bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers. A double‐blind crossover study.
Authors: Ammon HP , Bieck PR , Mandalaz D , Verspohl EJ
Published: July 2012

In a double‐blind crossover trial, the effect of 4 week daily ingestion of eight cups of regular coffee (corresponding to 504 mg caffeine) vs eight cups of decaffeinated coffee was studied. Blood pressure, heart rate and urinary catecholamines were measured in eight healthy, young volunteers. In both groups, regular coffee immediately led to a significant increase in mean blood pressure (+ 3 and + 5 mm Hg respectively). The difference between both groups, however, existed only in the first 3 to 5 days of ingestion of regular coffee. On day 5 after ingestion of regular coffee, and thereafter in weekly intervals, no significant increase in catecholamine excretion was observed. The data suggest that long‐term consumption of large amounts of coffee leads to only a small and transient rise in mean blood pressure. This may be due to an adaptation phenomenon. Therefore, continuous heavy coffee ingestion (eight cups/day for 4 weeks) by young persons does not appear to involve a risk of the development of hypertension.
Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.
Authors: Flouvat BL , Imbert C , Dubois DM , Temperville BP , Roux AF , Chevalier GC , Humbert G
Published: July 2012

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half‐life was 15.09 +/‐ 0.68 h (mean +/‐ s.e. mean) (RI) and 12.9 +/‐ 1.0 h after dialysis (RD), but there was a significant decrease in half‐life during dialysis (4.25 +/‐ 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/‐ 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/‐ 0.09 l/kg) and female patients (0.59 +/‐ 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half‐life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half‐life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/‐ 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half‐dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.
Prolonged plasma half‐life after oral isosorbide dinitrate in patients with angina pectoris.
Authors: Fung HL , Parker JO
Published: July 2012

The plasma concentration of isosorbide dinitrate (ISDN) was monitored up to 24 h after a chronic oral dose of 60 mg in six patients with coronary artery disease. A terminal half‐life of 7.7 +/‐ 2.6 h (mean +/‐ s.d.) was observed. The presence of this prolonged disappearance phase provided at least a partial explanation for the observed accumulation of ISDN in plasma after chronic dosing on a six hourly regimen.
Delta‐9‐tetrahydrocannabinol and gastric emptying.
Authors: Bateman DN
Published: July 2012

The effects of delta‐9‐tetrahydrocannabinol (0.5 and 1 mg i.v.) on gastric emptying of liquid were investigated in seven normal volunteers and compared with placebo. Despite significant change in pulse rate and psychological parameters consistent with cannabis activity there was no significant effect on the pattern of gastric emptying. It is therefore suggested that an anti‐emetic action of delta‐9‐tetrahydrocannabinol does not involve a change in gastric emptying.
The effect of enalapril on serum prolactin.
Authors: McNabb WR , Brooks BA , Noormohamed F , Lant AF , Gomez HJ , Cirillo VJ , Hichens M , Bolognese JA
Published: July 2012

Twelve healthy male volunteers received single daily oral doses of enalapril (EN) 10 mg for 8 consecutive days. Serum samples for prolactin (PRL) assay were taken on day 0 (baseline) at 12.00 h and 16.00 h, and on days 1 and 8 at 08.00 h (pre‐drug), 12.00 h and 16.00 h. The 08.00 h values on day 1 served as the pre‐drug baseline. There were no significant changes from baseline in serum PRL levels on days 1 and 8. All mean serum PRL levels on day 8 were significantly (P less than 0.01) lower than the upper limit of the normal range (2‐15 ng/ml) found for healthy males in this laboratory. It is concluded that therapeutic doses of EN (10 mg/day, p.o.) for 8 consecutive days do not raise mean serum PRL levels above the normal range in healthy male volunteers.
Multicentre controlled trial of tienilic acid in hyperuricaemic, hypertensive subjects, with intensive monitoring of liver function.
Authors: Orchard MA , Ritter JM , Shepherd GL , Lewis PJ
Published: July 2012

1 Tienilic acid, a diuretic with potent uricosuric properties, has been compared with conventional diuretic therapy, mainly thiazide, in a parallel group (random allocation) multicentre study in hyperuricaemic hypertensives (n = 96). 2 The study was designed to last 1 year but tienilic acid was withdrawn for suspected hepatotoxicity before the study was complete. Mean follow‐up was 8.5 (range 1‐12) months and the mean daily dose of tienilic acid was 278 (range 125‐500 mg). 3 Blood pressure levels on tienilic acid and on conventional diuretics were similar. 4 Serum potassium and sodium levels were also similar in the two groups, but serum urea and creatinine rose somewhat more in the tienilic acid group. 5 Serum uric acid fell dramatically in the patients on tienilic acid from 0.56 to 0.32 mmol/l, but did not alter significantly in the control group. 6 There were no problems with renal failure or urate deposition probably because patients were instructed to drink plenty of fluid when tienilic acid was started, because initial dose was low and because all previous diuretics were stopped for 3 days before tienilic acid was started. 7 Mean liver function indices did not rise in either group. Mild elevation in liver enzymes occurred in one control patient and one patient on tienilic acid; the latter drug was stopped and the values returned to normal. 8 The general incidence of side‐effects was low. 9 Our impression was that tienilic acid was a useful drug. Whether it could have been used safely with monitoring of liver function will not now be known.
Effect of the benzodiazepine antagonist Ro 15‐1788 on flunitrazepam‐ induced sleep changes.
Authors: Gaillard JM , Blois R
Published: July 2012

