Review Article Ravi Kant Upadhyay et al. / Journal of Pharmacy Research 2010, 3(12),3123-3128 ISSN: 0974-6943 Available online through http://jprsolutions.info Allergic and toxic responses of insect and it’s immunotherapy Ravi Kant Upadhyay*, Shoeb Ahmad Department of Zoology, D D U Gorakhpur University, Gorakhpur, 273009. India Received on:06-08-2010; Revised on: 18-09-2010; Accepted on:12-11-2010 ABSTRACT Insect venom is a poisonous substance that contains a complex mixture of certain proteins, enzymes, small , certain inorganic elements and acids. These venom components are responsible for multiple pharmacological effects in different organisms and act like . These act at cellular level and break the normal barrier to leak out molecules across the cell membrane and form ion channels by attaching themselves to the membrane surface. Venom allergens cause immuno- stimulation of body tissues and show strong T cell responses in hypersensitive patients and signify the production of allergen specific IgE antibodies and generate anaphylactic reactions.. These also trigger a cascade of mediators including histamine, leucotrienes, and platelet activating factors, enzymes and peptides. Venom toxins make fast release of certain chemicals i.e. serotonins, kinins, prostaglandins and leukotrienes that results in visible clinical symptoms related to paralysis, inflammation, swelling and itching. Insect venom toxins elevate the level of blood sugar, lactate, glucagon and cortisol and cause massive destruction of RBCs and nerve cells. Besides this, insect venom possess highly potent short peptides, which act upon ion channels of excitable cells and inhibit the activity of important metabolic enzymes like ACP ALP, GPT, GOT, LDH, AChE and Creatinine phosphokinase. Melittin is a short that shows cytotoxicity and cause intra- vascular hemolysis of RBCs, leucocytes, platelets and vascular endothelium. It is highly basic peptide that inserts itself into the phospholipid bi-layer of cell membranes. It in conjugation with PLA2 causes active pancreatitis and rhabdomyolysis in patients. Indeed, it appears that peptide toxins are strong blockers, which selectively act on various ion channels. This review aims to emphasize use of specific immunoglobulins in immunotherapy of patients to detoxify the effect of venom toxins. Immunotherapy contributes to decrease the number of mast cells, do activation of eosinophils, and induce T cell tolerance to the venom allergens. It subside the toxic effects of venom toxins and much ably revert the enzyme activity.

Key words: Insect venom, allergy, honeybee, toxic responses, sting, immunotherapy

INTRODUCTION

Arthropods mainly insects such as honeybee (Apis) (Edstrom, 1992, Dotimas VENOM COMPOSITION et al., 1987), social wasps (Vespula, Vespa, and Polistes), Paper wasps, hornets Arthopods mainly Apis, Bombus, Xilocopa, Vespula, Dolichovespula, and (Hoffman, 1996) and some species (Blum, 1978) possess venom glands Polistes species possess pharmacologically different types of venom toxins and discharge them to make territorial defense (Hider,1988;Blum,1981). These (Hoffman and Jacobson 1984) with diverse function and structural composi- insects after sensing little disturbance with in the territory and foraging sites tion (Blum, 1981, Lindsay and Bashford, 2001; Siphadauang and Noga, 2001). (Reisman, 1994), start searching the nuisance element and inflict toxic venom Their mechanism of action is unique causing electro-physiological inhibition into the body of victim (Nabil et al., 1998). Venom is inflicted by using of various ionic channels in nerve cell membrane (Schmid-Antomarchi et