piperidines and Heart-Diseases

Topics: Anesthesia, Conduction; Anesthetics, Intravenous; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heart Diseases; Humans; Pain, Postoperative; Piperidines; Remifentanil

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Topics: Arrhythmias, Cardiac; Astemizole; Benzimidazoles; Butyrophenones; Cetirizine; Cisapride; Heart Diseases; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Serotonin Receptor Agonists; Terfenadine; Triprolidine

The electrocardiographic effects of ebastine and its active metabolite, carebastine, have been studied alone and in relevant drug-interaction studies in various patient populations. The overall cardiac tolerability of ebastine is excellent. In ebastine dose-ranging studies in adults and children, there were no meaningful dose-related changes in the QTc interval. At high doses of ebastine (5 to 10 times the recommended dose), a modest 10.3 msec increase in QTc was observed. Recommended doses of ebastine had no meaningful effect on QTc in the elderly or in patients with renal or hepatic insufficiency. Interaction studies involving ebastine with ketoconazole revealed a significant increase in the serum ebastine concentration and in the elimination half-life of ebastine, with a modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone) and a plateau QTc-ebastine relationship at higher ebastine levels. Similar, though more minor, QTc findings were observed during coadministration of ebastine with erythromycin. No QTc effects were noted when ebastine was administered with theophylline, and the QTc was similar when ebastine was administered with or without food. These findings indicate that ebastine is well tolerated and, in contrast to terfenadine and astemizole, has no clinically meaningful effect on the QTc interval even at high serum concentrations. As with other 'safe' antihistamines, which have shown similar modest increases in QTc when coadministered with ketoconazole, caution should be exercised when administering ebastine to patients having the long QT syndrome or hypokalaemia, and in patients receiving azole antifungals or macrolide antibacterials.

Topics: Aged; Butyrophenones; Child; Drug Interactions; Electrocardiography; Heart Diseases; Histamine H1 Antagonists; Humans; Piperidines

Topics: Animals; Bronchoconstriction; Butyrophenones; Guinea Pigs; Heart Diseases; Histamine H1 Antagonists; Piperidines; Potassium Channels; Rats; Structure-Activity Relationship; Terfenadine

Ca2+ overload is known to play a major role in cell dysfunctioning in ischaemia/reperfusion and in cardiac glycoside intoxication. Suppression of Ca2+ overload or its consequences may therefore improve cellular function in these pathological conditions. Recent evidence suggests that Ca2+ overload occurs secondary to Na+ overload. Both depressed efflux and increased influx mechanisms have been mentioned as factors contributing to Na+ load. Prevention of this initial Na+ overload, without interfering with the normal Na+ current during the action potential, may therefore represent a novel pharmacological approach in the management of Ca2+ overload. The new cardioprotective drug R 56865 potently protects the heart against Ca2+ overload: ischaemia induced and ouabain induced arrhythmias and cell death are prevented in the absence of negative inotropism (no L-type Ca2+ channel blockade). At least three interactions at the cellular level may be held responsible for protection in these conditions. First, excessive Na+ entry into myocardial cells due to non-inactivating Na+ channels in depolarised cells is inhibited at concentrations that do not affect action potential configuration or contractile force. This leads to prevention of Na+ overload and subsequent Ca2+ overload and cell death. Second, R 56865 inhibits the transient inward current in Ca(2+)-(over)loaded cells, thus effectively preventing after-depolarisations and triggered propagated contractions. It has been proposed that R 56865, independent of its action on Na+ loading, might reduce oscillatory Ca2+ release from the intracellular Ca2+ stores, without interfering with the normal release mechanisms. Third, the drug attenuates K+ efflux in Na+ and Ca2+ loaded cells. In this way, R 56865 may contribute to prevention of action potential shortening and inhomogeneous repolarisation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Benzothiazoles; Calcium; Calcium Channels; Heart; Heart Diseases; Humans; Myocardium; Piperidines; Potassium Channels; Sodium; Sodium Channels; Thiazoles

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

Topics: Adenine; Aged; Antihypertensive Agents; Female; Heart Diseases; Hematologic Neoplasms; Humans; Hypertension; Incidence; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Stroke

Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50 mg/m(2) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 g/m(2)/72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor-risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5-31 months, 58% in CR 11.4-30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21-31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients.

