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.

Comparative study of encainide and disopyramide in chronic ventricular arrhythmias: a double-blind placebo-controlled crossover study.

Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hemolytic uremic syndrome as a complication of gemcitabine treatment: report of six cases and review of the literature]. / Syndrome hémolytique et urémique secondaire à la gemcitabine: à propos de six observations et revue de la littérature.

UNLABELLED: Hemolytic uremic syndrome is a rare condition during gemcitabine therapy. METHODS: We report six new cases of hemolytic uremic syndrome related to gemcitabine, three issued from a retrospective study of 136 consecutive patients treated with gemcitabine for which a systematic screening of this side effect has been performed and 29 cases with clinical data available identified in the literature in order to better characterised frequency and clinical presentation of this side effect. RESULTS: In our series, frequency of HUS is 2.2% and is higher than this previously reported (0.015%) or estimated with the data of clinical trials analysed (0.072 %). For 35 cases with clinical data available, the patients were always treated for a local advanced and/or metastatic disease. For our cases and for literature cases, at the time of diagnosis of hemolytic uremic syndrome, mean number of doses received (mean+/-standard deviation. Minimum/maximum)) (personal cases: 26.5+/-6.6. 16/36, literature cases: 21+/-11. 8/54), cumulative dose received (g/m2) (personal cases : 24.5+/-6.3. 16/31.6, literature cases: 21.7+/-12.4. 2.4/54) and duration of treatment (months) (personal cases: 8.2+/-1.9. 5.6/11, literature cases: 8.5+/-4.0. 3/18) are very closed and high individual variations observed for these factors are not consistent with a time and/or dose dependant toxicity. New-onset hypertension or exacerbation of underlying hypertension is the most common clinical manifestation, with mild anemia; thrombocytopenia is inconstant. The degree of severity of renal failure is highly variable. The existence of subacute clinical form with progressive worsening of the symptoms and biological form at the time of diagnosis suggest the interest of a systematic clinical and biological screening of this side effect, before each injection of gemcitabine. Early prognosis is linked to the evolution of hemolytic uremic syndrome and after hemolytic uremic syndrome healing, cancer progression. Treatment include gemcitabine discontinuation, antihypertensive drugs and if necessary fresh frozen plasma. CONCLUSIONS: Systematic clinical and biological screening of hemolytic uremic syndrome during gemcitabine therapy should allow to better know this complication, to recognize and treat it earlier with a potential positive impact for patients.

Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol.

OBJECTIVE: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. METHODS: Three groups of dogs were studied. Group I (n = 8) received no treatment. Group II (n = 7) and group III (n = 8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. RESULTS: Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9 +/- 0.4 pM in control dogs, 3.1 +/- 0.2 pM in group III, P < 0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P < 0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P < 0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69 +/- 12 ms in untreated dogs, 41 +/- 8 ms in group II (P < 0.05) and 34 +/- 8 ms (P < 0.05) in group III at PCL = 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208 +/- 5 ms versus 188 +/- 9 ms at PCL = 1000 ms, P < 0.05). The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. CONCLUSION: Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias.

Prediction of sotalol-induced maximum steady-state QTc prolongation from single-dose administration in healthy volunteers.

The relationship between racemic sotalol plasma concentrations and QTc interval prolongation after both single-dose and repeated administration of three sotalol oral doses was studied in a randomized crossover protocol performed in 10 healthy volunteers. QTc interval increase was significant after the three single-dose sotalol administrations and was significantly related to the administered dose (p < 0.0001). In 21 of 30 analyses, QTc interval was linearly correlated with sotalol plasma concentrations. After the 320 mg dose, the linear model was a best fit for 90% of the cases, and no hysteresis was observed. After repeated sotalol administration, 69 of 87 QTc interval measurements at steady state could be predicted from the plasma concentration versus effect relationship established after single-dose 320 mg administration. Seventeen of 18 errors (94%) corresponded to QTc intervals that were significantly lower than predicted. These findings suggest that a short-term individual linear model determined after a 320 mg test dose of sotalol allows a good prediction of expected maximal increase in QTc duration in healthy subjects.

Influence of amiodarone on genetically determined drug metabolism in humans.

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of CYP2D6 and CYP2C19 activity in vivo in humans: a cocktail study with dextromethorphan and chloroguanide alone and in combination.

OBJECTIVES: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent. METHODS: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs. RESULTS: All subjects were extensive metabolizers for both CYP2D6 and CYP2C19. Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide. This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma. Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration. The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration. CONCLUSION: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CYP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients.

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.

Comparison of four beta-blockers as assessed by 24-hour ECG recording.

beta-Blockers are used as if they were equivalent. With ECG recordings in 42 patients we investigated the effect on sinus heart rate of four beta-blockers given at three successive daily doses. Heart rate was dose-dependently decreased by all drugs except acebutolol, the effect of which decreased at a higher dosage. The maximal effects of metoprolol, nadolol, and propranolol were similar but the drugs differed in potency (dosage producing 50% of maximal effect, calculated from the dose-effect relationships; nadolol, 0.3 mg/day; metoprolol, 120 mg/day; propranolol, 47 mg/day). Similar relationships were found with drug plasma concentrations (concentration producing 50% of maximal effect: nadolol, 3.5 ng/ml; metoprolol, 21 ng/ml; propranolol, 36 ng/ml) and with supine or upright heart rates and blood pressures. However, the drugs were not equivalent: In addition to its greater potency, nadolol differed from propranolol and metoprolol in the slope of its dose-response curve. We conclude that beta-blockers can be compared by ECG recordings and that nadolol is different from the other beta-blockers without intrinsic sympathomimetic activity.

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.

Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations.

In 65 patients a single oral dose of amiodarone (30 mg/kg) produced an antiarrhythmic effect on supraventricular or ventricular arrhythmias within 3 to 8 hours and lasted for 17 to 19 hours. On the second day a 15-mg/kg dose reproduced this effect within 3 to 9 hours. Plasma concentration of amiodarone increased to a maximum (2.2 +/- 1.7 mg/liter) mean +/- standard deviation) at 6 +/- 3.5 hours and plasma levels of N-desethylamiodarone (NDA) rose to 0.2 +/- 0.08 mg/liter at 12 +/- 6.4 hours. Sixty-one other patients were given a single 30-mg/kg dose 7 hours to 4 days before open heart surgery. Biopsies of the right atrial and left ventricular walls were taken during surgery. Myocardial concentration of amiodarone was maximal in the atrium after 7 hours (13 +/- 8 mg/kg) and in the ventricle after 24 hours (17 +/- 11 mg/kg). NDA myocardial concentration increased progressively until 24 hours and then remained stable over 4 days (1.5 mg/kg). The amiodarone myocardial to plasma concentration ratio was similar in the atrium and in the ventricle and averaged 22 and 10 for amiodarone and NDA, respectively. A significant relation existed between amiodarone concentration and the effect on ventricular premature complexes (r = 0.74, p less than 0.001) and between amiodarone plasma concentration and the effect on the atrioventricular conduction (r = 0.58, p less than 0.001). The plasma concentration of amiodarone corresponding to a 60% decrease in arrhythmias averaged 1.5 to 2 mg/liter.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers.

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.

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.

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.

Comparative hemodynamic study of a new aminosteroid: LND-623 with its 20 alpha-isomer: LND-369, and with digoxin and digoxigenin-rhamnoside in the anesthetized dog.

Hemodynamic effects of LND-623, a new aminosteroid lacking the C17 lactone ring and the C14 hydroxyl group common to the natural glycosides, were studied in the pentobarbital-anesthetized dog and compared to those of its 20 alpha-isomer LND-369 and of digoxin and digoxigenin-rhamnoside (DRh). Twenty-four mongrel dogs were divided into 4 groups. Group I received either LND-623 or saline on study day 1 and the other drug or saline 1 wk later. Saline was replaced by digoxin in group II, digoxigenin-rhamnoside in group III, and LND-369 in group IV. All drugs except LND-369 were infused as 3.10(-9) mol.kg-1.min-1 over 20 minutes. LND-369 was infused at twice the dose. LND-623 increased left ventricular dP/dt for at least 3 h with a peak at end-infusion or 15 min later, accompanied by a transient vasopressor effect. LND-369 induced, at twice the dose, an inotropic effect of comparable magnitude but of shorter duration. Inversely, it provoked a more marked and prolonged vasopressor effect than its 20 beta-isomer, LND-623. Maximal digoxin inotropic effect occurred later but was of comparable magnitude to that induced by LND-623. Its vasopressor effects reached a plateau rapidly and remained sustained until min 200. Digoxigenin-rhamnoside inotropic but not vasopressor effects are weaker than those of LND-623. It is concluded that LND-623, although lacking the most common structural features of the natural cardiac glycosides, provoked rapid and sustained inotropic activities with transient vasopressor effects. These time-course effects differ from digoxin, and these differences are unrelated to their sugar-moiety characteristics. LND-623 inotropic effect is twice as potent as its 20 alpha-isomer.

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.

[Applications analytiques des oxocarbones-I: composition et constantes de stabilite des complexes molybdiques de l'ion bromanilate: dosage spectrophotometrique du molybdene(VI)]. / Applications analytiques des oxocarbones-I: composition et constantes de stabilite des complexes molybdiques de l'ion bromanilate: dosage spectrophotometrique du molybdene(VI).