al., specialized sting apparatus attached with venom gland found in the last seg- 1985). These contain a number of charged residues including several positively ment of body. Stinging is a natural defense mechanism that is very swift and charged amino acids, which are biologicaly active (Hawgood and Bon, 1991). occurs almost instantaneously (Dotimas and Hider, 1987). It is triggered by Pharmacologically, insect are a rich source of biologicaly different pheromone secretion after alarming (Hider, 1988). It is highly painful (Mietka- molecules such as alkaloids, terpenes, polysaccharides, biogenic amines (His- Ciszowski 2007) and provokes allergic and toxic reactions in the patients tamine) and organic acids, but the majority of them are peptides and proteins (Golden, 2006). It shows reflex action in the muscles (Hermann, 1971), do (Schmidt, 1986). Venom of Apis species is a mixture of biogenic amines such immobilization of invaders or predators (Frazier, 1976) and causes itching, as histamine, serotonin, dopamine, noradrenaline, apamin, melittin and phos- swelling, redness, irritation in skin and headache in patients. On an pholipase A2 (Table 2) (Wongsiri et al., 1987) and shows compositional simi- average 8 out of 1000 individuals show allergic reactions to sting and 4 of larities to social wasp venom, especially to Vespula, Vespa and Polistes genera these i. e. 50% become severely sensitive (Frazier, 1976). Besides insects, (Nakazima, 1986). Apis mellifera venom contains low molecular weight com- scorpion and utilize venom toxins for self-defense and hunting the ponents such as serotonin, histamine, acetylcholine, several kinins, enzymes prey (Fitzgeralg and Flood, 2006; Benton, et al., 1963). However, multiple phospholipase A2 and hyaluronidase, polypeptides such as melittin and apamin insect stings cause anaphylaxis, dyspnea, collapse, rhabdomyolysis and pig- and mast cell degranulating pepetides. Wasp venom lacks serotonin and adrena- ment induced acute renal failure and severe pancreatitis. Insect venom causes line amongst biogenic amines (Banks and Shipolini, 1986) while ant venom respiratory distress syndrome (Franca et al, 1994). Heavy envenomation in contains simple organic acids and complex mixture of proteins and enzymes. groups causes obstruction of respiratory tube that contributes hypoxia and It causes allergy, inflammation, itching and show toxic responses in respiratory failure in patients. If timely treatment is not provided to such (Fundenberg et al., 1980). Bee venom contains melittin peptide that provokes patients it results in death of the victim (Schmacher and Egen 1995, Mckenna allergic reactions (Table 2) (Fennel et al., 1968). Similarly, hornetin a highly 1992, Tungent and Clark 1993). Insect venom show very high proteolytic basic protein isolated form Vespa flavitarsus shows hemolytic activity in red activity (Hoffaman and Jacobson 1996) and exhibit coagulant, fibrinolytic blood cells and damage presynaptic nerve cells (Ho and Ko, 1986). Besides (Koh et al, 2001; Mackessy 1996) and hemorrhagic activities (Bjarnheimer this, few venom enzymes such as phospholipases, hyaluronidase, and acid and Fox 1994, Mackessy 1996). Bee venom causes hyperglycemia (Scheuer et phosphatase also act as allergens (Tonismagi et al., 2006). Contrary to this al, 1969), liver and muscle necrosis and elevate the serum enzyme activity Vespula maculifrons, Vespula maculate, and Vespula arenaria venom protiens (Tunget and Clark 1993). Venom components mainly melittin shows cyto- show different allergic reactions due to presence of phospholipase A1B, hyalu- (hemolysis) while apamin act as . In addition to it