Arvind K. Chaturvedi

A multi-chemical death involving caffeine, nicotine and malathion

Death of a 21-year-old man who was found in a shower stall in his residence is described in the study. At the scene, a 3/4 filled blue glass bottle labeled Black Leaf 40 (an insecticide containing nicotine), a white plastic pitcher 1/3 full of thick white fluid, a beer mug 1/4 full of thick white fluid, and an empty carton of milk were found. In addition, a can of malathion and an empty bottle labeled caffeine also were found in the vicinity. Autopsy was performed, and the gross examinations of organs revealed no specific findings to account for the death. However, marked congestion in lung, liver, spleen and kidney were noted at microscopic level. Autolytic degenerative changes were also observed in stomach, small bowel and colon. Toxicological analyses of the autopsy samples (blood, urine, liver and gastric contents) revealed the presence of caffeine and nicotine in each sample. Malathion was found to be present only in gastric content. Caffeine and nicotine were analyzed by utilizing gas liquid chromatography-nitrogen phosphorus detector, while malathion was by gas liquid chromatography-flame photometric detector. Analyses of the fluids from the bottle, pitcher and mug disclosed the presence of nicotine in the concentrations of 17.8%, 3.7% and 5.7% (w/w), respectively. The fluids from the pitcher and mug also contained 2.7-2.9% malathion. Results conclude the death was associated with caffeine, nicotine and malathion.

Effects of mecamylamine, nicotine, atropine and physostigmine on the phencyclidine-induced behavioral toxicity

Phencyclidine (PCP) has multifaceted actions on the cholinergic functions, including interaction with the central and peripheral cholinergic receptors. Therefore, to evaluate the possible involvement of the nicotinic and muscarinic acetylcholine (ACh) receptors during the behavioral toxicity of PCP, influence of various cholinergic modifiers on the PCP-induced behavioral effects in male Swiss mice was studied. PCP-induced (45 mumol/kg, IP) behavioral toxicity (circular movements, side-to-side head movements, and hyperactivity leading to convulsions) was blocked by pretreating the animals with secondary- or tertiaryamino -cholinergic modifiers, mecamylamine (ME; 14.9 and 29.9 mumol/kg), nicotine (NI; 12.3 and 30.8 mumol/kg) and physostigmine (PH; 0.16 and 0.31 mumol/kg). NI at 1.5 mumol/kg significantly potentiated the PCP-induced convulsions. Atropine (AT; 14.4 and 28.8 mumol/kg) pretreatments shortened the onset of circular movements. The locomotor activity of PCP (16.4 mumol/kg) was blocked by ME, NI, and PH. AT at 7.2 mumol/kg significantly potentiated the PCP-locomotion by 62%. These observations indicated that the behavioral actions of PCP, at least in part, are mediated by the central nicotinic and muscarinic ACh receptors. The involvement of cholinergic receptors in conjunction with the dopaminergic actions of PCP during these behaviors also has been discussed.

The role of hepatic microsomal enzymes in the modulation of phencyclidine-induced toxicity

The LD50 of phencyclidine (PCP, 234 mumol/kg, i.p.) in male Swiss mice decreased by 62% in animals pretreated with 2-diethylamino-2,2-diphenylvalerate hydrochloride (SKF-525A, 40 mg/kg), and increased by 74% and 20% in animals pretreated with sodium phenobarbital (75 mg/kg), and 3-methylcholanthrene (70 mg/kg), respectively, No Significant change in the LD50 was observed with cysteine or diethylmaleate pretreatment. The treatment with PCP at 179 mumol/kg/day i.p. for 7 days resulted in body weight decrement in the first 2 days and gradual increment thereafter. The increase was only 33% of the control group. The food intake was also lower in the PCP treated group of animals. PCP withdrawal led to an increase in food intake as well as body weight at a normal rate. The ratio of liver weight to body weight was not significantly higher than that of control during the treatment period. The administration of PCP for 7 days did not alter the activities of liver function enzyme markers. However, within 12 h of the initial PCP treatment a 85% increase in activity of serum glutamicoxalacetic transaminase was observed. Later the enzyme activity reached close to normal levels. No liver lesions at the light microscopic level were observed. Treatment of mice for 4 days with PCP (179 mumol/kg) caused no significant change in pentobarbital sleeping time.

