Herbs and Herbal Constituents Active Against Snake Bite

7/31/2019 Herbs and Herbal Constituents Active Against Snake Bite

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Sundara Veerraju

Herbs and herbal constituents active against snake bite

1* 1 1 1 1Antony Gomes , Rinku Das , Sumana Sarkhel , Roshnara Mishra , Sanghamitra Mukherjee ,

Shamik Bhattacharya & Aparna Gomes2 2

Laboratory of Toxinology & Experimental Pharmacodynamics, Department of Physiology, University of Calcutta,1

92 A P. C. Road, Kolkata 700 009, India

Drug Development/Diagnostics & Biotechnology Division, Indian Institute of Chemical Biology,2

4, Raja S. C. Mullick Road, Kolkata 700 032, India

Snake bite, a major socio-medical problem of south east asian countries is still depending on the usage of antisera as the

one and only source of treatment, which has its own limitations. In India, mostly in rural areas, health centres are

inadequate and the snake bite victims mostly depend on traditional healers and herbal antidotes, as an alternative treatment.

The present review has been focussed on the varied folk and traditional herbs and their antisnake venom compounds, which

might be a stepping stone in establishing the future therapy against snake bite treatment and management.

Keywords : Alternative medicine s, Herbal compound, Snake bite, Snake bite treatment, Snake venom

transaminase, hyaluronidase, phosphodiesterase,IntroductionSnake bite, till date remains a public health hazard nucleotidase, ATPase and nucleosidases (DNA and

in tropical countries, especially in India. Accurate RNA). Very few non-protein components have beenrecords to determine the exact epidemiology or isolated from snake venom, an anticonvulsant

even mortality in snake envenomation cases are non-protein cardiotoxin is among them . The2

inadequately available . Hospital records fall far pathophysiologic basis for morbidity and mortality1

short of the actual number owing to the dependenceis the disruption of normal cellular functions by

on traditional healers and practitioners. In India, on an these enzymes and toxins.average 2,50,000 snake bites are recorded in a single The treatment for snake bite is as variable as the

year. There are 52 poisonous species of snakes bite itself. The only available treatment is the usageavailable in India, of which majority of the bites andof antivenom against snake bite. The first antivenom

(called an anti-ophidic serum) was developed bymortality are attributed to species likeOphiophagushannah (king cobra),Naja naja(spectacled cobra), Albert Calmette, a French scientist of the Pasteur

Daboia russelli(Russell's viper), Bungarus caeruleus Institute in 1895, against the Indian Cobra (Naja naja).(common krait) and Echis carinatus (saw-scaled Antivenom binds to and neutralizes the venom,

viper). stopping further damage, but do not reverses thedamage already done. Some individuals may react toSnake venom, the most complex of all poisons

is a mixture of enzymatic and non-enzymatic toxicthe antivenom with an immediate hypersensitivity

compounds as well as other non-toxic proteins, reaction . Other alternative treatment involves the3

usage of folk and traditional medicines in snake bites.non-proteins, including carbohydrates and metals thatis stored in poison glands. There are more than twenty Medicinal herbs are the local heritage with global

importance. Various plants have been used againstdifferent enzymes including procoagulant enzymes,snake bite, in folk and traditional medicine. Inhaemorrhagins, cytolytic or necrotic toxins, pre-

synaptic and post-synaptic neurotoxins, phospholipases Ayurvedic system of medicine different plants andtheir compounds are reported to possess antisnakeA2, B, C, D, hydrolases, phosphatases (acid andvenom activity. But they also possess their individualalkaline), protease s, esterases, acetylcholinesterase,toxicities and most of the folk medicinal plants have

no scientific validation. This review is an attempt to

focus on the antivenom treatment of snake bite, its* Correspondent authorFax: 91 033 2351 9755 limitations, herbal antagonists and herbal constituentsE-mail: [email protected]; [email protected]

active against snake bite and its future.Telephone: 91 033 2350 8386 (Extn. 229) 094331 39031 (M)


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866 INDIAN J EXP BIOL, SEPTEMBER 2010

Antivenom treatment of snake envenomation and The roots of the plant Ophiorrhiza mungo,

its limitations Peristrophe bicalyculata, Gymnema sylvestreThe most common and effective method of treating Gloriosa superba, Cucumis colosynthis, Alangium

snake bite victims is through antivenom, a serum salvifolium,leaves o Enicostemma axillare,

made from the venom of the snake. In India, Calycopteris floribunda, Calotropis gigantea,4polyvalent antivenom is prepared by Central Aristolochia indicaare used in Ayurvedic medicine.

Research Institute, Kasauli, Simla, and the HaffkineAyurveda states the usage of specific plants against

Corporation, Parel, Mumbai. The WHO has specific snake bites, e.g. root extract of Abrusdesignated the Liverpool School of Tropical Medicine precatorius is used against krait bite, leaf paste of

as the international collaborating centre for antivenom Azadirachta indicawith rock salt is used against

production and/or testing . Antivenoms, in most viper bites. Leaves and bark ofCasearia sylvestris,4

countries are costly and may be in limited supply.(guacotonga) are used as a standard Ayurvedic

Antivenoms for therapeutic use are often preserveddrug to treat snake bite in Columbia, India, etc.as freeze-dried ampoules, but some are available Aristolochia indicais used as a decoction for snake

only in liquid form and must be kept refrigerated.bite. Seeds ofPsoralea corylifolia are used both in

