwode C).

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Table 1: Major venomous snakes of the world Family

Species

Major componentsa

Mechanisms of action

Clinical manifestations b

Viperidae

Daboia russelli Echis carinatus Hypnale hypnale Trimeresurus sp. Vipera sp. Macrovipera sp. Calloselasma sp

Phospholipase A2 (PLA2) isoforms

Hydrolyse membrane phospholipids in a Ca2+ dependent manner and increase release of free proteins

Serine protease like factor V and X activator

Affect blood coagulation system of victim

Hemorrhage, coagulation defects, acute renal failure, cardiotoxicity, local tissue necrosis, pulmonary hemorrhagic edema, renal failure and hematuria.

Haemorrhagic metalloprotease Hyaluronidases

Degrade extracellular matrix proteins and shows cytotoxicity on endothelial cells Degradation of hyaluronic acid in the extracellular matrix facilitates the diffusion of toxins from the site of a bite into the circulation

Nucleases, nucleotidases and phosphoesterases

Release of purines, a multitoxin, during snake envenomation

L-amino acid oxidase (LAAO)

Generates hydrogen peroxide and affects platelet aggregation, induction of apoptosis, haemorrhagic effects, and cytotoxicity

Disintegrins C-type lectins Cysteine-rich secretory protein and vascular endothelial growth factor (VEGF)

Hemagglutination, platelet aggregation and vasculogenesis

Bitis sp. Bothrops sp. Crotalus sp. Agkistrodon sp. Lachesis sp.

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Table 1: Major venomous snakes of the world (Continued) Family

Species

Major componentsa

Mechanisms of action

Clinical manifestations b

Elapidae

Naja sp. Bungarus sp. Dendroaspis sp. Micrurus sp. Acanthophis sp. Micropechis sp. Pseudonaja sp. Oxyuranus sp. Notechis sp. Austrelaps sp. Hoplocephalus sp.

Acetylcholinesterase (Except Mamba snakes)

Depletion of neurotransmitter from the nerve terminals, degeneration of nerve terminals and intramuscular axons.

Neurological and neuromuscular problem, paralysis, ventilatory failure, diuresis and death in a short duration of time.

Cardiotoxin

Depolarization and degradation of the plasma membrane of skeletal muscle cells. Degrades synaptosomal phosphatidylcholine

Neurotoxic PLA2

Pre or post-synaptic neurotoxin Metalloproteases

a b

Reversible blocking of neural transmission by competitively binding to the nicotinic acetylcholine receptors (nAChRs) Bleeding disorder due to degradation of fibrinogen

Disintegrins, warparins

Affects Na+-K+ ATPase

Phosphoesterase (low amount)

Release of purines, a multitoxin

These major components are common to the family of snakes. These clinical manifestations are common to the family of snakes.

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Table 2: List of plants having antivenom potentiala

Inhibition of snake venom

Name of plant

Parts/extracts used

Aristolochia bracteolata, Tylophora indica and Leucas aspera (1:1:1)

Aqueous extracts of leaves and roots

Daboia russelli russelli and Naja naja

Sakthivel et al. 2013

Piper longum

Ethanolic extract of fruits, especially piperin.

Daboia russelli

Shenoy et al. 2013

Aristolochia indica

Aqueous extract of root

Daboia russelli russelli

Bhattacharjee and Bhattacharyya 2013; Meenatchisundaram et al. 2009

Bombacopsis glabra

Triacontyl p-coumarate (PCT) isolated from root bark

Bothropoides pauloensis

Mendes et al. 2013

Crocus sativus

Crocin

Daboia russelli

Sebastin et al. 2013

Renealmia alpinia

Alcoholic extract

Metallo- and serine proteinases present in snake venoms

Patiño et al. 2013

Artemisia absinthium

Methanolic extract

Montivipera xanthina

Nalbantsoy et al. 2013

Solanum campaniforme

Alcoholic extract of leaves

Bothrops pauloensis

Torres et al. 2013

Sapindus saponaria

Callus

Bothrops and Crotalus sp.

da Silva et al. 2012

Persimmon proanthocyanidin

Alcoholic extract

Naja atra

Xu et al. 2012

Butea monosperma

Ethanolic extract of stem bark

Daboia russelli

Tarannum et al. 2012

Mikania laevigata

Ethanolic extract of leaves

Philodryas olfersii

Collaço et al. 2012

Tanacetum parthenium, Andrographis paniculata and Curcuma sp.

