piperidines and sabeluzole

Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?. Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants.. The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed.. Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

Topics: Aged; Alzheimer Disease; Cross-Cultural Comparison; Donepezil; Ethnicity; Galantamine; Humans; Indans; Nootropic Agents; Phenylcarbamates; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine; Thiazoles; White People

This paper is the text of a talk given at the European Respiratory Society meeting in Berlin in September 1997 in a symposium organized by the Sleep Disorders Working Group. It covers new treatments for obstructive sleep apnoea which are not established as standard treatments. Although postural treatment was proposed a long time ago, few studies have investigated its efficacy in clinical practice. However, in view of the data concerning postural sleep apnoea, it certainly deserves more consideration. Oral appliances appear to have become more popular as an alternative to continuous positive airway pressure (CPAP) when surgery is not desired or not desirable. A few controlled studies have been undertaken to establish its efficacy, which is less constant and less predictable than with CPAP. Other experimental approaches include nerve and muscle stimulation, for which preliminary results are promising. In the area of drug treatment, there is nothing new. Finally, the questions of what to do when treatment does not work and who should receive treatment are addressed.

Topics: Combined Modality Therapy; Controlled Clinical Trials as Topic; Female; Humans; Laser Therapy; Male; Orthodontic Appliances; Piperidines; Polysomnography; Prognosis; Sleep Apnea Syndromes; Thiazoles; Treatment Outcome

The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction.. The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules).. The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers.. These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.

Topics: Adult; Antitussive Agents; Cytochrome P-450 CYP2D6; Dextromethorphan; Humans; Liver; Liver Diseases; Male; Middle Aged; Oxidation-Reduction; Piperidines; Thiazoles

Sabeluzole, a new benzothiazole derivative, has been shown to be neurobiologically active preclinically and clinically appears to exert beneficial effects on memory. In this study, sabeluzole (5 or 10 mg twice daily vs. placebo) was investigated in patients with probable Alzheimer's disease over 1 year, with assessments of cognitive performance and structural changes. Cognitive performance was measured using the Alzheimer's Disease Assessment Scale periodically during treatment. Potential structural correlates in the frontal horn, caudate, third ventricle and hippocampal regions were examined by obtaining computerized tomographic (CT) images before and after treatment. Patients receiving sabeluzole evidenced greater stability than did placebo-treated patients in some cognitive measures. CT measures showed no significant changes from baseline, but some weak associations were found between relative preservation of cognitive function and smaller structural declines in the third ventricle and hippocampus. Cognitive outcome measures suggest that sabeluzole may have potential in slowing the cognitive deterioration of Alzheimer's disease. Furthermore, the method used to explore potential benefits on a morphologic level, although negative in this study, could yet have potential.

Topics: Aged; Alzheimer Disease; Brain; Cognition; Double-Blind Method; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Thiazoles; Tomography, X-Ray Computed

The effect of sabeluzole (SAB), an agent with anti-excitatory amino acid activity, on sleep, breathing and daytime symptoms was investigated in 13 patients with obstructive sleep apnea (OSA). There was marked interindividual variation in both the effect on sleep and breathing and the plasma concentration of SAB. However, individual plasma drug concentration was highly correlated (r = 0.82, p = 0.02) with a reduction of the oxygen desaturation index during sleep (ODI) after treatment with SAB. Further investigation of this and agents of this type are warranted in patients with OSA.

Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Humans; Male; Middle Aged; Piperidines; Sleep Apnea Syndromes; Sleep Stages; Sleep, REM; Thiazoles

Sabeluzole, a new benzothiazol derivative, has shown positive effects on memory function in animals and in normal volunteers. The present study reports the results of sabeluzole, in memory-impaired patients with localization-related (partial) epilepsy. A randomized, double-blind placebo-controlled parallel-group design was used. A total of 38 patients entered a prospective baseline. Five patients dropped out from the study, thus 33 patients were randomly assigned to either a 12-weeks treatment with sabeluzole (n = 14) or placebo (n = 19). The treatment phase was preceded by a titration phase of 4 weeks to obtain serum levels of sabeluzole between 50 and 130 ng/ml. In order to maintain blindness, a sham titration was carried out in the placebo group. The number of 'responders', i.e. patients with a > 1 SD improvement on at least three of the memory tests was 9 out of 14 (64.3%) in the sabeluzole group and 7 out of 19 (36.8%) in the placebo group. This suggests a clinically relevant effect of sabeluzole. The analysis of the memory tests showed a statistically significant improvement with sabeluzole on the verbal long-term memory test. This could represent a specific drug effect and is in line with previous results of normal volunteer studies that also found improvement mainly restricted to the area of verbal long-term memory.

Topics: Adult; Affect; Cognition; Double-Blind Method; Epilepsy; Female; Functional Laterality; Humans; Intelligence Tests; Male; Memory; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Piperidines; Psychomotor Performance; Reaction Time; Speech; Thiazoles

Topics: Adult; Aged; Autonomic Nervous System; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurologic Examination; Peripheral Nerves; Piperidines; Thiazoles

Two groups of patients suffering from polyneuropathy were treated by sabeluzol. The first group--a double blind placebo controlled study consisting of 30 diabetics of type II did not prove either significant differences of their subjective complaints or changes of their objective findings (the dose of sabeluzole being 2 x 10 mg/d). The second group--open study--consisting of 26 patients suffering from polyneuropathy of various origin, treated by sabeluzole 3 x 10 mg/d. The therapeutic effect was significantly higher in comparison to the above mentioned lower doses of the medicament (manifesting statistical significance of 5 and 10%); the authors make a point of sabeluzol's therapeutic efficacy, especially in cases with acute polyneuropathy onset and point out the necessity of several months lasting treatment. Positive effect upon the pseudoneurasthenic syndrome in many patients indicates its usefulness also in other disorders than are these of polyneuropathy.

Topics: Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Nervous System Diseases; Piperidines; Thiazoles

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Electromyography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Degeneration; Neurologic Examination; Peripheral Nerves; Piperidines; Sensory Thresholds; Synaptic Transmission; Thiazoles

The effects of chronic treatment (5 mg b.i.d. for 2 days followed by 10 mg b.i.d. for 5 days) with R 58 735 on human memory functions were studied in healthy elderly (age greater than or equal to 50 years) volunteers in a double-blind placebo-controlled study. Serial learning of nonsense syllables was better under R 58 735, and relearning 1 week after termination of the treatment was superior to relearning of similar material initially learned under placebo. Free recall of nonsense syllables was significantly better when these were learned under active compound. Proactive inhibition induced by consecutive presentation of word lists was attenuated by R 58 735. Short-term memory functions, retrieval accuracy from semantic memory and unprepared reaction times were unchanged. R 58 735 ameliorated both learning and recall in conditions of age-related mild hypofunction in healthy volunteers. The compound seems to have had positive effects on encoding and consolidation of new material.

Topics: Cognition; Double-Blind Method; Female; Humans; Learning; Male; Memory; Middle Aged; Piperidines; Reaction Time; Thiazoles

In a first double-blind, placebo-controlled parallel experiment, 20 volunteers with a median age of 45 years were treated for 1 week with either sabeluzole (R 58735) or placebo. Before and after the treatment period, they were subjected to a Selective Reminding Procedure in which a 20-word list had to be learned. No differences between the two groups were seen for total recall, short-term retrieval, total long-term retrieval, random long-term retrieval and long-term storage. However, a significant improvement in consistent long-term retrieval (cLTR) was seen for the subjects treated with sabeluzole. This effect was restricted to the group of the poor performers, i.e. those with a baseline cLTR of 50% or less. In a second experiment, 12 healthy elderly volunteers with a median age of 59 years were subjected to the same test procedure. They were treated with sabeluzole in a single-blind fashion. Again the cLTR improved significantly in the group of poor performers. It was thus confirmed that sabeluzole ameliorates retrieval functions and primarily so in poor performers.