1 The modifications of human sleep induced by benzodiazepines, and particularly by flunitrazepam, are complex. Stage 4 and paradoxical sleep are both decreased; however, these two effects have a different evolution during and after single or short‐term drug administration. 2 The benzodiazepine antagonist Ro 15‐1788 also tends to depress stage 4, but with immediate recovery in the post‐drug night, and does not modify paradoxical sleep. 3 In combined administration, this drug totally reverses the hypnogenic effect of flunitrazepam, as well as its effect on paradoxical sleep but not the decrease of slow wave sleep. 4 Some of the benzodiazepine‐induced alterations of sleep may be related to receptors different from central benzodiazepine receptors, or to mechanisms not directly connected to this type of receptors.
A clinical pharmacological comparison of diclofensine (Ro 8‐4650) with nomifensine and amitriptyline in normal human volunteers.
Authors: Culig J , Ehsanullah RS , Hallett C , Iliopoulou A , Matheson I , Turner P
Published: July 2012

1 Ten healthy male volunteers participated in a double‐blind placebo‐ controlled crossover comparison of the pharmacodynamic profiles of single oral doses of diclofensine 25 mg and 50 mg, nomifensine 75 mg and amitriptyline 50 mg. 2 Diclofensine did not influence salivary flow or consistently affect pupil diameter and had no significant effect on subjective measurements of sedation and mood. It had no effect on reaction time, or on critical flicker frequency. 3 By contrast, amitriptyline significantly reduced salivary flow, produced significant sedation and impairment of mood, prolonged reaction time, and appeared to decrease (but not significantly) critical flicker frequency. 4 Nomifensine significantly reduced (i.e. improved) reaction time, and inhibited salivary flow. 5 Diclofensine did not significantly influence heart rate, blood pressure, systolic time intervals or high speed electrocardiogram. 6 No significant treatment‐related differences were observed in serum prolactin, cortisol or growth hormone levels.
Development of tolerance and cross‐tolerance to the psychomotor actions of lorazepam and diazepam in man.
Authors: Aranko K , Mattila MJ , Seppala T
Published: July 2012

1 Development of tolerance and cross‐tolerance to lorazepam and diazepam in man was assessed in a double‐blind and cross‐over trial where eight pretrained healthy students volunteered for four 1 week treatment periods started at 1 month intervals. 2 In each period acute psychomotor responses to oral lorazepam 3 mg and diazepam 15 mg were recorded on day 1, as well as on day 8 after 1 week's treatment twice daily with diazepam 5 mg, lorazepam 1 mg, and placebo. At each session several objective psychomotor tests and subjective assessments were done before the drug intake and 1, 2.5, and 4 h after it. 3 In general, the effects of lorazepam were stronger and of longer duration than those of diazepam at the doses used. When comparing the single‐dose responses on days 1 and 8, tolerance to lorazepam effects and some cross‐tolerance developed on several functions measured. Tolerance but not cross‐tolerance developed on choice reaction errors whereas the opposite was found on flicker fusion. No definite tolerance was found on subjective effects. 4 The results tally with an assumption that tolerance to benzodiazepine actions develops at different rates on various parameters measured.
Comparison of the effects of single doses of atenolol and labetalol on airways obstruction in patients with hypertension and asthma.
Authors: Jackson SH , Beevers DG
Published: July 2012

1 The effects of atenolol (100 mg), a cardioselective beta‐adrenoceptor blocking agent, and labetalol (300 mg), a combined alpha‐ and non‐ selective beta‐adrenoceptor blocking agent given in single doses were examined in a double‐blind placebo controlled study in 11 asthmatic patients with hypertension. Changes in forced expiratory volume in one second (FEV1) were measured. 2 There were no significant differences between the effects of the active drugs, approximately half the patients having higher FEV1 values during each of the two active treatments. When compared with placebo, labetalol significantly reduced the effect of inhaled salbutamol on FEV1. 3 Whilst beta‐adrenoceptor blockings drugs cannot be recommended in patients with airways obstruction, should they inadvertantly be given, labetalol like atenolol may be considered relatively safer then pure non‐selective beta‐adrenoceptor blocking drugs.
Use of a bioassay in healthy men to evaluate diuretic‐spironolactone combinations.
Authors: McInnes GT , Shelton JR , Perkins RM , Harrison IR , Clarke JM
Published: July 2012

The plasma potassium responses to 1 week's treatment with metolazone 0.625 mg, 1.25 mg and 2.5 mg in combination with spironolactone 50 mg, and metolazone 2.5 alone were examined in a double‐blind, crossover study in twelve healthy subjects. Spironolactone attenuated the hypokalaemia induced by metolazone–addition of spironolactone 50 mg to metolazone 2.5 mg raised plasma potassium by 0.18 mmol/l (P less than 0.025). In the presence of spironolactone, a linear log metolazone dose‐ plasma potassium response relationship (P less than 0.01) was demonstrated. Spironolactone was unable to compensate fully for metolazone's hypokalaemic effect although in combination with metolazone 0.625 mg and 1.25 mg, plasma potassium concentration was maintained close to pretreatment levels. The human bioassay employed provided conveniently quantitative information which allows the rational development of a fixed dose diuretic‐spironolactone combination tablet.
Effects of thromboxane synthetase inhibition on arachidonate metabolism and platelet behaviour.
Authors: Parry MJ
Published: July 2012