The majority of snake antivenoms are administeredAyurveda and Siddha against snake bite.Origanum

intravenously. The intramuscular route has been dictamnusjuice is consumed in wine to cure snakequestioned in some situations as they are not bite. Tea made from the leaves ofCecropia peltatais

uniformly effective. Antivenom should be given used as a cure for a wide variety of ailments includingas quic kly as possible so that the venoms side snake bite.Achyranthes aspera, is used in treatment

effects can be managed. Antivenom should be given of bleeding, renal complications, scorpion bite, snake

only if the range of spe cificity is stated which bite, etc.includes the species known or thought to have been

The first scientific investigation regarding theresponsible for the bite. Liquid antivenom that

herbal antidotes was from Knowles. He screened5turned opaque should not be used because

several plants/plant constituents, used by localprecipitation of protein indicates loss of activity

healers, but failed to report their efficacies againstwhich is directly proportional to increased risk

snake envenomation, either due to sublethal dose ofof reactions.

venom or non lethal dose. Later, Mhaskar and Caius6

In India, other centres which are involved in challenged the effectiveness of herbal antidotesmanufacturing of antivenom are Bharat Serums by screening 314 plants and 184 combinations againstand Vaccines Ltd., Mumbai, Serum Institute, Pune,venom induced lethality, ignoring the systemicKing Institute, Chennai, Vins Bio-products Ltd.; changes induced by snake venom. This pioneering6

and Biological E Ltd., Hyderabad,etc.Antivenom theory was later contradicted by various reports onserum (AVS) manufacturers recommend skin effectiveness of herbal antidotes against systemicsensitivity testing to predict adverse AVS reactions.toxicities as well as lethality. The ether solubleBut, the usefulness of skin testing is doubtful, fraction of Aristolochia species, inactivates Najaas skin testing carries the risk of inducing naja venom and reduces haemorrhage causedan acute reaction and delays the initiation of AVSby Trimeresurus flavoviridisand Vipera russelliiadministration. venoms .Eclipta prostrataL. (Asteraceae) is used7 ,8

as an anti-venom against snake bite in China and

Herbal antidotes active against snake bite in Brazil. Schumanniophyton magnificum, EcliptaIn almost all parts of the world, where venomousprostrata orAristolochia shimadai , have the

snakes occur, numerous plant species are used as capacity to inhibit phospholipase A2, other enzymes

folk medicine to treat snake bite. Generally an (e.g. ATPase) along with other physiological and

aqueous, methanol or ethanol extract is prepared outbiochemical properties (such as effects on uterine

of the plant parts. Topical application of the tone or the protection of mitochondrial membranes).

plant or its sap onto the bitten area, chewing leavesAntihaemorrhagic effect of persimmon tannin fromDiospyros kaki is also well known. The survivalor barks or drinking plant extracts or decoctions

or injecting the extrcts are some procedures intendedtime was prolonged after pretreatment with extracts

to counteract snake venom activity. of Diodia scandensand Andrographis paniculata .9


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867GOMES et al. : HERBAL ANTIDOTE & SNAKE BITE TREATMENT

Rhizomes of Curcuma Sp. inactivated postsynaptic fruits o Citrus limon; leaves, branches and stem of

neurotoxin of the Thai cobra (Naja naja siamensis) Ficus nymphaeifoliaand moderate neutralizationin mice . Aqueous extracts of the bark of were shown by the whole plants ofAristolochia10

Schumanniophyton magnificumand the leaves of grandiflora, Columnea kalbreyeriana, Sida acuta,

Mucuna pruriens var. utilis,Strophanthus gratus and Selaginella articulata and PseudoelephantopusStrophanthus hispidushave the ability to prolong spicatus; rhizomes ofRenealmia alpinia; the stem of

the clotting time when administered along with a Strychnos xinguensis; leaves, branches and stems of

standardised dose of Echis carinatus venom . Hyptis capitata, Ipomoea cairica, Neurolaena lobata,1 1

The survival time of male abino mice was increasedOcimum micranthum, Piper pulchrum, Siparuna

by the extract of the leaves ofGuiera senegalensis thecaphora, Castilla elastica and Allamanda

when compared to theEchis carinatusand Naja cathartica; the macerated ripe fruits ofCapsicumnigricollisvenom treated animals .Bothrops atrox rutescens; the unripe fruits ofCrescentia cujete;12

venom induced haemorrhage was completely leaves and branches of Piper arboreum andPassifloraneutralized by the extracts of the stem barks of quadrangularis . Mucuna pruriens var. utilisseed15

Brownea rosademonte, Tabebuia rosea,the whole aqueous extract significantly inhibited the Echis

plants ofPleopeltis percussa, Trichomanes elegans, carinatusvenom induced myotoxic, cytotoxic and

rhizomes of Heliconia curtispatha, leaves and coagulation activities in experimental animals .1 6

branches ofBixa orellena, Phylodendrum tripartitum, Aqueous and alcoholic extracts of dried roots

Struthanthus orbicularis, Gozalagunia panamensis, of Mimosa pudicainhibited lethality, myotoxicitythe ripe fruit ofCitrus limon leaves, branches and and toxic enzymes of Naja kaouthiavenom .1 7

stems ofFicus nymphaeifolia .Partial protection Oral administration of garlic could be used as a13

of haemorrhage was also shown by Aristolochia prophylactic tool against cobra venom inducedgrandiflora, Columnea kalbreyeriana, Sida acuta, histological and histochemical patterns of the gastric