Crude extracts, purified

Ophiophagus

compounds

hannah

(whole venom/ components)

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Reference

Salama et al. 2012



Table 2: List of plants having antivenom potentiala (Continued)

Name of plant

Parts/extracts used

Inhibition of snake venom (whole venom/ components) Echis carinatus

Reference

Hope-Onyekwere et al. 2012; Scirè et al. 2011; Fung et al. 2010; 2011; Guerranti et al. 2008

Mucuna pruriens

Seed

Calloselasma rhodostoma and Naja sputatrix

Nectandra angustifolia

Ethanolic extract of leave and essential oil

Bothrops neuwiedi diporus

Torres et al. 2011a

Solanum campaniforme

Solanidane steroidal alkaloids isolated from leaves

Bothrops pauloensis

Torres et al. 2011b

Mangifera indica

Aqueous extract of stem bark


Dhananjaya et al. 2011

Ethanolic extract from seed kernels

Calloselasma rhodostoma and Naja naja kaouthia

Leanpolchareanchai et al. 2009

Schizolobium parahyba

Aqueous extract of leaves

Bothrops sp.

Vale et al. 2011; 2008; Mendes et al. 2008

Fagonia cretica

Methanolic extract from the leaves and twigs

Naja naja karachiensis

Razi et al. 2011

Mimosa pudica

Tannin isolate

Naja kaouthia

Ambikabothy et al. 2011

Aqueous root extracts

Echis carinatus and Daboia russelli russelli

Meenatchisundaram and Michael 2009

Marsypianthes chamaedrys

Inflorescence and leaf extracts

Bothrops atrox

Magalhães et al. 2011

Hibiscus aethiopicus

Aqueous extract of whole plant

Echis ocellatus and Naja n. nigricollis

Hasson et al. 2010

Argusia argentea

Rosmarinic acid

Trimeresurus flavoviridis

Aung et al. 2010

Dipteryx alata

Hydroalcoholic extract of bark

Bothrops jararacussu

Puebla et al. 2010; Nazato et al. 2010

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Table 2: List of plants having antivenom potentials a (continued)


Name of plant

Parts/extracts used

Curcuma zedoaroides

Acetone extract of rhizome

Ophiophagus hannah

Lattmann et al. 2010

Mikania glomerata

Aqueous leaf extract

Crotalus durissus

Floriano et al. 2009

Anacardium occidentale

Bark extract

Neutralize the viper venom hydrolytic enzymes such as phospholipase, protease, and hyaluronidase

Ushanandini et al. 2009

Vitis vinifera

Methanolic extract of seed

Daboia russelli

Mahadeswaraswamy et al. 2009

Echis carinatus

Mahadeswaraswamy et al. 2008

Eclipta alba

Extracts from both native and genetically modified plant

Crotalus durissus terrificus and Bothrops jararacussu

Diogo et al. 2009

Mouriri pusa, Byrsonima crassa, Davilla elliptica and Strychnos pseudoquina

Methanolic extracts of leaves

Bothrops jararaca

Nishijima et al. 2009

Morus alba

Leaf extract

Daboia russelii

Chandrashekara et al. 2009

Azadirachta indica

Methanolic leaf extract

Cobra and viper venom

Mukherjee et al. 2008

Casearia sylvestris

Ellagic acid derivatives from aqueous extract


Da Silva et al. 2008

Galactia glauscescens

Ethanolic extract of leaves

Crotalus durissus terrificus

Dal Belo et al. 2008

Curcuma longa

Turmerin protein

Naja naja

Echinacea purpurea

Aqueous extract of root

Bothrops asper

Pentaclethra macroloba

Aqueous extract of bark Triterpenoid saponin inhibitors


Bothrops sp.