Topics: Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Female; Flavonoids; Follow-Up Studies; Heart Diseases; Humans; Hyperkalemia; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Piperidines; Polyamines; Premedication; Remission Induction; Risk; Sepsis; Sevelamer; Transplantation, Homologous; Treatment Outcome; Tumor Lysis Syndrome; Young Adult

To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD).. Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks.. Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer's Disease Assessment Scale-cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, -1.65 [p = 0.003]; 10 mg, -2.09 [p = 0.0002]). Greater improvements on the Clinician's Interview-Based Impression of Change-plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% (p = 0.004) of the 5 mg group and 32% (p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%).. Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Risk Factors; Smoking; Stroke; Treatment Outcome

We sought to assess the incidence and clinical significance of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI).. Elevated creatine kinase-MB (CK-MB) is prognostically important after PCI, but the prognostic significance of elevated cTnI after PCI is uncertain.. In a prospective substudy of the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) trials, which randomized patients with acute coronary syndromes (ACS) to receive aspirin or sibrafiban, we measured cTnI (positive, > or =1.5 ng/ml) and CK-MB (positive, > or =7 ng/ml) in 481 patients with PCI. Samples were collected immediately before and at 0, 8 and 16 h after PCI and analyzed by a core laboratory. The primary end point was the Kaplan-Meier estimate of death, myocardial infarction or severe, recurrent ischemia at 90 days.. Overall, 230 patients (48%) had elevated cTnI after PCI. Such patients underwent PCI sooner and were more likely to have coronary stenting. Elevated cTnI was associated with nonsignificantly higher risks of the primary end point (11.5% vs. 8.7%; p = 0.15) and of death (1.8% vs. 0.4%; p = 0.4) and a significantly higher risk of death or infarction (10.6% vs. 4.2%; p = 0.005). This pattern was more pronounced for patients who became positive only after PCI: primary end point, 20.7% vs. 10.1% for patients who remained negative after PCI (p = 0.05); death, 5.2% vs. 0% (p = 0.02); death or infarction, 18.1% vs. 4.1% (p = 0.007).. Elevated cTnI, often observed after PCI in patients with ACS, is associated with worse 90-day clinical outcomes. This marker, therefore, is a useful prognostic indicator in such patients.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Aspirin; Biomarkers; Creatine Kinase; Creatine Kinase, MB Form; Disease-Free Survival; Female; Heart Diseases; Humans; Isoenzymes; Male; Middle Aged; Myocardial Infarction; Oximes; Piperidines; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Sensitivity and Specificity; Stents; Troponin I

Our objective was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of lotrafiban, an oral glycoprotein IIb/IIIa inhibitor, in patients with a recent myocardial infarction, unstable angina, transient ischemic attack, or stroke.. A 12-week, double-blind, multi-center, placebo-controlled, parallel-group, phase II study of lotrafiban (the Anti-platelet Useful Dose Study) was conducted in patients. Lotrafiban or placebo was administered as a twice daily oral dose at four dose levels (5-100 mg) for 12 weeks with daily doses of aspirin (300-325 mg). The pharmacokinetics of lotrafiban were characterized with the use of a population approach and were described by a two-compartment model with first order absorption and first order elimination. The pharmacodynamic data, ex vivo platelet aggregation, were described with the use of a direct effect inhibitory sigmoidal model with a baseline. The relationship between the severity of bleeding episodes and predicted steady-state lotrafiban exposure was characterized by logistic regression.. Pharmacokinetic analysis showed that increasing age and decreasing creatinine clearance resulted in increased exposure to lotrafiban. The concentration-effect relationship was steep, with near complete inhibition of platelet aggregation at lotrafiban concentrations in excess of 20 ng/mL. Logistic regression showed that at exposures that exceeded approximately 835 ng. h/mL, the severity of adverse bleeding events increased considerably; this suggested that dosing recommendations should be generated to minimize the likelihood of patients having an area under the plasma concentration-time curve from 0 to 24 hours in excess of this value.. Patients whose age exceeded 65 years or whose creatinine clearance was less than 60 mL/min should be given a lower dose of lotrafiban than younger patients with good renal function.

Topics: Adult; Age Factors; Aged; Benzodiazepines; Creatinine; Demography; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Diseases; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Sex Factors

