scorpion envenoming syndrome; India; Androctonus; Buthus; Centruroides; Leiurus quinquestriatus; Tityus species
ON SCORPION ENVENOMING SYNDROME. PROBLEMS OF MEDICAL ETHICS AND ACCOUNTABILITY IN MEDICAL RESEARCH IN INDIA
K. RADHA KRISHNA MURTHY1 CORRESPONDENCE TO: K. Radha Krishna Murthy, D. Sc., D., M.N.A.M.S., Professor & Head, Department of Physiology, Seth G. S. Medical College & K. E. M. Hospital, Parel, Mumbai 400 012, India. E-mail: firstname.lastname@example.org
1 Department of Physiology, Seth G. S. Medical College & K. E. M. Hospital, Parel, Mumbai 400 012, India.
KEY WORDS: scorpion envenoming syndrome, India, Androctonus, Buthus, Centruroides, Leiurus quinquestriatus, Tityus species.
Extent of the Problem
Death due to scorpion envenoming syndrome is a common event in the world in general and especially in tropical and subtropical countries. Venom from scorpions all over the world that belong to Androctonus, Buthus, Centruroides, Leiurus quinquestriatus, and Tityus species of the Buthidae family is highly toxic. India itself harbors 99 species [out of about 600 species in the world] of scorpions and 45 of these species of scorpions are considered as having the most highly toxic venom. All these 45 species belong to the Buthidae family, as against most of the other countries, which harbor far less number of venomous scorpion species. The consequences of scorpion envenoming syndrome have been underestimated in health statistics of developing countries due to inadequate detection and/or data entry of cases. There is not even a guess estimate regarding the number of deaths due to the nocturnal visitors. Moreover, most standard textbooks of Medicine or Cardiology dismiss scorpion envenoming in a few lines. This is probably why the problem of scorpion envenoming syndrome has overall been either ignored or neglected by the scientific community of developed countries.
Being aware of and concerned about this problem, I read with great interest Karnads article (18), and the responses and opinions of Deshpande and Alex (10) and the Bawaskars (5-9) in national (from India) and international publications. Therefore, a need to review some of the views and practices in the field of scorpion envenoming research from an ethical point of view was perceived.
Consider the Bawaskars opinion, Human scorpionism is entirely different from experimental" (6,8). One must consider the international opinion in this context to evaluate the opinion of the Bawaskars.
Statements like Animal experimentation differs from human envenoming or Experimental considerations are different from clinical situations, cannot be accepted. Some of the most important information about haemodynamic effects of scorpion envenomation was obtained from Dr. Guerons work on experimental animals, Ismail (16,17).
The therapeutic agents should not be used for treatment of scorpion stings unless previous laboratory tests indicated their safety and effectiveness, Stahnke (36).
Experimental treatment protocols are required to check the value of drugs in the treatment of scorpion envenoming, Ismail (16,17).
Human and experimental animal studies are required in order to verify the assumption that interleukin-6 and other cytokines are involved in the pathogenesis of scorpion envenoming syndrome (35).
About the use of newer drugs and scorpion envenoming syndrome
Although newer drugs were recently used in the management of scorpion venom-induced hypertension, in particular, hydralazine, prazosin, and nifedipine the selection of these drugs was based mainly on some recognized merits of the drugs rather than a deeper understanding of the action mechanisms of scorpion venom (16,17).
Having considered these international opinions, the work of the Bawaskars can also be evaluated objectively.
The Bawaskars have no experimental support and hence have neither given development of treatment protocols based upon their experimental findings, nor have they explained the pathophysiological effects of scorpion venoms and their reversal by prazosin for their upholding the safety and effectiveness of prazosin therapy. They simply have made the following statements. Prazosin enhances insulin secretion by blocking alpha receptors over beta cells of the pancreas. Hyperkalaemia and hyperglycemia exist in the victims due to autonomic storm. Prazosin increased endogenous insulin secretion thus acts like a glucose-insulin-potassium drip and protects and prevents myocardial injury caused by liberated fatty acids and oxygen free radicals, and prevents lethal cardiac arrhythmias and sudden death. How could they do this without even providing references? This is because this happens to be the work of my colleagues and mine (22,34) in which we have demonstrated the reversal of metabolic and electrocardiographic changes by Indian red scorpion (Mesobuthus tamulus, earlier called Buthus tamulus) venom by the administration of insulin, alpha-blocker, and sodium bicarbonate (28), or insulin alone (30) in experimental animals. Based on these experimental studies, we have successfully demonstrated the efficacy of insulin administration in reversing haemodynamic changes and pulmonary oedema in children and adults stung by scorpions of the Buthidae family (25,31,38,39). We have also demonstrated the efficacy of species-specific scorpion antivenom (SAV) in experimental scorpion envenoming and in patients stung by scorpions of the Buthidae family (20,32). We have demonstrated not only acute hyperglycemia and hyperkalemia but also all other changes mentioned by the Bawaskars in acute myocarditis produced by scorpion venom injection in experimental animals (22,34), long before the Bawaskars made these statements in their publications (5,6,8,9).
Another instance is also interesting
I happened to explain in detail to HS Bawaskar the role of insulin related to prazosin on December 8, 1990 at 5:30 P.M. in the symposium Contribution of Physicians to the Development of Clinical Pharmacology at the 23
rd Annual Conference of Indian Pharmacological Society, held in Mumbai. I was invited as one of the speakers in the symposium. Within a few days of my explanation, on January 15, 1991 the Bawaskars submitted an abstract Prazosin inhibits the suppression of insulin secretion caused by
Mesobuthus tamulus (Indian red scorpion) envenoming to the 10
th World Conference on Animal, Plant and Microbial Toxins, 1991 (5). The National University of Singapore organized this conference, which they (the Bawaskars) did not attend. The Bawaskars, in their abstract, have reported the suppression of insulin secretion in a scorpion sting victim and enhancement of insulin secretion by Prazosin! It is important to note that insulin measurements are carried out using radioimmunoassay technique in a laboratory recognized by BARC (the Bhabha Atomic Research Center), Mumbai, India. To the best of my information, neither the Bawaskars are recognized to handle radioactive material nor have they worked at a Center recognized by BARC. In case a third person performed insulin measurements, the Bawaskars have not mentioned his/her name as co-author. Since the Bawaskars have worked at Mahad, District Raigad, Maharashtra, it is difficult to even imagine how they have [if at all] collected and preserved the samples and later sent them to a BARC recognized laboratory elsewhere for insulin measurements. It is necessary for the scientific community [and every one for that matter] to know and the Bawaskars to explain the source of their findings, how the measurements of insulin were made, and the basis of the abstract presentation.