Topics: Adult; Double-Blind Method; Female; Humans; Male; Memory; Middle Aged; Piperidines; Random Allocation; Thiazoles

Consistent retrieval during serial learning of nonsense syllables was investigated under sabeluzole (10 mg b.i.d. for 7 days) and placebo. The same material was relearned 1 week after withdrawal of the drug. During learning a twofold improvement in retrieval efficiency was seen when volunteers learned new material under steady-state levels of sabeluzole. During relearning, material originally learned under sabeluzole was significantly better retrieved than material learned under placebo. The results suggest that sabeluzole influences basic mechanisms involved in storage and retrieval of new information.

Topics: Double-Blind Method; Humans; Learning; Memory; Piperidines; Random Allocation; Serial Learning; Thiazoles

The objective of this study was to develop and characterize a biodegradable drug-loaded nerve guide for peripheral nerve regeneration. Sabeluzole, a nerve growth agent, was selected as model compound. Four biodegradable polymers were selected for this study: a copolymer of polylactic acid and polycaprolactone (PCL); a copolymer of polyglycolic acid and polycaprolactone PCL; a copolymer of PCL/polydioxanone (PDO) and PDO. Placebo and drug loaded nerve guides were obtained by melt compression and melt extrusion. It was observed that melt compression and melt extrusion are feasible techniques to prepare the nerve guides. Based on the physicochemical characterization, all samples show absence of crystalline sabeluzole, indicating the formation of an amorphous dispersion. The in vitro release measurements show that the release of sabeluzole is complete, reproducible and can be controlled by the proper selection of the polymer. The release mechanism for all samples follows Fickian release behaviour.

Topics: Absorbable Implants; Animals; Biocompatible Materials; Body Fluids; Diffusion; Drug Implants; Drug Stability; Equipment Failure Analysis; Humans; Lactic Acid; Materials Testing; Nerve Growth Factors; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Piperidines; Polyesters; Polymers; Prosthesis Design; Temperature; Thiazoles

Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties, and is currently under development for Alzheimer's disease. Recently, it was reported that repeated treatments with sabeluzole protect cultured rat hippocampal neurons against NMDA- and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indirectly, on tau proteins. We found that repeated treatments during development of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resistant to the excitotoxicity induced by glutamate. Also, sabeluzole treatment specifically prevented the glutamate-induced increase of tau expression without modifying the basal pattern of expression of tau proteins, as shown by measurement of mRNA and protein levels. In human neuroblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced cell death. Both effects were prevented by sabeluzole. Our data indicate that increased tau expression is a common response to different types of cells to neurotoxic agents, and that sabeluzole-induced neuroprotection is functionally associated with the prevention of the injury-mediated increase of tau expression.

Topics: Animals; Cell Death; Dose-Response Relationship, Drug; Glutamic Acid; Humans; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; tau Proteins; Thiazoles; Time Factors

Topics: Animals; Anti-Ulcer Agents; Female; Gastric Acid; Piperidines; Rats; Rats, Wistar; Thiazoles

Several new bioanalogues of (+/-)-N-methyl-N-(1-[3-(4-fluorophenoxy)-2-hydroxy-propyl]piperidin++ +-4-yl) benzothiazol-2-amine (1, sabeluzole, CAS 104383-17-7) were prepared by reacting 1,2-epoxy-3-aryloxypropanes with 4-arylaminopiperidines. Some of these derivatives showed enhanced activity in the potassium cyanide hypoxia test and in the pentetrazol convulsion test in mice compared to 1.