In the present study, we investigated the effect of remifentanil on cerebral blood flow velocity (CBFV). We investigated 20 patients (ASA physical status III) scheduled for elective coronary artery bypass graft surgery. Anesthesia was induced with remifentanil 5 microg/kg IV (Group 1, n = 10) or 2 microg/kg IV (Group 2, n = 10) and was maintained with 3 microg x kg(-1) x min(-1) IV (Group 1) or 1 microg x kg(-1) x min (-1) IV (Group 2). Pancuronium (0.1 mg/kg IV) was administered for muscle relaxation. Assisted ventilation followed by controlled ventilation via a mask was performed with the PaCO2 kept constant. Mean cerebral blood flow velocity (Vmean) was measured in the middle cerebral artery using a transcranial Doppler sonography system. Mean arterial pressure (MAP) was kept constant by the IV administration of norepinephrine. Measurements were made at baseline and every minute after remifentanil infusion for 10 min. Data were analyzed by using analysis of variance and a post hoc t-test (P < 0.05). Heart rate, MAP, and PaCO2 did not change over time in either group. Vmean did not change in Group 2. In contrast, there was a 31% decrease of Vmean in Group 1 (P < 0.05). The results show that large-dose, but not moderate-dose, remifentanil reduces CBFV unrelated to any changes in systemic hemodynamics in isocapnic cardiac patients.. Transcranial Doppler sonography was used to monitor remifentanil-induced changes in cerebral perfusion. We found that large doses of remifentanil reduced cerebral blood flow velocity despite constant perfusion pressure. This may implicate a central mechanism for cerebral hemodynamic effects of remifentanil.

Topics: Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Carbon Dioxide; Cerebrovascular Circulation; Coronary Artery Bypass; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Remifentanil; Ultrasonography, Doppler, Transcranial

Lubeluzole is a novel benzothiazole compound that has shown neuroprotective activity in preclinical models of ischemic stroke. The present multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of lubeluzole in the treatment of ischemic stroke.. Seven hundred twenty-one patients with clinical symptoms of acute ischemic stroke were randomized to receive either lubeluzole (7.5 mg over 1 hour, followed by a continuous daily infusion of 10 mg for up to 5 days) or placebo. Treatment was initiated within 6 hours of symptom onset. Mortality at 12 weeks was the primary efficacy end point. Secondary efficacy end points included neurological recovery (based on the National Institutes of Health Stroke Scale [NIHSS]), functional status (based on the Barthel Index), and level of disability (based on the Rankin Scale). Safety assessments included standard and continuous electrocardiographic monitoring, physical examination, measurements of vital signs, clinical laboratory evaluation, and adverse events reports.. The overall mortality rate at 12 weeks for lubeluzole-treated patients was 20.7% compared to 25.2% for placebo-treated patients (NS). Controlling for relevant covariates, the degree of neurological recovery (NIHSS) at week 12 significantly favored lubeluzole over placebo (P = .033). Lubeluzole treatment similarly resulted in significantly greater improvements in functional status (Barthel Index) (P = .038) and overall disability (Rankin Scale) (P = .034) after 12 weeks. A global test statistic confirmed that lubeluzole-treated patients had a more favorable clinical outcome at 12 weeks (P = .041). The safety profile of lubeluzole resembled that of placebo.. Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cerebrovascular Disorders; Double-Blind Method; Female; Heart Diseases; Humans; Male; Middle Aged; Mortality; Neuroprotective Agents; Piperidines; Survival Analysis; Thiazoles; Treatment Outcome

Cardiac dysfunction is secondary to acute mesenteric ischemia (AMI) and abdominal aortic aneurysms (AAA). The underlying cause of distant organ damage in the heart is the formation of oxidative stress caused by ischemia-reperfusion. In this study, we investigated the possible protective effects of a novel mitochondria-targeted antioxidant MitoTEMPO on contractile dysfunction and structural defects of the rat papillary muscle caused by abdominal ischemia-reperfusion (AIR).. In the experiments, adult Wistar-Albino rats were used and animals were divided randomly into 3 groups; sham-operated group (SHAM), an IR group that had aortic cross-clamping for 1 h followed by 2 h reperfusion, and a third group that received protective 0.7 mg/kg/day MitoTEMPO injection for 28-day before IR. As a result, it was observed that MitoTEMPO injection had a protective effect on the mechanical activities and structural properties of the papillary muscle impaired by AIR. Our study also showed that AIR disrupted the contractile function of the papillary muscle for each stimulation frequency and post-potentiation responses tested. This is common for each measured and calculated mechanical parameter and MitoTEMPO injection showed its protective effects.. Consequently, calcium homeostasis seems to be impaired by AIR, and MitoTEMPO may exert its protective effect through energy metabolism by directly targeting the mitochondria.

