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Biomedical subjects

S Laganière

Publications and source records attributed to S Laganière.

At least 19 recordsLinked to original sources
PubMed2005

Morphogenetic plasticity of adult human pancreatic islets of Langerhans.

The aim of this study was to investigate the phenotypic plasticity of pancreatic islets of Langerhans. Quiescent adult human islets were induced to undergo a phenotypic switch to highly proliferative duct-like structures in a process characterized by a loss of expression of islet-specific hormones and transcription factors as well as a temporally related rise in the expression of markers of both duct epithelial and progenitor cells. Short-term treatment of these primitive duct-like structures with the neogenic factor islet neogenesis-associated protein (INGAP104-118) induced their reconversion back to islet-like structures in a PI3-kinase-dependent manner. These neoislets resembled freshly isolated human islets with respect to the presence and topological arrangement of the four endocrine cell types, islet gene expression and hormone production, insulin content and glucose-responsive insulin secretion. Our results suggest that adult human islets possess a remarkable degree of morphogenetic plasticity. This novel observation may have important implications for understanding pancreatic carcinogenesis and islet neogenesis.

Adult↗
PubMed1996

Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 2. Hemodynamic and drug disposition studies.

We assessed hepatic functions and systemic and splanchnic hemodynamics in a new model of hepatic sinusoidal fibrosis. Fibrosis was induced by the simultaneous administration for 8 weeks of diethyl-stilbestrol (DES) (10 mg twice weekly, subcutaneously) and cholesterol-supplemented diet (1%) in rabbits. A marked and progressive impairment of hepatic function was observed during the 8 weeks of treatment with a significant decrease in indocyanine green (ICG) systemic clearance (-89%; P < .001) and aminopyrine elimination (-69%; P < .001). In fibrotic animals, hyperdynamic circulation was found with an increased cardiac output (+73%, P < 0.01) and a decreased peripheral vascular resistance (-50%; P < .005), as evaluated by the microsphere technique in animals that were awake. The total portal venous inflow was not significantly modified in fibrotic rabbits. However, since there was a marked increase in the liver weight, the portal venous inflow was significantly decreased when expressed per gram of liver weight (-30%; P < .05). In contrast, the hepatic artery blood flow was markedly increased, even when expressed per gram of liver weight (+95%; P < .01). Portal pressure was significantly increased in treated rabbits (from 7.4 +/- .4 to 14.4 +/- .6 mm Hg, P < .01). This new experimental model could prove useful to evaluate the influence of extensive perisinusoidal fibrosis on exchanges between plasma and hepatocytes, particularly of protein-bound substances.

Animals↗
PubMed1996

Pharmacokinetic and pharmacodynamic interactions between diltiazem and quinidine.

OBJECTIVES: To examine the pharmacokinetic and pharmacodynamic interactions between quinidine and diltiazem because both drugs can inhibit drug metabolism. METHODS: Twelve fasting, healthy male volunteers (age, 24 +/- 5 years; weight, 75 +/- 10 kg) received a single oral dose of diltiazem (60 mg) or quinidine (200 mg), alone and on a background of the other drug, in a crossover study. Background treatment consisted of 100 mg quinidine twice a day or 90 mg sustained-release diltiazem twice a day for 2 day before the study day. RESULTS: Pretreatment with diltiazem significantly (p < 0.05) increased the area under the curve of quinidine from 7414 +/- 1965 to 11,213 +/- 2610 ng.hr/ml and increased its terminal elimination half-life (t1/2) from 6.8 +/- 1.1 to 9.3 +/- 1.5 hours. Its oral clearance was decreased from 0.39 +/- 0.1 to 0.25 +/- 0.1 L/hr/kg, whereas the maximal concentration was not significantly affected. Diltiazem disposition was not significantly affected by pretreatment with quinidine. Diltiazem pretreatment increased QTc and PR intervals and decreased heart rate and diastolic blood pressure. No significant pharmacodynamic differences were shown for diltiazem alone versus quinidine pretreatment. CONCLUSION: Diltiazem significantly decreased the clearance and increased the t1/2 of quinidine, but quinidine did not alter the kinetics of diltiazem with the dose used. No significant pharmacodynamic interaction was shown for the combination that would not be predicted from individual drug administration.

Adult↗
PubMed1996

Rate-dependent effects of sematilide on ventricular monophasic action potential duration and delayed rectifier K+ current in rabbits.

