bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of azepexole and clonidine on baroreceptor mediated reflex bradycardia and physiological tremor in man.
Authors: Harron DW , Riddell JG , Shanks RG
Published: July 2012

The effects of oral administration of azepexole 10 mg, clonidine 300 micrograms and placebo on baroreceptor mediated reflex bradycardia and physiological tremor were investigated in six healthy volunteers. Both azepexole and clonidine reduced (P less than 0.05) systolic (120.5 +/‐ 2.5 to 105.0 +/‐ 3.3 mm Hg; 115.8 +/‐ 2.6 to 104.7 +/‐ 2.8 mm Hg respectively) and diastolic (52.5 +/‐ 2.6 to 47.2 +/‐ 1.4 mmHg; 53.7 +/‐ 1.6 to 49.0 +/‐ 1.5 mmHg respectively) pressure when compared to placebo and to pre‐treatment values. This reduction in pressure was not accompanied by a change in heart rate. Both azepexole and clonidine enhanced (P less than 0.05) baroreflex sensitivity to increases in systolic arterial pressure with phenylephrine. Clonidine facilitated (P less than 0.05) baroreflex sensitivity during the strain phase of the Valsalva manoeuvre, whereas azepexole reduced it (P less than 0.05). Neither clonidine nor azepexole altered finger tremor when compared to placebo or pre‐treatment values. Azepexole produced (P less than 0.05) sedation compared to placebo but not when compared to pre‐treatment values. Clonidine caused significant increases in sedation when compared to both placebo and to pre‐treatment values. The differences between azepexole and clonidine may be due to the greater specificity of azepexole for the alpha 2‐adrenoceptor than clonidine.
The peripheral vascular effects of diltiazem‐dose‐response characteristics.
Authors: Finch MB , Johnston GD
Published: July 2012

The acute effects of increasing doses of diltiazem on peripheral blood flow were observed in six subjects. Each subject received, in random order, a single oral dose of placebo or diltiazem 60, 120 or 180 mg. Supine heart rate, blood pressure, skin temperature, digital systolic pressure, forearm and digital blood flow were recorded before and at 1, 2, 3, 4 and 6 h post‐dosing. Plasma diltiazem concentrations were measured at each time interval and at 12 and 24 h after the 120 mg dose. At doses of 120 and 180 mg, diltiazem significantly increased digital blood flow at 1, 2, 3, 4 and 6 h post‐dosing and forearm blood flow at 2 and 3 h following 180 mg and 3 h following 120 mg. No correlation was observed between plasma diltiazem concentration and changes in peripheral blood flow.
Evidence against an acetylcholine releasing action of cisapride in the human colon.
Authors: Burleigh DE , Trout SJ
Published: July 2012

The effect of cisapride (R51619) on intrinsic cholinergic nerve activity of human sigmoid taenia coli muscle strips (taenia) was assessed using radiolabelling techniques. Taeniae previously incubated with [3H]‐choline were exposed to cisapride (0.41 and 4.1 microM), placebo solution and electrical field stimulation (EFS; 10 Hz, 1 ms, 200 mA for 480 pulses). Cisapride did not affect unstimulated (basal) release of radioactive material nor the release evoked by EFS. It was concluded that cisapride did not demonstrate a cholinomimetic effect in human sigmoid taenia coli muscle strips.
A comparison of the cardiovascular effects of (+)‐sotalol and (+/‐)‐ sotalol following intravenous administration in normal volunteers.
Authors: Johnston GD , Finch MB , McNeill JA , Shanks RG
Published: July 2012

In a placebo controlled open study in six healthy male volunteers (+)‐ sotalol in the dose range 0.125 mg kg‐1‐2.0 mg kg‐1 intravenously, was found to have little or no beta‐adrenoceptor blocking activity in comparison to the racemic mixture (+/‐)‐sotalol. The repolarization effects of (+)‐ and (+/‐)‐sotalol on the QTc interval however were comparable over the same dose range. The beta‐adrenoceptor blocking activity and repolarization effects of sotalol appear to be unrelated.
Metoprolol metabolism and debrisoquine oxidation polymorphism‐ population and family studies.
Authors: McGourty JC , Silas JH , Lennard MS , Tucker GT , Woods HF
Published: July 2012

The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha‐ hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117‐04, the end‐product of O‐dealkylation. The distribution of the log10 metoprolol to H117‐04 (M/H117‐04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117‐04 values. These results indicate that both the alpha‐hydroxylation and O‐dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. In a sub‐group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post‐exercise heart rate at 24 h after dosing.
Pharmacokinetics of the trimethoprim‐sulphamethoxazole combination in the elderly.
Authors: Varoquaux O. , Lajoie D. , Gobert C. , Cordonnier P. , Ducreuzet C. , Pays M. , Advenier C.
Published: July 2012

