bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of age, sex and body weight on the dapsone acetylation phenotype.
Authors: Philip PA , Gayed SL , Rogers HJ , Crome P
Published: July 2012

The acetylation of dapsone (DDS) was determined by estimation of the ratio of monoacetyldapsone (MADDS) to DDS concentrations in plasma following a single dose of DDS in 337 white British subjects (193 female; 144 male). The percentage of slow DDS acetylators in the whole group was 60.3%. There was no statistically significant difference in this proportion between 191 elderly subjects (age greater than 65 years) and 143 young subjects (age less than 30 years). Although there was a small (66.3%) but significant (P = 0.033) preponderance of slow acetylators in the young male group there was no difference in the distribution of acetylator phenotypes between the sexes among either the elderly group or in the whole population studied. No correlation was found between absolute body weight and MADDS/DDS ratios.
Lack of influence of cigarette smoking on triazolam pharmacokinetics.
Authors: Ochs HR , Greenblatt DJ , Burstein ES
Published: July 2012

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15‐30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml‐1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half‐life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min‐1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.
Comparative study of once‐daily administration of captopril 50 mg, hydrochlorothiazide 25 mg and their combination in mild to moderate hypertension.
Authors: Kayanakis JG , Baulac L
Published: July 2012

Two hundred and eleven patients with mild or moderate hypertension, mean age 53.5 +/‐ 9.5 years (range 24‐70) were randomised double‐blind to treatment with either captopril 50 mg (C50), hydrochlorothiazide 25 mg (HCTZ 25), the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg (C50/HCTZ 25) or placebo. Blood pressure, heart rate, body weight and side effects were assessed at the end of the run‐in period on placebo and after 4, 6, 8 weeks treatment at the same time, 20‐24 h after the last dosing. Routine biochemical examinations were carried out on all patients after the placebo period as well as after 4 and 8 weeks. Blood pressure significantly decreased in all groups, but the mean percentage change from baseline was highly statistically significant at 8 weeks, for C50 and C50/HCTZ 25 groups. The incidence of clinical side effects was low and not statistically different for the four groups with few specific adverse effects (one transient alteration of taste in captopril group). No patient was withdrawn from the study due to side effects. A better anti‐ hypertensive efficacy was obtained with the fixed combination captopril 50 mg/hydrochlorothiazide 25 mg once daily compared to placebo or each component alone, and without any difference in side effects.
Observations on spontaneous improvement in patients with podagra: implications for therapeutic trials of non‐steroidal anti‐inflammatory drugs.
Authors: Bellamy N , Downie WW , Buchanan WW
Published: July 2012

1 The natural history of acute gouty arthritis was studied in 11 volunteers with podagra. 2 Two patients withdrew from the study on day 4 because of severe persistent pain. Of the remaining patients all showed some improvement in pain by day 5 and in swelling by day 7. Tenderness improved in seven patients by day 7 but two continued to experience the same amount of discomfort as at trial entry. In spite of these improvements only three patients noted resolution of their pain during the study period. 3 These data indicate that while the majority of patients show spontaneous improvement, resolution is unlikely over a period of 7 days without the use of effective non‐steroidal anti‐ inflammatory medication. 4 Documentation of the natural history of the acute gouty attack may assist clinical investigators in interpreting the results of uncontrolled evaluations of non‐steroidal anti‐ inflammatory drugs.
Haemodynamic effects of atenolol, labetalol, pindolol and captopril: a comparison in hypertensive patients with special reference to changes in limb blood flow, heart rate and left ventricular function.
Authors: Roberts DH , Tsao Y , Grimmer SF , Winstanley PA , Orme ML , Breckenridge AM
Published: July 2012

1 To compare the haemodynamic effects of secondary characteristics of beta‐adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with previously untreated mild to moderate hypertension were prescribed either atenolol 50‐100 mg day‐1, labetalol 200‐800 mg day‐1, pindolol 10‐30 mg day‐1 or captopril 25‐100 mg day‐1 and observed for 6 months. 2 Over this period: (a) All four drugs produced similar reductions in blood pressure at rest (P less than or equal to 0.01) and after exercise (P less than or equal to 0.01). (b) All four drugs significantly decreased resting forearm (P less than or equal to 0.01) and calf blood flow (P less than or equal to 0.01). They all also caused a significant reduction in the increased calf blood flow following exercise (P less than or equal to 0.01). (c) No drug produced a change in resting forearm vascular resistance, while resting calf vascular resistance was decreased by captopril and pindolol, unaltered by labetalol and increased by atenolol. Post‐exercise calf vascular resistance was increased by atenolol, labetalol and pindolol but unaltered by captopril. (d) Although all four drugs produced a fall in resting heart rate this was significantly greater for atenolol and labetalol (P less than or equal to 0.01). All four treatments however significantly reduced the increase in heart rate following exercise (P less than or equal to 0.01). (e) No drug produced any significant change in resting and post‐exercise stroke volume/ejection fraction. 3 It is concluded that despite differing modes of action all four drugs reduce limb blood flow. This primarily appears to be a consequence of reduced perfusion pressure associated with limited autoregulation of skeletal muscle circulation. The reduction in arterial vascular resistance produced by captopril and pindolol is inconsistent and does not appear of major benefit in preserving limb blood flow. The reduction in perfusion with the agents studied may in part be related to a fall in cardiac output associated with decreased heart rate. This suggests that captopril may exert antisympathetic activity when used as an antihypertensive agent.
The penetration of erythromycin into human bronchial mucosa.
Authors: Mattie H , Hoogeterp JJ , Kaajan JP , Hermans J
Published: July 2012

