bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute effects of intravenous phenytoin on the frequency of inter‐ictal spikes in man.
Authors: Milligan N , Oxley J , Richens A
Published: July 2012

Phenytoin was administered intravenously to six adult epileptic patients in doses ranging from 500–1000 mg (equivalent to 5.6 mg/kg‐ 20 mg/kg body weight). A significant decrease in the frequency of inter‐ ictal spikes in the EEG was seen and this effect was most marked 10–20 min after the infusion, when the mean spike count was reduced to 27% (s.d. 17%) of the control (P less than 0.05). In one subject the decrease in inter‐ictal spikes coincided with a decrease in fit frequency. Adverse reactions affecting the vestibular system occurred in three patients at doses of 15–20 mg/kg. No cardiovascular complications were observed in any subject. The overall results suggest that doses of 7.5–10 mg/kg would be sufficient to significantly reduce the frequency of inter‐ictal spikes in the EEG.
Effects on psychological performance of the benzodiazepine, loprazolam, alone and with alcohol.
Authors: McManus IC , Ankier SI , Norfolk J , Phillips M , Priest RG
Published: July 2012

The effects of a new 1,4 benzodiazepine hypnotic, loprazolam (1.0 mg) and alcohol (0.7 g/kg body weight) were investigated over a 15 h period in eight healthy male medical students, in a placebo controlled balanced design. Loprazolam when given alone impaired performance on a manual dexterity task, on a test of mental arithmetic, on a tracking task and it impaired memory as judged by the name and address memory test. Given alone, alcohol impaired performance on the simple reaction time task and on the tracking task. Performance on the memory test and choice reaction time test actually improved. No evidence was found suggesting a potentiation of effect when loprazolam and alcohol were given together. However, (a) on the manual dexterity task the alcohol, having no effect on its own, alleviated the loprazolam‐induced impairment. (b) In the tracking task both alcohol and loprazolam impaired performance when given alone but not when given together. (c) The memory test was impaired by loprazolam, improved by alcohol and the effect of the combination is the expected sum of the two effects. Similarly for the arithmetic task the effect of the combination of the alcohol and loprazolam effects is the expected sum of the independent effects. The bulk of the evidence on the interaction suggests that alcohol mitigates the effects of loprazolam. In no sense could the drug be said to be having a sobering influence.
Preliminary evaluation of pinacidil in hypertension.
Authors: Ramsay LE , Freestone S
Published: July 2012

In a balanced single‐blind placebo controlled study in six hypertensive patients treated with diuretic and beta‐adrenoceptor blocker, a single oral dose of 10 mg pinacidil lowered blood pressure significantly, by a maximum of 26/13 mm Hg lying and 15/12 mm Hg standing at 3 h. The duration of action was less than 6 h. Chronic treatment of four patients (mean dose 20 mg twice daily for 3–7 weeks) lowered blood pressure by only 15/7 mm Hg. All four patients experienced side‐effects of the type often observed during treatment with potent vasodilators. In the formulation studied pinacidil is unlikely to offer any advantage over the antihypertensive drugs currently available.
Childhood leukaemia: a relationship between intracellular 6‐ mercaptopurine metabolites and neutropenia.
Authors: Lennard L , Rees CA , Lilleyman JS , Maddocks JL
Published: July 2012

6‐Mercaptopurine is extensively used in the treatment of childhood lymphoblastic leukaemia to prolong the duration of remission achieved with other drugs. The response to remission maintenance therapy varies widely. We investigated the relationship between red blood cell 6‐ thioguanine nucleotide, a metabolite of 6‐mercaptopurine, and myelosuppression in 22 children with acute lymphoblastic leukaemia in remission. The peripheral neutrophil count was used as an index of myelosuppression. 6‐Mercaptopurine dose was related to 6‐thioguanine nucleotide concentration (r = 0.4; P less than 0.001; n = 90; y = 18.51 + 0.36 x). Large individual variations around the regression line are observed. Neither 6‐mercaptopurine dose nor 6‐thioguanine nucleotide concentration was related to the neutrophil count at the time of sampling (day 0) or 7 days later. Both 6‐mercaptopurine dose and 6‐ thioguanine nucleotide concentration correlated with the neutrophil count at day 14 (r = −0.33; P less than 0.01; n = 90 and r = −0.3; P less than 0.01; n = 90 respectively). This delay is compatible with a cytotoxic action on bone marrow stem cells. Excluding children with other, uncontrolled, potentially myelosuppressive influences the correlation between 6‐thioguanine nucleotide concentration and neutropenia improved (r = −0.6; P less than 0.001; n = 37). A significant degree of neutropenia was observed by day 14 if the 6‐ thioguanine nucleotide concentration (day 0) was greater than 210 pmol/8 × 10(8) RBCs. The assay of 6‐thioguanine nucleotide may highlight those individuals with pharmacokinetic resistance. Two children on continuous high dose 6‐mercaptopurine, had low red blood cell 6‐thioguanine nucleotide concentrations and neutropenia was not observed.
The effect of posture on the sympathoadrenal response to theophylline infusion.
Authors: Warren JB , Turner C , Dalton N , Thomson A , Cochrane GM , Clark TJ
Published: July 2012

