Behavioural and biochemical changes after simultaneous and post-treatment of vitamin A and D on cadmium toxicity.

In the present study, an investigation was undertaken to assess the protective efficacy in cadmium toxicity of vitamins administered simultaneously as well as post-treatment. Rats were treated with cadmium 1 mg/kg body weight (bw) powdered vitamin A chewable tablet 500 IU/kg bw/day and injectable vitamin D(3) (made into a suspension with gum tragacanth in 100 ml distilled water) 100 IU/kg bw/day, mixed with powdered pellet feed and fed to experimental animals. Spontaneous motor activity and Rota Rod Endurance time was recorded after both simultaneous (for 21 days) and post-treatment (42 days). Vitamin treated animals by themselves behaved like controls but attenuated the cadmium effect when given Cd simultaneously or as post-treatment. While the biochemical changes were assayed, vitamins which did not have any influence on their own, given simultaneously and as post-treatment, antagonized the cadmium effect on heart, liver tissues and serum. Both simultaneous and post-cadmium and -vitamin treatments significantly increased the activities of the enzymes aspartic amino transferase, alanine aminotransferase, acid phosphatase and alkaline phosphatase in tissues and serum. Simultaneous and post-vitamin treatment with Cd had an effect of bringing back the activity of the enzymes closer to control values. These data suggest that treatment with vitamin A and D can minimise the Cd effect when given to the population exposed to Cd.

Effect of acute pretreatment of lead on picrotoxin-induced convulsions in rats.

The effect of acute exposure to lead acetate (LA)/lead nitrate (LN) on onset and severity of convulsions induced by a low dose of picrotoxin was examined in rats. Both LA and LN reduced the time of onset and exacerbated the severity of convulsions, with a resultant high lethality. On comparison, it was noted that in the LA-pretreated group, convulsion scores and incidence of tonus and mortality were much higher; the appearance of tonus was more delayed than in the LN-pretreated group. In lead-pretreated animals, the potentiation of picrotoxin-induced convulsions was accompanied by higher lead levels in blood (p < 0.001). However, the whole-brain lead levels were not significantly different in these animals compared to the controls. The difference in the degree of potentiation by the two forms of lead could possibly be attributed either to the role of a combination of anions and cations or to the variable cerebral uptake and regional distribution of lead or due partly to the extent of competitive interaction involving d-aminolaevulinic acid--whose level is known to be elevated consequent to lead-induced disruption of haem biosynthesis--at GABA receptors.

Effects of endosulfan and aldrin on muscle coordination and conditioned avoidance response in rats.

The deteriorative effects after chronic endosulfan exposure on muscle coordination, learning and memory of rats were compared with that produced by aldrin which has been reported to have similar effects in experimental animals. A rota-rod apparatus was used to study the muscle coordination and learning and memory were tested by recording the response to unconditioned and conditioned stimuli using a pole-climbing apparatus. Aldrin but not endosulfan inhibited motor coordination in both sexes. A greater motor deterioration occurred in male group. This finding, together with the previous data which shows inhibition by its metabolite of motor activity, suggests that its metabolic product is responsible for this action. Like aldrin, endosulfan inhibited both learning ability and conditioned avoidance response. A change in the activities of brain monoamines or inhibition of perception and reflexes or both were proposed for these behavioural effects, since the former was reported to be produced by both compounds and the latter was found to occur in aldrin treated rats.

Effect of preperfusion of ascending concentrations of lead on digoxin-induced cardiac arrest in isolated frog heart.

The present work investigated the effect of preperfusion of ascending concentrations of lead acetate (LA) (10(-9), 10(-7) and 10(-5) M) on digoxin (DGN) cardiotoxicity in isolated frog heart, in order to look for any consequent variations in its lead-induced potentiation. The DGN perfusion time(s) and DGN exposure (micrograms DGN/10 mg heart weight) for, and myocardial DGN level (ng DGN/g wet tissue) at, cardiac arrest were the parameters evaluated so as to assess cardiotoxicity. Both sodium acetate and LA (10(-7) M) preperfusion led to a diminution in cardiac rate at 10 min of DGN perfusion without altering the contractility compared to the DGN alone group. With regard to DGN perfusion time for cardiac arrest, preperfusion of ascending concentrations of LA induced a corresponding decrease which was statistically significant (P < 0.05). On the other hand, in the experimental group that received preperfusion of 10(-9) M LA, the DGN exposure for cardiac arrest was not significantly different from that of the control, whereas in the 10(-7) and 10(-5) M groups, it was significantly lower (P < 0.05). In the experimental group that received preperfusion of 10(-7) M LA, the significant reduction in DGN perfusion time and DGN exposure was well corroborated by a diminution in the myocardial DGN level (4.01 +/- 0.17 ng/g wet tissue in comparison with the control value of 5.72 +/- 0.4 ng/g wet tissue, P < 0.05) at cardiac arrest. Taken together, these data reveal that with the preperfusion of LA in ascending concentrations, there is a relative increase in LA-induced potentiation of DGN cardiotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a hazardous interaction between ethanol and the insecticide endosulfan in rats.