1 The effects of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on arachidonic acid and collagen‐induced platelet aggregation and arachidonate acid metabolism were studied both in vitro and ex vivo in the presence and absence of sources of prostaglandin I2 synthetase. 2 In platelets activated by exogenous arachidonic acid, the anti‐ aggregatory activity of dazoxiben was weak compared with indomethacin, despite comparable inhibition of TXB2 production. This was due to the accumulation of pro‐aggregatory metabolites, principally endoperoxides. 3 The anti‐aggregatory activity of dazoxiben, both in vitro and ex vivo, was higher and more consistent when platelets were stimulated by collagen, threshold levels of which resulted in an endoperoxide accumulation only 2‐3% of that achieved with exogenous arachidonic acid. 4 The anti‐aggregatory activity of dazoxiben is enhanced if drug equilibration is facilitated by prolonging the preincubation time from 2 to 15 minutes. 5 Incubation of platelets with pig aortic microsomes, which act both as aggregant and a source of PGI2 synthetase, facilitates the conversion to PGI2 of some endoperoxides accumulated after dazoxiben, resulting in augmented anti‐aggregatory activity. 6 Leukocytes as well as blood vessels have the capacity to generate PGI2 from platelet derived endoperoxides. This was demonstrated by the increases in 6‐keto‐PGF1 alpha accompanying decreased TXB2 production in clotted whole blood from volunteers treated with dazoxiben. 7 It was concluded that a closer approach to in vivo conditions allowing a fuller expression of the mechanism of action of dazoxiben could be achieved in vitro by stimulating platelets with a pathophysiological activator such as collagen in the presence of a source of PGI2 synthetase.
Effect of dazoxiben on platelet‐vessel wall interaction.
Authors: Davies JA , Menys VC
Published: July 2012

1 Platelet monolayer adhesion to damaged rabbit aorta and to collagen‐ coated glass was quantified in a perfusion device. Addition of the thromboxane synthetase inhibitor dazoxiben (UK 37248) 1 and 10 microM reduced adhesion to damaged blood vessel by about 45% at both concentrations, but did not affect adhesion to collagen‐coated glass. 2 Measurement by RIA indicated virtual abolition of thromboxane B2 production in the presence of the drug and a slight trend to an increase of 6‐oxo‐prostaglandin F1 alpha concentration in experiments using aorta. Inhibitory activity of dazoxiben was abolished by previous exposure of the aorta to 15‐HPETE(?), an inhibitor of prostacyclin synthetase. 3 The results indicate that dazoxiben inhibits platelet adhesion to vascular subendothelium possibly by promoting synthesis of PGI2 from re‐directed platelet endoperoxides.
Acute arterial thrombosis in rabbits: reduced platelet accumulation after treatment with dazoxiben hydrochloride (UK 37,248‐01).
Authors: Randall MJ , Wilding RI
Published: July 2012

1 Acute thrombosis was induced in the carotid arteries of anaesthetized rabbits by local electrical stimulation (1 mA for 2 min) of the vessel wall. Histological findings confirmed the platelet‐rich composition of the thrombus. Platelet accumulation at the stimulus site was quantitated with 111Indium‐labelling of autologous platelets. 2 In rabbits injected intravenously with either the thromboxane synthetase inhibitor dazoxiben 2 mg/kg or aspirin 10 mg/kg, accumulation of labelled platelets was considerably reduced. Animals which received vehicle injection only, showed no such reduced thrombus formation. 3 In separate experiments in anaesthetized rabbits, the levels of thromboxane B2 (TXB2) and 6‐keto‐prostaglandin F1 alpha in clotting blood were measured in blood samples taken from animals which had received the above drug treatments. Aspirin markedly reduced the production of both arachidonate metabolites. In contrast, dazoxiben almost totally inhibited TXB2 production but caused a 3.5‐fold increase in the levels of 6‐keto PGF1 alpha. 4 These findings demonstrate an antithrombotic effect and confirm the mechanistic selectivity of a thromboxane synthetase inhibitor.
Haemodynamic and metabolic effects of dazoxiben at rest and during atrial pacing.
Authors: Kiff PS , Bergman G , Atkinson L , Jewitt DE , Westwick J , Kakkar VV
Published: July 2012

1 Thromboxane B2 (TXB2) levels were measured in three sites (coronary sinus, pulmonary artery, and femoral artery) at rest and during atrial pacing in 11 patients with stable angina pectoris. 2 There was a highly significant increase in arterial TXB2 on pacing (by up to 820 pg/ml) but there was no change in the thromboxane levels at the other two sites. 3 Dazoxiben 200 mg orally abolished the increase in arterial TXB2, but had no effect on systemic, pulmonary or coronary haemodynamics, no effect on myocardial metabolism and a variable effect on atrial pacing time to angina.
Effects of dazoxiben, an inhibitor of thromboxane synthetase, on forearm vasoconstriction in response to cold stimulation, and on human blood vessel prostacyclin production.
Authors: Cowley AJ , Jones EW , Hanley SP
Published: July 2012

