bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum alpha 1‐acid glycoprotein and the binding of drugs in obesity.
Authors: Benedek IH , Fiske 3d WD , Griffen WO , Bell RM , Blouin RA , McNamara PJ
Published: July 2012

Although clinically relevant, drug‐protein interactions in the morbidly obese population have not been studied thoroughly. The objective of this study was to evaluate serum chemistry profiles and the degree of serum protein binding of propranolol, diazepam and phenytoin in the serum of four female, morbidly obese (greater than 190% of ideal body weight) and eight control female subjects. Serum triglyceride concentrations were higher and high‐density lipoproteins were lower in the obese subjects than in the control group. Serum albumin and total protein concentrations in the obese were not different from controls. Unexpectedly, alpha 1‐acid glycoprotein concentrations were doubled in the obese subjects (mean obese value 121 mg/100 ml vs 62.9 mg/100 ml for the control subjects). Obese subjects had a mean fraction unbound (fu) for propranolol of 0.086, which was significantly different from the controls (fu = 0.123). The binding of diazepam was decreased slightly in the obese subjects. The binding of phenytoin was similar in both groups. The altered serum chemistry of obesity may play a significant role in the drug management of the obese patient by altering drug‐protein interactions.
Pharmacokinetic and clinical considerations in the choice of a hypnotic.
Authors: Amrein R , Eckert M , Haefeli H , Leishman B
Published: July 2012

Not only has insomnia become much more frequent in the last hundred years but its causes have also changed considerably. In the treatment of insomnia, benzodiazepines‐because of their additional anxiolytic effect‐offer substantial advantages over other sleep‐inducing agents. The residual fraction‐the quotient of plasma concentration at 12 h after drug intake to maximum plasma concentration‐makes it possible to differentiate between the benzodiazepines according to their suitability as anxiolytics or hypnotics. Midazolam has the lowest residual fraction of all known benzodiazepines and thus, administered in the appropriate dosage, also has the shortest duration of activity.
Efficacy and safety of midazolam in the treatment of night terrors in children.
Authors: Popoviciu L , Corfariu O
Published: July 2012

Midazolam, in an oral dose of 15 mg, and placebo were administered to 15 children aged 6‐15 years in treatment of night terrors. After an initial adaptation night, the patients received placebo for 2 nights, followed by 15 mg midazolam for 2 nights and placebo again on the final 2 nights. Eight‐hour nocturnal polygraphic recordings were made after the administration of both placebo and midazolam. The patients were continuously monitored by means of closed circuit infra‐red television. Ten of the patients manifested simple episodes while five had attacks associated with motor automatisms and EEG anomalies. The total sleep time was lengthened by midazolam in most of the children; sleep architecture was favourably modified, mainly in terms of the amount and proportion of REM sleep (accompanied by dreams) and stage 2 sleep. Night terrors were eliminated by midazolam in all except one patient. REM sleep latency also decreased as did the number of nocturnal arousals (clinical and/or EEG). In the five cases with a background of organic cerebral disorders, the EEG anomalies and these attacks were suppressed by midazolam especially during the first sleep cycles. Patients' subjective assessment of the quality of sleep was favourable. Midazolam was well tolerated with no side‐effects.
Sleep laboratory and performance evaluation of midazolam in insomniacs.
Authors: Hauri P , Roth T , Sateia M , Zorick F
Published: July 2012

This study evaluated laboratory sleep and performance after placebo, after 5, 10 and 20 mg of midazolam and after 30 mg of flurazepam. EEG recordings showed that 20 mg of midazolam significantly decreased sleep latency and stage 1 sleep, increased stage 2 sleep, and delayed the onset of the first REM period when compared with placebo. Subjective reports from the patients showed that the dose decreased the frequency of awakenings. In the morning, 9 h after drug ingestion, performance on most tests was affected very little by 20 mg of midazolam. However, performance on two psychomotor tests was slightly impaired after 20 mg of midazolam, while a test of free recall was slightly improved. On most variables, 5 mg of midazolam acted like placebo, while 10 mg of midazolam was intermediate between placebo and 20 mg of midazolam. Preliminary data suggest that 20 mg of midazolam may be as efficacious in inducing sleep as 30 mg of flurazepam, but may show fewer performance decrements in the morning.
Midazolam: effects on psychomotor performance and subjective aspects of sleep and sedation in normal volunteers.
Authors: Gudgeon AC , Hindmarch I
Published: July 2012

Twelve healthy volunteers each received acute doses of placebo and 5, 10, 15 and 20 mg of midazolam. Seven subjects were tested before and 1, 4 and 7 h after treatment. Five subjects were given the same five treatments nocturnally and tested the following morning, 10‐12 h after treatment. Tests on various measures of sedation (choice reaction time and critical flicker fusion) and of drowsiness (line analogue rating scales) showed midazolam at 15 and 20 mg dose levels to be a potent sedative agent. The present results suggest that the activity of midazolam is at a maximum 1 h after ingestion and that the effects of the drug have dissipated 7 h after treatment.
Hypnotic efficacy of midazolam in pre‐surgical patients: a dose‐finding study.
Authors: Du Cailar J , Holzer J , Jullien Y , Passeron D
Published: July 2012

