bluuebunny/crossref_metadata_2025 huggingface dataset:
The physiological and pharmacological role of presynaptic alpha‐ and beta‐adrenoceptors in man.
Authors: Brown MJ , Struthers AD , Burrin JM , Di Silvio L. , Brown DC
Published: July 2012

Two studies were performed each in six normal volunteers in order to find evidence of either a physiological or pharmacological role of presynaptic alpha‐ and presynaptic beta‐adrenoceptors in man. In Study 1 subjects received a 60 min infusion of guanfacine 3 mg (alpha 2‐ adrenoceptor agonist) preceded by either idazoxan (alpha 2‐adrenoceptor antagonist) or vehicle. Guanfacine reduced plasma noradrenaline concentration by approximately 30% and this fall was not antagonised by the alpha 2‐receptor antagonist. The 30‐fold increase in plasma growth hormone, measured as a marker of the central action of guanfacine, was almost completely blocked by idazoxan. A comparison of the drug concentrations of idazoxan and guanfacine, together with their relative affinities for alpha 2‐adrenoceptors, suggested that the idazoxan could not block the peripheral actions of guanfacine and that these were responsible for the fall in plasma noradrenaline concentration. In Study 2 adrenaline 0.05 micrograms kg‐1 min‐1 was infused for 80 min preceded by either idazoxan or vehicle. After vehicle, adrenaline caused no change in plasma noradrenaline concentration whereas it rose approximately 25% after administration of idazoxan. This was probably due to unmasking of presynaptic beta‐adrenoceptor stimulation by adrenaline when the opposing inhibitory autoreceptor was blocked.
Decreased vascular responsiveness to noradrenaline following regular ethanol consumption.
Authors: Howes LG , Reid JL
Published: July 2012

Ten normal volunteers consumed 80 g of ethanol per day or abstained from ethanol for 4 consecutive days prior to measurements of blood pressure, heart rate, vascular responsiveness to noradrenaline (NA) and angiotensin II (AII) infusions and sympathetic responsiveness to isometric handgrip exercise in an open, random order, crossed study. Supine systolic and diastolic pressures and heart rates, and erect systolic pressures rose significantly following ethanol. Vascular responsiveness to NA infusions was reduced in all subjects following ethanol, while responses to AII infusions did not show a consistent pattern of change. Plasma renin activity, plasma NA and adrenaline concentrations, and concentrations of the NA metabolite 3,4 dihydroxyphenylethylene glycol (DHPG) did not significantly differ following ethanol and control treatments. The rise in plasma NA following 2 min isometric handgrip at 50% of maximal effort was greater following ethanol (0.24 +/‐ 0.21 nM) than control (0.12 +/‐ 0.10 nM) but the difference did not reach statistical significance. The pressor effect of regular ethanol consumption and the reduced vascular reactivity to NA may both be the result of an increase in sympathetic activity that was not large enough to measurably alter resting plasma NA concentrations.
Haemodynamic dose‐response effects of intravenous nisoldipine in coronary artery disease.
Authors: Silke B. , Frais MA , Muller P. , Verma SP , Reynolds G. , Taylor SH
Published: July 2012

The circulatory consequences of slow‐calcium channel blockade with a new dihydropyridine nisoldipine were evaluated at rest and during exercise‐induced angina in 16 patients with angiographically proven coronary artery disease. In 10 patients resting cardiac stroke output (thermodilution) and pulmonary artery occluded pressure were determined following four intravenous nisoldipine injections (cumulative dosage of 1, 2, 4 and 8 micrograms kg‐1). The exercise effects of nisoldipine were evaluated by comparing the effects of the 8 micrograms kg‐1 cumulative dosage with a control exercise period at the same workload. At rest nisoldipine reduced systemic vascular resistance and mean arterial pressure, and increased heart rate, cardiac and stroke volume indices. During 4 min supine‐bicycle exercise nisoldipine reduced systemic mean arterial pressure and vascular resistance; this resulted in augmented cardiac and stroke volume indices at an unchanged pulmonary artery occluded pressure. In six additional patients rest and exercise ejection fractions were measured using a nonimaging nuclear probe. Nisoldipine (4 micrograms kg‐1) resulted in a small trend to increase left ventricular rest and exercise ejection fraction. These data demonstrated improved rest and exercise cardiac performance following nisoldipine in patients with severe coronary artery disease.
A free lignocaine index as a guide to unbound drug concentration.
Authors: Routledge PA , Lazar JD , Barchowsky A. , Stargel WW , Wagner GS , Shand DG
Published: July 2012

A free lignocaine index was developed on the basis of measurements of plasma lignocaine and its principle binding protein, alpha 1‐acid glycoprotein (AAG) in 80 samples from 16 patients admitted to the coronary care unit and given prophylactic lignocaine therapy. The free drug fraction, fu, of lignocaine was determined by equilibrium dialysis and its relationship to AAG and total lignocaine concentration (T) defined by multiple linear regression analysis as l/fu = 1.45 + 0.023 (AAG) ‐0.129 (T) (multiple r = 0.872, P less than 0.001). This relationship was used to calculate the 'free lignocaine index' as fu X T and compared with the observed value obtained by equilibrium dialysis of 178 samples from 41 separate subjects who received lignocaine after suspected myocardial infarction. There was a highly significant relationship (r = 0.933, n = 178, P less than 0.001) between the observed and predicted values. We conclude that the free drug index may be useful in rapidly assessing the unbound (free) concentration of lignocaine in plasma.
Antipyrine clearance and metabolite formation in children with congenital adrenal hyperplasia.
Authors: Teunissen MW , Bruining GJ , De Jongh BM , Tenkate‐Westerhof EW , Breimer DD
Published: July 2012

