Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.

INTRODUCTION: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). METHODS: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. RESULTS: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. DISCUSSION: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.

Clinical and non-clinical investigations using positron emission tomography, near infrared spectroscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences.

Vinpocetine (Cavinton, Gedeon Richter, Budapest) is widely used as a neuroprotective drug in the prevention and treatment of cerebrovascular diseases. Vinpocetine is a potent inhibitor of the voltage-dependent Na(+) channels and a selective inhibitor of the Ca(2+)/caldmoduline-dependent phosphodiesterase 1. The clinical efficacy has been supported by several previous studies. Positron emission tomography (PET) is a powerful method to evaluate the fate, the site of action, the pharmacological and physiological effects of a drug in the brain and other organs. We have demonstrated in monkey that the [11C]-labelled vinpocetine rapidly enters the brain after intravenous (i.v.) injection, the maximal uptake being approximately 5% of the total injected radioactivity. The distribution pattern of vinpocetine in the brain was heterogenous, with the highest uptake in the thalamus, basal ganglia and visual cortex. These findings were confirmed in healthy humans, where the i.v. administered [11C]-labelled vinpocetine had a similar distribution pattern. The highest uptake in the brain was 3.71% of the total administered radioactivity. Quite recently, we have shown that [11C]-labelled vinpocetine administered orally to healthy human volunteers also rapidly appears in the brain and shows a similar distribution pattern, the highest uptake being 0.71% of the total administered radioactivity. In two separate sets of clinical studies where chronic ischaemic post-stroke patients were either treated with a single infusion (Study 1) or with daily vinpocetine infusion for 2 weeks (Study 2), we have shown that vinpocetine increases the regional cerebral glucose uptake and to a certain extent glucose metabolism in the so-called peri-stroke region as well as in the relatively intact brain tissue. The 2-week-long treatment also increased the regional cerebral blood flow (CBF) especially in the thalamus, basal ganglia and visual cortex of the nonsymptomatic hemisphere. We have demonstrated the cerebral perfusion-enhancing and parenchymal oxygen extraction-increasing effects of vinpocetine in subacute ischaemic stroke patients by near infrared spectroscopy (NIRS) and transcranial Doppler (TCD) methods.

[Cerebral uptake and regional distribution of [11C]-vinpocetin after intravenous administration to healthy men: a PET study]. / [11C]-vinpocetin agyi felvétele és regionális eloszlása egyszeri intravénás adás után emberben: PET vizsgálatok.

INTRODUCTION: Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. The exact mechanism of action of the drug is still not known. The objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain. Three healthy persons were examined with positron emission tomography (PET) and [11C]-vinpocetine. RESULTS: The uptake of [11C]-vinpocetine in brain was rapid and on average as a maximum 3.7% of the total radioactivity injected was in the brain 2 minutes after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, the upper brain stem, the striatum and the cortex. CONCLUSIONS: The brain regions showing increased uptake in the human brain correspond to those in which vinpocetine has previously been shown to induce elevated metabolism and blood flow by PET clinical studies in patients with chronic ischaemic post-stroke condition.

[Human positron emission tomography with oral 11C-vinpocetine]. / Pozitronemissziós tomográfiás humán vizsgálatok orálisan adott [11C]vinpocetinnel.

INTRODUCTION: Positron emission tomography (PET) is a useful tool for the investigation of certain physiological changes and for the evaluation of the distribution, and receptor binding of drugs labelled with positron emitting isotopes. Vinpocetine (ethyl-apovincaminate) is a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases. In the clinical practice vinpocetine is usually administered to the patients in intravenous infusion followed by long-term oral treatment. Until presently human data describing vinpocetine's kinetics and brain distribution came from ex vivo (blood, plasma, liquor) and post mortem (brain autoradiography) measurements. AIM: The authors wished to investigate the kinetics and distribution of vinpocetine in the brain and body after oral administration with PET in order to prove, that PET is useful in the non-invasive in vivo determination of these parameters. METHOD: Vinpocetine was labelled with carbon-11 and the radioactivity was measured by PET in the stomach, liver, brain, colon and kidneys in healthy male volunteers. The radioactivity in the blood and urine was also determined. RESULTS: After oral administration, [11C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the oral administration of the labelled drug (average maximum uptake: 0.7% of the administered total dose). Brain distribution was heterogeneous (with preferences in the thalamus, basal ganglia and occipital cortex), similar to the distribution previously reported by the authors after intravenous administration. CONCLUSIONS: Vinpocetine, administered orally to human volunteers, readily entered the bloodstream from the stomach and the gastrointestinal tract and thereafter passed the blood-brain barrier and entered the brain. Radioactivity from [11C]vinpocetine was also demonstrated in the kidneys and in urine. The study demonstrates that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally administered labelled drugs active in the central nervous system in the living human body.

[TRH analogs at Gedeon Richter Ltd.: highlights of experimental and clinical efficacy of posatirelin]. / TRH analógok kutatása a Richter Gedeon Rt.-nél: a posatirelin kisérletes és humán farmakológiai hatásai.

