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.

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.