The hypnotic effect of midazolam on the sleep of pre‐surgical patients was studied in 99 patients (53 males, 46 females) due to undergo surgery the following day. One tablet of 15 mg midazolam was administered at 21.00 h and a second was given 45 min later if the subject had not fallen asleep, sleep‐onset latency being measured from the time the second tablet was taken. Eighty patients required 1 tablet and 19 required 2 tablets. According to the subjective assessment, patients receiving 1 tablet fell asleep in 22.9 +/‐ 14.9 min and those taking 2 tablets fell asleep in 38.4 +/‐ 25.3 min (difference significant P less than 0.05). There was no statistically significant difference between the 1‐ and 2‐tablet groups with regard to sleep duration, number of awakenings, overall assessment of the night's sleep, sleep quality and state on awakening. Factors which had a statistically significant influence on the dosage requirement were (a) sex, 30.4% females requiring a second tablet v. 9.4% males; (b) age, the mean age of the 2‐tablet group being 36.5 v. 47 years in the lower dose group; (c) weight, patients with lower body weight requiring the higher dosage, mean 57.5 v. 66 kg; (d) current insomnia or a history of sleeping problems; (e) previous use of hypnotics; (f) degree of insomnia, moderate/severe insomnia needing a higher dosage (42% v. 21%).(ABSTRACT TRUNCATED AT 250 WORDS)
Midazolam dosage studies in institutionalized geriatric patients.
Authors: Beck H , Salom M , Holzer J
Published: July 2012

Three different dosage studies were carried out with midazolam in 47 institutionalized geriatric patients (17 males: mean age 82.9 years; 30 females: mean age 81.3 years) who were suffering from insomnia of long standing. Study I investigated the hypnotic efficacy of midazolam versus placebo in a double‐blind, cross‐over trial comparing the 7.5 and 15 mg doses of midazolam in 18 subjects. Both midazolam doses shortened sleep onset latency by 40 min (15 mg) and 31 min (7.5 mg). Both doses increased total sleep time compared with placebo. In study II, a comparative, cross‐over trial in 10 subjects, an initial dose of 7.5 mg midazolam was sufficient to reduce the subjective appreciation of sleep onset time to less than 60 min on 66 of 70 study nights. Oxazepam (25 mg) had a comparable favourable effect but less frequently (53 of 70 nights). In study III, individual dose limits were investigated in 19 insomniac patients. The minimum effective dose was 7.5 mg. The maximum tolerated dose was in the range 15 to 52.5 mg according to the subjects' assessment. The most common optimum dose was 15 mg (10 of 19 patients). The higher doses prolonged sleep but midazolam appears to have a wide margin of safety as residual sedative effects appeared only after very high doses (four of 19 for 30 mg; eight of 19 for 37.5 mg). In some patients, 7.5 mg was the minimum dose that was effective in shortening sleep latency.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative clinical studies with midazolam, oxazepam and placebo.
Authors: Feldmeier C , Kapp W
Published: July 2012

The efficacy and safety of midazolam compared with oxazepam and placebo were investigated in 50 hospital patients (19 males, 31 females; age range 21 to 74 years) in a double‐blind parallel group study. On the first 2 nights (selection phase), patients received only placebo. On the next 5 nights, they received either 15 mg midazolam, 15 mg oxazepam or placebo. They received no medication on the last 2 nights and were kept under observation (withdrawal phase). Compared with placebo, both benzodiazepines shortened sleep onset latency, reduced the number of awakenings and improved sleep quality. All 3 compounds were well tolerated with only few, mild side‐effects (headache, nausea) in the 2 verum groups. Psychometric performance was not impaired on the morning following drug administration. The overall patients' assessments showed 80% satisfaction with midazolam, 66% with oxazepam and 10% with placebo. Midazolam and oxazepam yielded similar results, although midazolam induced sleep more rapidly and was rated more favourably by the patients. Midazolam, in a dose of 15 mg, is thus an effective, fast‐ acting, well‐tolerated hypnotic without residual effects and is suitable for the treatment of insomnia of mild to moderate degree. Oxazepam in a dose of 15 mg is also well suited for the treatment of sleep disorders, particularly if a rapid onset of action is not required.
Hypnotic efficacy and safety of midazolam and oxazepam in hospitalized female patients.
Authors: Fischbach R
Published: July 2012

This double‐blind study in 60 hospitalized female patients comparing midazolam 15 mg, oxazepam 15 mg and placebo, demonstrated an inter‐ group difference in favour of midazolam with regard to efficacy. The sleep parameters of onset latency and duration were improved by midazolam. All three compounds were very well tolerated and no withdrawal symptoms were observed. Midazolam, in an oral dose of 15 mg, can thus be regarded as an effective, well‐tolerated agent for the treatment of sleep disorders.
Comparative study of midazolam and vesparax in moderate or severe insomnia in female surgical patients.
Authors: Philipp E , Kapp W
Published: July 2012

A double‐blind study was conducted in 60 female patients with moderate or severe insomnia, hospitalized for gynaecological surgery. After an initial 2‐day placebo selection phase, 30 subjects received 15 mg midazolam and the remaining 30 received 1 tablet Vesparax (= 50 mg hydroxyzine, 150 mg secobarbital, 50 mg brallobarbital) for 5 nights. This verum phase was immediately followed by a 2‐day placebo withdrawal phase in order to study the occurrence of rebound phenomena. Both verum compounds were effective in hastening sleep onset, increasing sleep duration, and improving sleep quality, without causing residual effects on the following day. There was no difference in effect between the two agents. Neither active drug caused rebound effects on withdrawal.
Efficacy and safety of midazolam and vesparax in treatment of sleep disorders.
Authors: Fischbach R
Published: July 2012