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Reference

Chethankumar and Srinivas 2008 Ferreira et al. 1992 Chaves et al. 2007 da Silva et al. 2005; 2007





Name of plant

Parts/extracts used

Pluchea indica

Beta-sitosterol and stigmasterol isolated from the root extract

viper and cobra venom

Gomes et al. 2007

Tamarindus indica

Seed extract

Daboia russelli

Ushanandini et al. 2006

Bridelia ndellensis

Alcoholic extract of bark

Neutralize snake venom toxicity

Mostafa et al. 2006

Crinum jagus

Methanolic extract of the bulb

Echis ocellatus, Bitis arietans and Naja nigricollis

Ode and Asuzu 2006

Hemidesmus indicus

Methanolic root extract

Daboia russellii and Naja kaouthia

Chatterjee et al. 2006

Croton urucurana

Aqueous extract

Bothrops jararaca

Esmeraldino et al. 2005

Cordia verbenacea

Rosmarinic acid


Ticli et al. 2005

Bauhinia forficate

Aqueous extract from aerial parts

Bothrops and Crotalus sp.

Oliveira et al. 2005

Musa paradisiacal

Juice

Crotalid venom

Borges et al. 2005

Annona senegalensis

Methanol extract of root bark

Naja nigricotlis nigricotlis

Adzu et al. 2005

Acalypha indica

Ethanolic extract of leaf


Shirwaikar et al. 2004

Baccharis trimera

Alcoholic extract

Bothrops neuwiedi and B. jararacussu

Januário et al. 2004

Eclipta prostrata

Butanolic extract

Calloselasma rhodostoma

Pithayanukul et al. 2004

Tabernaemontana catharinensis

Aqueous extract

Crotalus durissus terrificus

de Almeida et al. 2004

Thea sinensis

Melanin

Agkistrodon sp. and Crotalus sp.

Hung et al. 2004

Parkia biglobosa

Water-methanol extract of stem bark

Naja nigricollis and Echis ocellatus

Asuzu and Harvey 2003


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Reference




Name of plant

Parts/extracts used

Inhibition of snake venom (whole venom/ components)

Reference

Mandevilla velutina

Aqueous extract

Inhibit some enzymatic and pharmacological activities of some snake venoms

Biondo et al. 2003

Casearia mariquitensis

Aqueous extract of leaves

Bothrops neuwiedi pauloensis

Izidoro et al. 2003

Marsypianthes chamaedrys

Methanolic extract

Antifibrinoclotting action against thrombin-like enzymes of snake venoms

Castro et al. 2003

Phenolic compound

Inhibitory activity against snake venom phosphodiesterase I

Ahmad et al. 2003

Mitragyna stipulosa

Non-alkaloidal extract of bark

Inhibit snake venom phosphodiesterase I activity

Fatima et al. 2002

Ehretia buxifolia

Ehretianone in the methanolic extract of the root bark

Echis carinatus

Selvanayagam et al. 1996

Brongniartia podalyrioides and B. intermedia

(-)-Edunol a prenylated pterocarpan isolated from the roots

Bothrops atrox

Reyes-Chilpa et al. 1994

Symplocos racemosa

a

The table provides information about antivenom plants reported in the last 20 years (1993-2013).

Additional information is available from cross references.

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Central and South America: South America is the third most affected area by snake envenomation after Africa and Asia (Chippaux 1998). Epidemiological data on snakebite envenomation in Latin America are limited due to improper reporting to health centers. In Brazil, there are 25,000 snake bite incidences per year with a mortality rate of about 0.45%. The snakes responsible for venomous bite are Bothrops (83.8%), Crotalus

(8.5%), Lachesis (3.4%) and Micrurus sp. (0.4%) (Sousa et al. 2013). Mexico and Central America collectively have an estimated 193 fatalities per year. The tropical areas of the Amazon basin and the southern tip of South America contribute an additional 100 and 4 death per year on an average respectively (Miller L). In Costa Rica, 22.4 per 1,00,000 inhabitants are admitted to hospitals annually due to snake bites (Rojas et al. 1997).

