cardiovascular-agents and lubeluzole

Topics: Acute Disease; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Antibodies; Brain Ischemia; Calcium Channel Blockers; Cardiovascular Agents; Cell Adhesion Molecules; Clinical Trials as Topic; Cytidine Diphosphate Choline; Cytokines; Drug Therapy, Combination; Fibrinolytic Agents; Free Radical Scavengers; gamma-Aminobutyric Acid; Growth Substances; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; N-Methylaspartate; Neuroprotective Agents; Nootropic Agents; Piperidines; Stroke; Thiazoles; Thrombolytic Therapy

The safety and tolerability of single escalating doses of lubeluzole were evaluated in healthy male volunteers in 2 studies. In the first of 2 randomized, single-blind, placebo-controlled, dose-escalation studies, 6 subjects received single 30-minute infusions of 2.5, 5, and 10 mg of lubeluzole, and 2 additional subjects received placebo. In the second study 6 different subjects received a 1-hour infusion of 15 mg of lubeluzole, 5 of whom received the 20-mg dose, and 2 received 25 mg of lubeluzole. Two additional subjects received placebo. Small increases and decreases in PQ, QRS, QT, QTc, and QTm intervals were noted after infusion of all lubeluzole doses and placebo, however, these changes were within the normal ranges for these values except for the QTc for the 25-mg dose of lubeluzole. Significant prolongation of the QTc interval was observed at the end of the 1-hour infusion in both subjects receiving the 25-mg dose of lubeluzole. No clinically relevant changes in systolic time intervals, heart rate, blood pressure, and clinical laboratory values were noted in subjects receiving 2.5-25 mg of lubeluzole or placebo. Adverse experiences, predominantly lightheadedness and dizziness, were reported by subjects receiving doses of lubeluzole greater than or equal to 10 mg. Lubeluzole, administered as single intravenous doses of 2.5-15 mg, is safe and well tolerated in healthy male volunteers.

Topics: Adult; Cardiovascular Agents; Dose-Response Relationship, Drug; Electrocardiography; Hemodynamics; Humans; Injections, Intravenous; Male; Piperidines; Single-Blind Method; Thiazoles

We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (< 6 hours) ischemic stroke in the carotid artery territory.. A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days.. The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P = .019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of > 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS).. In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiovascular Agents; Carotid Artery Diseases; Cerebrovascular Disorders; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Intravenous; Logistic Models; Male; Middle Aged; Multivariate Analysis; Piperidines; Placebos; Safety; Thiazoles

Lubeluzole [(S)-9] has been synthesized by a convergent synthesis, alkylation of N-methyl-N-piperidin-4-yl-1,3-benzothiazol-2-amine (4) with (+)-(R)-1-chloro-3-(3,4-difluorophenoxy)propan-2-ol [(+)-(R)-8] being the key step. Alcohol (+)-(R)-8 was obtained from commercially available (R)-epichlorohydrin [(R)-6], while the thiazole derivative 4 was easily obtained starting from N-protected piperidin-4-one (1) in a three-step procedure. The same method was used in order to obtain both the (R)-stereoisomer of lubeluzole [(R)-9] and its racemate [(RS)-9]. Overall yields ranged from 20% to 35%. The enantiomeric excess values for (S)-9 and (R)-9 were 97% and 94% respectively, as analyzed by chiral HPLC.

Topics: Cardiovascular Agents; Molecular Structure; Piperidines; Stereoisomerism; Thiazoles

1-Chloro-3-(3,4-difluorophenoxy)-2-propanol was kinetically resolved by lipase-catalyzed esterification with vinyl butanoate in organic medium to yield the (S)-butanoate and the (R)-alcohol as the remaining substrate. In an enantioconvergent synthesis the mixture was subject to Mitsunobu esterification in one pot which converted the (R)-alcohol to the (S)-ester. The (S)-butanoate was hydrolyzed by lipase catalysis to give (S)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol. The two enantiopure chiral building blocks were used for synthesis of Lubeluzole and its enantiomer respectively.

