Symposium

Cleistanthus collinus poisoning

Anugrah Chrispal Department of Medicine, Unit 2, Christian Medical College, Vellore, Tamil Nadu,

ABSTRACT collinus, a toxic shrub, is used for deliberate self-harm in rural South India. MEDLINE (PUBMED) and Google were searched for published papers using the search/ MeSH terms “,” “Euphorbiaceae,” “Diphyllin,” “Cleistanthin A,” Cleistanthin B” and “Oduvanthalai.” Non-indexed journals and abstracts were searched by tracing citations in published papers. The toxic principles in the leaf include arylnaphthalene lignan lactones — Diphyllin and its glycoside derivatives Cleistanthin A and B. Toxin effect in animal models demonstrate neuromuscular blockade with muscle weakness, distal renal tubular acidosis (dRTA) and type 2 respiratory failure with conflicting evidence of cardiac involvement. Studies suggest a likely inhibition of thiol/thiol enzymes by the lignan-lactones, depletion of glutathione and ATPases in tissues. V-type H+ ATPase inhibition in the renal tubule has been demonstrated. Mortality occurs in up to 40% of C. collinus poisonings. Human toxicity results in renal tubular dysfunction, commonly dRTA, with resultant hypokalemia and normal anion gap . Aggressive management of these metabolic derangements is crucial. Acute respiratory distress syndrome (ARDS) is seen in severe cases. Cardiac rhythm abnormalities have been demonstrated in a number of clinical studies, though the role of temporary cardiac pacemakers in reducing mortality is uncertain. Consumption of decoctions of C. collinus leaves, hypokalemia, renal failure, severe metabolic acidosis, ARDS and cardiac arrhythmias occur in severe poisonings and predict mortality. Further study is essential to delineate mechanisms of organ injury and interventions, including antidotes, which will reduce mortality.

Key Words: Cleistanthin A and B, Cleistanthus collinus poisoning, Oduvanthalai

INTRODUCTION and expertise contribute to high mortality rates (up to 10-20%) associated with deliberate self-harm in these regions.[3] Deliberate Self-inflicted fatality accounts for 1.5% of all deaths, making it the self-harm in developing countries occurs predominantly among 10th highest cause of death globally. With an approximate annual individuals aged 15-40 years, is usually of low intentionality with mortality of 14.5 suicides per 100,000 people, the estimated minimal psychiatric morbidity, and occurs essentially in rural global burden of suicide deaths is 1 million annually.[1] Self- populations.[2,3] inflicted injuries and, specifically, self-poisoning are major public health problems in the developing world, with 63% of global Suicide rates in South India are high, as evidenced by an overall deaths from self-harm occurring in the Asia Pacific region. [2] suicide rate of 71.4 per 100,000 people in a community-based That being said, the overall incidence of poisoning is probably study.[5-7] Though poisoning is relatively uncommon underestimated due to inadequate reporting.[3,4] Easy access to globally, it is a common method of self-poisoning in the Indian highly toxic poisons, with limited access to medical facilities subcontinent.[3,5,8-11] The most common types of plant poisons consumed in South India are Cleistanthus collinus (C. collinus) and [5] Address for correspondence: Thevetia peruviana (yellow oleander). C. collinus poisoning appears Dr. Anugrah Chrispal, E-mail: [email protected] to be almost exclusive to the southern Indian states of Tamil Nadu and Pondicherry. In excess of 1000 cases of C. collinus Access this article online poisoning were reported from various parts of Tamil Nadu Quick Response Code: between 1926 and 1985.[12] Subsequently, there have been a Website: www.onlinejets.org number of published clinical reports and studies from the region, which will be referred to in this review.[13-25] Inexplicably, despite the plant being distributed in various regions of India, no reports DOI: 10.4103/0974-2700.96486 about poisoning are available from other parts of India, though there is mention of cases from pre-independence Bengal.[17]

160 Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 Chrispal: Cleistanthus collinus poisoning

