piperidines and Arterial-Occlusive-Diseases

Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.. Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.. The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

Topics: Administration, Oral; Adolescent; Arterial Occlusive Diseases; Benzodiazepines; Double-Blind Method; Drug Evaluation; Female; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Myocardial Ischemia; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Research Design; Secondary Prevention; Stroke

A clinical trial was performed to assess the effects on quality of life of a treatment (ifenprodil tartrate 20 mg, 3 times daily for one year) in patients suffering from peripheral arterial obliterative disease of the lower extremities with intermittent claudication. A specific questionnaire--ARTEMIS--was used to evaluate quality of life. The study enabled the responsiveness over time of the ARTEMIS questionnaire to be checked. During this open, prospective, multicentre study, patients requiring treatment for peripheral arterial disease of the lower extremities and recruited by angiologists and general practitioners filled in the complete or short form of the ARTEMIS questionnaire, respectively, at baseline, and at 3, 6, 9 and 12 months. 4821 patients were recruited. 4494 questionnaires were analysed (169 from the angiologist group and 4325 from the general practitioner group). The majority of the patients (mean age 67 years) were men (70%), either former or current smokers (68%), with high blood pressure (54%), hyperlipidaemia (48%) and type 2 (non-insulin-dependent) diabetes mellitus (16%), and with a 3-year history of intermittent claudication (+/- 3.5) on average. Quality-of-life scores improved (as from month 3) between baseline and month 12. This progression was significant for all dimensions of the reduced questionnaire (p < or = 0.0001) and for 12 of the 15 dimensions of the complete version. These quality-of-life results should be measured against the global clinical improvement, which was rated as good by the investigators (70% of cases). Treatment tolerability was assessed for the 4821 patients recruited and was judged satisfactory. The number and type of serious events and recorded deaths corresponded to events commonly observed in this elderly population. These results show how the ARTEMIS quality-of-life scales can be used in community practice during symptomatic treatment with a vasoactive agent such as ifenprodil, to assess quality-of-life improvements in patients suffering from stage II peripheral arterial disease of the lower extremities.

Topics: Aged; Arterial Occlusive Diseases; Female; Humans; Male; Piperidines; Prospective Studies; Quality of Life; Regional Blood Flow; Time Factors; Vasodilator Agents

Authors report results on a comparative multicenter double blind trial carried out to assess the efficacy of Ifenprodil tartrate (*) (60 mg a.d.) versus placebo in symptomatic treatment of stable peripheral arterial occlusive disease (Fontaine stage II). Ninety four patients were included in this six months, two parallel group study (2 homogeneous groups) which shows a statistically significant functional improvement in the treatment group versus the placebo group. After six months of treatment, the maximum walking distance (MWD)--main assessment criteria--was 126.0 +/- 18.5 meters in the Ifenprodil group versus 46.4 +/- 20.2 meters in the placebo group (p = 0.005). This represents an improvement of 62.1% in the Ifenprodil group versus 21.0% in the placebo group. An improvement of at least 50% in MWD was observed in 41.3% of patients treated by Ifenprodil and in only 12.5% of patients receiving placebo (p = 0.002). The evolution of ankle/brachial systolic post exercise index from JO to J180 was not significantly different in the two groups. Clinical and biological tolerance of Ifenprodil tartrate was excellent.

Topics: Aged; Arterial Occlusive Diseases; Chronic Disease; Double-Blind Method; Female; Humans; Leg; Male; Middle Aged; Piperidines; Placebos; Vasodilator Agents

Topics: Arterial Occlusive Diseases; Double-Blind Method; Female; Humans; Leg; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Prospective Studies; Random Allocation; Vasodilator Agents