Antipyrine salivary clearance and half‐life and the rate of formation of three principal metabolites of antipyrine (4‐hydroxyantipyrine, 3‐ hydroxymethylantipyrine and norantipyrine) were assessed in nine children with congenital adrenal hyperplasia, six of whom were salt‐ losers and three of whom were non‐salt‐losers. No differences were found in comparison with data obtained in normal children.
Amiodarone reduces plasma warfarin clearance in man.
Authors: Watt AH , Stephens MR , Buss DC , Routledge PA
Published: July 2012

Amiodarone is an effective antiarrhythmic agent whose use is associated with several drug interactions one of which is potentiation of the action of warfarin. The mechanism of this interaction has hitherto been unclear. We examined possible mechanisms in eight patients. Total plasma warfarin clearance was found to be reduced by amiodarone. No change was detected in the binding of warfarin to plasma proteins. No relationship was found between plasma amiodarone concentrations and the change in warfarin clearance.
Vasodilatory effect of nicardipine and verapamil in the forearm of hypertensive as compared with normotensive man.
Authors: Hulthen UL , Bolli P. , Buhler FR
Published: July 2012

The intent of this study was to determine whether or not increased calcium‐influx‐mediated vasoconstriction is a primary pathogenetic disturbance in essential hypertension. Ten normotensive subjects (NT) (aged 45 +/‐ 12 years) and 23 patients with essential hypertension (EH) were studied. Twelve of the patients (aged 42 +/‐ 12 years) were classified as having mild EH and 11 patients (aged 49 +/‐ 11 years) as having moderate EH. Forearm blood flow and intra‐arterial blood pressure were measured. Forearm vascular resistance (FVR) was calculated under basal conditions, during reperfusion following 10 min arterial occlusion, and after infusion into the brachial artery of sodium nitroprusside (0.15 and 0.6 microgram min‐1 100 ml‐1 tissue for 2 min each) and the calcium‐influx inhibitors nicardipine (5 and 40 micrograms min‐1 100 ml‐1 tissue for 1 min each) and verapamil (80 micrograms min‐1 100 ml‐1 tissue for 1 min). FVR after 10 min arterial occlusion was lower in mild EH than in moderate EH and still lower in NT. FVR was comparable in the three groups following infusion of maximal doses of sodium nitroprusside, nicardipine, and verapamil. To allow for the vasodilator response to arterial occlusion, the decrease in FVR measured after each drug was divided by that obtained after arterial occlusion in each individual. The adjusted vasodilator response to nicardipine and verapamil, but not to sodium nitroprusside, was greater in moderate EH than in NT and mild EH. In the latter two groups the adjusted vasodilator responses were comparable.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium channel blockers‐are they diuretics?
Authors: Young MA , Watson RD , Stallard TJ , Littler WA
Published: July 2012

Seven untreated patients with essential hypertension but without target organ damage were admitted to hospital. Urine was collected the following day from 08.00 to 13.00 h, 13.00 to 18.00 h, and 18.00 to 08.00 h. The protocol was repeated the next day following 30 mg oral nicardipine. Intra‐arterial blood pressure (IABP), plasma volume, and plasma renin activity (PRA) also were measured daily. Following the single‐dose study, the patients were treated as outpatients and received oral nicardipine 20, 30, or 40 mg four times daily. They were readmitted 2 months later for further study, at which time the protocol was repeated. Urine output between 08.00 and 13.00 h significantly increased after the single‐ and multiple‐dose studies. Following the single‐dose study, this diuresis was associated with a natriuresis. Urine output increased over the 24 h following multiple‐dose treatment, but this increase was not statistically significant. During the multiple‐dose 24 h study, there was an increase in urinary potassium (P less than 0.05). Mean IABP was reduced significantly after the single‐ and multiple‐dose studies (P less than 0.02 and less than 0.05, respectively). During the study, there were no significant changes in plasma volume, weight, or plasma renin activity.
Effect of nicardipine in elderly hypertensive patients.
Authors: Forette F. , Bellet M. , Henry JF , Hervy MP , Poyard‐Salmeron C. , Bouchacourt P. , Guerret M.
Published: July 2012

The purpose of this study was to test tolerance and the antihypertensive effect of nicardipine, a new calcium antagonist, in 31 elderly patients aged 57‐95 years. The study was conducted as a double‐ blind trial. The patients were allocated randomly to either active or placebo treatment. Sixteen patients were given 10‐30 mg of nicardipine three times a day (mean dose, 69.4 mg per day); 15 other patients received a matching placebo. After 4 weeks, nicardipine lowered mean blood pressure, and the changes in systolic and diastolic blood pressure were significantly greater in the nicardipine group than in the placebo group. Nicardipine was tolerated very well, and orthostatic hypotension was never observed. There was no change in heart rate. Plasma renin activity (PRA) was measured in eight patients. There was no correlation between PRA and the antihypertensive effect of nicardipine. A pharmacokinetic study performed in 15 elderly patients showed a fast rate of absorption and also higher plasma levels than those observed in hypertensive adults (mean age, 54 years). This trial demonstrates the effectiveness of nicardipine in elderly hypertensive patients.
Blood pressure, heart rate and A‐V conduction responses to nicardipine in hypertensive patients receiving atenolol.
Authors: Kolloch R. , Stumpe KO , Overlack A.
Published: July 2012