1 In this paper the pharmacokinetic relation between concentrations of erythromycin in plasma and in bronchial mucosa was established. 2 Sixteen patients undergoing bronchoscopy received 1 g erythromycin by continuous infusion in 30 min. 3 Two bronchial mucosal samples were taken from each patient sometime after drug administration. Concentrations were determined in the mucosal sample and in several plasma samples collected at different times before the mucosal sample. 4 Rate constants for the distribution between plasma and tissue were calculated on the basis of the assumption of passive diffusion of the free drug. 5 Mean values of the distribution rate constants, calculated by a nonlinear curve fitting procedure, were 2.40 h‐1 for distribution from plasma to tissue and 1.28 h‐1 for that from tissue to plasma. 6 These values correspond to a half‐life for the distribution of the free drug of 33 min and a free fraction of the drug in mucosal tissue of 0.20.
Drug interaction between propafenone and metoprolol.
Authors: Wagner F , Kalusche D , Trenk D , Jahnchen E , Roskamm H
Published: July 2012

1 The steady‐state plasma concentrations of metoprolol and propafenone were determined in patients being treated with one of these drugs alone and during combined treatment with both drugs. In addition, single dose studies with metoprolol, propafenone and the combination of both drugs were performed in healthy volunteers to determine the pharmacokinetics and the time course of beta‐adrenoceptor blocking activity. 2 In four patients being treated with metoprolol first and subsequently with propafenone in addition steady‐state levels of metoprolol increased two to five fold with simultaneous treatment with propafenone. 3 In four patients being treated with the drug combination first and thereafter with propafenone alone no changes in the steady‐state levels of propafenone were observed between both treatment periods. 4 Adverse effects of the drug combination were observed in two patients (one patient experienced severe nightmares and the other left ventricular failure). 5 When single oral doses of metoprolol (50 mg) and propafenone (150 mg) and the combination of both were administered to healthy subjects, an approximately two‐fold decrease of the oral clearance of metoprolol was seen when propafenone was given in addition. No conclusive changes in the pharmacokinetics of propafenone could be detected in the presence of metoprolol. 6 Duration of beta‐ adrenoceptor blocking activity of a single dose of metoprolol in healthy volunteers as measured by reduction of exercise‐induced tachycardia increased when propafenone was given in addition. 7 The dose of metoprolol should be reduced when propafenone is given in addition.
Exercise‐induced hyperkalaemia: effects of beta‐adrenoceptor blocker vs diuretic.
Authors: Cleroux J , Peterson M , Leenen FH
Published: July 2012

Four groups of eight normotensive male volunteers performed a 60 min bicycle exercise test before and after 2 weeks of either placebo, hydrochlorothiazide (HCTZ, 25 mg day‐1), pindolol (PIND, 10 mg day‐1) or both drugs in combination using a double‐blind, randomized design. During exercise on placebo serum potassium increased by 0.8 mmol l‐1. HCTZ significantly decreased potassium levels at rest and during exercise by 0.2 mmol l‐1. PIND did not affect resting potassium levels but potentiated the increase by 0.4 mmol l‐1 at the end of exercise, and delayed the return to normal of serum potassium after exercise. The addition of HCTZ to PIND offset the potentiating effect of PIND on exercise‐induced hyperkalaemia (only after prolonged exercise) and accelerated the return to baseline after exercise. The results indicate that the hypokalaemic effect of HCTZ can oppose the hyperkalaemic effect of PIND during prolonged physical exercise and particularly during recovery.
Tolbutamide 4‐hydroxylase activity of human liver microsomes: effect of inhibitors.
Authors: Purba HS , Back DJ , Orme ML
Published: July 2012

Eight samples of human liver have been characterised for microsomal protein content, cytochrome P‐450 content, tolbutamide 4‐hydroxylase and ethinyloestradiol 2‐hydroxylase activities. Cytochrome P‐450 content correlated significantly with ethinyloestradiol 2‐hydroxylase activity but not with tolbutamide 4‐hydroxylase activity. There was no significant correlation between ethinyloestradiol 2‐hydroxylase and tolbutamide 4‐hydroxylase activities. The maximum tolbutamide 4‐ hydroxylase activity was 0.45 nmol min‐1 mg‐1 microsomal protein, with a Km value of 74 microM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non‐competitive or mixed non‐competitive inhibitors of tolbutamide 4‐hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P‐450 which appears to be distinct from those isozymes metabolising many other drugs.
Cimetidine increases serum mebendazole concentrations. Implications for treatment of hepatic hydatid cysts.
Authors: Bekhti A , Pirotte J
Published: July 2012

