bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients.
Authors: Choonara IA , Scott AK , Haynes BP , Cholerton S. , Breckenridge AM , Park BK
Published: July 2012

The disposition of, and pharmacological response to, a single intravenous dose of vitamin K1 (10 mg) was studied in eleven patients on daily warfarin therapy. The pharmacokinetics of vitamin K1 in patients were similar to those reported previously in healthy volunteers, terminal half‐life 1.7 h. All patients had been taking warfarin for at least 3 months. Steady state warfarin plasma concentrations ranged from 0.5 to 1.4 micrograms ml‐1. Prothrombin complex activity ranged from 15 to 28.5%. There was considerable inter‐ individual variation in pharmacodynamic response as expressed by prothrombin complex activity (PCA) and Factor VII. The maximum values for PCA and Factor VII were reached at 24‐96 h and 24‐48 h, respectively, after the administration of vitamin K1. Vitamin K1 (10 mg) has a long duration of action (greater than 168 h) in terms of clotting factor synthesis in patients on steady state warfarin. All the patients on warfarin had measurable levels (CPmax 0.3‐1.2 micrograms ml‐ 1) of vitamin K1 2, 3‐epoxide. There was a significant correlation between the pharmacodynamic response as expressed by change in % PCA and the AUC for vitamin K1 2,3‐epoxide (P less than 0.05).
Comparison of the haemodynamic effects of bucindolol, propranolol and pindolol in healthy volunteers.
Authors: O'Connor PC , Finch MJ , Harron DW , Meredith PA , McDevitt DG , Shanks RG
Published: July 2012

The effects of single oral doses of bucindolol (50, 100, 200 and 400 mg), pindolol (10 mg), propranolol (160 mg) and placebo on arterial pressure and heart rate in the supine and standing positions and exercise heart rate were compared in 12 healthy male volunteers. Supine heart rate was significantly greater after all four doses of bucindolol and pindolol in comparison to propranolol. Bucindolol had no significant effect on standing heart rate which was significantly reduced by pindolol and propranolol. Bucindolol, pindolol and propranolol significantly reduced an exercise tachycardia for at least 24 h after drug administration. Supine systolic pressure was not affected by any treatment but supine diastolic pressure was significantly reduced by bucindolol (200 and 400 mg) and by pindolol. All doses of bucindolol, propranolol and pindolol significantly reduced standing systolic blood pressure. There was a significant linear trend for reductions in standing systolic blood pressure and increasing doses of bucindolol. Standing diastolic blood pressure was significantly reduced by bucindolol 200 and 400 mg. Faintness and light headedness occurred in 6 of 12 subjects after 200 mg bucindolol and in 8 of 10 subjects after 400 bucindolol. After bucindolol, analysis of plasma samples demonstrated the presence of bucindolol, 5‐hydroxy and 6‐ hydroxy bucindolol and indolyl‐t‐butylamine. These observations indicate that in man, bucindolol is a beta‐adrenoceptor blocking drug with hypotensive activity and probably partial agonist activity. It is unlikely that the hypotensive effects result from blockade of beta‐ adrenoceptors or from the drug's partial agonist activity.
Single‐blind study of epoprostenol and 6‐keto‐prostaglandin E1 in man: effects of platelet aggregation and plasma renin.
Authors: Miyamori I. , Morise T. , Yasuhara S. , Takeda Y. , Koshida H. , Takeda R.
Published: July 2012

The effects of epoprostenol (PGI2, 2‐8 ng kg‐1 min‐1) and 6‐keto‐ prostaglandin E1 (6‐keto‐PGE1, 7.5‐30 ng kg‐1 min‐1) on ADP‐induced platelet aggregation, blood pressure (BP), heart rate and plasma renin activity (PRA) were studied in six healthy male volunteers. During graded intravenous administration of PGI2, platelet aggregation was inhibited at a minimum dose of 4 ng kg‐1 min‐1. The dose required to produce the same degree of platelet inhibition was approximately 15 ng kg‐1 min‐1 for 6‐keto‐PGE1. Diastolic BP was significantly reduced and PRA was increased by PGI2 at a dose greater than 8 ng kg‐1 min‐1. In contrast, 6‐keto‐PGE1 did not produce BP and PRA changes up to a dose of 30 ng kg‐1 min‐1. These data indicate that PGI2 has approximately four times more potent antiplatelet activity than 6‐keto‐PGE1 on a molar basis in man. The cardiovascular and PRA changes were less prominent for 6‐keto‐PGE1 than PGI2.
The metabolism and pharmacokinetics of nicardipine hydrochloride in man.
Authors: Graham DJ , Dow RJ , Hall DJ , Alexander OF , Mroszczak EJ , Freedman D.
Published: July 2012

Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. After intravenous infusion of nicardipine at 5 mg‐1 for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. Steady‐state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10‐40 mg three times daily. Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.
Noninvasive assessment of the haemodynamic effects of nicardipine in normotensive subjects.
Authors: Campbell BC , Kelman AW , Hillis WS
Published: July 2012