C. collinus poisoning appears to be a problem of the rural analysis of aqueous extracts of fresh C. collinus leaves, the other population, favored by young women as a method of deliberate major phytoconstituents detected are 3-O-methyl-d-glucose, self-harm. A study on acute poisoning in villagers reported that benzenetriol (pyrogallic acid), 1.6- anhydro-â-D-glucopyranose 87.8% of women consumed plant poisons, 44.5% of whom (levoglucosan), heptacosane, 2-hydroxy-7-methoxy-4,5- consumed C. collinus.[10] This female preponderance with C. collinus diphenyl-5 hindeno [1.2-d] pyrimidine and eicosane.[27] poisoning is evident across most clinical studies. Easy availability and free access to the plant are probably why women prefer this Animal models have revealed intriguing effects of the toxic method of deliberate self-harm. principles at the cellular level. Cleistanthins can cause neutrophilic granulocytosis in rats, mice, cats and monkeys.[41] It can also Methodology prevent granulocytopenia induced by cyclophosphamide.[42] MEDLINE (PUBMED), the Cochrane Database, Clinicaltrials. Alcoholic crude extracts from the entire plant have shown anti- gov, and Google/Google Scholar were searched for published proliferative properties against human epidermal carcinoma of papers using the search/MeSH terms “Cleistanthus collinus,” the nasopharynx in tissue culture.[43] The cytotoxic effects of “Euphorbiaceae,” “Diphyllin,” “Cleistanthin A,” Cleistanthin these glycosides have been elegantly demonstrated on tissue cell B” and “Oduvanthalai.” Non-indexed journals and abstracts were culture lines.[44] Cleistanthin A arrests cells growth by inhibiting searched by tracing citations in published papers. In addition, DNA synthesis and cell division, by causing DNA strand breaks authors and other clinicians involved in the published trials were and hence DNA damage. It also induces cell apoptosis.[45-47] In contacted to clarify certain aspects (personal communications addition, Cleistanthin A inhibits membrane metalloprotein-9, of unpublished data). which reduces proliferating cell viability significantly.[48] Cleistanthin B is clastogenic and induces micronuclei formation The plant: Cleistanthus collinus and chromosomal aberrations. It inhibits cellular proliferation The Euphorbiaceae (spurge family) are a family of flowering by causing a G1 phase arrest and induces cellular apoptosis.[49,50] with 300 genera and around 7,500 species. Most are herbs, These experimental findings suggest a possible role for these but some, especially in the tropics, are also shrubs or trees. The compounds as anti-neoplastic agents. Cleistanthus, belonging to the family Euphorbiaceae, comprises 140 species native to the region between Africa and Animal models—target organ injury and proposed the Pacific islands.C. collinus is a toxic deciduous shrub [Figure 1] mechanisms of action that grows in hilly deciduous forests of Central and South India, Studies on a murine phrenic nerve–diaphragm preparation Malaysia and Africa.[21,26,27] C. collinus in India is popularly known revealed that extracts of the leaf inhibited muscle contraction in: Hindi as Garari; Tamil, as Oduvanthalai; Telugu, as Vadise; , as Nilapala; and Bengali, as Karlajuri.[17,21]

All parts of the plant are potentially toxic.[17] The leaves are commonly used for poisoning humans (suicide or homicide) and animals (cattle and fish poison) and as an abortifacient, especially in rural South India.[21] Extracts of leaves, roots and fruits have been used in acute gastrointestinal disorders. The method of ingestion of the plant for deliberate self-harm includes swallowing the crushed plant parts;, chewing the leaves; consuming a paste/juice of the leaves or a decoction prepared by boiling the leaves in water.[17]