We studied the effect of posture on the sympathoadrenal response to intravenous theophylline in six normal subjects. On three separate occasions they received an intravenous infusion of either theophylline (6 mg/kg) while supine, theophylline (6 mg/kg) while standing or saline as placebo while standing. With the subjects standing theophylline caused tremor, a peak heart rate of 99 +/‐ 6 beats/min, and an elevation of plasma cyclic AMP from 9.3 +/‐ 0.7 to 15.1 +/‐ 1.7 nmol/1 (mean +/‐ s.e. mean). There was a small, but significant, elevation of plasma adrenaline, noradrenaline and glucose. The elevation in plasma catecholamines was insufficient to explain either the sympathomimetic effects of theophylline or the rise in plasma cyclic AMP. Theophylline had little or no effect with the subjects supine. The mean peak theophylline concentration following infusion was significantly higher with the subjects upright than when supine (18.3 c.f. 12.4 mg/l, P less than 0.025). However, adequate plasma levels of theophylline were obtained in all subjects when lying or supine. Analysis of individual data suggests that differences in plasma levels of theophylline are unlikely to account for the increased effects seen on standing. The mechanism of action of theophylline cannot be explained by increased secretion of catecholamines alone. Theophylline appears to amplify the increased sympathetic activity associated with standing and this is probably by phosphodiesterase inhibition.
Pharmacokinetic observations on piroxicam in young adult, middle‐aged and elderly patients.
Authors: Woolf AD , Rogers HJ , Bradbrook ID , Corless D
Published: July 2012

Nineteen out of 21 patients with painful conditions of the locomotor system aged between 27 and 94 years completed a study in which they received 20 mg piroxicam daily for 14 days. Plasma piroxicam concentrations were estimated by high performance liquid chromatography. Pharmacokinetic analysis of the data showed the half‐ life and systemic clearance of piroxicam to be unaffected by age. The apparent volume of distribution in older patients was higher than that of younger subjects. Multiple regression analysis showed that creatinine clearance and plasma albumin concentration had insignificant effects on the systemic piroxicam clearance. Although improvement in joint pain and stiffness occurred during the 2 week study period, this could not be correlated with plasma piroxicam concentration.
The effect of glucagon on the swallowing of capsules.
Authors: Channer KS , Bolton R , Al‐Hilli S , Nakielny R , Virjee JP
Published: July 2012

Glucagon (0.3 mg) given intravenously to 45 patients with normal oesophageal motility significantly reduced oesophageal transit of hard gelatin capsules when swallowed in the supine position with 15 ml water, compared to an age/sex matched group. This is taken to represent an effect on oesophageal peristalsis which has not previously been recognised.
Hormonal effects and metabolic clearance rate of the enkephalin analogue DAMME in man.
Authors: Gilchrist N , Bolton JE , Donald RA , Livesey JH , Roud HK , Nicholls MG
Published: July 2012

The enkephalin analogue DAMME (0.25 mg) and normal saline were administered by slow intravenous injection to six normal male subjects in a double‐blind crossover study. Plasma DAMME concentrations were measured by a specific radioimmunoassay. A significant rise in plasma growth hormone and prolactin and a significant fall in plasma corticotrophin and cortisol concentrations were observed. The fall in pancreatic polypeptide concentration just failed to reach significance. No significant changes were observed in insulin, glucagon, glucose, adrenaline and noradrenaline. Serum concentrations of DAMME were initially high (greater than 6.7 nmol/1) corresponding with the observed maximum plasma growth hormone and prolactin responses. The serum DAMME concentration was readily detectable when plasma growth hormone and prolactin had returned to control levels, but corticotrophin and cortisol were still significantly depressed.
Influence of sex and oral contraceptive steroids on paracetamol metabolism.
Authors: Miners JO , Attwood J , Birkett DJ
Published: July 2012

Paracetamol metabolism was investigated in eight healthy males, eight healthy females and eight healthy females receiving oral contraceptive steroids (OCS). Paracetamol clearance was 22% greater in males compared to the control female group. This difference was entirely due to increased activity of the glucuronidation pathway in males, there being no sex‐related differences in the sulphation or oxidative metabolism of paracetamol. Paracetamol clearance in females using OCS was 49% greater than in the control females. Glucuronidation and oxidative metabolism were both induced in OCS users (by 78% and 36% respectively) but sulphation was not altered. Although sex‐related differences in paracetamol metabolism are unlikely to be of clinical importance, induction of paracetamol metabolism by OCS may have clinical and toxicological consequences.
Serum protein binding of propylthiouracil.
Authors: Kampmann JP , Hansen JE Molholm
Published: July 2012

Serum protein binding of propylthiouracil (PTU) was measured by ultrafiltration in healthy and hyperthyroid patients. The serum protein binding in 12 euthyroid subjects was 76.2 +/‐ 1.2% (mean +/‐ s.d.), not significantly different from the values in 10 hyperthyroid patients: 76.6 +/‐ 1.3% Binding was unaffected by incubation time and temperatures between 25 and 37 degrees C, but increased from 76.5 to 79.1% when pH changed from 7.4 to 7.9. PTU is predominantly bound to albumin with two classes of binding groups with different number of binding sites and affinity. Displacement experiments showed interaction with acetylsalicylic acid, warfarin and phenylbutazone, but not with antipyrine and nortriptyline or other basic drugs.
Can the biochemical responses to a beta 2‐adrenoceptor stimulant be used to assess the selectivity of beta‐adrenoceptor blockers?
Authors: Smith S Rolf , Kendall MJ , Worthington DJ , Holder R
Published: July 2012