Topics: Animals; Anticonvulsants; Cell Survival; Cyanides; Hypoxia; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Piperidines; Seizures; Thiazoles

Sabeluzole (R58735, Janssen Research Foundation) increased rates of axonal transport in short term tissue culture experiments and in rats with streptozotocin-induced diabetes. The drug was tested for its subacute (3 days) net effect on axonally transported substances in motor, sensory, and adrenergic axons of normal adult rats. Sabeluzol was given once daily for 3 days, 1 or 10 mg/kg/day intraperitoneally. Immunofluorescence was used to identify transported material. Three or 6 hr after crushing the sciatic nerves, to interrupt anterograde and retrograde intraaxonal transport, cytofluorimetric scanning was used to quantitate accumulated immunoreactive material. Compared with vehicle treated control rats, no clear differences in the net amounts of accumulated material, or in rates of accumulation, were detected in any axonal type. Since the short-term crush procedure interrupts ongoing axonal transport, the accumulation pattern reflects the transport characteristics in the crushed axons. The absence of clear increases in transport of several substances in this study indicates that sabeluzole did not enhance net axonal transport above control levels in peripheral axons of normal adult rats. Possible reasons for the discrepancy with earlier observations on the effect of sabeluzole on fast axonal transport is discussed.

Topics: Animals; Axonal Transport; Biological Transport; Calcitonin Gene-Related Peptide; Male; Mixed Function Oxygenases; Piperidines; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Synaptophysin; Thiazoles

Author trie to prove a possible positive effect of sabeluzole in patients with diabetic polyneuropathy. All patients were examined by EMG stimulating method for n. tibialis sin., n. peroneus sin. and n. medianus dx. The distal motor latency, motor conduction velocity and sensory conduction velocity with areas of motor evoked responses were evaluated. The realised test had lower sensitivity than the originally planned one and the expected positive effect of sabeluzole was not proved by this method.

Topics: Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electromyography; Humans; Piperidines; Thiazoles

The memory enhancing properties of sabeluzole nad flunarizine were evaluated in two experimental paradigms in male rats. First, we studied the protective action of both drugs against a chlordiazepoxide-induced impairment of habituation. Sabeluzole (5 or 25 mg/kg) or flunarizine (10 mg/kg) were administered sc 1 hr before and chlordiazepoxide (20 mg/kg) immediately after the acquisition session. In the retention session 72 hr later, chlordiazepoxide treated animals displayed higher locomotor and exploratory activities and this effect was blocked by pretreatment with sabeluzole or flunarizine. The results suggest that both drugs prevented amnesic effect of chlordiazepoxide. The second paradigm was the social memory test in which the time spent in social investigation behaviour toward a familiar or a novel juvenile conspecific was used to measure the duration of the memory that the animal forms of the juvenile. Sabeluzole (25 mg/kg) or flunarizine (3 mg/kg) were injected to the adults immediately after the initial exposure. Reexposure to the same or a novel juvenile was done 2 hr later. In contrast to controls, sabeluzole-treated animals showed a significant reduction in social investigation during reexposure to the same juvenile. Since there was no effect on investigation of a novel juvenile, results suggest that sabeluzole-treated rats are able to remember longer the individual characteristics of juvenile rats obtained through olfactory cues during a short social interaction. The time spent by adults treated with flunarizine in the investigation the same juvenile during reexposure was similar to that observed during the initial exposure. It means that flunarizine was ineffective in enhancing short-term olfactory memory.

Topics: Animals; Chlordiazepoxide; Flunarizine; Habituation, Psychophysiologic; Male; Memory; Piperidines; Rats; Thiazoles