1 In healthy male volunteers dazoxiben (UK 37248), an inhibitor of thromboxane synthetase, abolished the arterial and venous vasoconstriction produced in the forearm by cold stimulation. 2 Aspirin alone had no effect on this vasoconstriction but negated the effect of dazoxiben. 3 In vitro dazoxiben increased the production of prostacyclin by human arteries and veins. 4 By reducing the synthesis of thromboxane A2, a potent vasoconstrictor, and by increasing the synthesis of prostacyclin, a potent vasodilator, dazoxiben may have a therapeutic role in conditions associated with abnormal vasoconstriction.
Effect of dazoxiben, a specific inhibitor of thromboxane synthetase, on acute pulmonary responses to E. coli endotoxin in anaesthetized cats.
Authors: Ball HA , Parratt JR , Zeitlin IJ
Published: July 2012

1 The effects of acute pretreatment with the thromboxane synthetase inhibitor dazoxiben 5 mg/kg intravenously (UK 37248‐01) were examined on the acute pulmonary responses of pentobarbitone‐anaesthetized cats to E. coli endotoxin 2 mg/kg intravenously. 2 E. coli endotoxin in control, untreated, cats resulted in a marked pulmonary hypertension, an increase in intra‐tracheal pressure (at a constant pulmonary inflation volume), an increase in both pulmonary arterial and aortic concentrations of thromboxane B2 (TXB2) and a reduction in systematic arterial PO2. 3 Dazoxiben prevented, or markedly reduced, the endotoxin‐ induced pulmonary release of TXB2, the decrease in systematic arterial PO2 and the pulmonary arterial hypertension, but did not modify the increase in intratracheal pressure. 4 These results may suggest that TXA2 is responsible for the endotoxin‐induced pulmonary arterial hypertension but that some other arachidonic acid derivative (prostaglandin F2 alpha) is responsible for the reduced lung compliance that follows the acute administration of E. coli endotoxin.
Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat.
Authors: Halushka PV , Cook JA , Wise WC
Published: July 2012

1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (less than 200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6‐ keto‐prostaglandin F1 alpha (6‐keto‐PGF1 alpha). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875 +/‐ 90 pg/ml (n = 9), iPGE was 1670 +/‐ 271 (n = 9) and i6‐keto‐PGF1 alpha was 1191 +/‐ 209 pg/ml (n = 10). By 4 h plasma iTXB2 was 1743 +/‐ 328 pg/ml (n = 5), iPGE was 2589 +/‐ 494 pg/ml (n = 9) and i6‐keto‐PGF1 alpha was 4251 +/‐ 984 pg/ml (n = 10). UK 37248 pretreatment resulted in a significant (P less than 0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193 +/‐ 28 pg/ml (n = 5) and 421 +/‐ 57 pg/ml (n = 5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6‐keto PGF1 alpha at 30 min and 4 h to 360 +/‐ 75 pg/ml (n = 10) (P less than 0.005) and 1920 +/‐ 513 pg/ml (n = 10) (P less than 0.05), respectively, iPGE plasma levels were not significantly changed in the UK 37248‐pretreated rats 30 min (2210 +/‐ 370 pg/ml (n = 9) or 4 h 3529 +/‐ 1093 pg/ml (n = 13) after endotoxin compared to the vehicle‐treated rats. 3 UK 37248 significantly (P less than 0.05) reduced the endotoxin mortality rate at 24 h from 69% (n = 13) to 30% (n = 13), UK 37248 also reduced splanchnic infarction from 90% (n = 20) to 6% (n = 16). 4 UK 37248 significantly improved the endotoxin‐induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.
Review of the animal pharmacology and pharmacokinetics of fluvoxamine.
Authors: Claassen V
Published: July 2012

1 Fluvoxamine maleate is a compound from the series of 2‐ aminoethyloximethers of aralkylketones which possesses marked inhibition effects on 5‐hydroxytryptamine (5‐HT) uptake by blood platelets and brain synaptosomes. In contrast, it has no effect on noradrenaline uptake processes. 2 Fluvoxamine is completely absorbed in rats and dogs; the main metabolic path was similar in rat, dog, hamster, mouse and rabbit. The metabolites of fluvoxamine are inactive with regard to aminergic uptake processes. 3 Fluvoxamine is neither sedative nor stimulating, shows a very low cardiotoxic effect and no affinity for the cholinergic receptor. On the basis of the pharmacological profile, a highly favourable therapeutic ratio of antidepressant effects vs disturbing side‐effects is predicted.
A double‐blind controlled clinical trial comparing fluvoxamine with imipramine.
Authors: Guelfi JD , Dreyfus JF , Pichot P
Published: July 2012

1 The effects of fluvoxamine to a maximum of 300 mg daily were compared with those of imipramine to a maximum of 200 mg daily, in 151 patients with primary major depression. 2 Four weeks of treatment with fluvoxamine resulted in 67.2% improvement (+/‐ s.d. 21.6) on the Hamilton Rating Scale for Depression (26 items). Treatment with imipramine showed 62.1% improvement (+/‐ s.d. 29.5) on this scale. 3 Fluvoxamine had no untoward effects on the cardiovascular system, while imipramine produced systematic increases in the postural fall in blood pressure. Dry mouth, nausea, daytime somnolence and tremor were seen with fluvoxamine treatment, while imipramine was associated with dry mouth, daytime somnolence, dizziness and tremor. 4 We conclude that fluvoxamine seems to have the same general antidepressant efficacy as imipramine. It was not associated with any safety problems and was generally well tolerated.
A double‐blind comparative study of the clinical efficacy of fluvoxamine and chlorimipramine.
Authors: Dick P , Ferrero E
Published: July 2012