The extent to which beta‐adrenoceptor blocking drugs counteract the biochemical responses to an infusion of terbutaline, a beta 2‐ adrenoceptor agonist, has been investigated. In this study the beta 1‐ selectivity of metoprolol was compared with the non‐selective beta‐ adrenoceptor blocker propranolol. The hypokalaemia produced by an infusion of terbutaline was reduced by low dose (50 mg) and high dose (200 mg) metoprolol and by low dose (40 mg) and high dose (160 mg) propranolol. The effects of propranolol on terbutaline induced hypokalaemia were more marked than those of metoprolol at both low dose (P = 0.01) and high dose (P = 0.05). Furthermore low dose metoprolol had less effect than high dose metoprolol (P = 0.05). The serum potassium appeared to rise slightly after propranolol. Low and high doses of both beta‐adrenoceptor blockers markedly reduced the terbutaline‐induced hyperglycaemia, but the differences between the two drugs were not statistically significant.
Dose‐response relationships of intravenous hyoscine butylbromide and atropine sulphate on heart rate in healthy volunteers.
Authors: Grainger SL , Smith SE
Published: July 2012

Heart‐rate responses to intravenous hyoscine butylbromide, atropine and physiological saline in cumulative dosage regimens have been recorded in six healthy subjects. Atropine sulphate induced bradycardia at low, and tachycardia at higher, dose levels whereas hyoscine butylbromide caused only tachycardia but with a flatter dose‐response relationship. Exact potency ratios could not be calculated because of the differing dose‐response curves. However, an approximate estimate from a comparison of equiactive doses at the upper part of the curve yielded a value less than one half that obtained from the drugs' affinity constants in guinea‐pig ileum. The findings suggest that, in addition to its action as a muscarinic antagonist, hyoscine butylbromide is a ganglion blocker in man as it is in animals.
Induction of drug‐metabolizing enzymes by tricyclic antidepressants in human liver: characterization and partial resolution of cytochromes P‐ 450.
Authors: Cresteil T , Celier C , Kremers P , Flinois JP , Beaune P , Leroux JP
Published: July 2012

Drug‐metabolizing enzyme activities were determined in liver microsomes from six kidney‐transplant donors, one tricyclic antidepressant‐treated and five untreated donors. The tricyclic antidepressant treatment modifies neither the overall cytochrome P‐450 content of the liver, nor enzymatic activities of 4‐nitroanisole demethylase, aniline hydroxylase, epoxide hydrolase and glutathione S‐transferase. Only benzphetamine and ketotifen demethylation and conjugation of bilirubin with UDP‐glucuronic acid are markedly augmented (more than two‐fold). Separation of the different cytochrome P‐450 fractions on a DEAE cellulose column indicates a modification of the elution pattern: the fraction increased by tricyclic antidepressants is responsible for the enhanced monooxygenase activity towards benzopyrene and benzphetamine.
Phenylbutazone‐warfarin interaction in man: further stereochemical and metabolic considerations.
Authors: Banfield C , O'Reilly R , Chan E , Rowland M
Published: July 2012

The pharmacokinetics and urinary metabolic profile of R and S‐warfarin, following administration of a 1.5 mg/kg oral dose of racemic warfarin, alone and 4 days into an oral regimen of 100 mg phenylbutazone three times a day, was investigated in three volunteers using a stereospecific h.p.l.c. fluorescent assay. The mean elimination half‐ life of S‐warfarin was increased from 25 to 46 h during phenylbutazone administration, whilst that of the R‐isomer was decreased from 37 to 25 h. The peak unbound concentrations of both warfarin enantiomers were higher during phenylbutazone administration, due to displacement. Displacement was not stereoselective. The unbound clearance of more potent S‐warfarin is decreased by four‐fold during phenylbutazone administration, due to substantial inhibition of both 6‐ and 7‐ hydroxylation, significant pathways of elimination of S‐warfarin in the absence of phenylbutazone. The unbound clearance of R‐warfarin is almost unchanged during phenylbutazone administration, due to the marginal effect of phenylbutazone on 6‐ and 7‐hydroxylation, themselves minor pathways of elimination of this enantiomer in the absence of phenylbutazone. The stereoselective reduction of S‐ and R‐warfarin, to their respective SS and RS‐alcohols, is also substantially inhibited during phenylbutazone administration. Collectively the data point to the complex effect of phenylbutazone administration on warfarin's pharmacokinetics.
Effect of posture on ampicillin pharmacokinetics, glomerular filtration rate and renal plasma flow in resting subjects.
Authors: Breiby M , Aarbakke J , Sundsfjord J , Goussius G , Pape J
Published: July 2012

Differences in drug kinetics between supine rest and ambulation have been reported, but the relative contribution of postural changes and changes in the level of physical activity has not been evaluated. Ampicillin pharmacokinetics, glomerular filtration rate (GFR) and renal plasma flow (RPF) were studied in six male volunteers at rest in the sitting and lying position with an interval of 1 week. After intravenous administration ampicillin kinetics, analyzed according to a two‐compartment open model, demonstrated significant changes in drug distribution when the position was changed from lying to sitting: alpha‐ increased by 50%, V1 and V beta increased by 19% and 22% respectively. Ampicillin clearance, the fraction of dose recovered from urine, GFR and RPF were, however, not influenced by the change in posture. Our data on effects of posture in resting subjects suggest that previously reported differences in drug elimination and RPF between lying and ambulatory subjects are largely due to differences in the level of physical activity.
Acute treatment of hypertensive crisis with nifedipine.
Authors: Huysmans FT , Sluiter HE , Thien TA , Koene RA
Published: July 2012