Another episode also requires mention
The Indian Council of Medical Research (ICMR), New Delhi, India has formed a Task-Force on Venoms and Toxins and set up A Study Group for the Treatment of Scorpion Sting and the first meeting was held on February 23, 1996 at the ICMR headquarters office, New Delhi. Dr. HS Bawaskar, a few others, and myself were members of this Task Force. The following recommendation emerged at the meeting. A comparative clinical trial may be conducted using the following three different treatment regimens: a) Prazosin, b) insulin-glucose, and c) scorpion antivenom. Even before the comparative clinical trial is commenced by ICMR, the Bawaskars have come to the following conclusions. Reversal of toxic effects by antivenom is only possible in experimental animals; Antivenom can not abolish the effects of catecholamines that are already secreted; Human scorpionism is entirely different from experimental; and Immunoglobulins (antivenom) took 40 times longer to reach peak tissue level as compared to venin (6,8). All these conclusions are not supported by experimental evidence. In fact, all these statements made by the Bawaskars are from Gueron and Ovsyshcher (14). The Bawaskars do not give the reference of Prof. Gueron and his co-investigators.
Yet another story of the Bawaskars also has to be narrated
The Bawaskars questioned the value of serotherapy without any experimental backing in 1991 (9 ) and in 2000 (5), merely on the basis of their experience with two cases. The Bawaskars have no firsthand information or experience with serotherapy in experimental envenoming. Even before we demonstrated the efficacy of the antivenom produced by the Haffkine Biopharmaceutical Corporation Ltd., Mumbai, the Bawaskars questioned the value of serotherapy. At that time, they did not have even an idea about how the antivenom looks like and published articles like Is Serotherapy Essential? My colleagues and I have demonstrated the efficacy of the antivenom produced by the Haffkine Biopharmaceutical Corporation, Mumbai in experimental animals (22-24,32,34) and is supported by successful clinical trials in three districts of Maharashtra (37).
Last but not the least, in their unpublished part of the letter to the Editor of Heart, the Bawaskars remarked that scientists working in tropical countries should not waste their intelligence, time, money, and animal sacrifice to study scorpion envenoming syndrome, and chapter on the management of scorpion sting should be closed (personal communication from Prof. SB Deshpande, Institute of Medical Sciences, Banaras Hindu University). These remarks of the Bawaskars actually discourage the spirit of the scientific inquiry, presupposing a demigod status for them. It is high time that the Bawaskars and others took a more compassionate view of the community they treat instead of adopting a demigod status. In what way do the Bawaskars think that the results obtained from our experimental scorpion envenoming (22-34) are different from human scorpionism ?
In addition to all above, the Bawaskars are also encouraging non-qualified people to use an allopathic drug, which is actually supposed to be administered by a qualified and registered medical practitioner with either M.B.B.S. (Bachelor of Medicine and Bachelor of Surgery) or a higher qualification (recognized by Medical Council of India) (6,8).
When questions were posed to the Bawaskars through the Journal of Tropical Medicine and Hygiene, Marathi Vigyan Parishad, The Journal of Association of Physicians of India, and Heart, they gave no response.
Director-General, Indian Council of Medical Research, New Delhi has informed me that the council has taken a serious view about the views expressed by the Bawaskars and shall take necessary action. It is not known as to what action has been taken so far by The Indian Council of Medical Research.
It is ironical that in spite of all this, HS Bawaskar was nominated for the National Awards like Padma Shri ! (A civil award given by the Government of India).
About the responsibility of the referees
The above discussion also raises the role of referees and editorial board in the publication of the articles. What is the responsibility of the referees? The referee is expected to be knowledgeable in the subject referred to by the Editor. The referee should give specific comments on the scientific value and originality of the research paper. In case the referee is not able to give adequate consideration to any part of the paper, he should feel free to suggest the name of an expert to whom it can be sent for further assessment. The referee is also expected to know whether a particular statement made by the author/s is original and which statement made by the authors is borrowed even if the author/s do not provide the references.
About the accountability in medical research in India
In this context, it is worth noting the opinion of Padmavibhushan Professor A.S. Paintal, who was in the Department of Science and Technology, Center for Visceral Mechanisms, Vallabhbhai Patel Chest Institute, Delhi University, Delhi and Director-General (retired), Indian Council of Medical Research, New Delhi) (21). Accountability is an important feature in medical research. Accountability does not exist in India. Political patronage of unscrupulous scientists is one of the most unfortunate things that afflict Indian science. Scientists seem to get anything done through lobbying, by maintaining a high level of public relation activities, so they feel unaccountable to anyone. Since self-imposed accountability does not exist in India, as it does in certain Western countries, India should develop a system for holding scientists accountable for the suffering of others. However, it would be much more desirable if medical scientists adopted self-imposed accountability. It would be appropriate if the government and authorities, such as the Indian Council of Medical Research (ICMR) developed yardsticks for holding individual scientists accountable for undesirable effects that occur in unsuspecting human beings as the result of their actions or decisions (21).
The present state of affairs is the result of intellectual lethargy. I have often said that our post-independence intellectual classes are mainly lotus eaters, only wishing to take painless decisions in order that they can carry on their lives in comfort, go abroad frequently for meetings and conferences, unperturbed by failures, or having to take farsighted decisions that could lead to failures. They are all good internationally inclined scientists, respectable committeemen, who never rock the boat. All these people have never been accountable for any decisions they have taken or not taken. Society must now insist on accountability before it is too late, Paintal (21).