Toxic constituents Analyses of extracts from the plant, including the leaves, reveal a complex group of compounds.[28-40] The toxic active principles Figure 1: Cleistanthus collinus in the leaves are arylnaphthalene lignan lactones—Diphyllin and its glycoside derivatives Cleistanthin A and Cleistanthin B; and Collinusin [Figure 2]. Diphyllin, Cleistanthin A and B were collectively known as “Oduvin” in the past.[28] In addition, the lignans Cleistanthin C, Cleistanthin D and Cleistanone, are present.[40] The toxicity of the plant has been attributed primarily to Cleistanthin A and B.[27]

These toxic principles, the arylnaphthalene lignans, are detected in acetone extracts but, are not seen or are present in minimal amounts in aqueous extracts.[27] On spectroscopic Figure 2: Chemical structure of Diphyllin, Cleistanthin A and B[26]

Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 161 Chrispal: Cleistanthus collinus poisoning by reducing excitability of nerve and muscle membranes, as well cholinesterase (potentially explaining neuromuscular blockade as blocking neuromuscular transmission.[51] It did not, however, effects).[60-61] It appears that C. collinus depletes glutathione and affect excitation-contraction coupling or muscle fiber contractility. ATPases in various tissues, including the liver, kidney, brain, This effect on the neuromuscular junction with acetylcholine skeletal muscle and heart, in animal models. The loss of ATPase receptor site blockade was further delineated in sciatic nerve– activity may be a result of oxidation of–SH (thiol) groups. It tibialis anterior muscle preparations in rats, with partial response appears that inhibition of the thiol/thiol enzymes by lignan to Neostigmine.[52-54] Intra-peritoneal injection of leaf extract in lactones may be an integral mechanism in the toxicity profile rats resulted in a neuromuscular disorder resembling myasthenia of C. collinus. Glutathione depletion with ATPase inhibition gravis, with a sequential decremental response demonstrated on and resultant cellular injury results in focal hepatic necrosis, nerve-evoked compound muscle action potentials. [55] The model glomerular degeneration and cerebral gliosis evident in animal demonstrated that the neuromuscular blockade was sustained models.[61] Though thiol-dependent enzyme depletion has been and possibly irreversible. established in animal models, it has not been clearly demonstrated in human subjects.[17,49,62] A detailed study of renal and cardio-respiratory functions in rat models revealed relatively more severe metabolic acidosis, Clinical profile of C. collinus toxicity in humans lower serum potassium and alkaline urine compared to controls, Clinical studies have described in detail the clinical profile of suggesting a type 1 renal tubular acidosis. Additionally, a type patients presenting with C. collinus poisoning [Table 1]. Patients 2 respiratory failure was observed in the test rats. The terminal may be asymptomatic or present with common gastrointestinal event in these test rats was respiratory arrest with bradycardia, symptoms of vomiting, nausea and abdominal pain; and, and subsequent cardiac arrest.[56] The type 2 respiratory failure occasionally, diarrhea, constipation, dysphagia, salivation, could be explained by the presence of neuromuscular blockade. abdominal distension and decreased bowel sounds. [13,14,16- 24] This study did not demonstrate the occurrence of ECG Cardio-respiratory presentations include chest pain, dyspnea, abnormalities. [56] Another study which examined the effect of tachypnea or bradypnea, tachycardia or bradycardia, hypotension the boiled extract on the rat heart had different observations. and cyanosis.[24] Documented clinical neurological abnormalities The study showed that low doses of extract caused transient are mydriasis with visual disturbances, muscle cramps and tachycardia with increased myocardial contractility, while high weakness, altered sensorium, giddiness, headache, altered doses caused arrhythmia and cardiac arrest. In addition, persistent speech, tremors and ptosis.[14,16-24] Fever within the first 96 renal excretion of sodium despite hyponatremia and renal failure hours of presentation, and dehydration have also been was observed in these rats.[57] documented. [14,24] In addition to hypokalemia with a normal anion gap metabolic acidosis, documented laboratory abnormalities In vitro exposure to C. collinus extract results in significant include leukocytosis, elevated hepatic transaminases, elevated inhibition of vacuolar H+ATPase (vesicular proton pump) creatine phosphokinase, hyponatremia, hyperbilirubinemia and activity in the renal brush border membrane. Inhibition of the coagulopathy.[17,18] V-type H+ATPase in the renal tubule could explain the presence of distal renal tubular acidosis demonstrated in animal models Renal dysfunction and electrolyte derangement and human subjects.[58] A separate study has demonstrated that Distal renal tubular acidosis with hyperchloremic normal anion specifically Diphyllin inhibits the V-type H+ATPase.[59] There gap metabolic acidosis; alkaline urine; and hypokalemia with is no evidence of inhibition of the sodium-potassium pump.[56] kaliuresis appears to be a consistent feature in patients with C. collinus poisoning.[17,25] These findings are also consistent with Animal studies on rats and rabbits have shown an inhibition conclusions drawn using animal models.[56] A detailed study of of thiol-dependent enzymes such as lactate dehydrogenase and renal tubular function revealed that the distal tubular cell was