Selaginella sp., Pseudele- phantopus spicatus , and hepatic tissue changes in rats .A water-methanol1 8

rhizomes ofRenealmia alpinia, stem ofStrychnos extract ofParkia biglobosastem bark extract couldxynguensis, leaves, branches and stem ofHyptis neutralize two snake venoms (Naja nigricollis, and

capitata, Ipomoea cairica, Neurolaena lobata, Echis ocellatus) in several experimental models.1 9

Ocimum micranthum, Piper pulchrum, Siparuna Phospholipase activity ofCrotalus durissus terrificusthecaphora, Castilla elastica, Allamanda cathartica, venom and only partial inhibition of Bothrops venoms

the macerated fruits ofCapsicum frutescens, unripe was shown by crude aqueous extract ofMandevillafruits ofCrescentia cujete,leaves and branches o velutina . The extract of the Brazilian plant20

Piper arboretumand Passiflora quadrangularis . Marsypianthes chamaedrys inhibited fibrinogen1 3

The stem barks ofBrownea rosademonte, Tabebuia clotting induced by several Brazilian snake venoms,rosea; rhizomes of Renealmia alpinia, Heliconia indicating that it affects thrombin-like enzymes .2 1

curtispatha; the whole plants ofPleopeltis percussa, Aqueous extract ofCasearia sylvestrisshowed anti

Trichomanes elegans; and the ripe fruits ofCitrus PLA2, hemorrhagic and myotoxic activities causedlimon, demonstrated 100% neutralizing capacity of by crude snake venoms and toxins. On the other22

snake (Bothrops atrox) venom within 48 hours. hand, Casearia mariquitensis inhibited some

Partial protection was also shown by the leaves, hematological and systemic alterations inducedbybranches and stem ofCostus lasius; the whole plant Bothrops neuwiedi pauloensis venom .Mandevilla2 3

of Sida acuta; rhizomes of Dracontium croatii; illustris inhibited phospholipase activity ofCrotalus

leaves and branches of Bixa orellana and durissus terrificus snake venom along withStruthanthus orbicularis . Bothrops atroxvenom prolongation of the survival time and a decrease1 4

induced haemorrhage was completely neutralized byin lethality . Mimosa pudicahas been reported to2 4

stem barks ofBrownea rosademonteand Tabebuia possess anti-hyaluronidase activity againstNaja naja,rosea; the whole plants of Pleopeltis percussa, Vipera russelliand Echis carinatusvenom . The2 5

Trichomanes elegansand Senna dariensis; rhizomes butanolic extract of Mimosa pudicaand Eclipta

ofHeliconia curtispatha ; leaves and branches ofBixa prostratapartially inhibited the hemorrhagic activityorellana, Philodendron tripartitum, Struthanthus but displayed very low anti-phospholipase A2 activity

orbicularis and Gonzalagunia panamensis ; ripe and did not inhibit proteolytic activity of Malayan pit


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viper venom . Edema, defibrination and coagulation russellivenom in a dose-dependent manner. Further,26

effects ofBothrops aspervenom were neutralized by the extract neutralized the degradation of thethe leaves and branches ofBixa orellen, Ficus B-beta chain of human fibrinogen and indirect

nymphaeifolia, Struthanthus orbicularis and hemolysis caused by venom. The extract exerted a

Gonzalagunia panamensis ; the stem barks of moderate effect on the clotting time. Edema,Brownea rosademonte andTabebuia rosea ; the whole hemorrhage and myotoxic effects along with

plant of Pleopeltis percussaand Trichomanes lethality, induced by venom were neutralized

elegans; rhizomes ofRenealmia alpinia, Heliconia significantly when different doses of the extractcurtispatha andDracontium croatii , and the ripe fruit were preincubated with venom before the assays.

of Citrus limon . The ethanol root extract of On the other hand, animals that receive d extract27

Acalypha indicapossesses potent snake venom 10 minutes after the injection of venom wereneutralizing properties . Aqueous extract of protected from venom induced toxicity .28 3 9

Tabernaemo ntana catharinensisinhibited the lethal Dichloromethane extract of leaves of Artemisiaactivity of Crotalus durissus terrificus snake venom campestris L neutralized the venom induced actions29

and partially neutralized myotoxic effect ofBothrops of viper Macrovipera lebetina .Ethanol extract40

araracussuvenom and two of its myotoxins of leaves o Galactia glaucescensprevented the

[bothropstoxin-I (BthTX-I), catalytically inactive, neuromuscular paralysis induced by Crotalusand II (BthTX-II), showing low PLA2 activity] . The durissus terrificus venom . Oedema, haemorrhage,3 0 41

methanol extract of the root bark of Annona myonecrosis and coagulation induced by IndiansenegalensisPers caused reduction in the Naja Echis carinatus (saw-scaled viper) venom were

nigricotlis nigricotlisvenom induced hyperthermia in neutralized by the methanol seed extract of

rats . Musa paradisiacaL.successfully neutralized Vitis vinifera L . The aqueous extract of31 42

viper venom actions inin vitroexperiments only . Schizolobium parahyba showed potent antisnake3 2