Science in our daily lives is a political orphan
Our scientific research in (India) areas that are important to our lives is next to nothing. In India in 1996-1997, as much as 64.1% of the total research and development investment went to just three departments, namely the Defense Research and Development Organisation, the Department of Space, and the Department of Atomic Energy. Add another 9.3% to science for industrial development, namely the Council of Scientific and Industrial research. Thus, nearly three-quarters of our research money went into areas that mean nothing to common people. Believe it or not, the Indian Council of Medical Research (ICMR), which is supposed to find answers to our myriad health problems, gets mere 1.1% research money (2)
Given these priorities, it is not surprising that all scientific heroes created by Indias establishment are nuclear or rocket scientists. As a result, scientists who work in the areas that affect our daily lives remain unknown and unimportant for the decision-making systems. They remain political orphans. Their own pusillanimity in keeping quiet on scientific issues that affect our lives makes the situation even more deplorable. In every modern Western nation, scientific issues are publicly debated which leads to public pressure on policy systems to deliver. But not in India, where scientists have taken silence to be their best insurance leaving, of course, thousands to die (2).
Now having seen these views and activities of the Bawaskars, and the opinion of Paintal and Anil Agarwal, the following account of scorpion envenoming research and practice is given to the benefit of the readers.
About pulmonary oedema and respiratory arrhythmias in scorpion envenoming syndrome
Clinical reports on scorpion sting victims described different types of abnormal respiratory movements that may lead to death. Thus, tachypnea, abnormal breathing pattern with gasping and apenic episodes, stridor with expiratory wheezing, and respiratory failure were reported. Pulmonary oedema, however, is a frequent complication in many humans, especially those stung by scorpions of several species; many patients died with pulmonary oedema (1,4-19,22-34,35,36,38,39).
The mechanism of acute pulmonary oedema induced by scorpion venom, however, is not completely understood (22). Many factors may be implicated in its genesis. Cardiogenic and non-cardiogenic factors are involved in the pathogenesis of pulmonary oedema following scorpion sting. Amaral et al. (1) reported predominantly unilateral pulmonary oedema. Unilateral pulmonary oedema secondary to left-sided heart failure seldom occurs in the absence of previous lung injury. This may be explained by a simultaneous and localized increase in pulmonary vascular permeability induced by scorpion venom. The patchy and peripheral distribution of lung oedema indicates increased vascular permeability. An increase in the ratio of tracheobronchial aspirate to plasma protein concentration; light microscopic features of the lung compatible with adult respiratory distress syndrome; electron microscopic findings compatible with acute lung injury; and increased alvelo-capillary membrane permeability in a 16-year old boy, who died with acute pulmonary oedema and shock after Tityus serrulatus sting was reported by Amaral et al (1). ARDS is a pulmonary manifestation of pan-systemic injury and multi-system-organ-failure (22). The chemical composition and the functional activity of surfactant are altered in ARDS. Surfactant deficiency could be the final common pathway in ARDS pathogenesis. The loss or insufficient quantity of surfactant may explain the pulmonary oedema associated with scorpion envenoming, since surfactant is preferentially formed from glucose and glycogen rather than from glycerol, and insulin is required for the formation of surfactant (22).
Few publications, however, deserve to be mentioned to explain the genesis of the scorpion-venom induced pulmonary oedema. Investigations from India and Saudi Arabia reported the effectiveness of aprotinin, the kallikrein-kinin inhibitor, in preventing the development of pulmonary oedema and decreasing the mortality rate of both rats and rabbits injected with lethal doses of L. quinquestriatus venom. The second report from Freire-Maia and De Matos showed the effectiveness of heparin or BN-52021, a PAF antagonist, in preventing acute pulmonary oedema by Tityus serrulatus venom in rat (11-13,16,17).
Bagchi and Deshpande (4) investigated the mechanism underlying the action of scorpion venom (
Mesobuthus tamulus concanesis, Pocock) on cardiac reflexes and the role of kinins in producing pulmonary edema. Intravenous injection of phenyldiguanide (PDG) produced reflex hypotension, bradycardia, and apnea. The PDG-induced reflex responses were augmented greatly after exposure to scorpion venom. Pretreatment with kallikrein-kinin inhibitor (aprotinin) blocked the venom-induced potentiation of the reflex and pulmonary water content. Captopril, an agent known to increase endogenous kinins, also augmented the PDG induced reflex to the same extent as scorpion venom. The results indicated the involvement of kinins and prostaglandins in the venom-induced augmentation of the cardiac reflexes. On the other hand, ondansetron, a 5-HT
3-receptor antagonist, failed to block the venom-induced increase in pulmonary water content, but blocked the reflex venom-induced augmentation. Further, histological examination also confirmed pulmonary oedema after envenoming. The histological features include oedema in alveoli, haemorrhage, necrosis, etc. The results showed that pulmonary oedema produced after envenoming is sensitive to aprotinin, indicating the participation of kinins in pulmonary oedema formation (4).
Sofer et al. (35) found a marked elevation of interleukin-6 in the serum of eight out of ten children following severe scorpion envenomation. These results imply that signs and symptoms following scorpion envenoming may partly be explained by the release of cytokines. Human and experimental animal studies are required to verify the assumption that interleukin-6 and other cytokines are involved in the pathogenesis of scorpion envenoming syndrome (35).
