No effect of probenecid on the renal and biliary clearances of digoxin in man.

1. The cardiac glycoside digoxin is subject to a number of pharmacokinetic interactions. This study concerns the influence of the anionic transport inhibitor probenecid on the steady-state kinetics of digoxin. 2. Six healthy young men were enrolled in the study. After an administration period of 6 days with digoxin only (0.5 to 1 mg p.o. day-1) or digoxin in combination with probenecid (2 g p.o. day-1; 8 days), digoxin was administered intravenously (0.7 oral dose) on day 7. Plasma and urine samples were taken over 48 h. The biliary clearance of digoxin was measured during day 8 by a duodenal perfusion technique. 3. Probenecid did not affect the plasma clearance (mean +/- s.d.: 255 +/- 80 vs 266 +/- 40 ml min-1), renal clearance (166 +/- 17 vs 155 +/- 10 ml min-1), biliary clearance (106 +/- 40 vs 111 +/- 50 ml min-1), elimination half-life (34.4 vs 35.2 h) or volume of distribution (538 +/- 241 vs 566 +/- 60 l) of digoxin. 4. Our results suggest that different systems exist in man for the renal and biliary secretion of probenecid and digoxin.     

Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of digoxin is dose-dependent.     

The effect of flecainide acetate, a new antiarrhythmic, on plasma digoxin levels

The possible effect of oral flecainide acetate on steady-state digoxin levels was assessed in 15 healthy men. Each volunteer received digoxin 0.25 mg daily (8 AM) for 22 consecutive days and flecainide 200 mg bid (8 AM and 8 PM) on days 11 through 15. Plasma digoxin and flecainide levels were measured by radioimmunoassay and gas-liquid chromatography methods, respectively. Flecainide levels were within the range associated with suppression of premature ventricular contractions in patients. Mean plasma digoxin levels just before the 8 AM dose were 0.46 ng/mL on days 9 and 10 (baseline), 0.57 ng/mL (P less than .05) on day 13, and 0.49 ng/mL (not significant [NS]) on day 15. Compared with a mean six-hour postdose baseline digoxin level of 0.58 ng/mL, postdose levels were 0.62 ng/mL (NS) and 0.65 ng/mL (P less than .05) on days 13 and 15, respectively. On an average for each subject, predose and six-hour postdose digoxin levels increased by 24 +/- 35% and 13 +/- 19%, respectively, during coadministration. The changes in electrocardiographic intervals and vital signs that occurred during concomitant drug administration were not clinically significant although a slight prolongation of the PR interval was noted in some subjects. Unless plasma digoxin levels are in the upper end of the therapeutic range, changes in magnitude as observed in this study should be clinically inconsequential for most patients.     

Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers.

1. Losartan (DuP 753, MK-954) is a novel, potent and highly selective AT1 angiotensin II receptor antagonist. The effect of multiple oral doses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2. In a double-blind and randomized fashion, subjects received 50 mg losartan or placebo once daily for 15 days in each period. At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively. 3. Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the study, no laboratory abnormalities were noted. 4. Multiple oral doses of losartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0.48h) of immunoreactive digoxin during losartan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml-1 h during placebo; not significant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 vs 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5. Multiple oral doses of losartan did not affect the pharmacokinetic parameters of oral digoxin AUC(0.48 h) during losartan 23.6 +/- 3.7 ng ml-1 h vs 22.4 +/- 2.6 ng ml-1 h during placebo; not significant, Cmax 3.5 +/- 0.7 ng ml-1 with vs 3.1 +/- 0.5 ng ml-1 without losartan; not significant and tmax 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 51.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6. We conclude that multiple oral doses of losartan (50 mg daily) do not alter the pharmacokinetics of immunoreactive digoxin, following either intravenous or oral digoxin. Furthermore, the co-administration of digoxin with losartan is well tolerated by healthy male volunteers.     

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.     

Acute haemodynamic effects of pinacidil in man.