In eight patients (five with peptic ulcer disease and three with hydatid cysts), the [14C]‐aminopyrine breath test (ABT) and maximum serum concentration of mebendazole following a dose of 1.5 g of mebendazole three times daily were determined before and after treatment with cimetidine (400 mg three times daily for 30 days). Serum mebendazole concentrations were measured in blood samples taken 2 h after each drug intake. Cimetidine lowered the 14CO2 specific activity (SA) at 1 h (P less than 0.01) and increased the maximum serum concentration of mebendazole (P less than 0.01). A significant correlation was found between SA at 1 h and the highest concentration of mebendazole before (r = −0.71, P less than 0.05) and after (r = − 0.82, P less than 0.05) cimetidine ingestion. Combined administration of cimetidine and mebendazole resulted in the complete resolution of previously unresponsive hydatid cysts.
Non‐invasive instrumental techniques to detect terfenadine and temelastine induced suppression of histamine weals in man.
Authors: Shall L , Marks R
Published: July 2012

1. The effectiveness of chronic dosing with temelastine (SK&F 93944) 75 mg twice daily and terfenadine 60 mg twice daily compared with placebo in inhibiting the weal and flare response to intradermal histamine was assessed using non‐invasive objective assessment techniques. 2. The mean weal thickness, as measured by the A‐scan pulsed ultrasound device, was significantly decreased by both temelastine and terfenadine when compared with placebo. 3. There was a significant reduction in both the areas of the weal and the weal and flare, as measured by a digitizing tablet linked to a microcomputer, following treatment with temelastine and terfenadine compared with placebo and also between temelastine and terfenadine. 4. No significant difference was found in blood flow in the weal or flare as measured by the laser doppler flowmeter among any of the groups tested. 5. The ultrasound and digitizer techniques aid objectivity and precision in the investigation of the effects of drugs on histamine induced weals. 6. Temelastine and terfenadine were found to possess antihistaminic effects on histamine induced weal and flare in the skin.
Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.
Authors: Gregov D , Jenkins A , Duncan E , Siebert D , Rodgers S , Duncan B , Bochner F , Lloyd J
Published: July 2012

1. The effect of dipyridamole on platelet function was measured in twelve normal subjects given 150 or 200 mg tablets as single and multiple doses, and in six subjects given single doses of 25, 50 and 100 mg and multiple doses of 50 mg 8 hourly. 2. Platelet aggregation was measured in response to ADP and collagen. In the subjects given 150/200 mg, the platelets were assayed for content of cyclic AMP and for formation of thromboxane after addition of collagen. The responses to ADP and collagen and the cyclic AMP content were assessed in both the presence and absence of added PGE1. The pharmacokinetics of dipyridamole were studied in all subjects. 3. One hour after 150/200 mg single doses of dipyridamole there was significant inhibition of platelet aggregation in response to both collagen and ADP. There was no detectable effect on aggregation at other time points or with lower doses of dipyridamole. The addition of PGE1 to platelets prior to testing did not enhance the effect of dipyridamole on platelet aggregation. 4. In multiple doses, dipyridamole (150/200 mg twice daily for 11 days) had no detectable effect on platelet aggregation. 5. Dipyridamole did not have any effect on platelet cyclic AMP content, whether or not PGE1 was added prior to assay. 6. Dipyridamole did not affect platelet thromboxane formation. 7. Plasma dipyridamole concentrations were maximal 1‐2 h after ingestion, at the same time that inhibition of platelet aggregation was detected. The concentrations declined in a biexponential fashion, with a terminal half life of 24.1 +/‐ 1.9 h (mean +/‐ s.e. mean). In six of the 17 subjects, the mean steady state plasma concentration was less than 75% of the value predicted from the single dose data.
Converting‐enzyme inhibition buffers the counter‐regulatory response to acute administration of nicardipine.
Authors: Bellet M , Sassano P , Guyenne T , Corvol P , Menard J
Published: July 2012

1. To investigate the interaction of angiotensin‐converting‐enzyme (ACE) inhibitor and calcium antagonist, we conducted a double‐blind randomized, placebo‐controlled crossover study of a new ACE inhibitor (CGS 14824 A, 20 mg) during intravenous administration (i.v.) of nicardipine in eight normotensive healthy subjects. Nicardipine was infused to give cumulative doses of 1.25, 3.75, and 8.75 mg after 10, 20 and 30 min. 2. ACE inhibition was demonstrated 24 h after the first CGS 14 824 A intake (61%). Three hours after the second dose this inhibition was more marked (98%). 3. I.v. nicardipine administration induced a significant and similar fall in systolic or diastolic blood pressure with and without ACE activity (−3/−6 vs −2/−8%), while tachycardia was significantly decreased by CGS 14 824 A (+14 vs +30%, P less than 0.02). The increase of plasma noradrenaline was also significantly blunted (+1.8 +/−0.3 vs +3.1 +/−0.7 pmol ml‐1, P less than 0.05). 4. Active and total plasma renin increased at the end of nicardipine infusion in the presence or absence of ACE inhibition. Inactive renin did not increase after nicardipine infusion under placebo. It was higher 3 h after the second intake of CGS 14 824 A and then increased after nicardipine infusion. 5. The rise in plasma aldosterone during i.v. calcium antagonist infusion was diminished after ACE inhibition (126 +/−39 vs 277 +/−120 pmol l−1, P less than 0.02). 6. In conclusion, converting‐enzyme inhibition buffers the rise in heart rate, plasma noradrenaline and plasma aldosterone induced by acute calcium blockade.
Inhibition of exercise‐induced asthma by nifedipine: a dose‐response study.
Authors: Rafferty P , Varley JG , Edwards JS , Holgate ST
Published: July 2012