1 We report the results of a comparative clinical trial of a new antidepressant drug fluvoxamine (a specific re‐uptake inhibitor of 5‐ hydroxytryptamine (5‐HT)) with chlorimipramine. Thirty‐two patients with mixed depression received one or the other drug at the same daily dosage of 150 mg. 2 In both drug groups there was an overall clinically significant improvement for all items on the Hamilton Rating Scale for Depression (67% improvement in both groups). 3 In the chlorimipramine group there were more digestive symptoms and anticholinergic effects; the difference with the fluvoxamine group approached statistical significance. 4 No clinically important effects of either treatment were observed on heart‐rate or blood pressure.
Clinical trials of fluvoxamine vs chlorimipramine with single and three times daily dosing.
Authors: de Wilde JE , Mertens C , Wakelin JS
Published: July 2012

1 Two double‐blind, randomised studies were performed to compare the efficacy of fluvoxamine and chlorimipramine in depressed patients. In the first study the effects of a single daily dosage of between 100 and 300 mg of fluvoxamine were compared with those of chlorimipramine at a dosage of 50‐150 mg daily in 43 out‐patients with endogenous depression. 2 In a second study using three times daily dosing with a daily dosage of 150‐300 mg for both fluvoxamine and chlorimipramine, 30 in‐patients with unipolar depression were assessed. 3 Four weeks of treatment with single daily dosing resulted in a mean improvement of 61.4% (+/‐ s.d. 31.7) on the Hamilton Rating Scale for Depression (HAMD) for fluvoxamine and of 65.3% (+/‐ s.d. 25.8) for chlorimipramine. In the study with three times daily dosing the mean results were 72.9% (+/‐ s.d. 22.3) improvement for fluvoxamine and 62.1% (+/‐ s.d. 28.5) for chlorimipramine. 4 At similar dosages, fluvoxamine had significantly less untoward effects on blood pressure than chlorimipramine. Anticholinergic effects were also fewer in the fluvoxamine group, as were nervous system symptoms, with the latter difference reaching statistical significance (P = 0.02). 5 We conclude that fluvoxamine, given in a single daily dose of 150‐250 mg, provides antidepressant efficacy similar to chlorimipramine. At this dosage it may be expected to produce less anticholinergic effects and have less influence on blood pressure than chlorimipramine.
Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressants and fluvoxamine.
Authors: Roos JC
Published: July 2012

1 The cardiovascular effects of the tricyclic antidepressants (TCAs) are reviewed and compared with those of fluvoxamine, a new 5‐ hydroxytryptamine (5‐HT) re‐uptake inhibitor. 2 The TCAs have important effects on the heart, related to their anticholinergic and quinidine‐ like properties. The major side effects in therapeutic dosage include heart rate increase, postural hypotension and slight prolongation of the intraventricular conduction time and QT interval. In toxic dosage (or normal dosage in patients with severe heart disease) both advanced heart block and ventricular arrhythmias can occur, together with clinically important loss of myocardial contractile force. 3 Fluvoxamine has no effects on the heart except for a statistically (but not clinically) significant slowing of the heart rate.
The pharmacokinetics of endralazine in essential hypertensives and in normotensive subjects.
Authors: Meredith PA , Elliott HL , McSharry DR , Kelman AW , Reid JL
Published: July 2012

The direct‐acting vasodilator, endralazine, in combination with a beta‐ adrenoceptor blocker significantly reduced the blood pressures of normotensive volunteers and of patients with essential hypertension. The mean terminal elimination half‐life for endralazine of 136 min in hypertensive patients did not differ significantly from the 155 min in normotensive subjects. In normal subjects the mean oral bioavailability for endralazine was 75% and the mean clearance was 780 ml/min. There were no significant pharmacokinetic differences between fast and slow acetylators. The administration of endralazine to steady state in the hypertensive patients was associated with an increase in terminal elimination half‐life and a decrease in the rate of absorption. However, there was no accumulation of endralazine with chronic dosing.
Oxyhaemoglobin equilibrium and chronic beta‐adrenoceptor blockade in coronary heart disease.
Authors: Jurgensen HJ , Wimberley PD , Brodthagen U
Published: July 2012

In 20 patients with coronary heart disease the effect of long‐term beta‐ adrenergic receptor blockade on the haemoglobin oxygen equilibrium was investigated. Study patients received alprenolol 200 mg twice daily for 12‐41 months (mean: 24 months) as a secondary preventive measure following a myocardial infarction. While on and again following gradual withdrawal of alprenolol, the patients performed a maximum bicycle ergometer test. Haemoglobin oxygen affinity as expressed by the P50 value, 2,3‐diphosphoglycerate (2,3‐DPG) and carbon monoxide haemoglobin were measured before and following exercise. Pre‐exercise P50 decreased from 25.2 +/‐ 0.3 mm Hg (mean +/‐ s.e. mean) while on beta‐adrenoceptor blocker to 24.6 +/‐ 0.4 mm Hg in the off‐treatment state (P less than 0.05). Five minutes after stopping exercise P50 was 25.1 +/‐ 0.3 in patients taking alprenolol as compared to 24.7 +/‐ 0.3 after withdrawal of the drug (P less than 0.01). It is concluded that the slight decrease in haemoglobin oxygen affinity in long‐term treatment with alprenolol, which is observed in the present study probably is without clinical bearing. The question should be further elucidated by analysis of coronary sinus blood samples.
Effects of intravenous endralazine in essential hypertension.
Authors: Hoffmann JJ , Thien T , van'Laar A T
Published: July 2012