The effect of streptozotocin induced diabetes and sabeluzole (SBZ) on sexual function was evaluated in male rats. SBZ is a benzothiazole derivative with antihypoxic and antiischaemic activities. Rats were rendered diabetic by intraperitoneal injection of streptozotocin, 60 mg./kg. body weight, and either left untreated or treated with 1.0 mg./kg. of SBZ. Two groups of control rats treated with or without SBZ were also evaluated. Seven weeks after the induction of diabetes, all rats were studied in vivo for mating behavior. Animals were sacrificed one week later, and detrusor strip response in vitro was evaluated. The reproductive organ weight, sperm content and motility as well as in vitro testosterone secretion and serum levels of LH and testosterone were determined. Diabetes induced significant reduction in mating behavior. The diabetic rats that received SBZ showed a significant improvement in mating behavior. The percentage of animals that exhibited ejaculation was 0% in the diabetic group compared to 70% in the controls and 38% in diabetic plus SBZ group. The strips of the detrusor muscle of the diabetic group showed a marked hypersensitivity to bethanechol HCL. In the diabetic plus SBZ group, the strips of the detrusor muscle showed a response similar to that of the control. The diabetic rats had significantly diminished reproductive organ weight, testicular sperm content, epididymal sperm content and sperm motility relative to the control. In addition, marked decrease in the serum level of testosterone and in vitro testosterone secretion was observed in diabetic rats. In the diabetic plus SBZ group, the reproductive organ weight, sperm content and motility as well as serum testosterone and in vitro testosterone secretion showed an improvement compared to diabetic rats. In summary, our data suggest that sex behavior and reproductive tract functions are markedly affected by streptozotocin induced diabetes. Sabeluzole treatment could be beneficial in reducing the deleterious effect of diabetes on sexual functions.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Epididymis; Male; Muscle Contraction; Muscle, Smooth; Organ Size; Piperidines; Rats; Sexual Behavior, Animal; Sperm Count; Sperm Motility; Streptozocin; Testis; Testosterone; Thiazoles; Urinary Bladder

The effects of sabeluzole, a drug that protects rat hippocampal neurones from glutamate- and N-methyl-D-aspartate (NMDA)-induced toxicity, were investigated in rat cerebellar granule cells in vitro with the whole-cell voltage clamp technique. Acute exposure of 0.1 microM sabeluzole for 20 min prior to experiments did not significantly affect glutamate receptor-mediated inward currents. Conversely, exposure of cultured granule cells to sabeluzole for 7 days reduced the NMDA-induced inward current and did not affect the non-NMDA responses evoked by kainic acid. The results suggest that chronic treatment with sabeluzole selectively reduces the functional NMDA response.

Topics: Animals; Cells, Cultured; Cerebellum; Membrane Potentials; N-Methylaspartate; Piperidines; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Thiazoles

The present paper reports two experiments is which an effect of sabeluzole and flunarizine upon behavioural consequences reflecting ischemic damage following cortical freezing lesions was evaluated in NMRI female mice. The parietal lesion was performed by applying a flat (2 mm in diameter) of a metal probe cooled to -75 degrees C on the exposed skull for 5 s. Flunarizine (15 mg/kg) was administered sc 1 hr before and 4 hr after performing the lesion and then, 1 mg/kg p.o. once daily for 14 days. Sabeluzole (5 mg/kg) was administered p.o. 1 hr before and 5 hr after performing the lesion and then, 5 mg/kg p.o. once daily for 14 days. Hole--board method was used to evaluate the exploratory head-dips activity of an animal in 5 sessions separated by 24 hr intervals during the postlesion testing from the 20th to the 24th day, i.e. from day 6 to 10 after finishing the treatment. The session lasted 5 min. In both experiments, the mean number of exploratory hole visits in lesioned female mice was significantly increased. Both flunarizine and sabeluzole reduced high hole exploration of lesioned mice to levels corresponding to those of the controls. Neither flunarizine nor sabeluzole affected significantly exploratory hole visit of control animals. Results showed that flunarizine as well as sabeluzole ameliorated behavioural disturbances reflecting the brain impairment induced through cortical freezing lesion. This effect is most probably related to the protective effect of both drugs against hypoxia induced in laboratory animals by several experimental procedures. The hole--board method seems to be suitable for the screening of compounds considered as cerebroprotective drugs.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Female; Flunarizine; Freezing; Mice; Piperidines; Thiazoles

The neuroprotective properties of the cognitive enhancer sabeluzole were investigated in rat brain neuronal cultures derived from the hippocampal formation of 17-day-old rat embryos. Measurement of the neuronal cytoskeletal microtubule-associated protein, MAP2, was used to assess survival of neurons after exposure of neuronal cultures to glutamate. MAP2 was quantified in neuronal cell homogenates by means of an enzyme-linked immunosorbent assay (ELISA) using a mouse monoclonal MAP2 antibody, peroxidase-labeled goat anti-mouse Ig antiserum, and 2,2'-azido-di-[3-ethylbenz-thiazoline] sulphonate (ABTS) as substrate. Exposure of 7-day-old neuronal cultures to 1 mM glutamate for 16 hours led to a three-fold increase in released lactate dehydrogenase (LDH) and a 40% decrease in cellular MAP2 content. Acute treatment of neuronal cultures with 10 microM sabeluzole yielded a 40% drop in released LDH induced by glutamate. Cultures treated chronically with 0.1 microM sabeluzole on days 1 and 4 in culture showed, after 1 week in culture, a MAP2 content and total LDH activity that was not different from control cultures. A 16-hour exposure to 1 mM glutamate did not induce LDH release or changes in MAP2 levels in sabeluzole-treated cultures. A single treatment with 0.1 microM sabeluzole between day 1 to 5 induced a 70-80% drop in glutamate-induced released LDH in 7-day-old neuronal cultures. Full and partial neuronal protection after chronic sabeluzole treatment at 0.1 microM was also observed for neurotoxicity induced by 5 mM N-methyl-D-aspartate (NMDA) and 1 mM kainic acid or 30 microM veratridine, respectively. Within a series of compounds such as Ca++ and Na+ channel antagonists, glutamate receptor antagonists and various neurotransmitter receptor antagonists, sabeluzole, chronically given, were the most potent for inhibition of released LDH induced by 1 mM glutamate (IC50-value: 34 +/- 13 nM). In conclusion, chronic sabeluzole treatment protects cultured rat brain neurons from excitotoxic aggression.

Topics: Amino Acids; Animals; Brain; Cells, Cultured; Glutamates; Glutamic Acid; L-Lactate Dehydrogenase; Microtubule-Associated Proteins; Neurons; Piperidines; Rats; Thiazoles; Time Factors

Morphological rearrangements, such as synapse number changes, have been observed in the adult mammalian brain after various experimental paradigms of learning and behavioral experience. The role of axonal transport in the physical translocation of material during this form of brain plasticity has not been fully appreciated. We show here by quantitative video microscopy that sabeluzole (R58735), a new memory-enhancing drug in humans, effectively increases fast axonal transport in rat neuronal cell cultures. Long-term incubation (24 hr) with sabeluzole in the concentration range between 0.1 and 1 microM increases both velocity and jump length of saltatory movements maximally by 20-30% in embryonic hippocampal neurons. Acute treatment only increases the velocity by 15-20%. Furthermore, the inhibition of axonal transport by 0.1 mM vanadate in N4 neuroblastoma cells is reversed by 1 microM sabeluzole. Observations on the kinesin-induced microtubule mobility in a reconstituted system show a 10% enhancement by sabeluzole at an optimal concentration of 2 microM, but no increase in kinesin ATPase activity. To our knowledge, this is the first pharmacological compound shown to increase fast axonal transport. The mechanism of fast axonal transport enhancement is discussed as a rationale for new therapeutic treatment in neuropathology.

Topics: Animals; Axonal Transport; Cell Line; Cells, Cultured; Embryo, Mammalian; Hippocampus; Kinesins; Memory; Microtubules; Neurites; Neuroblastoma; Neurons; Piperidines; Rats; Thiazoles

The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type. After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng.ml-1. On repeated dosing (10 mg b.d.), steady-state was virtually attained after 3 days of treatment. Steady-state mean trough and peak plasma concentrations fluctuated between 53 and 94 ng.ml-1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h. Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen.

Topics: Aged; Alzheimer Disease; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Thiazoles

The memory enhancing properties of sabeluzole were evaluated in two experimental paradigms in rats. First, we determined the protective action of sabeluzole against a chlordiazepoxide-induced impairment of habituation. Sabeluzole (5 or 25 mg/kg, SC) was administered 1 h before and chlordiazepoxide (20 mg/kg, SC) immediately after the acquisition session. In the retention session 72 h later, chlordiazepoxide-treated animals displayed higher locomotor and rearing activities and this effect was blocked by pretreatment with sabeluzole. The results suggest that sabeluzole prevented the amnesic effect of chlordiazepoxide. The second paradigm was a social recognition test in which the behaviour toward a familiar or a novel conspecific was investigated. Time spent in social investigation and time spent sniffing of scent traces left on the floor was estimated during exposure of an adult to a juvenile male rat. Sabeluzole (25 mg/kg, SC) was injected into the adults immediately after the first exposure. Reexposure to the same or a novel juvenile was performed 120 min later. In contrast to control, sabeluzole-treated animals showed a significant reduction in social investigation during the second exposure to the same juvenile. Time spent sniffing the floor was significantly decreased in sabeluzole-treated males. Since there was no effect on investigation of a novel juvenile, results suggest that sabeluzole-treated rats are able to remember longer the individual characteristics of juvenile rat obtained through olfactory cues.

Topics: Animals; Chlordiazepoxide; Cognition; Habituation, Psychophysiologic; Male; Memory, Short-Term; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Social Behavior; Thiazoles

In the CA1 region of hippocampal slices prepared from guinea-pigs, which had been orally treated with sabeluzole, long-term potentiation was significantly enhanced in those slices obtained from animals given 2.5 or 10.0 mg/kg. In an active avoidance task oral treatment of guinea-pigs with 2.5 or 10.0 mg/kg of sabeluzole significantly increased learning. The dose of 0.63 mg/kg was inactive in both paradigms. These results provide new evidence supporting the involvement of LTP in learning.

Topics: Animals; Avoidance Learning; Dose-Response Relationship, Drug; Electric Stimulation; Electrophysiology; Guinea Pigs; Hippocampus; Learning; Piperidines; Thiazoles

Unilateral photochemical infarcts were produced in the hind limb sensorimotor neocortex of 243 rats by intravenous injection of the fluorescein derivative Rose Bengal and focal illumination of the intact skull surface. Facial contact stimuli governed the degree and recovery rate of contralateral tactile/proprioceptive forelimb placing reactions. Contralateral forelimb placing recovered, whereas hind limb placing was resistant to recovery. Infarcted rats displayed marked recovery of spontaneous limb usage (beam traversing). However, deficits in isolated tactile/proprioceptive hind limb placing reactions endured. Posttreatment with the class IV calcium antagonist flunarizine after neocortical infarction protected sensorimotor function in a dose-dependent manner. This protective effect may be due to the peculiar ionic channel blocking profile of flunarizine. Scopolamine hydrobromide reinstated contralateral placing errors in infarcted rats at a dosage that did not affect neurologically intact rats. The cognitive enhancer sabeluzole, a novel benzothiazol derivative, dose-dependently blocked the anticholinergic-induced deterioration of a sensorimotor deficit in rats.

Topics: Animals; Calcium Channel Blockers; Cerebral Infarction; Flunarizine; Male; Movement; Nervous System; Physical Stimulation; Piperidines; Rats; Rats, Inbred Strains; Scopolamine; Somatosensory Cortex; Thiazoles

Topics: Alzheimer Disease; Animals; Carbolines; Cholinesterase Inhibitors; Humans; Memory Disorders; Nicotine; Piperidines; Rats; Receptors, Cholinergic; Receptors, GABA-A; Receptors, Nicotinic; Thiazoles