Calcium antagonists reduce myocardial contractility in vitro. Nicardipine is a dihydropyridine derivative with enhanced selectivity for vascular smooth muscle. We have studied the pharmacokinetics and the haemodynamic effects that occur in man following bolus intravenous administration of nicardipine. Ten normotensive male subjects received either nicardipine or placebo i.v., allocated in a randomised double‐ blind manner, over 60s. Plasma nicardipine concentration, blood pressure, heart rate, and systolic time intervals were measured before dosing and at frequent intervals between 1 and 360 min post dosing. At 160 micrograms kg‐1, adequate plasma levels of nicardipine were obtained to permit analysis of individual pharmacokinetic variables, and significant and consistent haemodynamic effects were seen. After injection of nicardipine, systolic BP and the QS2 (measure of total electromechanical systole) and QT intervals were not altered. The changes in BP and heart rate were consistent with arteriolar vasodilatation. The changes in PEP and LVET suggest an increase in cardiac contractility, which is unlikely to be a direct effect of nicardipine on the myocardium but rather a result of afterload reduction. The close correlation of nicardipine plasma level with haemodynamic effect should permit accurate dose titration. The net increase in contractility should allow nicardipine to be administered safely with beta‐adrenoceptor blocking drugs.
Intracranial effects of nicardipine.
Authors: Gaab MR , Czech T. , Korn A.
Published: July 2012

Preliminary investigations indicated that the calcium antagonist nicardipine improved cerebral vascular circulation and cerebral metabolism. Therefore we examined the effect of nicardipine on the cerebral vessels, cerebral oxygen tension, and intracranial pressure (ICP) in patients with cerebrovascular disturbances. In patients with previous minor stroke undergoing surgery for extra‐intracranial anastomosis, we applied nicardipine topically to the operation site by means of a perfusor and measured the diameter of the cerebral vessels. After several minutes, the topically applied nicardipine produced marked dilatation in the small arterial cortical vessels and relaxation of vasospasm. In the two patients studied so far, we observed a rapid increase in the cerebral PO2, which remained elevated after the initial peak as long as the infusion continued. With a lower dose the increase in the intracranial pulse amplitude (PAICP) was antagonized by the considerable drop in blood pressure which occurred after 10 mg h‐1 nicardipine. The results indicate that nicardipine dilates the cerebral vessels and increases the cerebral oxygen tension.
A study of the long‐term efficacy and tolerability of oral nicardipine in hypertensive patients.
Authors: Taylor SH , Frais MA , Lee P. , Verma SP , Jackson N. , Reynolds G. , Silke B.
Published: July 2012

This study was designed to evaluate the efficacy of oral nicardipine in 91 patients with uncomplicated essential hypertension over a period of 12 months. All patients started on a fixed nicardipine dose of 30 mg three times daily which was adjusted in the range 10‐40 mg three times daily, where necessary to achieve a target diastolic blood pressure less than 95 mm Hg. At 6 weeks, blood pressure (mean +/‐ s.e. mean) was reduced from an average of 190 +/‐ 22/112 +/‐ 8 to 167 +/‐ 23/96 +/‐ 11 mm Hg supine and from 180 +/‐ 21/113 +/‐ 7 to 154 +/‐ 17/95 +/‐ 11 mm Hg standing and remained controlled in all patients throughout the study. A total of 96 unwanted experiences were reported by 49 patients (54%); 17 (19%) reported a single symptom once and two (2%) reported a single symptom more than once. The most frequently reported adverse experiences were peripheral oedema in 27 (28%) and headaches in 15 patients (16%). The majority of the adverse experiences occurred in the first 3 months of treatment. Ten patients (11%) withdrew from the study during this time and eight (9%) in the subsequent 9 months because of drug‐related side effects; five others (5%) withdrew for unrelated reasons. The incidence of adverse experiences was dose‐related. Three patients reported unwanted effects on 10 mg three times daily, eight on 20 mg three times daily, 36 on 30 mg three times daily, and 12 on 40 mg three times daily oral nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicardipine for stable angina pectoris.
Authors: Scheidt S. , Lewinter MM , Hermanovich J. , Venkataraman K. , Freedman D.
Published: July 2012

Nicardipine, 30 and 40 mg thrice daily, was administered to 66 patients with stable angina pectoris in a multicentre, randomised, double‐blind, cross‐over trial. With nicardipine therapy, duration of exercise and cumulative oxygen consumption increased, while times to onset of angina and 1 mm ST segment depression were prolonged. Anginal frequency and nitroglycerin consumption declined with use of nicardipine, but this did not reach statistical significance. Resting heart rate increased slightly and resting blood pressure decreased. Two patients on nicardipine and one on placebo sustained acute infarction. Otherwise, side effects were generally mild and transient.
Relationship between plasma concentrations and cardiac beta‐ adrenoceptor blockade‐a study with oral and intravenous bopindolol.
Authors: Aellig WH , Nuesch E , Engel G , Grevel J , Niederberger W , Rosenthaler J
Published: July 2012

