Phytochemical reinvestigation of Xysmalobium undulatum roots (Uzara).

Four major cardenolide glycosides of Xysmalobium undulatum (L.) R. Br. roots (Uzara) have been isolated for the first time in pure form. The structures were elucidated by spectral analyses and determined as sophorosides and their 17-epimers, respectively. Thus, the structural elucidation of uzarin and xysmalorin, the two main glycosides, has been completed. The corresponding H-17beta isomers, allouzarin and alloxysmalorin, were characterized as genuine compounds.

Felbamate and meprobamate: a comparison of their anticonvulsant properties.

The anticonvulsant effect of felbamate and meprobamate were compared in a series of models for seizure activity and regarding their neurotoxic action. In the MES test, felbamate was active below neurotoxic doses. Meprobamate had an ED50 in the range of neurotoxic doses. The s.c. PTZ test was influenced by meprobamate in a fairly low dosage (ED50 66 mg/kg), but for felbamate no clearly dose-related effect could be shown up to 150 mg/kg. Reflex epilepsy in gerbils was stronger suppressed by meprobamate (ED50 34 mg/kg) than by felbamate (ED50 63 mg/kg). In amygdala kindled rats, meprobamate proved to be the most active compound, both regarding treatment of fully kindled rats, development of kindling and independent discharges from a mirror focus (secondary epileptogenesis), which were fully suppressed by oral treatment with 80 mg/kg for 30 days. Both drugs were weakly effective in a model for absence epilepsy in rats. The unexpectedly high activity of meprobamate justifies a second look at the anticonvulsant properties of the drug, especially since it was extensively used as an anxiolytic drug in the past with few obvious serious side effects.

[The tissue cage in dogs--a pharmacologic model for the representation of plasma and tissue kinetics]. / Die Gewebekammer ("tissue cage") beim Hund--ein pharmakologisches Modell zur Darstellung von Plasma- und Gewebekinetik.

Determination of pharmacokinetic data from plasma often is not sufficient in order to predict or to explain the clinical efficacy of drugs, e.g., in non steroidal antiinflammatory drugs (NSAID) with short elimination half lives in plasma a discrepancy appears between elimination half life and clinical effect. We have studied the tissue kinetics of a drug having a long elimination half life (naproxen) in comparison with phenylbutazone and flunixin, having a short elimination half life in dogs after oral application. Tissue fluid was obtained by using so called "tissue cages" implanted laterally in the neck. An inflammatory response was produced by injecting 1-2 ml of 2% carrageenan into the chamber. The drug concentrations were determined throughout the experiments both in plasma and tissue fluid. Naproxen concentrations (elimination half life of about 72 h in dogs) achieved equilibrium between tissue fluid and plasma concentration. In the case of phenylbutazone, concentration in tissue fluid declined with a definitely longer half life than in plasma and exceeded plasma concentrations after some hours. Flunixin concentrations in plasma and exudate attained equilibrium after 2-5 h. Of clinical importance is the finding that after this time flunixin accumulated in inflammatory exudate and the concentration in exudate exceeded that in plasma two to ten times, then declined with an almost identical half-life. The number of leukocytes in exudate as a measure of inflammation was reduced during 2 days after phenylbutazone, 3-4 days after flunixin and 5-7 days after naproxen. This allows therapy with a lower dosage than calculated on the basis of plasma concentrations in the case of phenylbutazone and flunixin, possibly also with other NSAIDs having a short plasma half life.

Interaction of mu-opioid antagonistic drugs with antiepileptics.

Interactions of the mu-opioid receptor antagonists, naloxone (0.3 and 1 mg/kg), cyprodime and clocinnamox (3 and 10 mg/kg for both drugs) with phenytoin (7 mg/kg), phenobarbital (7 mg/kg), carbamazepine (10 mg/kg) and valproic acid (130 mg/kg) were investigated using the electroconvulsive threshold in mice as a model in order to elucidate a possible role of mu-receptor mediated reactions in the mechanism of action of antiepileptic drugs. All 3 mu-antagonists are devoid of an effect on the electroconvulsive threshold. Pretreatment with the mu-antagonists resulted partly in an increase of anticonvulsant action, partly in a decrease, and partly the pretreatment had no effect on the electroconvulsive threshold. The anticonvulsant effect of phenytoin was antagonized dose-dependently by naloxone, that of phenobarbital by the dose of 10 mg/kg of clocinnamox. A common denominator of the mu-antagonistic interactions with anticonvulsants cannot be found and the effects observed are therefore considered as "unspecific".