Our objective was to define the actions of sematilide in rabbits and to assess the contribution of the delayed rectifier (IK) to rate dependence of action potential duration (APD) in rabbit ventricular myocardium. In studies in vivo, New Zealand White rabbits were used to obtain dose/response curves of the effects of sematilide on APD from contact monophasic action potentials (MAP), ventricular effective refractory period (VERP), and ECG. Sematilide or placebo was administered as an i.v. bolus followed by a 45-min infusion in the following cumulative manner: infusion 1 (1 mg/kg bolus + 8 micrograms/kg/min); infusion 2 (2 mg/kg + 20 micrograms/kg/min); and infusion 3 (7 mg/kg + 68 micrograms/kg/min). At each infusion level, VERP and APD at 75% repolarization (APD75) were measured during cardiac pacing between 200- and 400-ms cycle length (CL). Serum sematilide levels were analyzed by high-performance liquid chromatography (HPLC). In studies in vitro, sematilide's effects on the delayed rectifier were assessed in isolated rabbit ventricular myocytes by using patch-clamp techniques. Sematilide infusion in vivo resulted in stable serum levels of 1.3 +/- 0.5, 3.7 +/- 1.4, and 13.4 +/- 1.8 micrograms/ml during infusions 1, 2, and 3, respectively. Maximal effects occurred at infusion 2, such that at 400 ms CL, sematilide widened predrug APD75 (145 +/- 5 ms) by 27 +/- 4% (p < 0.001 vs. placebo), and at 200-ms CL, sematilide prolonged predrug APD75 (115 +/- 10 ms) by only 18 +/- 4% (p < 0.001 vs. placebo; p < 0.05 vs. 400-ms CL). Similar effects were observed in VERP. Sematilide enhanced rate dependence of APD and produced the same degree of APD prolongation at a given CL, during accommodation to and recovery from rapid pacing. Rabbit ventricular myocytes appeared to have at least two types of delayed rectifier. Sematilide selectively blocked IKr, and block was not relieved by repetitive stimulation. In conclusion, the APD-widening effect of sematilide was independent of previous pacing history. Sematilide had little influence on background processes likely responsible for shortening APD because of rapid repetitive stimulation.

Action Potentials↗
PubMed1995

Simultaneous determination of diltiazem and quinidine in human plasma by liquid chromatography.

A novel method for simultaneous determination of diltiazem and quinidine in human plasma is described. Plasma is alkalinized and extracted with methyl tert.-butyl ether. The ether phase is separated and evaporated. The residue is reconstituted in 0.2 ml of mobile phase containing 56 mM octanesulfonic acid then washed twice with n-hexane. Aliquots are chromatographed on a silanol-deactivated reversed-phase column using a mobile phase containing aqueous H2SO4 (0.01 M, pH 2)-methanol-acetonitrile (45:45:10) and 10 mM octanesulfonic acid. Peaks are monitored with a UV detector set at 237 nm and a fluorescence detector using an excitation set at 247 nm and a 270 nm UV cut-off filter at the emission. Calibration and standard curves were linear from 1 to 130 ng on-column for diltiazem and from 2 to 600 ng on-column for quinidine. Limits of quantitation were 2 and 4 ng/ml for diltiazem and quinidine, respectively. Recoveries from spiked plasma were 94.0 to 102.5% (R.S.D. 6.0-11.4%) for diltiazem and 98.5% to 104.1 (R.S.D. 7.7-8.7%) for quinidine over the ranges studied. In vitro stability was studied in spiked plasma samples stored at -80 degrees C for sixteen months. Both diltiazem and quinidine remained within 10% from nominal values. For ex vivo stability at -80 degrees C, a plasma sample obtained from a volunteer 2 h after oral administration of diltiazem (60 mg) was analysed for two days after sampling and eighteen months later. The mean deviation from initial measured was 4.7%.

Chromatography, High Pressure Liquid↗
PubMed1994

High-performance liquid chromatographic assay for sematilide in plasma using solid-phase extraction microcolumn technology.

A simple and sensitive high-performance liquid chromatographic assay for quantification of sematilide in rabbit plasma was developed. After extraction of samples via solid-phase extraction on C8 microcolumns, baseline resolution was achieved on a reversed-phase 5 microns Inertsil ODS-2 column using isocratic conditions with mobile phase consisting of water-glacial acetic acid-acetonitrile-methanol-triethylamine (93.5:4.0:1.5:0.5:0.5) and UV detection at 254 nm. The assay did not require evaporation or reconstitution steps. The injection interval was 8 minutes. The inter-day coefficient of variation for replicate analysis of spiked samples was less than 7.6% and the accuracy was more than 97% over the standard curve range (0.128 to 3.191 microM) using 0.5 ml of plasma. The assay has been successfully applied to pharmacokinetic studies in rabbits.