The effects of endralazine, administered intravenously, on blood pressure, heart rate, forearm blood flow, plasma renin activity, aldosterone, adrenaline and noradrenaline were studied in five patients with essential hypertension. Endralazine reduced peripheral vascular resistance, resulting in decrease in mean arterial pressure from 141 to 116 mm Hg and increase in heart rate from 67 to 92 beats/min. Plasma renin activity, adrenaline and noradrenaline increased significantly after endralazine infusion. All effects observed are consistent with endralazine acting as a peripheral vasodilating drug.
The haemodynamic effect of intravenous flecainide acetate in patients with coronary artery disease.
Authors: Serruys PW , Vanhaleweyk G , Van Den Brand M , Verdouw P , Lubsen J , Hugenholtz PG
Published: July 2012

Flecainide acetate has been shown to be a potent antiarrhythmic agent which is active for more than 8 h, whether given intravenously or orally. However, the negative inotropic effect demonstrated in animal studies could hamper the potential clinical utility of the drug. Ten patients with coronary artery disease but without cardiac failure were given intravenous flecainide (2 mg/kg). Stroke index (SI), left ventricular systolic pressure (LVP), end diastolic pressure (EDP) and LV contractility indices (max dP/dt, VCE 40 mm Hg, peak VCE, Vmax from total pressure (TP] were measured immediately before and 10 min after flecainide, under resting conditions and during atrial pacing with heart rates up to 133 +/‐ 4.2 beats/min (mean +/‐ s.e. mean). It is demonstrated that flecainide has a negative inotropic effect, not only under resting conditions, but also less apparently during pacing‐ induced tachycardia. The effect appears to be dose‐related and may result in a reduction of cardiac performance.
Effect of urine pH on the elimination of phenoperidine.
Authors: Milne LA , Williams NE , Calvey TN , Murray GR , Chan K
Published: July 2012

The effect of urine pH on the plasma concentration and elimination of phenoperidine and its main metabolites was studied in six volunteers. The clearance of unchanged phenoperidine in acid urine was significantly greater than in neutral or alkaline urine. By contrast, the elimination of its basic metabolites was enhanced in uncontrolled or alkaline urine. Other pharmacokinetic parameters were not significantly affected.
The effect of a 5‐HT antagonist, ketanserin, on blood pressure, the renin‐angiotensin system and sympathoadrenal function in normal man.
Authors: Zoccali C , Zabludowski JR , Isles CG , Murray GD , Inglis GC , Robertson JI , Fraser R , Ball SG
Published: July 2012

The role of endogenous 5‐hydroxytryptamine (5‐HT) in the control of blood pressure, the renin‐angiotensin system and sympatho‐adrenal function was investigated in normal man. Ketanserin (a specific 5‐HT2 antagonist) administered intravenously caused a small decrease in blood pressure in salt‐depleted recumbent subjects. A more marked postural fall in pressure occurred in both sodium‐depleted and repleted normal subjects. Plasma active renin concentration and angiotensin II increased after administration of ketanserin, but plasma aldosterone, cortisol and noradrenaline were unchanged. 5‐HT may be important in the control of blood pressure in man and specific 5‐HT2 receptor antagonists could be a useful new class of antihypertensive agents.
Transient in oxygen uptake after step‐increase of workload under beta‐ adrenoceptor blockade or vasodilation.
Authors: Hendriks FF , Schipperheyn JJ
Published: July 2012

The effect of vasodilation (with nifedipine) or beta‐adrenergic receptor blockade (with propranolol, alprenolol or metoprolol) on the rate of rise of oxygen uptake and heart rate were studied in 14 healthy subjects after a step‐wise increase of workload from a light to a moderate exercise intensity. Under beta‐adrenergic receptor blockade steady state oxygen uptake at both workload levels was equal to control values; heart rate went up to 111 min‐1 (s.d.:15) vs 150 min‐1 (s.d.:24) for the control experiments. The half‐times of the oxygen uptake transient were unchanged. After vasodilation with nifedipine heart rates were higher (20% for the lower and 12% for the higher exercise level) but steady state oxygen uptake levels and rate of rise were also unchanged. It is concluded that the rate of rise of oxygen supply to working skeletal muscles after a stepwise increase of load is not reduced either by a beta‐adrenergic receptor blocking drug nor by a vasodilating agent. Discomfort during exercise appears to be a subjective phenomenon related to reduced skin circulation and sweating under beta‐adrenergic receptor blockade, or to headache and congestion after vasodilatory drug administration. These side‐effects are not caused by a reduced oxygen supply of muscle, neither under steady state situations nor under rapid changing workload conditions.
Blood monocyte aryl hydrocarbon hydroxylase activity in psoriasis.
Authors: Mason G , Rawlins MD , Shuster S
Published: July 2012

The activity of aryl hydrocarbon hydroxylase (AHH) in monocytes from 13 healthy control subjects and in 16 patients with discoid psoriasis was measured. The mean basal monocyte AHH activities of the control and psoriatic groups were 3.4 +/‐ 0.47 and 4.46 +/‐ 0.55 respectively (pmol 3‐OHBP h‐1 10(‐6) cells). This difference was not significant. The mean induced monocyte AHH activities in the control and psoriatic groups were 56.4 +/‐ 10.8 and 77.8 +/‐ 16.0 pmol 3‐OHBP h‐1 10(‐6) cells respectively but this difference was not significant. The mean induction ratios in the control and psoriatic groups were 16.5 +/‐ 1.8 and 20.4 +/‐ 3.6 respectively. Again, this difference was not significant. We conclude therefore, that monocyte aryl hydrocarbon hydroxylase activity is not reduced in psoriasis.
Quinine disposition kinetics.
Authors: White NJ , Chanthavanich P , Krishna S , Bunch C , Silamut K
Published: July 2012