Pharmacokinetics of oxcarbazepine in the dog.

Oxcarbazepine has been proven to be a promising new antiepileptic drug for the treatment of human epilepsy. Unlike carbamazepine, it is not oxidatively metabolized in humans, and therefore causes almost no induction of hepatic enzymes at clinically effective dosages. Though showing similar efficacy to carbamazepine, it has been reported to cause significantly fewer side-effects. It was the purpose of the present study to determine whether oxcarbazepine might be suitable for the treatment of canine epilepsy. In single-dose experiments, 40 mg/kg oxcarbazepine as a suspension was administered to seven dogs via gastric tube. Plasma concentrations reached peak concentrations of 2.4-8.8 micrograms/mliter at about 1.5 h and declined with an elimination half-life of approximately 4 h. The corresponding concentrations of its metabolite, 10,11-dihydro-10-hydroxycarbamazepine, did not exceed 1 micrograms/mliter. During continued treatment for 8 days, doses of 30 and 50 mg/kg were administered orally in capsules to two dogs three times a day. Plasma concentrations showed a pronounced decline from day 3, and the terminal half-life decreased to 2 h and 1 h. This is considered to be the result of oxcarbazepine inducing its own metabolism. The data reveal that oxcarbazepine, compared with former results with carbamazepine, offers no advantage for the treatment of epileptic dogs.

Stimulation-dependent effect of antiepileptic drugs in amygdala kindled rats on both seizure score and duration of afterdischarges.

The ED50 for abolition of generalized seizures and reduction of afterdischarges to 20% of the control duration was determined in kindled rats for phenobarbital, carbamazepine, phenytoin, valproic acid, clonazepam, and diazepam, both at a stimulation intensity of 200 microA and at 10 microA above the threshold for generalized seizures (threshold stimulation). Phenobarbital, carbamazepine, and valproic acid acted in a stimulus-dependent manner, i.e. the ED50 was higher at 200 microA than at threshold stimulation. Phenytoin had the same ED50 irrespective of the stimulus intensity. Generalized seizures and afterdischarges were suppressed by the same doses of the drugs mentioned. The benzodiazepines, clonazepam and diazepam, had a differential effect: they suppressed generalized seizures at low doses, whereas afterdischarges were only suppressed incompletely at relatively high doses. The ED50 of both benzodiazepines was independent of stimulus intensity. In order to avoid erroneous conclusions a standardization of kindling parameters, especially stimulation intensity, is proposed when drug effects are to be compared.

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.

Active transport of benzylpenicillin across the blood-milk barrier.

Passage of benzylpenicillin across the mammary gland epithelium was studied both after systemic administration of benzylpenicillin in four goats and after intramammary infusion in three goats and two cows. The results after benzylpenicillin administration alone were compared with the results after combined administration of benzylpenicillin and probenecid. The studies on passage of benzylpenicillin through the blood-milk barrier showed, when milk to plasma ultrafiltrate ratios of benzylpenicillin were plotted versus time for each half of the udders, that active transport takes place from blood to milk during steady-state plasma concentrations. Active transport was demonstrated by inhibition with probenecid: (1) The entry of benzylpenicillin into milk was slowed down under the influence of probenecid. The AUC (area under the curve)-values during the first 30 min. were reduced by 66 +/- 9% compared with the AUC-values found without coadministration of probenecid. (2) In the presence of probenecid and during equilibrium between blood and milk concentrations, benzylpenicillin reached concentration ratios in the ultrafiltrates of milk and plasma which corresponded to those expected for diffusion alone. Without probenecid these ultrafiltrate concentration ratios were more than two times higher indicating an active transport of benzylpenicillin from blood to milk. After intramammary infusion of benzylpenicillin, active transport was demonstrated from milk into blood. The absorption rate for benzylpenicillin from the mammary gland was reduced by probenecid, as measured by the ratio of benzylpenicillin to urea absorption half-life, which was increased by 40-50% in the presence of probenecid.

Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150-170 kD (bigbig) prolactin.