Ten patients with a hypertensive crisis and a decreased renal function were treated with 10 (n = 7) or 20 (n = 3) mg nifedipine sublingually. Blood pressure was reduced in 60 min from 211 +/‐ 4/134 +/‐ 5 to 172 +/‐ 6/107 +/‐ 6 mm Hg. The decrease of blood pressure was accompanied by a rise in heart rate from 83 +/‐ 6 to 98 +/‐ 5 beats/min. In all seven patients with an encephalopathy signs of this complication were reduced. No serious side‐effects were observed.
Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation.
Authors: Ochs HR , Greenblatt DJ , Knuchel M
Published: July 2012

Healthy volunteers received a single dose of triazolam (0.5 mg) or oxazepam (30 mg) on two occasions, once in the control state and again during coadministration of isoniazid (INH) base, 180 mg day. INH coadministration prolonged triazolam half‐life (3.3 vs 2.5 h, P less than 0.05) and increased total area under the curve (38.6 vs 26.5 ng ml‐ 1 h, P less than 0.01) consistent with a reduction of apparent oral clearance (3.9 vs 6.8 ml min‐1 kg‐1, 0.05 less than P less than 0.1). INH coadministration had no influence on the kinetics of oxazepam. INH impairs hepatic microsomal oxidation of triazolam, leading to reduced first‐pass hepatic extraction as well as prolonged half‐life. However INH had no influence on oxazepam conjugation.
Relationship between plasma concentration and effect of midazolam after oral and intravenous administration.
Authors: Crevoisier C , Ziegler WH , Eckert M , Heizmann P
Published: July 2012

In a double‐blind, cross‐over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg‐1 midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active alpha‐hydroxy metabolite were measured at the same time. The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self‐assessment and investigator's subjective assessment). The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg‐1 and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. Particularly in the first few hours after oral administration the effect is intensified by the alpha‐ hydroxy metabolite of midazolam which is formed by first‐pass metabolism. At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. Correlation of the measured effects with the total (midazolam + alpha‐hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.
Midazolam in the treatment of sleep disorders in geriatric patients.
Authors: Lachnit KS , Proszowski E , Rieder L
Published: July 2012

The use of hypnotics in the elderly must be approached with special care in view of possible changes in pharmacokinetic behaviour and drug interactions in older patients. In a randomized, double‐blind study in a large geriatric department, midazolam was compared with the barbiturate combination Vesparax with regard to efficacy and safety. The comparison of the efficacy of the 2 hypnotics showed them to be almost identical in this respect. Side‐effects, however, were more frequent with Vesparax. Furthermore, in the Vesparax group, unlike in the midazolam group, a troublesome cumulation of effect was observed, together with relatively frequent signs of hangover. It is concluded that, in appropriately titrated dosage, midazolam is an effective and well‐tolerated hypnotic for use in the elderly.
Midazolam and anaesthesia.
Authors: Gemperle M , Kapp W
Published: July 2012

By virtue of its physico‐chemical properties and its rapid biotransformation, midazolam is an important addition in certain areas in anaesthesia. Of particular importance are its good local tissue tolerance after intramuscular injection, the absence of venous irritation, and the rapid start of metabolism with good control of action. Midazolam is suitable for both oral and intramuscular administration as premedication in anaesthesia. The compound can also be used for the induction of anaesthesia in combination with analgesics.
Pharmacokinetics and metabolism of brotizolam in animals.
Authors: Bechtel WD
Published: July 2012

Distribution, and excretion of [14C]‐brotizolam were determined after oral and intravenous administration in the rat, dog, rhesus monkey, and, in part, in cattle. Main metabolites were identified. Brotizolam was rapidly and extensively absorbed. In the rat, dog, and monkey blood levels were analysed according to the time and height of maximum radioactivity concentration. Elimination half‐lives ranged from 14.8 to 20.8 h. Whole body autoradiographic studies in the rat showed that [14C]‐brotizolam and its metabolites were distributed throughout the organism. The placenta was crossed, and brotizolam was found in the milk of rats as well as in that of cows. In the rat, dog and monkey, brotizolam was almost completely metabolized into hydroxylated compounds which were rapidly eliminated as conjugates. After multiple‐ dose treatment, neither a tendency to accumulation of brotizolam and its metabolites nor enzyme induction were found in the rat or monkey.
Pharmacokinetics and metabolism of brotizolam in humans.
Authors: Bechtel WD
Published: July 2012

Pharmacokinetic studies were performed in healthy young volunteers and in elderly patients after oral administration of single doses (0.5 mg), increasing doses (0.5‐1.5 mg), and multiple doses (1.0 mg) of brotizolam. Brotizolam was absorbed quickly from the gastro‐intestinal tract. Elimination half‐lives were in the range of 3.6‐7.9 h. In healthy young volunteers as well as in elderly patients, there was neither a tendency for brotizolam to accumulate nor was there any indication of enzyme induction. Brotizolam was metabolized almost completely into hydroxylated compounds which were conjugated prior to renal excretion. After oral administration of [14C]‐brotizolam, two‐ thirds of excretion of radioactivity was renal and was completed within 4 days.
Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration.
Authors: Jochemsen R , Wesselman JG , Hermans J , Van Boxtel CJ , Breimer DD
Published: July 2012