mast ronidase and some other allergenic compounds (Mueller et al., 1982). Inter- cell degranulating peptides show anaphylactic reactions. Besides this, enzymes estingly, insect venom is a pool of allergic and toxic peptide and enzymes, like phospholipase A2 causes acute pancreatitis and do pulmonary failure. It is which show diverse arrays of biological activity. Some of these are described in joined by melittin which in conjugation with PLA2 act upon RBCs, leucocytes, detail as following blood platlets and vascular endothelium. (A). PEPTIDES *Corresponding author. Ravi Kant Upadhyay (i) MELITTIN Melittin occurs in the bee venom is responsible for the major allergic reac- Department of Zoology, tions, which are alkaline in nature (Edstrom, 1992). Chemically, it is com- D D U Gorakhpur University, posed of 26 amino acids with amphipathic nature that allows it to interact Gorakhpur, India 273009 Journal of Pharmacy Research Vol.3.Issue 12. December 2010 3123-3128 Ravi Kant Upadhyay et al. / Journal of Pharmacy Research 2010, 3(12),3123-3128 with lipid membrane, which in turn facilitate its permeability to erythrocyte degranulation peptides (Hoffman, 1996) which causes massive release of his- and other cell membranes (Schmidt, 1982). Its tetrameric form causes a con- tamine (Gmachl, and Kreil, 1995; Hider and Dotimas, 1987) and binds to stant skin nerve depolarization and severe pain (Edstrom,1992) Melittin specific protein membrane receptors (Hider and Ragnarson, 1981). These are shows lytic effects on erythrocytes and damage intracellular membranes such rich in a-helix, and present two bonds in its structure (Dotimas et al., as lysosomes (Dotimas and Hider, 1987; Habermann, 1972) and release en- 1987) (Table 1). zymes (Henger and Habermann, 1972). Due to melittin action, leucocytes diameter is reduced, membrane disintegrated and increased matrix density. (B) ENZYMES Melittin induces the cardiotoxicity and causes transient increase in spontane- (i) PHOSPHOLIPASE A2 (PLA2) ous heart beat rate followed by decrease and cessation of heartbeat and do Phospholipase is highly active enzyme that exert more deleterious effects morphological degradation of muscles (Yalcin and Savci, 2007). It depolarizes such as myotoxic, neurotoxic, cardiotoxic and inflammation in experimental the diastolic potential and inhibits the generation of action potential (Okamoto (Hawood and Bon, 1991). It binds to cellular receptors, causes physi- et al., 1995), block activity of chloinergic neurotransmitters and slow down ological alterations and catalyzes the hydrolysis of glycerophospholipids to neuromuscular actions and become paralyzed (Nabil et al., 1998). produce free fatty acids (Nicolas et al., 1997; Prenner et al., 1992). It also Melittin also affects the structure and function of smooth as well as skeletal shows synergistic properties with melittin and cause lysis of erythrocytes and muscles. It slows down the mechanical contraction of gastroncemius and inhibits Na+K+-ATPase activity (Bernheimer and Rudy, 1986; Watala and duodenal muscles. (Table 1). Kowalczyk, 1990; Costa and Palma, 2000). In addition, carbohydrate residues present in the bee venom PLA2 molecule play an important role in induction It shows inhibitory effects on hepatocellular carcinoma (Liu et al., 2002) and of IgE synthesis after envenomation (Prenner et al., 1992). These residues induces apoptosis in many cancer cell lines (Ip et al., 2008a). It inhibits tumor have low significance in relation to the deglycosilated molecule in in vivo IgE cell metastasis by reducing cell motality and migration via suppression of Rac synthesis (Okano et al., 1999) (Table 