Protein supplemented diet was protective against the deleterious action of endosulfan on body growth and liver. Hepatomegaly and a reduction of body weight produced concurrently by endosulfan and ethanol were greater in male rats, suggesting that males are more susceptible than female rats to the metabolic stress caused by their interaction. Chronic endosulfan exposure resulted in a prolongation of ethanol sleeping time in female and not in male rats. This finding suggests failure of female rats to metabolize ethanol readily on account of their greater susceptibility than male rats to the hepatotoxic action of endosulfan.

Effect of preperfusion of lead and aminophylline on digoxin cardiotoxicity.

An attempt has been made to investigate the cardiotoxicity of an interaction of Lead acetate (LA), Aminophylline (APH) and Digoxin (DGN), employing an isolated frog heart preparation. While DGN-Cardiotoxicity was potentiated by LA-preperfusion, it was antagonized by APH-preperfusion as revealed by data reflecting the mean DGN perfusion time (Sec) and mean DGN exposure (microgram/10 mg heart weight) for cardiac arrest. In an experimental group involving interaction of LA, DGN and APH, preperfusion of APH has significantly diminished but not fully abolished LA-induced potentiation of DGN-cardiotoxicity. On the other hand, perfusion of APH after LA resulted not only in annulment of LA-induced potentiation but also in an eventual residual protective effect of APH. It was striking that simultaneous preperfusion of APH and LA led to exacerbation of LA-induced potentiation. The results of this interaction study involving two widely prescribed cardioactive drugs, are considered to be of immense pharmaco-toxicological interest.

Effect of phenobarbitone pretreatment on isoniazid-induced lipid changes in plasma, liver and adipose tissue in the rabbit.

The subacute effect of a low dose of isoniazid (INH) (10 mg/kg/day for 11 days) in phenobarbitone sodium (PB)-pretreated rabbits (60 mg/kg/day for 4 days) on various lipid parameters in plasma, liver and adipose tissue was investigated. While treatment with PB or INH alone did not alter the lipid levels in plasma and tissues, INH treatment in PB-pretreated rabbits elevated the levels of plasma total lipid and cholesterol. In adipose tissue there was a decrease in total lipid, triglyceride and cholesterol and an elevation in free fatty acid. In contrast, all these parameters were found to be elevated in the liver. It is proposed that the enhanced release of primary amine functional groups from INH during microsomal induction by PB treatment caused increased deposition of lipids in the liver, which is presumably an outcome of enhanced breakdown and mobilization of lipids from the adipose tissue. It is suggested that the assessment of lipid profile would be a useful tool to monitor drug interactions involving INH with hepatotoxic potential.

Effect of aminophylline preperfusion on digoxin-induced cardiac arrest in isolated frog heart.

Digoxin (DGN) and aminophylline (theophylline ethylenediamine, APH) being frequently prescribed cardioactive drugs, the present study investigated the effect of APH (10(-4) M) preperfusion on DGN-cardiotoxicity employing the isolated frog heart preparation. The mean DGN perfusion time (sec) and mean DGN exposure (microgram/10 mg heart wt.) for cardiac arrest were the parameters studied. APH preperfusion caused a significant elevation in both the parameters, signifying that it afforded protection against DGN-cardiotoxicity. This protective effect was not observed with the preperfusion of ethylenediamine (EDA) instead of APH, which led to the inference that the protective effect of APH was solely due to its theophylline component. The present finding that APH-pretreatment might modulate DGN-cardiotoxicity, of considerable pharmaco-toxicological interest.

Effect of subacute administration of isoniazid and pyridoxine on lipids in plasma, liver and adipose tissues in the rabbit.

The effect of subacute intraperitoneal administration of Isoniazid (INH) on various lipid parameters was studied in liver and adipose tissue in addition to plasma. In the liver, its effect on various phospholipid fractions was also assessed. The changes in lipid profile reflected INH-induced hepatic steatosis. While pyridoxine alone did not alter any of these lipid parameters, its concurrent administration with INH prevented almost all the INH-induced lipid changes. The enhanced lipid mobilization into liver, and a fall in phosphatidylcholine with a concomitant rise in phosphatidylethanolamine in liver impeding lipoprotein synthesis, might be responsible for the hepatic steatosis. Pyridoxal, a pyridoxine metabolite, might have trapped the primary amine functional group of acetylhydrazine and thus prevented the steatosis.

A functional interaction between GABA and 5-HT in inhibiting picrotoxin-induced myoclonus in rats.

Pretreatment with 5-hydroxytryptophan (5-HTP), a precursor of 5-HT, antagonised while pretreatment with p-chlorophenylalanine (PCPA), a 5-HT depletor, potentiated the myoclonus induced by picrotoxin, a GABA antagonist. Pretreatment with aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, antagonised picrotoxin-induced myoclonus. The combined effect of the least protective doses of AOAA and 5-HTP was greater than the sum of their individual inhibitory effects on picrotoxin-induced myoclonus. Further, AOAA failed to inhibit picrotoxin-induced myoclonus in PCPA pretreated rats. These findings suggest that the central 5-HT-ergic system exerts a facilitatory influence on the GABA-ergic system and thus it is involved in the antimyoclonic action of GABA.