1. The effect of three single doses of nifedipine on exercise‐induced asthma has been examined in 11 asthmatic subjects. 2. On four separate days patients undertook 6 min of exercise on a treadmill 30 min after taking placebo or nifedipine 10, 20 or 30 mg administered double‐blind and in random order. 3. Nifedipine had no significant effect on resting FEV1 measurements. 4. Nifedipine, in doses of 10, 20 and 30 mg, inhibited exercise induced bronchoconstriction, reducing the maximum fall in FEV1 from 30.8 +/‐ 3.5% after placebo to 21.9 +/‐ 3.4% (NS), 13 +/‐ 3.4% (P less than 0.01) and 15 +/‐ 3.9% (P less than 0.01) respectively. 5. This study has shown that the protective effect of nifedipine against exercise‐induced asthma is dose related with the maximum inhibitory effect being observed with a single dose of 20 mg.
Lack of correlation between methotrexate concentrations in serum, saliva and sweat after 24 h methotrexate infusions.
Authors: Schroder H , Jensen KB , Brandsborg M
Published: July 2012

1 Methotrexate (MTX) concentrations were studied in serum, mixed saliva and sweat during and after 24 h continuous MTX infusions (0.5‐6 g m‐2) in 14 patients with various malignant diseases. 2 The serum‐MTX concentrations declined in a biphasic manner, but the MTX elimination in saliva and sweat varied to a much greater extent. 3 Saliva/serum and sweat/serum ratios during the MTX infusion were 2.3% and 0.55% respectively. The ratios had increased significantly 20 and 44 h postinfusion. 4 No correlations were demonstrated between salivary‐ and serum‐MTX concentrations during the MTX infusion or 20 and 44 h later. 5 Markedly delayed renal MTX excretions were demonstrated in two patients. In one of them the salivary MTX elimination was also retarded, whereas this was not seen in the other one. 6 We conclude that measurements of MTX concentrations in mixed saliva cannot substitute for serum‐MTX determinations in the monitoring of patients after 24 h MTX infusions.
Application of stable isotope methodology to study the pharmacokinetics, bioavailability and metabolism of nitrendipine after i.v. and p.o. administration.
Authors: Mikus G , Fischer C , Heuer B , Langen C , Eichelbaum M
Published: July 2012

1. The pharmacokinetics, bioavailability and metabolism of nitrendipine were studied in six healthy volunteers (three females, three males) using [13C4]‐nitrendipine as a biological internal standard. In the first study the drug was administered simultaneously by the i.v. [13C4] and p.o. (solution) routes and in a second study two oral preparations (13C4‐solution and commercial tablet) were administered, also simultaneously. 2. The mean terminal elimination half‐life was 8.3 +/‐ 3.2 h (range 3.4 to 16 h) with no differences between the intravenous and oral route of administration. Total plasma clearance averaged 18.7 +/‐ 0.6 ml min‐1 kg‐1 and volume of distribution at steady state 5.4 +/‐ 2.4 1 kg‐1. 3. Following oral administration of nitrendipine solution the percentage of dose absorbed was 88.4 +/‐ 16.0% based on urinary excretion of metabolites. Despite its almost complete absorption, absolute bioavailability of the solution was only 22.6 +/‐ 6.7% due to extensive presystemic elimination. The bioavailability of the commercial tablet relative to the solution was 82.2 +/‐ 20.3%. 4. Both after i.v. and oral administration the drug was extensively metabolized with less than 0.5% of the dose excreted as unchanged drug in urine. Cleavage of the two ester functions in position 3 and 5, respectively, to carboxylic acids and further hydroxylation of the methyl groups in position 2 and 6 of the pyridine ring to the corresponding hydroxymethyl carboxylic acids constituted the major urinary metabolites accounting for 35.0 +/‐ 16.5% (i.v.) and 32.8 +/‐ 20.4% (p.o.), respectively, of the dose administered. 5. Binding of nitrendipine to plasma proteins was high with a fraction unbound of only 0.02 +/‐ 0.012 (range 0.011 to 0.036).
An assessment of the partial agonist activity of Ro 31‐1118, flusoxolol and pindolol in man.
Authors: McCaffrey PM , Riddell JG , Shanks RG
Published: July 2012

1. The effects of single oral doses of three beta‐adrenoceptor partial agonists (Ro 31‐1118, flusoxolol and pindolol), two beta‐adrenoceptor antagonists (propranolol and atenolol), two beta‐adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31‐ 1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31‐1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta‐adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31‐1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31‐1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31‐1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta‐adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta‐adrenoceptor antagonists. 10. While Ro 31‐ 1118 and flusoxolol are antagonists mainly at the beta 1‐adrenoceptor they have agonist activity at both beta 1‐ and beta 2 adrenoceptors. 11. While pindolol is a non‐selective antagonist its agonist activity is mainly at the beta 2‐adrenoceptor.
Development of optimal infusion regimens for epoprostenol using radio labelled platelet uptake over atherosclerotic lesions in man.
Authors: Sinzinger H , Fitscha P , Kaliman J , Silberbauer K , O'Grady J
Published: July 2012

