Dogs were treated with clorazepate, which is known to be completely metabolized to desmethyldiazepam. 2 mg/kg t.i.d. were given orally for 5-6 weeks, a dose regimen providing plasma concentrations of desmethyldiazepam in the range known to be therapeutic in man. The rate of development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold for pentetrazole before, during and after cessation of treatment. The development of tolerance was not as clear and pronounced as that found after treatment with diazepam and clonazepam in earlier studies with dogs. The seizure threshold was elevated by a factor of 1.2-3.5 during the first 2 weeks of treatment; during the following weeks, tolerance developed in only 2 out of 6 dogs (decline of the pentetrazole threshold in spite of rising or unchanged plasma concentrations). 36 h after withdrawal of clorazepate, the convulsive threshold had fallen below the control values in all dogs, but 1 week later it had returned to the control level. One day after cessation of treatment, 2 out of 6 dogs showed withdrawal seizures, which, in 1 case, were lethal. This shows that severe withdrawal symptoms, even lethal seizures, may appear after abrupt discontinuation of chronic clorazepate treatment, in spite of the relatively low tolerance liability of clorazepate.

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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.

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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

Anticonvulsant drugs used in the treatment of epilepsy.

The pharmacology of anticonvulsant drugs is reviewed with emphasis placed on the treatment of canine and feline epilepsy. Due to pharmacokinetic reasons, only phenobarbital, primidone, and, with certain limitations, the benzodiazepines can be used in dogs. Bromides may be given additionally in cases that cannot be controlled with phenobarbital or promidone therapy. In cats, diazepam has been shown to be very useful because no tolerance develops to the antiepileptic effect in this species.

Animals↗

PubMedDate not supplied

Tolerance to antiepileptic drug effects. Experimental evidence and clinical significance.

The development of tolerance to the anticonvulsant effect of drugs has been demonstrated in animal experiments for most antiepileptic drugs. This evidence is reviewed, including the methodological approach and the differentiation into 'metabolic' and 'functional' tolerance. Clinical evidence of the development to antiepileptic drug effects is equivocal: The existence of tolerance is generally accepted for the benzodiazepines which often lose their antiepileptic effect during prolonged treatment. For this group of drugs tolerance is a major clinical problem. With other antiepileptic drugs some degree of tolerance may develop, but this can hardly be recognized as such under clinical conditions, and is thus not considered to be of major importance for treatment of epilepsy.

Animals↗

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↗