Figure 1: Handling of traditional medicinal plants in India. a. Series of shops selling medicinal herbs even at late evening in a suburban railway station near Kolkata, India; b. Aristolochia indica; c. Azadirachta indica; d. Ocimum sanctum and e. Andrographis paniculata grown in herbal gardens near Kolkata. Photographic credits, PB (a, c-e) and Angana Bhattacharyya (b).

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Brazilian Indians have an ancient tradition of using ‘guaco’ (Mikania cordifolia and M. glomerata) for snake bites. They prepare a decoction of the leaves and administer orally. They also apply the juice of leaves or stem directly onto the bitten part. Other Red Indian tribes in Amazonian rainforest use the crushed leaf and stem topically on snake bites and the decoction of leaves/stem as a drink. Several Indian tribes also believe that the fresh aromatic smell of crushed leaves may drive snakes away (Ruppelt et al. 1991; Maiorano et al. 2005; Floriano et al. 2009; Collaço et al. 2012). People of Serra da Jibóia, Brazil, use homemade remedies against snake envenomation from the plants like Allium cepa, Allium sativum, Anacardium occidentale, Annona crassiflora, Amburana cearensis, Euterpe edulis, Joannesia princeps, Mucuna urens, Zephyranthes sp. etc (Fita et al. 2010). Otero et al. (2000a) reported an inventory of plants used by traditional healers to treat snake bites in Colombia. They documented the methods of preparation, mode of administration, dosage and results of treatment. They reported 77 species of plants belonging to 41 families like, Acrocomia ierensis, Aristolochia rugosa, Aristolochia trilobata, Barleria lupulina, Bauhinia cumanensis, B. excisa, Cecropia peltata, Cola nitida, Costus scaber, Nicotiana tabacum, Allium sp. and Renealmia alpinia. Eclipta prostrate is highly recognized as snakebite antidote in the vast region of Southern United States to South America. Mesua ferrea bark is mostly used to treat snake bites (Santamaría 1978). The Maya text recommended the application of boiled leaves of Clerodendrum ligustrinum as a wash for snake bites (Roys 1931). The Choco and Cuna Indians in Panama use Chrysothemis friedrichsthaliana as a snakebite treatment regime. Negroes in Panama apply boiled shoots of Heliconia bihai on foul ulcers resulting from snakebites (Morton 1981). In Venezuela, Serpicula brasiliensis is boiled in water and used for snakebite (Reis and Lipp 1982).

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Mestizos and the native peoples in the Upper Amazon use a wide variety of plants to treat snakebites. Ethnobotanists Evans and Raffauf (1990) enlisted 29 plants while Duke and Vasquez (1994) enlisted 12 plants used for this purpose. Local inhabitants use to apply a poultice, made up of banana leaf, filled with the finely chopped tuber of Dracontium loretense around the site of envenomation. They also apply Laportea aestuans and Solanum sessiliflorum, as well as chewed leaves of Nicotiana rustica and applied directly to the wound. The patient was also given a coldwater infusion of Dracontium loretense to drink or Solanum sessiliflorum fruit boiled with sugar (Beyer 2008). Bauhinia cumanensis or Bauhinia excisa were used to treat snakebites in Trinidad and Tobago. They made tinctures with alcohol or olive oil and kept in rum flasks called 'snake bottles'. The other plants used are Aristolochia rugosa, Acrocomia aculeate, Barleria lupulina, Cola nitida, Nicotiana tabacum and Pithecellobim unguis-cati. Emergency medicines are obtained by chewing a three-inch piece of the root of Cecropia peltata and administering this chewed-root solution to the bitten area. Another indigenous plant used is Renealmia alpinia that are crushed together with the juice of Costus scaber (Lans et al. 2001). Guahibo, the nomadic people of Savannas and gallery forests of South America, extensively used plants as antidotes. The traditional healers, known as ‘shaman’ play significant role for curing snake envenomations. They produce tobacco smoke along with chanting and then the cigarette was soaked in a cup of water to produce ‘tobacco water’, which was sprinkled on the patient’s head and extremities. According to their belief, this smoke-blowing treatment had a strong psychological effect on patient (Zethelius and Balick 1982). North America: Approximately 45,000 snakebites occur annually in the United States, 8000 of which are from venomous snakes and among them only 5 people die each year. This number is quite low due to