The antihypertensive effect of the combined use of the new calcium channel blocker nicardipine and atenolol was assessed in a double‐ blind, placebo‐controlled trial involving twenty hypertensive patients. Atenolol 100 mg once daily was given to all patients. In addition, either placebo or nicardipine, in increasing doses (5‐20 mg three times daily), was allocated randomly to the patients. Compared with placebo, nicardipine had an additional dose‐dependent, blood‐pressure‐lowering effect in the hypertensive patients who had been pretreated with atenolol. An increase in the heart rate was not observed, suggesting that atenolol prevented reflex activation of sympathetic nerve tone caused by the vasodilating properties of nicardipine. The combination of both atenolol and nicardipine was well tolerated by all patients; side effects were minor and did not cause discontinuation of the treatment. No effects on A‐V conduction were observed. It is concluded that the combined administration of nicardipine and atenolol is a useful treatment for hypertension that is well accepted by the patients.
Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris.
Authors: Rousseau MF , Vincent MF , Cheron P. , van den Berghe G. , Charlier AA , Pouleur H.
Published: July 2012

The effects of intravenous nicardipine (2.5 mg) on the left ventricular (LV) inotropic state, LV metabolism, and coronary haemodynamics were analysed in 22 patients with angina pectoris. Measurements were made at fixed heart rate (atrial pacing), under basal state, and during a cold pressor test. After nicardipine, coronary blood flow and oxygen content in the coronary sinus increased significantly. The indices of inotropic state increased slightly, and the rate of isovolumic LV pressure fall improved. Myocardial oxygen consumption was unchanged despite the significant reduction in pressure‐rate product, but LV lactate uptake increased, particularly during the cold pressor test. When nicardipine was administered after propranolol, the indices of inotropic state were unaffected. The lack of direct effect of nicardipine on LV inotropic state was further confirmed by intracoronary injection of 0.1 and 0.2 mg in a separate group of 10 patients. It is concluded that the nicardipine‐induced coronary dilatation seems to improve perfusion and aerobic metabolism in areas with chronic ischaemia, resulting in reduced lactate production and augmented oxygen consumption.
Immediate and long‐term effects of nicardipine, at rest and during exercise, in patients with coronary artery disease.
Authors: Visser CA , Jaarsma W. , Kan G. , Koolen JJ , Lie KI
Published: July 2012

Haemodynamic effects of nicardipine were studied in 12 patients with documented coronary artery disease. Following nicardipine 10 mg, given intravenously to patients at rest, the heart rate increased, mean arterial pressure decreased, cardiac index increased, and systemic vascular resistance decreased significantly. Compared with the control exercise values, significant increases in heart rate and cardiac index and significant decreases in mean arterial pressure, systemic vascular resistance, and left ventricular end diastolic pressure occurred when nicardipine, 10 mg i.v., was given to the patients during exercise. All 12 patients complained of angina during the exercise phase, but following treatment with nicardipine, 10 mg i.v., only four patients reported angina when exercising to the same level. Exercise capacity on oral nicardipine treatment tended to increase whilst the ejection fraction response to exercise did not change. Thus, nicardipine was a potent vasodilator, which produced a marked reduction of systemic vascular resistance and left ventricular end diastolic pressure during exercise.
The acute haemodynamic effects of oral nicardipine.
Authors: McCredie RM , McKenzie WB , McGill DA
Published: July 2012

The haemodynamic effects of oral nicardipine at two different doses were assessed in fifteen patients at rest following diagnostic cardiac catheterisation. Six patients received four doses of 20 mg nicardipine hydrochloride orally every 8 h, and nine patients received four doses of 30 mg orally every 8 h. No side effects were encountered with either dose. At both dose levels, there was a significant fall in systemic vascular resistance, significant increases in heart rate and cardiac output, and no change in stroke volume index. No changes were seen in pulmonary vascular haemodynamics, and there were no significant changes in mean arterial pressure. Plasma levels of nicardipine reached a peak within 1 h. In parallel with the haemodynamic effects, the plasma concentrations achieved after the third and fourth doses were higher than after the first dose. These haemodynamic changes are consistent with a vasodilator effect, which produces a decrease in peripheral vascular resistance. It would appear that the 30 mg dose has a more potent vasodilator action than the 20 mg dose and, in the patients studied, this larger dose was not associated with any side effects.
Prevention of vasospastic angina with nicardipine.
Authors: Pepine CJ , Gelman JS
Published: July 2012

Anti‐ischaemic effects and safety of nicardipine were assessed in 14 patients with vasospastic angina using a placebo comparison, cross‐over design study for 8‐13 weeks. The average daily dose of nicardipine for optimal angina prevention was 84 mg (range 40‐160 mg). Nicardipine administration, as compared with placebo, significantly reduced anginal frequency and nitroglycerin consumption during the single‐ and double‐ blind phases of the study. Nicardipine appears to be effective in the prevention of vasospastic angina and not to cause major adverse effects.
The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man.
Authors: Lahtela JT , Gachalyi B , Eksyma S , Hamalainen A , Sotaniemi EA
Published: July 2012

