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Biomedical subjects

W Löscher

Publications and source records attributed to W Löscher.

At least 19 recordsLinked to original sources
PubMed1992

Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.

2-Amino-5-phosphonovalerate↗
PubMed1992

Increase of serotonin in plasma during onset of halothane-induced malignant hyperthermia in pigs.

The levels of serotonin (5-HT) were determined in platelet-free and platelet-rich plasma before and during the onset of halothane-induced malignant hyperthermia (MH) in genetically MH-susceptible pigs. During MH onset, the free (i.e. physiologically active) levels of 5-HT in plasma rose concomitantly with the increases in muscle tone, body temperature, venous pCO2 and plasma lactate. Since pharmacological stimulation of 5-HT2 receptors has recently been shown to trigger MH in susceptible pigs, the finding of increased 5-HT plasma levels during onset of halothane-induced MH may indicate that 5-HT is involved in the mechanisms by which volatile anesthetics trigger this myopathic syndrome.

Animals↗
PubMed1992

Pharmacological, toxicological and neurochemical effects of delta 2(E)-valproate in animals.

The E isomer of 2-ene-valproic acid (delta 2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on delta 2(E)-VPA and VPA indicate that delta 2(E)-VPA may be a useful antiepileptic drug itself. delta 2(E)-VPA has the same wide spectrum of anticonvulsant activity as VPA with a somewhat higher anticonvulsant potency in rodent and dog models of different seizure types. As VPA, delta 2(E)-VPA increases presynaptic gamma-aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. delta 2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses delta 2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, delta 2(E)-VPA does not induce teratogenic effects, whereas VPA is teratogenic in these models. Pilot rat studies on liver toxicity of VPA and VPA metabolites suggest that delta 2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, delta 2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy.

Abnormalities, Drug-Induced↗
PubMed1992

The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems.

The non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), induces in rats a characteristic behavioural syndrome with ataxia, stereotypies and hyperlocomotion. At least part of this behavioural syndrome is thought to be related to interactions between glutamatergic and dopaminergic neurotransmission. Based on recent biochemical evidence that serotonin (5-HT) might also be involved in the effects of MK-801 several 5-HT receptor ligands were tested for effects on MK-801-induced behaviours. The 5-HT1A receptor ligands, ipsapirone and NAN-190, which are known to display antagonist-like properties in functional models of postsynaptic 5-HT1A receptor activity attenuated or blocked the hyperlocomotion and head weaving observed after administration of MK-801, whereas the 5-HT2 receptor antagonist, ritanserin, was ineffective in this respect. The dopamine receptor antagonist, haloperidol, and the alpha 1-adrenoceptor antagonist, prazosin, also attenuated behaviours induced by MK-801. In contrast to its effects on stereotypies induced by MK-801, ipsapirone potentiated rather than attenuated the stereotyped behaviour induced by the dopamine receptor agonist, apomorphine, indicating that antagonism of MK-801-induced stereotypies by ipsapirone may not be related to the dopaminergic system. The data indicate that, in addition to catecholaminergic systems, serotonergic neurotransmission is significantly involved in the mechanisms by which MK-801 alters behaviour in rats.

Adrenergic beta-Agonists↗
PubMed1992

Development of tolerance to the anticonvulsant effect of vigabatrin in amygdala-kindled rats.

The anticonvulsant, adverse and biochemical effects of the novel antiepileptic drug vigabatrin (gamma-vinyl GABA), which increases GABA (gamma-aminobutyric acid) levels by inhibition of the GABA degrading enzyme GABA aminotransferase, were examined in amygdala-kindled rats after acute and chronic administration. Vigabatrin proved to be a potent anticonvulsant drug at acute doses (100-200 mg/kg), but during chronic administration, the anticonvulsant activity of the treatment was lost already in the second week of treatment. Tolerance also developed to the adverse effects, i.e. hypothermia, sedation and motor impairment. Determination of vigabatrin in plasma indicated that tolerance was not due to declining drug levels. Furthermore, determination of endogenous amino acids in plasma showed that GABA levels were highly elevated throughout the period of treatment, although the extent of GABA accumulation decreased in the second week. After cessation of chronic treatment with vigabatrin, there was no clear indication of withdrawal symptoms, except a prolonged seizure or afterdischarge duration in experiments with 100 mg/kg per day. The data suggest that chronic treatment with vigabatrin may be associated with a loss of anticonvulsant efficacy, at least when the drug is given as monotherapy.

Amino Acids↗
PubMed1992

Effects of pharmacological manipulation of dopaminergic and cholinergic neurotransmission in genetically dystonic hamsters.