In a double‐blind parallel study in which a placebo phase preceded and followed the double‐blind verum phase, midazolam 15 mg and Vesparax (150 mg secobarbital, 50 mg brallobarbital, 50 mg hydroxyzine) were administered to 30 female patients aged 20‐76 years, suffering from insomnia secondary to neuromuscular disease. Both products were shown to be efficient hypnotics maintaining a constant level of effect. Midazolam proved to be better tolerated and, in contrast to Vesparax, did not cause hangover, nor did rebound phenomena ensue after its withdrawal.
Biochemical pharmacology of paradoxical sleep.
Authors: Gaillard JM
Published: July 2012

The role of noradrenergic cells in the regulation of paradoxical sleep is still controversial, and experimental data have given rise to contradictory interpretations. Early investigations focused primarily on chemical neurotransmissions. However, the process of information transmission between cells involves many other factors, and the cell surface is an important site for transduction of messages into modifications of the activity of postsynaptic cells. alpha‐ adrenoceptors are believed to play an important role in the control of wakefulness and paradoxical sleep. Experimental evidence suggests that physiological modulation of receptor sensitivity, possibly by specific neuro‐modulators, may be a key mechanism in synaptic transmission. In the investigation of the mechanisms involved in paradoxical sleep regulation, lesions of the locus coeruleus have given equivocal results. Collateral inhibition, probably mediated by alpha 2‐ adrenoceptors, appears to be a powerful mechanism. The exact temporal relationship between noradrenergic cell activation and paradoxical sleep production is not established, but 5‐HT appears to be involved. Differences between paradoxical sleep and waking may be related to a physiological modulation of alpha 2‐adrenoceptor sensitivity.
Pharmacology and hypnogenic properties of brotizolam in animals.
Authors: Kuhn FJ , Boke‐Kuhn K , Danneberg P , Lehr E , Stockhaus K
Published: July 2012

Brotizolam differs in pharmacological profile from other diazepines by virtue of its hypnogenic potency. It increases, whereas other diazepines reduce, sleep in the cat. With increasing doses, the latency to rapid eye movement sleep is lengthened and the proportion is reduced. Brotizolam has anxiolytic, anticonvulsant and muscle relaxant properties. The effective anxiolytic and muscle relaxant doses are somewhat lower than those of diazepam, and the effective anti‐ convulsant dose is ten times lower. Barbiturate synergism in mice is lower with brotizolam than with diazepam, while alcohol‐induced coma is prolonged over the same dose range. Side‐effects of brotizolam are similar to those of other diazepines, but the therapeutic range is more favourable. Physical dependence as tested in the monkey seems to be low.
Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects.
Authors: Jochemsen R , Wesselman JG , Van Boxtel CJ , Hermans J , Breimer DD
Published: July 2012

Pharmacokinetics of oral brotizolam (0.50 mg) and triazolam (0.50 mg) were studied in healthy young volunteers. The plasma concentration profile of brotizolam can be described as a one compartmental open model with first‐order absorption. The absorption of triazolam was less regular and in half of the subjects was not consistent with first‐order kinetics. Inter‐individual variability in absorption rate (peak times) was larger for brotizolam. Mean peak times were 1.1 +/‐ 1.0 h for brotizolam and 1.2 +/‐ 0.5 h for triazolam. Mean peak concentrations were 7.3 +/‐ 3.1 ng/ml and 5.0 +/‐ 3.9 ng/ml respectively. The elimination half‐life of brotizolam was twice that of triazolam with mean values of 5.0 +/‐ 1.1 h and 2.6 +/‐ 0.7 h respectively. There was no correlation between the half‐lives of the two drugs. Protein unbound fraction was similar for triazolam and brotizolam with mean values of 9.9 +/‐ 1.5% and 8.4 +/‐ 0.7% respectively.
Pharmacokinetics of brotizolam in renal failure.
Authors: Evers J , Renner E , Bechtel WD
Published: July 2012

Kinetics of brotizolam (0.25 mg) were studied in patients with different degrees of renal failure after single and repeated oral ingestion. Serum levels were analysed by radio‐immunoassay. Patients were divided into three groups according to their renal function, i.e. creatinine clearance values of 45‐80, 15‐45, or less than 15 ml/min. The mean elimination half‐life was 6.9‐8.15 h, with a considerable variation of the peak concentration and elimination half‐life in slight to moderate renal failure. There was no delay in elimination in severe renal failure and there was no drug accumulation. No dose adjustment is necessary for brotizolam in renal failure.
Effect of brotizolam on the averaged photopalpebral reflex in man.
Authors: Tanaka M , Isozaki H , Mizuki Y , Inanaga K
Published: July 2012

The photopalpebral reflex (PPR) is a useful method to assess level of arousal. Healthy males were given either brotizolam (0.0625, 0.125, 0.25 or 0.5 mg) or placebo within a double‐blind, crossover design. Changes in PPR and subjective assessments were observed for 5 h after medication. Prolongation of the latencies of PPR were dose dependent, and the amplitude tended to be reduced. These effects appeared within 30 min, and lasted about 4 h. The dose‐response curve of the maximum prolongation of the latencies was linear. Sleepiness and slight ataxia were observed after drug ingestion. Sleepiness was correlated with the prolongation of the PPR latencies. Brotizolam could be a potent hypnotic, with rapid onset and moderate duration of action, and it has no severe side‐effects.
Brotizolam: studies of effects on sleep and on performance in young adulthood and in middle age.
Authors: Nicholson AN
Published: July 2012