We have studied in vivo induction of serum prolactin (PRL) levels in four females and one male, and regulation of PRL in the menstrual cycle in three females all with hyperprolactinemia with large amounts (72-92%) of bigbig PRL (MW 150-170 kD). Metoclopramide (MTC) iv induced a 4-29-fold increase in little PRL (25 kD PRL) at 30 min, while the increase in 150-170 kD PRL was 1.1-2.2-fold. The maximal response in 150-170 kD PRL was seen after 2-6 h, and the decrease after the maximal PRL values for 150-170 kD PRL was delayed compared to the decrease in 25 kD PRL. The different kinetics for 25 kD PRL and 150-170 kD PRL was responsible for the prolonged increase in total PRL seen in the subjects with large amounts of 150-170 kD PRL compared to the controls. The percentage of 150-170 kD PRL decreased to 29-60% at 30 min and returned to unstimulated values after 6-24 h. In contrast, prolonged stimulation of PRL secretion, as in the luteal phase, did not change the percentage of 150-170 kD PRL. In a male subject secreting large amounts of 150-170 kD PRL the increase in PRL after MTC was less, while the temporal changes in the 25 kD PRL levels were almost the same as in the females.

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.

Effect of psychotropic agents on a model of absence epilepsy in rats.

The effect of different groups of psychotropic agents on the spontaneous absence-like paroxysms in the ECoG of rats was studied in order to evaluate the specificity of the model for antiabsence drugs. Morphine-like analgesics increased the number of paroxysms, whereas this was depressed or the discharges were completely abolished by the following drugs: d-amphetamine, tricyclic antidepressants, centrally acting anticholinergics and L-DOPA, NMDA antagonists and memantine. Since the latter drugs have been reported to be effective in petit mal epilepsy, or the NMDA antagonists and memantine, have a potential anticonvulsant effect, the results are in favour of the usefulness of the model for antiabsence drugs.

[The use of narcotics in veterinary practice and hospitals in the Federal Republic of Germany including Berlin-West]. / Verwendung von Betäubungsmitteln in tierärztlichen Praxen und Kliniken im Gebiet der Bundesrepublik Deutschland einschliesslich Berlin-West.

An inquiry on the use of narcotics was carried through among practising veterinary surgeons and in animal hospitals. Of 5907 questionnaires sent out 2725 (46.1%) were returned; 86.3% of these stated the use of narcotics. There was a negative correlation between the use of narcotics and the age of the veterinary surgeons. Levomethadone, pentobarbital and fentanyl were used most often, the other narcotics were only mentioned in 1-2% of the questionnaires or not at all. Narcotics were primarily ordered for the veterinary "house pharmacy" and for use in practice, prescriptions for the individual patient being the exception.

Monoamine turnover in the brain of mice during development of tolerance to the anticonvulsant effect of clonazepam.

Mice were treated for 14 days with clonazepam, 0.5 mg/kg i.p. twice daily, during which time partial tolerance to the anticonvulsant effect against pentetrazole developed. The development of tolerance was paralleled by a reduced turnover of noradrenaline in the whole brain, and of dopamine in the midbrain. The turnover of 5-HT was increased during the first week of treatment, but decreased thereafter. These changes in monoamine turnover, which are thought to be GABA-mediated, are consistent with an increased seizure susceptibility, and may contribute to the development of tolerance to the anticonvulsant effect of benzodiazepines.

Importance of histamine for seizure susceptibility.

The influence of drugs affecting the turnover of histamine in brain and histamine antagonists on pentetrazole seizure threshold in mice was studied. A rise in histamine brain concentration as well as treatment with central acting H1-, but not H2- and H3-antagonists led to an increase of the convulsive threshold. It is therefore concluded that histamine has a certain anticonvulsant effect which is mediated through H1-receptors.

Effects of solvents and detergents on the contractions of isolated smooth muscle preparations.