In an inbred line of Syrian hamsters, attacks of sustained dystonic postures of the limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage). The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtSZ) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading the type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. The effects of drugs which alter dopaminergic or cholinergic functions in the brain were studied in selectively bred dystonic hamsters and age-matched non-dystonic controls. The dopamine precursor levodopa (injected together with carbidopa) and the dopamine receptor agonist apomorphine increased the severity of dystonia in hamsters when administered prior to the age of maximum severity of dystonia. A very similar effect was observed with the cholinomimetic pilocarpine. In contrast, the dopamine receptor antagonist haloperidol caused a marked overall reduction in dystonic movements. Anticholinergic drugs, i.e. trihexyphenidyl and biperiden, increased the latency to onset of the dystonic attack, but did not reduce its severity. No differences were observed between dystonic and non-dystonic hamsters with respect to extent and duration of stereotypies induced by dopaminergic and cholinergic drugs or hypolocomotion and catalepsy produced by haloperidol. The data suggest that dopaminergic hyperactivity might be involved in the pathophysiology of dystonia in dtSZ mutant hamsters.

Acetylcholine↗
PubMed1992

Pharmacokinetics, anticonvulsant efficacy, and adverse effects of trans-2-en-valproate after acute and chronic administration in amygdala-kindled rats.

The trans isomer of 2-en-valproate (trans-2-en-VPA), an unsaturated metabolite of the clinically established antiepileptic valproate (VPA), was examined in the kindling model of epilepsy. As in the case of VPA, trans-2-en-VPA exerted potent anticonvulsant effects against partial seizures and secondarily generalized clonic seizures in amygdala-kindled rats after i.p. administration of acute doses. The anticonvulsant potency of trans-2-en-VPA appeared to be higher than that of VPA, especially in the case of secondarily generalized seizures. However, as previously reported for effects of valproate in the kindling model, trans-2-en-VPA exerted anticonvulsant effects against kindled seizures only at doses which were associated with motor impairment. Pharmacokinetic experiments with trans-2-en-VPA indicated non-linear kinetics with dose-dependent elimination rate and enterohepatic recirculation. According to the initial rapid decline in plasma concentrations of trans-2-en-VPA, the duration of anticonvulsant action in kindled rats was short-lasting so that an experimental protocol with 3 daily administrations was chosen for chronic experiments with this drug. During chronic treatment of kindled rats with 3 times daily injection of 100 mg/kg trans-2-en-VPA for 2 weeks, there was a marked reduction of anticonvulsant activity during the second week of treatment. This loss of anticonvulsant activity was not due to metabolic tolerance, i.e. reduction of drug levels by increased drug metabolism. Furthermore, additional experiments with altered experimental protocol indicated that the loss of anticonvulsant activity was not due to contingent tolerance, i.e. involvement of learning processes due to too frequent drug testing. However, the size of chronic treatment dose was important for the rate and degree of tolerance development, since an increase of dosage to 150 mg/kg 3 times daily resulted in significant anticonvulsant effects throughout the period of treatment with almost no indication of tolerance. The date indicate that trans-2-en-VPA is as effective as valproate in the kindling model. In view of previously reported experimental evidence that trans-2-en-VPA might have a lower hepatotoxic and teratogenic potential as valproate, the present study substantiates that trans-2-en-VPA might be an interesting alternative to valproate in antiepileptic therapy.

Amygdala↗
PubMed1992

Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant beta-carboline abecarnil.

The effects of the benzodiazepine (BZ) receptor antagonists flumazenil (Ro 15-1788) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam or the novel BZ receptor ligand abecarnil (ZK 112119). Abecarnil, a beta-carboline, is thought to act as partial (low efficacy) and/or subtype selective agonist at central BZ receptors. Diazepam and abecarnil were administered at doses which, based on previous experiments on anticonvulsant activity, resulted in about equieffective drug concentrations during treatment. In dogs treated with diazepam, 6 mg/kg/day p.o., for 2 weeks, severe abstinence symptoms, including seizures, were precipitated in all animals by i.v. infusion of the BZ receptor antagonists, differences being found in the type of symptoms caused by flumazenil and ZK 93426. In dogs treated with abecarnil, 4 mg/kg/d s.c., for 6 weeks, only relatively mild abstinence symptoms were precipitated by infusion of flumazenil or ZK 93426, although pharmacologically active plasma concentrations of abecarnil had been maintained throughout the period of treatment. This suggests that BZ receptor ligands which act as partial and/or selective agonists might be more favourable than traditional agonists, such as diazepam, regarding the induction of physical dependence.