Topics: Animals; Heart Diseases; Ischemia; Organophosphorus Compounds; Oxidative Stress; Piperidines; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury

Sepsis is one of the most prevalent diseases in the world. The development of cardiac dysfunction in sepsis results in an increase of mortality. It is known that Bruton's tyrosine kinase (BTK) plays a role in toll-like receptor signaling and NLRP3 inflammasome activation, two key components in the pathophysiology of sepsis and sepsis-associated cardiac dysfunction. In this study we investigated whether pharmacological inhibition of BTK (ibrutinib 30 mg/kg and acalabrutinib 3 mg/kg) attenuates sepsis associated cardiac dysfunction in mice. 10-week old male C57BL/6 mice underwent CLP or sham surgery. One hour after surgery mice received either vehicle (5% DMSO + 30% cyclodextrin i.v.), ibrutinib (30 mg/kg i.v.), or acalabrutinib (3 mg/kg i.v.). Mice also received antibiotics and an analgesic at 6 and 18 h. After 24 h, cardiac function was assessed by echocardiography

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Benzamides; Cecum; Disease Models, Animal; Heart; Heart Diseases; Inflammasomes; Ligation; Male; Mice; Mice, Inbred C57BL; Piperidines; Protein Kinase Inhibitors; Punctures; Pyrazines; Pyrazoles; Pyrimidines; Sepsis

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.

Topics: Animals; Cecum; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Heart Diseases; Humans; Linagliptin; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Pyrrolidines; Sepsis; Signal Transduction

To study prospectively influences of donepezil, an acetylcholinesterase inhibitor against Alzheimer disease, on cardiovascular system, we evaluated cardiovascular changes occurring during new initialized treatment with donepezil in 49 dementia patients over 6 months. No patient suffered from cardiovascular events. In clinical changes between baseline and the first evaluation after donepezil treatment, heart rate and plasma brain natriuretic peptide (BNP) levels as a marker for heart failure did not change (BNP: 59.62 ± 62.71 pg/mL at baseline to 53.18 ± 42.34 pg/mL at first evaluation; P = 0.262). We further examined plasma BNP levels in 2 groups into which the patients were divided at baseline according to the cut-off plasma BNP level of 60 pg/mL. In patients with high level of BNP, the BNP levels decreased after administration of donepezil (116.39 ± 76.58 pg/mL at baseline to 82.24 ± 46.64 pg/mL at first evaluation; P = 0.011) with the tendency to be reduced in the follow-up period. BNP did not change in patients with low level of BNP. Donepezil seemed to be safe in patients with dementia without symptomatic heart disease and significantly decreased plasma BNP levels in patients with subclinical chronic heart failure.

Topics: Aged; Aged, 80 and over; Cardiovascular Physiological Phenomena; Donepezil; Female; Follow-Up Studies; Heart Diseases; Heart Failure; Humans; Indans; Male; Piperidines; Prospective Studies; Registries; Treatment Outcome

Cardiovascular toxicity represents one of the major reasons for the termination of the development of drugs, even in late development phases. This growing issue is often not restricted to specific therapeutic areas, and it is gaining critical importance, in particular for chronically administered drugs, highlighting the limitations in terms of sensitivity of the current investigational paradigms. Furthermore, drug-related changes may become evident after long-term administration for different reasons, including accumulation of the drug in the heart. This article describes how the integrated use of investigational tools represents a powerful approach for the early identification and characterization of cardiotoxicity in preclinical development. Cardiac changes were observed in the dog after long-term oral administration of casopitant, a neurokinin 1 receptor antagonist, developed for the treatment of depression and anxiety. Different approaches and sensitive biomarkers were used in a time-course study to investigate the onset, progression, and reversibility of the lesion. The integrated evaluation of cardiovascular parameters, electron microscopy, troponin I, and natriuretic peptide results highlighted any minimal early changes, allowing the full and deep characterization of the lesion. The outcome of this study was the driver for drug development decision making on casopitant and backup drugs.

Topics: Administration, Oral; Animals; Biomarkers; Creatine Kinase, MB Form; Dogs; Drug Evaluation, Preclinical; Heart Diseases; Male; Microscopy, Electron, Transmission; Models, Animal; Myocardium; Natriuretic Peptide, Brain; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperazines; Piperidines; Troponin I