Table 1: Clinical observational studies conducted between 1980 and 2010 (>10 patients) Primary author; place; time of Number of Sex (female) Mortality Hypokalemia Cardiac abnormality # (%) Respiratory failure recruitment patients No. (%) No. (%) No. (%) Nagaraj; Thanjavur; 1980-1981 25 21 (84) 14 (56) UC 14 (56) UC Thomas; Vellore; 1982-1986 32 19 (59.3) 9 (28) 23 (72) Sudden cardiac arrest in 8 patients Sudden respiratory arrest in 3.1% Thomas; Vellore; 1988 15 11 (73.3) 2 (18.1) 9 (60) 2 (13.3) UC Shankar; Vellore; 1991-1999 127 79 (62) 38 (30) 91 (74) Bradycardia documented in 28.3%. Respiratory arrest documented 7 (6) DAMA Abnormal ECG documented in 23.6% in 9.4% Subhramanyam; Pondicherry; 1998-2000 46 28 (60.9) 15 (32.6) <3.1 mmol/L 8 (17.3) UC UC Devaprabhu; Vellore; 2000-2006 114 76 (67) 38 (43.3) 81 (66.5) Documented in 31.4% of patients Documented in 21.6% of who died patients who died (type unclear) Nampoothiri; Vellore; 2007-2009 32 19 (59.4) 4 (12.5) 20 (62.5) Bradycardia in 1 (3.1). ST depression 12.5% (type 1) in 3 (9.3) UC: This information could not be clearly documented from the information in the article; DAMA: Discharged against medical advice