About insulin and scorpion envenoming syndrome
My associates and I have reported that the administration of insulin alone (28) or insulin and alpha-blocker (30) successfully reversed metabolic and ECG changes in experimental scorpion envenoming. Insulin administration along with alpha-blocker produced little more glycogenesis and lipogenesis and reversed the rise in plasma angiotensin II levels (22) than insulin administration alone (30). However, alpha-blockers are known to stimulate the gastric acid secretion; this may in turn, aggravate the existing sub-clinical or clinical acute pancreatitis (31), known to occur in some patients, into a fully blown-up fulminating acute pancreatitis in some scorpion sting victims. In 1989, we have demonstrated experimental acute pancreatitis and acute myocarditis due to scorpion envenoming (29). Our experimental results of acute pancreatitis were later on confirmed by Sofer et al from Israel, who observed pancreatitis in scorpion sting children. Abdominal and mild epigastric pain were the complaint of 36% patients, and a mild elevation of serum amylase levels was found in 20% of these victims (39).
About alpha blockers and scorpion envenoming syndrome (28)
If stimulation of nerves to the pancreas inhibits insulin secretion via the release of catecholamines (via alpha adrenoceptor stimulation to the pancreas), then it is logical to convert the inhibitory response to an excitatory response by using alpha blocking drugs. If alpha-blockers are acting by release of insulin, we can very well administer insulin instead of alpha blockade dependent insulin release to reverse metabolic, electrocardiographic, haemodynamic changes, non-cardiogenic respiratory pulmonary oedema (ARDS-like syndrome), and many other changes induced by scorpion venom.
About prazosin (alpha-adrenergic antagonist) (16,17 ) and scorpion envenoming syndrome
Prazosin (alpha-adrenergic antagonist) is found to enhance insulin secretion in scorpion sting victims with suppressed insulin secretion (prior to prazosin treatment) (5,6,8,9). The use of prazosin will be more effective when combined with a diuretic and/or a beta-blocker than when used alone, but diuretics and beta-blockers are contra-indicated in scorpion sting victims. Alpha-blockers can prevent the actions caused by released catecholamines, preventing further damage. Alpha-blockers cannot reverse tissue damage that has already been caused by catecholamines. Thus, insulin remains the only choice as the physiological antagonist to the actions of catecholamines.
About scorpion antivenom (SAV) and the opinion of Gueron and Ovsyshcher
Part of the statement made by Gueron and Ovsyshcher is given below for ready reference. This is substantiated by a study on the pharmacokinetics of the effects of the radioactively labeled antivenom, showing that the venom is very rapidly distributed to the tissue, with an estimated half-life of 5.6 min. The peak tissue concentrations of the venom are reached within 37 min. The immunoglobulins (antivenom) take about 40 times longer to reach peak tissue concentration, and this explains the ineffectiveness of scorpion antivenom given 15 min following the injection of scorpion venom (16,17). It confirms the ineffectiveness of serotherapy with antivenom injected several hours after scorpion sting, due to the lack of opportunity for the antivenom to interact with the venom in the compartment. In conclusion, there is no definite specific treatment which will prevent the cardiovascular manifestations of scorpion sting (14,15).
About scorpion antivenom and the opinion of Freire-Maia and Campos (13)
Freire-Maia and Campos have responded to the letter of Gueron and Ovsyshcher. Part of this statement is given below for ready reference. Gueron and Ovsyshcher (13) quoted papers by Ismail and colleagues to confirm the ineffectiveness of serotherapy. The pharmacokinetic studies involved the IV injection of radioactive labeled scorpion venom, antivenom, and immunoglobulins in anaesthetized rabbits. These data clearly show that venom is distributed very rapidly to the tissues, whereas antivenom and immunoglobulins are distributed at a much slower rate. However, as we (Freire-Maia and Campos) have said earlier, scorpions usually inoculate the venom into the interstitial space (producing an immediate and sometimes insupportable pain) and not directly into the blood circulation. Therefore, antivenom should be injected directly into a vein, as soon as possible, to neutralize the circulating venom and the venom, which is being absorbed from the site of the sting. Moreover, it seems likely that antivenins or immunoglobulins injected IV could act at the tissue level the following day. This possible effect of antivenom would be important to neutralize some persistent effects of scorpion venom, such as sinus tachycardia, leucocytosis and hyperglycemia (11-13). According to Gueron and Ovsyshcher most of the available commercial antivenins have a low efficiency in the treatment of scorpion envenoming. We (Freire-Maia and Campos) think that the best thing is to improve their efficiencies (11-13).
Immunotherapy for scorpion envenoming syndrome in Brazil
Using ELISA, Freire-Maia and his colleagues have shown that in rats injected with Tityus serrulatus venom, a great affinity of venom to the tissues and slow elimination half-life. Immunotherapy should be given to patients stung by scorpion as soon as possible after hospitalization. Severity of scorpion envenoming is related to plasma venom concentration. The high levels of plasma scorpion venom antigens were cleared one hour after antivenom infusion, and high concentrations of circulating antivenom persisted for at least 24 hours, confirming the efficacy of immunotherapy to neutralize circulating venom. Some symptoms, such as local pain decreased one hour after the starting of immunotherapy, whereas the other symptoms disappeared 12-48 hours later, and mortality rate was reduced to 0.28% (13).
About antivenom and the opinion of Ismail
Pharmacokinetic studies with labeled A. crassicauda venom showed that venom was unique among scorpion venoms. It follows a tri-exponential pattern characteristic of a three-compartment open model comprising a central blood compartment, a rapidly equilibrating shallow compartment and a slow equilibrating deep tissue compartment. The overall elimination half-life was 24 hours, indicating that the venom has the slowest elimination of all known scorpion venoms. This correlated well with the long mean residence time in the body, MRT of 33.7 h and in the peripheral compartment of 96 h. The long time of venom in the body might explain the increased risk of toxicity and good potential for the treatment with serotherapy even hours after the sting. Data obtained following SQ injection of the labeled venom into rabbits revealed a biphasic curve characterized by a rapid initial phase followed by a much slower ascending phase. Peak blood concentration was not reached during the 12 h sampling time. A slight decrease in blood radioactivity occurred at 24 h and the 48 h sampling times. Complete absorption of L. quinquestriatus venom from the SQ site was estimated to take place within 7-8 h.
Elimination of scorpion venom, however, is a slow process with estimated half-life of 4.2-24 h. This would offer a good therapeutic potential for the treatment with antivenom even many hours following the sting (16,17).