Pentaclethra macroloba exhibited full inhibition venom activity . The active fractions of4 3, 4 4

of hemorrhagic and nucleolytic activities induced Aristolochia indica, Hemidesmus indicus, Strychnosby several snake venoms, along with partial inhibition nux vomica, Gloriosa supe rba, Eclipta prostrata,

of myotoxic, lethal, phospholipase and edema and Andrographis paniculata neutralized rattle

activities. It totally inhibitedBothrops jararacussu snake venom induced actions . The animals4 5

metalloprotease induced hemorrhage in in vivo that received orally the extract of Aristolochia

model . Aqueous extracts of Croton urucurana odoratissima leaves w ere protected againstBothrops3 3

antagonized the hemorrhagic activity ofBothrops atrox venom as mortality of experimental animals

araraca venom and proanthocyanidins were involved decreased from 100 to 80% .46

in this activity . Aqueous extracts of fresh roots, The methanol root extracts ofVitex negundo Linn.34

stems or leaves ofMikania glomerata, efficiently and Emblica officinalis significantly neutralized

neutralized different toxic, pharmacological, and the Vipera russelli andNaja kaouthia venom

enzymatic effects induced by venoms from Bothropsinduced lethal activity in vivo studies; Vipera russelliand Crotalus snakes. Cordia verbenacaeinhibited venom-induced haemorrhage, coagulant, defibrino-3 5

paw edema induced by Bothrops jararacussu genating and inflammatory activity were significantly

snake venom . Aqueous extract from aerial parts neutralized by both plant extracts . Hemidesmus3 6 47

of Bauhinia forficatais a promising source of indicus root extracts effectively neutralized Viper

natural inhibitors of serine-proteases involved in venom-induced lethal, haemorrhagic, coagulant,

blood clotting disturbances induced by Bothrops andanticoagulant and inflammatory activities . An48

Crotalus crude venoms. The methanol bulb extractactive compound from the Strychnus nux vomica37

of Crinum jagussignificantly protected mice from whole seed extract, neutralised Daboia russelli

death, myonecrosis and haemorrhage induced by venom induced lethality, haemorrhage, defibrino-the lethal effects ofEchis ocellatus, Bitis arietans genating, PLA2 enzyme activity andNaja kaouthia

andNaja nigricollis venoms . Tamarind seed venom induced lethality, cardiotoxicity, neurotoxicity,3 8

extract inhibited the PLA2, protease, hyaluronidase, PLA2 enzyme activity, and it also inhibited viperl-amino acid oxidase and 5'-nucleotidase enzyme venom induced lipid peroxidation in experimental

(major hydrolytic enzymes) activities of Vipera animals (Table 1).4 9


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Table 1List of plants used against snake envenomation

Scientific name Parts of the plant used Scientific name Parts of the plant used

Abrus precatorius roots Echinacea angustifolia

Acalypha indica roots Echinacea pallida

Achyranthes aspera Echinacea purpurea

Acorus calamus Linn rhizomes Eclipta prostrata L.

Actaea racemosa Emblica officinalis roots

Alangium salvifolium roots Enicostemma axillare leavesAllamanda cathartica leaves, branches, stem Equisetum giganteum rhizomes

Aloe barbadensis leaves Ficus lacor latex

Andrographis piniculata Ficus nymphaeifolia leaves, branches, shoot

Annona senegalensis Pers root, bark Ficus religiosa flower

Antidesma bunius Linn . leaves Galactia glauscescens leaves

Arctium lappa Gonzalagunia panamensis leaves, branches

Aristolochia grandiflora whole plant Guiera senegalensis leaves

Aristolochia odoratissima leaves Gymnema sylvestre roots

Aristolochia shimadai Heliconia curtispatha rhizomes

Artemisia campestris L leaves Hemidesmus indicus roots

Azadirachta indica leaves Hyptis capitata leaves, branches, stem

Biophytum sensitivum whole plant Impatiens balsamina flower

Bixa orellana leaves, branches, shoot Ipomoea cairica leaves, branches, stem

Bombax ceiba Linn shoot, leaves Leucas linifolia

Brownea rosa de monte stem, barks Lysimachia nummularia L.

Buchnania lanzan Spr stem, bark Mandevilla illustris

Calotropis gigantea leaves, roots Marsypianthes chamaedrys

Calycopteris floribunda leaves Melianthus major flower

Capsicum frutescens fruit Mikania glomerata roots, stems, leaves

Casearia mariquitensis Mimosa pudica roots, whole plantCasearia sylvestris leaves & bark Moringa oleifera Lamk shoot, leaves

Cassia occidentalis roots Mucuna pruriens var. utilis seeds

Castilla elastica leaves, branches, stem Mucuna pruriens var. utilis leaves

Cecropia peltata leaves Musa paradisiaca

Cinnamomum zeylanicum Nerium indicum Mill leavesCitrus limon fruit Nerium oleander

Columnea kalbreyeriana Neurolaena lobata leaves, branches, stem

Cordia verbenacae Ocimum micranthum leaves, branches, stem

Costus lasius leaves, branches, stem Oldenlandia corymbosa L

Crescentia cujete fruit Ophiorrhiza mango roots

Crinum jagus bulb Origanum dictamnu seeds

Croton urucurana Papever somniferum

Cucumis colocynthis roots Paris polyphylla roots

Curcuma longa rhizomes Parkia biglobosa

Diodia scandens Passiflora quadrangularis leaves, branches

Diospyros kaki Pentaclethra macroloba

Dracontium croatii rhizomes Peristrophe bicalyculata roots

Sida acuta whole plant Siparuna thecaphora leaves, branches, stem

Philodendron tripartitum shoot, leaves Strophanthus gratus leavesPiper arboretum leaves, branches Strophanthus hispidus leaves

Piper pulchrum leaves, branches, stem Struthanthus orbicularis leaves, branches, shoot