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.
Experimental pain induced by electrical and thermal stimulation of the skin in healthy man: sensitivity to 75 and 150 mg diclofenac sodium in comparison with 60 mg codeine and placebo.
Authors: Stacher G , Steinringer H , Schneider S , Mittelbach G , Winklehner S , Gaupmann G
Published: July 2012

Models with experimentally induced pain in healthy man might be useful for the screening for analgesic effects of new drugs. Experimental pain models have been shown to discriminate reliably between the effects of opioid analgesics and placebo but their sensitivity to nonsteroidal anti‐inflammatory agents is disputed. This study investigated whether it would be possible by using electrically and thermally induced cutaneous pain to discriminate reliably the effects of single oral doses of 75 and 150 mg diclofenac sodium on the one hand and 60 mg codeine on the other from those of placebo. Forty‐eight healthy subjects participated each in four experiments in which they received, in random double‐blind fashion, each of the treatments. Every experiment comprised eight series of measurements, two before and six after drug administration, carried out at 30 min intervals. Diclofenac sodium produced significant dose‐related increases of threshold and tolerance to electrically and threshold to thermally induced pain. Codeine 60 mg was significantly superior to placebo in all pain measures. Its analgesic effects were stronger than those of diclofenac 75 mg but weaker than those of diclofenac 150 mg. Neither 150 mg nor 75 mg diclofenac caused more side effects than placebo, whereas codeine 60 mg elicited a high frequency of side effects. No severe adverse effects occurred after any one treatment. The results suggest that both electrically and thermally induced cutaneous pain are well suited to evaluate analgesic effects not only of opioids but also of nonsteroidal anti‐inflammatory drugs.
Relationship between plasma concentrations of clonidine and mean arterial pressure during an accidental clonidine overdose.
Authors: Domino LE , Domino SE , Stockstill MS
Published: July 2012

The time course of toxicity in a 28 year old man following a 100 mg accidental overdose of clonidine hydrochloride is compared with the decline of plasma clonidine over 5 days. The concentration data were analyzed by nonlinear least squares regression, and fitted to a model which dissociated the blood pressure effects into pressor and depressor components. According to this analysis, there appeared to be two phases of toxicity over time‐a hypertensive, and a hypotensive phase. The hypotensive and the hypertensive phases may result primarily through differential stimulation of central alpha 2‐, alpha 1‐, and vascular post‐synaptic alpha 2‐adrenoceptors as plasma concentrations fall.
Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.
Authors: Loft S , Sonne J , Pilsgaard H , Dossing M , Poulsen E
Published: July 2012

We investigated the effect of concomitantly administered disulfiram and cimetidine on antipyrine elimination. On day 1, 2, 4 and 6 of two periods of 6 days one sample antipyrine saliva clearance (APC) was measured in nine healthy volunteers. From day 2 to 6 of period I disulfiram 400 mg day‐1 was administered and on day 5 and 6 cimetidine 1000 mg day‐1 was added. In period II only cimetidine was given (on days 5 and 6). On day 4 of period II APC was increased 1.3 fold, probably due to self‐induction by repeated antipyrine administration. Taking this into account disulfiram and cimetidine separately decreased APC 0.64 and 0.70 times, respectively. When both inhibitors were given APC was reduced 0.52 times. The results suggest that the effects of cimetidine and disulfiram on antipyrine elimination are additive.
Debrisoquine oxidation in an Australian population.
Authors: Peart GF , Boutagy J , Shenfield GM
Published: July 2012

The standard laboratory method for determination of debrisoquine phenotype has been modified and shortened with no loss of sensitivity. Debrisoquine metabolic ratios (MR) at 4 and 8 h showed excellent correlation indicating that collection time can also be shortened. Same day phenotyping is therefore possible. One hundred normal, Caucasian Australian subjects were phenotyped (46 males, 54 females) and 6% were poor metabolisers (PM) of debrisoquine. Fifty of the original subjects were also acetylation phenotyped and 34% were fast and 66% slow acetylators. One PM of debrisoquine was a fast acetylator of sulphadimidine and four PM were slow acetylators. This was a non‐ significant association.
Enalapril in moderate to severe hypertension: a comparison with atenolol.
Authors: Webster J , Petrie JC , Robb OJ , Trafford J , Burgess J , Richardson PJ , Davidson C , Fairhurst G , Vandenburg MJ , Cooper WD , et al
Published: July 2012

Patients with moderate to severe essential hypertension (mean untreated supine blood pressure 190/112 mm Hg) received once daily enalapril 20‐ 40 mg or atenolol 50‐100 mg, supplemented if required by hydrochlorothiazide 25‐100 mg, in a randomized observer‐blind trial. Both regimens produced a highly significant reduction in supine and standing blood pressure. There was no significant difference in the antihypertensive effects of enalapril and atenolol when they were used as monotherapy. After hydrochlorothiazide was added to patients not achieving ‘target’ blood pressure, the fall in systolic pressure was significantly greater in the enalapril group than in the atenolol group, despite similar dosage of hydrochlorothiazide in the two groups. At the end of 6 months' treatment, a supine diastolic blood pressure of 90 mm Hg or below was achieved in 74% of patients on enalapril plus hydrochlorothiazide and 56% of patients on atenolol plus hydrochlorothiazide. This difference was not statistically significant. A small rise in plasma urea and creatinine was observed in the enalapril group and a small rise of urea only in the atenolol group. These changes were statistically significant but of uncertain clinical importance. This study confirms that once daily enalapril and atenolol, both alone and in combination with hydrochlorothiazide, are effective drugs in the management of moderate to severe hypertension.
The pharmacokinetics of doxazosin in elderly normotensives.
Authors: Vincent J , Meredith PA , Elliott HL , Reid JL
Published: July 2012