162 Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 Chrispal: Cleistanthus collinus poisoning the most susceptible although proximal tubular injury, and in capillary level has been suggested.[17] Type 2 respiratory failure has more severe forms, global tubular dysfunction with diminished not been clearly documented in observational human studies unlike glomerular filtration rate (GFR) may occur. Metabolic acidosis animal models, though respiratory arrests have been mentioned. with defective urinary acidification was almost a universal phenomenon, often persisting even at discharge. There appeared Neuromuscular weakness to be a progression of the severity of renal injury — metabolic Neuromuscular weakness in humans has rarely been documented acidosis in patients with mild tubular injury; to more severe as opposed to animal studies, which have shown a consistent forms exhibiting metabolic acidosis and hypokalemia; to the effect of C. collinus toxins on the neuromuscular junction.[18,23] most severe forms showing tubular dysfunction and decreased A clinical case presenting with a myasthenia gravis–like picture GFR—resulting in metabolic acidosis, hypokalemia, renal failure with response to Neostigmine has been reported.[23] Muscular and in the majority of these patients, death.[25] Renal failure, weakness in patients could also be attributed to hypokalemia and oliguric in most instances, has been documented across clinical possibly to hypokalemia-associated .[63] studies, though its etiology is probably multifactorial: direct toxin effect secondary to hypotension and, possibly, secondary Mortality in C. collinus poisoning to hypokalemic rhabdomyolysis. Mortality occurs in up to 40% of patients with C. collinus poisoning. Death usually occurs within 3-7 days (majority of deaths occurring Hypokalemia is evident in a majority of symptomatic patients, on the third day) of consumption.[17,20] Consumption of a boiled usually at presentation or within the first 48 hours of ingestion. decoction of leaves (rather than other methods of ingestion) has Kaliuresis appears to be the main mechanism underlying this consistently been shown to result in higher mortality rates across abnormality, though vomiting and dehydration may have a role. clinical studies. A larger number of leaves (>60) consumed was Hyponatremia has also been documented. Hypomagnesemia also associated with a higher rate of mortality.[17] Hypokalemia may have an additional role in refractory hypokalemia, though has been found to be more severe in patients who died.[17,24] this requires to be confirmed by further study. Associations with mortality include older age, underlying chronic disease, altered sensorium, tachycardia (>120/min) or bradycardia Cardio-respiratory dysfunction (<60/min), fever, hypotension, abnormal vision, tachypnea, The toxic principles, being glycosides, would be expected dyspnea, persistent abdominal pain, giddiness after 24 hours, to cause cardiac effects. Clinical reports have shown cardiac respiratory arrest, severe acidosis, renal failure and ARDS.[17,24,25] rhythm abnormalities.[13-21,24] A retrospective study showed electrocardiogram (ECG) abnormalities such as sinus tachycardia, Management sinus bradycardia, flat “P” waves, prolonged QT and QTc Assessment and initial management intervals, ST segment depression and inverted “T” waves, in Airway, breathing and circulation should be assessed and 95% of patients with C. collinus poisoning.[13] A prospective appropriately stabilized. The patient’s level of consciousness study documented premature ventricular complexes as the and ability to protect the airway, hemodynamic stability and level most common arrhythmia on continuous cardiac monitoring. [15] of hydration need to be gauged. Mechanical ventilation may be Malignant cardiac rhythms such as ventricular fibrillation and required in the setting of respiratory failure. An urgent 12-lead asystole have also been documented.[18] ST-T changes appeared ECG with rhythm strip should be obtained to identify any rhythm to occur more frequently in patients that died.[17] Elevated cardiac disturbance, and the patient should be initiated on continuous enzymes have been documented in patients with poisoning, cardiac monitoring. Cardiac monitoring may need to be sustained suggesting a possibility of direct cardiac myotoxicity.[17] The for up to 5 days in symptomatic patients. Initial lab investigations degree to which the dominant metabolic derangements affect should include serum electrolytes (potassium, sodium, bicarbonate cardiac function is still unclear. and magnesium), creatinine, arterial blood gas and a chest radiograph. In case of vomiting, an antiemetic could be used. Mortality occurs despite patients having prophylactic temporary cardiac pacemakers insertion (TPI).[25] In view of this fact and Decontamination taking into account that recent animal studies have not shown In patients who have taken decoctions, it is unlikely that gastric cardiac rhythm abnormalities,[56] further studies on cardiac lavage beyond 1-2 hours post-ingestion is of benefit. A risk dysfunction in humans and the role of TPI are urgently needed. assessment will need to be made since patients who consume crushed leaves usually do not manifest significant toxicity. The Shock is associated with mortality. It has been hypothesized that benefit of lavage needs to be considered with caution as itsutility shock occurs due to inappropriate peripheral .[20] in this particular poisoning is unclear. Whether there is a cardiogenic component in shock is unclear in literature. A small non-randomized study on the use of multiple doses of activated charcoal on 26 patients with C. collinus poisoning Type 1 respiratory failure and adult respiratory distress syndrome presenting within 24 hours demonstrated a mortality benefit.[22] (ARDS) have been documented and have been associated with Activated charcoal was administered every 6 hours for 4 days. All mortality. A possible defect in oxygen transfer at the alveolar- of the 12 patients in the “multi-dose charcoal” group survived

Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 163 Chrispal: Cleistanthus collinus poisoning and 8 (57.14%) of the 14 in the “no charcoal” group survived. with C. collinus poisoning will be of benefit, and further studies on The small size of the study population requires that the results be its indications and its duration of use are needed before definite taken with caution. Large randomized controlled trials conducted recommendations can be made. for yellow oleander and the use of activated charcoal have been inconclusive in demonstrating mortality benefit,[9,64] and further Antidotes study is required to determine whether activated charcoal will be N-acetylcysteine, L-cysteine, melatonin and thiol-containing of benefit in patients with C.collinus poisoning. A single dose of compounds have all been suggested as possible antidotes for activated charcoal may be considered in patients presenting to management of C. collinus toxicity.[12,60,66,67] In one case report, the emergency department with C.collinus poisoning. N-acetylcysteine has been reported to be used, but the benefit of this intervention is unclear.[20] Neostigmine was used, with Definitive management probable clinical benefit, for a patient who presented with a The mainstay of C. collinus poisoning management is monitoring myasthenic crisis–like syndrome.[23] and correction of electrolyte imbalances, namely, hypokalemia and metabolic acidosis [Figure 3].[25,65] In a study, the strongest Diagnostics protective risk factor was higher plasma potassium levels (a Enzyme-linked immunosorbent assays (ELISAs) for Cleistanthin risk reduction of 58% in mortality per 1 mmol/L increase in A and B have been developed. The kits can detect levels plasma potassium level).[24] Aggressive preemptive correction of Cleistanthin A and B as low as 3 ng/mL and 2 ng/mL, of potassium and, acidosis is crucial. Aggressive management respectively. The simplicity of the ELISA makes it a feasible of shock with crystalloids and inotropes (both epinephrine and test for use in clinical and forensic toxicology for confirmation dobutamine have been used) is indicated. Renal function needs of diagnosis.[68-71] Other techniques that have been used for to be monitored carefully with strict intake-output monitoring, detection of toxin in blood and urine include high performance central venous access and serum creatinine levels. liquid chromatography (HPLC), spectrophotometry and thin- layer chromatography.[32,37-39,72,73] The precise role of cardiac pacing in the setting of C. collinus poisoning is a matter of conjecture as the evidence for preventing In one case series, digoxin assays were found to be positive in 16 deaths through its use is inadequate.[15,25] It is likely, however, out of 27 C. collinus poisoning cases, with higher levels of digoxin that it would be indicated in the setting of cardiac rhythm detected in fatal cases. The authors felt that the test was neither abnormalities such as bradycardia and QTc prolongation, and likely to be of diagnostic value nor was it likely to strengthen a may need to be placed electively in patients with severe poisoning. case for the use of anti-Dig Fab fragment in the management It is unlikely that elective pacemaker insertions for all patients as there was phytotoxin cross-reactivity.[17]

Investigations at admission – 12 Lead ECG, Electrolytes (Serum potassium, bicarbonate, sodium and magnesium), ABG and CXR

Hypokalemia Acidosis Renal Failure Dysarrhythmia Respiratoryfailure Shock

S.K+ <4.0 Ph <7.35 OR S.HCO3 CVP low – fluid Continuous cardiac Maintain SaO2 >90% Insert central line Oral Correction <24 replacement with monitoring Oxygen therapy as CVP <10 - rush in Syr.KCL 20ml Q6H Consider Oral crystalloids Transvenous cardiac required fluids Correction CVP 12-14 diuretic pacing (TPI) is Mechanical ventilation CVP >15 – challenge definitely indicated if indicated appropriate inotropic S.K+ <3.5 Persistent oliguria if the patient has support - adrenaline IV Correction Ph <7.30 OR S.HCO3 consider Dialysis Bradyarrhythmias Inj. KCL 3g in 500ml <16 (HR<60/m) or QT NS over 4hrs Consider IV Correction prolongation (QTC Daily Creatinine <0.44 sec) and possibly monitoring electively in all severe poisonings (patients Monitoring Severe acidosis not Nephrology consult S.K+ estimation Q4h responding to therapy who have consumed S.Bicarb testing Q6h –consider DIALYSIS decoctions) Cardiac monitoring Benefit of Elective TPI for all Oduvan poisonings is unclear