Toxicological evaluation of the leachate from a closed urban landfill

Landfilling is one of the commonly used methods of disposal of solid wastes in small and medium size municipalities. Leachate produced in the landfills can contaminate underground sources of water. Though precautionary measures to reduce the risk of leachate migration into underground sources of water are included in the selection of sites for landfilling and in their design and construction, the risk of contamination is not completely eliminated. Though chemical and in vitro toxicity tests on leachates have been conducted, not many studies are related to long-term toxicity of leachate in animal models. Therefore, toxicological evaluation of leachates is needed in order to predict possible undesirable effects of consumption of leachate-contaminated water on human populations. In this study, leachate obtained from a close landfill, which served a city population of about 60,000, was evaluated for its toxicity to mice. Animals were given leachate as drinking water for 65 days, and general toxicity to selected end points was observed.

Toxicity of 1-phenylcyclohexene and its interaction with phencyclidine☆☆☆

The toxicity of 1-phenylcyclohexene (PC), a pyrolysis product of phencyclidine (PCP), and its interaction with PCP were evaluated. The ip LD50 of PC in Swiss male mice was 22 mmol/kg. Treatment of mice with PC at 2.2 mmol/kg/day, ip, for up to 7 days increased the liver/body weight ratio, which returned to normal within 7 days after PC withdrawal. Increases of 32% in serum glutamic-oxalacetic transaminase (SGOT) and 94% in serum glutamic-pyruvic transaminase (SGPT) were observed within 4 hr following the initial (Day 1) dose of PC. Smaller increases in the SGOT activity continued following Day 2 and 3 PC administrations. The SGPT activity remained elevated after these treatments. Activities of both enzymes, however, returned to normal within 24 hr following daily PC injections. No pathologic changes were observed in liver, brain, spleen, kidneys, and lungs with light microscopy. PC treatment for 4 days at 2.2 or 4.4 mmol/kg produced proliferation along with dilatation and fragmentation of the endoplasmic reticulum in liver. Scattering of ribosomes in the cytoplasm and dilatation of rough-surfaced cisternae were prominent at the higher dosage. Pretreatment of animals for 4 days with PC (1.1, 2.2, and 4.4 mmol/kg, ip) decreased pentobarbital- (60 mg/kg) induced sleeping time by 27, 64, and 80% and lowered PCP- (16.4 mumol/kg) stimulated locomotor activity by 18, 28, and 41%, respectively. Pretreatment of animals with PC for 1 hr inhibited (ED50: 2.3 mmol/kg) the PCP-induced locomotion. These results indicate that the PC treatment during a 7-day period produces some undesirable effects on liver function, which are reversible on its discontinuation. However, PC also weakens toxic effects of PCP.

Toxicological findings in a multi-drug death involving propoxyphene, caffeine, phenacetin, acetaminophen and salicylate.

The toxicological findings of a multi-drug related fatal poisoning are described here. A 35-year-old Caucasian male found dead on the kitchen floor was a known user of abused drugs and had been taking aspirin alone or in combination with phenacetin and caffeine for the relief of joint pains. The gross examination of the organs at autopsy revealed slight grooving of the uncus and various stages of necrosis in the renal papillae. Histological examination confirmed the gross appearance of pulmonary congestion and edema, cerebral edema and interstitial nephritis of the tubules. Toxicological evaluation of the blood and urine samples disclosed the presence of propoxyphene (51 and 250 mg/l), salicylate (185 and 2750 mg/l), caffeine (16 and 37 mg/l), and phenacetin (9.6 and 20 mg/l). Furthermore, acetaminophen also was present in the plasma (54 mg/l) and urine. A gas liquid chromatographic method for simultaneous analysis of phenacetin and caffeine utilizing a nitrogen phosphorus detector was proposed.