In testing poorly soluble substances in-vitro on isolated organs, organic solvents and solubilizers are used to increase water-solubility. To facilitate selection of appropriate substances, the effects of eleven of these chemicals have been studied in the following isolated smooth muscle preparations: guinea-pig ileum stimulated by carbachol, histamine, 5-HT or single field stimuli; rat fundus stimulated by 5-HT; and mouse vas deferens stimulated by noradrenaline or trains of field stimuli. Nine solvents (acetone, diethyleneglycol monoethylether, dimethyl sulphoxide, ethanol, glycerol, methanol, polyethylene glycol 400, 1,2-propanediol, Tetraglycol (tetrahydrofurfurylalcohol polyethyleneglycolether)) and two detergents (Triton-X 100 and Tween 80) were examined. The vas deferens proved to be most resistant, whereas rat fundus and guinea-pig ileum were more sensitive to the effects of solvent when present from 1 to 10 g L-1. Most solvents caused non-specific, concentration-dependent reversible inhibition of contractions. Dimethyl sulphoxide in high concentrations increased the contractile responses of guinea-pig ileum stimulated by 5-HT and in both experiments with electrical stimulation. Polyethylene glycol 400 augmented the response of mouse vas deferens to electrical stimulation. Overall, 1,2-propylene glycol and polyethylene glycol 400 had the least effect and can be used in a concentration of 3 g L-1, and in qualitative studies even up to 10 g L-1. Glycerol, both monohydric alcohols and dimethyl sulphoxide produced more intense effects and should not exceed concentrations of 1-3 g L-1. Stronger inhibition was caused by diethyleneglycol monoethylether, acetone and Tetraglycol, and the bath concentrations of these substances should not exceed 0.5-1g L-1. Of the detergents only Tween 80 is suitable as a solubilizer in smooth muscle preparations in-vitro, forming micelles at 10 mg L-1 a concentration tolerated by isolated organs in this study.

Pharmacokinetics, anticonvulsant efficacy and adverse effects of the beta-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), a novel beta-carboline with high affinity for central benzodiazepine (BZ) receptors, has been shown recently to be a potent anxiolytic and anticonvulsant in animal models whereas lacking ataxia-producing effects, a profile typical for a partial agonist at BZ receptors. In the present study abecarnil was tested in dogs after acute and chronic administration. Pharmacokinetic studies showed that abecarnil was eliminated rapidly after i.v. or p.o. administration, but elimination was delayed substantially after s.c. injection. After i.v. injection, the drug penetrated rapidly into the cerebrospinal fluid, but maximum concentrations reached in cerebrospinal fluid were only 6 to 8% of those in plasma. Anticonvulsant potency of abecarnil in dogs was studied by means of seizures induced by i.v. infusion of pentylenetetrazol. After i.v. administration of single doses, abecarnil was about half as potent as diazepam, dose-dependently increasing the pentylenetetrazol threshold by doses of 0.1-1 mg/kg. In contrast to diazepam, most dogs injected with abecarnil at anticonvulsant doses showed no ataxia. During chronic s.c. administration of abecarnil for 6 weeks, the anticonvulsant efficacy of the drug increased markedly during the first week(s) of treatment, possibly indicating drug accumulation in the brain. During the subsequent weeks of treatment, there was a slight reduction in anticonvulsant potency. No withdrawal symptoms were observed after cessation of the 6-week administration period. Furthermore, injection of the BZ antagonist Ro 15-1788 (flumazenil), 1 mg/kg i.v., after 5 weeks of treatment did not precipitate withdrawal symptoms except slight tremor in two of seven dogs studied.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diuretics]. / Diuretika.

The pharmacology of the commonly used diuretic agents is reviewed, with special reference to the "high ceiling" diuretics and the benzothiadiazines, which are widely used in veterinary medicine. The different clinical indications in veterinary medicine are discussed.

Apomorphine-induced emesis in the dog--routes of administration, efficacy and synergism by naloxone.

Apomorphine proved to be more effective as an emetic in dogs after s.c. administration than after i.m. injection with doses of 0.04 and 0.1 mg/kg. This effect is explained by an anti-emetic effect mediated by mu-receptors in the vomiting centre in the brain, which, in contrast to the chemoreceptor trigger zone, is within the blood-brain barrier. A certain delay between the stimulation of D2-receptors in the chemoreceptor trigger zone (causing emesis) and mu-receptors in the vomiting centre (producing anti-emesis) therefore results, leading to a self-limiting emesis. Blockade of the mu-receptors by naloxone increased and prolonged the effect of apomorphine. A relatively narrow range of apomorphine concentrations on s.c. administration is then effective to stimulate the chemoreceptor trigger zone, but can hardly inhibit the vomiting centre, and must therefore be considered the most suitable route for administration of apomorphine.

Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy.

Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 micrograms/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 micrograms/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model.

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.