Figure 3: Proposed protocol of management based on current evidence

164 Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 Chrispal: Cleistanthus collinus poisoning

CONCLUSION 13. Thomas K, Dayal AK, Gijsbers A, Seshadri MS. Oduvanthalai leaf poisoning. J Assoc Physicians India 1987;35:769-71. C. collinus poisoning is a problem in rural South India. The renal 14. Nagaraj S. Cardiac toxicity of Oduvanthalai (Cleistanthus collinus) common tubule appears to be an important target of injury. Distal renal leaves poisoning in Tamil Nadu (Report of 25 cases). Antiseptic tubular acidosis results in hypokalemia and metabolic acidosis, 1987;84:33-5. correction of which is integral to the management of this 15. Thomas K, Dayal AK, Narasimhan, Ganesh A, Seshadri MS, Cherian AM, poisoning. The determination of the exact mechanism and extent et al. Metabolic and cardiac effects of Cleistanthus collinus poisoning. J Assoc Physicians India 1991;39:312-4. of cardio-respiratory involvement requires further study, though evidence suggests that careful monitoring and management is 16. Aleem HM. Oduvan leaf poisoning. J Assoc Physicians India 1991;39:973-4. important. Further research is needed to fully understand the 17. Subrahmanyam DK, Mooney T, Raveendran R, Zachariah B. A clinical mechanisms of toxicity in C. collinus poisoning, as well as potential and laboratory profile ofCleistanthus collinus poisoning. J Assoc Physicians India 2003;51:1052-4. antidotes, to reduce mortality. 18. Eswarappa S, Chakraborty AR, Palatty BU, Vasnaik M. Cleistanthus collinus poisoning: Case reports and review of literature. J Toxicol Clin Toxicol ACKNOWLEDGMENTS 2003;41:369-72. 19. Sarathchandra G, Prabhasankar P, Sekharan PC, Annapoorani S, Murthy I would like to express my gratitude to Professor Anand Zachariah; and PB. Toxicology of Cleistanthus collinus, an indigenous plant: Acute toxicity the members of Toxicology Special Interest Group, CMC, Vellore, who study. Ind J Toxicology 1996;3:9-17. have done significant work in the area of Cleistanthus collinus poisoning 20. Benjamin SP, Fernando ME, Jayanth JJ, Preetha B. Cleistanthus collinus and who helped develop the protocol of management cited in this poisoning. J Assoc Physicians India 2006;54:742-4. article. I would also like to thank the staff of Department of Physiology, 21. Devaprabhu S, Manikumar S, David SS. Toxico-epidemiology and CMC, Vellore, who have done significant work with animal models and prognostic profile of patients with Cleistanthus collinus poisoning. Indian J Cleistanthus collinus poisoning and consequently have provided crucial Trauma Anaesth Crit Care 2007;8:642-6. insights to the mechanisms of toxicity. I thank the Department of 22. Raja G, Kumaran SS, Chandrasekaran VP. Outcome of Cleistanthus collinus Medicine, Units 1, 2, 3; and the Department of Medical ICU, CMC, poisoning with and without charcoal. Acad Emerg Med 2007;14:e111. Vellore, where many of the patients of Cleistanthus collinus poisoning are 23. 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Journal of Emergencies, Trauma, and Shock I 5:2 I Apr - Jun 2012 165 Chrispal: Cleistanthus collinus poisoning