The pharmacokinetics of a co‐trimoxazole preparation (Bactrim Forte) containing trimethoprim (TMP) 160 mg and sulphamethoxazole (SMZ) 800 mg were determined in six young adults (29.3 +/‐ 4.4 s.d. years) and six elderly people (78.6 +/‐ 6.6 s.d. years). Following oral administration of a single dose, the pharmacokinetic parameters of SMZ and its N4‐ acetylated metabolite (N4SMZ) were similar in both groups. However Cmax of TMP was greater (2.06 +/‐ 0.29 s.d. vs 1.57 +/‐ 0.32 s.d. mg l‐1; P less than 0.01) and its area under the curve was larger (34.30 +/‐ 6.98 s.d. vs 23.87 +/‐ 3.82 s.d. mg l‐1 h; P less than 0.001) in elderly people than in younger subjects. Total clearance (CL/F) of TMP normalized to body weight was not significantly different in the two groups. There was no significant difference in serum protein binding of TMP and SMZ between the two groups. Urinary excretion of TMP, SMZ and N4SMZ was reduced by about 50% in the elderly compared to the young subjects. Renal clearance of TMP was significantly lower in the elderly group (19 +/‐ 10 s.d. vs 55 +/‐ 14 s.d. ml h‐1 kg‐1; P less than 0.001). Renal clearance of SMZ was not significantly different in the two groups. A study of plasma concentrations of TMP, SMZ and N4SMZ during continuous dosing in seven elderly patients treated for urinary or respiratory infections showed that steady state was reached after 3 days of treatment and that plasma drug concentrations were about two to three times higher than those observed after a single dose.
Cardiovascular pharmacology of nicardipine in animals.
Authors: Takenaka T. , Asano M. , Shiono K. , Shibasaki M. , Inagaki O.
Published: July 2012

The haemodynamic, antianginal and antihypertensive effects of nicardipine, a vascular selective calcium antagonist, were studied in experimental animals. In the canine isolated coronary artery, nicardipine relaxed potassium‐induced contraction and suppressed 3,4‐ diaminopyridine‐induced rhythmic contractions more effectively than nifedipine, verapamil or diltiazem. In anaesthetised rats, nicardipine prevented the elevation of ST segment induced by intracoronary injection of methacholine. In anaesthetised dogs, nicardipine produced a greater vasodilatation in vertebral, carotid, and coronary vessels than in mesenteric, femoral, and renal vessels and did not affect myocardial oxygen consumption. In conscious monkeys, nicardipine given intravenously lowered blood pressure and gave rise to reflex tachycardia but did not prolong the A‐V conduction time. Nicardipine given orally lowered blood pressure in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR), and deoxycorticosterone acetate/salt hypertensive rats (DOCA/Salt), as well as in normotensive rats. Long‐term treatment with nicardipine given orally for 12 weeks effectively lowered high blood pressure in the three types of hypertensive rats, reduced cardiac hypertrophy in SHR and DOCA/Salt rats, and prevented mortality from stroke in DOCA/Salt rats. Combined treatment with nicardipine and a beta‐adrenoceptor blocking agent (indenolol) showed an antihypertensive effect similar to that obtained with nicardipine alone. Conscious renal hypertensive dogs given repeated oral administration of nicardipine for 14 days did not develop tolerance to the hypotensive activity of nicardipine. Under the same conditions, tolerance to hydralazine developed within 4 days.
Influence of nicardipine on blood pressure, renal function and plasma aldosterone in normotensive volunteers.
Authors: van Schaik BA , Hene RJ , Geyskes GG
Published: July 2012

The influence of the calcium antagonist nicardipine on intrarenal sodium handling and angiotensin II induced secretion of aldosterone was investigated in 18 normotensive volunteers after the first dose and after 1 week of treatment (20 mg three times daily). A short‐lasting natriuresis was observed, which was caused by a decreased reabsorption of sodium localised in both proximal and distal tubules. Log plasma renin activity (PRA) fell significantly on each day during angiotensin II infusion, while log‐plasma aldosterone (PA) rose significantly. The log PRA/log PA ratio was increased during nicardipine treatment. The secretion of aldosterone, induced by angiotensin II, was not influenced by nicardipine treatment. No effect of the drug on adrenal responsiveness to angiotensin II was found.
The effect of acute and chronic nicardipine therapy on forearm arterial haemodynamics in essential hypertension.
Authors: Levenson J. , Simon AC , Bouthier J. , Maarek BC , Safar ME
Published: July 2012

