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Biomedical subjects

H H Frey

Publications and source records attributed to H H Frey.

At least 37 records · Page 2Linked to original sources
PubMed1988

Tolerance to the anticonvulsant effect of clorazepate and clonazepam in mice.

The rate of development of tolerance to the benzodiazepines clorazepate and clonazepam against pentetrazole-induced seizures in mice was compared. Treatment with clorazepate (0.1% solution as drinking water) for 21 days led to tolerance beginning at day 7. When mice were treated with clonazepam (0.5 mg/kg twice daily intraperitoneally), tolerance was evident already at the fourth day of treatment. Twenty-four hours after cessation of treatment the seizure threshold was significantly decreased after treatment with both drugs. Clorazepate, a prodrug of the main metabolite of diazepam, desmethyldiazepam, regards further interest for anticonvulsant therapy because of a relatively slow onset of tolerance.

Animals↗
PubMed1988

Effect of mu- and kappa-opioid agonists on the electroconvulsive seizure threshold in mice and antagonism by naloxone and MR 2266.

The effects of mu-agonists (morphine, fentanyl) and kappa-agonists (U-50,488, U-69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U-69,593. The antagonism of the anticonvulsant effect by the mu-antagonist naloxone and the kappa-antagonist MR 2266 was receptor-specific only with fentanyl and U-50,488. The other opioid agonists were either antagonized by both drugs (morphine, U-69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of mu- and kappa-stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U-50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
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

One to three day dose intervals during subchronic treatment of epileptic gerbils with gamma-vinyl GABA: anticonvulsant efficacy and alterations in regional brain GABA levels.

gamma-Vinyl GABA (GVG), an irreversible inhibitor of GABA degradation, was administered to seizure-susceptible gerbils at different dosage regimens. After acute i.p. administration, GVG dose dependently protected the animals against air blast-induced seizures with an ED50 of 50 mg/kg. After oral administration, GVG exerted similar anticonvulsant potency. However, during subchronic daily oral dosing of 100 mg/kg GVG, tolerance developed to the anticonvulsant effect of the treatment. No tolerance was observed with daily oral dosing of 50 mg/kg or every other day and every third day dosing of 100 mg/kg GVG. The disadvantage of the two latter dosage regimens was that no sufficient seizure control was obtained on the days between two administrations. Determination of GABA levels in 11 brain regions of gerbils after subchronic treatment with the different dosage regimens of GVG indicated that tolerance during treatment with daily administration of 100 mg/kg GVG could be the consequence of feedback reduction of GABA synthesis. The data suggest that the choice of suitable dosage regimens for chronic treatment is more critical with GVG than with other antiepileptic drugs, because compensatory mechanisms within the GABA system may develop when GVG-induced GABA accumulation is too marked.

Aminocaproates↗
PubMed1987

Endogenous opioids and post-ictal increase in seizure threshold in Mongolian gerbils.

In gerbils, the convulsive thresholds both for electroconvulsions and for pentetrazole-induced convulsions were increased when determined 15 min after a convulsion elicited by an air blast to the back of the animals. Contrary to a recently offered hypothesis, this sign of post-ictal depression could not be reversed by pretreatment with the morphine antagonists naloxone and naltrexone. This result speaks against a mediation of post-ictal depression by endogenous opioids.

Animals↗
PubMed1987

Induction of seizures by air blast in gerbils: stimulus duration/effect relationship.

In air blast-induced seizures in gerbils, there is a relationship between the duration of the air blast and the incidence of 'major' convulsions. An ET50 of 9.6 sec was determined in untreated controls; pretreatment with anticonvulsant drugs shifted the stimulus/effect curve to the right. This 'stimulus summation' phenomenon makes a clearly defined challenge necessary when drug effects are to be evaluated.

Animals↗
PubMed1987

Interactions between morphine-like analgesics and anticonvulsant drugs.