Effects of brotizolam (0.2, 0.4 and 0.6 mg), on sleep and performance, were studied in young adults. All doses increased total sleep time, improved the sleep efficiency index, and reduced drowsy sleep and number of awakenings. Brotizolam (0.4 and 0.6 mg) also reduced awake activity. There was some evidence of a delay to the first REM period, but only 0.6 mg reduced the total duration of REM sleep. There were no changes in slow wave sleep. Visuomotor coordination was impaired up to 15.0 h after overnight ingestion of 0.6 mg, but there were no residual effects after the overnight ingestion of 0.2 mg, and with 0.4 mg residual effects did not persist beyond 9.5 h. In middle‐aged subjects 0.25 and 0.5 mg were studied. The lower dose (0.25 mg) increased total sleep time, and improved the sleep efficiency index, shortened sleep onset latency, and reduced drowsy sleep. The effect of the higher dose (0.5 mg) was more marked. In a performance study using digit symbol substitution, no residual effect was observed after 0.25 mg brotizolam. Brotizolam is a short‐acting hypnotic. Doses up to 0.25 mg are likely to prove adequate over the main span of life and be free of adverse effects on sleep and residual effects on performance.
Comparative study on the efficacy of and the tolerance to the triazolodiazepines, triazolam and brotizolam.
Authors: Goetzke E , Findeisen P , Welbers IB
Published: July 2012

Efficacy of and tolerance to 0.25 mg brotizolam and 0.25 mg triazolam were compared in hospitalised patients (aged 20 to 69 years) with sleep difficulties. Over 6 days there were no differences in efficacy and tolerance. The physicians reported the effectiveness of the drugs as good‐to‐satisfactory in 88.6% with brotizolam and 92.0% with triazolam. The patients reported with both drugs reduced time to fall asleep, less awakenings, increased duration of sleep and improved condition on awakening.
An assessment of physiological finger tremor as an indicator of beta‐ adrenoceptor function.
Authors: Arnold JM , McDevitt DG
Published: July 2012

Physiological finger tremor has been assessed as an indicator of beta‐ adrenoceptor function. Tremor was not correlated with the sex, age, weight or height of the subjects and was stable over 5 min when the hand and fingers were held horizontally. It was not increased by mental arithmetic, the Valsalva manoeuvre or 3 min exercise. Satisfactory dose‐ response curves could be constructed for the isoprenaline enhanced increases in finger tremor. In six subjects, practolol 120 mg produced a small shift to the right of the isoprenaline dose‐response curve for finger tremor (dose ratio 2.1) but propranolol 40 mg was seven times more effective (dose ratio 17.1). Physiological finger tremor appears to be a stable parameter which may be useful in the investigation of the selectivity of beta‐adrenoceptor blocking drugs.
Enzyme induction with rifampicin; lipoproteins and drug binding to alpha 1‐acid glycoprotein.
Authors: Feely J. , Clee M. , Pereira L. , Guy E.
Published: July 2012

Hepatic enzyme induction has been reported to increase lignocaine binding, alpha 1‐acid glycoprotein concentration and high density lipoprotein (HDL) cholesterol. In eight volunteers treated with rifampicin for 3 weeks there was no significant alteration in these three variables although their antipyrine clearance was significantly increased. In 10 patients with pulmonary tuberculosis treated with rifampicin (mean 5 months) the degree of serum protein binding of lignocaine, alpha 1‐acid glycoprotein and HDL‐cholesterol concentration was not different from that of matched control patients. These results suggest that differential induction of these variables may occur.
The efficacy and pharmacokinetics of sodium salicylate in post‐ operative dental pain.
Authors: Seymour RA , Rawlins MD , Clothier A
Published: July 2012

Sodium salicylate, 537 mg and 1074 mg were compared in a double‐blind cross‐over study in 24 patients with post‐operative pain following removal of impacted lower third molars. No significant analgesic effect was observed after either dose of sodium salicylate, either overall or at any time point during the 5 h investigation period. Peak plasma concentrations of salicylate after 537 mg were observed at 30 min after dosage, whereas peak plasma salicylate concentrations after 1074 mg sodium salicylate occurred at 45 min after dosage.
Calcium antagonists and endocrine status: lack of effect of oral verapamil on pituitary‐testicular and pituitary‐thyroid function.
Authors: Semple CG , Thomson JA , Beastall GH , Lorimer AR
Published: July 2012

Calcium ions seem to be essential for the release of many hormones. The calcium antagonist verapamil which is used as an anti‐arrhythmic and anti‐anginal agent has an inhibitory effect on the release of follicle stimulating hormone (FSH), luteinising hormone (LH), and thyrotrophin stimulating hormone (TSH) when given as an intravenous infusion to normal volunteers. As verapamil is usually given orally we studied pituitary‐testicular and pituitary‐thyroid function before and after completing a 4‐week course of oral verapamil. The oral preparation did not have any significant effect on the endocrine parameters studied.
Effect of the 5‐hydroxytryptamine type 2 receptor antagonist, ketanserin, on blood pressure, the renin‐angiotensin system and sympatho‐adrenal function in patients with essential hypertension.
Authors: Zabludowski JR , Zoccali C , Isles CG , Murray GD , Robertson JI , Inglis GC , Fraser R , Ball SG
Published: July 2012