The acute haemodynamic effects of i.v. pinacidil 0.2 mg kg-1 infused over 8 min were studied in 10 normotensive patients undergoing cardiac catheterisation. Mean arterial pressure fell from 94 +/- 3 mmHg (mean +/- s.e. mean) before infusion to 74 +/- 3 mmHg at 10 min after commencing infusion (P less than 0.001) and during this time heart rate increased from 75 +/- 4 to 106 +/- 7 beats min-1 (P less than 0.001). Significant changes were recorded until the end of the observation period (70 min after commencing infusion). Cardiac index increased from 3.2 +/- 0.2 to 4.0 +/- 0.2 l min-1 m-2 (P less than 0.001) and systemic vascular resistance fell from 16 +/- 1 to 10 +/- 1 units (P less than 0.001) at 10 min after commencing infusion. By the end of the observation period, the values had returned to pre-infusion levels. Only small changes in pulmonary haemodynamics were observed. These results indicate that pinacidil acts as a peripheral arteriolar vasodilator, and as such may have a role in the treatment of arterial hypertension and of cardiac failure.     

The effect of oral verapamil therapy on antipyrine clearance.

The influence of chronic verapamil treatment on antipyrine elimination was studied in eight angina patients. Antipyrine half-life (mean +/- s.d.) was 13.1 +/- 1.15 h at the start of therapy and 16.6 +/- 3.05 h (P less than 0.05) during chronic oral administration of verapamil (80-120 mg four or three times daily for 4 to 7 months). There was a significant decrease in antipyrine clearance (mean +/- s.d, 43.2 +/- 16.8 ml min-1 vs 28.7 +/- 16.6 ml min-1, P less than 0.01) while the change of distribution volume was insignificant. Verapamil elimination was also found to be impaired after chronic dosing as compared to single administration. Half-lives measured from the concentration vs time and urinary excretion rate vs time curves were both prolonged and oral clearance was decreased. Our results suggest that the inhibition of drug-metabolizing enzymes accounts for the impairment of verapamil elimination on chronic administration.     

A dose-ranging study to evaluate the beta-adrenoceptor selectivity of single doses of betaxolol.

1. Six normal subjects were given single oral doses of betaxolol 10 mg (B10), 20 mg (B20), 40 mg (B40), 80 mg (B80), propranolol 40 mg (P40), or placebo (PL) in a single-blind randomised cross-over design. 2. beta 1-adrenoceptor blockade was assessed by reductions in exercise heart rate. Betaxolol produced dose-related reductions in exercise heart rate (beats min-1) up to a ceiling at B40, after which B80 showed a lesser effect: (158 +/- 8 PL, 128 +/- 3 B10, 123 +/- 2 B20, 116 +/- 4 B40, 136 +/- 10 B80, 135 +/- 4 P40). All doses of betaxolol (except B80) produced greater reductions compared with P40: (B10 P less than 0.001, B20 P less than 0.005, B40 P less than 0.001). 3. beta 2-adrenoceptor blockade was assessed by attenuation of finger tremor and cardiovascular responses to graded infusions of i.v. isoprenaline. Dose-response curves were constructed and the doses required to increase heart rate by 25 beats min-1, finger tremor by 200%, calf blood flow by 0.5 ml dl-1 min-1, and decrease diastolic blood pressure by 10 mm Hg, after each treatment were calculated. These were then compared with placebo responses and expressed as dose-ratios. 4. Dose-ratios for finger tremor showed significant attenuation by all doses of betaxolol (compared with PL): B10 1.5 +/- 0.18 (P less than 0.05), B20 2.62 +/- 0.45 (P less than 0.005), B40 2.55 +/- 0.33 (P less than 0.001), B80 2.48 +/- 0.48 (P less than 0.01); and by P40 6.49 +/- 1.12 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of ketanserin on left ventricular function, metabolism and coronary blood flow

An acute intravenous bolus of 10 mg ketanserin (a specific 5-HT antagonist) caused an abrupt fall in left ventricular systolic pressure of 17 +/- 9.2 mm Hg (P less than 0.025) in ten patients undergoing cardiac catheterisation for chest pains. A fall in pulmonary artery diastolic pressure of 2.1 +/- 0.74 mm Hg (P less than 0.02) was also observed. No changes in resting heart rate occurred and the response to pacing was largely unmodified by ketanserin, except for a reduction in pulmonary vascular resistance (3.70 +/- 1.27 units to 2.97 +/- 1.44 units, P less than 0.05), at the fastest rate (136 +/- 3 beats/min). At the highest pacing rate coronary sinus blood flow fell (83 +/- 12 ml 100 g-1 min-1 to 68 +/- 8 ml 100 g-1 min-1, P less than 0.05), as did myocardial oxygen consumption (18 +/- 2 ml-1 min to 14 +/- 1 ml min-1, P less than 0.05) after the drug. No changes in the parameters of left ventricular contractile function could be attributed to ketanserin, save for a modest increase in the ejection fraction (48 +/- 6% to 57 +/- 6%, P less than 0.05) in seven patients. There were no alterations in myocardial metabolism of lactate, pyruvate, hydroxybutyrate, glycerol nor free fatty acids after ketanserin. The findings are consistent with a peripheral site of action of this drug and its blood pressure lowering effect in the subjects suggest a non-specific hypotensive action rather than an anti-hypertensive effect.     