The pharmacokinetics of doxazosin were studied in 12 normotensive elderly volunteers aged 62‐89 years. There was marked inter‐individual variability in all the parameters derived but the disposition of doxazosin was similar in both sexes. These results were compared to those of a group of young normotensive volunteers aged 23‐39 years studied previously under comparable conditions. The volume of distribution increased significantly with age although the bioavailability and clearance were not significantly different in the two groups. These results suggest that age is unlikely to influence the disposition of doxazosin to a clinically significant extent.
Effect of labetalol on limb haemodynamics in patients following coronary artery bypass graft surgery.
Authors: Halperin JL , Mindich BP , Rothlauf EB , Reder RF , Litwak RS , Kupersmith J
Published: July 2012

Labetalol is a competitive inhibitor of alpha‐ and beta‐adrenergic receptors and has an antihypertensive action. To determine limb haemodynamic effects, we measured calf blood flow and venous capacitance by venous occlusion plethysmography before and after oral labetalol in 10 patients 3‐7 days following coronary bypass surgery. Vascular resistance was calculated as the ratio of mean arterial pressure to arterial flow. The peak effect of labetalol was taken as the point of maximum blood pressure decline, and this interval was selected for evaluation of the limb haemodynamic response. Ninety to 120 min after administration of 100‐200 mg of labetalol the mean blood pressure fell from 88 +/‐ 3 to 79 +/‐ 3 mm Hg; (P less than 0.005). The mean arterial blood flow registered 5.1 +/‐ 1.0 ml 100 ml‐1 limb tissue min‐1 which was not significantly different from the control value of 4.4 +/‐ 0.8 ml 100 ml‐1 limb tissue min‐1. The calculated index of limb vascular resistance was not affected by labetalol administration, averaging 37 +/‐ 12 mm Hg 100‐1 ml limb tissue min‐1 before labetalol and 30 +/‐ 11 mm Hg ml‐1 100 ml limb tissue min‐1 at the time of peak hypotensive effect. There was a slight but statistically significant increment in limb venous volume to 1.9 +/‐ 0.3 from 1.5 +/‐ 0.3 ml 100 ml‐1 limb tissue (P less than 0.025). Placebo administration produced no consistent changes in blood pressure, arterial blood flow, vascular resistance or venous capacitance.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacological basis for the use of alpha 1‐adrenoceptor antagonists in the treatment of essential hypertension.
Authors: Davey MJ
Published: July 2012

Effective preventive antihypertensive therapy is more likely to be achieved with drugs whose mechanisms and sites of action are congruent with the underlying aetiology and pathophysiology than by drugs that lower blood pressure by means unrelated to the process of hypertension. A vast amount of experimental and clinical data exist in favour of the neurogenic hypothesis. Thus hyperactivity of the sympathetic nervous system plays a major role in the pathogenesis and maintenance of essential hypertension and a generalized increase in peripheral vascular resistance is the fundamental haemodynamic abnormality. Reduction in increased sympathetic activity by alpha‐adrenoceptor blockade was one of the earliest pharmacological attempts to treat hypertension. However the discovery of postjunctional alpha 1‐ adrenoceptor antagonists represented the crucially important step in the development of agents to combat specifically adrenergic predominance in essential hypertension. This has yielded antihypertensive drugs of high specificity which preserve feedback control of transmitter noradrenaline release and consequently cause minimal reflex activation of the sympathetic nervous system. These properties have important clinical implications with respect to the therapeutic application of alpha 1‐adrenoceptor antagonists in the treatment of hypertension, and in addition explain why the clinical expectations of the early alpha‐adrenoceptor antagonists remained unfulfilled. Alpha 1‐Adrenoceptor antagonists represent an attractive alternative choice for initial therapy in all grades of hypertension.
Acute renal effects of doxazosin in man.
Authors: de Leeuw PW , Van Es PN , de Bos R , Birkenhager WH
Published: July 2012

To evaluate the role of alpha 1‐adrenoceptors in the regulation of renal blood flow and renin secretion, we infused doxazosin in incremental doses (group I, n = 5) or at a fixed rate of 1 microgram kg‐ 1 min‐1 (group II, n = 6) into the renal artery of hypertensive patients just prior to diagnostic renal angiography. In group I, stepwise increasing doses of doxazosin were associated with increases in renal perfusion and, at doses above 1 microgram kg‐1 min‐1, also with a fall in blood pressure. Compared with observations in control subjects, doxazosin enhanced renal renin release at rest but did not modify the renin response to isometric exercise in group II. alpha 1‐ Adrenoceptors are involved in causing renal vasoconstriction and inhibition of renin secretion. However, the latter is only of importance in resting subjects.
A long‐term double‐blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension.
Authors: Frick MH , Halttunen P , Himanen P , Huttunen M , Porsti P , Pitkajarvi T , Poyhonen L , Pyykonen ML , Reinikainen P , Salmela P , et al
Published: July 2012