Intravenous quinine dihydrochloride (5 mg kg‐1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/‐ 1 s.d.) after the infusion were 5.1 +/‐ 1.3 mg 1(‐1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half‐time (t 1/2, lambda 1) was 1.89 +/‐ 0.54 min (mean +/‐ 1 s.d.), elimination half‐time (t 1/2, z) 11.1 +/‐ 2.1 h, apparent volume of the central compartment (V1) 0.57 +/‐ 0.32 1 kg‐1, total apparent volume of distribution 1.80 +/‐ 0.37 1 kg‐1 and total clearance 1.92 +/‐ 0.45 ml min‐1 kg‐1.
A comparison of diclofensine and desmethylimipramine using tyramine pressor tests in normal subjects.
Authors: Jackson SH , Turner P , Ehsanullah RS
Published: July 2012

Eight male volunteers received placebo, diclofensine 25 mg, diclofensine 50 mg and desmethylimipramine (DMI) 50 mg at least a week apart. Using tyramine pressor tests, no statistically significant differences between the noradrenaline reuptake blocking effects of the three active treatments could be demonstrated. Visual analogue rating scales showed an increase in dryness of the mouth at 3 h after DMI but no similar effect after either dose of diclofensine.
An assessment of the contribution of clonidine metabolised from alinidine to the cardiovascular effects of alinidine.
Authors: Harron DW , Arndts D , Finch M , Shanks RG
Published: July 2012

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2‐7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/‐ 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/‐ 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/‐ 0.15 and 0.86 +/‐ 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/‐ 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/‐ 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)
Prediction of maintenance oral theophylline dosage using single oral doses in patients with obstructive airways disease.
Authors: Taylor DR , Kinney CD , McDevitt DG
Published: July 2012

This study was designed to test whether single oral doses of theophylline, rather than the specified single intravenous infusions, could be used with a nomogram designed to predict the maintenance oral dose necessary to establish plasma theophylline concentrations of 10 micrograms ml (Koup et al., 1979) in patients with obstructive airways disease. A test dose of theophylline (5 mg kg) was administered on two separate occasions as an oral elixir and as an intravenous infusion. Exactly 6 h after each test dose, plasma theophylline concentration was measured, and the result used to predict daily maintenance dose requirements. During subsequent oral administration, a sustained‐ release preparation was given in equally divided 12‐hourly doses, and ‘steady‐state’ concentrations were measured at trough. Nineteen patients completed the study, and on doses ranging from 4.2 to 21.1 mg kg‐1 day‐1, trough concentrations of 5.4 to 15.8 micrograms ml (mean 10.0 +/‐ 0.7 micrograms ml) were achieved. No significant differences were noted between the dose predictions made following either the oral or the intravenous test doses, and the predictive accuracy using the oral route was not compromised. This would suggest that the test dose of theophylline may be administered orally, instead of intravenously, with this nomogram without reducing its efficiency.
Hydralazine and prazosin in the treatment of hypertension.
Authors: Vandenburg MJ , Sharman VL , Wright P , Drew PJ , Barnes JN
Published: July 2012

We report the results of an observer blind crossover trial in 31 patients with essential hypertension comparing the hypotensive effect of four doses of prazosin and of hydralazine used as the third step of triple therapy and additional data on the efficacy of low dose combinations of these two drugs. Both drugs had an appreciable antihypertensive effect, 1 mg of prazosin being equivalent to 12.5 mg of hydralazine. Increasing the dose of prazosin from 4 to 8 mg twice daily and hydralazine from 50 to 100 mg twice daily did not consistently reduce blood pressure. The combination of the two drugs at low doses resulted in the blood pressure of more patients being controlled (diastolic blood pressure 90 mm Hg or below) than when either drug was used alone at high dose. The symptoms reported by patients were similar for both drugs. The combination did not lead to an increased reporting frequency. The trial demonstrates one of the problems of a crossover study, namely a treatment/period interaction.
Pulmonary effects in man of oral prizidilol hydrochloride (SK&F 92657), a new antihypertensive agent.
Authors: Edmondstone WM , Waller JF , Manghani KK , Hill PL , Bell AJ , Denison DM
Published: July 2012

The effects on heart rate, blood pressure and pulmonary function of single oral doses of prizidilol hydrochloride (400 mg SK&F 92657) and propranolol (40 mg) were compared with placebo in nine healthy volunteers, in a double blind crossover study. Prizidilol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Diastolic blood pressure was lowered to the same extent by both prizidilol and propranolol. Propranolol significantly reduced the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the maximal expiratory flow at 50% vital capacity (MEF 50). Prizidilol had no effect on flow‐volume loop parameters. Effective pulmonary blood flow was not altered by propranolol, but it was significantly increased by prizidilol. Oral prizidilol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.
Effect of timolol on clinical features and echocardiographic assessment of left ventricular function in hyperthyroidism.
Authors: Griffiths BE , Creagh FM , Lazarus JH , John R , Kadury S
Published: July 2012

