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Biomedical subjects

J M Poirier

Publications and source records attributed to J M Poirier.

At least 19 recordsLinked to original sources
PubMed1999

Determination of acyclovir in plasma by solid-phase extraction and column liquid chromatography.

After oral administration, valacyclovir, the L-valyl ester of acyclovir, converts to the antiherpes virus drug, acyclovir. The bioavailability of acyclovir after valacyclovir administration is between 3- to 4.5-fold higher than that achieved after oral acyclovir administration. Therefore, despite the drug's short terminal half-life (3 hours), acyclovir plasma concentrations obtained after oral administration of the prodrug offer a more convenient dosage regimen in patients with herpes zoster than that required after acyclovir administration. Acyclovir is also used for viral infection prophylaxis in patients with hematologic disorders and in those who have undergone solid organ transplantation. We have described a simple and selective liquid chromatographic method for the determination of acyclovir in plasma using a new polymeric reversed-phase sorbent for solid-phase extraction. A mean acyclovir absolute recovery of 90% was found after elution of the drug from the cartridge with the mobile phase. This procedure allowed us to measure 62.5 ng/mL of acyclovir with an acceptable precision using a plasma volume of 250 microL, and no drug was found to interfere with the assay. This method is suitable for the therapeutic monitoring of acyclovir in patients who have been given a wide variety of coadministered drugs.

Acyclovir↗
PubMed1998

Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol.

INTRODUCTION: Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects. METHODS AND RESULTS: We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7). CONCLUSION: In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.

Animals↗
PubMed1998

Optimisation of itraconazole therapy using target drug concentrations.

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.

Antifungal Agents↗
PubMed1998

[Recent aspects of monitoring the dosage of aminoglycosides and vancomycin].

The narrow range of therapeutic serum concentrations of aminoglycosides and vancomycin and the great variations in their pharmacokinetics from one person to another makes it important to monitor patients at risk that are treated with them. The technique of customizing dosages based on the population pharmacokinetics enables an effective treatment to be rapidly established from a few measurements of serum concentrations. Aminoglycosides may be given as single daily doses because of their concentration-dependent activity. The high peak concentration produces an enhanced, prolonged bactericidal activity, while a low residual concentration reduces the risk of toxicity. The effect of vancomycin is time-dependent. Giving it by continuous i.v. infusion maximizes the time during which the serum antibiotic concentration is effective but non-toxic. Monitoring serum concentrations can help reduce health care costs. But medical training in pharmacokinetics is needed for the optimal use of these therapeutic tools.

Aminoglycosides↗
PubMed1997

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.

OBJECTIVE: The pharmacokinetics of a single i.v. dose of the new racemic beta-adrenoceptor-blocker nebivolol [0.073 mg base.kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). METHODS: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. RESULTS: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. CONCLUSION: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

Adrenergic beta-Antagonists↗
PubMed1997

Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.

AIMS: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. METHODS: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed. RESULTS: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. CONCLUSIONS: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

Adipose Tissue↗
PubMed1997

Plasma itraconazole concentrations in patients with neutropenia: advantages of a divided daily dosage regimen.

A group of 36 patients in the hematology department of Saint-Antoine Hospital, Paris, France, was on chemotherapy. The patients were also given antiacid drugs to prevent gastrointestinal toxicity and itraconazole as prophylaxis against aspergillosis. The antifungal drug was given as 100-mg capsules three times a day shortly after meals. The plasma itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography at steady state. Of 36 patients, 29 (81%) had adequate plasma itraconazole concentrations (> or = 250 ng/ml) after 8 +/- 2 days. The 7 patients with low plasma itraconazole concentrations were given 200 mg three times a day. Of the 36 patients, 34 (94%) had effective plasma concentrations within 2 weeks of the beginning of treatment. The two remaining patients were lost to follow-up. The proposed itraconazole regimen provides effective prophylaxis against aspergillosis and represents a substantial economic advantage over a single daily dose of 400 to 600 mg. The marked intrapatient and interpatient variations in plasma itraconazole indicate the need for regular therapeutic drug monitoring to ensure effective plasma itraconazole concentrations in all neutropenic patients.

Adolescent↗
PubMed1997

Epidemiological aspects of diabetes in Cameroon: what is the role of tropical diabetes?

Diabetes is a worldwide public health problem made more acute in Africa by low socio-economic standards. Cases with an unusual clinical course are frequent and probably related to tropical diabetes, a syndrome that has not yet been precisely defined. This study reports the results of a prospective study carried out in Cameroon on 550 diabetic patients attending the Yaounde Central Hospital who were followed between December 1990 and July 1994. They were classified according to WHO criteria into 136 insulin-dependent diabetes mellitus (IDDM) (24.7%), 405 non-insulin- dependent diabetes mellitus (NIDDM) (73.7%) and 9 diabetes secondary to other diseases (1.6%). No cases of malnutrition-related diabetes mellitus (MRDM) were found, but 18 subjects were considered to have so-called "African diabetes". Investigation of the cohort showed epidemiological and clinical features markedly different from those of Caucasian diabetic subjects. The age of onset in IDDM occurred in all age groups, with a mean (+/- SD) close to that of NIDDM (40.9 +/- 4.8 years vs 49 +/- 10.9; P < 0.001). A clear male preponderance was found (M/F sex ratio = 1.63), as it has been reported in most studies from sub-Saharan Africa, in contrast with the slight female predominance noted in the Sahel and Saharan countries. An increased prevalence of young and non-obese NIDDM was also found. Seventy-nine NIDDM cases (19.5%) were detected in individuals under 40 years of age, including 31 with normal weight. Many atypical features were noted: IDDM in obese patients, NIDDM in ketotic subjects and patients with varying insulin requirements, all of which led to difficulties in classifying many diabetic patients according to current practices. All these uncommon features are concordant with the nature of tropical diabetes, including not only MRDM but also African diabetes which occurs in individuals older than MRDM patients who show no signs of malnutrition. Thus, tropical diabetes is apparently a syndrome with aetiological heterogeneity which requires further definition through clinical, genetic and immunological studies.

Adult↗
PubMed1996

Cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in the conscious dog.

We studied the cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in conscious dogs. Sinus rate, corrected sinus recovery time and Wenckebach point were measured in 6 intact dogs. Atrial rate, ventricular rate and atrial effective refractory period were measured in 6 atrioventricular-blocked dogs. In both groups, we also determined blood pressure and plasma drug concentrations. Each dog received, with at least an 8-day interval, propafenone (hydrochloride) and 5-hydroxypropafenone (hydrochloride) in 4 successive intravenous injections, 30 min apart, at 0.5, 0.5, 1 and 2 mg kg(-1). Propafenone increased sinus rate and atrial rate more markedly than 5-hydroxypropafenone, and also transiently ventricular rate, whereas 5-hydroxypropafenone decreased it weakly. Propafenone shortened corrected sinus recovery time and increased Wenckebach point at the highest dose only, whereas 5-hydroxypropafenone did not modify corrected sinus recovery time and increased Wenckebach point less markedly than propafenone. Both drugs produced an identical atrial effective refractory period lengthening. Propafenone either increased mean blood pressure (in intact dogs) or decreased it (in atrioventricular-blocked dogs) at the highest dose only, whereas 5-hydroxypropafenone did not produce any effect on this parameter. Overall, these results show that propafenone and 5-hydroxypropafenone exhibit cardiac electrophysiological effects, reflecting (a) direct vagolytic action for both drugs associated with cardiodepressant effects for 5-hydroxypropafenone, and (b) marked atrial antiarrhythmic properties for 5-hydroxypropafenone probably involved in the therapeutic effect of propafenone.

Animals↗
PubMed1996

[Value of video-assisted thoracic surgery in internal medicine. Apropos of 7 cases].

Since a few years, the medical thoracoscopy has already been used specially for the diagnostic and therapeutic taking up of the pleural pathology. Behind it, the video-assisted thoracic surgery has been improved since 1990. As a surgical technology, it proved its interest refering to the classical thoracotomy by lessening operative morbidity and mortality. The authors discuss its main indications about seven cases, recruted in the internal medicine service and operated in the thoracic surgery service of the Val-de-Grâce hospital. Some of these indications are now admited by most of the authors: 1) diagnostic aims: pulmonary biopsy in case of interstitial pathology, of pulmonary peripheral under-pleural nodule and sometimes of solid tumors of the mediastinum, specially of some lymph-nodes. 2) Therapeutic aims: the spontaneous pneumothorax treatment of the adult remains the most classical indication; the thoracic sympathectomy, the creation of pleuropericardial windows and the resection of benign tumors of the mediastinum are now well acknowledged indications.

Humans↗
PubMed1996

[Development of blood pressure level over a three years period in non-insulin dependent diabetic subjects according to their microalbuminuria].