Pleopeltis percussa whole plant Strychnos nux vomica seeds

Prenanthes alba leaves Strychnos xinguensis stem, leaves, branches

Pseudelephantopus spicatus whole plant Tabebuia avellanedae bark

Psoralea corylifolia seeds Tabebuia rosea stem barks

Raphanus sativus tuber Tabernaemontana catharinensis

Rauwolfia serpentine whole plant Tamarindus indica

Renealmia alpinia rhizomes Trichomanes elegans whole plant

Rhizoma paridis roots Ulmus rubra


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of the crude venom and of isolated PLA2s inTable 1List of plants used against snake envenomationContd.

experimental models.Scientific name Parts of the plant used

AlkaloidsAtropine is found in some of theSchizolobium parahyba leavesSchumanniophyton magnificum bark Solanacae family members and it exerted inhibitorySelaginella articulata whole plant action against the venom of green and black mamba Senna dariensisida acuta whole plant

(Dendroaspis angusticepsand D. polylepsis); theseVitex negundo Linn rootsvenoms are mainly responsible for neuro-transmitterVitis vinifera L seeds

Woofordia fruitcosa release at cholinergic nerve terminals, therefore itXanthium sibiricum leaves was suspected that a cholinergic blocker like atropine

may reduce their effects. AIPLAI ( AzadirachtaHerbal constituents active against snakeindicaPLA2 inhibitor) was purified from the

envenomationmethanol leaf extract ofAzadirachta indica(Neem);AcidsAristolochic acid, contained in Aristolochiait inhibited the cobra andRussell's vipervenomsproduces increase in immune response and it also(RVVs) phospholipase A2 enzymes in a dose-inhibits the lytic activity and the edematose propertiesdependent manner. AIPLAI significantly inhibitedof some phospholipases of snake venoms. 2-OH-4-5 0PLA2 enzymes, higher in cobra venom (Naja najamethoxy benzoic acid, isolated and purifiedand Naja kaouthia) compared to that of crude RVVfrom Hemidesmus indicus, possessed potent(Daboia russelli) when tested under the sameantiinflammatory, antipyretic and antioxidantcondition .54properties of viper venom . Lethality induced by5 1

Coumestan and steroidsViper and cobra venomViper venom was maximally neutralized withneutralization was shown by beta sitosterol and2-hydroxy-4-methoxy benzoic acid and anisic acid,stigmasterol, isolated from the methanol root extractboth in in vitroand in vivostudies. The compoundof Pluchea indica . The active fraction could2-OH-4-methoxy benzoic acid also showed adjuvant 5 5

also antagonize venom-induced changes in lipideffects and antiserum action potentiation againstperoxidation and superoxide dismutase activity.Vipera russellivenom The exact mechanisms of52 .Wedelolactone has been identified as a coumestanevenom neutralization were not established, except forcontained inEclipta prostrataL. and was suggested2-hydroxy-4-methoxy benzoic acid, where theto be an active component in fighting against snakefunctional groups, methoxy and hydroxy were partly

venoms . Wedelolactone, sitosterol and stigmasterolresponsible for the neutralization of the lethal effect 5 6

inhibits the effect of South American rattle snake .and haemorrhagic activity. The venoms of common 5752

Indian snakes Vipera russelli, Echis carinatus, Naja Enzymes, peptides and pigmentsSnake venomkaouthiaand Ophiophagus hannahwere taken molecule are composed of three-dimensional proteins

to evaluate the lethal, haemorrhagic and and some non-protein components. These proteinsdefibrinogenation action neutralization with four could be dissolved with natural solvents like

compounds (2-hydroxy-4-methoxy benzoic acid from bromelain and papain. Bromelain is found in

Hemidesmus indicus, anisic acid from Pimpinella pineapple (Ananas comosus) and papain is presentanisum, salicylic acid from Filipendula ulmaria, Salix in papaya fruit (Carica papaya). Thus these two

albaand aspirin from Salix alba) in experimental natural proteolytic enzymes could be used to

animals. Lethal action of venom were maximally neutralize snake venom proteins. A peptide compoundneutralized with 2-hydroxy-4-methoxy benzoic acid with a molecular weight of 6000 Da, reported to

and anisic acid, both inin vitroand in vivostudies. possess anticardiotoxic activity against cobra venomHaemorrhagic activity of Viper and Echis venom was isolated from the plant Schumanniphytonwas neutralized with salicylic acid . Rosmarinic acid, magnificum . Turmerin, a protein from turmeric53 58

a new antidote against snake (Bothrops jararacussu) (Curcuma longaL.) inhibits the enzymatic activity and

venom, was isolated which possessed phospholipaseneutralizes cytotoxicity, oedema and myotoxicity ofA2 (from Cordia verbenacea)inhibitor activity; multitoxic phospholipase A2 of cobra (Naja naja) .59

it also inhibited most of the myotoxic activity Melanin extracted from black tea was reported for thewith partial inhibition of edema along with the first time to possess antivenom activity againstability to potentiate commercial equine polyvalent Agkistrodon contortrix laticinctus, Agkistrodon halys

antivenom in neutralizing lethal and myotoxic effects blomhoffiiand Crotalus atroxsnake venoms .60


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Glycoprotein and glycosides A multiform source, cabenegrin A-I and cabenegrin A-II were

glycoprotein (whose oligosaccharide chains were isolated, which have been found to be an anti-snakefunctional) was isolated fromMucuna pruriensseeds, oral antidote . Similarly the extract of a South6 8

neutralized Echis carinatusvenom induced actions. American plant, Harpalyce brasiliana Benth ,6 1