Bopindolol, an esterified beta‐adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio‐receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. After intravenous administration the half‐life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one‐compartment model occurred with a half‐life of about 4 h. There were indications for a longer beta phase of elimination with a half‐life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%. Cardiac beta‐adrenoceptor blockade was determined as the reduction in exercise‐induced tachycardia. With oral doses the maximum effect was reached after 3 h (‐29 beats min‐1 after 1 mg, ‐40 beats min‐1 after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (‐33 beats min‐1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies with fenoldopam, a dopamine receptor DA1 agonist, in essential hypertension.
Authors: Harvey JN , Worth DP , Brown J , Lee MR
Published: July 2012

A series of studies were undertaken to assess the effect of oral fenoldopam, a specific DA1 dopamine receptor agonist on blood pressure and renal function in patients with mild essential hypertension. Six patients with essential hypertension were entered into a dose‐ranging study and received either placebo, 25, 50 or 100 mg fenoldopam. A significant, dose‐related reduction in diastolic blood pressure, and increase in heart rate was demonstrated (both P less than 0.05), maximal at 45 min to 1 h. Fenoldopam increased plasma renin activity. In a double‐blind study, seven patients received a single dose of fenoldopam 100 mg or placebo. Fenoldopam produced a significant fall in systolic (P less than 0.05) and diastolic (P less than 0.01) blood pressure and renal vascular resistance (P less than 0.01). Urine flow rate (P less than 0.05), sodium excretion (P less than 0.01), plasma renin activity (P less than 0.05) and plasma aldosterone (P less than 0.05) increased. Five patients underwent measurement of the above parameters following a single dose of fenoldopam 100 mg with a repeat of these measurements after they had taken fenoldopam 100 mg four times daily for 1 month. The acute response of blood pressure to the single dose appeared unchanged but tachyphylaxis was evident in the responses of heart rate, plasma renin activity and plasma aldosterone.
Plasma amiodarone concentrations during intravenous infusion.
Authors: Watt AH , Hutchings A , Stephens MR , Routledge PA
Published: July 2012

Amiodarone is a useful antiarrhythmic agent whose pharmacokinetics are incompletely characterised. In order to optimise efficacy of an antiarrhythmic drug, information regarding plasma concentrations achieved during use of the drug is necessary. We report plasma amiodarone and desethylamiodarone concentrations in eight patients following intravenous infusion at a rate of 175 mg h‐1 for the first 2 h, followed by infusion at a rate of 50 mg h‐1 for a further 46 h a regimen very similar to that recommended by the manufacturers. In at least three of eight patients plasma concentrations were below the suggested therapeutic range of 1.0‐2.5 mg l‐1 from 3 to 16 h after the infusion was started. Our data suggests that larger doses of intravenous amiodarone than those previously recommended may be necessary to obtain optimal benefit from the drug.
A comparison of the pharmacokinetics of propranolol in obese and normal volunteers.
Authors: Bowman SL , Hudson SA , Simpson G , Munro JF , Clements JA
Published: July 2012

The pharmacokinetics of intravenous and oral propranolol have been compared in six obese and six normal subjects matched for age and sex. After intravenous administration there was no difference in plasma clearance but the volume of distribution was greater (V = 339 l vs 198 l) and the half‐life was longer (t1/2 = 5.0 h vs 3.0 h) in the obese group. No important difference in the rate of oral absorption was observed. A trend towards higher systemic availability in the obese group (35% vs 27%) was not statistically significant.
Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise.
Authors: Lund‐Johansen P , Omvik P , Haugland H
Published: July 2012

The acute and chronic haemodynamic effects of doxazosin were studied in 14 patients (10 males, four females) with essential hypertension, at rest supine and sitting and during 100 W bicycling exercise. Blood pressure (BP) was recorded intra‐arterially in the brachial artery, cardiac output (CO) was measured by Cardiogreen and heart rate (HR) by ECG. One hour after injection of doxazosin 0.5‐1.0 mg i.v., mean arterial pressure (MAP) was reduced by 8% at rest supine, 12% at rest sitting and 10% at 100 W (all changes statistically significant), associated with a reduction in total peripheral resistance index (TPRI) of 5% at rest supine, 9% at rest sitting (P less than 0.01) and 14% at 100 W (P less than 0.001). HR was slightly increased (5%, NS) and cardiac index (CI) was unchanged during rest and slightly increased during exercise (4%, P less than 0.05). Patients were then given doxazosin capsules (2‐16 mg once daily), aiming at a casual BP of less than or equal to 140/90 mmHg without side‐effects. Central haemodynamics were restudied after 1 year. After 1 year of doxazosin treatment, MAP was reduced by 13% at rest supine, 16% at rest sitting and 17% at 100 W (all P‐values less than 0.001). TPRI was reduced by 19% at rest supine, 20% at rest sitting and 18% at 100 W (all changes statistically significant). CI was increased by 8% at rest supine (P less than 0.05) but was unchanged sitting and at 100 W. It is concluded that doxazosin lowers BP through a reduction in TPRI acutely as well as chronically, without reductions in CO. BP control was maintained over 1 year without side‐effects. Thus, doxazosin normalizes central haemodynamics in patients with mild to moderate essential hypertension, both at rest and during exercise.
Salt and hypertension.
Authors: MacGregor GA
Published: July 2012