By using simultaneous recording curves obtained with pulsed Doppler velocimetry and strain gauge mechanography, forearm arterial haemodynamics were studied in 26 patients with mild to moderate essential hypertension. Fifteen patients received a single oral dose of nicardipine 40 mg, and 11 patients were treated with nicardipine 30 mg three times daily for 3 months. In both groups of patients there was a similar and significant (P less than 0.001) reduction in mean, systolic, and diastolic pressures. There was a slight increase in heart rate (P less than 0.05) after the single dose, but no change after 3 months of treatment. The diameter, blood velocity, and blood flow of the brachial artery increased significantly in both treatment groups. The decrease in forearm vascular resistance was significant for both treatment groups. Brachial artery compliance increased (P less than 0.01) and characteristic impedance decreased (P less than 0.01) after both single‐dose and long‐term therapy with nicardipine. In patients who received nicardipine for 3 months, there were close correlations between the baseline serum calcium level and the percent change in vascular resistance (r = ‐0.73, P less than 0.01), blood flow (r = 0.89, P less than 0.001), and blood velocity (r = 0.91. P less than 0.001) of the forearm. No correlation was found between the baseline serum calcium and the change in arterial pressure. This study provided evidence that the blood‐pressure‐lowering effect of nicardipine was accompanied by a direct vasodilatory action in the small and large arteries of the forearm. An increase in peripheral blood flow with concomitant improvement of arterial compliance are the consequences of these arterial actions.
The effect of nicardipine on blood pressure, its variability and reflex cardiac control.
Authors: Littler WA , Young MA
Published: July 2012

Eight untreated patients with essential hypertension (average casual blood pressure 180/110 +/‐ 27/12 mm Hg) were studied following control, acute (a single oral dose of 30 mg nicardipine hydrochloride), and chronic (2 months nicardipine oral therapy) treatment periods. During the 2 month treatment period, ambulatory mean intra‐arterial (IABP), measured when the patients were awake, fell from 165/105 +/‐ 6/12 (control) to 150/96 +/‐ 14/12 mm Hg (P less than 0.05), but heart rate remained unchanged (84 +/‐ 12 control vs 80 +/‐ 9 beats min‐1). There was an absolute reduction in blood pressure in response to tilting, the Valsalva manoeuvre, and exercise handgrip, but the percent increase in pressure following nicardipine was not significantly different from that in the control period. There was no change in baroreflex sensitivity after either acute or chronic treatment, but the set point of the reflex was reset to a lower pressure following chronic therapy. Both single and multiple doses of nicardipine significantly reduced intra‐arterial pressure. Chronic therapy was associated with return of the heart rate to control values, which was due to resetting of the baroreflex control mechanism.
Action of compounds with effective in vivo mineralocorticoid activity on ion transport in leucocytes.
Authors: Baron DN , Green RJ
Published: July 2012

We have studied the in vitro short‐term effects of aldosterone (1.0‐ 1000 nmol l‐1), cortisol (0.5‐5.0 mumol l‐1), fludrocortisone (1.0‐10 nmol l‐1) and carbenoxolone (0.5‐3 mmol l‐1) on 86rubidium influx (a model for potassium), 22sodium efflux, and [3H]‐ouabain binding capacity in intact human leucocytes. No effect of aldosterone (at concentrations present in Conn's syndrome) or fludrocortisone could be demonstrated on cation fluxes or [3H]‐ouabain binding compared to controls. No significant effect of cortisol, at concentrations either physiological or present in Cushing's syndrome, could be demonstrated on cation fluxes or [3H]‐ouabain binding compared to controls. Carbenoxolone significantly increased 86Rb influx and 22Na efflux at concentrations known to cause hypokalaemia in man. The effect was not blocked by propranolol. No effect could be demonstrated for [3H]‐ ouabain binding.
Stereoselective disposition of mexiletine in man.
Authors: Grech‐Belanger O , Turgeon J , Gilbert M
Published: July 2012

The pharmacokinetics of S‐(+)‐ and R‐(‐)‐mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half‐lives of the two enantiomers were similar but the AUC of the S‐(+)‐enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 +/‐ 0.12 (s.d.) and 0.80 +/‐ 0.21, respectively. Urinary excretion of mexiletine conjugates consisted mainly of the R‐(‐)‐enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 +/‐ 3.10. Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 +/‐ 0.48 and the renal clearance of the R‐(‐)‐enantiomer was significantly higher (P less than 0.02) than that of the S‐(+)‐enantiomer.
Cimetidine absorption in humans during sucralfate coadministration.
Authors: D'Angio R , Mayersohn M , Conrad KA , Bliss M
Published: July 2012

Cimetidine absorption after a single 300 mg oral dose was evaluated in six normal subjects in the absence or presence of sucralfate. Sucralfate was ingested four times a day for 2 days prior to and for two additional doses on the day of cimetidine ingestion. Sucralfate coadministration had no statistically significant influence on the rate or extent of cimetidine absorption.
The alpha 1‐adrenoceptor antagonist profile of doxazosin: preclinical pharmacology.
Authors: Alabaster VA , Davey MJ
Published: July 2012