Pharmacokinetics and bioavailability of brotizolam after i.v. and oral administration were studied in healthy young volunteers. Kinetic parameters after i.v. administration were: volume of distribution 0.66 +/‐ 0.19 1/kg, total plasma clearance 113 +/‐ 28 ml/min, distribution half‐life 11 +/‐ 6 min, and elimination half‐life 4.8 +/‐ 1.4 h (mean values +/‐ s.d.). Kinetic parameters after oral administration were: absorption lag‐time 8 +/‐ 12 min, absorption half‐life 10 +/‐ 11 min, and elimination half‐life 5.1 +/‐ 1.2 h (mean values +/‐ s.d.). Bioavailability of brotizolam was 70 +/‐ 22% when calculated by comparing oral and intravenous area‐under‐curve values, corrected for intra‐individual half‐life differences. An alternative calculation method, which is relatively independent of large clearance variations, provided a bioavailability of 70 +/‐ 24% (range: 47‐117%).
Pharmacokinetics of brotizolam in the elderly.
Authors: Jochemsen R , Nandi KL , Corless D , Wesselman JG , Breimer DD
Published: July 2012

Disposition of brotizolam in patients aged 71‐93 years was compared with that of healthy young subjects aged 21‐26 years. The mean elimination half‐life of brotizolam was about twice as long in the elderly as in the young subjects: 9.3 (4.0‐19.5) h and 4.8 (3.1‐6.3) h respectively. Increase in elimination half‐life was attributable to a decrease in hepatic clearance, i.e. 40 (20‐58) ml/min in the elderly and 109 (77‐156) ml/min in the young. Volume of distribution and protein binding were the same with mean values of 0.56 (0.45‐0.72) l/kg and 9.0 (6.8‐11.9) % in the elderly and 0.63 (0.40‐0.77) l/kg and 8.4 (7.5‐9.4) % in the young. Absorption rate of brotizolam was relatively slow in the elderly with a mean peak time of 1.7 h compared with 1.1 h in the young. Mean bioavailability was almost 70% for both groups. Normalized for body weight and dose (0.25 mg) mean peak concentrations were 247 (137‐395) ng ml‐1 kg in the young and 343 (251‐446) ng ml‐1 kg in the elderly. It is unlikely that substantial drug accumulation will occur if elderly patients ingest 0.25 mg brotizolam nightly.
Effects of brotizolam on the sleep of chronic insomniacs.
Authors: Mamelak M , Csima A , Price V
Published: July 2012

Effects of 0.5 mg brotizolam on the sleep of chronic insomniacs were assessed electroencephalographically and subjectively over 14 days. Brotizolam (0.5 mg) increased total sleep time, decreased drowsy (stage 1) sleep and increased stage 2 sleep. At this dose it also decreased slow wave and rapid eye movement sleep. On withdrawal there was evidence of insomnia in some subjects during the first night. The drug was well tolerated. Further studies are indicated with lower doses of the drug.
Efficacy and acceptability of brotizolam in the elderly.
Authors: von Delbruck O , Nagel C , Lichterfeld A
Published: July 2012

Efficacy of and tolerance to brotizolam were studied over 6 days in elderly patients (62 to 93 years) suffering from sleep disturbance requiring medication: 62.9% used 0.125 mg and 32.0% used 0.25 mg. Effectiveness of brotizolam was assessed as good‐to‐satisfactory in 87.1% of the patients. Efficacy of and tolerance to brotizolam were compared with nitrazepam in mainly elderly patients (56‐91 years) with sleep disturbances requiring medication. Efficacy was assessed as good‐ to‐satisfactory in 89.8% of patients with 0.125 mg brotizolam, 93.9% with 0.25 mg brotizolam and 95.9% with 5 mg nitrazepam. Patients reported improved sleep with all three preparations. The dose range of brotizolam recommended for the elderly is 0.125‐0.25 mg, though for the vast majority of patients the lower dose will be sufficient.
Hypnotic activity of brotizolam: a study in general practice.
Authors: Uzzan B , Warot D , Chermat P , Dantlo B , Bornstein S , Simon P
Published: July 2012

A double‐blind, crossover study was carried out in general practice on the hypnotic activity of 0.25 mg brotizolam in patients aged between 18 and 70 years complaining of insomnia (11 men, 28 women). Patients reported that they slept better, that they awoke less frequently and that they slept longer with brotizolam than with placebo. Overall the patients preferred brotizolam to placebo, and subjective assessments of well‐being after brotizolam did not differ from those after placebo. Brotizolam was well tolerated and there were no incidents of note.
Trazodone enhances sleep in subjective quality but not in objective duration.
Authors: Montgomery I. , Oswald I. , Morgan K. , Adam K.
Published: July 2012