Studies comparing different communities have suggested that the amount of salt in the diet may play an important role in determining blood pressure levels within a particular community. Intervention studies have also suggested that salt intake may play an important role in determining blood pressure levels in man. In animals, where more clearcut experiments can be done, an increase in salt intake both in inherited forms of hypertension and experimental hypertension causes a further rise in blood pressure. Recent work has suggested that this rise in blood pressure could be related to an inherited or imposed defect in the kidney's ability to excrete sodium, which will give rise to greater compensatory mechanisms to overcome the sodium retention. These compensatory mechanisms might eventually be responsible for the development of high blood pressure. In patients who have already developed high blood pressure, restricting the amount of salt in the diet does cause a fall in blood pressure in many patients. However, short‐term reduction of salt intake in normotensive subjects causes little, if any, fall in blood pressure. The effectiveness of short term salt restriction in lowering blood pressure in adults therefore appears to be related to the severity of the high blood pressure and, probably more directly, to the suppression of the renin system that occurs as blood pressure rises.
The Danish studies on verapamil in acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction.
Authors: Krikler DM
Published: July 2012

A double‐blind study comparing verapamil with placebo was conducted in 16 Danish departments of internal medicine with coronary care units (CCU). All patients below 75 years of age admitted to the CCU with a suspicion of acute myocardial infarction (AMI) were evaluated. Of 7415 patients, 3917 were excluded on admission because of heart failure, heart block, other severely disabling diseases, or treatment with beta‐ adrenoceptor blockers or calcium antagonists. Treatment was started in 3498 patients with 0.1 mg kg‐1 verapamil i.v. and 120 mg orally on admission followed by 120 mg three times daily, or matched placebo. Treatment was continued for 6 months for patients verified to have had an AMI according to all three WHO criteria. Treatment was stopped in patients for whom the diagnosis of AMI was ruled out. Of 1436 patients with AMI, 717 were treated with verapamil and 719 with placebo. After 6 months, 92 patients (12.8%) in the verapamil group and 100 patients (13.9%) in the placebo group were dead (NS). Fifty patients (7%) in the verapamil group and 60 patients (8.3%) in the placebo group had reinfarctions (NS). After 12 months, 109 patients (15.2%) in the verapamil group and 118 patients (16.4%) in the placebo group were dead (NS). It is concluded that verapamil treatment used in the early phase of an AMI does not improve survival. Based on the experience from the first study we are at present performing a further secondary prevention study with verapamil to a modified design.
Comparison of transdermal nitrate and isosorbide dinitrate in chronic stable angina.
Authors: Nicholls DP , Moles K , Gleadhill DN , Booth K , Rowan J , Morton P
Published: July 2012

The effects of transdermal nitrate (TN) (Transiderm‐Nitro TTS, Geigy Pharmaceuticals, one 10 cm2 patch daily) and oral isosorbide dinitrate (ISDN) (Sorbitrate, Stuart Pharmaceuticals, 10 mg three times daily) were compared in a group of 20 patients with chronic stable angina pectoris. Treadmill exercise duration was prolonged from a median time of 365 s to 428 s after ISDN (P less than 0.05), but was unchanged after TN. The difference between the active treatments was not significant. Weekly consumption of glyceryl trinitrate (GTN) increased during treatment with TN from a median value of 5.5 to 6.3 (P less than 0.05). A decrease was observed after ISDN (7.8 to 3.9, P = NS), and the difference between the drugs was significant (P less than 0.01). Systolic arterial pressure was significantly lower during the ISDN than during the TN treatment period in both the supine (135 +/‐ 5 vs 128 +/‐ 5 mm Hg; P less than 0.05) and standing positions (134 +/‐ 5 vs 122 +/‐ 5 mm Hg; P less than 0.05). No change in weekly attack rate, the degree of ST depression at angina on treadmill testing, or the number of episodes of ST depression recorded during a 24 h period by Holter monitoring was observed after either drug. In this study, an antianginal effect was demonstrated for ISDN but not for TN. It is suggested that the dose of TN may have been inadequate to demonstrate such an effect, and further studies using a higher dose schedule will be required.
Investigation of patients with abnormal response to warfarin.
Authors: Bentley DP , Backhouse G , Hutchings A , Haddon RL , Spragg B , Routledge PA
Published: July 2012

In 55 patients in whom warfarin control had been satisfactory for at least 4 months, warfarin dose, plasma warfarin concentration and plasma clearance were measured. The mean dose to maintain the BCR (INR) between 2.3 and 3.3 was 5.1 +/‐ 2 mg day‐1 (range 1.5‐10 mg). Plasma warfarin concentrations and warfarin clearance were log‐normally distributed with 95% confidence limits between 0.8 and 2.4 mg l‐1 and 2.5 and 8.71 day‐1 respectively. These confidence limits were used to construct algorithms which correctly predicted the cause of abnormal warfarin sensitivity in two patients and resistance in two further patients. These algorithms should help to identify the cause of abnormal warfarin responsiveness in the clinical setting.
The influence of enzyme induction on polymorphic sparteine oxidation.
Authors: Eichelbaum M , Mineshita S , Ohnhaus EE , Zekorn C
Published: July 2012