The antihypertensive efficacy of the new alpha 1‐adrenoceptor antagonist doxazosin is described, and its selectivity for alpha 1‐ adrenoceptors is reported from both in vivo and in vitro studies. Groups of beagle dogs with chronic perinephritic hypertension were given doxazosin orally, and systolic blood pressure was recorded indirectly from an exteriorized carotid loop. Dogs given doxazosin 0.5 mg kg‐1 daily for 10 days showed consistent daily falls in systolic pressure in addition to a progressive reduction in daily pre‐dose pressures. A clear indication of antihypertensive action in excess of 24 h post dose was evident. Heart rate changes were minimal. In pentobarbitone anaesthetized dogs pretreated with desimipramine, doxazosin 10‐500 micrograms kg‐1 i.v. reduced responses of the nictitating membrane to electrical stimulation of the vagosympathetic‐ depressor nerve trunk (an alpha 1‐adrenoceptor response) but had no effect on the chronotropic response of the heart to electrical stimulation of the ansa subclavia. In contrast, the prejunctional alpha 2‐adrenoceptor antagonist activity of yohimbine 10‐100 micrograms kg‐1 i.v. was manifest as a marked dose‐related increase in both the heart rate and nictitating membrane responses. The lack of effect of doxazosin on postjunctional alpha 2‐adrenoceptors in vivo was demonstrated in the anaesthetized cat. Doxazosin at 50 and 100 micrograms kg‐1 i.v. inhibited pressor responses to injected phenylephrine (an alpha 1‐adrenoceptor agonist) but had no effect on pressor responses to either alpha‐methylnoradrenaline (an alpha 2‐ adrenoceptor agonist) or angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
The metabolism and kinetics of doxazosin in man, mouse, rat and dog.
Authors: Kaye B , Cussans NJ , Faulkner JK , Stopher DA , Reid JL
Published: July 2012

The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C‐labelled compound. Bioavailability and pharmacokinetic studies were also conducted with nonlabelled drug, using a specific h.p.l.c. method. Following both oral and intravenous administration, the major route of elimination of drug‐related compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog. The drug is extensively metabolized, e.g. only about 5% of the dose was excreted unchanged in man. Metabolism in man mainly involves 6‐ and 7‐ O‐demethylation and 6′ and 7′‐hydroxylation. These and some minor products were common to the mouse, rat or dog and man. Plasma protein binding was high in all species studied, ranging from 95.3% in the rat to 98.3% in human patients. Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63% reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min‐1 kg‐1 (dogs), 30 ml min‐1 kg‐1 (rats) and 1.2 ml min‐1 kg‐1 (human subjects). Mean plasma half‐life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half‐life of doxazosin provides the basis for once‐daily dosing.
Clinical pharmacological studies with doxazosin.
Authors: Elliott HL , Meredith PA , Vincent J , Reid JL
Published: July 2012

The clinical pharmacology of doxazosin is reviewed from studies in normotensive young (21‐39 years) and elderly (62‐89 years) subjects following oral (2 mg) and intravenous (1 mg) administration. In young subjects the mean bioavailability was 65% and the mean terminal elimination half‐lives were 9.5 and 10.5 h following acute intravenous and oral administration respectively. These parameters were similar in the elderly with bioavailability of 69% and half‐lives of 8.8 and 11.9 h. The apparent volume of distribution and clearance were significantly higher in elderly (1.7 1 kg‐1 and 140 ml min‐1) than in young subjects (1.01 kg‐1 and 83 ml min‐1). In both groups blood pressure reductions were most marked in the standing position and the maximum effect did not occur until 5‐6 h, even after intravenous administration. The blood pressure reduction produced by doxazosin was associated in the young with a significant increase in heart rate to 108 beats min‐1 (placebo, 82 beats min‐1) but this increase was significantly attenuated in the elderly at 91 beats min‐1 (placebo, 77 beats min‐1). Pressor response studies in the young subjects confirmed the alpha 1‐adrenoceptor antagonist activity of doxazosin with significant rightward shifts of the dose‐response curves for the selective alpha 1‐adrenoceptor agonist phenylephrine. Using the technique of concentration‐effect analysis, both the degree of alpha 1‐adrenoceptor antagonism and the hypotensive effect can be correlated with the concentration of doxazosin in the 'effect compartment'.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium antagonists and their mode of action: an historical overview.
Authors: Nayler WG , Dillon JS
Published: July 2012

The Ca2+ antagonists are a novel group of drugs useful in management of a variety of cardiac disorders. They differ from one another in terms of their chemistry, tissue specificity and selectivity. As a group, however, they share the common property of slowing Ca2+ entry through voltage‐activated, ion‐selective channels. Some of them exhibit other properties, including that of interfering with Na+ transport. At least one of them, diltiazem, has an intracellular action. Specific high and low affinity binding sites have been identified for two of the major groups of Ca2+‐antagonists, with the binding sites for verapamil and its derivatives being distinct from those which can be occupied by the dihydropyridines. The number (Bmax) and affinity (KD) of these binding sites changes under certain pathological conditions‐including a reduction in ischaemia and in spontaneous hypertension, an increase in the latter, at present, only demonstrated for the dihydropyridine binding sites. The sensitivity of a particular tissue to these drugs will depend upon a number of factors including the number of binding sites that are present, the contribution made by the Ca2+ entering through the voltage‐activated channels to the functioning of the tissue, and properties which are peculiar to a particular type of Ca2+ antagonist, for example, whether, as in the case of verapamil, they exhibit use‐dependence.
The mechanism of action of calcium antagonists relative to their clinical applications.
Authors: Singh BN
Published: July 2012