availability of good transportation and medical facility. The state of North Carolina has the highest frequency of snakebites with an average of 19 bites per 1,00,000 people followed by Arkansas, Texas, Georgia, West Virginia, Mississippi, Louisiana, and Oklahoma (Parrish 1966; Russell 1980). Between 1960 and 1990, only 12 fatalities per year from snakebite were reported (Juckett and Hancox 2002). There are about 25 species of venomous snakes among the 120 species indigenous to United States. Western and Eastern diamondback rattlesnakes cause up to 95% of all snakebiterelated deaths in the United States (Gold et al. 2002). The majority of the snakes are pit vipers (subfamily Crotalinae), e.g. rattlesnakes, cottonmouths and copperheads. The coral snake (Elapidae) is the native venomous snake in United States (Gold et al. 2004). Artemisia fillifolia, Echinacea sp., Eryngium yuccifolium, Gentiana villosa, Gutierrezia sarothrae, Hypericum perforatum, Juniperus sp., Lesquerella fendleri, Ligusticum poteri, Nicotiana sp., Podophyllum peltatum and Polygala senega are used as folklore plants to treat snake bite by Native American (Huntley et al. 2005). There is little information on how the Ohlone, Native American people of the Central and Northern California coast, dealt with snakebites. They generally treat a person who was bitten by a rattlesnake, by giving a tea made from rattlesnake weed (Daucus pusillus). They also use to make an incision followed by suction to the area of the bite. The Ohlone protect themselves from snake bites by placing fresh leaves of the Oregon ash tree (Fraxinus latifolia) in their sandals (Website 4). Comanche tribe of Texas, Oklahama and New Mexico use Ageratina sp., Lophophora williamsii and the bark of Alnus sp. for treating snakebite (Graham JS). Australia: Despite the enormous species of venomous snakes in Australia, only 2 to 4 deaths occur every year from snakebites. In Australasia ecozone, like Papua New Guinea, Solomon Islands and Vanuatu where hu170

man settelement in the fringe area of dense rain forest causes human-snake habitat conflict, snakebite is an almost daily occurrence and venomous snakebite is a serious public health problem (Kasturiratne et al. 2008). In New Guinea, majority of the bites are caused by the death adders (Acanthophis sp.) and few are by the endemic small-eyed snake (Micropechis ikaheka) and other local species. Few numbers of terrestrial snakes like eastern brown snakes (Pseudonaja textilis), death adders, mulga snake (Pseudechis australis), taipans snake (Oxyuranus sp.), tiger snakes (Notechis scutatus), copperheads (Austrelaps sp.) and broad-headed snake (Hoplocephalus sp.) are found in the Pacific Islands, although sea snakes are common in coral reefs. Among these the eastern brown snake is highly venomous resulting in up to 60% of all deaths due to snakebites (Mirtschin et al. 2002). Williams et al. (2003) reported the snakebite incidences in Mekeo region of Central province between 1997 and 2001 as 561.9 cases per 100,000 populations per yaer. At present, there is no data on the incidence of snakebite related morbidity or mortality in other regions of Papua New Guinea. In some areas of Papua New Guinea, the following plants are used for treating snakebites: Alphitonia incanea, Cerbera floribunda, Maclura sp., Mangifera minor, Melanolepis multiglandulosa, Musa paradisica, Nicotinia tabacum, Osmoxylon micranthum, Osmoxylon micranthum and Passiflora foetida. People use to apply the sap or extract of bark onto the bitten area and sometimes ingest the juice of the plant/ plant parts (Mebs 1996; 2000). In the Morobe province of Papua New Guinea, the sap of the stem of cooked banana (Musa paradisiaca) is smeared onto the site of bite. The sap of the leaf of Codiaceum variegatum is also ingested and rubbed into the bite area (Woodley 1991). In Madang province of Papua New Guinea, the dry leaf of Nicotiana tabacum is consumed to treat snake envenomation (Petir et al. 1997).