Nine volunteer poor sleepers, of mean age 61 years, took trazodone 150 mg nightly for 3 weeks, preceded by 2 weeks and followed by 1 week of matching blanks, in order to examine the effects of electrophysiologically‐recorded and subjectively‐rated sleep. The second of the initial weeks of matching blanks served as a baseline week. In the subjective ratings, sleep improved in quality on trazodone, significantly so in the first and second weeks of intake, though with significant rebound insomnia on the second withdrawal night. Trazodone halved the frequency of arousals interrupting sleep, and it reduced the time spent in stage 1 (drowsiness). It increased the duration of slow‐wave sleep (stages 3 + 4), with a negative rebound following withdrawal. It reduced the time spent in REM sleep, with a rebound above baseline levels after withdrawal. Trazodone did not change total sleep duration, nor the time required to fall asleep. The effects of trazodone were sustained or became enhanced during the period of intake. They persisted for over 24 h after the last dose, and rebound effects were maximal on the second withdrawal night.
The contribution of genetically determined oxidation status to inter‐ individual variation in phenacetin disposition.
Authors: Devonshire HW , Kong I. , Cooper M. , Sloan TP , Idle J.R. , Smith RL
Published: July 2012

The oxidative O‐de‐ethylation and aromatic 2‐hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/‐ 14.9% dose/0‐8 h; PM: 29.2 +/‐ 8.7% dose/0‐8 h, 2P less than 0.05) and significantly less 2‐hydroxylated metabolites (EM: 4.7 +/‐ 2.3% dose/0‐ 8 h; PM: 9.7 +/‐ 3.5% dose/0‐8 h, 2P less than 0.005) than the PM group. Apparent first‐order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (kml) were higher in the EM group (EM: k = 0.191 +/‐ 0.151 h‐1; kml = 0.091 +/‐ 0.025 h‐1; PM: k = 0.098 +/‐ 0.035 h‐1, 2P less than 0.05, kml = 0.052 +/‐ 0.019 h‐1, 2P less than 0.05) than the PM group. The apparent first‐order rate constant for 2‐hydroxylation displayed no significant inter‐phenotype differences. Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter‐individual variability in phenacetin disposition encountered in this study.
Heart rate and blood pressure responses to intravenous boluses of isoprenaline in the presence of propranolol, practolol and atropine.
Authors: Arnold JM , McDevitt DG
Published: July 2012

Six healthy subjects were studied on two occasions. Graded bolus injections of isoprenaline sulphate were given intravenously and control dose‐response curves were drawn for the changes in heart rate and blood pressure. In a random order each subject received an intravenous infusion of either propranolol or practolol and further dose‐response curves were constructed PRE‐ and POST‐atropine (0.04 mg/kg). Exercise tachycardia was reduced 26.1 +/‐ 2.7% by propranolol and this was not significantly different from the reduction by practolol (21.2 +/‐ 1.9%). Propranolol attenuated the isoprenaline tachycardia (dose ratio 43.7) and after atropinisation the dose ratio was not significantly altered (41.1). Practolol also attenuated the isoprenaline tachycardia (dose ratio 4.4) but after atropinisation the dose ratio was significantly increased to 8.8, though this remained significantly less than the dose ratio for propranolol. At a heart rate increase of 25 beats/min, the isoprenaline‐induced control fall in mean blood pressure was 9‐11 mm Hg. After propranolol administration this fall was converted to a small increase of + 2.3 +/‐ 1.3 mm Hg. Following practolol, however, the mean blood pressure reduction was 19.7 +/‐ 2.9 mm Hg. Practolol did not significantly block the isoprenaline‐induced fall in diastolic pressure. The difference in potency of propranolol and practolol, demonstrated by their effect on isoprenaline induced tachycardia at doses shown to have equal effects on exercise tachycardia, is contributed to but not fully explained by the reflex withdrawal of cardiac vagal tone which occurs with cardioselective but not non‐selective antagonists.
Suppression of plasma cortisol after oral administration of oxazepam in man.
Authors: Gram LF , Christensen L , Kristensen CB , Kragh‐Sorensen P
Published: July 2012

In seven healthy male subjects plasma cortisol was measured at 20 min intervals from 07.00 to 13.00 h, during a drug free control test and after oral administration of 30 and 60 mg oxazepam. A significant suppression of the plasma cortisol levels for about 2 h after 30 mg oxazepam, and for about 3 h after 60 mg oxazepam was observed. The suppression wore off before the oxazepam plasma concentration started to decline significantly.
Captopril: pharmacokinetics, antihypertensive and biological effects in hypertensive patients.
Authors: Richer C , Giroux B , Plouin PF , Maarek B , Giudicelli JF
Published: July 2012

The kinetics of captopril plasma levels and of the drug‐induced plasma converting enzyme activity (PCEA), plasma renin activity (PRA) and diastolic blood pressure (DBP) modifications were studied over 24 h after oral administration of captopril, 1 mg/kg, to ten hypertensive patients. Free unchanged captopril pharmacokinetic parameters were: t1/2, alpha: 0.45 +/‐ 0.06 h; tmax: 0.98 +/‐ 0.13 h; Cmax: 1.31 +/‐ 0.20 mg l‐1; t1/2,z: 0.66 +/‐ 0.13 h; V: 0.614 +/‐ 0.104 1 kg‐1 and CLtot: 0.690 +/‐ 0.082 l h‐1 kg‐1. At 6 h captopril was no longer detectable in plasma. The onset of PCEA inhibition and of DBP decrease closely followed the rise of captopril's plasma levels, while that of PRA increase was delayed. In contrast, while captopril rapidly disappeared from plasma, its biological and antihypertensive effects were long‐lasting. The lack of correlation between the relative bioavailability of captopril and the induced reduction in DBP (evaluated by the corresponding AUCs) suggests that free unchanged captopril plasma monitoring is not an adequate indicator of hypertensive patients' potential responsiveness to captopril's blood pressure lowering effects.
The effects of acute or chronic ingestion of propranolol or metoprolol on the physiological responses to prolonged, submaximal exercise in hypertensive men.
Authors: Wilcox RG , Bennett T , Macdonald IA , Herbert M , Skene AM
Published: July 2012