The synergistic protective effect of propranolol & aminooxyacetic acid against picrotoxin-induced myoclonus in rats.

The effect of propranolol was assessed against myoclonus induced by picrotoxin (a known GABA antagonist) in a dose of 3 mg/kg and allylglycine (the inhibitor of GABA synthesis and release) in a dose of 150 mg/kg. A dose-dependent (0.5-2 mg/kg) protective effect was found against both models. Pretreatment of rats with a GABA-reducing dose (100 mg/kg, nonmyoclonic) of allylglycine produced no change in the effect of propranolol against picrotoxin-induced myoclonus. Propranolol thus inhibited myoclonic responses when both the receptor activity and the functional pool of GABA were impaired, suggesting that it produces as antimyoclonic action without the involvement of GABA. However, the drug seems to show a synergistic action with GABA-ergic agents, as greater protection was observed in rats treated concurrently with propranolol and amino-oxyacetic acid, an inhibitor of GABA degradation.

The antimyoclonic action of clonazepam through a GABA--independent mechanism.

The present study investigates whether clonazepam exerts its antimyoclonic action through a GABA independent mechanism. We have studied the antimyoclonic effect of clonazepam and compared it with that of aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, against myoclonus induced by picrotoxin, a GABA receptor antagonist and allylglycine, a drug which inhibits synthesis and release of GABA. We have also investigated the effect of clonazepam against picrotoxin-induced myoclonus in rats pretreated with either AOAA or submyoclonic dose of allylgylycine. Clonazepam pretreatment inhibited both picrotoxin and allylglycine-induced myoelonus whereas AOAA was effective in inhibiting only picrotoxin-induced myoclonus. The protective effect of clonazepam against picrotoxin-induced myoclonus was potentiated by AOAA pretreatment. Moreover, clonazepam afforded protection against picrotoxin-induced myoclonus in rats pretreated with a submyoclonic GABA reducing dose of allylglycine. These findings indicate that a GABA independent mechanism may also be involved in the antimyoclonic action of clonazepam.

The effect of beta-adrenoceptor antagonists alone and in combination with a GABA-elevating agent on isoniazid-induced convulsions in rats.

A delay in the onset of isoniazid-induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta 1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid (GABA) elevating agent, aminooxyacetic acid (AOAA). The findings indicate that the GABA-mediated anticonvulsant action of AOAA seems to be additive with that resulting from beta 1 but not beta 2-blockade.

Synergistic anticonvulsant action of diazepam & clonazepam with amino-oxyacetic acid against isoniazid-induced convulsions in rats.

The protective effect of two benzodiazepine compounds, diazepam and clonazepam was tested against isoniazid (INH)- induced convulsions in rats pretreated with the gamma-amino-butyric acid (GABA) transaminase inhibitor viz., aminooxyacetic acid (AOAA), and the result was compared with that produced by the two drugs independently. Rats treated 6 h and not 30 min previously with AOAA showed a dose-dependent inhibition of INH-induced convulsions. In these animals both diazepam and clonazepam showed a greater protective effect than that produced by them alone. It is suggested from these findings that, even if their anticonvulsant mechanisms are distinct, with or without the involvement of GABA, AOAA and the benzodiazepine compounds seem to act synergistically against INH-induced convulsions.

Biogenic amine status in acute fulminant hepatocellular failure in children.

This study involved pediatric cases with Acute fulminant hepatocellular failure (AFHF) put on conventional therapy at the Hospital for children, Madras. In these cases, the biogenic amine status was studied at the time of admission, during therapy and at the time of recovery in responders. The CSF 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and Homovanillic acid (HVA), blood 5-HT and 5-HIAA, and urinary 5-HIAA followed almost a similar pattern of changes during the course of AFHF: increase at precoma, further increase at coma, return towards control at recovery. In striking contrast, urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) registered a decrease at precoma, a further fall at coma and a value closer to control at recovery. The results suggest the usefulness of assay of these parameters in monitoring cases of AFHF during therapy and in offering prognosis for these cases.

Evidence for synergism between the antimyoclonic actions of 5-hydroxytryptophan and clonazepam in rats.

The protective effect of the precursor of 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP) against myoclonus induced in rats by picrotoxin and allylglycine was demonstrated. The inhibition by 5-HTP of picrotoxin-induced myoclonic movements was found to correlate well with an increased 5-HT release from the cerebral cortex. p-Chlorophenylalanine (PCPA) pretreatment aggravated the actions of both picrotoxin and allylglycine by shortening their myoclonic latencies. These findings suggest that there is an antimyoclonic effect of 5-HT in the brain. The protective effect of clonazepam against these two myoclonic models was found to be potentiated in 5-HTP-pretreated animals. Only a partial inhibition of its protective effect resulted from PCPA pretreatment. These data suggest that a beneficial synergism is likely to occur between 5-HTP and clonazepam for the inhibition of myoclonus and that a 5-HTergic mechanism does not play a significant role in the antimyoclonic action of clonazepam.