The effects of antipyrine (1200 mg day‐1), phenobarbitone (100 mg day‐ 1) and rifampicin (600 mg and 1200 mg day‐1, respectively) administration for 7 days on sparteine metabolism and 6 beta‐ hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta‐hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P‐450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.
Renal failure does not impair the metabolism of morphine.
Authors: Woolner DF , Winter D , Frendin TJ , Begg EJ , Lynn KL , Wright GJ
Published: July 2012

The pharmacokinetics of morphine were measured using gas chromatography‐ mass spectrometry (GCMS) with specific ion monitoring after the intramuscular administration of papaveretum to four patients with renal failure (one anephric) and three normals. The apparent t1/2 of absorption and t1/2 of elimination were significantly shorter in the patients with renal failure (P less than 0.05). Morphine glucuronides are eliminated slowly in these patients as expected. Renal failure does not impair the elimination of morphine.
States of anxiety and their induction by drugs.
Authors: Lader M , Bruce M
Published: July 2012

Syndromes of anxiety include generalized anxiety states, various forms of phobic disorder and panic attacks. It is unclear whether panic attacks are a separate syndrome from anxiety states or a more severe form. Drug‐induced states of anxiety should provide useful models of the mechanisms of anxiety and its treatment. High‐risk populations might be identifiable. Catecholamine infusions produce marked peripheral changes without fully reproducing the central feelings. Lactate infusions also produce anxiety‐like states lacking full credibility. Experience with the benzodiazepine‐receptor contragonists, the beta‐carbolines, is limited but panic states have been reproduced following their use. Caffeine produces an anxiety state in high dose and some panic states have been induced. The critical evaluation of drug‐induced anxiety states is a promising way of elucidating the mechanisms, psychological and physiological, associated with clinical anxiety.
Pharmacodynamic profile of bisoprolol, a new beta 1‐selective adrenoceptor antagonist.
Authors: Leopold G , Ungethum W , Pabst J , Simane Z , Buhring KU , Wiemann H
Published: July 2012

The pharmacodynamic profile of bisoprolol, a new beta 1‐selective adrenoceptor antagonist, was investigated in four independent studies including 36 healthy male volunteers. Using the model of exercise‐ induced tachycardia (ET) the beta‐adrenoceptor blocking properties of bisoprolol (2.5‐40 mg) were examined in comparison to metoprolol (50 and 100 mg), propranolol (40 and 80 mg) and atenolol (50 and 100 mg). The maximal reduction of ET was achieved between 1 and 4 h following single oral administration. The dose‐response relationship using individual maximal reduction of ET showed, on a molar basis, that bisoprolol is about 5, 7 and 10 times more effective than propranolol, atenolol and metoprolol, respectively. In the model of insulin‐induced hypoglycaemia bisoprolol behaved as a beta 1‐selective adrenoceptor antagonist. There was a good correlation (r = 0.94) between the log bisoprolol concentration and the reduction in exercise‐induced tachycardia. Bisoprolol is a potent new cardioselective beta‐ adrenoceptor antagonist with a competitive action at beta 1‐ adrenoceptors.
Theophylline pharmacokinetics after intravenous infusion with ethylenediamine or sodium glycinate.
Authors: Caldwell J , Staib AH , Cotgreave IA , Siebert‐Weigel M
Published: July 2012

Six healthy volunteers received two theophylline preparations by short intravenous infusion, at weekly intervals in a randomized cross‐over design. The solubilizer was ethylenediamine or sodium glycinate. Plasma concentrations of theophylline and ethylenediamine were measured by h.p.l.c. for up to 24 h after dosing. The pharmacokinetics of theophylline did not show any significant intra‐subject variation associated with the solubilizing agent used.
Protein binding of chloroquine enantiomers and desethylchloroquine.
Authors: Ofori‐Adjei D , Ericsson O , Lindstrom B , Sjoqvist F
Published: July 2012

The protein binding of racemic chloroquine, its enantiomers and desethylchloroquine to plasma, purified human albumin, and alpha 1‐acid glycoprotein (alpha 1‐AGP) was determined by equilibrium dialysis. The binding was not concentration dependent. (+)‐Chloroquine bound more to plasma (66.6 +/‐ 1.9%) and albumin (45.9 +/‐ 0.8%) than (‐)‐chloroquine (48.5 +/‐ 2.4% and 35.3 +/‐ 0.6%, respectively). These differences were statistically significant. (‐)‐Chloroquine bound more to alpha 1‐AGP (47.5 +/‐ 0.7%) than (+)‐chloroquine (34.5 +/‐ 0.5%). The binding of desethylchloroquine to alpha 1‐AGP is higher than to albumin (38.9 +/‐ 0.9% and 21.1 +/‐ 0.4%, respectively.
Effect of captopril on changes in plasma noradrenaline induced by sodium nitroprusside.
Authors: Becker RH , Struthers AD , Brown MJ
Published: July 2012