About the ineffectiveness of low SAV doses
Ismail and his co-investigators showed that low doses of antivenom are unable to neutralize completely electrocardiographic effects of the venom in experimental animals. The ineffectiveness of antivenom in the prevention or abolition of cardiovascular manifestations of scorpion envenoming had been ascribed to the low titers of commercial antivenoms used. At least 25-50 times the Israeli and 10-20 times the Saudi doses were required to neutralize the effects of an average L. quinquestriatus sting (1-2mg/dry venom) (16,17).
About our studies on Tc 99m-scorpion venom: labeling, biodistribution, and scintiimaging
We have been successful in labeling scorpion (Mesobuthus tamulus concanesis, Pocock) venom with Tc 99m using direct tin reduction procedure. Biodistribution studies were carried out in Wistar rats at different time intervals after IV administration of labeled venom. Scintiimages were obtained after scorpion envenoming using a large field of view gamma camera to ascertain venom pharmacological action in the body. The labeled venom was excreted through renal and hepatobiliary pathways. An immunoreactivity study was carried out in rabbits after IV injection of labeled scorpion venom followed by injection of the species-specific antivenom. A threefold increase in uptake by the kidneys was observed compared with that seen with scorpion venom alone. Venom neutralization in the kidneys was higher than in the liver (20).
About our work on experimental scorpion envenoming and species-specific- scorpion antivenom
We have demonstrated the reversal of metabolic, hormonal, cardiovascular, electrocardiographic, cardiac enzyme changes, and haemodynamic disturbances by species-specific scorpion antivenom (SAV)(22-34) in the experimental animals and in patients with severe scorpion envenoming syndrome (37).
About experimental scorpion envenoming as a tool
Many scientists have used experimental scorpion envenoming to explain cardiovascular manifestations. We have demonstrated acute myocarditis; cardiac sarcolemmal defects; enzymatic changes in the heart, liver, and skeletal muscles; metabolic and electrocardiographic changes; non-cardiac pulmonary oedema; adult respiratory distress syndrome (ARDS); disseminated intravascular coagulation (DIC); acute pancreatitis; changes in endocrine secretions (deficiency or suppression of insulin secretion; increase in angiotensin-II and glucagons levels; changes in thyroid hormones; glucorticoid levels; and many other abnormalities.
In support of Dr. Stahnkes opinion cited above, in opposition of Bawaskars views, it has to be noted that recent discoveries utilizing scorpion venom as a tool have served to recognize the ionic channels or map certain receptors and contributed to the development of medical sciences.
Based on the results obtained from our experimental work, we have suggested that the following drugs have no place in the treatment of scorpion stings because they are of no use or may do more harm (30).
1. cardiac glycosides,
3. parasympatholytic drugs,
5. beta blockers,
6. vasopressor agents,
7. snake antivenom,
8. local injection of: a) epinephrine and b) emetine.
In fact, the results of our experimental work have provided six or more modalities of therapeutic intervention, not only for scorpion envenoming but also other conditions:
1. use of insulin (insulin-glucose infusion) (31,39),
2. use of alpha-blocker (18),
3. use of insulin + alpha blocker + sodium bicarbonate (16,17,28,30,38,39),
4. use of scorpion antivenom (37),
5. use of insulin-glucose infusion in the patients of ARDS having MSOF (33),
6. use of angiotensin converting enzyme inhibitor (captopril).
About the use of insulin in scorpion sting victims
We have demonstrated the efficacy of insulin administration in reversing haemodynamic changes and pulmonary oedema in children and adults stung by the Indian red scorpion Mesobuthus tamulus concanesis, Pocock either at Western Maharashtra (Mumbai) (28) or at Kurnool Medical College, Kurnool (36,37) (South India).
About insulin-glucose infusion and metabolic modulation of acute myocardial infarction
Recently, the American Heart Association published in their journal a landmark study Metabolic Modulation of Acute Myocardial Infarction The ECLA Glucose-Insulin-Potassium Pilot Trial. This article was followed by an editorial Glucose-Insulin-Potassium for Acute Myocardial Infarction Remarkable Results from a New Prospective, Randomized Trial(3).
About the use of insulin-glucose infusion in ARDS patients with multi-system-organ-failure
Blood gases improved between 2-8 h resulting in normal biochemical profile, radiological clearance of lungs, and clinical improvement within five days when insulin infusion was given in addition to conventional therapy to ARDS patients with multi-system-organ-failure (33).
About the use of insulin + alpha blocker + sodium bicarbonate
Reversal of the ECG changes induced by Buthus tamulus venom in dogs after treatment with insulin (16,17,22,25,28,30,31) and sodium bicarbonate in intensive care treatment of severe cases of envenoming by L. quinquestriatus and A. crassicauda stings was observed. Insulin is known to stimulate K+ uptake by skeletal muscle and hepatic cells while sodium bicarbonate stimulates the movement of extracellular K+ back into cells by effects more complex than the pH-induced K+ redistribution (17).
About scorpion antivenom in India
Very few countries in the world have succeeded in producing an effective and specific scorpion antivenom (SAV). In our hands, antivenom is found to be effective in the prevention or abolition of various clinical manifestations of experimental scorpion envenoming syndrome (22-34), as well as in the treatment of human scorpionism in clinically controlled trials (37).
We fully agree with Ismail that if a sufficient dose of antivenom is used, adjunctive therapy is seldom required. However, we advocate the maintenance of acid-base-fluid-electrolyte balance in scorpion sting victims. We emphasize that it is essential to correct the acid-base-balance, abnormal gaseous exchange, fluids and electrolytes, and maintenance of vital functions in all scorpion sting victims besides SAV administration.
About the necessity of potent serotherapy
Serotherapy for scorpion envenoming syndrome with effective antivenoms in appropriate doses is unsurpassed in reducing morbidity and mortality by scorpion stings. It would be especially effective in developing countries where the frequency of scorpion stings is high and the means to treat victims in intensive care units are nearly absent (16,17,22-34). The need of the hour is the preparation of potent antivenoms of high efficacy against venoms of local venomous scorpions (16,17).