Animals↗
PubMed1994

A comparison of lumbar epidural and intravenous fentanyl infusions for post-thoracotomy analgesia.

This double-blind randomised study compared the analgesic efficacy, respiratory effects, side effects, and pharmacokinetic disposition of 24 hr lumbar epidural and intravenous infusions of the same dosage regimen of fentanyl (1.5 micrograms.kg-1 bolus then 1 microgram.kg-1.hr-1 infusion) in 50 patients after thoracotomy. Patients received either epidural fentanyl and intravenous normal saline, or epidural normal saline and intravenous fentanyl, for postoperative analgesia, after a standard low-dose alfentanil and isoflurane general anaesthetic. Visual analogue pain scores were lower in the epidural group (P < 0.05) only at two hours postoperatively, and there was no difference in the amount of supplementary morphine self-administered by patient-controlled analgesic pump. A mainly spinal analgesic effect probably occurred in the first few hours since fentanyl was not detectable in the plasma of patients in the epidural group until two hours after bolus injection; its concentration was less at that time than after intravenous injection (P < 0.05). Thereafter there was no difference in the plasma concentration profiles between the two groups. Seven patients in the epidural group and ten patients in the intravenous group received naloxone for PaCO2 > 50 mmHg, and one patient in the intravenous group had the infusions stopped because of PaCO2 elevation and somnolence. In patients who did not receive naloxone, the epidural route produced better analgesia throughout the study period (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1994

Amrinone and N-acetylamrinone assay in human plasma using solid-phase extraction and reversed-phase chromatography.

A simple and sensitive liquid chromatographic assay for simultaneous quantitation of amrinone and N-acetylamrinone in human plasma was developed. The method involves extraction of samples via activated solid-phase extraction Bond Elut C18 disposable columns, followed by chromatographic separation on a reversed-phase phenyl column using isocratic condition and UV detection. The assay can measure concentrations of both compounds over the range 0.075-10 micrograms ml-1. The injection interval is 11 min. The inter-day relative standard deviation (RSD) for replicate analysis of spiked samples is less than 10% and the accuracy more than 94% for both compounds over the standard curve range. The assay has been successfully applied to pharmacokinetic studies in humans.

Amrinone↗
PubMed1992

Intravenous nifedipine for prevention of myocardial ischaemia after coronary revascularization.

We sought to determine the pharmacokinetic and pharmacodynamic behaviour of a continuous infusion of nifedipine given for prevention of myocardial ischaemia following coronary artery bypass graft (CABG) surgery. Patients scheduled for elective CABG, who had good left ventricular function, were included. Only normotensive patients who did not require treatment with vasoactive drugs and were bleeding less than 100 ml.hr-1 following surgery were included. The patients were randomly distributed into two groups: a control group not receiving any treatment and a treated group receiving a bolus (3 micrograms.kg-1.min-1 for 5 min) and maintenance (0.2 micrograms.kg-1.min-1) infusion of nifedipine, starting upon arrival in the recovery room and continuing for four hours. Patients given nifedipine were compared with control patients in order to determine the effects of nifedipine on haemodynamic function and on the postoperative incidence of hypotension, hypertension, myocardial ischaemia and infarction. Continuous 2-lead Holter monitoring was used to detect myocardial ischaemia. Infarction was diagnosed by 12-lead ECGs and by assessment of the MB-isoenzyme creatine kinase. The infusion of nifedipine rapidly achieved and maintained plasma concentrations between 30 and 40 ng.ml-1. The pharmacokinetic studies revealed a systemic clearance of nifedipine of 0.371 +/- 0.101 L.hr-1.kg-1, an apparent volume of distribution of 0.764 +/- 0.288 L.kg-1 and an elimination half-life of 1.4 +/- 0.6 hr. No correlation was found between plasma concentration of nifedipine and mean arterial pressure (MAP). The incidence of postoperative hypotension (MAP < 70 mmHg) and hypertension (MAP > 100 mmHg) was comparable between the groups. All haemodynamic variables were similar in both groups during the study period. Of 23 patients who received nifedipine, none showed evidence of ischaemia within six hours of starting the infusion. During the same period, five of 24 patients in the control group had ST-segment deviation suggestive of myocardial ischaemia (P = 0.05, Fisher's exact test). Three patients in the control group and none in the nifedipine group suffered perioperative myocardial infarction (P = NS). In conclusion, the continuous infusion of nifedipine used in this study is safe and reduces the incidence of myocardial ischaemia in normotensive patients with good left ventricular function following CABG. Further studies of larger number of patients are required to determine the role of calcium entry blockers following coronary artery surgery.