There is much animal data to suggest that angiotensin II has a regulatory role in noradrenaline release. We sought evidence for such a mechanism in man by pretreating six normal volunteers with captopril (50 mg) or placebo and then infusing them with incremental doses of sodium nitroprusside. Pretreatment with captopril had no significant effect on the mean arterial pressure, heart rate or plasma noradrenaline response to sodium nitroprusside, despite increasing plasma renin activity. This suggests that in normotensive salt replete man, normal levels of angiotensin II do not exert any tonic effect on noradrenaline release.
Pharmacokinetics of the new benzodiazepine antagonist Ro 15‐1788 in man following intravenous and oral administration.
Authors: Roncari G , Ziegler WH , Guentert TW
Published: July 2012

During clinical pharmacology studies with the benzodiazepine antagonist Ro 15‐1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15‐1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg‐1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min‐1 resulted in a short elimination half‐life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose‐proportionality in the areas under plasma concentration‐time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20‐90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.
Different effects of metoclopramide and domperidone on arginine‐ vasopressin secretion in man.
Authors: Chiodera P , Volpi R , Delsignore R , Marchesi C , Salati G , Camellini L , Rossi G , Coiro V
Published: July 2012

This study was performed in order to investigate the dopaminergic mechanism involved in the control of arginine‐vasopressin (AVP) secretion in normal men. Plasma AVP concentrations were measured before and after the administration of an i.v. bolus of 10 mg metoclopramide or domperidone to twelve healthy males. Metoclopramide, a cerebral and peripheral antagonist of dopaminergic receptors, significantly stimulated AVP secretion, whereas domperidone, a dopamine antagonist which does not cross the blood‐brain barrier, was without effect. These data suggest that metoclopramide stimulates the release of AVP by blocking dopaminergic receptors in structures located inside the blood‐ brain barrier. Alternatively, it is possible that the stimulation of AVP release induced by metoclopramide does not occur through inhibition of dopamine receptors but rather through interaction with other neuroendocrine pathways.
The effect of inhaled 5‐hydroxytryptamine (5‐HT, serotonin) on airway calibre in man.
Authors: Cushley MJ , Wee LH , Holgate ST
Published: July 2012

Since platelet activation has been incriminated in the pathogenesis of asthma, we have investigated the effect of one of its major granule‐ derived mediators, 5‐hydroxytryptamine (5‐HT, serotonin) on airway calibre in normal (12), atopic non‐asthmatic (12) and atopic asthmatic subjects (16). On separate days subjects inhaled increasing concentrations of 5‐HT and methacholine, and airway response was measured as FEV1, Vmax30 and sGaw. All subjects bronchoconstricted with methacholine, geometric mean provocation concentrations causing a 20% fall in FEV1 (PCf20) for the normal, atopic non‐asthmatic and atopic asthmatic subjects being 28.6, 18.3 and 0.71 mM respectively. In contrast, 5‐HT up to a maximum concentration of 77 mM had no consistent effect on FEV1, Vmax30 or sGaw in any of the subject groups. Thus, in contrast to a variety of animals, 5‐HT is unlikely to serve as a significant bronchoconstrictor mediator in man.
Obesity effects on nitrazepam disposition.
Authors: Abernethy DR , Greenblatt DJ , Locniskar A , Ochs HR , Harmatz JS , Shader RI
Published: July 2012

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/‐ s.e. mean body weight 107 +/‐ 9 kg; percent ideal body weight [IBW] 166 +/‐ 12%) and 14 normal body weight (63 +/‐ 3 kg; percent IBW 98 +/‐ 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/‐ 10.3‐obese vs 119 +/‐ 14.6 ng ml‐1; NS) and time required after drug administration to reach peak concentration (1.52 +/‐ 0.24‐obese vs 1.59 +/‐ 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half‐life was markedly increased in obese subjects (33.5 +/‐ 2.2 vs 23.9 +/‐ 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/‐ 45 vs 137 +/‐ 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/‐ 12.4 vs 66.8 +/‐ 12.4 ml min‐ 1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound‐19.7 +/‐ 0.4‐obese vs 17.9 +/‐ 0.3%; P less than 0.005). Correction of both Vd (2.62 +/‐ 0.17‐obese vs 2.22 +/‐ 0.19 l kg‐1; NS) and clearance (0.93 +/‐ 0.06‐ obese +/‐ 1.07 +/‐ 0.07 ml min‐1 kg‐1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of oral verapamil therapy on antipyrine clearance.
Authors: Rumiantsev DO , Piotrovskii VK , Riabokon OS , Slastnikova ID , Kokurina EV , Metelitsa VI
Published: July 2012