1) but have vast significance in signal 1-dependent pathway (Liu et al., 2002). Melittin also inhibits progression of transduction, lipid metabolism and membrane remodeling (Ahmad et al., 1996). breast cancer (Ip et al., 2008b) and acts as both tumor promoter and suppres- sor (Chiou et al., 1993) (Table 1). Like melittin Phospholipase A2 also exert (ii) ACID PHOSPHATASE significant antibacterial activities (Perumal et al., 2006) and disintegrate bac- Another insect venom allergen is acid phosphatase (Benton, 1967) that oc- terial membrane in a detergent-like manner (Ladokhin and White, 2001). Bee curs in venom as dimmer of a protein chain. It is allergenic glycoprotein that venom melittin shows strong antimicrobial activity against gram +ve and show allergic reactions (Hoffmann, 1996; Barboni et al., 1987) and a potent gram -ve bacteria (Upadhyay and Ahmad, 2008). releaser of histamine from human basophils. (Whan et al., 1984). It shows strong T cell responses in hypersensitive patients and interacts with IgE (ii) APAMIN antibody molecules (Grunwald et al., 2006). It facilitates the production of Apamin is bee venom peptide that acts as a neurotoxin and induces multiple specific immunoglobulin of E type antibodies after envenomation in stung physiological effects (Hider and Ragnarson, 1981). It blocks Na+ K+ channels patient (Grunwald et al., 2006) (Table 1). in neurons (Hider, 1988) and binds with high affinity to post-synaptic mem- brane receptors and cause hyper-polarization of adrenergic, cholinergic and purinergic nerve fibers. It also generates neurotensin-induced effects and blocks (iii) HYALURONIDASE (HYAL) post-synaptic functions, but does not show any lytic activity in mammalian Hyaluronidase (HYAL) is alkaline glycoprotein rich in aspartic acid glutamic cells (Edstrom, 1992) (Table 1). acid, which occurs abundantly in connective tissues, mainly in the interstitial space (Hanh et al., 1986). HYAL functions as a “spreading factor”, since it (iii) MASTOCYTE DEGRANULATING PEPTIDE (MCD) degrades the hyaluronic acid to non-viscous segments, allowing the fast spread- Bees and yellow wasps venom contains high concentration of mastocyte ing of the venom compounds through the interstitial space (Kemeny et al., 1984; Kubelka et. al., 1995) (Table 1). Table 1. Toxic responses of toxins isolated from insects and other animal groups.

Common name Scientific name Toxin isolated Physiological symptoms

Funnel web Hololena curta Curatotoxin Block neuromuscular transmission Funnel web spider Agelenopsis aperta a-Agatotoxin,Robustoxin, Act both pre- and post synaptically and cause neuromuscular block Atracotoxin and Versutoxin Block K+ channel Black widow spider Latrodectus mactans tredecimguttatus a-Latrotoxin Act selectively on presynaptic nerve endings and cause massive release of neurotransmitters Hunting spider Plectreurys tristis Plectoxin Neuromuscular paralysis spider gigas Grammotoxin Banana spider Phoneutria nigriventer Phoneutriatoxin Block both Na+ and K+ channels and cause neuromuscular paralysis Yellow Scorpion Leiurus quinquestriatus hebraeus Charydotoxin, Agiotoxion Block K+ channel and Block high conductance calcium activated Scorpion Isometrus vittatus Isom Tx1 Depolarize the axon following paralysis Scorpion Buthus judaicus BjTx-1 & BjTx-2 Both the toxins increase the release of Ca++ From Ca++ loaded sarcoplasmic reticulum Chinees scorpion Buthus martensi BmBKTx1 & BmPO2 Yellow Scorpion Tityus serrulatus Tityustoxin Increase glutamate release that leads to long lasting increase in Ca++ and cell death TsTx-K a Block K+ channel Indian red scorpion Mesobuthus tamulus concanesis Iberiotoxin