A glycoprotein, (WSG) was isolated from a folk commonly called Portuguese Snake Herb, alsomedicinal plant Withania somnifera . The WSG yielded cabenegrin A-II (phenolic pterocarpan in6 2

inhibited the phospholipase A2 activity of NN-XIa-nature). Edunol, a pterocarpan isolated from

PLA2 isolated from the cobra venom (Naja naja), Harpalyce brasiliana , used in the northeast ofcompletely at a mole-to-mole ratio of 1:2 (NN-XIa-Brazil against snake bites and roots of two

PLA2: WSG) but failed to neutralize the toxicity Mexican 'snakeweeds', Brongniartia podalyrioides6 2

of the molecule. However, it reduced the toxicity asand Brongniartia intermedia(Leguminosae), reducedwell as prolonged the death time of the experimentalthe expected mortality of mice previously treated with

mice approximately 10 times when compared to Bothrops atrox venom along with antimyotoxic,69

venom alone. The WSG also inhibited several otherantiproteolytic and PLA2 inhibitor properties .7 0

PLA2 isoforms from the venom to varying extent. TanninsThe tannin from persimmon, a fruit fromHyaluronidase activity of cobra (Naja naja ) and viper Diospyrus kakiinhibits edema in mice, induced by sea

(Daboia russelli) venoms were inhibited by WSG. snake and also improved the survival rate in miceIt also inhibited hyaluronidase activity of Indian injected with Laticauda semifasciataandTrimeresuruscobra (Naja naja) venom . Benzoylsalireposide63 , 64 lavoviridisvenom . Ellagic acid, a compound71and salireposide isolated fromSymplocos racemosa isolated from the aqueous extract ofCasearia sylvestrisinhibited phosphodiesterase I activity against has been reported to possess anti snake venom activity,snake venom. The methanol extract of the mainly against Bothrops genus .72stem bark of Schumanniophyton magnificumand

TerpenoidsGlycyrrhizin, a natural triterpenoidschumanniofoside, a chromone alkaloidal glycoside

saponin extracted from the root of Glycyrrhiza glabrawas isolated which reduced the lethal effect of

(licorice), with a molecular mass of 840 Da, hasblack cobra (Naja melanoleuca) venom in mice.

been characterized as a thrombin inhibitor. This7 3This effect was maximum when the venom was

compound is known for its anti-inflammatory activitymixed and incubated with the extract or

and Glycyrrhizin also exhibitsin vivoantithromboticschumanniofoside. It is thought that the mode o

properties against snake venom; it prevents bothaction is by oxidative inactivation of the venom.in vitro and in vivo venom-induced changes

PhenolsPLA2 activity ofBothrpos aspervenom in hemostasis, suggesting a potential antiophidicwas neutralized by 4-nerolidylcatechol isolated activity . A potassium salt of gymnemic acid, which74

from Piper umbellatumand Piper peltatum . The6 5 is a triterpenoid glycoside obtained fromGymnemaethanol extract from seed kernels of Thai sylvestre inhibits ATPase inNaja Najavenom .7 5, 7 6

mango (Mangifera indicaL.) and its major phenolic Lupeol acetate, isolated from the root extract ofprinciple (pentagalloyl glucopyranose) exhibited Indian sarsaparillaHemidesmus indicus R.Br. coulddose-dependent inhibitory effects on phospholipase significantly neutralize lethality, haemorrhage,A2, hyaluronidase and L-amino acid oxidase of defibrinogenation, edema, PLA2 activity inducedCalloselasma rhodostomaand Naja naja kaouthia by Daboia russelli venom. It also neutralizedvenoms in in vitrotests. The anti-hemorrhagic and Naja kaouthia venom induced lethality,anti-dermonecrotic activities of seed kernal against

cardiotoxicity, neurotoxicity and respiratory changesboth venoms were clearly supported by in vivotests .6 6 in experimental animals .Bothrops neuwiedi and77The plant polyphenols from the aqueous extracts Bothrops jararacussuvenom induced hemorrhagic,of Pentace burmanica, Pithecellobium dulce,Areca fibrinogenolytic and caseinolytic activities of classcatechuand Quercus infectoria block non-selectively P-I and III metalloproteases were neutralized bythe nicotinic acetylcholine receptor by precipitation neo-clerodane diterpenoid, isolated fromBaccharisofNaja kaouthiavenom .6 7 trimera . Oleanolic acid inhibited sPLA (2) activities7 8

PterocarpanesThe aqueous alcohol extract of of Vipera russelliand Naja najasnake venoms in athe root of a South-America plant calledCabeca concentration-dependent manner. Inhibition of in

de Negrais used against snake venom. From this vitroand in vivosPLA2 activity by oleanolic acid


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explains the observed anti-inflammatory properties o identified catequines, flavones, anthocyanines and

several oleanolic acid-containing medicinal plants. condensated tannins, which may be responsible7 9

The pentacyclic triterpenes (free or as glycosides) are for the inhibitory effect observed, probably owing to

found widely in several antisnake venom plants the chelation of the zinc required for the catalytic

(Aegle marmelos,Centipeda minima,Aloe barbadensis, activity of Bothrops aspervenom's hemorrhagicPhyllanthus niruri, Alstonia scholaris, Phyllanthus metalloproteinases. Plant-derived, aristolochic acid,

emblica, Elephantopus scaber, etc.) and provide nearly indomethacin, quercetin, curcumin, tannic acid, and

20% protection against snake venom . Quinovic acid-3- flavone exhibited inhibition, with aristolochic80