1. Epoprostenol (prostacyclin, PGI2) has been evaluated in clinical trials in peripheral vascular disease and other conditions chiefly on the basis of its platelet inhibitory properties. These therapeutic evaluations have proceeded in the absence of evidence as to the optimum infusion regimen for epoprostenol and the choice of schedules of administration has been arbitrary. We have tried to establish an optimum infusion regimen in patients with peripheral vascular disease in terms of maximal inhibition of platelet deposition on atherosclerotic lesions in vivo together with maximal inhibition of platelet aggregation ex vivo. 2. One hundred and twenty three patients with atherosclerotic peripheral vascular disease and increased platelet uptake at atherosclerotic sites were selected. Epoprostenol was administered at a fixed dose of 5 mg kg‐1 min‐1 for 0.5‐24 h daily for 3‐7 days. 3. Infusion of epoprostenol for 6 h daily for up to 5 days caused maximum decrease in platelet uptake without tachyphylaxis and without loss of the inhibitory effect of epoprostenol on platelet aggregation responses. Longer daily infusion periods were associated with progressive loss of the anti‐aggregatory effect of epoprostenol without any greater decrease in platelet uptake. Shorter daily infusion periods produced smaller decreases in platelet uptake.
Antiplatelet effects of oral diltiazem, propranolol, and their combination.
Authors: Ring ME , Corrigan JJ , Fenster PE
Published: July 2012

1. The antiplatelet effects of a single oral dose of the calcium entry blocker diltiazem (60 mg), the beta‐adrenoceptor blocker propranolol (40 mg), and their combination were studied in five healthy subjects. 2. Platelet aggregation and ATP release induced by adrenaline and ADP and ADP induced platelet thromboxane A2 generation were significantly inhibited (P less than 0.05) by either diltiazem or propranolol, although propranolol tended to have greater inhibitory effects on platelet function than diltiazem that did not reach statistical significance. 3. Combination therapy resulted in additive antiplatelet effects that were significantly (P less than 0.05) greater than either drug alone. 4. These data indicate that combined administration of a calcium entry blocker and a beta‐adrenoceptor blocker results in additive inhibitory effects on platelet function. These effects may mediate part of the therapeutic efficacy of combination therapy in patients with coronary artery disease.
Inter‐relationship among individual vitamin K‐dependent clotting factors at different levels of anticoagulation.
Authors: Chan E , Aarons L , Serlin M , Breckenridge A , Rowland M
Published: July 2012

1. The effect of subtherapeutic doses of warfarin on the activities of the four vitamin K‐dependent clotting factors was studied at steady state in five patients each of whom had completed a therapeutic course of anticoagulation. 2. The four clotting factor activities were shown to be depressed to a similar extent for a given dose of warfarin. 3. The prothrombin complex activity was significantly lower than that of any of the clotting factors.
Parkinson's disease in the elderly: response to and optimal spacing of night time dosing with levodopa.
Authors: Leeman AL , O'Neill CJ , Nicholson PW , Deshmukh AA , Denham MJ , Royston JP , Dobbs RJ , Dobbs SM
Published: July 2012

1. Insomnia is an even more frequent complaint in elderly patients with Parkinson's disease than might be expected from the effect of age alone on sleep. 2. A double‐blind, placebo‐controlled trial in eleven patients with Parkinson's disease of mean (s.d.) age 80(5) years, showed that nocturnal dosing with levodopa produced a clinically significant improvement in sleep both as assessed subjectively and by measurement of number of spontaneous moves in bed. 3. Despite the long interval between tablet administration and morning assessment, walking time was faster on mornings following active treatment.
Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers.
Authors: Lin JH , Chremos AN , Chiou R , Yeh KC , Williams R
Published: July 2012

The comparative effect of famotidine or cimetidine on theophylline disposition was determined in healthy volunteers. Cimetidine, but not famotidine, caused a reduction in the rate of elimination of theophylline. The mean total body clearance of theophylline was reduced from 57.6 ml min‐1 before cimetidine to 39.5 ml min‐1 during cimetidine; and the half‐life was prolonged from 8.7 h before cimetidine to 12 h during cimetidine. The volume of distribution and renal excretion of theophylline were not affected by either famotidine or cimetidine.
Meptazinol and pentazocine: plasma catecholamines and other effects in healthy volunteers.
Authors: Manner T , Kanto J , Scheinin H , Scheinin M
Published: July 2012