Platelet aggregation in response to 5-hydroxytryptamine was investigated in 40 normal subjects, in 45 patients with acute myocardial infarction, and in 65 patients with peripheral arterial obstructive disease. It was found that of the 110 patients with cardiovascular disease, 40% had a biphasic irreversible platelet aggregation, whereas this phenomenon occurred in only 7.5% of the normal population. A double-blind placebo-controlled study further showed that a subacute treatment with ketanserin, a selective 5-HT2-receptor antagonist both on platelets and on vascular tissue, efficiently abolished the irreversible platelet aggregation in patients hyperreactive to 5-hydroxytryptamine. In an additional open study, including 10 patients with peripheral arterial obstructive disease, a chronic treatment with ketanserin 40 mg t.i.d. for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta thromboglobulin levels. Since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerotic diseases, where platelet activation is thought to be involved.

Topics: Aged; Arterial Occlusive Diseases; beta-Thromboglobulin; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Ketanserin; Male; Middle Aged; Myocardial Infarction; Piperidines; Placebos; Platelet Aggregation; Serotonin

Topics: Aminopyrine; Anesthesia, Inhalation; Anesthesia, Intravenous; Arterial Occlusive Diseases; Benzophenones; Clinical Trials as Topic; Dipyrone; Drug Combinations; Humans; Nitrous Oxide; Piperidines

Topics: Aged; Ancrod; Arterial Occlusive Diseases; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Humans; Hyperemia; Intermittent Claudication; Lactates; Middle Aged; Physical Exertion; Piperidines; Pyruvates

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.

Topics: Administration, Oral; Animals; Arterial Occlusive Diseases; Brain Infarction; Cerebral Arterial Diseases; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Injections, Intravenous; Isoquinolines; Macaca fascicularis; Middle Cerebral Artery; Models, Molecular; Piperidines; Pyridines; Rats; Structure-Activity Relationship; Tetrahydroisoquinolines; Venous Thrombosis

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Camphanes; Cannabinoids; Coronary Artery Disease; Dronabinol; Epinephrine; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in maintaining genomic integrity and in the repair of DNA strand breaks. However, the activation of PARP by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The excessive activation of PARP causes a rapid depletion of intracellular energy leading to cell death. The present study examined the effect of post-ischemic pharmacological inhibition of PARP in a rat focal cerebral ischemia model. In Long-Evans rats, focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery (CCA) occlusion for 90 min. A PARP inhibitor, 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ; IC50=1 microM/l) was injected i.p. 30 min after the onset of MCA occlusion (control: 10, 20, 40 and 80 mg/kg; n=7 each). Twenty-four hours later, the total infarct volume was measured. Regional blood flow in the right parietal cortex decreased to approximately 20% of the baseline following MCA occlusion in all groups. PARP inhibition lead to a significant decrease in damaged volume in all treated groups with the largest reduction in the 40 mg/kg group (111.5+/-24. 8 mm3, mean+/-SD, p<0.01), compared to the control group (193.5+/-28. 6 mm3). We also found there was a significant increase of poly(ADP-ribose) immunoreactivity in the ischemic region, as compared to the contralateral side, with DPQ treatment diminishing poly(ADP-ribose) production. These findings indicate that DPQ exerts its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors may be effective for treating ischemic stroke, even when the treatment is initiated after the onset of ischemia.

Topics: Animals; Arterial Occlusive Diseases; Cerebral Infarction; Cerebrovascular Circulation; Enzyme Inhibitors; Immunohistochemistry; Ischemic Attack, Transient; Isoquinolines; Male; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Long-Evans

Topics: Animals; Arterial Occlusive Diseases; Cerebral Arteries; Excitatory Amino Acid Antagonists; Immunohistochemistry; Interneurons; Ischemic Attack, Transient; Male; Mice; Parietal Lobe; Parvalbumins; Piperidines

The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.. Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.. The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001).. CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Topics: Animals; Arterial Occlusive Diseases; Brain; Brain Edema; Brain Ischemia; Cats; Cerebral Arteries; Cerebral Infarction; Dialysis Solutions; Excitatory Amino Acid Antagonists; Female; Lactates; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Receptors, N-Methyl-D-Aspartate; Staining and Labeling; Tetrazolium Salts