Inhibitor of K+ channel Emperor Scorpion Pandinus imperator Imperatoxin Make the action potential prploged Scorpion Androctonus mauretanicus Block nerve impulse transmission Yellow brown Scorpion Centruroides margaritatus Block the activation of sodium channel Maxican Scorpion Centruroides noxius hoffmann Noxiustoxin Inhibit K+ channel Honeybee Apis mellifera Melittin Intese local pain, intravascular hemolysis, depolarization of heart and skeletal muscle Apis indica Apamin Inductor of convulsions, specifically act on synaptic functions in central nervous system and Apis dorsets make disbalance in Na+ and Ca++ channels Apis javana Histamin Induce pain Apis florae Hyaluronidase Facilitate the venom to spread throughout the victims body and cause pain, break down connective tissue Phospholipase A2 Breaks phospholipids and cause pores in biological membrane. It also posses myotoxic, carditoxic, anticoagulation activity and edema induction Acid phosphatase Induce allergic responses Protease Tissue necrsis Dopamin & Norepinephrine Hypotention, headache, vomiting and dysrhythmiasis European beewolf(Solitary wasp) Philanthus triangulum Philanthotoxin Depolarize the axon and causes paralysis Garden DaggerWasp (Solitary Wasp) Megascolia flavifrons Bradykinin Block synaptic transmission Eastern Yellow-jacket Wasp Vespula maculifrons Hornetin Intravascular hemolysis Vespula flavitarus Kinin Make the contraction fast of small muscle, laryngs and lunds Yellow-legged hornet Vespa verutina Phospholipase A1 hydrolyses membrane pospholipase and make pores in the biological membrane VT-1, VT-2a and VT-2b Potentially act on blood cell and cause hemolysis Asian giant Hornet Vespa mandarinia Mandaratoxin Block neuromuscular function Jumper ant Myrmecia pilosula Pilosulin 1 Cause cell lysis and induce allergic responses Tick Ixodes holocyclus Holocyclotoxin Muscular paralysis

Journal of Pharmacy Research Vol.3.Issue 12. December 2010 3123-3128 Ravi Kant Upadhyay et al. / Journal of Pharmacy Research 2010, 3(12),3123-3128 imbalance in biomolecules and certain metabolic enzymes (Schmidt, 1982; (iv) PROTEASES Tonismagi et al., 2006). Protease is an enzyme that shows high levels of proteolytic activity in con- nective tissues (Hoffmann and Jacobson, 1996) and cause moderate necrosis Another bee venom enzyme hylarunidase, acts as a spreading factor and allows (Lima et al., 2000; Kamiguti and Handa, 1985). It also occurs in venom of the toxic substances to infiltrate the tissues and rupture blood cells while social wasp (Polistes infuscatus), Vespa orientalis (Haim et. al., 1999). Polybia phospholipase A2 does not show general hypersensitivity and toxicity to the paulista, Polybia ignobilis, Agelaia pallipes pallipes, Apoica pallens and ant tissues but indirectly inhibits thrombokinase, dehydrogenase and transaminase (Eciton burchelli) (Schmidt et. al., 1986). These insects also contain several activity (Betten et al.,2006). It also inhibits oxidative phosphorylation. It isoenzymes, which are responsible for caseinolytic and gelatinolytic activities causes severe inflammation, swelling, rhabdomyolysis renal-insufficiency (Sousa et al., 1999; 2001). In association with PLA2, HYAL, and acid phos- (Daher Ede et al.,2003) and induces neuronal inflammation in mammals phatase Bombus venom protease shows tryptic amidase specificity and show (Schuetze et al.,2002). It causes multi-organ dysfunction, neuromuscular fail- strong allergenic reactions. Similarly Bombus species such as Bombus impa- ure and show fatalities when stung in groups. More specifically, citrate present tiens, Bombus fraternus, and Bombus bimaculatus also exhibit tryptic