1. This double‐blind, random‐order study was designed to compare the clinical effects and the plasma catecholamine responses after i.v. administration of meptazinol at doses 0.7 and 1.4 mg kg‐1, pentazocine at doses 0.3 and 0.6 mg kg‐1 and saline placebo to six healthy volunteers. 2. Mean arterial pressure was not affected by either drug. Heart rate showed slight drug‐related changes. Respiratory rate fell slightly with both drugs, but independently of dose. 3. The critical flicker fusion threshold‐test and Maddox wing readings could both clearly differentiate active drugs from placebo. Meptazinol caused more nausea and dysphoria as expressed with visual analogue scales. Both analgesics caused short‐lived feelings of euphoria. 4. After pentazocine plasma noradrenaline increased almost two‐fold in 10‐20 min. The effect of meptazinol was slightly smaller, whereas meptazinol caused a pronounced increase in plasma adrenaline concentrations in two of six subjects. Pentazocine had a smaller, but significant effect on plasma adrenaline. 5. We conclude that the effects of meptazinol in healthy volunteers do not differ markedly from those of pentazocine, although it may cause more nausea and dysphoria. The pronounced increase in plasma adrenaline concentrations in two of six subjects calls for caution in its use in patients with cardiac diseases.
Treatment of bronchial asthma with terfenadine; a randomized controlled trial.
Authors: Taytard A , Beaumont D , Pujet JC , Sapene M , Lewis PJ
Published: July 2012

1. Terfenadine, a histamine H1‐receptor antagonist, was studied in 52 patients with stable mild perennial asthma with an allergic basis. 2. After a placebo run‐in period, patients were randomly allocated to either terfenadine 120 mg twice daily or placebo. After 2 weeks they were crossed over to the other treatment. Forty‐six patients completed the study. 3. Terfenadine was significantly more effective than placebo as measured by peak expiratory flows and by symptom scores. 4. These results suggest that histamine may play a more significant role in asthmatic bronchoconstriction than is currently recognised.
Modification of intracellular glucose metabolism in human skin fibroblast preincubated with p‐chlorophenoxyisobutyrate.
Authors: Nishide T , Shirai K , Saito Y , Yoshida S
Published: July 2012

1. The effect of p‐chlorophenoxyisobutyrate (CPIB) on glucose metabolism human skin fibroblasts was examined. 2. CPIB increased the incorporation of 2‐deoxy‐D‐[U‐14C]glucose into skin fibroblasts. 3. CPIB decreased [14C]CO2 production from D‐[U‐14C]glucose but did not affect pyruvate dehydrogenase activity. 4. CPIB reduced fatty acid oxidation activity and cholesterol synthesis but increased triglyceride synthesis. 5. These effects of CPIB were observed both in the presence and in the absence of insulin. 6. One possible mechanism of CPIB on reducing plasma glucose may be due to the increase of glucose incorporation into the cells and triglyceride synthesis in the cells.
Disopyramide pharmacokinetics and metabolism: effect of inducers.
Authors: Kapil RP , Axelson JE , Mansfield IL , Edwards DJ , McErlane B , Mason MA , Lalka D , Kerr CR
Published: July 2012

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non‐smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/− 2.0 micrograms ml‐1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1‐acid glycoprotein (AGP). 2. Smokers and non‐smokers exhibited similar half‐ lives (6.48 +/− 1.49 vs 6.66 +/− 1.02 h), apparent total body clearances (0.100 +/− 0.020 vs 0.117 +/− 0.034 l h‐1 kg‐1), mean renal clearances (0.043 +/− 0.0093 vs 0.057 +/− 0.013 l h‐1 kg‐1) and apparent intrinsic metabolic clearances (0.057 +/− 0.015 vs 0.060 +/− 0.024 l h‐1 kg‐1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non‐smokers resulted in an increase in the AUC of the active metabolite N‐despropyl disopyramide (MND), but not significantly (3.8 +/− 1.6 vs 4.1 +/− 2.3 micrograms ml‐1 h). Similar results were observed in smokers (3.5 +/− 1.4 vs 3.9 +/− 2.0 micrograms ml‐1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non‐smokers was significantly decreased upon phenobarbitone treatment (43 +/− 6% vs 25 +/− 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/− 6% vs 31 +/− 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/− 19.9 mg dl‐1 vs 68.0 +/− 40.7 mg dl‐1) or smokers (64.5 +/− 15.7 vs 67.9 +/− 14.9). Similarly, when AGP concentration was estimated in serum from non‐ smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/− 1.3 vs 47.9 +/− 16.8 mg dl‐1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.
Human orthostatic reflexes after taking temazepam at night.
Authors: Patrick JM , Dikshit MB , Macdonald IA , Fentem PH
Published: July 2012

1. Cardiovascular orthostatic reflexes have been studied at night in 12 healthy male subjects who were given two soft gelatin capsules each containing 0 or 10 mg temazepam at 21.30 h. 2. The changes in heart rate, blood pressure and forearm blood flow on consecutive 5 min exposures to lower body negative pressure (suction) at 30, 40 and 50 mm Hg were measured before and then 1.5 and 9.5 h after giving doses of 10 or 20 mg temazepam in a placebo‐controlled double‐blind cross‐over study. 3. Pre‐suction resting values were not affected by temazepam, but 1.5 h after giving the capsules there were significant differences in the responses to suction between the placebo and 20 mg temazepam experiments: the tachycardia after 20 mg temazepam was about one‐third greater and the forearm vasoconstriction was about 50% less. The effect of the 10 mg dose was equivocal. No residual effects were detected the next morning. 4. These alterations in orthostatic reflexes soon after the administration of temazepam at night did not impair the maintenance of arterial blood pressure in these healthy subjects.
Is the ISA of pindolol beta 2‐adrenoceptor selective?
Authors: Aellig WH , Clark BJ
Published: July 2012