We have studied the physiological responses to 50 min of intermittent, moderate exercise in hypertensive men after the ingestion of a single dose of placebo, propranolol or metoprolol, and also after 28 days treatment. In addition, subjective assessments of mood were made during the last 7 days of each period of chronic treatment. Heart rate and blood pressure, both at rest and during exercise, were significantly reduced by a single dose of propranolol or metoprolol; more marked effects were observed after chronic treatment. Ventilation and gas exchange during exercise were only slightly disturbed by single doses of propranolol or metoprolol, whereas chronic treatment had no effect. Perceived exertion scores were increased after a single dose of either drug, compared to placebo, and the effect of propranolol was greater than that of metoprolol. With chronic treatment there were fewer differences between the perceived exertion scores during exercise, although ‘leg’ fatigue remained greater after propranolol than after placebo. Sweating from the forehead during exercise was enhanced by a single dose of either beta‐adrenoceptor antagonist, with propranolol having the greater effect. After chronic treatment the effect of propranolol was diminished, whereas the effect of metoprolol was maintained. Very few disturbances of mood were found after chronic ingestion of the beta‐adrenoceptor antagonists.
The effects of acute or chronic ingestion of propranolol or metoprolol on the metabolic and hormonal responses to prolonged, submaximal exercise in hypertensive men.
Authors: Macdonald IA , Bennett T , Brown AM , Wilcox RG , Skene AM
Published: July 2012

We have studied the effects of single oral doses of, and of 28 days treatment with, placebo, propranolol or metoprolol, on the metabolic and hormonal responses to prolonged exercise in hypertensive men. Blood glucose levels fell during exercise on all occasions. No additional effects of the beta‐adrenoceptor antagonists, compared to placebo, were observed. The exercise‐induced increase in plasma potassium was enhanced after a single dose of propranolol or metoprolol, and also after chronic treatment with propranolol. Chronic treatment with either drug led to an increase in plasma potassium levels at rest. The growth hormone response to exercise was potentiated by a single dose of metoprolol or propranolol, and after chronic treatment with the drugs. A single dose of propranolol (but not metoprolol) was associated with a marked increase in plasma cortisol and adrenaline levels during exercise. After chronic treatment no such increase occurred. In both the acute and chronic phases of the study, blood lactate levels were higher during exercise in the presence of either propranolol or metoprolol compared to placebo, whereas non‐esterified fatty acid levels were lower. A single dose of metoprolol produced a significantly greater reduction in blood glycerol levels during exercise than a single dose of propranolol. After chronic treatment, both propranolol and metoprolol produced similar reductions in blood glycerol levels during exercise. After a single dose, both drugs significantly augmented the increase in plasma noradrenaline levels during exercise. A similar effect was seen after chronic treatment.
Acute effects of ketanserin on left ventricular function, metabolism and coronary blood flow.
Authors: Walker JM , Wilmshurst PT , Juul SM , Coltart DJ
Published: July 2012

An acute intravenous bolus of 10 mg ketanserin (a specific 5‐HT antagonist) caused an abrupt fall in left ventricular systolic pressure of 17 +/‐ 9.2 mm Hg (P less than 0.025) in ten patients undergoing cardiac catheterisation for chest pains. A fall in pulmonary artery diastolic pressure of 2.1 +/‐ 0.74 mm Hg (P less than 0.02) was also observed. No changes in resting heart rate occurred and the response to pacing was largely unmodified by ketanserin, except for a reduction in pulmonary vascular resistance (3.70 +/‐ 1.27 units to 2.97 +/‐ 1.44 units, P less than 0.05), at the fastest rate (136 +/‐ 3 beats/min). At the highest pacing rate coronary sinus blood flow fell (83 +/‐ 12 ml 100 g‐1 min‐1 to 68 +/‐ 8 ml 100 g‐1 min‐1, P less than 0.05), as did myocardial oxygen consumption (18 +/‐ 2 ml‐1 min to 14 +/‐ 1 ml min‐1, P less than 0.05) after the drug. No changes in the parameters of left ventricular contractile function could be attributed to ketanserin, save for a modest increase in the ejection fraction (48 +/‐ 6% to 57 +/‐ 6%, P less than 0.05) in seven patients. There were no alterations in myocardial metabolism of lactate, pyruvate, hydroxybutyrate, glycerol nor free fatty acids after ketanserin. The findings are consistent with a peripheral site of action of this drug and its blood pressure lowering effect in the subjects suggest a non‐specific hypotensive action rather than an anti‐hypertensive effect.
Twice daily slow‐release theophylline vs placebo for ‘morning‐dipping’ in asthma.
Authors: Davies PD , Fennerty AG , Benfield GF , Parrish RW , Campbell IA
Published: July 2012