Controversy about the use of captopril
We were the first to demonstrate an elevation of plasma angiotensin II levels in dogs and rabbits by Mesobuthus tamulus concanesis, Pocock) envenoming (26). With these results from experimental scorpion envenoming, captopril (angiotensin converting enzyme inhibitor) was thought to be the drug of choice to treat scorpion stung victims (18). Gueron and his colleagues have appreciated the report that captopril was extremely successful in the management of scorpion stings in India (11). However, Ismail disapproves the use of captopril vehemently by arguing, The question to be posed is not about the effectiveness of captopril but on how dare someone use such a drug to treat scorpion sting victims without previous experimental studies? Because, captopril, by inhibiting the kininase II enzyme, leads to accumulation of bradykinin, the neurohumoral agent incriminated, at least experimentally, in pulmonary oedema of scorpion envenoming (16,17).
All this foregoing highlights the urgency of the effort [experimental and clinical] required to explain the pathophysiology and therapeutic effects of drugs in the scorpion envenoming syndrome, curb the baseless and harmful views, opinions, and unethical practices and also establish accountability in the field of medical research.
The author thanks the Department of Atomic Energy; the Bhabha Atomic Research Centre; the Government of India; the Indian Council of Medical Research (ICMR), New Delhi; and the Haffkine Biopharmaceutical Corporation Limited, Parel, Mumbai for their financial assistance in carrying out research work on scorpion envenoming.
1 AMARAL CFS., REZENDE NA. Both cardiogenic and non-cardiogenic factors are involved in the pathogenesis of pulmonary oedema after scorpion envenoming. Toxicon, 1997, 35, 997-8.
2 ANIL AGARWAL. Science in our daily lives is a political orphan. Built to last or structured to fall ? Special report. The Sunday Times Of India. 4 Feb., 2001, p.14.
3 APSTEIN CS. Glucose-insulin - potassium for acute myocardial infarction. Remarkable results from a new prospective, randomized trial. Circulation, 1998, 98, 2223-6.
4 BAGCHI S., DESHPANDE SB. Indian red scorpion (Buthus tamulus) venom induced augmentation of cardiac reflexes is mediated through the mechanisms involving kinins in urethane anaesthetized rats. Toxicon, 1998, 36, 309-20.
5 BAWASKAR HS. On the management of scorpion stings. Heart, 2000, 83, 585-6.
6 BAWASAKAR HS., BAWASKAR PH. Prazosin inhibits the suppression of insulin secretion caused by Mesobuthus tamulus (Indian red scorpion) envenoming. In: WORLD CONGRESS ON ANIMAL, PLANT AND MICROBIAL TOXINS, 10, Singapore, 1991. Abstracts...Singapore: International Society on Toxinology, 1991. 315.
7 BAWASKAR HS., BAWASKAR PH. Treatment of cardiovascular manifestations of human scorpion envenoming: is serotherapy essential? J. Trop. Med. Hyg., 1991, 94, 156-8.
8 BAWASKAR HS., BAWASKAR PH. Scorpion sting. J. Assoc. Physicians India, 1998, 46, 388-92.
9 BAWASKAR HS., BAWASKAR PH. Envenoming by scorpions and snakes (Elapidae), their neurotoxins and therapeutics. Trop. Doct., 2000, 30, 23-5.
10 DESHPANDE SB., ALEX AB. On the management of scorpion stings. Heart, 2000, 83, 585.
11 FREIRE-MAIA L., CAMPOS JA. Response to the letter to the editor by Gueron and Ovsyshcher. On the treatment of the cardiovascular manifestations of scorpion envenomation. Toxicon, 1987, 25, 125-30.
12 FREIRE-MAIA L., MATOS IMD. Heparin or a PAF antagonist (BN-52021) prevents the acute pulmonary edema induced by Tityus serrulatus scorpion venom in the rat. Toxicon, 1993, 31, 1207-10.
13 FREIRE-MAIA L., CAMPOS JA., AMARAL CFS. Approaches to the treatment of scorpion envenoming. Toxicon, 1994, 32, 1009-14.
14 GUERON M., OVSYSHCHER I. What is the treatment for the cardiovascular manifestations of scorpion envenomation? Toxicon, 1987, 25, 121-4.
15 GUERON M., MARGULIS G., ILIA R., SOFER S. The management of scorpion envenomation 1993. Toxicon, 1993, 31, 1071-83.
16 ISMAIL M. Serotherapy of the scorpion-envenoming syndrome is irrationally convicted without trial. Toxicon, 1993, 31, 1077-83.
17 ISMAIL M. The scorpion-envenoming syndrome. Toxicon, 1995, 33, 825-58.
18 KARNAD DR. Haemodynamic patterns in the patients with scorpion envenomation. Heart, 1998, 79, 485-9.
19 KARNAD DR., DEO AM., APTE N., LOHE AS., THATTE S., TILWE GH. Captopril for correcting diuretic induced hypotension in pulmonary oedema after scorpion sting. Br. Med. J., 1989, 298, 1430-1.
20 MURIGESAN S., RADHA KRISHNA MURTHY K., NORONHA OPD., SAMUEL AM. Tc 99m scorpion venom: labeling, biodistribution, and scintiimaging. J. Venom. Anim. Toxins, 1999, 5, 35-46.
21 PAINTAL AS. Accountability in Medical Research. Curr. Sci., 1994, 966, 905-7.
22 RADHA KRISHNA MURTHY K. The scorpion-envenoming syndrome: A different perspective. The physiological basis of the role of insulin in scorpion envenoming. J. Venom. Anim. Toxins, 2000, 6, 4-51.
23 RADHA KRISHNA MURTHY K., ABBAS ZARE. The use of antivenom reverses hematological and osmotic fragility changes of erythrocytes caused by Indian red scorpion Mesobuthus tamulus concanesis, Pocock in experimental envenoming. J. Venom. Anim. Toxins, 2001, 7, 113-138.