1. Pindolol is a beta‐adrenoceptor blocking drug with ISA (also called partial agonist activity). This means that in addition to blocking the effects of beta‐adrenoceptor agonists, it produces some stimulation of beta‐adrenoceptors. 2. In vitro studies with pindolol show that its maximum stimulant action is similar to that of isoprenaline in tissues possessing mainly beta 2‐adrenoceptors, but is negligible in tissues possessing mainly beta 1‐adrenoceptors. This suggests selective stimulation of beta 2‐adrenoceptors. 3. In man the arteriodilator effects observed after intra‐arterially infused pindolol at concentrations within the same range as those producing an antihypertensive effect also suggest a stimulant action on vascular beta 2‐adrenoceptors. 4. The fact that pindolol prevents the reduction of resting heart rate and cardiac output observed after drugs lacking ISA at first sight suggests stimulation of cardiac beta 1‐ adrenoceptors. However, human atria possess not only beta 1‐ but also beta 2‐adrenoceptors, stimulation of which would produce the same effect. 5. Although all beta‐adrenoceptor antagonists lower blood pressure, recent experiments have shown that those agents with combined beta 1‐adrenoceptor blocking activity and ISA at those receptors are less effective. This observation lends weight to the thesis that pindolol does not stimulate beta 1‐adrenoceptors since it lowers blood pressure as effectively as drugs lacking ISA. 6. The evidence available therefore suggests that although pindolol blocks both beta 1‐ and beta 2‐subtypes, it selectively stimulates beta 2‐adrenoceptors.
Milk transfer of phenoxymethylpenicillin during puerperal mastitis.
Authors: Matheson I , Samseth M , Loberg R , Faegri A , Prentice A
Published: July 2012

1 The milk excretion of phenoxymethylpenicillin (PMP) was studied from both breasts in patients with mastitis (n = 12) and healthy volunteers (controls, n = 4) to investigate the hypothesis that milk transfer of PMP is higher in mastitic than in non‐mastitic breasts. 2 Patients were included according to clinical symptoms of mastitis. Milk (and serum from controls) were sampled 0, 1, 2, 3, 4, 6 and 8 h after a single oral dose of 1320 mg PMP. Penicillin concentrations in milk and serum were measured by an agar diffusion technique. 3 Maximum milk concentrations (Cmax) of PMP in patients were higher (P less than 0.05) in mastitic than in non‐mastitic breasts. The latter concentrations were higher (P less than 0.05) than those in breast milk from healthy controls. In milk from the mastitis patients (both breasts) the Cmax was reached after 2 h with a subsequent rapid decline in concentration. In milk from the healthy controls the PMP concentration reached a plateau after 4 h. The area under the milk concentration vs time curve (AUC0‐8h) was not different for mastitic vs non‐mastitic breast milk in patients nor for mastitic vs control breast milk. This can be explained by higher rates of appearance and disappearance of PMP in the breast milk of mastitis patients compared with healthy controls. In mastitic breast milk there was a moderate (P less than 0.01) increase in sodium and albumin compared with non‐mastitic milk. However, milk potassium, glucose and lactose values were within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)
Saturation of the tubular excretion of beta‐lactam antibiotics.
Authors: Bins JW , Mattie H
Published: July 2012

1 The saturability of the tubular excretion of cloxacillin, benzylpenicillin and cephradine was investigated. 2 Volunteers received a continuous infusion of one of the antibiotics at increasing infusion rates in order to maintain constant plasma concentrations at three different levels. Blood and urine samples were taken every 30 min. Sufficient urinary flow was ensured by a saline infusion (500 ml h‐1). 3 Renal clearance of the antibiotic was calculated for the non‐protein bound fraction of the drug. 4 Tubular clearance and tubular excretion rate were estimated by using the renal clearance of the antibiotic minus the glomerular filtration rate; the latter was considered to be equal to creatinine clearance. 5 Data were fitted to a Scatchard transformation and, by nonlinear methods, to a Michaelis‐Menten equation. 6 Parameters of saturability, i.e. EC50 and maximal tubular excretion rate, were established. The values found for EC50 were 7.7, 93.0 and 266 mg l‐1 for cloxacillin, benzylpenicillin and cephradine, respectively. The values calculated for the maximal tubular excretion rate were 1017, 5535 and 4537 mg h‐1, respectively.
Acute inotropic effects of intravenous nifedipine and its vehicle compared with saline: a double‐blind study of systolic time intervals in normal subjects.
Authors: Walley TJ , Heagerty AM , Woods KL , Bing RF , Pohl JE , Barnett DB
Published: July 2012