The effect of pretreatment with morphine-like analgesics on the anticonvulsant effect of phenytoin and phenobarbital against electroconvulsions and of phenobarbital and ethosuximide against pentetrazole-induced convulsions was studied in mice. High doses of morphine (4 mg/kg subcutaneously), fentanyl (100 micrograms/kg subcutaneously), pethidine and pentazocine (4 and 8 mg/kg subcutaneously) increased the anti-electroshock effect of phenytoin; that of phenobarbital was likewise increased by morphine (2 and 4 mg/kg), fentanyl (25-100 micrograms/kg) and pentazocine (2-8 mg/kg), whereas pethidine had no corresponding effect. There was no consistent effect of pretreatment with the analgesics studied on the anticonvulsant effects of phenobarbital and ethosuximide in the pentetrazole seizure threshold test.

Analgesics, Opioid↗
PubMed1986

Effect of opiates on the parameters of seizures in rats with full amygdaloid-kindled convulsions.

The effect on the parameters of seizures of opiates, administered in doses used clinically for analgesic effects, was studied in rats with full amygdaloid-kindled seizures. The largest dose of fentanyl studied (100 micrograms/kg) had a pronounced inhibitory effect on kindled seizures: severity of seizures, duration of seizures and duration of afterdischarge were significantly reduced to 36, 40 and 37% of controls, respectively, and the latency of seizures was significantly increased to 168% of untreated animals. The largest dose of pentazocine (16 mg/kg) also significantly inhibited the duration of seizures and duration of afterdischarge. Morphine (1-4 mg/kg) and meperidine (4-16 mg/kg) had a tendency to inhibit the duration of seizure and afterdischarges but did not significantly affect any of the measured parameters of seizures. Fentanyl, meperidine and pentazocine resulted in a lowering, whereas morphine caused a slight elevation, of the threshold for initiation of kindled seizures. The data suggest that fentanyl, in relatively small doses, may cause an inhibition of the intensity of behavioural and electrographic seizures but, paradoxically, an increased sensitivity to induction of seizures in rats with full amygdaloid-kindled seizures.

Amygdala↗
PubMed1986

Effect of morphine and morphine-like analgesics on susceptibility to seizures in mice.

In mice, the influence of small (analgesic range) doses of morphine, fentanyl, meperidine and pentazocine on the thresholds for seizures induced by electroshock and pentetrazole was studied. The antinociceptive ED50 was determined against writhing induced by acetic acid or morphine (0.43 mg/kg, s.c.), fentanyl (0.018 mg/kg, s.c.), meperidine (2.6 mg/kg, s.c.), and pentazocine (2.0 mg/kg, s.c.). The electroconvulsive threshold was significantly elevated at doses slightly greater than (fentanyl and meperidine) or about twice the antinociceptive ED50 (morphine and pentazocine). Naloxone antagonized this effect in the case of morphine and fentanyl, but not in the case of meperidine and pentazocine. The threshold for clonic convulsions induced by intravenous infusion of pentetrazole was not influenced by morphine, fentanyl and meperidine, in the dose range studied, but was slightly increased by the smaller doses (2 and 4 mg/kg) of pentazocine. The tonic phase of pentetrazole-induced convulsions was suppressed by the larger doses of fentanyl, meperidine and pentazocine, though smaller doses of pentazocine significantly reduced the threshold for the extensor phase.

Analgesics↗
PubMed1986

Physical dependence on clonazepam in dogs.

Six dogs were, under constant environmental conditions, treated for 7 weeks with clonazepam (0.5 mg/kg b.i.d. orally). Already after 1 week of treatment, slight symptoms of withdrawal could be elicited by intravenous injection of flumazepil (Ro 15-1788). When clonazepam was finally withdrawn, a self-limiting abstinence syndrome was observed in all dogs, consisting of behavioral alterations (listlessness, wet dog shakes, dorsal recumbency), tremor, a severe clonic-tonic seizure in 1 case, hyperthermia, and weight loss. The syndrome was most pronounced on days 2 and 3 after withdrawal, after 1 week all signs of physical dependence had disappeared.

Animals↗
PubMed1986

Anticonvulsant effect of morphine and morphine-like analgesics in Mongolian gerbils.