The chemical research for dissociation of the central nervous system effects of thyrotropin-releasing hormone (TRH) from its hormonal activity resulted in the selection of RGH-2202 (posatirelin) for further development. Posatirelin showed stronger vigilance enhancing effect than TRH in a variety of commonly used neuro-psychopharmacological model in mice, rats and cats. This drug had positive effects in animal models of disturbed consciousness, and counteracted the decline of learning and memory capacity shown by aged or memory impaired rats. Posatirelin had a trophic effect on neurons both 'in vitro' and 'in vivo' as well. Activation of various neurotransmission systems has been demonstrated, but the "modulatory" action of this neuropeptide-like compound is too complex to be explained by a single mechanism. Posatirelin practically had no hormonal activity or other significant side effects either in animal studies or in clinical trials. The arousal level increasing and the neuronotrophic effects appeared in part in trials of human brain injuries and cerebral infarction. Patients suffering in dementia syndromes of either vascular or degenerative origin and treated chronically with posatirelin showed significant improvement in intellectual performance, in orientation, motivation and memory function in all well controlled trials.

[Investigation of vasoactive agents with indole skeletons at Richter Ltd]. / Indolvázas vegyületek kutatása a Richterben.

Investigation of agents with indol skeleton was started in Richter Ltd. 50 years ago. This paper presents the results obtained by Richter's scientists. At first, a vasoactive alcaloid, vincamine was extracted from the leaves of Vinca minor in industrial quantity in 1955. This agent selectively improves the cerebral blood supply. Vincamine (Devincan) is used for the treatment of cerebrovascular disorders from 1959. Vinpocetine (Cavinton), the most powerful vasoactive compound was produced by transforming the chemical structure of vincamine. Cavinton is a cis(3S,16S)-derivate of vincamine having antianoxic, antiischaemic and neuroprotective properties. Therefore, it is frequently used in the therapy of cerebral disorders of vascular origin. Cavinton was introduced into clinical practice in 1978. At present, Cavinton tablets are approved in 47 countries. The third compound, vintoperol is a trans(3S,16R)-derivate of vincamine. Vintoperol proved to be a powerful enhancer of blood flow in the lower extremities. Because of its toxic side effects the agent is not used in clinical practice.

[Investigation of neuromuscular blocking agents at Richter Ltd]. / Szteroid izomrelaxánsok kutatása a Richterben.

Investigation of new neuromuscular blocking agents was started 30 years ago in Richter Ltd. This paper presents the results obtained by Richter's scientists. 2 compounds out of 100 bisquaternary ammonio steroid having androstane skeleton were selected for further pharmacological study. One of these agents, pipecuronium bromide (Arduan) elicited long-lasting block of neuromuscular transmission without cardiovascular side effects in both animal experiments and clinical studies. Arduan is a powerful competitive antagonist of acetylcholine, since it can bind pre- and postsynaptic (N1) receptors of the transmitters. It has no remarkable cumulative effect. Neostigmine rapidly and completely antagonized the neuromuscular blockade caused by pipecuronium. Arduan was introduced into clinical practice. The second compound, RGH-4201 (Duador) evoked a neuromuscular block of short duration. It showed slight atropin-like cardio-vagolytic effect in animal experiments. In the clinical studies, however, the cardiovascular side effects were found to be too strong. Therefore, it was not introduced in clinical practice.

[Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic acid derivatives as potential therapeutic tools in ischemic stroke]. / A vinpocetin neuroprotektív hatásai in vivo és in vitro. Apovinkaminsav származékok mint az ischemiás stroke lehetséges terápiás eszközei.

The aim of the present study was to review neuroprotective therapy from the preclinical point of view as a potential tool for the treatment of stroke, as well as to discuss neuroprotective effects of the apovincaminic acid derivative vinpocetine (Cavinton). Our own in vivo and in vitro experiments were aimed at further characterizing pharmacological effects involved in the vinpocetine-induced neuroprotection. The effect of vinpocetine on infarct volume (obtained by 2,3,5-triphenyltetrazolium-chloride staining) was studied in permanent middle cerebral artery occlusion (MCAO) in rats (3 mg/kg i.p., 30 min postischemia). Vinpocetine treatment significantly decreased infarct volume (by 42%, p < 0.05) compared to control, which was better than the effect of nimodipine (17%) or MK-801 (18%). Neurotoxicity measurements were made in primary cortical cell culture using LDH release as an indicator. Vinpocetine dose-dependently inhibited prolonged (24 h) or transient (15 min) glutamate, and transient N-metil-D-aspartate (NMDA) or veratridine (0.1-1 mM) induced excitotoxicity (IC50 = 2-7 x 10(-6) M). In these tests the neuroprotective potency of vinpocetine was lower than that of MK-801, but it was similar to those of flunarizine or nimodipine. These results together with former literature data indicate that apovincaminic acid derivatives possessing strong neuroprotective potential may play an important role in the therapy of ischemic stroke.

Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine.

Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [(11)C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [(11)C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [(11)C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally administered labelled CNS drugs in the living human body.