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H H Frey

Publications and source records attributed to H H Frey.

At least 55 records · Page 3Linked to original sources
PubMed1985

[Pharmacologic principles in the treatment of epilepsy in the dog and cat].

The pharmacokinetics of antiepileptic drugs used for the treatment of human epilepsies is reviewed for dogs and cats. In dogs, especially phenobarbital and primidone must be regarded as useful drugs for chronic treatment on account of their elimination rate and bioavailability. Phenytoin, carbamazepine, valproic acid and benzodiazepines are eliminated so rapidly that a therapeutic value cannot be expected. In cats, phenytoin, phenobarbital, valproic acid and diazepam must be regarded as suited for chronic treatment, but there is a definite lack of clinical experience. Phenobarbital and primidone are useful for treatment of clonic-tonic generalized seizures (grand mal) in dogs. The effect of primidone depends mostly on its metabolite phenobarbital. Since primidone, given in high dosage for longer periods of time, gives rise to liver damage, phenobarbital is regarded as the drug of first choice. A status epilepticus may be treated by i.v. injection of diazepam, clonazepam, phenytoin or lidocaine. In cats with grand mal, treatment with daily doses of about 1 mg/kg diazepam may be tried. It proved effective for longer time periods without development of tolerance. There is no reliable clinical experience with other drugs in this species.

Animals↗
PubMed1985

Evaluation of epileptic dogs as an animal model of human epilepsy.

In 126 epileptic dogs with spontaneously recurring generalized tonic-clonic (grand mal) seizures, epidemiological aspects and the efficacy of chronic oral treatment with common antiepileptic drugs were studied. Furthermore, the pharmacokinetics of antiepileptic drugs in dogs was compared with the values known for man. As in man, idiopathic epilepsy appeared to be more common than symptomatic epilepsy in dogs. There was a preponderance of male vs. female animals. When the breeds of the epileptic dogs were compared to the distribution of breeds in the hospital population, breed-related differences in the prevalence of epilepsy were found. The highest prevalence was seen in Cocker spaniels, Miniature schnauzers, Collies and Bassets. The total prevalence of dogs with epilepsy was 0.55%. Comparison of pharmacokinetics of antiepileptic drugs showed that some drugs were suited for maintenance therapy in dogs (primidone, phenobarbital, ethosuximide, trimethadione) whereas others appeared not to be ideally suited because of their short half-lives (phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, nitrazepam). This was confirmed by the evaluation of antiepileptic drug efficacy in epileptic dogs. 46 dogs were treated with primidone at daily doses of 14-104 mg/kg for 6-60 months. During medication with primidone, effective plasma levels of its metabolite phenobarbital could be maintained. Complete control of seizures or a reduction of seizure frequency by at least 75% was achieved in 39% of the dogs at phenobarbital concentrations of 5-49 micrograms/ml. Similar figures were obtained during chronic treatment with phenobarbital at daily doses of 2.5-13 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence.

Dogs were treated with clonazepam, 0.5 mg/kg orally, b.i.d., for 3-6 weeks. The development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold by infusion of pentetrazole, 10 min after i.v. injection of 0.1 mg/kg clonazepam. In all 6 dogs tolerance was apparent after 1-2 weeks of treatment; in 1 dog the anticonvulsant effect had been totally lost after 3 weeks of treatment. Tolerance is regarded to be "functional" since the elimination half-life of clonazepam increased considerably with the duration of the treatment. One day after withdrawal of clonazepam the convulsive threshold had fallen below the control value in all dogs, but 1 week later it had recovered to the control level. Other signs of physical dependence after withdrawal were hyperthermia in 2 dogs as well as anorexia with weight loss in 5 out of the 6 dogs. In anesthetized dogs, relaxed by suxamethonium and ventilated, the effect of repeated injections of clonazepam on the EEG spiking activity maintained by an infusion of pentetrazole was studied; there was no indication for the development of acute tolerance.

Animals↗
PubMed1984

Development of tolerance to the anticonvulsant effect of diazepam in dogs.