O-alpha-L-rhamnopyranoside , quinovic acid-3-O-beta- acid and quercetin completely inhibited the81

D-fucopyranoside, and quinovic acid-3-O-beta-D- hyaluronidase enzyme activity . Further, these90

glucopyranosyl (1-->4)-beta-D-fucopyranoside isolated inhibitors not only reduce the local tissue damage butfrom the ethyl acetate extract ofBridelia ndellensis also retard the easy diffusion of systemic toxins and

barks and Mitragyna stipulosashowed significant hence increase survival time. Medicinally importantinhibitory activity against snake venom phospho- herbal compounds (acalyphin, chlorogenic acid,

diesterase-I . Triterpenoid saponin from Pentaclethra stigmasterol, curcumin and tectoridin) were screened82 ,8 3

macroloba,inhibited antiproteolytic and anti- against Russell's viper PLA2 . These compounds9 1

hemorrhagic actions induced by Bothrops snake showed favorable interactions with the amino acidvenoms. These inhibitors were able to neutralize residues at the active site of Russell's viper PLA2,

the hemorrhagic, fibrin(ogen)olytic, and proteolytic thereby substantiating their proven efficacy asactivities of class P-I and P-III metalloproteases isolated anti-inflammatory compounds and as antidotes.

from Bothrops neuwiediand Bothrops jararacussu An active compound (SNVNF) was isolated and

venoms . Ursolic acid a common constituent of purified from the whole seed extract ofStrychnos84

many medicinal plants, inhibited PLA2 enzymes nux vomica , which could effectively antagonise

purified fromVipera russelli,Naja najavenom . Daboia russelli venom induced lethality,8 5

haemorrhage, defibrinogenating, oedema, PLA2Quinonoid xantheneEhretianone, a quinonoidenzyme activities and Naja kaouthiainduced lethality,xanthene isolated from the root bark ofEhretiacardiotoxicity, neurotoxicity, PLA2 enzyme activities.buxifolia. Roxb. has been reported to possess antiHexane extract of Curcuma longa rhizomes,snake (Echis carinatus) venom activity .8 6

ar-turmerone also inhibited the proliferation and the9 2

ResveratrolHong Bei Si Chou is a herbal natural killer cell activity of human lymphocytes.medicine used to treat snake bite in Guangxi

This compound has anti lethal activity against venomprovince of China. It was found that resveratrol

of Crotalus durissimus terrificus. Moreover when it(3,4',5-trihydroxytransstilbene) isolated from the

was injected in mice it showed anti- hemorrhagicethyl acetate part of Hong Bei Si Chou could

activity against Bothrops jararaca venom. (Table 2).antagonize snake toxins bothin vivoand in vitro .8 7

Alkaloid (12-methoxy-4-methylvoachalotine) extract Mechanism of snake venom neutralization byofTabernaemontana catharinensisinhibited lethality herbal compoundsinduced by Crotalus durissus terrificus snake Herbal compounds that possess snake venomvenom .88 neutralization properties in experimental animal

Miscellaneous chemical groups and compounds models (in vivoand in vitro) usually follows threeSeveral plant constituents like flavonoids, quinonoid,protocols(1) venom- herbal compounds mixed

xanthene, polyphenols and terpenoids possesses together, (2) herbal compounds followed by venom,protein binding and enzyme inhibiting properties and and (3) venom followed by herbal compounds. Amongalso inhibit snake venom phospholipase A2 (PLA2)these, the third technique is similar to clinicalactivities of both Viper and Cobra venom. Total conditions. The venom dose is one of the critical8 9

inhibition of hemorrhage was observed with the factors, on which the herbal compounds could showethanol, ethyl acetate and aqueous extracts of Bursera their neutralizing effects. Higher the venom dose, lesssimaruba, Clusia torresii, Clusia palmana, Croton the fold of neutralization. So, what is desirable is thatdraco, Persea americana, Phoebe brenesii, Pimentathe venom should be tried from lower to higher dose.dioica, Sapindus saponaria, Smilax cuculmecaand For this, a huge number of animals are required, whichVirola koschnyi . Chemical analysis of these extracts is sometimes very difficult from animal ethical issues.8 3


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Table 2List of herbal compounds active against snake envenomation

Compound Plant source Reference

Acids

Aristolochic acid Aristolochia sp. 502-OH-4-methoxy benzoic acid Hemidesmus indicus 51, 522-hydroxy-4-methoxy benzoic, anisic acid, Hemidesmus indicus, Pimpinella anisum, Filipendula ulmaria, 53

salic ylic acid, aspirin Salix alba

Rosmarinic acid Cordia verbenacea

Alkaloids

Atropine Dendroaspis angusticeps and D. polylepsisAIPLAI ( Azadirachta indica PLA2 inhibitor) Azadirachta indica 54

Coumestan and Steroids

Beta sitosterol and stigmasterol Pluchea indica 55,57Wedelolactone Eclipta prostrata L. 56,57

Enzymes, Peptides and Pigment s

Bromelain Ananas comosusPapain papaya

Peptide Schumanniphyton magnificum 58Turmerin Curcuma longa L 59

Melanin Black Tea 60

Glycoprotein and Glycosides

Glycoprotein Mucuna pruriens 61WSG Withania somnifera 62, 63

Benzoylsalireposide and salireposide Symplocos racemosa 64

Phe nols

4-nerolidylcatechol Piper umbellatum and Piper peltatum 65

Pentagalloyl glucopyranose Mangifera indica L 66polyphenols Pentace burmanica , Pithecellobium dulce , Areca catechu and 67