Animals↗
PubMed1992

Regional alterations in brain amino acids during the estrous cycle of the rat.

Concentrations of 11 amino acids, including the neurotransmitters GABA, glutamate, aspartate, glycine and taurine, were determined in 12 brain regions of female rats during different stages of the estrous cycle. In addition, amino acids and sex hormone levels were determined in plasma. All sample collections were done in the forenoon between 9 and 11 a.m. Most regional amino acid levels measured did not change significantly during estrous cycle, but significant alterations were found for GABA and glutamate in hypothalamus. Both amino acids were slightly decreased in hypothalamus during proestrus, which might reflect an alteration of GABA turnover in response to the high estrogen levels during this stage. A decreased glutamate level during proestrus was also found in thalamus, while both glutamate and GABA did not vary throughout estrous cycle in any of the other examined regions, including substantia nigra, amygdala, striatum, cortex and hippocampus. When diestrus was subdivided according to progesterone levels, high levels of this hormone seemed to be associated with effects on metabolism of certain amino acids, including glycine in substantia nigra, alanine in thalamus and threonine in pons/medulla. However, the few changes in regional amino acid concentrations found during the estrous cycle were so small that the functional significance of these changes cannot be ascertained without further determination of the cellular or subcellular compartments of brain tissue involved.

Amino Acids↗
PubMed1992

Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. I. Biochemical, histopathological and pharmacokinetic studies.

E-2-en-Valproate (E-2-en-VPA; trans-2-en-VPA) and VPA were studied for potential hepatotoxicity in young male Sprague-Dawley rats. Both drugs were administered daily at 750 mg/kg i.p. (divided into three doses a day) for 7 consecutive days. Clinical chemistry parameters were studied before and after the period of treatment. Furthermore, the drug pharmacokinetics and metabolism were analyzed at onset and end of the prolonged administration. Treatment with VPA induced hyperammonemia and other alterations in liver function tests which were not observed after treatment with E-2-en-VPA, although plasma levels of both drugs were comparable. The pharmacokinetics of VPA and E-2-en-VPA in young rats were similar, but analysis of metabolites by gas chromatography-mass spectrometry indicated marked differences in the metabolite profile, e.g., a lack of the suspected hepatotoxic metabolite 4-en-VPA in plasma of rats treated with E-2-en-VPA. Histopathological examination of liver sections showed that VPA and E-2-en-VPA did not induce degenerative liver lesions or significant alterations in hepatic content and distribution of lipids and glycogen at the doses administered. Only one of the VPA treated rats showed fatty infiltration (microvesicular steatosis). The data demonstrate that, although E-2-en-VPA is more potent than VPA as an anticonvulsant in rats, it does not exert more potent hepatotoxic effects and does not alter ammonia metabolism. Thus the data substantiate previous experimental studies that E-2-en-VPA might be a valuable substitute for VPA.

Animals↗
PubMed1992

Lack of changes in seizure susceptibility during the estrous cycle in kindled rats.

The threshold and pattern of focal and generalized seizures in fully kindled rats during the estrous cycle were investigated. Two groups of rats were studied; one was kindled from stimulation of the basolateral amygdala, the other from stimulation of the anterior portion of the posterior piriform cortex. Determinations of the threshold for focal afterdischarges were either carried out in the morning (between 8 and 9 a.m.) or in the afternoon (between 2 and 3 p.m.). In all experiments, stable and reproducible afterdischarge thresholds were obtained during the different stages of the estrous cycle. The only significant alteration was a reduced seizure duration during metestrus and/or the first day of diestrus in amygdala kindled rats. The data indicate that the natural changes in sex hormone levels during the estrous cycle in rats do not affect seizure susceptibility, at least in the kindling model of epilepsy.

Animals↗
PubMed1992

Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin.

A series of 5 generalized tonic-clonic seizures within 30 min was induced by repeated transauricular electrical stimulation in mice. In this model, the anticonvulsant potency of intravenous valproate was compared with diazepam and phenytoin. All 3 drugs proved capable of rapidly suppressing the seizures after intravenous bolus injection. Potent anticonvulsant activity of diazepam and valproate was already obtained after 30 s, while phenytoin's onset of action was somewhat slower. In contrast to diazepam, valproate and phenytoin suppressed the seizures at non-sedative doses. ED50s for blockade of generalized tonic-clonic seizures throughout the 30-min period of repeated electrical stimulation were 6.6 mg/kg for diazepam, 28 mg/kg for phenytoin and 212 mg/kg for valproate. Determination of valproate in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue. The data indicate that an intravenous formulation of valproate might be a useful alternative to phenytoin as a non-sedative anticonvulsant for diazepam-resistant status epilepticus.