The amino-terminal pro-brain natriuretic peptide (NT-proBNP) is released into the plasma predominantly from ventricular cardiomyocytes, particularly in patients with chronic cardiac diseases, although small amounts are detectable in the plasma of healthy subjects. While NT-proBNP has been widely exploited in human medicine, limited literature is available related to its characterization in veterinary medicine (e.g., correlation with damage and specificity) and, particularly, in the context of preclinical drug safety assessment. This paper describes the analytical performance characteristics and the biological variability of NT-proBNP in male beagle dogs by using a commercially available enzyme-linked immunosorbent assay. Male beagle dogs were treated with Casopitant, an NK1 receptor antagonist under development for depression and anxiety, which, when administered chronically to dogs, caused cardiac toxicity. Heart weight increase, myocardial necrosis, degeneration, and inflammation associated with high serum levels of cardiac troponin I characterized the end stage pathology observed in dogs treated orally at 40 mg/kg for 39 weeks. Based on these data, ad hoc studies were designed in order to evaluate the possible relationship between NT-proBNP serum levels and both standard toxicology endpoints, such as the organ weight and histology, as well as nonstandard endpoints such as macroscopic morphometry and echocardiography. Early changes of NT-proBNP serum levels were observed following 2 weeks of treatment onward, preceding most, if not all of the anatomical and functional changes. The results obtained demonstrate that NT-proBNP acts as an early biomarker of cardiac changes, representing a sensitive and predictive marker of drug-induced cardiac liability.

Topics: Administration, Oral; Animals; Antidepressive Agents; Anxiety Disorders; Biomarkers; Depression; Dogs; Drug Administration Schedule; Echocardiography; Enzyme-Linked Immunosorbent Assay; Heart Diseases; Humans; Male; Natriuretic Peptide, Brain; Neurokinin-1 Receptor Antagonists; Organ Size; Peptide Fragments; Piperazines; Piperidines; Predictive Value of Tests; Risk Factors; Troponin I

To lower the incidence and severity of fetal cardiovascular depression during maternal fetal surgery under general anesthesia.. We hypothesized that supplemental intravenous anesthesia (SIVA) with propofol and remifentanil would lower the need for high-dose inhalational anesthesia and provide adequate maternal depth of anesthesia and uterine relaxation. SIVA technique would minimize prolonged fetal exposure to deep inhalational anesthetics and significant intraoperative fetal cardiovascular depression.. Fetal hypoxia and significant fetal hemodynamic changes occur during open fetal surgery because of the challenges such as surgical manipulation, hysterotomy, uterine contractions, and effects of anesthetic drugs. Tocolysis, a vital component of fetal surgery, is usually achieved using volatile anesthetic agents. High concentrations of volatile agents required to provide an appropriate degree of uterine relaxation may cause maternal hypotension and placental hypoperfusion, as well as direct fetal cardiovascular depression.. We reviewed medical records of 39 patients who presented for ex utero intrapartum treatment and mid-gestation open fetal surgery between April 2004 and March 2009. Out of 39 patients, three were excluded because of the lack of echocardiographic data; 18 patients received high-concentration desflurane anesthesia and 18 patients had SIVA with desflurane for uterine relaxation. We analyzed the following data: demographics, fetal medical condition, anesthetic drugs, concentration and duration of desflurane, maternal arterial blood pressure, intraoperative fetal echocardiogram, presence of fetal bradycardia, and need for intraoperative fetal resuscitation.. Adequate uterine relaxation was achieved with about 1.5 MAC of desflurane in the SIVA group compared to about 2.5 MAC in the desflurane only anesthesia group (P = 0.0001). More fetuses in the high-dose desflurane group compared to the SIVA group developed moderate-severe left ventricular systolic dysfunction over time intraoperatively (P = 0.02). 61% of fetuses in the high-dose desflurane group received fetal resuscitative interventions compared to 26% of fetuses in the SIVA group (P = 0.0489).. SIVA as described provides adequate maternal anesthesia and uterine relaxation, and it allows for decreased use of desflurane during open fetal surgery. Decreased use of desflurane may better preserve fetal cardiac function.

Topics: Adult; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Inhalation; Anesthetics, Intravenous; Desflurane; Echocardiography; Female; Fetal Diseases; Fetus; Gestational Age; Heart Diseases; Heart Valve Diseases; Hemodynamics; Humans; Intraoperative Complications; Isoflurane; Monitoring, Intraoperative; Piperidines; Pregnancy; Propofol; Remifentanil; Treatment Outcome; Uterus

Topics: Animals; Atherosclerosis; Cannabinoids; Clinical Trials as Topic; Heart Diseases; Humans; Metabolic Diseases; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, LDL; Rimonabant; Weight Gain

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Germany; Heart Diseases; Humans; Indans; Piperidines; Syncope