Quercus infectoria

Pterocarpanes

Cabenegrin A-I and cabenegrin A-II Cabeca de negro 68

Edunol Harpalyce brasiliana 69, 70

Tannins

Tannin Diospyrus kaki 71

Ellagic acid Casearia sylvestris 72

Terpeinoids

Glyc yrrhizin Glycyrrhiza glabra 73, 74

Potassium salt of gymnenic acid Gymnema sylvestre 75, 76

Lupeol acetate Hemidesmus indicus R.Br 77Neo-clerodane Baccharis trimera 78

Oleanolic acid 79

Pentacyclic triterpenes Aegle marmelos , Centipeda minima , Aloe barbadensis , 80Phyllanthus niruri , Alstonia scholaris , Phyllanthus emblica ,

Elephentopus scaberQuinovic acid-3-O-beta-D-fucopyranoside, Bridelia ndellensis Mitragyna stipulosa 82, 83

and quinovic acid-3-O-beta-D-lucopyranosyl

(1-->4)-beta-D-fucopyranoside

Triterpenoid saponin Pentaclethra macroloba 84

Ursolic acid Eriobotrya japonica 85

Quinonoid xanthene

Ehretianone Ehretia buxifolia . Roxb. 86

Resveratrol

Resveratrol(3,4',5-trihydroxytransstilbene) Hong Bei Si Chou 87

Alkaloid (12-methoxy-4-methylvoachalotine) Tabernaemontana catharinensis 88

(Contd .)


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Table 2List of herbal compounds active against snake envenomationContd.

Compound Plant source Reference

Miscellaneous Chemical Groups and

Compounds

Flavonoids, quinonoid, xanthene, polyphenols Bursera simaruba, Clusia torresii, Clusia. palmana, Croton draco, 89and terpenoids Persea americana, Phoebe brenesii, Pimenta dioica, Sapindus

saponaria, Smilax cuculmeca and Virola koschnyi .Aristolochic acid, indomethacin, quercetin, 90

curcumin, tannic acid, and flavoneAcalyphin, chlorogenic acid, stigmasterol, Lonicera japonica, Hemidemus indicus, Curcuma longa 91curcumin and tectoridin

SNVNF Strychnos nux vomica 92Ar- turmerone Curcuma longa 93

How the herbal compounds neutralize the toxic comprising of black pepper, long pepper and ginger,

venom constituents with in the body? Till date, for treating digestive ailments, etc. In ayurveda therethere is no definite answer or mechanism. Many could be combination ranging from two to twenty

hypothesis have been proposed such as (1) proteinformulations, in fixed doses. Thus it is evident thatprecipitation hypothesis , (2) enzyme inactivation ayurveda not only uses herbal components, but along44

hypothesis , (3) chelation hypothesis, (4) adjuvant with it various metal ions and spices are also9 3 83

action hypothesis , (5) anti-oxidant hypothesis , important part of combination formulation. It is well5 2 7 7

(6) protein folding hypothesis, (7) combination recognized in ayurveda that a medicinal plant may

hypothesis and many more. The above hypothesisneed to be administered with other plants, that is in5 2

have their own limitations. Among these, protein combination, in order to exert its therapeutic effect.

precipitation-inactivation hypothesis is more The second plant may potentiate the action of theacceptable. However, more emphasis should be first, while the third might help to prevent the toxicityfocused on this area in the near future. of the second plant. Recently emphasis has been given

to the age old concept of combination therapy inFuture of antivenom and herbal therapy

several pathophysiological condition like cancer ,9 4The limitations of AVS are well known and the

tuberculosis, malaria and AIDS. We are also hopeful95world is looking for an alternative for snake bite that snake bite treatment may be benificial by this

treatment. Till date no suitable alternative measuresapplication and gradually the herbal compounds mayare available, except the natural herbal remedies,find an alternative to the AVS.

which are showing promising expectations. Theadvantages of herbal compounds are that, they are

Conclusionscheap, easily available, stable at room temperatureRecently, the World Health Organization estimatedand could neutralize a wide range of venom antigen.

that 80% people worldwide rely on herbal medicinesIn many cases, the whole herbal extracts are morefor some aspect or other for their primarypowerful than the individual herbal compounds. Thehealthcare . World Health Organization has shown9 6herbal compounds could effectively neutralize snakegreat interest in documenting the use of medicinalvenom in presence of AVS, which is another advantageplants used by tribals from different parts of theof herbal compounds. It may be opined that theworld. Many developing countries have intensifiedidentified herbal compounds having AVS potentiatingtheir efforts in documenting the ethnomedicalactions might be selected for further trials.

data and scientific research on medicinal plants.It is now obvious that the future of AVS is lyingOnce these local ethnomedical preparations areon the shoulder of herbal compounds and combinationscientifically evaluated and disseminated properly,of these two antidotes may find a suitable alternativepeople will be better informed regarding efficaciousto the snake bite treatment in the near future.herbal drug treatment and improved health statusinCombination therapy is an old practice ofseveral pathophysiological conditions including snakeAyurvedic medicine. Various therapeutic, ayurvedicbite in the near future. It is our responsibility toformulations are available commercially, eg.,identify, cultivate and culture these eco-friendly herbsArticulin-F comprising of a fixed combination of

Boswellia serrata, Withania somnifera, Curcuma for the alleviation of human suffering and death

longa, Zinc for treating osteoarthritis, Trikatu against snake bite.


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Herbs and Herbal Constituents Active Against Snake Bite