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Role of melatonin against oxidative tissue damage induced by Cleistanthus collinus in rat brain. Indian J Med 47. Meenakshi J, Shanmugam G. Cleistanthin A, a diphyllin glycoside Res 2009;130:467-74. from Cleistanthus collinus, is cytotoxic to PHA-stimulated (proliferating) 67. Sarathchandra G, Murthy PB. Efficacy of L-cysteine in countering human lymphocytes. Drug Dev Res 2000;51:187-90. Cleistanthus collinus poisoning an indigenous phytotoxin. Ind Vet J 48. Meenakshi J, Shanmugam G. Inhibition of matrix metalloproteinase-9 2000;77:209-11. (MMP-9) activity by cleistanthin A, a diphyllin glycoside from Cleistanthus 68. Ragupathi G‌, Prabhasankar P‌, Sundaravadivel B‌, Annapoorani KS, collinus. Drug Dev Res 2000;50:193-4. Damodaran C. Of Cleistanthus collinus toxins by enzyme-linked 49. Pradheepkumar CP, Paneerselvam N, Rajesh S, Shanmugam G. Cytotoxic immunosorbent assay. Toxicol Mech Methods 1994;4:204-13. and genotoxic effects of cleistanthin B in normal and tumour cells. 69. Ragupathi G, Prabhasankar P, Sekharan PC, Annapoorani KS, Damodaran Mutagenesis 1996;11:553-7. C. Enzyme-linked immunosorbent assay for the phytotoxin cleistanthin A. 50. Kumar CP, Pande G, Shanmugam G. Cleistanthin B causes G1 arrest and J Immunoassay 1992;13:321-38. induces apoptosis in mammalian cells. Apoptosis 1998;3:413-9. 70. Ragupathi G, Prabhasankar P, Sekharan PC, Annapoorani KS, Damodaran 51. Nandakumar NV, Pagala MK, Venkatachari SA, Namba T, Grob D. Effect C. Enzyme-linked immunosorbent assay (ELISA) for the determination of Cleistanthus collinus leaf extract on neuromuscular function of the isolated of the toxic glycoside cleistanthin B. Forensic Sci Int 1992;56:127-36. mouse phrenic nerve-diaphragm. Toxicon 1989;27:1219-28. 71. Ragupathi G, Prabhasankar P, Sekharan PC, Annapoorani KS, Damodaran 52. Vijayalakshmi KM, Nanadakumar NV, Pagala MK. Confirmatoryin vivo C. Dipstick ELISA kit for the detection of Cleistanthus collinus toxins. electrodiagnostic and electromyographic studies for neuromuscular Hindustan Antibiot Bull 1992;34:6-12. junctional blocking action of Cleistanthus collinus leaf extract in rat. Phytother 72. Ragupathi G, Prabhasankar P, Sekharan PC, Annapoorani KS, Damodaran Res 1996;10:215-9. C. Novel solid-state fluorodensitometric method for the determination of 53. Vijayalakshmi KM, Nanadakumar NV. Confirmatoryin vivo electrodiagnostic haptens in protein-hapten conjugates. Demonstration with a toxic glycoside and electromyographic studies for a new neuromuscular junctional blocking of Cleistanthus collinus. J Chromatogr 1992;574:267-71. agent from Indian medicinal plant . Electroencephalogr Cleistanthus collinus 73. Annapoorani KS, Damodaran C, Chandrasekharan P. High pressure liquid Clin Neurophysiol 1995;97:218. chromatography separation of arylnaphthalene lignan lactones. J Liq 54. Vijayalakshmi KM, Nanadakumar NV. Electrocardiac and electromyographic Chromatogr 1985;8:1173-94. studies on the effects of Cleistanthus collinus leaf extract in rat. J Med Aromat Plant Sci 1998;20:1009-12. How to cite this article: Chrispal A. Cleistanthus collinus poisoning. J Emerg Trauma Shock 2012;5:160-6. 55. Nanadakumar NV, Vijayalakshmi KM. Experimental myasthenia gravis- like neuromuscular impairment with Cleisthanthus collinus leaf extract Received: 09.01.11. Accepted: 10.01.11. administration in rat. Phytother Res 1996;10:121-6. Source of Support: Nil. Conflict of Interest: None declared.

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