The influence of chronic verapamil treatment on antipyrine elimination was studied in eight angina patients. Antipyrine half‐life (mean +/‐ s.d.) was 13.1 +/‐ 1.15 h at the start of therapy and 16.6 +/‐ 3.05 h (P less than 0.05) during chronic oral administration of verapamil (80‐ 120 mg four or three times daily for 4 to 7 months). There was a significant decrease in antipyrine clearance (mean +/‐ s.d, 43.2 +/‐ 16.8 ml min‐1 vs 28.7 +/‐ 16.6 ml min‐1, P less than 0.01) while the change of distribution volume was insignificant. Verapamil elimination was also found to be impaired after chronic dosing as compared to single administration. Half‐lives measured from the concentration vs time and urinary excretion rate vs time curves were both prolonged and oral clearance was decreased. Our results suggest that the inhibition of drug‐metabolizing enzymes accounts for the impairment of verapamil elimination on chronic administration.
Population study of triazolam pharmacokinetics.
Authors: Friedman H , Greenblatt DJ , Burstein ES , Harmatz JS , Shader RI
Published: July 2012

The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20‐44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post‐dose. The overall mean +/‐ s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 +/‐ 0.3 (1.7‐9.4) ng ml‐ 1; time of peak, 1.3 +/‐ 0.1 (0.5‐4.0) h after dose; elimination half‐ life, 2.6 +/‐ 0.1 (1.1‐4.4) h; total AUC: 19.1 +/‐ 1.1 (4.4‐47.7) ng ml‐ 1 h; oral clearance, 526 +/‐ 38 (175‐1892) ml min‐1. All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov‐Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. Peak plasma level was highly correlated with clearance (r = −0.85, P less than 0.0001), and AUC (r = 0.85, P less than 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = −0.01). Triazolam clearance may vary widely even within a homogeneous group of healthy young men.
Inter‐subject and ethnic differences in paracetamol metabolism.
Authors: Critchley JA , Nimmo GR , Gregson CA , Woolhouse NM , Prescott LF
Published: July 2012

The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.
Beta‐adrenoceptor antagonists increase sinus arrhythmia, a vagotonic effect.
Authors: Bittiner SB , Smith SE
Published: July 2012

The influence of vagal and sympathetic efferent activity on sinus arrhythmia in man has been studied in six healthy subjects by administration of hyoscine butylbromide and/or various beta‐ adrenoceptor blocking drugs using a microcomputer‐linked electrocardiogram system. Sinus arrhythmia was quantitated as the s.d. of the R‐R interval. Sinus arrhythmia was almost abolished by hyoscine butylbromide irrespective of the absence or presence and nature of the beta‐adrenoceptor blocking drug. Atenolol and metoprolol alone prolonged the mean R‐R interval and increased sinus arrhythmia. Oxprenolol, a drug with modest partial agonist or intrinsic sympathomimetic activity (ISA), prolonged the mean R‐R interval to a lesser extent but had no effect on sinus arrhythmia. Xamoterol, which has high ISA, shortened the mean R‐R interval but had no effect on sinus arrhythmia. These data yielded a non‐linear relationship between sinus arrhythmia and mean R‐R interval. Exaggerated sinus arrhythmia appears to accompany beta‐adrenoceptor blockade only in the absence of ISA when bradycardia ensues. These findings are consistent with the hypothesis that the exaggeration in sinus arrhythmia is due to a central vagotonic effect secondary to the action of the drugs in the periphery. Changes in R‐R interval induced by the adrenoceptor blocking drugs were altered to some extent by vagal blockade. This observation is consistent with the hypothesis that changes in heart rate induced by such drugs are determined in part by a change in vagal tone.
The hypnotic effects of an antihistamine: promethazine.
Authors: Adam K , Oswald I
Published: July 2012

Twelve volunteer poor sleepers of mean age 59 years took placebo on one night, promethazine 20 mg on one night and promethazine 40 mg on one night, in a double‐blind balanced order study. Sleep in the EEG laboratory was increased by nearly 1 h after either dose of promethazine, and sleep interruptions were reduced. Slow‐wave sleep was unaffected, but the larger dose reduced the percentage of sleep spent as REM sleep. Sleep was improved subjectively by both doses of promethazine which appears to be an effective hypnotic.
The effect of low‐dose phenobarbitone on three indices of hepatic microsomal enzyme induction.
Authors: Price DE , Mehta A , Park BK , Hay A , Feely MP
Published: July 2012

The effects of low‐dose phenobarbitone on three indices of hepatic enzyme induction were studied. Eight healthy volunteers took phenobarbitone 7.5 mg daily for 4 weeks followed by 15 mg daily for 4 weeks; five subjects took 30 mg daily for a further 2 weeks. Phenobarbitone 15 mg daily produced a significant rise in antipyrine clearance (P less than 0.05). Phenobarbitone 30 mg daily produced a further rise, but probably because of the reduced numbers of subjects, this did not achieve significance (P = 0.06). Urinary 6‐beta‐ hydroxycortisol and D‐glucaric acid levels did not change significantly and remained within the range seen in subjects not taking enzyme‐ inducing drugs. We conclude that phenobarbitone 7.5 mg daily produces little (if any) enzyme induction whereas 15 mg, or more, may have the potential to produce drug interactions through enzyme induction.
The effect of isoxicam on neutrophil and monocyte function.
Authors: Martinez JG , Murakami SI , Scheinberg MA
Published: July 2012