24 RADHA KRISHNA MURTHY K., HAGHNAZARI L. The blood levels of glucagon, cortisol, and insulin following the injection of venom by the scorpion Mesobuthus tamulus concanesis, Pocock in dogs. J. Venom. Anim. Toxins, 1999, 5, 47-55.
25 RADHA KRISHNA MURTHY K., HASE NK. Scorpion envenoming and role of insulin. Toxicon, 1994, 32, 1041-4.
26 RADHA KRISHNA MURTHY K., VAKIL AE. Elevation of plasma angiotensin levels in dogs by Indian red scorpion (Buthus tamulus) venom and its reversal by administration of insulin and tolazoline (alpha-blocker). Indian J. Med. Res., 1988, 88, 376-9.
27 RADHA KRISHNA MURTHY K., BILLIMORIA FR., KHOPKAR M., DAVE KN. Acute hyperglycemia and hyperkalemia in acute myocarditis produced by scorpion (Buthus tamulus) venom injection in dogs. Indian Heart J., 1986, 38, 71-4.
28 RADHA KRISHNA MURTHY K., VAKIL AE., YEOLEKAR ME., VAKIL YE. Reversal of metabolic and electrocardiographic changes induced by Indian red scorpion (Buthus tamulus) venom by administration of insulin, alpha-blocker and sodium bicarbonate. Ind. J. Med. Res., 1988, 88, 450-7.
29 RADHA KRISHNA MURTHY K., MEDH JD., DAVE BN., BILLIMORIA FR. Acute myocarditis and reduction of H+ ion concentration in gastric secretions in experimental acute myocarditis produced by Indian red scorpion (Buthus tamulus) venom. Indian J. Exp. Biol., 1989, 27, 242-4.
30 RADHA KRISHNA MURTHY K., VAKIL AE., YEOLEKAR ME. Insulin administration reverses the metabolic and electrocardiographic changes by Indian red scorpion (Buthus tamulus) venom in the experimental dogs. Ind. Heart J., 1990, 48, 35-42.
31 RADHA KRISHNA MURTHY K., SHENOI R., VAIDYANATHAN P., KELKAR K., SHARMA N., NEETA B., RAO S., MEHTA MN. Insulin reverses haemodynamic changes and pulmonary oedema in children stung by Indian red scorpion (Mesobuthus tamulus concanesis, Pocock). Ann. Trop. Med. Parasitol., 1991, 85, 651-7.
32 RADHA KRISHNA MURTHY K., KANKONKAR RC., ZARE AM., MALATHI A, BALASUBRAMANYAM P., YEOLEKR ME. Reversal of metabolic and electrocardiographic changes by scorpion antivenin administration in experimental myocarditis induced by Indian red scorpion (family Buthidae) venom. Recent Adv. Toxinol. Res., 1992, 2, 61-9.
33 RADHA KRISHNA MURTHY K., BHAMBURE NM., ABHYANKAR NY., PHADKE AY., SOMAN SS., SHAC AC., DESHMUKH SN. Insulin administration in adult respiratory distress syndrome following septic shock. Indian Practitioner, 1992, 45, 641-4.
34 RADHA KRISHNA MURTHY K., ABBAS ZARE, HAGHNAZARI L. The use of serotherapy to reverse ECG and cardiac enzyme changes caused by scorpion Mesobuthus tamulus concanesis, Pocock envenoming. J. Venom. Anim. Toxins, 1999, 5, 154-71.
35 SOFER S., GUERON M., WHITE RM., LIFSHITZ M., APTE RN. Interleukin-6 release following scorpion sting in children. Toxicon, 1996, 34, 389-92.
36 STAHNKE HL. The genus Centruroides (Buthidae) and its venom. In: BETTINI S. Ed. Handbook of experimental pharmacology, arthropod venoms. Berlin: Springer, 1978: 277-307.
37 TAHERBHAI M. A report on clinical trials of anti-scorpion venom-serum conducted in three districts of Maharashtra namely Thane, Raigad and Ratnagiri. Maharashtra, 1992. 58p. (A report submitted to government of Maharashtra-India ).
38 USHA KIRAN P. A retrospective study on treatment of red scorpion sting. Vijayawada: Andhra Pradesh University of Health Sciences, 1996. 109 p. ( M.D. Thesis)
39 YUGANDHAR B., RADHA KRISHNA MURTHY K., SATTAR SA. Insulin administration in severe scorpion envenoming. J. Venom. Anim. Toxins, 1999, 5, 200-19.
Received October 25, 2001
Accepted november 28, 2001
1AMARAL CFS., REZENDE NA. Both cardiogenic and non-cardiogenic factors are involved in the pathogenesis of pulmonary oedema after scorpion envenoming. Toxicon, 1997, 35, 997-8.
2ANIL AGARWAL. Science in our daily lives is a political orphan. Built to last or structured to fall ? Special report. The Sunday Times Of India. 4 Feb., 2001, p.14.
3APSTEIN CS. Glucose-insulin - potassium for acute myocardial infarction. Remarkable results from a new prospective, randomized trial. Circulation, 1998, 98, 2223-6.
4BAGCHI S., DESHPANDE SB. Indian red scorpion (Buthus tamulus) venom induced augmentation of cardiac reflexes is mediated through the mechanisms involving kinins in urethane anaesthetized rats. Toxicon, 1998, 36, 309-20.
5BAWASKAR HS. On the management of scorpion stings. Heart, 2000, 83, 585-6.
6BAWASAKAR HS., BAWASKAR PH. Prazosin inhibits the suppression of insulin secretion caused by Mesobuthus tamulus (Indian red scorpion) envenoming. In: WORLD CONGRESS ON ANIMAL, PLANT AND MICROBIAL TOXINS, 10, Singapore, 1991. Abstracts...Singapore: International Society on Toxinology, 1991. 315.