To elucidate the role of cerebral adenosine triphosphate (ATP)-sensitive K+ channels (KATP) on arterial pressure regulation during acute cerebral ischemia in spontaneously hypertensive rats (SHR), intracerebroventricular (i.c.v.) injections of either glibenclamide, a specific blocker of KATP, or pinacidil, a KATP opener, were performed in SHR and Wistar-Kyoto rats (WKY). Intracerebroventricular injections of glibenclamide elicited a vasopressor response in WKY with bilateral ligation of the carotid arteries, whereas the response was smaller in SHR. It increased plasma AVP, but decreased pituitary AVP in WKY with ligation, but not in SHR. Systemic administration of an AVP V1 receptor antagonist, OPC-21268, abolished the vasopressor responses to i.c.v. injections of glibenclamide in WKY. Bilateral ligation of the carotid arteries augmented the vasodepressor responses to i.c.v. injections of pinacidil in WKY, but not in SHR. Cerebral KATP may play a role in buffering a rise in arterial pressure by inhibiting the release of AVP from the pituitary glands during acute cerebral ischemia in WKY, but this mechanism might be deranged in SHR, probably due to impaired responsiveness of cerebral KATP to ischemia.

Topics: Adenosine Triphosphate; Adrenergic alpha-Antagonists; Animals; Antidiuretic Hormone Receptor Antagonists; Antihypertensive Agents; Arginine Vasopressin; Arterial Occlusive Diseases; Blood Pressure; Brain Ischemia; Carotid Arteries; Cerebral Cortex; Glyburide; Guanidines; Hypertension; Hypoglycemic Agents; Injections, Intravenous; Injections, Intraventricular; Ligation; Male; Pinacidil; Piperidines; Potassium Channels; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY

A simultaneous analysis of both the variations of the flow in the stenosis artery and the distal PO2, was carried out during an injection of an alpha-blocker: the Tartrate d'Ifenprodil, on twenty-five patients afflicted with occlusive disease of the lower limbs requiring surgery. The measurements were taken under general anaesthesia, before any surgical operation, the hemodynamic and ventilatory balance being monitored by radial manometry and arterial gas analysis. We observe an increase of proximal arterial flow and at the same time an improvement of the distal TcPO2. Moreover, the variations of microcirculation flow measured by TcPO2 are correlated with proximal flow variations, this relation: delta TcPO2 = K delta Q + A is more true in the first and the second stages of Fontaine. With the same (Tartrate d'Ifenprodil) posology, the distal benefit measured by transcutaneous oximetry is less important in advanced stages compared with other stages (everything else being equal). The transcutaneous measurement of the distal oxygen pressure, allows an objective view of microcirculatory improvement obtained by a vasoactive substance (ifenprodil tartrate) considering the specific nature of each patient arteriopathy.

Topics: Adult; Aged; Arterial Occlusive Diseases; Blood Gas Monitoring, Transcutaneous; Female; Humans; Leg; Male; Microcirculation; Middle Aged; Piperidines; Regional Blood Flow; Vasodilator Agents

Topics: Acid-Base Equilibrium; Aged; Aminopyrine; Analgesics; Arterial Occlusive Diseases; Benzophenones; Dipyrone; Drug Combinations; Drug Evaluation; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Time Factors

Topics: Adult; Analgesics; Angiography; Arterial Occlusive Diseases; Drug Combinations; Fibrinolysin; Fibrinolysis; Humans; Infusions, Parenteral; Injections, Intra-Arterial; Male; Papaverine; Piperidines; Procaine

Topics: Acute Disease; Anesthesia, Epidural; Arterial Occlusive Diseases; Carboxylic Acids; Chronic Disease; Embolism; Gangrene; Humans; Piperidines; Sympatholytics; Thromboangiitis Obliterans; Thrombosis; Vasodilator Agents