1 Isoxicam was found to inhibit monocyte and neutrophil cell chemotaxis at therapeutic concentrations. 2 The effect was observed after in vitro incubation of normal cells and in vivo in patients with rheumatoid arthritis. 3 Compared to other NSAIDs studied in our laboratory, isoxicam was shown to have a broader spectrum of inhibitory action on the cells involved in the chronic inflammation associated with rheumatoid arthritis.
Radiological evaluation of erosions: a quantitative method for assessing long‐term remittive therapy in rheumatoid arthritis.
Authors: O'Brien WM
Published: July 2012

1 The most reliable method for evaluating possible remission‐inducing properties in a drug is to measure how well it prevents the appearance of new erosions in serial X‐rays of the hands. 2 I have reviewed the literature on the development, over the last 25 years, of a standard method for quantitatively assessing the progress of erosions radiologically. 3 The only drugs thus far shown to be genuinely remission‐inducing are cyclophosphamide, high‐dose penicillamine, and (most consistently over several decades) gold‐thiols, all drugs with life‐threatening toxicity. 4 The search for a non‐steroidal drug with remission‐inducing properties is crucial in our efforts to find a safe drug to control the progression of rheumatoid arthritis.
The dose‐dependent systemic availability of prednisone: one reason for the reduced biological effect of alternate‐day prednisone.
Authors: Frey FJ , Ruegsegger MK , Frey BM
Published: July 2012

An analysis of the literature was performed, revealing that in many studies both the desired and the undesired effects are decreased in alternate‐day prednisone regimens as compared with the daily regimens. In the present report evidence is given that part of the diminished biological effect of dose‐spacing regimens is attributable to a decreased total exposure to prednisolone. Following a high dose of 0.8 mg kg‐1 of oral prednisone or prednisolone the plasma concentration vs time curves of total prednisolone, unbound prednisolone and prednisolone bound to albumin or transcortin were always less than four times higher than following a low dose of 0.2 mg kg‐1 of prednisone or prednisolone. This dose‐dependent systemic availability of prednisolone explains partly the diminished biological effect when the same total amount of prednisone or prednisolone is divided into several small doses as opposed to a single oral dose.
Alterations in isoprenaline sensitivity in patients with cirrhosis: evidence of abnormality of the sympathetic nervous activity.
Authors: Ramond MJ , Comoy E. , Lebrec D.
Published: July 2012

Isoprenaline sensitivity and plasma catecholamine concentrations were studied to assess the sympathetic nervous activity in 13 patients with alcoholic cirrhosis and were compared with five controls. In patients with cirrhosis, the dose of isoprenaline required to increase the resting heart rate by 25 beats min‐1 (chronotropic dose 25 or CD25) ranged from 2.50 to 34.73 micrograms (median: 4.47 micrograms) and was significantly higher than in controls (range: 0.66 to 2.76 micrograms, median: 1.34 micrograms). In cirrhotic patients, CD25 values were significantly correlated with plasma albumin concentration, resting heart rate and wedged hepatic venous pressure. In patients with cirrhosis, plasma noradrenaline concentrations ranged from 192 to 978 pg ml‐1 (median: 444 pg ml‐1) and adrenaline concentrations ranged from 5 to 183 pg ml‐1 (median: 47 pg ml‐1). No correlation was found between noradrenaline or adrenaline concentrations and CD25 values in cirrhotic patients. In conclusion, in patients with cirrhosis, beta‐adrenoceptor responsiveness assessed by isoprenaline sensitivity is altered.
A correlation between serum mebendazole concentrations and the aminopyrine breath test. Implications in the treatment of hydatid disease.
Authors: Bekhti A. , Pirotte J. , Woestenborghs R.
Published: July 2012

In 25 patients an [14C]‐aminopyrine breath test (ABT) was performed immediately before the oral administration of 1.5‐2 g of mebendazole three times daily. The concentration of mebendazole in serum was measured 2 h after each drug intake. A significant correlation was found between the results of ABT and the serum drug concentrations obtained after the second and third intake, as well as the highest concentration value. The ABT was repeated in six patients during a continuous treatment with mebendazole. In all of them this test indicated an increase in 14CO2 production with continued treatment. The results support the view that mebendazole is metabolized by the liver monooxygenase activity and behaves as an enzyme inducer.
Intravenous adenosine in the treatment of supraventricular tachycardia: a dose‐ranging study and interaction with dipyridamole.
Authors: Watt AH , Bernard MS , Webster J. , Passani SL , Stephens MR , Routledge PA
Published: July 2012

Increasing doses of adenosine were given by rapid intravenous bolus to seven patients with spontaneous supraventricular tachycardia. Adenosine restored sinus rhythm in 10 of 14 episodes of narrow complex tachycardia. In those patients in whom adenosine produced only transient ventricular slowing the underlying rhythm was atrial flutter. Transient dyspnoea occurred in all patients. In two patients taking dipyridamole the mean dose of adenosine which produced an electrophysiologic effect (restoration of sinus rhythm or ventricular slowing to under 100 beats min‐1) was 1.0 +/‐ 0.52 mg, whereas in other patients the mean dose was 8.8 +/‐ 2.6 mg, suggesting potentiation of the action of adenosine by dipyridamole.