Ketanserin, a 5‐HT type 2 receptor antagonist, was administered intravenously to nine patients with essential hypertension in a double‐ blind placebo controlled study to investigate the drug's effects on blood pressure, heart rate, the renin‐angiotensin system and sympatho‐ adrenal function. Average blood‐pressure for the group prior to injection of the drug was 150 +/‐ 7/94 +/‐ 4 (s.e. mean) mm Hg and decreased significantly (P less than 0.01) to 137 +/‐ 8/88 +/‐ 5 mm Hg during the 2 h after injection; heart rate increased immediately after injection of ketanserin, reaching a maximum of 81 +/‐ 4 beats/min. After drug administration systolic and diastolic blood pressure decreased on tilting, but the heart rate response was not different from that with placebo. Ketanserin did not affect the blood pressure response to graded infusion of the alpha 1‐adrenoceptor agonist phenylephrine. Plasma active renin, angiotensin II and aldosterone concentrations increased slightly but not significantly after the drug; plasma noradrenaline increased transiently. 5‐HT may be important in the maintenance of blood pressure but alternative mechanisms for the action of ketanserin in reducing blood pressure require investigation.
Influence of food on the absorption of the p‐chlorophenolic ester of chlorophenoxyisobutyric acid in man.
Authors: Houin G , Shastri RA , Barre J , Pinchon B , Tillement JP
Published: July 2012

A study was designed to investigate the effect of a fatty meal on the absorption of chlorophenoxyisobutyric acid (CPIB) in six healthy adult volunteers after oral administration of the p‐chlorophenolic (PCP) ester of CPIB. Plasma concentrations of CPIB when administered with food were higher than those observed in the fasting state. The Cmax in the former case was 24.0 +/‐ 4.6 mg l‐1 as against a value of 15.2 +/‐ 6.9 mg l‐1 in the latter (P less than 0.01). The pharmacokinetic parameters measured were found to be linear with the dose administered. This could be due to low plasma concentrations of CPIB unable to cause a saturation of the plasma protein binding of this drug. It is concluded that a fatty meal enhances the absorption of this hypolipidaemic drug.
The effect of two beta‐adrenoceptor blockers (mepindolol and atenolol) on blood lipids and platelet aggregation in normal volunteers and essential hypertensive patients.
Authors: Luque Otero M , Fernandez Pinilla C , Escriba Polo A , Rodriguez Vazquez M , Martell Claros N , Fernandez‐Cruz A
Published: July 2012

beta‐adrenoceptor blocking agents are widely used as treatment of essential hypertension. We studied the action of a new non cardioselective beta‐adrenoceptor blocker, mepindolol, comparing its effects on blood pressure, blood lipids and platelet aggregation with those of a cardioselective beta‐adrenoceptor blocker, atenolol. Blood pressure fell significantly in the patients treated with both drugs. Triglycerides rose non‐significantly only in volunteers treated with mepindolol. We did not find any significant changes in cholesterol, free fatty acids, lipoproteins and platelet aggregation.
The effects of acetylsalicylic acid on swelling, pain and other events after surgery.
Authors: Skjelbred P
Published: July 2012

In a double‐blind crossover study acetylsalicylic acid (ASA) in low (2 g daily) or high (4 g daily) dosage was tested against placebo in two groups of 20 patients who each underwent identical oral surgical procedures on two separate occasions. Medication started 3 h post‐ operatively and continued for 3 days. ASA in low dosage tended to increase the postoperative swelling, which on day 3 and 6 averaged 109 and 133% respectively of that with placebo (P greater than 0.05). In contrast, ASA in high dosage tended to reduce the swelling, which on day 3 and 6 averaged 85 and 90% respectively of that with placebo (P greater than 0.05). Comparison of the two groups receiving ASA in low or high dosage revealed a significant difference in their effect on swelling; day 3, P = 0.05. Pain was significantly reduced with ASA, but there appeared to be no greater analgesic effect with 4 g ASA daily than with 2 g ASA daily. There was, however, a substantial increase in the number of patients who reported tinnitus after taking 4 g ASA daily. Subjective postoperative bleeding scores were significantly increased with 2 g ASA daily, but not with 4 g ASA daily. None of the dosages of ASA appeared to reduce the swelling as efficiently, give better pain relief, or as high preference scores as previously obtained in studies when paracetamol and short term glucocorticoid administration were tested against placebo in this model.
Pharmacokinetics of primaquine in man: identification of the carboxylic acid derivative as a major plasma metabolite.
Authors: Mihaly GW , Ward SA , Edwards G , Orme ML , Breckenridge AM
Published: July 2012

A method is described for the simultaneous determination of the carboxylic acid and N‐acetyl‐derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/‐ 23.5 ng/ml at 3 +/‐ 1 h, followed by an elimination half‐life of 7.1 +/‐ 1.6 h, systemic clearance of 21.1 +/‐ 7.1 l/h, volume of distribution of 205 +/‐ 371 and cumulative urinary excretion of 1.3 +/‐ 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/‐ 307 ng/ml at 7 +/‐ 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N‐acetyl primaquine was not detected in plasma or urine. Following [14C]‐primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]‐radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N‐ acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.
A rapid method for determination of acetylation phenotype using dapsone.
Authors: Philip PA , Roberts MS , Rogers HJ
Published: July 2012