ami- in venom inhibits phospholipase A2 activity (Fenton et al., 1995). dase activity (Hoffman and Jacobson, 1996), coagulant, fibrinolytic (Koh, et. Similarly, hyalarunidease secreted from Vespula vulgaris possess two iso-aller- al., 2001; Mackessy, 1996) and hemorrhagic activities (Bjarnheimer and Fox, gen that effect T-cells and effector cells and show allergic responses (Seppala 1994) (Table 1). et al., 2009). Wasp sting affects alanine amino transferase and creatine kinase iso-enzyme levels in human patients. In such patients after administration of PHARMACOLOGICAL EFFECTS adrenaline helps to inhibit the diffusion of allergic and inflammatory cytokines and reduce the severity of injury (Xia et al.,2009).More specifically, venom Insect venom toxins show multiple pharmacological effects within victim’s susceptibility varies with person to person and increase with the age (Golden, body after envenomation (Hider, 1988; Lipps and Khan, 2000). It shows 1989; 2006). In old persons, it shows fast reactions with more severe symp- visible clinical symptoms related to paralysis, inflammation, swelling and toms (Van Der Linden et al., 1994) but beekeepers develop systemic relation- itching. (Fagan et al., 1982). Venom toxins cause fast release of certain ship to bee sting due to repetitive antigenicity (Fernandez, 2005; Przybilla, chemicals i. e. histamine, serotonin, kinins, prostaglandins and leukotrienes. 1999) that desensitize the allergic responses and inflammatory reactions Envenomation also causes a significant increase in glucose and lactate concen- (Munstedt et al., 2010). tration (Rothchild and Rothchild, 1979; Reid, 1961) elevate the level of circulatory blood sugar, glucagon and cortisol (Murthy and Hanghanazari, Table 3. Lethality of insect venoms in different animals. 1999). It decreases the level of Adenosine deaminase, IgE, histamine and nerve growth factor (Ratech et al., 1985; Lipps and Khan, 2001). Venom toxins also significantly altered the collagen and myoglobin level (Hirschhorn, Name of Insect Scientific name LD50 Animal model 1999; Maly et al., 1997), which leads to immune suppression and causes multi- organ dysfunction (Frederiksen, 1966; Bollinger et al., 1996). It also affects Bees European bee Apis mellifera 2.17mg/kg mice the level of cytokines in serum and induces pathological changes in liver and Africanized bee Apis mellifera 2.84mg/kg mice kidney. (Soffer et al. 1996). Rock bee Apis indica 8.2 µg/gm mice 4.13µg /gm insect Table 2. Venom composition of Apis mellifera Giant bee Apis mellifera 4 mg/kg mice Common honey bee Apis javana 21.6µg/gm mice Class of compound Component Percentage of dry weight Small honey bee Apis florea 16.8µg/gm mice Wasps Organic constituents Histamine 0.66-1.67 Eastern Yellow- jacket Vespula maculiforms 3.5 mg/kg mice Dopamine 0.13-1.05 Yellow jacket wasp Vespula squamosa 3.3 mg/kg mice Vespula maculate 4.1 mg/kg mice Noradrenaline 0.1-0.72 Vespula arenaria 2.5 mg/kg mice Polypeptides Melittin 41-50 Vespula flavitarus 0. 42µg/gm mice Melittin-F 0.01 1.2 µg/mg insect Apamin 3.01 Garden Dagger Wasp Megascolia flavifrons 2.2 µg/mg Insect Peptide 401 (mast cell degranulating 2.03 (Solitary Wasp) peptide) European beewolf Philanthus triangulum 1.89µg/mg insect Secapin 0.45 (Solitary wasp) Tertiapin 0.12 Hornets Procamine A,B 1.42 Yellow-legged hornet Vespa verutina 0 .02 µg/gm mice Lesser banded hornet Vespa affinisindosinesis 0.01-0.04µg/gm mice Enzymes Phaspholipase A2 10-12 Greater banded hornet Vespa tropica leafmansi 0.01-0.06µg/gm. mice Hyalusronidase 1-2.3 Yellow vented hornet Vespa analis analis 0.01-0.02µg/gm mice Acid phosphomonoesterase 1.0 Hornet Vespa verutina 0.02 µg/gm mice ?