We report the results of a double‐blind control crossover trial of slow release theophylline Nuelin S.A. in improving symptoms of ‘morning‐ dipping’ in twelve asthmatic patients. Sleep disturbance was lessened and ‘morning‐dipping’, though not abolished, was improved by 24% (P less than 0.01). Mean peak expiratory flow‐rate (PEFR) on waking was significantly higher on active drug (262 l/min vs 226 l/min, P less than 0.001) as were the evening PEFRs (316 l/min vs 285 l/min, P less than 0.05). Seven of the 12 patients achieved 26% improvement in mean PEFR (P less than 0.05) with plasma theophylline levels in the range 28‐ 44 mumol/l. The other five patients improved by 9% (P less than 0.02) with levels in the range 55‐66 mumol/l. Mean plasma cyclic AMP 4‐6 h after theophylline was significantly higher than with placebo (27.0 nmol/l vs 17.6 nmol/l, P less than 0.05) but significant correlations between cyclic AMP and theophylline levels, and cyclic AMP and PEFR were not demonstrated. A total of nine patients, 33% of those originally recruited for this study, withdrew prior to the double‐blind phase because of unacceptable side‐effects of theophylline, namely nausea and headache.
Pharmacokinetics of digoxin alone and in the presence of indomethacin therapy.
Authors: Finch MB , Johnston GD , Kelly JG , McDevitt DG
Published: July 2012

The effects of maintenance indomethacin therapy on single dose digoxin pharmacokinetics and dynamics were studied in six healthy volunteers with normal renal function. Indomethacin did not alter the elimination half‐life, systemic clearance or distribution of digoxin. No pharmacodynamic interaction as assessed by changes in the systolic time intervals QA2 and LVET was found. This study does not lend support for a significant digoxin‐indomethacin interaction in man.
Drug metabolite concentration‐time profiles: influence of route of drug administration.
Authors: Houston JB , Taylor G
Published: July 2012

In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration‐time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration‐time data have been carried out. A route dependence in metabolite concentration‐time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 l/h (medium to highly cleared). Oral drug administration produces a triphasic metabolite concentration‐time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first‐pass metabolite production. The route dependence in the shape of the metabolite concentration‐time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration‐time profile such that the consequence of first‐pass metabolite formation may be reduced.
Alterations in prednisolone disposition as a result of time of administration, gender and dose.
Authors: Meffin PJ , Brooks PM , Sallustio BC
Published: July 2012

The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time‐averaged prednisolone free fraction was 22% higher (P less than 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. Mean total prednisolone clearance and steady‐state distribution volume were two‐fold higher at the high vs the low dose (P less than 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady‐state distribution volume.
Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission.
Authors: Gatti G , Perucca E , Frigo GM , Notarangelo LD , Barberis L , Martini A
Published: July 2012

The kinetics at steady state of prednisone and its metabolite prednisolone were determined in nine nephrotic children during the active phase of the disease and in remission. There were no differences in serum prednisone levels between the two occasions. Prednisone levels were lower than prednisolone levels. Total serum prednisolone levels were significantly lower during the active phase than in remission (AUC: 2452 +/‐ 207 vs 3392 +/‐ 293 ng ml‐1 h respectively). Half‐life values were similar on both occasions. The binding of prednisolone to serum proteins was markedly impaired during the active phase as compared to the remission. Free fraction values correlated positively with total drug concentration. A negative correlation between free fraction and serum albumin level was found during the active phase. Free prednisolone levels during the active phase did not differ significantly from those observed during remission (AUC: 937 +/‐ 128 vs 847 +/‐ 81 ng ml‐1 h respectively). These data indicate that pharmacokinetic changes are unlikely to be responsible for alterations in steroid responsiveness in nephrotic patients with hypoalbuminaemia.
The influence of urinary pH on flecainide excretion and its serum pharmacokinetics.
Authors: Muhiddin KA , Johnston A , Turner P
Published: July 2012

The effect of urinary pH on flecainide excretion has been evaluated in six healthy subjects after a single oral dose of 300 mg flecainide administered as the acetate salt. The cumulative urinary excretion of unchanged flecainide under acidic conditions (134.0 +/‐ 16.1 mg; mean +/‐ s.e. mean) was significantly higher than under alkaline conditions (22.3 +/‐ 7.6 mg; mean +/‐ s.e. mean) (P less than 0.01). Under alkaline conditions, tmax (time to reach peak concentration) was reduced (P less than 0.01), while elimination half‐life, AUC(0‐32) and AUC(0‐infinity) were increased (P less than 0.01).
Urinary bile acid and bile alcohol excretion does not reflect the genetic polymorphism of debrisoquine hydroxylation.
Authors: Karlaganis G , Kupfer A , Preisig R
Published: July 2012

Excretion of the major urinary bile alcohol 27‐nor‐5 beta‐cholestane‐3 alpha, 7 alpha, 12 alpha, 24,25‐ pentol, and of cholic, chenodeoxycholic, deoxycholic and lithocholic acid was measured in 24 h urine collections of 10 extensive and seven poor metabolizers of debrisoquine. There was no significant difference of the excretion of these cholesterol metabolites between the two groups, indicating that cholesterol hydroxylation to bile alcohols and bile acids is probably not controlled by the same genes responsible for the ‘debrisoquine‐ type’ hydroxylation polymorphism.