In dogs the development of tolerance to the anticonvulsant effect of diazepam was followed by weekly determinations of the convulsive threshold for pentetrazole, 10-15 min after intravenous (i.v.) injection of 0.25 or 0.5 mg/kg diazepam. As soon as after 1 week of oral treatment with diazepam, 0.25 or 0.5 mg/kg three times daily (t.i.d.), the pentetrazole threshold showed a decline or even a fall to the control level in spite of unaltered or rising concentrations of diazepam and its active metabolites. Tolerance also developed when the dogs were treated with chlorazepate, 2 mg/kg t.i.d., between the weekly diazepam injections for threshold determination. The results favor a functional type of tolerance since there was no indication of a more rapid inactivation of diazepam. Treatment with desmethyldiazepam (2 mg/kg i.v. for threshold determination and oral treatment with the desmethyldiazepam precursor chlorazepate, 2 mg/kg t.i.d.) did not produce tolerance. In further experiments in dogs anesthetized, relaxed with suxamethonium and ventilated, a spike-wave activity in the EEG was induced and maintained by an injection and subsequent infusion of pentetrazole. Out of 6 dogs, receiving 4-5 i.v. injections of 0.25-0.5 mg/kg diazepam, 2 showed the phenomenon of acute tolerance, i.e. the effect of the drug on the spiking activity in the EEG became less from one injection to the next, and thus paralleled a situation which may be observed during treatment of clinical status epilepticus. No acute tolerance was observed in corresponding experiments with desmethyldiazepam.

Animals↗
PubMed1984

Kinetics of penetration of common antiepileptic drugs into cerebrospinal fluid.

The rate of entry of common antiepileptic drugs and some active metabolites into cerebrospinal fluid (CSF) was studied in anesthetized dogs from which blood and CSF samples were withdrawn at short intervals. Diazepam, its active metabolites desmethyldiazepam and oxazepam, clonazepam, and ethosuximide entered the CSF very rapidly with mean half-times to equilibrium between 3 and 7 min. Valproic acid, phenytoin, phenobarbital, and carbamazepine went in more slowly, but mean penetration half-times were still only 12-18 min. Primidone, its metabolite phenylethylmalondiamide , and the active metabolite of carbamazepine, i.e., carbamazepine-10,11-epoxide, passed into CSF considerably slower, with half-times of 40-50 min. In order to evaluate to what extent physicochemical properties determine the penetration rates of antiepileptic drugs into the CSF, three factors were examined: the degree of ionization of the respective drugs at physiologic pH, the plasma protein binding, and the lipid-solubility, measured by organic solvent/buffer distribution ratios. Ionization was not considered as a rate-limiting factor, because all compounds except valproic acid were highly non-ionized at pH 7.4. No correlation was found between penetration rates and plasma protein binding, but at equilibrium, the ratio between CSF and total plasma concentrations was almost equal to the free fraction of drug in plasma. A significant correlation was found between penetration rate and the benzene/buffer distribution ratio of antiepileptic drugs, which indicates that the lipid-solubility, rather than the protein binding or the degree of ionization, plays the major role in determining the differences in rate of entry of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Anticonvulsant effect of primidone in the gerbil. Time course and significance of the active metabolites.

The anticonvulsant effect of primidone was determined in gerbils, in which seizures were elicited by a blast of compressed air, over the time range of 30 min to 18 h after oral administration. ED50s remained fairly constant from 1 to 12 h after administration: 46-73 mumol/kg with the minimal value at 6 h. Of the metabolites, phenobarbital was maximally effective at 2 h after administration (ED50 35 mumol/kg), whereas phenylethylmalondiamide (PEMA) only had a weak anticonvulsant effect (ED50 1.55 mmol/kg at 2 h). By determination of primidone and its active metabolites in plasma and brain at 1, 4 and 12 h after administration of the respective ED50s, it could be shown that unchanged primidone is mostly responsible for the anticonvulsant effect of the first hours, but, at 12 h, only phenobarbital could be detected in both tissues. PEMA could not be detected in brain. From the effective brain concentrations at different times it could be calculated that primidone and phenobarbital have the same anticonvulsant potency on a molar base in the gerbil. The concentrations necessary to control seizures in this model were considerably lower than those needed to suppress convulsions in maximal seizure models in mice and rats.