1. The inotropic effects of intravenous nifedipine and its vehicle were studied noninvasively in a double‐blind placebo controlled crossover fashion using systolic time intervals in 12 normal subjects. 2. Nifedipine caused vasodilation, a fall in systolic and diastolic blood pressure, and increased heart rate. The vehicle alone caused vasodilation and decreased systolic blood pressure, without a change in heart rate. 3. Nifedipine increased left ventricular ejection time (LVET) and decreased pre‐ejection period (PEP) and the ratio PEP/LVET, whereas the vehicle alone had the opposite effect. Neither treatment affected the total duration of electromechanical systole. 4. These results suggest that the vehicle has a negative inotropic effect, which is overcome by the indirect positive inotropic effect of nifedipine when they are administered together systemically.
Pulmonary disposition of pethidine in postoperative patients.
Authors: Persson MP , Hartvig P , Wiklund L , Paalzow L
Published: July 2012

1. Two methods of pethidine administration, namely constant‐rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2. Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3. The mean total plasma clearance was 810 ml min‐1 and the volume of distribution was 3.11 kg‐1. 4. A flow model was used to describe the disposition of pethidine in man. The concentration‐time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5. Constant‐rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.
Inhibition of the enzyme, GABA‐aminotransferase in human platelets by vigabatrin, a potential antiepileptic drug.
Authors: Rimmer E , Kongola G , Richens A
Published: July 2012

1. The effect of the new antiepileptic drug, vigabatrin (gamma‐vinyl GABA), on the platelet enzyme, GABA‐aminotransferase (GABA‐T) was investigated in volunteers and patients. Platelets GABA‐T activity was assayed using a radioenzymic method. 2. Three single oral doses of vigabatrin (1 g, 2 g and 4 g) were given to six healthy male volunteers in an open randomised cross over study and compared with a baseline period preceding the three treatments. 3. Significant inhibition of the platelet GABA‐T was produced by treatment with all three doses and a dose‐response relationship was demonstrated. The minimum enzyme activities after 1 g, 2 g and 4 g doses were 43%, 30% and 21% respectively compared with the control values. 4. A significant depression of enzyme activity occurred at 30 min after drug administration and the values remained below control values for 72 h post‐dose, outlasting the presence of the drug itself in the plasma. 5. Eight patients with chronic refractory epilepsy were treated with vigabatrin for 6 weeks. After taking the 2 g daily dose for 1 week there was a marked reduction in platelet enzyme activity in all subjects but the enzyme inhibition produced by the 3 g dose was not significantly different from that produced by the 2 g dose, even after 4 weeks treatment with the larger dose. The mean enzyme activity was approximately 30% throughout the active treatment period. One week after stopping vigabatrin, the enzyme levels were not significantly different from the baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption of 5‐aminosalicylic acid from colon and rectum.
Authors: Bondesen S , Schou JB , Pedersen V , Rafiolsadat Z , Hansen SH , Hvidberg EF
Published: July 2012

In order to clarify the characteristics of absorption of 5‐ aminosalicylic acid (5‐ASA) from the colon, a neutral solution was instilled into the right part of the colon and the rectum, respectively, in six volunteers. A laxative (bisacodyl) and liquid meals were given prior to each instillation. No significant difference could be demonstrated between the two parts of the large bowel, but the absorption was considerably restricted compared with previous results obtained from the jejunum. The results confirm in a direct manner earlier observations on 5‐ASA released from sulphasalazine.
Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics and first dose effect of prazosin.
Authors: Lennard MS , McGourty JC , Silas JH
Published: July 2012

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of a single oral dose of prazosin has been studied in eight hypertensive patients (four extensive and four poor metabolisers). No significant differences between the two phenotypes were observed in either the area under the plasma prazosin concentration‐time curve, the terminal half‐life or the first‐dose effect of prazosin.
Age‐related changes in the pharmacokinetics and pharmacodynamics of nifedipine.
Authors: Robertson DR , Waller DG , Renwick AG , George CF
Published: July 2012

1. The effects of age on the pharmacology of nifedipine were investigated in 11 young and six elderly normotensive volunteers. 2. Following 2.5 mg of nifedipine i.v. the plasma clearance of nifedipine was 348 +/‐ 83 (s.d.) ml min‐1 in the elderly compared with 519 +/‐ 125 ml min‐1 in the young (P less than 0.05) and the AUC in the elderly was significantly greater at 125 +/‐ 28 ng ml‐1 h compared with 83.9 +/‐ 19 ng ml‐1 h (P less than 0.05). The Vss was similar in both age groups. 3. Following 10 mg oral sustained release nifedipine the AUC was 281 +/‐ 64 ng ml‐1 h in the elderly compared with 136 +/‐ 56 ng ml‐1 h in the young (P less than 0.002) and Cmax in the elderly was significantly greater at 36.8 +/‐ 11.8 ng ml‐1 compared with 22.3 +/‐ 5.8 ng ml‐1 (P less than 0.05). The trend towards an increased bioavailability in elderly subjects (36%) was supported by a significantly lower nitropyridine metabolite/nifedipine ratio in the elderly. 4. Absorption rate limited kinetics of the sustained release formulation were indicated by the prolonged t1/2 compared with i.v. administration. In the elderly t1/2 (oral) was significantly greater than in the young (elderly 6.7 +/‐ 2.2 h, young 3.8 +/‐ 1.4 h, P less than 0.05). 5. Haemodynamic changes in the young were confined to a tachycardia following i.v. administration. In the elderly, supine BP fell significantly following both oral and i.v. nifedipine while the heart rate remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)