The bromanilate ion B(2-) is a cyclic aromatic anion related to oxocarbons. We have shown by ultraviolet-visible spectrophotometry that it forms two 1:1 complexes with molybdenum(VI) in aqueous solution at pH 6. The variation of the conditional stability constants with acidity allows the calculation of the number of protons involved in each equilibrium. The formulae of the two complexes differ by a proton. The pK is 2.30. Molybdenum(VI) can be determined with bromanilic acid, H(2)B, at 340 nm in 3 or 1.4M perchloric acid. The accuracy is better than with chloranilic acid, H(2)C, when the concentration is about 1 mg/l. The better results obtained with H(2)B at high acidities are accounted for by the difference between the pK(1) values of the two acids (0.22 for H(2)B and 0.45 for H(2)C).

[Applications analytiques des oxocarbones-II: composition des complexes tungstiques des ions bromanilate et chloranilate: dosage spectrophotometrique du tungstene(VI)]. / Applications analytiques des oxocarbones-II: composition des complexes tungstiques des ions bromanilate et chloranilate: dosage spectrophotometrique du tungstene(VI).

The complexes formed from tungsten(VI) and chloranilate (C(2-)) and bromanilate (B(2-)) have been studied in aqueous solution and as solids, by ultraviolet, visible and infrared spectroscopy. At pH 3-4, the complexes have the composition ligand:tungsten = 2. At pH < 2, only the 1:1 complexes are found. The two reagents allow the spectrophotometric determination of W(VI) (lambda, = 335 nm for H(2)C and 340 nm for H(2)B) in 1.4M HClO(4), at concentrations of about 1 mg/l. The conditional stability constants of the two 1:1 complexes in this medium have been calculated. The tungsten complexes are more stable than the corresponding molybdenum complexes, and the complexes of B(2-) are more stable than the complexes of C(2-) [with W(VI) and Mo(VI)]. It is shown that this result is due to the difference between the pK(1), values of the acids H(2)B and H(2)C. The infrared spectra of the complexes of B(2-) and C(2-) with Mo(VI) and W(VI) are discussed in order to define the interaction between the metal ions and the ligands.

Comparison of propranolol and sotalol pharmacokinetics in obese subjects.

Six obese subjects (mean +/- s.d. : 145.1 +/- 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (+/-)-propranolol base (0.108 mg kg-1 of ideal body weight) or of (+/-)-sotalol base (1.06 mg kg-1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 +/- 2.9 L h-1; volume of distribution during the terminal phase = 79.8 +/- 19.8 L or 0.9 +/- 0.2 L kg-1; terminal half-life = 6.2 +/- 1.6 h). For propranolol, total clearance (44.3 +/- 15.9 L h-1) and volume of distribution (230.5 +/- 48.2 L or 2.7 +/- 0.7 L kg-1) were significantly less than control values. The terminal half-life (3.9 +/- 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.

Transitory increased blood pressure after upper airway surgery for snoring and sleep apnea correlates with the apnea-hypopnea respiratory disturbance index.

A transitory increase in blood pressure (BP) is observed following upper airway surgery for obstructive sleep apnea syndrome but the mechanisms implicated are not yet well understood. The objective of the present study was to evaluate changes in BP and heart rate (HR) and putative factors after uvulopalatopharyngoplasty and septoplasty in normotensive snorers. Patients (N = 10) were instrumented for 24-h ambulatory BP monitoring, nocturnal respiratory monitoring and urinary catecholamine level evaluation one day before surgery and on the day of surgery. The influence of postsurgery pain was prevented by analgesic therapy as confirmed using a visual analog scale of pain. Compared with preoperative values, there was a significant (P < 0.05) increase in nighttime but not daytime systolic BP (119 5 vs 107 3 mmHg), diastolic BP (72 4 vs 67 2 mmHg), HR (67 4 vs 57 2 bpm), respiratory disturbance index (RDI) characterized by apnea-hypopnea (30 10 vs 13 4 events/h of sleep) and norepinephrine levels (22.0 4.7 vs 11.0 1.3 g l-1 12 h-1) after surgery. A positive correlation was found between individual variations of BP and individual variations of RDI (r = 0.81, P < 0.01) but not between BP or RDI and catecholamines. The visual analog scale of pain showed similar stress levels on the day before and after surgery (6.0 0.8 vs 5.0 0.9 cm, respectively). These data strongly suggest that the cardiovascular changes observed in patients who underwent uvulopalatopharyngoplasty and septoplasty were due to the increased postoperative RDI.