The effect of timolol, a beta‐adrenoceptor blocking drug on the clinical status, thyroid status and left ventricular function as measured by serial M‐mode echocardiographic recordings was assessed in a double‐blind randomised study in 18 hyperthyroid patients. A significant clinical improvement was documented after 2 weeks of timolol treatment compared with placebo. There was no evidence that timolol impaired peripheral monodeiodination of thyroxine (T4). There were significant increases in left ventricular fractional shortening (Fr. Sh.) and velocity of circumferential shortening (Vcf) as well as a significant decrease in the left ventricular systolic internal dimension (LVIDs) (all P less than 0.01) in the untreated thyrotoxic patients compared with a normal euthyroid control group. After timolol treatment (2/52) there were significant increases in LVIDs and LVIDd and a significant decrease in Vcf (all P less than 0.05). No further changes occurred after a further 2/52 treatment with carbimazole. The cardiac data suggest that both an augmented sympathetic drive and a direct effect of thyroid hormone on myocardial contractility are mediators of the haemodynamic changes in hyperthyroidism.
Increased platelet adhesion and aggregation in hypertensive patients: effect of atenolol.
Authors: Markel A , Brook JG , Levy Y , Aviram M , Youdim MB
Published: July 2012

Fourteen patients with established hypertension followed a double‐blind crossover‐styled trial to study the effects of 100 mg/day atenolol compared to placebo. Atenolol was found to be an effective antihypertensive agent, reducing both systolic and diastolic blood pressure. Hypertensive patients appear to have increased in vitro platelet adhesion and aggregation. Atenolol significantly reduced platelet adhesion, but had little effect on aggregation. This may be important in contributing towards the now‐recognised cardio‐protective effect of the beta‐adrenoceptor blocking agents. Blood chemistry and haematological parameters were unchanged; but whereas plasma cholesterol and plasma triglyceride levels remained normal, there was a significant fall in plasma high‐density lipoprotein cholesterol levels. Side effects were very few.
Assay‐dependent kinetics of heparin: evidence for rapid in vivo activation of heparin.
Authors: McGowan FX , Nash PV , Bjornsson TD
Published: July 2012

Multiple blood samples were collected over the first 15 min after an i.v. injection of 25 units/kg of heparin in four healthy subjects. Plasma heparin activity in each sample was determined by a chemical neutralization assay using polybrene and a bioassay based on activated partial thromboplastin time. Chemically assayed heparin declined much more rapidly than bioassayed heparin over the first 5‐7 min after the dose. Subsequently, both heparin activity vs time curves declined with a similar terminal half‐life. Slopes of the in vivo 1n APTT vs plasma heparin activity (determined by chemical neutralization) relationships were significantly greater than those of the corresponding in vitro relationships between 1n APTT vs heparin activity added to plasma. A possible explanation for these heparin assay differences is a rapid in vivo enhancement of the anticoagulant effect of heparin. How such enhancement may occur, however, is presently unclear.
beta‐Adrenoceptor hypersensitivity after stopping oxprenolol: discrepant findings not attributable to methodology.
Authors: Singh H , Rimmer A , Lewis MJ , Henderson AH
Published: July 2012

Using isoprenaline and glyceryl trinitrate (GTN) induced tachycardia we have compared the rebound beta‐adrenoceptor hypersensitivity on stopping slow‐release and conventional oxprenolol in young normotensive subjects. Heart rate on standing with GTN rose after stopping slow‐ release and conventional oxprenolol to peak levels on day 2 or 3 significantly greater than corresponding control levels off treatment on day 5. The isoprenaline CD25 (the dose required to increase heart rate by 25 beats/min) fell after stopping conventional oxprenolol to a significantly lower level on day 3 than the control level off treatment on day 5. Contrary to a recent report describing no rebound beta‐ adrenoceptor hypersensitivity on stopping slow‐release oxprenolol we have demonstrated it after stopping slow release as well as conventional oxprenolol.
No effect of food intake on clobazam absorption.
Authors: Cenraud B , Guyot M , Levy RH , Brachet‐Liermain A , Morselli PL , Moreland TA , Loiseau P
Published: July 2012

The kinetics of clobazam taken 3 h before, during, and 3 h after a standard hospital meal were studied in six healthy volunteers. Peak plasma levels were significantly lower when the drug was taken with or after meals suggesting that the rate of absorption was reduced by food. The mean area under the concentration vs time curve was not affected by the time of drug administration indicating that the meal had no effect upon the extent of absorption.
Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants.
Authors: Brodie MJ , Forrest G , Rapeport WG
Published: July 2012

Steady state carbamazepine (CBZ) plasma concentrations were similar in 15 epileptics receiving monotherapy and in 24 patients taking CBZ in combination with one other anticonvulsant. The ratio of CBZ 10, 11‐ epoxide (CBZ‐E) to the parent drug was significantly higher (P less than 0.01) in those patients taking concomitant phenytoin (n = 9), phenobarbitone or primidone (n = 9), and valproic acid (n = 6) than in the patients receiving CBZ alone. In the monotherapy group, there was a significant correlation between CBZ‐E/CBZ ratio and the concentration of the parent drug (P less than 0.05). If CBZ‐E has equipotent anticonvulsant properties to CBZ in man as is the case in animal models, routine CBZ‐E concentrations may provide further refinement in the therapeutic drug monitoring of CBZ.