To better define the efficacy and safety of rimonabant, the first selective cannabinoid type 1 (CB(1)) receptor antagonist, in a large population of overweight and obese patients using pooled efficacy data from three Phase III nondiabetes Rimonabant in Obesity and Related Metabolic Disorders (RIO) studies, selected efficacy data from the RIO-Diabetes study, and pooled safety data for all four RIO studies.. The RIO studies enrolled patients who were either overweight (BMI >27 kg/m(2)) with at least one comorbidity (i.e., hypertension, dyslipidemia, or, for RIO-Diabetes, type 2 diabetes) or obese. All patients received daily treatment with rimonabant (5 or 20 mg) or placebo for 1 year plus a hypocaloric diet (600 kcal/day deficit) and advice on increased physical activity. RIO-Europe (n = 1,508), RIO-North America (n = 3,045), and RIO-Lipids (n = 1,036) excluded patients with type 2 diabetes; untreated dyslipidemia was an entry requirement for RIO-Lipids. RIO-Diabetes (n = 1,047) required the presence of type 2 diabetes inadequately controlled by sulfonylurea or metformin monotherapy.. The pooled intention-to-treat population comprised 5,580 patients without diabetes (3,165 completed treatment) and 1,047 patients with diabetes (692 completed treatment). Most efficacy measures improved during the 4-week placebo run-in period, except that HDL cholesterol decreased as expected in the early phase of a hypocaloric diet. After 1 year of randomized treatment, changes from baseline with 20 mg rimonabant in the nondiabetic population were as follows: body weight -6.5 kg, waist circumference -6.4 cm, HDL cholesterol +16.4%, triglycerides -6.9%, fasting insulin -0.6 muU/ml, and homeostasis model assessment for insulin resistance (HOMA-IR) -0.2 (all P < 0.001 vs. placebo). In the diabetic population, 20 mg rimonabant reduced A1C levels by 0.6% (P < 0.001 vs. placebo). Regression analysis of change in HDL cholesterol, triglycerides, adiponectin (in RIO-Lipids), and A1C (in RIO-Diabetes) versus body weight at 1 year by ANCOVA suggested that 45-57% of the effect of rimonabant could not be explained by the observed weight loss. At 1 year, adverse events more frequently reported with rimonabant were gastrointestinal, neurological, and psychiatric in nature. Serious adverse events were infrequent and almost equivalent to placebo. Overall discontinuation rates were similar across treatment groups, except discontinuation from adverse events, which occurred more frequently with 20 mg rimonabant versus placebo (most commonly, depressive disorders [1.9 vs. 0.8%], nausea [1.4 vs. 0.1%], mood alterations with depressive symptoms [1.0 vs. 0.6%], and anxiety [1.0 vs. 0.3%]). A thorough review of psychiatric and neurological adverse events was performed.. In overweight/obese patients, 20 mg/day rimonabant produced weight loss and significant improvements in multiple cardiometabolic risk factors such as waist circumference, A1C, HDL cholesterol, and triglycerides. Rimonabant was generally well tolerated, with more frequently reported adverse events being gastrointestinal, neurological, and psychiatric in nature.

Topics: Cannabinoid Receptor Antagonists; Cannabinoids; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diet, Reducing; Exercise; Heart Diseases; Humans; Metabolic Diseases; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Safety

Topics: American Heart Association; Animals; Cardiotonic Agents; Heart Diseases; Humans; Piperidines; Potassium Channel Blockers; PPAR delta; Pyrazoles; Rimonabant; Thiazoles

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.

Topics: Animals; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Memantine; Neuroprotective Agents; Patient Selection; Piperidines; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Stroke

Patient-controlled analgesia (PCA) using intravenous opioids is increasing in popularity for children aged 5 years and over. To our knowledge there are no reports on the use of PCA in children with remifentanil in the postoperative period. We report successful use of remifentanil for intravenous (IV) PCA in a child scheduled for suprasellar arachnoid cystectomy with Axenfeld-Rieger syndrome who needed good postoperative analgesia because of accompanying serious problems.

Topics: Abnormalities, Multiple; Analgesia, Patient-Controlled; Analgesics, Opioid; Arachnoid Cysts; Child; Eye Diseases; Genes, Dominant; Heart Diseases; Humans; Infusions, Intravenous; Male; Monitoring, Intraoperative; Pain Measurement; Pain, Postoperative; Piperidines; Remifentanil; Syndrome

Topics: Astemizole; Butyrophenones; Heart Diseases; Histamine H1 Antagonists; Humans; Piperidines; Terfenadine

Topics: Estrogen Antagonists; Estrogen Replacement Therapy; Female; Heart Diseases; Humans; Lipids; Piperidines; Raloxifene Hydrochloride

Topics: Drug Approval; France; Government Agencies; Heart Diseases; Humans; Infant; Infant, Newborn; Parasympatholytics; Piperidines; Risk

Topics: Anti-Ulcer Agents; Child; Cisapride; Drug Prescriptions; Heart Diseases; Humans; Infant; Infant, Newborn; Infant, Premature; Piperidines

Terfenadine and astemizole belong to the second generation histamine H1 antagonists and are widely prescribed for allergic and upper respiratory diseases. The popularity of the newer H1 antihistamines is due to their ability to provide relief from allergic symptoms without the undesirable side effect of sedation commonly associated with first generation H1 receptor antagonists such as diphenhydramine and promethazine. Recent clinical evidence that the second generation histamine H1 antagonists terfenadine and astemizole have the potential for inducing life threatening ventricular arrhythmias has raised questions as to whether other drugs in this class have similar cardiotoxic potential. The objective of this study was to evaluate and compare the arrhythmogenic potential of a series of second generation antihistamines in a quantitative experimental model predictive of adverse ECG effects in man. Antihistamines were given intravenously and electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. To determine the relative cardiotoxic potential of the antihistamines, the lowest dose producing significant prolongation of the QTc interval was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by histamine at 10 micrograms/kg i.v. (antihistamine ED50). The second generation antihistamines studied were astemizole (CAS 68844-77-9), carebastine (CAS 90729-42-3), cetirizine hydrochloride (CAS 83881-52-1), ebastine (CAS 90729-43-4), norastemizole (CAS 75970-99-9), terfenadine (CAS 50679-08-8) and terfenadine carboxylate (CAS 83799-24-0). The second generation antihistamines astemizole, ebastine and terfenadine produced pronounced dose-dependent QTc interval prolongation effects. These arrhythmogenic effects occurred at doses that were between 1 and 4 times their respective peripheral antihistamine doses. These drugs produced significant disruption of the ECG wave form including large amplitude, morphologically aberrant T-waves and, in some cases, torsades de pointes-type arrhythmias. In contrast, terfenadine carboxylate (100 mg/kg i.v.), norastemizole (20 mg/kg, i.v.) and carebastine (50 mg/kg, i.v.), the major metabolites of terfenadine, astemizole and ebastine, were largely devoid of adverse ECG effects. Similarly, cetirizine (20 mg/kg, i.v.) was also found to not alter ECG or cardiova

Topics: Animals; Arrhythmias, Cardiac; Benzimidazoles; Blood Pressure; Electrocardiography; Guinea Pigs; Heart Diseases; Heart Rate; Hemodynamics; Histamine H1 Antagonists; Male; Models, Biological; Piperidines

Second generation antihistamines are widely used because of their efficacy in treating allergic disorders without significant sedative side effects. Recent clinical evidence shows that some of the early prototypes in this class, namely terfenadine and astemizole, have the potential for producing torsade de pointes, a rare form of ventricular arrhythmia that is life-threatening. Important questions have been raised as to whether this is a property shared by newer, recently-introduced second generation antihistamines. The objective of this study was to characterize and compare the ECG and cardiovascular effects of terfenadine (CAS 50679-08-8) and ebastine (CAS 90729-43-4), a new second generation antihistamine, in an experimental animal model predictive of the cardiotoxic proclivity of these agents. Also, the drug interaction effect of the antifungal drug ketoconazole (CAS 65277-42-1) was evaluated, which blocks hepatic first-pass biotransformation of ebastine and terfenadine leading to increased cardiotoxity of terfenadine in man, on the ECG effects of terfenadine and ebastine in this animal model. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) were administered intravenously to anesthetized guinea pigs. Electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured during the course of the experiment. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. In separate studies in conscious guinea pigs, the effect of oral ketoconazole (200 mg) on the ECG effects of oral terfenadine (60 mg) and ebastine (10 mg) was studied. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) produced significant prolongation of the QTc interval and disruption of the ECG signal when given intravenously to anesthetized guinea pigs. The ECG effects were characterized by large amplitude, morphologically aberrant T-waves, and instances of arrhythmogenic activity. Both drugs produced pronounced bradycardia and hypotension. In conscious animals, pretreatment with oral ketoconazole significantly enhanced the QTc interval prolongation effects of terfenadine and ebastine. Oral terfenadine and ebastine, when given alone at the doses tested, were devoid of adverse QTc interval prolongation effects in the conscious guinea pig. In separate studies in conscious guinea pigs, oral loratadine (10 mg; CAS 79794-75-5) given alone or in animals pretreated with ketoconazole did not affect ECG parameters. The present st

Topics: Animals; Butyrophenones; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Electrocardiography; Guinea Pigs; Heart Diseases; Histamine H1 Antagonists; Ketoconazole; Liver; Male; Mixed Function Oxygenases; Piperidines; Terfenadine; Torsades de Pointes

Topics: Animals; Anti-Arrhythmia Agents; Guinea Pigs; Heart Diseases; Heart Rate; Lidocaine; Ouabain; Piperidines; Structure-Activity Relationship

The effects of pirmenol in the treatment of ventricular arrhythmias were studied in 6 patients with heart disease and in 11 control subjects. In the patients with heart disease, ventricular arrhythmias were associated with myocardial infarction in 3, with mild aortic stenosis in 2 and with hypertrophic cardiomyopathy in 1. Pirmenol was administered in a 100 mg, 150 mg or 200 mg twice daily dosing schedule. Dosages were increased if necessary, until response, defined as greater than 70% suppression in the rate of premature ventricular contractions, occurred. Arrhythmia suppression was maintained in all 6 patients with heart disease at 52 weeks of follow-up.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Double-Blind Method; Female; Heart Diseases; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

The influence of cardiac function as measured by the left ventricular ejection fraction on the pharmacokinetic variables of a new antiarrhythmic drug, lorcainide, was investigated in 20 cardiac patients. Patients were divided into two groups: those with normal (ejection fraction greater than .40) or depressed (ejection fraction less than .40) left ventricular function. The elimination half-life, plasma clearance rates, or volume of distribution of lorcainide were not significantly different in patients with either normal or depressed cardiac function. A decrease in arrhythmia frequency could be correlated to plasma lorcainide concentration in the majority of patients, and it was noted that at least 0.1 mg/L of lorcainide was required for the presence of an antiarrhythmic effect. Three unusual cases are presented to illustrate the importance of measuring plasma drug concentrations and calculating the drug pharmacokinetics and to correlate these to the antiarrhythmic response in order to minimize the risk of plasma drug accumulation and side effects. A review of published data shows a three- to sixfold interpatient variation in the elimination half-life of lorcainide with practical implications in its use as an antiarrhythmic drug.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Piperidines

Topics: Angina Pectoris; Aniline Compounds; Arrhythmias, Cardiac; Calcium; Cardiomegaly; Diuretics; Heart Diseases; Heart Failure; Humans; Hypertension; Indapamide; Nifedipine; Perhexiline; Piperidines; Pyridines; Verapamil

The cardiovascular effects of a single i.v. dose (2 mg/kg over 5 min) of lorcainide were studied in 14 patients with heart disease. In the haemodynamic part of the study (6 patients), the aortic and pulmonary systolic, diastolic and mean pressures, left ventricular systolic and end-diastolic pressures, cardiac output and the rate of rise of left ventricular pressure were measured before and for 30 min after administration of the drug. Lorcainide produced a slight and short-lasting decrease in the aortic and pulmonary systolic pressures, and all other pressure values remained unchanged. The cardiac output and systemic vascular resistance were not altered by lorcainide. It consistently depressed the rate of rise of left ventricular pressure (maximum mean decrease 19%). In the angiographic part of the study (8 patients), the ejection fraction and the mean velocity of circumferential fiber shortening were measured before and 5 min after lorcainide. In all but one patient, lorcainide decreased the ejection fraction (mean decrease 11.6%), and the mean velocity of circumferential fiber shortening was uniformly diminished by lorcainide (mean decrease 29.7%). Thus, lorcainide moderately impaired myocardial performance in patients with normal and reduced left ventricular function without producing hypotensive side effects.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Pressure; Cardiac Output; Female; Heart; Heart Diseases; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Time Factors; Vascular Resistance

Topics: Adult; Aged; Electrocardiography; Female; Heart Diseases; Heart Rate; Humans; Male; Middle Aged; Perhexiline; Piperidines; Pulse

Topics: Anesthesia, Obstetrical; Benperidol; Female; Heart Diseases; Humans; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Adult; Aged; Asthma; Biliary Tract Diseases; Dioxoles; Drug Tolerance; Duodenal Diseases; Dysmenorrhea; Esophagitis; Female; Gastritis; Heart Diseases; Humans; Kidney Calculi; Male; Middle Aged; Migraine Disorders; Muscles; Piperidines; Spasm

Topics: Adolescent; Adult; Aged; Female; Gastrointestinal Diseases; Heart Diseases; Humans; Male; Middle Aged; Piperidines; Psychophysiologic Disorders; Tranquilizing Agents

Topics: Amides; Clopamide; Diuretics; Female; Heart Diseases; Humans; Male; Middle Aged; Natriuresis; Piperidines