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats

Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg-1 day-1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl-glycyl-glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 +/- 9 vs 391 +/- 7 nmol mL-1 min-1, P less than 0.001; 184 +/- 8 vs 142 +/- 10 nmol mg-1 min-1 P less than 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA-treated rats (0.35 +/- 0.02 vs 0.51 +/- 0.02 nmol mg-1 min-1, P less than 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg-1 day-1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg-1 day-1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA-treated rats was increased, while its activity in the renal cortex was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans

Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

The effect of propranolol, verapamil and dantrolene treatment on cardiac hypertrophy, enhanced myocardial contractility and tachycardia in the hyperthyroid rat

Experimentally induced hyperthyroidism is associated with cardiac hypertrophy, tachycardia and elevated myocardial contractility. To investigate the possibility of ameliorating the cardiac changes pharmacologically, hyperthyroid rats were treated with propranolol, verapamil or dantrolene. Cardiac hypertrophy was assessed from the heart mass: body mass ratio and cardiac function was measured in vitro. Both verapamil and propranolol reversed the cardiac hypertrophy of the hyperthyroid animals from 0.92 +/- 0.02 mg.g-1 to 0.70 +/- 0.01 mg.g-1 (P less than 0.001) and 0.72 +/- 0.02 mg.g-1 (P less than 0.001) respectively. Verapamil was effective in reducing the spontaneous heart rate from 331 +/- 8 beats.min-1 to 273 +/- 7 beats.min-1 (P less than 0.001) while propranolol reduced the dP/dtmax of the hyperthyroid hearts from 4089 +/- 87 mmHg.s-1 to 3497 +/- 97 mmHg.s-1 (P less than 0.001). Dantrolene had no effect on any parameter. We conclude from our results that cardiac hypertrophy of the hyperthyroid heart can be reversed by treatment with propranolol and verapamil probably via their inotropic and chronotropic properties.     

Effects of atropine on left ventricular volumes and ejection and filling rates at rest and during exercise.

1. The influence of the parasympathetic nervous system on left ventricular function including ejection and filling rates was studied by radionuclide cardiography in eight healthy young men at rest and during upright exercise. 2. After parasympathetic blockade induced by atropine, the mean heart rate (HR) at upright rest increased from 67 to 114 beats min-1, cardiac output (CO) from 4.05 to 5.17 1 min-1 (both P less than 0.001), and the diastolic blood pressure by 13 mm Hg (P less than 0.01). 3. Stroke volume (SV), left ventricular end diastolic and end systolic volume all decreased significantly after atropine. The relative ejection time increased from 0.33 to 0.51 of the cardiac cycle length (P less than 0.001), and the appropriate ejection and filling rates increased by 13% (P less than 0.05) and 147% (P less than 0.001), respectively. Haemodynamic changes in the supine position were virtually the same. 4. During exercise atropine increased HR from 115 to 146 beats min-1 (P less than 0.001) and CO by 12% (P less than 0.05), whereas SV decreased by 12% (P less than 0.05) and the systolic blood pressure by 16 mm Hg (P less than 0.001). Changes in ejection and filling rate of the left ventricle were of the same nature as those found at rest. 5. Thus apart from its HR limiting properties, secondary effects of parasympathetic nervous tone are dilatation of the left ventricle and enhancement of ejection, effects that are counteracted by atropine.     

