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Biomedical subjects

A Hashem

Publications and source records attributed to A Hashem.

25 records · Page 2Linked to original sources
PubMed1988

[The effect of neuroleptics and neuroleptic/analgesic combinations on the sensitivity to seizures in mice].

UNLABELLED: Combinations of neuroleptic and morphine-like analgesic drugs are used alone for minor surgery or as anesthetic premedication. While morphine-like analgesics given in the therapeutic dose range show anticonvulsant properties, there is evidence indicating that neuroleptics are rather proconvulsant. This study was performed to investigate the influence of the most widely used combinations pethidine/promethazine and fentanyl/droperidol on seizure susceptibility. METHODS: Thresholds for convulsions induced by electroshock and pentetrazole infusion were used as models for seizure susceptibility. The drugs tested were injected s.c. 20-30 min before determination of the seizure threshold. RESULTS: Pethidine/promethazine and fentanyl/droperidol reduced the susceptibility to seizures induced by electroshock. Promethazine and droperidol alone elevated the threshold only at the highest doses used (2 mg/kg and 2.5 mg/kg respectively). Promethazine, whether given alone or in combination with pethidine, showed no effect on the threshold for pentetrazole-induced convulsions. Droperidol alone lowered the threshold for pentetrazole-induced clonic convulsions only at the lowest dose used (0.625 mg/kg), but lowered that for tonic convulsions at all doses studied (0.625, 1.25 and 2.5 mg/kg). The combination of fentanyl and droperidol lowered the threshold for both clonic and tonic convulsions at the two lower doses (12.5 micrograms/kg fentanyl + 0.625 mg/kg droperidol and 25 micrograms/kg fentanyl + 1.25 mg/kg droperidol). Only the highest dose studied (50 micrograms/kg fentanyl + 2.5 mg/kg droperidol) showed no significant effect. CONCLUSION: Pethidine and fentanyl show anticonvulsant properties in mice, but it is evident from our results that there is some interaction between their combinations with neuroleptics and seizure susceptibility. This is more pronounced with the combination fentanyl/droperidol in the model of pentetrazole-induced convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1987

Anticonvulsant efficacy of clonazepam and the beta-carboline ZK 93423 during chronic treatment in amygdala-kindled rats.

Amygdala kindling in rats represents an animal model of partial epilepsy with secondary generalization. Benzodiazepines are active against this type of epilepsy in man but their usefulness is limited by the development of tolerance. This study examined the effects of chronic treatment with the benzodiazepine clonazepam and the beta-carboline ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester), a full agonist at brain benzodiazepine receptors, on amygdala-kindled seizures in rats. The pharmacokinetics as well as the acute anticonvulsant potency of the drugs were determined prior to the chronic experiments. Based on the data thus obtained clonazepam and ZK 93423 were administered 3 times daily at a dose of 1 or 5 mg/kg i.p., respectively, for 2 weeks. During this treatment period, both compounds significantly reduced seizure severity without indication of tolerance. However, the marked initial effects on seizure duration and/or duration of afterdischarges recorded from the amygdala were attenuated or lost during the 2 weeks of treatment. A pronounced tolerance was also observed with respect to side-effects (sedation, ataxia, muscle relaxation) occurring during treatment. Plasma drug level determinations suggested that the tolerance was of functional nature. The data indicate that, compared to benzodiazepines, the beta-carboline ZK 93423 has no advantage in terms of anticonvulsant potency, side-effects and development of tolerance in the amygdala kindling model of epilepsy.

Amygdala↗
PubMed1986

Identification of glucuronide metabolites of T-2 toxin and diacetoxyscirpenol in the bile of isolated perfused rat liver.

Isolated rat livers were perfused with either 2 mg T-2 toxin or diacetoxyscirpenol (DAS) in a recirculating perfusion system. To identify glucuronide conjugates, equal amounts of bile samples were incubated with and without (control) a beta-glucuronidase preparation and analyzed by capillary gas liquid chromatography-chemical ionization mass spectrometry. Enzyme treatment of bile obtained from liver perfused with T-2 toxin resulted in the detection of a total of 954 micrograms HT-2 toxin (control 6 micrograms), demonstrating that excretion into the bile was mainly as glucuronide conjugates. Minor metabolites of T-2 toxin in bile were identified as 3'-hydroxy HT-2 toxin (TC-3), 3'-hydroxy-7-hydroxy HT-2 toxin (TC-6), and the glucuronide form of T-2 triol (trace amount). The glucuronide conjugates of monoacetoxyscirpenol (340 micrograms) and scirpenetriol (10 micrograms) were found in bile obtained from liver perfused with DAS, while nonconjugated metabolites were not detected. It is assumed that considerable amounts of T-2 toxin and DAS were metabolized biphasically. In phase I both trichothecenes were deacetylated, in phase II the metabolites were conjugated giving rise to the glucuronic acid adducts.

Animals↗
PubMedDate not supplied

Histamine in brain--its role in regulation of seizure susceptibility.

The influence of drugs affecting the turnover and levels of histamine in brain and histamine antagonists on pentetrazole (PTZ)-induced and electroconvulsive seizure threshold in mice was studied. A 1.5-2-fold rise in histamine brain concentration (induced by treatment with histidine or metoprine), led to a concomitant increase of PTZ-induced seizure threshold. A histidine decarboxylase inhibitor (brocresine) induced a depletion of brain histamine by about 75% for at least 8 h, the seizure threshold was, however, only reduced at 6 and 8 h after the injection. At shorter intervals, the seizure threshold was substantially increased. Treatment with centrally acting H1 antagonists (dimethindene and promethazine) in non-sedative dosage diminished the PTZ seizure threshold significantly; no changes were seen after treatment with H2 and H3 antagonists (oxmetidine, ranitidine, zolantidine or thioperamide) and a H3 agonist (R-alpha-methylhistamine). The electroconvulsive threshold was hardly influenced. It is concluded that histamine has a certain anticonvulsant effect which is mediated through H1 receptors.

Animals↗
PubMedDate not supplied

Metabolism of central neurotransmitters during development of tolerance to the anticonvulsant effect of clonazepam and of physical dependence on the drug in dogs.

In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Plasma and tissue kinetics of phenylbutazone and naproxen in dogs.

By means of tissue cages in which a sterile inflammation was induced after injection of carrageenan, plasma and tissue kinetics of two NSAIDs were followed. The first one, phenylbutazone, is characterized by a fairly short elimination half-life (3-6 hours) in dogs, whereas the other one, naproxen, has an average half-life of 67 hours in this species. After a single oral dose of 15 mg/kg, phenylbutazone reached concentrations of 13-20 micrograms/ml in the exudate from the tissue cages. Plasma peak concentrations of 49-75 micrograms/ml were reached. Due to a considerably longer half-life in the exudate than in plasma (7.3-18 hours), the concentration in the exudate exceeded that in plasma at about 20 hours. Naproxen (5 mg/kg, orally) showed a parallel decline in plasma and exudate concentrations for more than 200 hours. Continued treatment for one week with phenylbutazone (15 mg/kg, BID) resulted in plasma concentrations with wide fluctuations between doses, but the concentration in the exudate remained at a constant level. After administration of naproxen (5 mg/kg on the first day and then 2 mg/kg once daily), plasma concentrations remained at 40-50 microgram/ml and those in the exudate at 20-30 microgram/ml throughout the treatment period. Both drugs caused a considerable fall of the leukocyte count in the exudate which may be used as an indicator of the anti-inflammatory effect.

Animals↗