As a class of therapeutic agents calcium antagonists have attracted increasing attention in recent years. Their major indications have been in the treatment of ischaemic myocardial syndromes, certain cardiac arrhythmias, hypertension, obstructive cardiomyopathies, and a number of lesser clinical disorders in which their role is less clearly defined. With the widening spectrum of therapeutic utility and an increasing plethora of newer agents under development, it is of importance to relate the overall pharmacodynamics of individual agents to their clinical effects. Calcium antagonists have a variable specificity for cardiac and peripheral activity. Based on such activity, it is useful to construct a classification of these compounds, new and old, into four categories. Type I agents, typified by verapamil and its congeners (tiapamil and gallopamil) and diltiazem, prolong AV nodal conduction and refractoriness with little effect on ventricular or atrial refractory period. These actions account for their direct antiarrhythmic properties. Type II agents include nifedipine and other dihydropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall haemodynamic effects are dominated by this peripheral vasodilatation and reflex augmentation of sympathetic reflexes. Type III agents include flunarizine and cinnarizine (piperazine derivatives), which, in vitro and in vivo, are potent dilators of peripheral vessels, with no corresponding calcium‐blocking actions in the heart. Type IV agents are agents with a broader pharmacologic profile (perhexiline, lidoflazine and bepridil); they block calcium fluxes in the heart, in the peripheral vessels, or both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. A clear understanding of the varied pharmacologic properties of the different classes of calcium antagonists is likely to provide a rational basis for the use of these agents in clinical therapeutics.
Pharmacokinetics of conventional and slow‐release verapamil.
Authors: Follath F , Ha HR , Schutz E , Buhler F
Published: July 2012

Verapamil is a racemic mixture of two optical isomers, the (‐)‐form being the more active component. Recent studies indicate a rapid hepatic transformation of (‐)‐verapamil, which results in different concentration‐effect relationships after oral and intravenous administration. In practice the important pharmacokinetic properties of verapamil are low bioavailability (20%), predominant elimination by metabolism (greater than 95%) and a relatively short half‐life (t1/2, beta is 3‐5 h). After repeated dosing, the rate of hepatic drug clearance seems to decrease. Slow release (SR) formulations of verapamil may offer certain therapeutic advantages during long‐term treatment. A comparison of conventional (C) and SR tablets in a 1‐week treatment of eight cardiac patients showed a relative bioavailability (AUCSR/AUCC) of 90 +/‐ 30%. More stable serum drug levels were maintained by 12‐hourly administration of SR verapamil. A further study using a new 240 mg SR preparation in patients with arterial hypertension showed that even a single daily dose can be sufficient for adequate blood pressure control over 24 h.
Verapamil in arrhythmia.
Authors: Krikler DM
Published: July 2012

The antiarrhythmic effects of verapamil were observed before it was appreciated that it was a calcium ion‐antagonist. Intravenous verapamil is highly effective in the termination of paroxysmal reciprocating atrioventricular tachycardia, whether associated with preexcitation or involving the atrioventricular node alone. It consistently slows and regularises the ventricular response in atrial fibrillation, and usually increases the degree of AV‐nodal block in atrial flutter though it occasionally induces a return to sinus rhythm. Given orally it is useful for the prophylaxis of atrioventricular reentry tachycardia, and also in modulating the atrioventricular nodal response in atrial fibrillation. Favourable response in ventricular tachycardia is exceptional and then seen in specific benign varieties. Verapamil is the agent of choice for the termination of paroxysmal supraventricular tachycardia.
Description of the time course of the prolactin suppressant effect of the dopamine agonist CQP201‐403 by an integrated pharmacokinetic‐ pharmacodynamic model.
Authors: Grevel J , Brownell J , Steimer JL , Gaillard RC , Rosenthaler J
Published: July 2012

Six male volunteers (mean age 24 years) received a single oral dose of 0.025 mg CQP201‐403 and placebo in a randomised double‐blind crossover design. Fifteen plasma samples were collected over 48 h and were assayed by radioimmunoassay for drug substance and prolactin (PRL). Three of the samples were drawn during sleep on the first study day. The pharmacological effect (E%) of CQP201‐403 was expressed as reduction in plasma PRL levels. The pharmacokinetic (PK)‐ pharmacodynamic (PD) model consisted of two kinetic compartments and an effect compartment linked to the central compartment. A sigmoid Emax model (Hill equation) described the relationship between the drug concentration in the effect compartment and E%. Curve‐fitting of PK and PD data provided individual parameter estimates which served to generate computer‐simulated PK and PD profiles after single and multiple doses in order to: investigate the in vivo concentration‐ effect relationship; evaluate the consequence of dosage reduction on the steady‐state PD profile; and study the robustness of the response to changes in drug potency and bioavailability.
The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.
Authors: Faulkner JK , McGibney D , Chasseaud LF , Perry JL , Taylor IW
Published: July 2012