Animals↗
PubMed1992

Abnormalities in amino acid neurotransmitters in discrete brain regions of genetically dystonic hamsters.

The concentrations of 11 amino acids, including the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, glycine, and taurine, were determined by HPLC in 12 brain regions of genetically dystonic (dtSZ) hamsters and age-matched nondystonic controls. Since dystonia in mutant dtSZ hamsters is transient and disappears after about 70 days of age, amino acids were determined at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In dtSZ hamsters with the maximum severity of dystonia, significant changes in concentrations of the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, and taurine were found in several regions involved in motor functions, e.g., cerebellum, thalamus, and corpus striatum. Most of these changes were not permanent but disappeared in parallel with dystonia, implicating a causal relationship between altered aminoacidergic neurotransmission and dystonia in mutant dtSZ hamsters.

Animals↗
PubMed1992

Atypical reactions to halothane in a subgroup of homozygous malignant hyperthermia(MH)-susceptible pigs: indication of a heterogenous genetic basis for the porcine syndrome.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In genetically susceptible pigs, MH can be induced by volatile, halogenated anaesthetics such as halothane. Within a series of pharmacological investigations, a fulminant MH could be induced in 59 of 66 homozygous halothane-susceptible pigs by a challenge with 3% halothane for 15 minutes. The typical MH was characterized by sudden appearance of tachycardia, muscle rigidity with typical extension of the hindlimbs, increase of body temperature, acidosis-caused by rapid increase of CO2 and lactate production-, hyperkalaemia and increased activity of creatine kinase (CK) and aspartate transaminase (AST). In seven homozygous MH-susceptible pigs, this typical MH could not be induced by halothane. These animals responded with sudden appearance of bradyarrhythmia and decrease of arterial pressure. In these MH-atypical pigs (MHA) neither the typical extension of hindlimbs nor a hyperthermia occurred. Compared to a group of 6 MH-susceptible pigs with typical reactions to halothane (MHS), the biochemical alterations were significantly retarded in MHA-pigs. These atypical reactions to halothane could be the effect of decreased cardiac output. Concerning the atypical reactions, we observed a familiar predisposition in MH-susceptible pigs. Although atypical reactions were not found in a group of homozygous halothane-nonsusceptible pigs (MHN), a possible explanation for atypical reactions could be a MH-independent halothane-susceptibility of the myocardium+ in MHA-pigs. On the other side the data may indicate that a primary defect in both the skeletal muscle and also the myocardium is involved in MH. The different reactions to halothane in MH-susceptible pigs could point to a genetic heterogeneity.

Animals↗
PubMed1992

[Homeopathy: an effective and risk-free alternative to conventional pharmacotherapy? Part 1: Hahnemann and his teaching].

The article considers the attractions and dangers of homeopathic therapy from the view of a pharmacologist. Homeopathic drugs may exert pharmacodynamic (but also toxic) effects at low dilutions (D0-D6), but there is no scientific proof for specific effects of higher dilutions except for substances with a high toxic potential. Most homeopathic drugs have no reasonable basis for clinical use but, in case of toxic compounds, especially those with carcinogenic or allergic potential, homeopathy may bear risks for the animal and, because of residues in food animals, also for humans. Thus, homeopathic treatment should not be used when effective conventional treatments are available, and the use of homeopathic drugs with toxic potential should be avoided.

Animals↗
PubMed1991

Antidystonic effects of the NMDA receptor antagonists memantine, MK-801 and CGP 37849 in a mutant hamster model of paroxysmal dystonia.

The effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were evaluated in an inbred line of Syrian golden hamsters, in which sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli. In this model of paroxysmal dystonia, the noncompetitive NMDA receptor antagonists memantine and MK-801 (dizocilpine) delayed the progression of dystonic attacks in a dose-dependent fashion. The novel competitive NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) was more effective than memantine and MK-801, because it retarded not only the progression but also reduced the severity of the dystonic movements. All compounds exhibited antidystonic effects at doses which did not cause marked ataxia or sedation. The data indicate that NMDA receptor antagonists might be interesting candidates for treatment of dystonia.

2-Amino-5-phosphonovalerate↗
PubMed1991

[Significance of pharmacokinetic parameters for effective drug therapy in house and domestic animals].

Aspects of pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacokinetic parameters (half-life time, elimination time, volume of distribution and bioavailability) are discussed. Treatment with food or drinking water demands additionally considerations to obtain a suitable drug level in the organism. Age- and sickness-dependent variations cause important changes of pharmacokinetic parameters. For an efficacious therapy, pharmacokinetic considerations are essential.

Animals↗