A rapid, simple one‐stage protein precipitation method for the estimation of plasma dapsone (DDS) and monoacetyldapsone (MADDS) concentration by high‐pressure liquid chromatography (h.p.l.c.) is described. Its performance in the assignment of acetylator phenotype was compared with a reference h.p.l.c. method utilising an extraction procedure and internal standard. The rapid h.p.l.c. technique combined with measurement of the plasma MADDS/DDS ratio is, in our opinion, the method of choice for the determination of the acetylator phenotype in population studies.
Objective evaluation of dextromethorphan and glaucine as antitussive agents.
Authors: Ruhle KH , Criscuolo D , Dieterich HA , Kohler D , Riedel G
Published: July 2012

Twenty‐four inpatients affected by chronic cough completed a single‐ dose double‐blind cross‐over study of placebo, glaucine 30 mg and dextromethorphan 30 mg. The study was carried out using a balanced incomplete block design, each patient receiving two of the three experimental treatments. Objective evaluation of cough was ensured by means of a writing cough recorder. Coughs after dextromethorphan and glaucine were fewer than coughs after placebo: however only glaucine was significantly different from placebo in reducing coughs. Treatments were well tolerated: clinical results included a reduction in pulse rate after both dextromethorphan and glaucine, and a large number of patients reporting side effects after dextromethorphan administration.
Influence of chronic dosing on theophylline clearance.
Authors: Efthimiou H , Morgan DJ , Ioannides‐Demos L , Raymond K , McLean AJ
Published: July 2012

Theophylline clearance was studied in normal healthy volunteers before and after chronic oral dosing. Oral theophylline clearance showed a significant decrease (P less than 0.001) from 59.3 +/‐ 6.48 ml/min (mean +/‐ s.e. mean, n = 10) to 48.0 +/‐ 6.4 ml/min. Steady‐state intravenous clearance decreased by 26 +/‐ 2% from 55.1 +/‐ 7.7 ml/min to 41.0 +/‐ 5.96 ml/min (mean +/‐ s.e. mean, n = 6; P less than 0.001) at constant steady‐state intravenous test concentrations (mean 15.0 +/‐ 1.6 micrograms/ml after chronic oral dosing), excluding significant concentration dependence. Extrapolation of acute clearance findings to maintenance requirement may not be valid even in the same individual, with theophylline therapy requiring on‐going review beyond acute stabilisation.
The effect of beta‐adrenoceptor antagonists on the pharmacokinetics and pharmacodynamics of warfarin after a single dose.
Authors: Bax ND , Lennard MS , Tucker GT , Woods HF , Porter NR , Malia RG , Preston FE
Published: July 2012

The effects of three beta‐adrenoceptor antagonists (propranolol, metoprolol and atenolol) on the serum kinetics and pharmacodynamics of warfarin given in a single oral dose (15 mg) were studied in six normal subjects. At the same degree of beta‐adrenoceptor blockade, as assessed by the decrease of exercise tachycardia, propranolol increased the area under the serum warfarin concentration time curve (AUC) by 16.3 +/‐ 14.2 s.d.% (P less than 0.01) and the maximum serum warfarin concentration by 23.0 +/‐ 14.3 s.d.% (P less than 0.001). Atenolol increased the maximum serum warfarin concentration by 12.5 +/‐ 12.3% s.d. (P less than 0.05) but was without effect on warfarin AUC. Metoprolol had no effect on warfarin kinetics. The extent of changes in the prothrombin time and the plasma clotting Factor VII activity caused by warfarin were not altered by any of the beta‐adrenoceptor antagonists.
Comparison of medroxalol and labetalol, drugs with combined alpha‐ and beta‐adrenoceptor antagonist properties.
Authors: Elliott HL , McLean K , Meredith PA , Sumner DJ , Reid JL
Published: July 2012

Medroxalol, a new drug which has been reported to possess both alpha‐ and beta‐adrenoceptor antagonist properties, was compared with labetalol in single dose studies in normotensive males. Oral doses of 400 mg of each drug significantly reduced blood pressure, both supine and erect, without significant changes in heart rate. The chronotropic and diastolic depressor responses to isoprenaline were significantly antagonised by both drugs, for at least 6‐8 h after drug administration. Medroxalol was associated with significantly greater beta‐adrenoceptor antagonism than labetalol. There was no significant antagonism by either drug of the pressor response to noradrenaline. However, in a sub‐group of subjects the responses to the selective alpha 1‐adrenoceptor agonist, phenylephrine, were consistent with modest alpha 1‐adrenoceptor antagonism. This was significant only for labetalol. The ratios of beta 1‐ to alpha 1‐adrenoceptor antagonism as calculated from the relative shifts of the isoprenaline and phenylephrine dose‐response curves, were 3 to 1 for labetalol and about 7 to 1 for medroxalol.
Lack of effect of domperidone on gastrin release: evidence for a peripheral activity of the drug.
Authors: Masci E , Caldara R , Testoni PA , Guslandi M , Cambielli M , Passaretti S , Tittobello A
Published: July 2012