The effects of rifampicin on the pharmacokinetics and pharmacodynamics of orally administered nilvadipine to healthy subjects

AIMS: To study the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nilvadipine. METHODS: Five healthy adult volunteers received nilvadipine (4 mg) orally before and after a 6 day treatment with rifampicin. Blood and urine were collected and assayed for plasma nilvadipine and urinary 6beta-hydroxycortisol and cortisol. RESULTS: The treatment with rifampicin reduced the mean (+/- s.d.) AUC of nilvadipine from 17.4 +/- 8.4 to 0.6 +/- 0.4 microg l-1 h (mean difference -16.8 microg l-1 h, 95% CI -9.4, 24.2 microg l-1 h). While the administration of nilvadipine alone elicited a significant (P < 0.05) hypotensive (mean difference for diastolic blood pressure -8 mmHg, 95% CI -4, -12 mmHg) and reflex tachycardia (mean difference 5 beats min-1, 95% CI 1, 9 beats min-1), the treatment with rifampicin abolished these responses. The urinary 6beta-hydroxycortisol/cortisol ratio showed a significant (P < 0.05) increase from 10.3 +/- 4.0 to 50.3 +/- 24.6 by rifampicin: mean difference 40.1, 95% CI 20.4, 59.8. CONCLUSIONS: Because rifampicin may greatly decrease the oral bioavailability of nilvadipine, caution is needed when these two drugs are to be coadministered.     

Effect of intravenous digoxin on the heart at rest and during isometric exercise: a noninvasive study in normal and autonomically blocked volunteers

Nine healthy volunteers were studied with echocardiography and systolic time intervals before and after administration of 1 mg digoxin intravenously at supine rest and during 3-min isometric handgrip exercise. Eight of them were also studied following autonomic blockade, atropine (0.04 mg/kg), and propranolol (0.2 mg/kg) administered intravenously, otherwise the study program was the same. At rest, intravenous digoxin decreased the heart rate from 61 +/- 3 to 50 +/- 2 beats/min (p less than 0.001). Blood pressure, preload [defined as left ventricular end-diastolic diameter (LVEDD)] or afterload [estimated as left ventricular midsystolic circumferential wall stress (WS)], did not change. Fractional shortening increased from 29 +/- 2 to 33 +/- 2% (p less than 0.05), and the electromechanic systole time index (QS2i) decreased from 522 +/- 7 to 500 +/- 5 ms (p less than 0.01). The results indicate improved contractility due to digoxin. During handgrip, the heart rate decreased from 73 +/- 5 to 65 +/- 5 beats/min (p less than 0.01) as a result of digoxin. The LVEDD, WS or ejection phase indices, and systolic time intervals, did not change, suggesting that digoxin does not affect inotropy during isometric exercise. There was no changes in heart rate, preload or afterload, as a result of intravenous digoxin during autonomic blockade. Fractional shortening rose from 25 +/- 1 to 29 +/- 2 (p less than 0.05) and QS2i fell from 561 +/- 3 to 533 +/- 4 ms (p less than 0.001). The results indicate increased inotropy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic beta-adrenoceptor responses to salbutamol given by metered-dose inhaler alone and with pear shaped spacer attachment: comparison of electrocardiographic, hypokalaemic and haemodynamic effects.

1. Seven normal subjects were given cumulative doubling doses of inhaled salbutamol either by metered-dose inhaler (MDI) alone, or in conjunction with a pear shaped spacer attachment (PSS). Dose increments were made every 20 min from 100 micrograms to 2000 micrograms. 2. Plasma potassium (K), electrocardiographic (ECG) and haemodynamic (HR, SBP and DBP) responses were measured at each dose increment. 3. There were falls in K (as mean and 95% CI) in response to salbutamol (P less than 0.001): 3.70 mmol l-1 (3.46-3.95) to 3.20 mmol l-1 (2.91-3.49) MDI, 3.78 mmol l-1 (3.61-3.95) to 3.18 mmol l-1 (3.06-3.30) PSS. 4. Salbutamol produced marked ECG effects including T wave flattening (P less than 0.001): 0.46 mV (0.24-0.68) to 0.22 mV (0.07-0.37) MDI, 0.50 mV (0.23-0.77) to 0.24 mV (0.07-0.41) PSS; and Q-Tc interval prolongation (P less than 0.001): 0.382 s (0.372-0.392) to 0.409 s (0.397-0.421) MDI, 0.378 s (0.358-0.398) to 0.410 s (0.388-0.432) PSS. U waves occurred in five subjects with MDI and in four with PSS. S-T segment depression was present in two subjects with MDI and in three with PSS. These changes were not however associated with ventricular extrasystoles. There were also significant chronotropic effects (P less than 0.001): 63 beats min-1 (57-70) to 79 beats min-1 (69-89) MDI, 58 beats min-1 (53-63) to 75 beats min-1 (69-81) PSS. 5. Comparison of dose-response curves for MDI alone and with PSS showed no significant differences, for any of the variables measured.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates.