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half‐life of 34 h, mean clearance of 7 ml min‐1 kg‐1 and a mean apparent volume of distribution of 21 l kg‐1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half‐life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half‐life of 45 h.
Enhancement by sodium salicylate of the blood glucose lowering effect of chlorpropamide‐drug interaction or summation of similar effects?
Authors: Richardson T , Foster J , Mawer GE
Published: July 2012

The ability of sodium salicylate (3 g) to enhance the blood glucose lowering action of chlorpropamide (200 mg) has been confirmed in healthy male volunteers who received an oral test dose of 50 g glucose. Salicylate raised the plasma concentration of insulin and lowered that of cortisol but did not alter the concentration of chlorpropamide. The area under the blood glucose concentration‐time curve was used as the measure of drug response and the significance of drug effects was assessed by analysis of variance. In one study on five volunteers the effect of combining salicylate and chlorpropamide was additive. In a second study on six volunteers 200 mg chlorpropamide, 3 g sodium salicylate and 100 mg chlorpropamide + 1.5 g salicylate were equi‐ effective. The enhancement of chlorpropamide action by salicylate in this single dose study is consistent with the summation of similar effects. It is not necessary to postulate an interaction.
Acute treatment with desipramine stimulates melatonin and 6‐sulphatoxy melatonin production in man.
Authors: Franey C , Aldhous M , Burton S , Checkley S , Arendt J
Published: July 2012

Acute administration of the antidepressant drug desipramine (DMI) in man, increased evening melatonin secretion, which reached peak plasma levels 2‐4 h earlier than after placebo administration. The increase at set time points 21.00 h‐22.00 h was directly proportional to an individual's integrated night‐time secretion of melatonin. We have shown that this stimulation was not an effect of DMI inhibition on the hepatic metabolism of melatonin to 6‐sulphatoxy melatonin (aMT6s), indeed aMT6s is in itself a good index of the evening melatonin rise. The stimulation of early evening melatonin by DMI might be exploited as a simple pineal function test.
Partial metabolic clearances as determinants of the oral bioavailability of propranolol.
Authors: Walle T , Walle UK , Olanoff LS , Conradi EC
Published: July 2012

The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side‐ chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium‐labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three‐fold, from 27.5 to 71.4 ml min‐1 kg‐1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min‐1 kg‐1. The clearance through side‐chain oxidation varied 2.4‐fold, from 10.9 to 25.8 ml min‐1 kg‐1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6‐fold, from 7.5 to 41.8 ml min‐1 kg‐1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side‐ chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.
The metabolic response to glucagon and glucagon‐(1‐21)‐peptide in normal subjects and non insulin dependent diabetics.
Authors: Owens DR , Vora J , Morris T , Luzio S , Ryder RE , Atiea J , Hayes TM
Published: July 2012

The metabolic effects of glucagon leading to hyperglycaemia are well recognised. However, the spasmolytic properties of glucagon have only relatively recently been utilised in clinical medicine. The marked hyperglycaemia accompanying the smooth muscle relaxant action of glucagon has led to the development of smaller peptides derived from glucagon which may retain the spasmolytic effects without the metabolic consequences. This study compares the metabolic and hormonal response to one such peptide, glucagon‐(1‐21)‐peptide, with the parent peptide glucagon. The results demonstrate that glucagon‐(1‐21)‐peptide has no metabolic effects comparable to glucagon. In normal subjects and non‐ insulin dependent diabetics, glucagon‐(1‐21)‐peptide has no stimulatory effect on the pancreatic beta‐cell.
Acute and chronic pharmacokinetics of asymmetrical doses of slow release choline theophyllinate in asthma.
Authors: Hibberd SG , Alveyn C , Coombes EJ , Holgate ST
Published: July 2012

The day and night pharmacokinetics of assymetrical doses of slow release choline theophyllinate (Sabidal SR 270) were compared at day 1 and at day 4 of treatment when steady state had been achieved. Ten patients with chronic asthma were given oral choline theophyllinate 424 mg at 09.00 h and 848 mg at 21.00 h for 4 days. At regular intervals during day 1 and day 4 of treatment theophylline concentrations were measured in plasma and dried blood spots by fluorimmunoassay. Theophylline concentrations measured from dried blood spots were slightly lower than those in plasma, the difference remaining constant at all time points during day 1 and day 4 of treatment. On day 1 the mean peak plasma theophylline concentration was 5.4 +/‐ 1.0 (+/‐ s.e. mean) micrograms ml‐1 4 h after the morning dose and 11.2 +/‐ 1.6 micrograms ml‐1 4 h after the evening dose which were significantly (P less than 0.01) different. Similarly the areas under the plasma theophylline concentration‐time curves at night were significantly (P less than 0.001) greater than those observed during the day. During day 4 mean peak plasma concentrations of theophylline after the morning and larger evening dose were 13.2 +/‐ 1.3 and 12.1 +/‐ 1.4 micrograms ml‐1 respectively, which were not significantly different. No significant difference was observed between the areas under the plasma theophylline concentration‐time curves during the day and at night. However the post‐ dose time to peak was significantly delayed at night (6 h) compared to the morning (2 h, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Excretion of trazodone in breast milk.
Authors: Verbeeck RK , Ross SG , McKenna EA
Published: July 2012