The effect of intravenous administration of domperidone, a dopamine receptor antagonist with peripheral activity, on basal and submaximal pentagastrin‐stimulated gastric acid secretion and gastrin release has been evaluated in healthy volunteers. No significant changes were observed in the parameters studied. The lack of effect on gastrin release appears to confirm that domperidone is unable to penetrate the blood brain barrier in appreciable amounts in adults.
Alterations in prednisolone disposition as a result of oral contraceptive use and dose.
Authors: Meffin PJ , Wing LM , Sallustio BC , Brooks PM
Published: July 2012

The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen‐progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. Mean free prednisolone clearance was reduced congruent to 30% in oral contraceptive users compared to control subjects (P less than 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre‐dose plasma cortisol concentrations were elevated two‐fold (P less than 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. Mean total prednisolone clearance and steady state distribution volume showed an approximate two‐fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P less than 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P less than 0.001) but free steady‐state distribution volume did not change with dose. At plasma prednisolone concentrations less than 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.
Comparison of two long‐acting forms of quinidine.
Authors: Leizorovicz A , Piolat C , Boissel JP , Sanchini B , Ferry S
Published: July 2012

The bioequivalence of two forms of long acting quinidine compounds was assessed (Kinidin durules and Longacor) using drug plasma level and QT ECG changes. Six healthy volunteers received each preparation on two occasions in random order. The wash out period between successive experiments was at least 7 days. There was no difference in tmax, Cmax and AUC for plasma level and adjusted QT. However, between patient variability was large. A 20% difference in plasma levels could not be excluded but the difference in QT max and QT AUC between the two preparations did not exceed 20% (P less than 0.05, Westlake's method). This study illustrates the fact that pharmacodynamic equivalence, let alone therapeutic equivalence, does not necessarily imply plasma level equivalence, as assessed by the current method.
Antihypertensive effect and degree of beta‐adrenoceptor blockade after short‐term and semi‐chronic propranolol therapy.
Authors: Leenen FH , Boer P , Mees Dorhout EJ
Published: July 2012

In patients with normal‐renin, mild (n = 6) or moderate (n = 6) hypertension, the antihypertensive effects of propranolol (80 mg/day) for 1 day or for 2 weeks were evaluated in relation to the degree of beta‐adrenoceptor blockade induced. A significant and similar fall in systolic blood pressure was observed after 1 day and 2 weeks on propranolol in both groups of patients. In contrast, diastolic blood pressure showed only a minor decrease after 1 day of therapy (‐2 +/‐ 2 and −3 +/‐ 1 mm Hg) but a significant drop (‐7 +/‐ 3 and −9 +/‐ 3 mm Hg) after 2 weeks in the mild and moderate hypertension groups, respectively. Plasma propranolol levels and decreases in resting heart rate and PRA were similar after 1 day and 2 weeks of treatment. Isoprenaline dose‐response curves for systolic and diastolic blood pressure, heart rate and PRA showed similar parallel shifts after 1 day and 2 weeks of treatment. The effect of graded bicycle exercise on these parameters were also similarly blunted. These results indicate that over time, systolic blood pressure decreases rapidly whereas diastolic blood pressure shows a delayed fall following initiation of low‐dose propranolol therapy, despite the same degree of beta‐ adrenoceptor blockade.
Clinical evaluation of two strategies for improving patient recall of prior drug therapy.
Authors: Bellamy N , Grace E , Hanna B , Grant E , Tugwell P , Buchanan WW
Published: July 2012

The ability to recall details of current and prior drug therapy was evaluated in two studies employing a total of 94 patients with inflammatory polyarthritis. Ten per cent of patients were unable to completely recall the names of their current anti‐inflammatory drugs and eighty‐three per cent of patients to completely recall the details of prior anti‐inflammatory drug therapy. Prompting firstly with the proprietary names of drugs and thereafter with a pill board substantially enhanced recall particularly for prior NSAID therapy. Nineteen per cent of responses obtained with verbal prompting were inaccurate. No such problems were encountered in responses obtained using the pill board. These findings indicate that a complete and accurate drug history can only be obtained in the majority of patients using recall enhancement strategies.
The use of Doppler ultrasound techniques to study the effects of isoprenaline and beta‐adrenoceptor blocking drugs on peripheral blood vessels in man.
Authors: Fitzgerald DE , Harry JD
Published: July 2012

A Doppler ultrasound technique has been used in six volunteers to determine the effects of intravenous isoprenaline on blood velocity and volume blood flow in the femoral artery and to investigate the effects of single oral doses of atenolol (50 mg) and propranolol (40 mg) on these effects and on heart rate changes. Isoprenaline increased the blood velocity and volume blood flow which was attenuated by propranolol and not by atenolol; the tachycardia of isoprenaline was inhibited by both drugs. The results show that the Doppler ultrasound measurements in the femoral artery can identify pharmacologically induced changes in peripheral blood vessels in the leg and warrants further investigation as a tool to study the pharmacology of peripheral blood vessels in man.
Effects of beta‐adrenoceptor antagonists on the pharmacokinetics of lignocaine.
Authors: Tucker GT , Bax ND , Lennard MS , Al‐Asady S , Bharaj HS , Woods HF
Published: July 2012