Topics: Cardiovascular Agents; Catalysis; Lipase; Piperidines; Propanols; Stereoisomerism; Substrate Specificity; Thiazoles

Topics: Acute Disease; Brain Ischemia; Cardiovascular Agents; Cerebrovascular Disorders; Humans; Piperidines; Thiazoles

The cardiovascular effects of the antihypoxic and neuroprotective drug, lubeluzole, were investigated using beagle dogs anesthetized with halothane. Endocardial-contact electrode catheter was used for continuous monitoring of monophasic action potential (MAP), which could provide a precise information of repolarization phase. Intravenous administration of an efficacious dose of lubeluzole (0.63 mg/kg, n = 6) slightly decreased both the heart rate and the blood pressure. It did not change PQ interval and QRS width, while it significantly prolonged QT interval, corrected QT (QTc) and the duration of the MAP during the observation period over 60 min. The effects of drug on repolarization phase were late-onset and long-lasting compared with the time course of plasma drug concentrations, which changed as predicted by the two-compartment theory of pharmacokinetics. Additional injection of lubeluzole (2.5 mg/kg, n = 6) showed qualitatively similar changes to those of lower dose, and did not induce the cardiovascular collapse in any dog. Neither afterdepolarization nor ventricular escaped beat was detected during the observation period. The drug concentration in cardiac tissue was correlated linearly with the plasma drug concentration at 60 min after the second drug administration. These results indicate that lubeluzole exerts only minor cardiovascular effects except the prolongation of the repolarization period. The monitoring of plasma drug concentration may be helpful to estimate the steady-state distribution of drug to the heart, but less helpful to predict the QT prolongation. In future clinical trials, care must be taken with patients, especially those at risk to have prolonged repolarization.

Topics: Action Potentials; Animals; Blood Pressure; Cardiac Catheterization; Cardiovascular Agents; Disease Models, Animal; Dogs; Electrocardiography; Heart; Heart Rate; Injections, Intravenous; Microelectrodes; Myocardium; Neuroprotective Agents; Piperidines; Rats; Thiazoles

In search of a better treatment for acute ischemic stroke, we evaluated the use of lubeluzole and hemodilution with diaspirin cross-linked hemoglobin (DCLHb) therapy to test whether treatment with two complementary acting compounds provides more potent protection than either treatment alone.. We used unilateral reversible middle cerebral artery (MCA) and common carotid artery (CCA) occlusion of various durations in Long-Evans rats to produce ischemic cortical lesions. We calculated the average maximal lesion volume (Volmax) and the time required to produce half maximal lesion size (T50) in control animals (n = 31) and evaluated the effects on cerebral perfusion and infarct size of treatment with lubeluzole (n = 23), hemodilution (to 30% hematocrit) with albumin (n = 17) or DCLHb (n = 23), and combined lubeluzole + DCLHb therapy initiated 15 minutes after MCA/CCA occlusion.. The Volmax produced by MCA/CCA occlusion in control animals was 138.5 +/- 7.7 mm3, and T50 was 98.5 +/- 10.2 minutes. Lubeluzole alone reduced Volmax by 53% with no significant effect on T50. In contrast to lubeluzole, DCLHb hemodilution prolonged T50 by 68% with no significant effect on Volmax. Prolongation of T50 by DCLHb was not due to hemodilution itself, since a similar degree of hemodilution with albumin had no effect. Finally, combined lubeluzole+DCLHb rescued 72% of the tissue and augmented the effect of lubeluzole alone by 40% (Volmax, 66.3 +/- 13.0 versus 39.4 +/- 12.2 mm3) while prolonging T50 by 31%.. Combination therapy for acute stroke using compounds with complementary action can result in more complete attenuation of neuronal damage and demonstrates the possible clinical utility of combined neuroprotective and reperfusion therapies.

Topics: Animals; Aspirin; Cardiovascular Agents; Cerebral Infarction; Cerebrovascular Disorders; Drug Therapy, Combination; Hemodilution; Hemoglobins; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Inbred Strains; Reperfusion; Thiazoles