The excretion of breast milk was studied in six lactating women following the oral administration of a single trazodone tablet (50 mg). The milk/plasma ratio of trazodone based on area under the plasma and milk curves was small: 0.142 +/‐ 0.045 (mean +/‐ s.d.). Assuming that the babies would drink 500 ml 12 h‐1, they would be exposed to less than 0.005 mg kg‐1 as compared to 0.77 mg kg‐1 for the mothers. It is concluded that exposure of babies to trazodone via breast milk is very small.
The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on‐off fluctuations.
Authors: Hardie RJ , Malcolm SL , Lees AJ , Stern GM , Allen JG
Published: July 2012

We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on‐off fluctuations whilst receiving long‐term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32‐80 mg h‐1 (0.5‐1.3 mg kg‐1 h‐1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l‐1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3‐OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two‐compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on‐ off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.
Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans.
Authors: Aderounmu AF , Salako LA , Lindstrom B , Walker O , Ekman L
Published: July 2012

The pharmacokinetics of chloroquine were studied after intramuscular and intravenous administration of the drug to healthy African adults. Chloroquine was analysed in plasma using an h.p.l.c. method and pharmacokinetic parameters were derived from the concentration‐time data using a non‐linear computer programme. A two‐compartment open model was assumed. Chloroquine was rapidly absorbed from an intramuscular site, producing a plasma concentration‐time profile similar to that obtained after a 15 min i.v. infusion of a comparable dose. The pharmacokinetics of chloroquine after i.m. and i.v. administration were characterised by a long half‐life and a very large volume of distribution. There was no significant difference between the values of each parameter obtained from the different routes. It is suggested that the high Cmax obtained after i.m. and i.v. administration of chloroquine might contribute to its toxicity when these routes are used in treatment.
Pharmacokinetics of intravenous and oral salbutamol and its sulphate conjugate.
Authors: Morgan DJ , Paull JD , Richmond BH , Wilson‐Evered E , Ziccone SP
Published: July 2012

The pharmacokinetics of salbutamol and its sulphate conjugate metabolite were investigated after intravenous and steady‐state oral administration of salbutamol to 10 healthy volunteers. With intravenous administration, total plasma clearance was 480 +/‐ 123 ml min‐1, elimination half‐life was 3.86 +/‐ 0.83 h and apparent volume of distribution was 156 +/‐ 381. Urinary excretion of unchanged drug and sulphate conjugate were 64.2 +/‐ 7.1% and 12.0 +/‐ 3.1% of the dose, respectively. With oral administration, systemic availability was 0.50 +/‐ 0.04, and urinary excretion of unchanged drug and sulphate conjugate were 31.8 +/‐ 1.9% and 48.2 +/‐ 7.3% of the dose, respectively. The drug eliminated on the first‐pass could be accounted for entirely as sulphate conjugate formed, presumably, in the intestinal wall. Renal clearance of salbutamol was 291 +/‐ 70 ml min‐1 after intravenous and 272 +/‐ 38 ml min‐1 after oral administration, while the renal clearance of the sulphate conjugate was 98.5 +/‐ 23.5 ml min‐1 after oral administration. Heart rate increased with increasing plasma salbutamol concentration, although a lag was evident. The effect on heart rate was lower after 24 h continuous oral salbutamol administration.
The effect of age on theophylline clearance in normal subjects.
Authors: Randolph WC , Seaman JJ , Dickson B , Peace KE , Frank WO , Young MD
Published: July 2012

Dose‐interval AUC and clearance of theophylline at steady‐state were determined in healthy male subjects in each of three age groups (18‐35, 36‐54 and 55‐70 years old). Mean AUC in the oldest group was significantly higher than in the youngest and clearance in both the middle and oldest groups was significantly lower than in the youngest. Though clearance was significantly correlated with age, age alone accounted for only 31% of the variability in clearance.
Inhibition of antipyrine metabolism by interferon.
Authors: Williams SJ , Farrell GC
Published: July 2012

Antipyrine clearance was measured before and 1 day after administration of a single intramuscular dose of recombinant human leukocyte alpha A interferon. In the nine patients studied, antipyrine clearance was reduced after interferon from 0.49 (0.21‐1.13) ml kg‐1 min‐1 (median (range)) to 0.41 (0.20‐1.07) ml kg‐1 min‐1, P less than 0.01. In individual patients, the decrement in antipyrine clearance was variable, ranging from 5‐47% (median, 16%). This study provides the first direct evidence that interferon inhibits hepatic oxidative drug metabolism in humans and alerts clinicians to the possibility of potentially toxic drug‐drug interactions.
The relationship between gastric emptying of semisolids and paracetamol absorption.
Authors: Petring OU , Adelhoj B , Ibsen M , Poulsen HE
Published: July 2012