Blood Pressure↗
PubMed1992

Effect of an acute dose of alcohol on the pharmacokinetics of oral nifedipine in humans.

Pharmacokinetic and pharmacodynamic interactions of alcohol and nifedipine were assessed in 10 healthy human volunteers. Doses of 20 mg (2 x 10-mg capsules) of nifedipine were administered with either 150 ml of orange juice or 75 ml of alcohol (94%) in 75 ml of orange juice according to a crossover randomized design. Plasma nifedipine levels were monitored for 16 hr after each dosing, along with pulse rate and blood pressure. The relative bioavailability of nifedipine, measured as AUC, was increased by 54% (533 vs 346 ng.hr/ml) after the dose of alcohol (P less than 0.0002). However, there were no significant differences between treatments in Cmax, tmax, or t1/2. Although there was no difference in the systolic and diastolic blood pressure and pulse rate between the two treatment groups, the time to reach peak heart rate was significantly faster in the group treated with alcohol (1.4 vs 2.2 hr). This study shows that ethanol increases the bioavailability of nifedipine and decreases the time for onset of increased heart rate.

Administration, Oral↗
PubMed1992

Intravenous nifedipine to treat hypertension after coronary artery revascularization surgery. A comparison with sodium nitroprusside.

We administered sodium nitroprusside (SNP) or nifedipine intravenously to patients who became hypertensive after elective coronary revascularization and compared their effects on hemodynamics and the electrocardiogram in a parallel, randomized, open-label study. Four of 21 patients treated with nifedipine required the addition of SNP to maintain mean arterial pressure less than 90 mm Hg, compared with 4 of 28 patients in the SNP group who required the addition of nifedipine. The success rates of nifedipine (81%) and SNP (86%) were not significantly different. There was no difference in the incidence of adverse ST-segment changes during drug infusion (4% versus 5%) or perioperative myocardial infarction (9.5% versus 10.7%) in the nifedipine versus SNP groups, respectively. The plasma nifedipine concentration (mean value +/- SD) at steady state for 21 patients receiving nifedipine was 119 +/- 42.5 ng/mL. The pharmacokinetic variables for nifedipine were as follows (mean values +/- SD): systemic clearance, 0.525 +/- 0.228 L.h-1.kg-1; apparent volume of distribution, 0.738 +/- 0.446 L/kg; and elimination half-life, 1.02 +/- 0.51 h. These values are similar to those reported previously in healthy volunteers. We conclude that intravenous nifedipine can be used safely to control hypertension after coronary revascularization but were unable to demonstrate an advantage of nifedipine compared with SNP in preventing postoperative ischemia or infarction in this group of patients who had good left ventricular function.

Blood Pressure↗
PubMed1991

Acute and chronic studies with the anticholinesterase Huperzine A: effect on central nervous system cholinergic parameters.

High affinity choline transport, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) were assessed in rats after acute and chronic administration of the AChE inhibitor Huperzine A. Acute treatment: Forty-five min after a single injection of Huperzine A (0.5 mg/kg i.p.) the activity of AChE was significantly decreased by 15-30% in hippocampus, striatum and septum. The activity of ChAT was not altered. In the hippocampus high affinity choline transport was attenuated by 25%, whereas no effect in the striatum was observed. After 90 min, both inhibition of AChE and attenuation of high affinity choline transport had returned to control values. A dose of 0.1 mg/kg (i.p.) did not produce significant effects. Similar results were obtained with physostigmine (0.25 mg/kg), although the duration of inhibition of AChE was shorter than that with Huperzine A. Chronic treatment: After 5 days (twice a day), at 0.5 mg/kg, the activity of AChE was significantly reduced by 20-30% in every region of the brain studied. High affinity choline transport in the hippocampus was reduced by 28%, 45 min after the last injection, but in the striatum there was no effect. The activity of ChAT was not affected in any region of the brain studied. Thus, acute or chronic treatment with Huperzine A: did not alter ChAT; reduced high affinity choline transport in the hippocampus in a transient manner; and had a longer duration of action as an AChE inhibitor than physostigmine. Moreover, tolerance to low-toxicity doses of Huperzine A was minimal, contrary to what has been observed with other inhibitors of AChE.