Europe: Snakebite is relatively a rare medical emergency in Europe due to cold climatic conditions, better standard of living and thin population density. In this continent including European Russia and Turkey, the annual number of snakebite cases is estimated to be 8,000 with only 15% severe cases (Chippaux 2012). Average estimated death is 5 and 6 per year in Western and Central Europe respectively. Eastern Europe has relatively more deaths of about 37 per year. In Europe, most of the venomous bites are caused by coastal viper (Vipera xanthina), nose-horned viper (Vipera ammodytes), asp viper (Vipera aspis) and Lataste's viper (Vipera latastei) (Chippaux 1998). In 16th century, Ribes nigrum was used by French monks to treat snakebite victims. European settlers use Sanicula marilandica roots to draw out snakebite venom (Website 5). Thymus vulgaris was used by the Greek and Roman as treatment for snake bite poisoning (Website 6). Overall, there is little information of antivenom plants in Europe. Need for scientific validations of antivenom plants Snake bite victims are generally treated by administration of horse or sheep-derived polyclonal antivenoms. However, despite being the only recommended treatment for the registered medical practitioners and success of the therapy, it is still important to search for synthetic and natural product inhibitors of venom that could complement serum therapy in terms of reducing morbidity and mortality and also to alleviate the side-effects of antiserum therapy. There is a wide gap between the supply and demand of the antivenoms. It will be wider in future because of procurement of snake venoms arising from stringency in animal ethics regulations. In contrast, among the enormous varieties of antiophidian plants used worldwide, only a few species have been scientifically investigated to explore the underlying secret of 171

this gift of nature to identify antivenom molecules and their mode of actions. Pereira et al. (1994) have screened 15 compounds, isolated from reputed antiophidian plants that showed significant protection to mice against the lethal action of the venom of Bothrops jararaca. Otero et al. (2000b) described the antivenom activity of ethanolic extracts of 12 plants among 74 plants used by traditional healers for snakebites in the North-West region of Colombia. Núñez et al. (2004) determined the neutralizing activity of ethanolic extracts of leaves and branches of 12 plants against the edema-forming, defibrinating and coagulant effects of Bothrops asper venom in Swiss Webster mice. Several researchers have compiled the reports on inbitory properties of various plants against snake venom induced toxicity (Daduang et al. 2005; Soares et al. 2005; Memmi et al. 2005; Samy et al. 2008; Gomes et al. 2010; Makhija and Khamar 2010; Dey and De 2012; Gupta and Peshin 2012). Table 2 summarizes the description and references of major antivenom plants that neutralize the toxic effects of different snake venoms in vitro and in vivo. Certainly, this list is not exhaustive. CONCLUSION There is an intricate relationship between human beings and plants from the beginning of civilization. At first, the use of medicinal plants for various ailments was instinctive similar to other animals. During evolution healing properties of certain plants were identified, noted and conveyed to the successive generations. Sometimes plants believed to possess antivenom properties do not show expected results in experiments done in vitro (Mebs 2000). It is possible that some plants may act as placebo to reduce fear and recovery from traumatic conditions of the victim. It should be acknowledged that snakes are one of the ten major causes of fear experienced by the human race (Tancer 2008). Therefore, the physiological changes associated with intense fear of a snake bite victim must not be overlooked.



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