The efficacy and safety of doxazosin and atenolol were compared following once‐daily administration for up to 1 year, with a minimum of 20 weeks' active treatment. According to response, patients received doxazosin 1‐16 mg day‐1 or atenolol 50‐100 mg day‐1. Mean daily doses at the final efficacy assessment (between 20 weeks and 1 year) were doxazosin 11.8 mg and atenolol 94.2 mg. Atenolol produced somewhat greater falls in blood pressure than doxazosin. The differences were statistically significant in the supine but not in the standing position. A small mean reduction in heart rate was produced by doxazosin whereas atenolol produced a marked bradycardia. Analysis of the same patient group at 20 weeks revealed similar overall profiles of activity except that atenolol produced greater falls in blood pressure than in the longer term analysis. Serum concentrations of HDL/total cholesterol ratio were raised in the doxazosin treatment group and lowered in the atenolol group. Triglyceride concentrations fell in the doxazosin group and rose in the atenolol group. Significant differences (P less than 0.001) were observed between treatment groups for these parameters, all differences being in favour of doxazosin. Pharmacokinetics of doxazosin, measured at steady state in 36 patients, showed dose‐related plasma concentrations, a mean half‐life of about 12 h and relatively low intersubject variation. The incidence of side‐ effects was slightly greater for patients in the doxazosin group. Drug‐ related side‐effects were mostly mild to moderate in severity with no serious drug‐related occurrences in either treatment group. No serious drug‐related abnormalities in laboratory biochemistry and haematology tests were observed in either treatment group.
The antihypertensive effects of doxazosin: a clinical overview.
Authors: Cox DA , Leader JP , Milson JA , Singleton W
Published: July 2012

Doxazosin is a long‐acting selective alpha 1‐adrenoceptor antagonist which has been shown to be effective and well tolerated in the treatment of hypertension given in once‐daily doses as monotherapy for up to 1 year or as an adjunct to thiazide or beta‐adrenoceptor blockers. Doxazosin has a pharmacokinetic profile in both young adult and elderly subjects which is compatible with once‐daily administration. This has been confirmed by measurement of steady state pharmacokinetics in patients receiving long‐term doxazosin therapy. In controlled double‐blind studies involving approximately 550 patients on doxazosin 1‐16 mg once daily, significant reductions in both standing and supine BP were maintained throughout the 24 h dosing interval. Effectiveness of doxazosin in terms of BP lowering and proportion of responders was similar to that achieved with hydrochlorothiazide 25‐100 mg once daily, atenolol 50‐100 mg once daily, nadolol 40‐160 mg once daily, metoprolol 100‐200 mg per day given twice daily, or prazosin 1‐ 20 mg per day given twice daily. Doxazosin was as effective in elderly patients as in the younger age group and was as effective in blacks as in caucasians. Doxazosin was well tolerated. Side‐effects were generally mild to moderate in severity. Overall incidence, including postural effects early in treatment, was similar to that seen with the comparative agents. In comparison with placebo, doxazosin favourably increased (P less than 0.05) the HDL/total cholesterol ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies on verapamil in the treatment of essential hypertension: a review.
Authors: Midtbo K , Hals O , Lauve O , van der Meer J , Storstein L
Published: July 2012

Various doses of verapamil, using the conventional and sustained release formulations, have been administered for the treatment of mild or moderate hypertension in different controlled studies for periods of 4‐6 weeks, involving a total of 103 patients, and in one long‐term trial for 1 year in 12 patients. A double‐blind comparison of verapamil and nifedipine showed that the two calcium antagonists had equal antihypertensive action. A significant blood pressure (BP) reduction was achieved with verapamil both at rest and during isometric exercise in the great majority of patients. No significant correlation was found between age and BP reduction, but pretreatment BP and pressure reduction correlated positively. Heart rate (HR) was moderately but significantly reduced by verapamil. The established wide interindividual differences in verapamil pharmacokinetics were confirmed. There was no significant correlation between plasma drug concentrations and BP reduction, but the dosage regimens with the highest mean plasma drug concentrations were associated with the greatest mean reduction in BP. A moderate, but significant, prolongation of AV‐conduction was demonstrated. QRS‐ and QT‐intervals were unaffected. Side‐effects, with all formulations of verapamil, were generally mild and often transient. No significant haematological or metabolic effects were observed during long‐term treatment. It is concluded that the calcium antagonist verapamil is an effective and safe drug. It can be considered as an alternative drug in mild and moderate essential hypertension.
Verapamil in angina pectoris.
Authors: Kelly DT
Published: July 2012

New knowledge of the pathophysiology of coronary disease has helped determine the therapy for angina pectoris. Calcium antagonists have the advantage of being direct coronary vasodilators as well as decreasing overall demand by systemic vasodilatation. Verapamil has the same anti‐ anginal effect during exercise as beta‐adrenoceptor blockers but has the advantage of increasing rather than decreasing the cardiac output and so fatigue both at rest and exercise commonly seen with beta‐ adrenoceptor blockers is not found with verapamil. The longterm incidence of side‐effects with verapamil are few and it can be used as a single anti‐anginal therapy in a three times daily dosage. Left ventricular function where normal and near‐normal is not depressed. Tolerance to therapy has not been recorded. The anti‐anginal effects have been shown to remain effective over at least a 5 year period. Verapamil should be considered as initial therapy for patients with stable angina pectoris.
Comparative disposition of codeine and pholcodine in man after single oral doses.
Authors: Findlay JW , Fowle AS , Butz RF , Jones EC , Weatherley BC , Welch RM , Posner J
Published: July 2012