Acetylcholinesterase↗
PubMed1989

Stereoselective high-performance liquid chromatographic assay for propranolol enantiomers in serum.

A simple and sensitive stereoselective high-performance liquid chromatographic assay for the quantitation of propranolol enantiomers in serum is described. The method involves conversion of the propranolol enantiomers to diastereomeric urea derivatives by reaction with the clinical reagent (+)-phenylethylisocyanate, followed by chromatographic separation of the diastereomeric products. Conditions of the derivatization reaction were optimized to achieve rapid and quantitative yield with either of the enantiomers. Baseline resolution of the diastereomers was achieved on a reversed phase C8 column with an isocratic mobile phase. Fluorescence detection afforded an absolute on-column detection limit of 100 pg. The assay has been applied to pharmacokinetic studies in humans and small laboratory animals.

Animals↗
PubMed1988

Alteration in the disposition and metabolism of S(-)-propranolol in rats with active respiratory viral infection.

Viral illness elicited marked changes in the disposition and metabolism of S(-)-propranolol in rats during the course of a recent viral outbreak in our rodent colony. A slower rate of gastrointestinal absorption and a much higher clearance of orally-administered S(-)-propranolol were observed. The apparent increase in metabolic clearance is partly attributed to a decrease in the serum protein binding of S(-)-propranolol. A direct stimulation of microsomal oxidative metabolism was also suggested by an increase in urinary recovery of the monohydroxyl metabolites of S(-)-propranolol. In addition, a greater portion of the phenolic metabolites were present in urine as the glucuronic acid conjugates, which may be explained by a concomitant stimulation in conjugative reaction. These observations are unusual in that existing reports indicate that viral illness in man and animals generally leads to an inhibition of oxidative drug metabolism.

Administration, Oral↗
PubMed1987

Altered S(--)-propranolol disposition in bilateral ureter-ligated rats.

Previous clinical studies indicate that the metabolic clearance of oral (+/-)-propranolol is reduced in end-stage renal failure patients. Animal models are needed to explore the mechanism(s) underlying the observed metabolic inhibition in man. The disposition kinetics of S(-)-propranolol were characterized after intravenous and peroral administration in rats with acute renal failure induced by bilateral ureteral ligation (BUL). No alteration in either the systemic clearance or the apparent volumes of distribution of S(-)-propranolol was observed in renal failure animals after a single intravenous dose of 1.5 mg/kg. In contrast, acute uremia did elicit a change in the bioavailability of orally administered S(-)-propranolol. At 36 h after ureteral ligation, the area under the serum concentration-time curve after a 6 mg/kg oral dose of S(-)-propranolol was significantly elevated in renal failure animals, which corresponded to an approximate two fold increase in its systemic availability (from 7.7 to 20.5%). Such an effect could not be demonstrated at times earlier than 36 h after ureteral ligation. Additional experiments were performed to evaluate whether concomitant changes in gastrointestinal absorption or serum protein binding of S(-)-propranolol could have contributed to the apparent increase in oral availability. The results lead to the hypothesis of an inhibited first-pass hepatic metabolism of S(-)-propranolol in acute renal failure and suggest a significant time delay in the onset of inhibition.

Acute Kidney Injury↗
PubMed1986

Adaptation of intestinal sugar and amino acid transport to gastric hyperalimentation.

These studies were undertaken to analyze the effects in dogs of the administration of liquid polymeric diets by gastric tube for 14 days on brush-border absorptive functions measured in vitro. Transport studies of D-glucose, L-leucine and L-alanine have been performed by a rapid filtration technique using brush border membrane vesicles isolated from different segments of the small intestine in order to get insights about events occurring directly at the membrane level. Our results clearly show that only the Na+ -gradient dependent pathways for sugars and neutral amino acids transport were modified in treated dogs as compared to chow-fed controls. The adaptation to the diets varied according to the intestinal segment considered and the effects were dependent on both the nature of the diet and the transport function analysed. These effects cannot be due to heterogeneity in the populations of vesicles isolated in the different situations and cannot be attributed to a modification of either the passive permeability of the membrane to solutes or ions or the membrane potential. Our results are best explained by changes in carrier densities along the small intestine in response to modification in the local concentrations of nutrients sequential to faster flow rates in the small intestine. The liquid nature of the polymeric diets, combined with their high fat and low residue content as compared to dog chow, could act in concert to promote faster rates of gastric emptying and intestinal transit, thus leading to modifications in nutrient availability along the small intestine.

Adaptation, Physiological↗