7BAWASKAR HS., BAWASKAR PH. Treatment of cardiovascular manifestations of human scorpion envenoming: is serotherapy essential? J. Trop. Med. Hyg., 1991, 94, 156-8.
8BAWASKAR HS., BAWASKAR PH. Scorpion sting. J. Assoc. Physicians India, 1998, 46, 388-92.
9BAWASKAR HS., BAWASKAR PH. Envenoming by scorpions and snakes (Elapidae), their neurotoxins and therapeutics. Trop. Doct., 2000, 30, 23-5.
10DESHPANDE SB., ALEX AB. On the management of scorpion stings. Heart, 2000, 83, 585.
11FREIRE-MAIA L., CAMPOS JA. Response to the letter to the editor by Gueron and Ovsyshcher. On the treatment of the cardiovascular manifestations of scorpion envenomation. Toxicon, 1987, 25, 125-30.
12FREIRE-MAIA L., MATOS IMD. Heparin or a PAF antagonist (BN-52021) prevents the acute pulmonary edema induced by Tityus serrulatus scorpion venom in the rat. Toxicon, 1993, 31, 1207-10.
13FREIRE-MAIA L., CAMPOS JA., AMARAL CFS. Approaches to the treatment of scorpion envenoming. Toxicon, 1994, 32, 1009-14.
14GUERON M., OVSYSHCHER I. What is the treatment for the cardiovascular manifestations of scorpion envenomation? Toxicon, 1987, 25, 121-4.
15GUERON M., MARGULIS G., ILIA R., SOFER S. The management of scorpion envenomation 1993. Toxicon, 1993, 31, 1071-83.
16ISMAIL M. Serotherapy of the scorpion-envenoming syndrome is irrationally convicted without trial. Toxicon, 1993, 31, 1077-83.
17ISMAIL M. The scorpion-envenoming syndrome. Toxicon, 1995, 33, 825-58.
18KARNAD DR. Haemodynamic patterns in the patients with scorpion envenomation. Heart, 1998, 79, 485-9.
19KARNAD DR., DEO AM., APTE N., LOHE AS., THATTE S., TILWE GH. Captopril for correcting diuretic induced hypotension in pulmonary oedema after scorpion sting. Br. Med. J., 1989, 298, 1430-1.
21PAINTAL AS. Accountability in Medical Research. Curr. Sci., 1994, 966, 905-7.
25RADHA KRISHNA MURTHY K., HASE NK. Scorpion envenoming and role of insulin. Toxicon, 1994, 32, 1041-4.
26RADHA KRISHNA MURTHY K., VAKIL AE. Elevation of plasma angiotensin levels in dogs by Indian red scorpion (Buthus tamulus) venom and its reversal by administration of insulin and tolazoline (alpha-blocker). Indian J. Med. Res., 1988, 88, 376-9.
27RADHA KRISHNA MURTHY K., BILLIMORIA FR., KHOPKAR M., DAVE KN. Acute hyperglycemia and hyperkalemia in acute myocarditis produced by scorpion (Buthus tamulus) venom injection in dogs. Indian Heart J., 1986, 38, 71-4.
28RADHA KRISHNA MURTHY K., VAKIL AE., YEOLEKAR ME., VAKIL YE. Reversal of metabolic and electrocardiographic changes induced by Indian red scorpion (Buthus tamulus) venom by administration of insulin, alpha-blocker and sodium bicarbonate. Ind. J. Med. Res., 1988, 88, 450-7.
29RADHA KRISHNA MURTHY K., MEDH JD., DAVE BN., BILLIMORIA FR. Acute myocarditis and reduction of H+ ion concentration in gastric secretions in experimental acute myocarditis produced by Indian red scorpion (Buthus tamulus) venom. Indian J. Exp. Biol., 1989, 27, 242-4.
30RADHA KRISHNA MURTHY K., VAKIL AE., YEOLEKAR ME. Insulin administration reverses the metabolic and electrocardiographic changes by Indian red scorpion (Buthus tamulus) venom in the experimental dogs. Ind. Heart J., 1990, 48, 35-42.
31RADHA KRISHNA MURTHY K., SHENOI R., VAIDYANATHAN P., KELKAR K., SHARMA N., NEETA B., RAO S., MEHTA MN. Insulin reverses haemodynamic changes and pulmonary oedema in children stung by Indian red scorpion (Mesobuthus tamulus concanesis, Pocock). Ann. Trop. Med. Parasitol., 1991, 85, 651-7.
32RADHA KRISHNA MURTHY K., KANKONKAR RC., ZARE AM., MALATHI A, BALASUBRAMANYAM P., YEOLEKR ME. Reversal of metabolic and electrocardiographic changes by scorpion antivenin administration in experimental myocarditis induced by Indian red scorpion (family Buthidae) venom. Recent Adv. Toxinol. Res, 1992, 2, 61-9.
33RADHA KRISHNA MURTHY K., BHAMBURE NM., ABHYANKAR NY., PHADKE AY., SOMAN SS., SHAC AC., DESHMUKH SN. Insulin administration in adult respiratory distress syndrome following septic shock. Indian Practitioner, 1992, 45, 641-4.
35SOFER S., GUERON M., WHITE RM., LIFSHITZ M., APTE RN. Interleukin-6 release following scorpion sting in children. Toxicon, 1996, 34, 389-92.
36STAHNKE HL. The genus Centruroides (Buthidae) and its venom. In: BETTINI S. Ed. Handbook of experimental pharmacology, arthropod venoms Berlin: Springer, 1978: 277-307.
37TAHERBHAI M. A report on clinical trials of anti-scorpion venom-serum conducted in three districts of Maharashtra namely Thane, Raigad and Ratnagiri. Maharashtra, 1992. 58p. (A report submitted to government of Maharashtra-India ).
38USHA KIRAN P. A retrospective study on treatment of red scorpion sting Vijayawada: Andhra Pradesh University of Health Sciences, 1996. 109 p. ( M.D. Thesis)
Publication in this collection
13 May 2002
Date of issue
25 Oct 2001
28 Nov 2001