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross‐over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/‐ 0.4 h (mean +/‐ s.d.)]. While codeine kinetics were adequately described by a one‐compartment open model with first‐order absorption, a two‐compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/‐ 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.
The effects of serum, lithium, ethacrynic acid, and a low external concentration of potassium on specific [3H]‐ouabain binding to human lymphocytes after incubation for 3 days.
Authors: Rapeport WG , Aronson JK , Grahame‐Smith DG , Harper C
Published: July 2012

We have quantified specific [3H]‐ouabain binding sites in normal human lymphocytes, and have measured the changes in the numbers of those sites which occur in response to various stimuli. We have confirmed previous findings that incubation for 72 h in the presence of fetal calf serum causes an increase in [3H]‐ouabain binding, and that this does not occur if the cells are incubated in fetal calf serum which has first been dialysed. During incubation of the lymphocytes for 3 days in the presence of dialysed fetal calf serum each of the following stimuli caused an increase in specific [3H]‐ouabain binding: addition of ethacrynic acid (1 mumol l‐1), addition of lithium (1 mmol l‐1), and reduction of the external potassium concentration (to 0.75 mmol l‐1). By analogy with the similar results in HeLa cells reported by others, we suggest that the increase in [3H]‐ouabain binding may, in the case of ethacrynic acid and the reduction of the external potassium concentration, be initiated by an increase in the intracellular sodium concentration. The mechanisms whereby fetal calf serum and lithium cause an increase in [3H]‐ouabain binding are not clear.
Pharmacodynamics and pharmacokinetics of single doses of ketanserin and propranolol alone and in combination in healthy volunteers.
Authors: Williams FM , Leeser JE , Rawlins MD
Published: July 2012

The potential interaction between ketanserin and propranolol has been investigated in eight healthy volunteers. Volunteers received single doses of placebo, propranolol (80 mg), ketanserin (20 mg), and propranolol (80 mg) plus ketanserin (20 mg) following a randomised double‐blind regimen. A single dose of ketanserin had little effect on resting heart rate and blood pressure and the effects of propranolol and ketanserin in combination were similar to those of propranolol alone. The inhibition of exercise induced tachycardia by propranolol was not affected by ketanserin. The pharmacokinetics of propranolol elimination were not influenced by the concurrent administration of ketanserin, nor the pharmacokinetics of ketanserin by propranolol.
The antisecretory effects of zaltidine, a novel long‐acting H2‐receptor antagonist, in healthy volunteers and in subjects with a past history of duodenal ulcer.
Authors: Laferla G , Buchanan N , Hearns J , Crean GP , McColl KE , Clucas AT
Published: July 2012

The potency and duration of the antisecretory action of zaltidine, a novel H2‐receptor antagonist, have been examined in healthy volunteers and in patients with previous duodenal ulceration. In eight healthy male volunteers single oral doses of 5 mg, 25 mg and 100 mg produced dose‐related inhibition of basal and pentagastrin‐stimulated acid output (M.A.O.) with an estimated ID50 of 40 mg for the latter. In eight subjects with duodenal ulceration single 100 mg and 200 mg doses produced 85% and 97% inhibition of M.A.O. at peak (3 h post‐dose) and 20% and 23% inhibition at 24 h, respectively; inhibition of basal acid output was 97% at 3 h and 50% at 24 h with both doses. The long duration of action of zaltidine is ascribed to its relatively slow elimination from the plasma.
Sparteine oxidation polymorphism in Greenlanders living in Denmark.
Authors: Brosen K
Published: July 2012

Sparteine oxidation appeared to be polymorphic in 185 healthy Greenlanders living in Denmark. Six subjects (3.2%) were phenotyped as poor metabolizers (PM) and 179 subjects as extensive metabolizers (EM). The metabolic ratio (MR) between sparteine and 2‐ + 5‐dehydrosparteine in a 12 h urine sample ranged from 0.06‐3.12 in EM and from 30‐480 in PM. The excretion of dehydrosparteines accounted for less than 2.2% of the dose in PM and ranged from 5.6%‐63% in EM. The urinary recovery (% of dose) of sparteine, 2‐dehydrosparteine and total sparteine + dehydrosparteines was lower in Greenlander EM than in Danish EM (Brosen et al., 1985). Incomplete urine collection in a substantial proportion of the Greenlanders could explain these discrepancies.
Dose‐dependent inhibition of phosphoinositide metabolism in human platelets by aspirin in vitro and in vivo.
Authors: Godfrey PP , Bochner F , Grahame‐Smith DG
Published: July 2012