Six healthy male subjects were given single oral doses of antipyrine (7 mg kg-1), trimethadione (4 mg kg-1) and debrisoquine (10 mg) before and during diltiazem treatment (30 mg three times daily orally for 8 days). Antipyrine clearance decreased from 33.7 +/- 9.1 to 22.5 +/- 4.9 ml min-1 (P less than 0.05, mean +/- s.e. mean) after diltiazem treatment without any significant change in apparent volume of distribution (0.59 +/- 0.06 to 0.60 +/- 0.04 1 kg-1), resulting in an increase in antipyrine elimination half-life from 13.4 +/- 4.8 to 19.7 +/- 3.2 h (P less than 0.05). The formation clearance of antipyrine to 4-hydroxyantipyrine was decreased significantly from 10.8 +/- 2.7 to 6.6 +/- 2.7 ml min-1 (P less than 0.05), while that to 3-hydroxymethylantipyrine and norantipyrine was not altered by diltiazem. The metabolic ratio of debrisoquine (urinary excretion of debrisoquine/4-hydroxydebrisoquine) was increased significantly from 0.70 +/- 0.05 to 1.95 +/- 0.20 (P less than 0.05), while that of trimethadione (serum concentration of dimethadione/trimethadione) was not changed significantly (0.48 +/- 0.08 vs 0.41 +/- 0.06) after diltiazem treatment. Diltiazem selectively inhibits cytochrome P-450 isoenzymes.     

The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine.

1. The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/- 1.9 vs 4.8 +/- 2.0 ml min-1 kg-1; P less than 0.05) and renal clearance (1.2 +/- 0.3 vs 0.63 +/- 0.25 ml min-1 kg-1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 +/- 0.7 vs 3.0 +/- 0.6 mg l-1 h; P less than 0.05) and its renal clearance was less (3.0 +/- 1.1 vs 1.54 +/- 0.38 ml min-1 kg-1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/- 21.7 vs 72.2 +/- 41.7 ms/(mg l-1); P less than 0.05).     

Acute and long-term efficacy of oral propafenone in patients with ventricular tachyarrhythmias.

The class Ic antiarrhythmic agent propafenone was studied by repeated electrophysiologic testing in 54 patients (43 male, aged 54 +/- 10 years, mean ejection fraction of 37.3 +/- 16.9%) with ventricular tachyarrhythmias. Forty patients (74%) had coronary artery disease. Programmed ventricular stimulation (S2, S2S3 during sinus rhythm and/or during S1S1 = 500, 430, 370, and 330 ms) off antiarrhythmic drugs induced sustained ventricular tachycardia, flutter, or fibrillation in all patients. After 450-900 mg of oral propafenone/day for 4-7 days, 51 patients were restudied. In the remaining three patients, spontaneous ventricular tachycardia occurred on drug therapy. Tachycardia induction was suppressed in 9 of 51 patients restudied (18%) and rendered more difficult to induce (basic stimulation drive greater than or equal to 40 beats/min higher than at control study) in another 7 patients (14%) (overall efficacy of 31%). The tachycardia rate decreased from 220 +/- 43 to 177 +/- 44 beats/min (p less than 0.01). The right ventricular effective refractory period increased from 232 +/- 22 to 252 +/- 22 ms (p less than 0.001). Responders to propafenone therapy had higher rates of inducible ventricular tachycardia at control (greater than 230 beats/min: 43%; less than or equal to 230 beats/min: 21%; p less than 0.05), higher ejection fractions, and lower left ventricular end-diastolic pressures than nonresponders. Eleven of the 16 patients showing a positive response to propafenone therapy in electrophysiologic testing were discharged on propafenone alone. During follow-up (17 +/- 12 months), nine patients remained free from ventricular tachycardia, one patient had a relapse, and one patient died of noncardiac death.(ABSTRACT TRUNCATED AT 250 WORDS)