Administration, Oral↗
PubMed1984

Evaluation of anticonvulsant drugs in gerbils with reflex epilepsy.

In more than 98% of randomly bred gerbils epileptic seizures could be evoked by blowing at the animals with compressed air (5 bars for 10 s). In contrast, only few animals showed seizures in response to environmental stimuli (e.g., new cage) and handling. Thus, administration of drugs was possible without precipitating seizures. The severity of the seizures was rated on a seven-point scale. Seizure severity increased with age and reached its maximum at about 7 months. Comparison of pharmacokinetics of common antiepileptic drugs showed that these drugs, except phenobarbital, were rapidly eliminated by the gerbil which, in this respect, resembled the mouse. For determination of anticonvulsant ED50S of antiepileptic drugs in gerbils there was differentiated between "minor" seizures (grade 1-2; myoclonic seizures) and "major" seizures (grade 3-5; generalized clonic-tonic seizures). Phenobarbital, phenytoin and carbamazepine were more potent against major seizures than against minor seizures, whereas the reverse situation was obtained with diazepam, valproic acid and ethosuximide. The relative activity of the different antiepileptic drugs against minor and major seizures in gerbils corresponded to the respective activity in traditional mouse models of petit mal and grand mal epilepsy. In further experiments, a series of GABAmimetic drugs was tested, namely, compounds that selectively increase gamma-aminobutyric acid (GABA)-mediated neuronal inhibition in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Pharmacokinetics of clonazepam in the dog.

After i.v. administration of 0.2 mg/kg clonazepam to dogs, plasma concentrations followed partly a biexponential and partly a monoexponential decline, the terminal elimination half-life (t0.5 beta or t0.5) being 1.4 +/- 0.3 hr. Over the dose range from 0.1 to 0.5 mg/kg the elimination rate was dose-dependent. At the highest dose level, one dog showed signs of a saturation kinetics. After oral administration absorption was rapid, but bioavailability poor and highly variable (20-60%). In spite of the high elimination rate in the single dose studies, clonazepam plasma concentrations in the range known as "therapeutic" in man could be maintained in subacute studies (1 week) by dosing 0.5 mg/kg b.i.d. or t.i.d. This is most likely explained by a saturation of metabolic inactivation and makes the dog a useful model for man when the drug is given continuously. Protein binding averaged 82% and is thus similar to man. Clonazepam passed the blood/CSF barrier rapidly (P = 0.217 min-1) so that steady state conditions were reached within 10-20 min.

Administration, Oral↗
PubMed1983

Anticonvulsant potency of common antiepileptic drugs in the gerbil.

In gerbils, 'minor' (myoclonic) and 'major' (clonic-tonic) seizures were induced by blowing at the animals with compressed air. The anticonvulsant ED50 of the following drugs was determined after oral administration against both types of seizures: phenytoin, phenobarbital, carbamazepine, sodium valproate, ethosuximide, and diazepam. Valproate, ethosuximide, and diazepam were most potent against 'minor' seizures which could not or only partially be suppressed by phenytoin or carbamazepine, respectively. The 'grand mal' drugs phenytoin, phenobarbital, and carbamazepine were, on the other hand, more potent against 'major' than against 'minor' seizures. When phenobarbital was administered for several days, a strong induction of hepatic microsomal enzymes occurred.

Animals↗
PubMed1983

High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy.