Influence of phencyclidine on the translocation of pentobarbital in mice

The influence of phencyclidine (PCP) on the tissue distribution of pentobarbital in male Swiss mice (20-25 g) was investigated. Animals pretreated with PCP (179 mumol/kg/day) for 4 days, i.p., were administered pentobarbital (60 mg/kg, i.p.) 24 h after the PCP injection, sacrificed at various time intervals, and tissues (serum, brain, liver and kidney) were collected. Pentobarbital levels in tissues were determined by the gas liquid chromatography. When compared to the control group, PCP treatment decreased the pentobarbital level by 68% in liver and increased the level by 97% in kidney at 45 min post-injection. No significant change in serum and brain pentobarbital level was noted with either group. These data indicate that PCP influences the translocation of pentobarbital.

Anticonvulsant and monoamine oxidase inhibitory properties of newer chlorostrylquinazolones

Abstract Eighteen newer methaqualone analogs, i.e., chlorostrylquinazolones, were tested for their anticonvulsant and monoamine oxidase inhibitory properties. Quinazolones possessing hydrazide moiety were found to be more potent inhibitors than their corresponding precursor esters. In this study 6-chloro-3-(4-benzhydrazide)-2-(2-chlorostyryl)-4-quinazolones was found to possess maximum anticonvulsant activity and provided 60% protection against pentylenetetrazol-induced convulsions in mice while 6-chloro-3-(4-benzhydrazide)-2-(2-hydroxy-5-nitrostyryl)-4-quinazolone caused maximum inhibition of 88% of the activity of rat brain monoamine oxidase. No direct correlationship could be observed between monoamine oxidase inhibitory and anticonvulsant properties of these substituted quinazolones.

Interaction between phencyclidine and its pyrolysis product, 1-phenylcyclohexene

The interaction between phencyclidine (PCP) and its pyrolysis product, 1-phenylcyclohexene (PC), at metabolic level was evaluated in Swiss male mice (21-24 g). PC (1.1, 2.2 and 4.4 mmol/kg/day for 4 days, IP, in corn oil) treatment to mice induced the in vitro metabolism (p less than 0.05) of amidopyrine (17%), aniline (12%), phenacetin (62-100%), pentobarbital (20-26%), PCP (25-80%) and benzo[a]pyrene (81-147%) in the 9000 g liver fraction and the hepatic microsomal contents of cytochrome P-450 (18-42%). The induction of the mixed function oxygenase (MFO) system was consistent with the decreases in the concentrations of IP administered pentobarbital (0.27 mmol/kg, in saline) and PCP (16.4, 32.8 and 65.6 mumol/kg, in saline) in the serum, brain, liver and kidneys of PC pretreated mice. At 1 hr after the above doses of PC, the in vitro metabolism of amidopyrine, aniline, or phenacetin was not inhibited. However, the biotransformation of benzo[a]pyrene was inhibited by 33 to 45%. Though PC after a single dose did not alter the tissue concentrations of PCP, it increased the pentobarbital concentrations in the tissues studied (p less than 0.05). These results indicate that PC has a potential to induce the MFO system after the 4-day treatment. This property of PC plays an important role in the reduction of the action of PCP by enhancing its metabolism, thereby decreasing its tissue levels.

1(2-benzoylethyl)pyridinium chloride: a new potent and selective inhibitor of bovine brain and human placental choline acetyltransferase.

A newly synthesized 1(2-benzoylethyl)pyridinium (BEP), an analog of the choline acetyltransferase (ChA) inhibitor (2-benzoylethyl)trimethylammonium (BETA), was evaluated for its ability to inhibit ChA from bovine brain and human placenta. Its ChA inhibitory properties were compared with that of BETA. BEP was found to be an effective inhibitor of ChA (I50: 10-18 microM). BEP, as well as BETA, was a linear noncompetitive inhibitor of ChA with respect to both substrates, acetylcoenzyme A and choline. BEP and BETA were poor inhibitors of electric eel acetylcholinesterase. These observations indicate that BEP is a potent and selective inhibitor of ChA. Furthermore, because of the possible delocalization of the positive charge at the N atom of the BEP molecule throughout the pyridine ring, it is anticipated that BEP would have a higher potential for lipid solubility, stability and selectivity than BETA.