-D-glucocidase 0.6 Asian giant hornet Vespa mandarinia 0.01-0.031µg/gm mice Lysophospholipase 1.0 Jumper ant Myrmecia pilosula 3.6mg/kg mice Venom toxins show strong visible allergic symptoms like redness, inflamma- Velvet ant Dasymutilla klugii 71mg/kg mice Paper wasp Polistes anadensis 2.4mg/kg mice tion, local and systemic reactions (Schumacher and Egen, 1995; Tunget and Harvester ant Pogonomyrmex Maricopa 0.12 mg/kg mice Clark, 1993), erythema, edema of skin, urticaria, angioedema and pruritus Bombus Scorpion (Sheely, 2003; Betten et al., 2006). It also shows some additional signs and Scorpion Buthus tamulus 1.3 mg/kg mice symptoms of venom intoxication include diffuse widespread headache weak- 0.8 µg/gm Insect ness, fatigue, dizziness, nausea, vomiting and diarrhea (Greenberg et al., 2005; Indian red scorpion Mesobuthus tamulus concanesis 1.12mg/kg mice 0.67µg/gm Insect Winston, 1994), hypotension, tachycardia, respiratory distress, acute renal Black scorpion Heterometrus fastigiousus 12.8 mg/kg mice failure, disseminated intravascular coagulation, and multiple organ dysfunc- Spiders Brown widow spider Latrodectus geometricus 0.225 mg/kg mice tions (Park, 2005; Schumacher et al., 1990). It also causes hemolysis of RBCs Funnel web spider Hololena curta 24.9 µg /gm Insect and make alterations in other hematological parameters (Upadhyay and Ticks Ahmad, 2010) which results in death of patient (Okamoto et al., 1995). Bee Tick Ixodes holocyclus 0.03 µg /gm Insect larvae venom toxins are highly toxic, which cause cardio-respiratory failure, renal insufficiency and neuromuscular paralysis (Wu et al., 1998). It also causes hyperalgesia in after envenomation (Chen et al., 2000; 2001) and induces biochemical changes/disorders in lipid protein matrix both in hydro- Insect venom toxins also cause some pharmacological changes in pregnant phobic core of lipid bilayer and at polar/non-polar interface of RBC mem- women after being stung (Rizk et al., 1998). It leads to poor outcome in both branes (Hussein et al., 2001). Mellitin does make rigidization of lipid bilayer, mother and fetus and cause anaphylactic reactions in pregnant woman. It alter reorganization of lipid assemblies and membrane protein rearrangements, increases uterine muscle contractions with severe pain, which results in pre- and consequently change the lipid protein interactions while phosphilipase A2 mature delivery (Habek et al.,2000).For example Samsun ant (Pachycondyla act as a cytotoxin and hydrolyses membrane phospholipids. Contrary to this, sennaarensis) venom causes swelling, abdominal pain, vaginal bleeding, uter- other toxins insert themselves into membrane and form channel through ine tenderness, and placental abruption and fetal distress in pregnant woman which small molecules may pass across the cell membranes leading to increase (Rizk et al., 1998). It also causes multicystic encephalomalacia (Erasmus et

Journal of Pharmacy Research Vol.3.Issue 12. December 2010 3123-3128 Ravi Kant Upadhyay et al. / Journal of Pharmacy Research 2010, 3(12),3123-3128 al., 1982) and retro-placental clot (Habek et al., 2000) in infants. In experi- esis (Swoboda et al., 2002), which are considered as non-cross-reactive aller- mental animals, it decreases the level of lactate and isocitrate dehydrogenase gens and successfully improve the condition of envenomated patients (King et activity (Shkenderov and Todorov, 1979). Both spider and scorpion exert al., 2001). It is considered as a valuable tool for treatment of their venom lethal effects in pregnant women (Kankonkar et al., 1998). induced allergic mechanism.