The effects of aspirin on the metabolism of phosphoinositides in human platelets were studied in vitro and in vivo. Eight volunteers received, at two‐weekly intervals, a single dose of 10, 30, 100 or 600 mg aspirin. Before the first dose platelets were taken and incubated in vitro with a range of concentrations (10 nM‐100 microM) of aspirin. Formation of inositol phosphates (IP) was measured in [3H]‐inositol labelled platelets after incubation with collagen and thrombin for 30 min, a time at which a maximal increase in [3H]‐IP was observed. The in vitro IC50 for inhibition of the response to collagen by aspirin was approximately 1 microM; the in vivo ID50 was 40‐50 mg. Aspirin did not fully inhibit the collagen stimulated IP formation either in vitro or in vivo, and the response to thrombin was unaffected. The ID50 and IC50 of aspirin is thus in accord with the doses of aspirin associated with inhibition of platelet aggregation and thromboxane production in other studies. The possible relevance of these data to the clinical uses of aspirin is discussed.
Clinical and rheological effects of nifedipine in Raynaud's phenomenon.
Authors: Waller DG , Challenor VF , Francis DA , Roath OS
Published: July 2012

Thirty‐four patients with Raynaud's phenomenon, 28 primary and six secondary, were entered into a double‐blind placebo controlled, randomized cross‐over trial of nifedipine treatment. Nifedipine was given as a 20 mg biphasic release formulation twice daily. Twenty‐nine patients completed the study, during which the mean number of attacks was reduced by 25% during nifedipine treatment (P less than 0.001). Twenty patients scored nifedipine higher than placebo on a five point rating scale (P less than 0.001). Unwanted effects were experienced by 26 patients during active treatment, resulting in withdrawal from the study in five. Red cell deformability and fibrinogen concentrations were not altered by nifedipine.
Antipyrine clearance and metabolism in patients with psoriasis.
Authors: Kubota K , Ishizaki T , Chiba K , Takagi A , Nakagawa A , Nakamura K
Published: July 2012

The kinetic parameters of antipyrine obtained from saliva samples and the appearance of major antipyrine metabolites (4‐hydroxyantipyrine, norantipyrine and 3‐hydroxymethylantipyrine) in urine samples were measured in 10 patients with psoriasis (six nonsmokers and four smokers) and in 20 healthy subjects (11 nonsmokers and nine smokers). The volume of distribution and total clearance of antipyrine were not significantly different between psoriatric patients and control subjects subdivided according to smoking habit. However, antipyrine half‐life was significantly (P less than 0.05) shorter in nonsmoking psoriatrics than in nonsmoking controls. There were no significant differences in mean values for the amounts (% dose) and partial clearances for production of major antipyrine metabolites between non‐ smoking patients and non‐smoking controls, between smoking patients and smoking controls, and between patients overall and controls overall. The total clearance of antipyrine and the partial clearances of antipyrine to its three main metabolites were significantly (P less than 0.05 to 0.01) greater in smoking controls than in nonsmoking controls, and the total clearance of antipyrine and the partial clearance to 4‐hydroxyantipyrine were significantly (P less than or equal to 0.05) greater in smoking patients than in nonsmoking patients. These findings provide no evidence that psoriasis is associated with an alteration in hepatic microsomal monooxygenase activity, at least insofar as the formation of major antipyrine metabolites is concerned.
Urinary metabolites of caffeine in pregnant women.
Authors: Scott NR , Chakraborty J , Marks V
Published: July 2012

In a study of caffeine and its metabolites in pregnant and non‐pregnant women, on average 56.8% of the administered caffeine dose was recovered in the urine in both groups. However, compared to the controls, the pregnant subjects produced smaller amounts of 1‐methylxanthine and 1‐ methyluric acid, whereas the excretion of most of the other metabolites, particularly 3,7‐dimethylxanthine and 3‐methylxanthine tended to be greater. It is suggested that hormonal influences on the hepatic caffeine metabolising enzymes might be implicated.
Does the benzodiazepine antagonist Ro 15‐1788 antagonize the action of ethanol?
Authors: Klotz U , Ziegler G , Rosenkranz B , Mikus G
Published: July 2012

Ethanol aggravates benzodiazepine‐induced central nervous depression by pharmacokinetic and/or pharmacodynamic interactions and Ro 15‐1788 reverses promptly the hypnotic effects of benzodiazepines. We therefore studied the acute effects of Ro 15‐1788 on the ethanol‐induced sedation in six healthy male subjects. Subsequently to an oral loading dose (0.54 g ethanol kg‐1) ethanol was infused for 4 h (0.15 g ethanol kg‐1 h‐1) and steady state blood levels between 0.9 to 1.2 g l‐1 were reached within 2 h. At steady state and during the elimination phase of ethanol an intravenous bolus of 0.5 mg Ro 15‐1788 or placebo was administered in a randomized, double‐blind crossover fashion. The marked sedative effects of ethanol as assessed by visual analogue scales (2 to 6 fold increase in the sedation index), and choice reaction time (25 to 40% prolongation) were not affected by Ro 15‐1788. However, the pharmaco‐EEG indicated that Ro 15‐1788 seems to reverse transiently the ethanol‐induced changes in total alpha, delta, and slow alpha bands. There was no pharmacokinetic interaction between both agents since elimination of Ro 15‐1788 (t1/2 = 1.2 +/‐ 0.7 h) and of ethanol (0.17 +/‐ 0.02 g l‐1 h‐1) were in good agreement with control values. Thus, it could be concluded that Ro 15‐1788 might affect for a short while the action of ethanol by interfering with the benzodiazepine receptors.