The effect of morphine, fentanyl, pethidine and pentazocine was studied in gerbils against air blast-induced seizures. Major, generalized seizures were suppressed by morphine (ED50 = 4.0 mg/kg s.c.), fentanyl (ED50 = 64 micrograms/kg s.c.), and pethidine (ED50 = 2.4 mg/kg s.c.), but not by pentazocine. The anticonvulsant effect of the drugs was lost with higher doses which partly induced spontaneous convulsions. The comparatively high potency of pethidine in this model may point to a role of other receptors (or processes) besides the mu-receptor for this drug.

Analgesics, Opioid↗
PubMed1986

Morphine-like analgesics and convulsive threshold for pentetrazole in dogs.

In dogs, the influence of morphine (1 mg/kg i.m.), fentanyl (10 and 30 micrograms/kg i.v.), meperidine (6 mg/kg i.m.), and pentazocine (3 mg/kg i.m.) on the pentetrazole seizure threshold was studied. Pentetrazole was infused i.v. at a rate of 10 mg/kg per min up to the first generalized myoclonic jerk. The analgesic treatments lowered the seizure threshold considerably in 5 out of 6 dogs, and fentanyl and pentazocine led to an increased incidence of clonic-tonic seizures after the end of the pentetrazole infusion.

Analgesics, Opioid↗
PubMed1985

Antagonism of N-methyl-D,L-aspartic acid-induced convulsions by antiepileptic drugs and other agents.

The effects of common antiepileptics, GABAmimetic drugs, excitatory amino acid antagonists as well as of clonidine, corynanthine, chlorpromazine and atropine were studied against clonic convulsions induced in mice by N-methyl-D,L-aspartic acid (NMDLA) after subcutaneous (340 mg/kg; ED97) and intravenous (105 mg/kg; ED97) administration. Among the antiepileptics studied, valproate (ED50: 340 mg/kg after subcutaneous injection of NMDLA) and diazepam (ED50: 0.78 mg/kg after intravenous and 14 mg/kg after subcutaneous injection of NMDLA) antagonized NMDLA-induced convulsions, whereas phenobarbital (up to 80 mg/kg), diphenylhydantoin (up to 50 mg/kg) and ethosuximide (500 mg/kg) were totally ineffective. Moreover, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid (but not glutamic acid diethyl ester), aminooxyacetic acid, cetyl GABA and clonidine protected strongly against the convulsant whereas progabide was only weakly active. THIP showed a higher activity against intravenous than against subcutaneous NMDLA. Baclofen and atropine even increased mortality and the remaining agents exerted no significant protective action. The data suggest that NMDLA-induced convulsions can be blocked effectively by direct antagonism of NMDLA-produced excitation, enhancement of GABA-mediated inhibition, and activation of central alpha 2-adrenoceptors. The possible efficacy of valproate in cases of epilepsy with a distinct rise in plasma excitatory amino acid levels should be carefully considered.

Animals↗
PubMed1985

Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison.

The efficacy of phenobarbital and primidone against canine epilepsy was compared in a controlled study. Thirty-five dogs showing generalized tonic-clonic seizures (grand mal), treated for a minimum of 6 months, were included in the study; fifteen of these were treated with phenobarbital, the other twenty with primidone. Both drugs were dosed according to the clinical requirement; the daily doses ranged from 5-17 mg/kg phenobarbital and from 17-70 mg/kg primidone. The plasma concentrations of phenobarbital, or of primidone and its metabolites phenobarbital and phenylethylmalondiamide (PEMA), were routinely monitored. Complete control of tonic-clonic seizures for 6 months, at least, was attained in six out of fifteen dogs of the phenobarbital group, and in five out of twenty dogs in the primidone group. A further six dogs on phenobarbital, and seven dogs on primidone, were classified as 'improved', i.e. the rate of seizures was reduced by at least 50%. The rest of the dogs were not improved by the treatment. The difference between the efficacy of phenobarbital and primidone was not significant, but primidone gave rise to signs of liver toxicity in fourteen out of twenty dogs, as indicated by considerable elevations of liver enzyme values (alanine transferase, glutamate dehydrogenase, alkaline phosphatase). Phenobarbital is, therefore, regarded as the drug of first choice for the treatment of canine epilepsy.

Animals↗