LETHALITY OF VENOM Besides this, in systemic allergen imunotherapy allergens cause cytokine shift Apis dorseta is a very dreadful and highly aggressive honey bee that inflicts with a significant decrease in the level of allergen specific IgE and T cell large amount of venom in the victim that causes massive inflammation, responses to the allergen (King et al., 1976) and provided protection to the swelling and pain (Humblet et al., 1982). It obstructs respiration due to exten- patients (Julet et al., 1996). It contributes to decrease mast cells or eosinophil sive swelling of tracheal region (Schumacher et al., 1992) and show very high activation, which might be improve after re-exposure of allergen (Simons et lethality and systemic reactions after envenomation (Youloten et al., 1995). al., 1996). It also shows anaphylactic reactions (Lockey, 1995). However, Usually bees stung victims survived high in number (Sherman, 1995) but some oral or nasal administration of such allergens can be provided for the induction times stinging occurs in the neck region blocks respiration due to tracheal of a successful T cell tolerance in the patients (Lowery et al., 1998). Besides swelling. However, severity of venom increase with increases in the quantity this, mucosal immunotherapy sublingual administration of native allergens is of venom injected (Schmidt, 1995). Lethality increases with the age (Golden, also being done to induce T cell tolerance to the venom allergen (Clavel et al., 1989). More specifically, three quarters of the victims who died due to bee 1998). For diagnosis of allergy basophil activation test are applied for fast stings are males with a mean age of 60 (Sasvary and Mueller, 1994) because therapeutic treatment of patients (Strum et al., 2009). venom toxin hardly acts upon liver and kidney cells that make metabolic alterations in body (Jones et al., 1999). In response to the venom toxins, B- Specific anti-allergens are required for fast recovery, which might be non- lymphocytes secrete a group of immunoglobulins and release g interferons. invasive to the patient. The major short peptides are used, which avoid the Each immunoglobulin released from B-lymphocyte recognizes different epitopes risk of systemic adverse reactions caused due to conventional immunotherapy and bind selectively (Jeanning et al., 1998; Paull et al., 1978; Kemeny et al., with native allergens. Naturally, T cells response to a given allergen and the 1983; 1989). Insect venom toxins are highly toxic to mammals (Table 3), major T cell epitopes vary person-to-person (Kammerer et al., 1997). Be- sides this, major HLA-restricted T cell epitopes also vary according to patient which show 3.5 mg/kg LD50 for mice (Neumann et al., 1986). The LD50 values of European bee and Africanized bee venom were ranged between 2.17-2.84 types (Smith and Chapman, 1996). To overcome such difficulties long pep- mg/kg (Schumacher et al., 1990). Melittin the major toxic component of bee tides of 44-60 amino acids have been designed which cover the whole sequence of Phospholipase A2 the major bee venom allergen. These long peptides are venom showed an LD50 of 4 mg/kg (Table 3) (Habermann 1972). Similarly, venoms of A. dorsata, A. cerana and A. florae exhibited nearly identical lethal highly suitable and able to induce a vigorous T cell response in bee venom dose (Schmidt, 1995). The estimated fatal dose of bee venom is 1.3 mg/kg for hypersensitive patients (Smith et al., 1998). It can be concluded that the anti- an average adult (Winston, 1994; Kolecki, 1999). venom or toxin specific immunoglobulins have wider therapeutic applications to restore all physiological alterations caused by insect venom toxins CLINICAL TREATMENT (Kankonkar et al., 1998). Venom immunotherapy provides long term protec- For an insect venom stung patients initial treatment of epinephrine, 1:1000, tion from severe systematic reactions in patients (Hafner et al., 2008). It does 0.3 to 0.5 ml is to be given intramuscularly and diphenhydramine (50 mg) not imply any adverse effect on body tissues and cells and is considered as a intravenously or orally (Clark and Schneir, 2004). In heavy stinging oxygen- safe and effective approach to save the envenomated patients (Cavallucci et ation is highly essentail to maintain acid-base balance of the body. Histamine al., 2010). More significantly, it reduces dysfunctional beliefs and removes out antagonists are also given to treat the vascular effects of the venom emotional distress in the patient (Confino-Cohen et al., 2009) Thus, immu- (Schumacher and Egen, 1995) while steroids are provided to prevent a delayed notherapy is highly effective to protect venom allergic patients. It is best hypersensitivity and acute toxic envenomation (Park, 2005). Besides this, solution of insect envenomation that effectively neutralizes toxic effects of Stinger can be scrap out of the skin by swiping method (Kalpan, 2004). This insect venom. method avoids risk of allergy and other skin reactions (Gabriel et al., 2004). In severe envenomation hospital, admission is highly recommended for the pa- REFERENCES 1. 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Journal of Pharmacy Research Vol.3.Issue 12. December 2010 3123-3128