UNLABELLED: The purpose of this study is to compare over a three year period blood pressure modifications of type 2 diabetic subjects who suffer of incipient nephropathy to those who remain unharmed of this complication. PATIENTS AND METHOD: This study population is composed of 83 normotensive (BP < 140/90 mmHg) type 2 diabetic patients not receiving cardio-vascular treatment and unharmed of nephropathy (microalbuminuria inferior to 30 mg/24 hours). An evaluation of the diabetes mellitus is undertaken at a three year interval (A0 and A3). These 83 subjects are distributed in two groups according to the 24 hours microalbuminuria rate at A3. In group I (n = 60), patients whose rate is lower than 30 mg/24 hours and in group II (n = 23), patients whose microalbuminuria is over 30 mg. For these two groups, the following elements are compared at A0 and A3: body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), serum creatinine, cholesterol and triglycerides. RESULTS: The two groups do not differ in age (57.1 +/- 12 vs 53.8 +/- 16.4 years), duration of diabetes mellitus (11.7 +/- 8.6 vs 13.3 +/- 10.4 years) or body mass index (25.9 +/- 3.8 vs 26.2 +/- 4 kg/m2). At the time of the initial evaluation at A0, none of the studied parameters shows a significant difference between the two populations. Comparison of statements undertaken at A3 shows that blood pressure of Group II patients is higher than in group I, but the difference is only significant for systolic blood pressure (132 +/- 12 vs 139 +/- 11 mmHg; p < 0.01). The balance of diabetes mellitus, serum creatinine and lipid levels do not differ between these two groups. The blood pressure level of Group I doesn't differ significantly at A0 and A3 (128 +/- 11 vs 132 +/- 12 mmHg for SBP; 77 +/- 9 vs 78 +/- 7 mmHg for DBP). On the contrary, patients who develop a nephropathy see their blood pressure increase, but only SBP has a significant risk (128 +/- 12 vs 139 +/- 11 mmHg; p < 0.01). Apparition of a microalbuminuria and increase of blood pressure of Group II are not accompanied by a significant variation of serum creatinine. CONCLUSION: This study shows that for normotensive type 2 diabetic patients the transition from normo to microalbuminuria is associated with increases in systollic blood pressure. This blood pressure modification occur early, contemporary of the apparition of microalbuminuria, but relationship of causality between this two factors remains to be specified.

Adult↗
PubMed1995

Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes.

OBJECTIVES: The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias. BACKGROUND: The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration. METHODS: Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes. RESULTS: Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone. CONCLUSIONS: The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.

Analysis of Variance↗
PubMed1995

Proarrhythmic effects of a quinidine analog in dogs with chronic A-V block.

The proarrhythmic effects of 3-hydroxy-hydroquinidine (3-OH-HQ) and quinidine were compared in a canine model of QT-dependent ventricular arrhythmias. Eight hypokalemic ([K+] < or = 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2-day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 micrograms/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3-OH-HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+39 +/- 18 and +28 +/- 22 msec, respectively) and after the high dose (+51 +/- 29 and +50 +/- 22 msec). Quinidine was more arrhythmogenic than 3-OH-HQ: 7/8 dogs (p < or = 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3-OH-HQ infusion (low dose: 1 dog). Addition of propranolol-induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3-OH-HQ). Thus 3-OH-HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring factor (bradycardia) reduced that difference.

Adrenergic beta-Antagonists↗
PubMed1995

The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexnorfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of ideal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 years. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (Vss) of d-F was significantly higher (969.7 +/- 393.3 l; 95% CI 688.6-1250 l) than in controls (668.7 +/- 139.6 l; 95% CI 568.9-768.5 l; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 l h-1 vs 37.3 +/- 10.6 l h-1) and the terminal half-life tended to be longer (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two groups indicated a positive correlation between Vss and % IBW (r = 0.544; P < 0.02). The oral bioavailability of d-F was 0.61 +/- 0.15 in obese subjects and 0.69 +/- 0.11 in controls. There was no significant difference between obese subjects and controls in Cmax, tmax and t1/2,z (Cmax: 20.1 +/- 6.7 and 27.3 +/- 6.2 micrograms l-1; tmax: 3.5 vs 3.0; t1/2,z: 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC ratio expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1.25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Relationships between acute and chronic beta-blocking effects of bisoprolol in healthy volunteers: a practical approach to predict intensity of beta-blockade.

Bisoprolol is a selective beta 1-adrenoceptor antagonist devoid of partial agonist activity that can be used for treatment of chronic and acute myocardial ischemia. In this condition, it is important to demonstrate that a stable beta-blocking effect at steady state can be predicted by a mathematical model determined by plasma concentration-effect relationship after an acute intravenous (i.v.) dose. This relation was studied in 10 healthy volunteers in a double-blind, randomized, cross-over, placebo-controlled study after a 5-min i.v. infusion of bisoprolol (5 mg) or placebo. Standardized exercise tests were recorded at different times for 48 h after infusion with simultaneous bisoprolol assay (high-performance liquid chromatography, HPLC) in plasma. After a 1-week interval, subjects received oral bisoprolol (10 mg once daily) for 5 days and exercise tests were repeated on day 5 before and 2, 3, and 4 h after dosing, with bisoprolol plasma level determined simultaneously. In the acute period, bisoprolol significantly decreased exercise heart rate (HR: peak effect -20.5 +/- 4%) as compared with placebo. There was a direct relationship (no hysteresis) between beta-blockade and plasma concentrations with a sigmoid (7 subjects) or a linear (3 subjects) best-fit model. After repeated bisoprolol administration, steady-state plasma levels were achieved and 88% of the observed decreases in exercise HR were within the 95% confidence interval (CI) for individual prediction. These data suggest that bisoprolol-induced beta-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.

Adult↗