The relationship between gastric emptying rate of semisolid Tc‐99m labelled Chelex‐100 resin/oatmeal and paracetamol absorption was determined simultaneously in seven healthy volunteers. There was no significant correlation between the half‐time of gastric emptying and the time of the peak serum paracetamol concentration. There was no significant correlation between the area under the serum paracetamol concentrations at 60 and 90 min and the % meal emptied in 60 and 90 min respectively. Three subjects showed a lag phase in gastric emptying pattern, while the other four showed the emptying curves without evidence of a delayed phase of emptying. Individual values of gastric emptying determined by the methods varied widely.
Microcalorimetric studies on the effect of adenosine receptor agonists and xanthine derivatives on overall metabolism in human platelets.
Authors: Edvinsson L , Ikomi‐Kumm J , Monti M
Published: July 2012

The direct overall metabolic effects of drugs acting on adenosine receptors in human platelets were evaluated using a sensitive microcalorimetric method. Adenosine induced a concentration‐dependent increase in the heat production rate at concentrations above 100 microM. The adenosine uptake inhibitor, dipyridamole (3 microM) did not modify the effect of adenosine. Two putative adenosine receptor agonists were tested: NECA (5‐N‐ethyl carboxamide adenosine) and PIA (L‐ N6‐phenylisopropyl‐adenosine). NECA induced, at significantly lower concentrations than adenosine, an enhanced heat production rate. Concentrations above 1 mM had no effect. PIA, on the other hand, invariably induced a reduction in the heat production rate already at a concentration of 100 microM. The two xanthine derivatives enprofylline (25 microM) and theophylline (100 microM) were tested at concentrations found during antiasthmatic therapy. Neither had any thermogenic effect by themselves nor showed any significant modification of the heat production rate induced by adenosine (300 microM). These results indicate that adenosine and NECA increase human platelet metabolism, whereas PIA has an opposite effect. The proposed adenosine receptor antagonists enprofylline and theophylline were without effects. This microcalorimetric study gives new insights into the complex nature of adenosine mechanisms in a human test system and indicates that the thermogenic effect of adenosine is unrelated to adenosine receptors.
Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.
Authors: Speirs CJ , Murray S , Boobis AR , Seddon CE , Davies DS
Published: July 2012

Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4‐hydroxylation of debrisoquine, the O‐deethylation of phenacetin and the 1′‐hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4‐hydroxylation in vivo. Quinidine was a potent inhibitor of the 4‐hydroxylation of debrisoquine and the 1′‐hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 microM, being around 100 times more potent in this respect than quinine. Very much higher (1000‐ fold) levels of quinidine were required to inhibit the O‐deethylation of phenacetin, being rather less potent in this than quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co‐administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26‐fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4‐ hydroxylase isozyme to the elimination of the drug tested.
Experience with isoxicam and catabolin.
Authors: Sheppeard H , Couchman KG
Published: July 2012

1 Synovial cells produce a protein factor, catabolin, that induces chondrocytes to resorb their own matrix with the release of glycosaminoglycan (GAG). 2 Studies were performed to determine the effect of isoxicam, a new NSAID, on GAG production in a catabolin system utilizing tissue culture of bovine nasal septum in a medium containing pooled synovial tissue from young pigs. 3 Using fresh medium containing no synovial tissue, the release of GAG by inherent cartilage breakdown was 49.7% after 8 days culture. GAG release at 8 days increased to 83.6% by the addition of synovial cells to the culture medium, due to the action of catabolin. 4 The incorporation of isoxicam, at concentrations from 5‐30 micrograms ml‐1, in the porcine synovial culture medium significantly reduced the GAG release to 70.9%. 5 Isoxicam at 50 micrograms ml‐1 added to fresh medium without synovial tissue had no effect on cartilage breakdown or GAG production. 6 The results of these experiments show that isoxicam is unlikely to impair cartilage metabolism and may even decrease cartilage resorption.
Pharmacokinetics of isoxicam in hepatic disease.
Authors: Ferry N , Cuisinaud G , Ouzan D , Trepo C , Sassard J
Published: July 2012

1 The pharmacokinetics of single and repeated oral doses of isoxicam, an extensively metabolized drug, were studied in patients with compensated and decompensated hepatic disease. 2 After a single oral dose, isoxicam was slowly absorbed and eliminated (half‐life ranging from 10.5 to 53.9 h). Its pharmacokinetics did not differ from those observed in healthy volunteers and were not significantly influenced by the severity of hepatic disease. However, the t1/2 of isoxicam was found to be inversely (r = −0.700, P less than 0.05 n = 14) related to the log gamma‐glutamyl transpeptidase plasma activity. 3 During chronic oral treatment in patients with compensated hepatic insufficiency, steady‐state was achieved after 7‐9 days of therapy. The mean elimination half‐life of isoxicam in five patients was 42.6 +/‐ 4.5 h, a value which was not statistically different from that obtained in the single dose study. 4 It was concluded that patients with hepatic insufficiency do not require a systematic modification of drug dosage but that long‐term treatment should be employed with caution in these patients.