Seven GABAmimetic drugs, namely cetyl gamma-aminobutyric acid (cetyl GABA), 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol, progabide, aminooxyacetic acid, alpha-acetylenic GABA, (-)-nipecotic acid ethyl ester and (+/-)-cis-4-hydroxynipecotic acid methyl ester, were tested for their potency to block "major" (generalized clonic-tonic) seizures in gerbils, induced by blowing at the animals with compressed air. Valproic acid was included as a reference standard. All drugs proved able to protect gerbils from induced seizures. Most effective were 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (ED50, 1.3 mg/kg i.p.), aminooxyacetic acid (0.9), cetyl GABA (4.5) and gamma-acetylenic GABA (2.1). A comparison with anticonvulsant ED50 values of common antiepileptics in the gerbil showed that these four GABAmimetics were clearly more potent than phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid and were only surpassed in potency by diazepam. Furthermore, most GABAmimetics proved strikingly more active in the gerbil compared with the classical electroshock and pentylenetetrazol seizure models in mice. After administration of gamma-acetylenic GABA, GABA increases in the brain of only about 40% were found sufficient to reach almost complete seizure protection in gerbils. The present data are compatible with the possibility that the GABA system is critically involved in the seizure-prone state in the gerbil.

Alkynes↗
PubMed1983

Antagonism of the 5-HT-induced bronchoconstriction in the cat.

In cats in which bronchoconstriction was induced and maintained by infusion of 5-HT, the bronchodilator effects of ketanserin, a related compound, cyproheptadine, clenbuterol and aminophylline were compared. The novel 5-HT2 antagonists ketanserin and R50970 were active in doses of about 10 nmol/kg, cyproheptadine was about 5 times less potent, but had a longer duration of action. Clenbuterol and aminophylline were only partially effective against 5-HT-induced bronchoconstriction. There was no reliable effect of the 5-HT antagonists against carbachol-induced bronchoconstriction.

Animals↗
PubMed1982

Treatment of canine epilepsy with primidone.

Forty-seven dogs with a history of generalized recurrent seizures were treated with primidone at a daily oral dosage of 13 to 100 mg/kg of body weight, divided into 2 to 3 doses. During treatment, plasma concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide, were determined at irregular intervals. Of the 30 dogs that finally could be evaluated, 20 were brought to excellent or good control of their seizures by daily primidone dosages ranging from 13 to 17 mg/kg and at plasma phenobarbital concentrations of 6 to 37 micrograms/ml. Of the other 10 dogs, 5 improved to a minor extent and 5 did not improve at all. It was concluded that treatment of seizures should start with a daily dosage of 10 to 15 mg/kg, with the dosage being increased to about 35 mg/kg within a few weeks. For dogs in which the seizures are not controlled by this dosage, a further increase should be tried until a plasma phenobarbital concentration of 30 to 40 micrograms/ml is reached or until signs of drug toxicosis develop. Monitoring of plasma phenobarbital concentrations is sufficient for the control of treatment with primidone.

Administration, Oral↗
PubMed1982

Transport of GABA at the blood-CSF interface.

The entry of GABA into cerebrospinal fluid (CSF) was studied in dogs anesthetized with pentobarbital and relaxed with suxamethonium. GABA was administered intravenously as a priming dose and subsequent maintenance infusion to compensate for the rapid elimination of the amino acid. Steady state concentrations of GABA in CSF were reached between 10 and 60 min after injection, the rate of entry tending to decrease with increasing plasma levels. During steady state conditions CSF concentrations showed great interindividual differences and varied between 0.03 and 5.1% of those in plasma. Probenecid and sodium valproate considerably enhanced the CSF/plasma concentration ratio of GABA. When GABA was directly injected into the liquor space, probenecid slowed down the elimination of GABA from CSF. The results suggest a transport of GABA into and out of CSF, the outward transport being inhibited by probenecid and sodium valproate.

Animals↗
PubMed1982

Anticonvulsant potency of unmetabolized diazepam.

The anticonvulsant potencies of diazepam and its metabolites desmethyldiazepam and oxazepam against convulsions elicited by intravenous injection of pentetrazole were determined in mice at times from 1-30 min after intravenous administration. Diazepam had its maximal potency (ED50 0.53 mumol/kg) at 1 min when only traces of desmethyldiazepam could be detected in plasma and brain. During the next 30 min, the drug was rapidly transformed to desmethyldiazepam and oxazepam, and its anticonvulsant ED50 rose by a factor of about 4. From the concentrations in brain at 50% protection, a potency ratio of 1.0:0.37:0.33 could be calculated for diazepam, desmethyldiazepam and oxazepam.

Animals↗