In theory, beta‐adrenoceptor antagonists could lower the clearance of free lignocaine in three ways (a) by decreasing hepatic blood flow, (b) by competing for plasma binding sites or (c) by inhibiting the enzymes responsible for metabolising lignocaine. The first mechanism has been demonstrated for propranolol and is probably common to all agents lacking intrinsic sympathomimetic activity. The second mechanism is discounted by data showing that propranolol, one of the more highly bound beta‐adrenoceptor antagonists, does not alter the free fraction of lignocaine in plasma. In vitro studies support the third mechanism for the more lipid‐soluble beta‐adrenoceptor antagonists, as does the fact that observed decreases in the clearance of lignocaine in vivo are generally greater than the anticipated maximum lowering of hepatic blood flow.
Stable oral availability of sustained release propranolol when co‐ administered with hydralazine or food: evidence implicating substrate delivery rate as a determinant of presystemic drug interactions.
Authors: Byrne AJ , McNeil JJ , Harrison PM , Louis W , Tonkin AM , McLean AJ
Published: July 2012

A study was made of the influence of hydralazine on the oral availability of a sustained release formulation of propranolol (Inderal LA). Sustained release propranolol 160 mg was given orally either alone or in combination with oral hydralazine 25 mg on separate occasions to six healthy volunteers. Blood and urine samples were collected post‐ dosing over 34 h. Peak concentrations of propranolol, time to peak and area under the plasma concentration‐time curve (AUC) were not altered by co‐administration of hydralazine with sustained release propranolol. Similarly, there was no change in recovery of 11C‐labelled propranolol and metabolites in those individuals to whom tracer label was given. These results contrast with previous reports of marked interaction between the conventional formulation of propranolol and hydralazine or food. Interactions were confirmed between hydralazine and conventional propranolol in three subjects who had been studied previously with sustained release propranolol. Analysis of metabolite profiles in one of these subjects established that the major metabolites do change under hydralazine stimulus. These results indicate that substrate delivery rates may determine presystemic drug interactions, suggesting capacity limitations of hydroxylation processes or short‐term flow redistribution following hydralazine, resulting in functional shunting past the hydroxylation enzymes. These results exclude global or lasting enzyme inhibition by hydralazine or simple flow‐sensitivity of presystemic clearance.
The interaction of cigarette smoking and beta‐adrenoceptor blockade.
Authors: Fox K , Deanfield J , Krikler S , Ribeiro P , Wright C
Published: July 2012

The importance of the interaction between smoking and propranolol (metabolised in the liver) and atenolol (excreted almost entirely in the urine) was investigated in a double‐blind placebo‐controlled trial. Resting and exercise heart rates were significantly greater during smoking than no‐smoking phases. Atenolol and propranolol significantly improved ST segment response after exercise whether or not the patients were smoking. Plasma propranolol significantly increased when patients stopped smoking whereas there was no such change in atenolol levels.
Effect of atenolol and metoprolol on the anticoagulant activity of acenocoumarin.
Authors: Mantero F , Procidano M , Vicariotto MA , Girolami A
Published: July 2012

In patients receiving long‐term acenocoumarin treatment, the effect on anticoagulant activity of atenolol (100 mg once‐daily) and metoprolol (100 mg twice daily) was compared in a randomised within‐patient open trial. No significant differences were demonstrated between mean prothrombin time and Thrombotest during treatment with atenolol, metoprolol or placebo. These data do not suggest the existence of an interaction between acenocoumarin and the moderately lipophilic beta‐ adrenoceptor blocker metoprolol, or the hydrophilic beta‐adrenoceptor blocker atenolol. The results are discussed in the light of published data for the highly lipophilic beta‐adrenoceptor blocker propranolol.
Pharmacokinetic and pharmacodynamic interactions between phenprocoumon and atenolol or metoprolol.
Authors: Spahn H , Kirch W , Mutschler E , Ohnhaus EE , Kitteringham NR , Logering HJ , Paar D
Published: July 2012

Pharmacological interactions in both directions between phenprocoumon and atenolol and metoprolol were investigated using a crossover trial. Co‐administration of phenprocoumon did not significantly affect Cmax, tmax, t1/2,22, AUC for atenolol or metoprolol. Co‐administration of metoprolol, but not atenolol, increased mean plasma phenprocoumon concentrations 4 and 6 h after dosing and was caused by a decrease in the apparent volume of distribution. This increase in plasma phenprocoumon was not associated with an increase in prothrombin time or in the total area under the concentration‐time curve. Although the transient increase of phenprocoumon plasma levels caused by metoprolol may be of little clinical significance after a single dose of phenprocoumon, a more important alteration in phenprocoumon disposition and effect should be considered in individual patients on long‐term therapy.
Comparison of beta‐adrenoceptor antagonists as modulators of drug metabolism: effect of lipophilicity on microsomal phase I and II reactions.
Authors: Ahokas JT , Davies C , Ravenscroft PJ
Published: July 2012

The effect of beta‐adrenoceptor antagonists with varying lipophilicity on microsomal phase I and II reactions was investigated using rat hepatic microsomes. The degree of inhibition of ethoxyresorufin deethylase paralleled octanol/water partition coefficients: propranolol greater than alprenolol greater than timolol greater than metoprolol greater than atenolol. Propranolol (highly lipophilic) and atenolol (hydrophilic) also had widely different effects on 7‐ethoxycoumarin deethylase inhibition and on disopyramide N‐dealkylation. However the inhibition of harmol conjugation was not related in the same way to octanol/water partition coefficient as was the phase I reactions.
Relative potency of prorenoate potassium and spironolactone in attenuating diuretic induced hypokalaemia.
Authors: McInnes GT , Harrison IR , Shelton JR , Perkins RM , Clarke JM
Published: July 2012

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double‐blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4‐35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs.