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D Garceau

Publications and source records attributed to D Garceau.

17 recordsLinked to original sources
PubMed1995

Pharmacodynamics and pharmacokinetics of clentiazem and diltiazem in closed-chest anesthetized dogs.

In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.

Analysis of Variance↗
PubMed1995

[Diabetic nephropathy].

Diabetic nephropathy morbidity and mortality rates are high for both Type I and Type II diabetes. The various stages of diabetic nephropathy have been well documented for Type I diabetes, but not for Type II. We examine the natural history of this problem and recommended treatments, with emphasis on the characteristics of each type.

Diabetes Mellitus, Type 1↗
PubMed1994

Clentiazem, diltiazem, and cold cardioplegia in isolated ischemic rabbit hearts: relation between additive cardioprotection, physicochemical properties, and preservation of myocardial lipid components.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

A dose-response study of clentiazem, a chloro-derivative of diltiazem, in patients with stable angina. CAMCAT Study Group.

OBJECTIVES: The efficacy and safety of clentiazem were assessed in 199 patients with stable angina in a dose-ranging, placebo-controlled, double-blind, parallel design study. BACKGROUND: To date, this is the first large efficacy and safety study of clentiazem in patients with stable angina. METHODS: After washout and a 1-week placebo run-in period, patients received 20, 40, 80 or 120 mg/day of clentiazem tablets or placebo as a twice-daily dosage for 1 week of treatment after 1 week of dose titration. A symptom-limited exercise tolerance test was performed 4 and 12 h after dosing at the end of treatment and results were compared with baseline measurements. RESULTS: At 4 h after dosing, improvement of exercise duration from baseline value was significantly greater with clentiazem at doses of 40 mg/day (63 +/- 11 s), 80 mg/day (99 +/- 10 s) and 120 mg/day (70 +/- 11 s) than with placebo (34 +/- 10 s). Moreover, clentiazem (80 and 120 mg/day) increased the time to onset of angina and to > or = 1 mm of ST segment depression significantly more than did placebo. At submaximal exercise, clentiazem (40, 80 and 120 mg/day) decreased rate-pressure product, mainly as a result of a decrease in heart rate. At 12 h after dosing, improvement of exercise duration from baseline was significantly greater with clentiazem in doses of 80 mg/day (77 +/- 9 s) and 120 mg/day (70 +/- 10 s) than with placebo (42 +/- 9 s). The incidence of treatment-related adverse events with placebo (27%) and clentiazem (29%) was similar. The most frequently reported treatment-related adverse events with clentiazem were asthenia, headache (both 7.9%), first-degree atrioventricular block and dizziness (both 4.4%). CONCLUSIONS: The results of this short-term study suggest that clentiazem given twice daily in doses of 80 or 120 mg/day is safe and effective monotherapy in the treatment of stable angina.

Aged↗
PubMed1993

Immunosuppressive properties of the benzothiazepine calcium antagonists diltiazem and clentiazem, with and without cyclosporine, in heterotopic rat heart transplantation.

In vitro studies have shown that calcium channel blockers (CCB) exert inhibitory effects on immunocompetent cells but conflicting results have been reported as to the translation of these effects into significant in vivo immunosuppression. In this study we evaluated the effects of the benzothiazepine-like calcium blockers diltiazem and clentiazem, given alone or associated with cyclosporine on survival improvement of heterotopic rat heart transplants. Inbred male rats of the Lewis strain were used as recipients and Wistar-Furth as donors. Following abdominal implantation of the graft, recipients were randomly divided into 9 groups (n = 5). Group 1 were control isografts (Lew-Lew); group 2 were control allografts (WFu-Lew), and group 3 were allografts treated with low-dose oral cyclosporine 2 mg/kg/day. Groups 4 and 5 were allografts treated with oral diltiazem 0.25 and 2.50 mg/kg/day. Groups 6 and 7 were treated with oral clentiazem, 0.25 and 2.50 mg/kg/day. Groups 8 and 9 consisted of allografts receiving low-dose cyclosporine with either diltiazem or clentiazem 2.50 mg/kg/day, all drugs were administered daily by gavage. Graft function was monitored by transabdominal palpation, and rejection was considered to be complete when no contraction of the graft could be detected. Mean survival time of untreated allografts was 6.4 +/- 0.5 days. Cyclosporine alone increased the mean survival time to 10.6 +/- 2.7 days (P < 0.05 vs. group 2). At all doses studied, diltiazem and clentiazem significantly increased mean survival time of allografts, clentiazem being slightly more potent than diltiazem. In addition, the observed beneficial effects of the benzothiazepine-like calcium channel blockers were dose-dependent. When combined with cyclosporine, diltiazem and clentiazem interacted synergistically (mean survival time increased to 16.8 +/- 3.4 days for diltiazem and 15.8 +/- 1.4 days for clentiazem). These results demonstrate that the benzothiazepine-like calcium channel blockers, as opposed to phenylalkylamines or dihydropyridines, afford significant immunosuppression when used alone. These observations, and the fact that they beneficially interact with cyclosporine, suggest that the benzothiazepine-like calcium antagonists should be considered the drugs of choice when CCBs are to be selected in transplanted patients.

Animals↗
PubMed1992

Effects of clentiazem (TA-3090) and nifedipine on basal circulating catecholamine levels and on stimulation-evoked adrenal catecholamine secretion in anesthetized dogs.

The effects of TA-3090 (clentiazem) and nifedipine on basal sympathoadrenal activity and on the adrenal medullary response during splanchnic nerve stimulation were studied in dogs anesthetized with sodium pentobarbital. Plasma concentrations of epinephrine and norepinephrine were measured in aortic and adrenal venous blood before and after acute administration of the drugs, as well as during left splanchnic nerve stimulation before and after administration of drugs. Following intravenous injections, TA-3090 (30, 100, and 300 micrograms/kg) did not affect basal circulating catecholamine levels, whereas nifedipine (10, 30, and 100 micrograms/kg) markedly increased aortic epinephrine and norepinephrine concentrations in a dose-dependent manner in correlation with progressive decreases in mean arterial pressure. The changes in aortic epinephrine and norepinephrine concentrations were inversely related to those in mean arterial pressure (r = 0.603, p < 0.01; r = 0.536, p < 0.01; respectively). In response to direct splanchnic nerve stimulation (2 Hz, 2 ms, 1 min, 12 V), adrenal venous epinephrine and norepinephrine concentrations significantly increased, with a high degree of reproducibility. The catecholamine responses to splanchnic nerve stimulation were not affected by either TA-3090 or nifedipine at any dose tested. The present results suggest that the increases in circulating catecholamine levels following nifedipine administration are due to baroreflex activation secondary to the drug-induced hypotension. The study indicates that both TA-3090 and nifedipine did not significantly affect L-type Ca2+ channels related to catecholamine release in the adrenal medulla under the present experimental conditions.

Adrenal Glands↗
PubMed1992

The effect of a new calcium channel blocker (TA-3090) on lipoprotein profile and intestinal lipid handling in rodents.

Recent interest has focused on findings that drugs used to lower blood pressure may adversely modify plasma lipids and lipoprotein metabolism. This observation may explain why pharmacologic control of hypertension has failed to reduce the incidence of morbidity and mortality from coronary artery disease. The present study aims to evaluate the effect of TA-3090, a new calcium channel blocker, on fasting plasma lipids and lipoproteins, as well as on processes of intestinal fat absorption. Rats were treated by gavage with TA-3090 (10 mg/kg twice daily) for 4 days and compared with controls (n = 6 per group). Plasma cholesterol was increased in the treated group to (mean +/- SE) 74 +/- 2 vs 60 +/- 4 mg/dl (P less than 0.01), due mainly to an increased high density lipoprotein-cholesterol level (50 +/- 2 vs 37 +/- 3 mg/dl, P less than 0.005). Notably plasma triglycerides (TG) and low density lipoprotein-cholesterol were not significantly affected. Another group of TA-3090-treated animals was given an intraduodenal fat meal, and the rise in plasma TG and chylomicrons followed over 4 hr. Postprandial hypertriglyceridemia and chylomicronemia were significantly lower at 2 hr (P less than 0.05) and 3 hr (P less than 0.01) compared with controls. In a separate group of animals, the addition of TA-3090 to a 2% intralipid infusion intraduodenally was associated with significantly reduced TG and chylomicron-TG transport into lymph (P less than 0.05). Furthermore, experiments in rats pretreated with TA-3090 intraperitoneally and then given 2% intralipid intraduodenally were shown to have a significant decrease in mean flow rate (27%), TG transport (31%) and chylomicron-TG output (37%), when compared with controls. In vitro studies using jejunal organ culture to examine the effect of TA-3090 on intracellular lipid synthesis and secretion revealed that the addition of the drug to the medium resulted in significantly decreased TG synthesis and secretion. These data suggest that TA-3090 could be effective in increasing HDL-cholesterol and reducing postprandial chylomicronemia. Our findings support a role for TA-3090 directly on enterocyte absorption and/or intracellular lipid transport, and thus indicate the importance of intracellular calcium on these processes.

Animals↗
PubMed1991

Effect of clentiazem on lipid profile, lipoprotein composition and aortic fatty streaks in cholesterol-fed rabbits.

Numerous experimental studies have reported that common antihypertensive drugs such as diuretics, beta-blockers, and methyldopa have adverse effects on plasma lipids and lipoproteins. The present study was designed to define the effect of clentiazem (10 mg/kg/day) an antihypertensive drug, on hyperlipidemia in rabbits on a cholesterol-rich diet (1%) for 12 weeks. Compared with controls, clentiazem treated rabbits had lower plasma concentrations of triglycerides (55%), total cholesterol (24%), free cholesterol (27%), esterified cholesterol (23%) and phospholipids (24%). The decrease in cholesterol was accounted for by a reduction of VLDL-cholesterol (13%), IDL-cholesterol (24%) and primarily LDL-cholesterol (45%). Neither HDL-cholesterol nor chemical composition of VLDL, IDL, LDL and HDL was altered. When the aortic atherosclerotic involvement was evaluated by computerized planimetry, a 24% reduction of lesions was noted in clentiazem treated animals (P less than 0.05). Similarly, cholesterol content extracted from aortic wall was decreased. Our data therefore demonstrated that clentiazem is a potential antiatherosclerotic agent capable of decreasing plasma lipids and atherogenic lipoproteins as well as aortic fatty streaks.

Animals↗
PubMed1991

Peripheral vasodilator and cardiac properties of the 1,5-benzothiazepine calcium antagonist analog, TA-3090, in dogs.

Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

5-Lipoxygenase inhibitors and allergic conjunctivitis reactions in the guinea-pig.

The role of leukotrienes as mediators of microvascular permeability changes (assessed through the accumulation of [99mTc]albumin) associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva was investigated by means of two novel, structurally dissimilar 5-lipoxygenase inhibitors, L-651,392 and L-651,896. Both compounds, when applied topically in vivo to the eyes of sensitized guinea-pigs as a 0.1% suspension significantly inhibited 5-lipoxygenase in the conjunctiva as assessed by ex vivo challenge with either antigen or ionophore A23187 and measurement of the release of leukotriene B4-immunoreactive material. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs produced changes in conjunctival permeability which were blocked in part by either mepyramine (H1-receptor antagonist) or the 5-lipoxygenase inhibitors. Combinations of mepyramine and L-651,896 resulted in near complete suppression of the permeability response, suggesting that the reaction is mediated only by histamine and leukotrienes.

Animals↗
PubMed1987

The role of leukotriene D4 as a mediator of allergic conjunctivitis in the guinea-pig.

The role of leukotriene D4 (LTD4) as a mediator of conjunctival microvascular permeability changes associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva has been investigated using two novel, selective LTD4 receptor antagonists, L-648,051 and L-649,923. Changes in microvascular permeability were measured through the accumulation of [99mTc]albumin. LTD4 administered intravenously produced dose-related increases in conjunctival microvascular permeability through a mechanism which does not involve the generation of prostaglandins as indicated by the failure of indomethacin to attenuate the response. The response to LTD4 was significantly blocked by the receptor antagonists, L-648,051 and L-649,923. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs caused significant increases in conjunctival microvascular permeability. Following a single challenge, the antigen response was largely blocked by mepyramine (H1 receptor antagonist), but was unaffected by L-648,051 and L-649,923. Following a second challenge (24 h later) a substantial portion of the response was inhibited by L-648,051 and L-649,923. Indomethacin failed to inhibit either challenge. These results suggest that LTD4 may have a role in chronic allergic conjunctivitis.

Animals↗
PubMed1985

Hepatic adrenoceptors involved in the glycogenolytic response to exogenous (-)-norepinephrine in the dog liver in vivo.

Effects of various sympathomimetic amines on the hepatic glucose mobilization were studied in anesthetized dogs. Phenylephrine (30, 100, 300 micrograms), isoproterenol (0.1, 1, 10 micrograms) and (-)-norepinephrine (0.5, 5, 50 micrograms) were injected into the common hepatic artery in three separate groups of dogs. Dose-dependent increases in hepatic venous glucose concentration were observed following the injections of these drugs. Aortic glucose concentration also increased significantly, but to a lesser extent as compared with that in hepatic venous blood. Peak responses were obtained 3 to 5 min after the drug administrations. The increases in hepatic venous glucose concentration induced by the injections of (-)-norepinephrine were significantly diminished to a similar extent in dogs treated with either phentolamine (2 mg/kg, i.v.) or (-)-propranolol (0.2 mg/kg, i.v.). The results indicate that in the dog liver in vivo, both hepatic alpha- and beta-adrenoceptors can be involved in the hepatic glycogenolysis. The glycogenolytic response to exogenously administered (-)-norepinephrine is mediated via alpha- as well as beta-adrenoceptors in the liver of anesthetized dogs.

Animals↗
PubMed1984

Correlation between endogenous noradrenaline and glucose released from the liver upon hepatic sympathetic nerve stimulation in anesthetized dogs.

The metabolic role of neurally released noradrenaline (NA) was studied in the liver of anesthetized dogs. Sustained stimulation with various frequencies was directly applied on the anterior plexus of hepatic nerves. Stimulation-induced changes in plasma concentrations of endogenous catecholamines in hepatic venous blood were determined in correlation with concomitant changes in those of glucose (GL). Mean basal values for hepatic venous NA, adrenaline, dopamine, and GL were 0.062, 0.022, 0.032 ng/mL, and 97.9 mg%, respectively. Among these catecholamines, NA was the only one being released significantly during stimulation. While hepatic venous NA increased rapidly during stimulation, being maximum within 3 min, hepatic venous GL increased gradually, reaching a maximum value 5 min after the onset of stimulation. A highly significant correlation (r = 0.90, P less than 0.001) was found between changes in hepatic venous NA and GL concentrations observed during stimulation at various frequencies (2-16 Hz). However, hepatic vasoconstricting responses to stimulation were not correlated with increased hepatic venous GL. An alpha-blockade with phentolamine (2 mg/kg, iv) resulted in diminished release of GL by approximately 50% (P less than 0.05) and reduced hepatic arterial vasoconstriction by approximately 47% (P less than 0.01) upon stimulation (8 Hz, 5 min), even though NA release was markedly enhanced. We conclude that in the dog, NA is the sole catecholamine released within the liver in response to direct hepatic nerve stimulation, and NA thus released mediates the hepatic glycogenolysis via alpha-adrenoceptors.

Animals↗
PubMed1982

Pharmacological evidence for the existence of a neuronal amine uptake mechanism in the dog liver in vivo.

The possibility of a neuronal uptake mechanism in the liver was studied in dogs anesthetized with sodium pentobarbital. Plasma catecholamine concentrations in hepatic venous blood were determined by a radioenzymatic assay following injections of tyramine (30-1000 micrograms) into either the common hepatic artery or the portal vein. Concomitant changes in hepatic vascular parameters and aortic catecholamine concentrations were also investigated. The mean basal values for hepatic venous and aortic catecholamine concentrations were found to be 0.081 +/- 0.007 ng/mL and 0.433 +/- 0.080 ng/mL, respectively. Injections of tyramine (300 and 1000 micrograms) into the hepatic artery increased hepatic venous catecholamine concentrations significantly to 0.109 +/- 0.017 ng/mL and 0.126 +/- 0.023 ng/mL (P less than 0.05, n = 7), respectively. Hepatic arterial vascular conductance decreased concomitantly by 29.7 and 44.9% (P less than 0.05, n = 7), respectively. Intraportal injections of tyramine did not bring about significant changes in either hepatic venous catecholamine concentrations or portal venous vascular conductance at any dose tested. After inhibition of monoamine oxidase with pargyline (10 mg/kg. i.v.), the effects of tyramine (1000 micrograms) injected into the hepatic artery were potentiated. The duration of action was approximately 10 min after pargyline pretreatment (control duration: 1 min). The effects of tyramine were absent after inhibition of the neuronal uptake mechanism with desipramine (1 mg/kg. i.v.). No drug tested had a significant effect on aortic catecholamine concentrations. The present results support the presence of the neuronal uptake mechanism in the dog liver.

Animals↗