bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta‐adrenoceptor agonists and theophylline.
Authors: Goldie RG , Spina D , Henry PJ , Lulich KM , Paterson JW
Published: July 2012

Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non‐diseased and from asthmatic lung obtained 3‐15 h post‐mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non‐diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta‐adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4‐ 5 fold in asthmatic bronchi compared with non‐diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2‐adrenoceptor function.
The influence of quinolone derivatives on theophylline clearance.
Authors: Wijnands WJ , Vree TB , Van Herwaarden CL
Published: July 2012

Enoxacin decreases the metabolic clearance of the bronchodilator theophylline not only in severely ill patients, but also in patients with stable chronic obstructive airways disease. In this comparative study, significantly increased plasma theophylline concentrations were measured during co‐administration of enoxacin (110.9%) and, to a lesser degree, also during co‐administration of pefloxacin (19.6%) and ciprofloxacin (22.8%). Total body clearance of theophylline was significantly decreased by enoxacin (63.6%), ciprofloxacin (30.4%) and pefloxacin (29.4%). The pharmacokinetic parameters of theophylline did not change during co‐administration of ofloxacin and nalidixic acid. There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4‐oxo metabolite of enoxacin, pefloxacin and ciprofloxacin.
Pharmacokinetic profile of indoprofen in elderly subjects.
Authors: Lund B , Egsmose C , Knudsen O , Andersen RB
Published: July 2012

Multiple dosing four times daily for 7 days of indoprofen 200 mg, a non‐ steroidal anti‐inflammatory drug with a short half‐life (t1/2), revealed drug accumulation in eight elderly subjects. This indicates a substantially longer t1/2 (11 h) than that reported in young persons (3 h). A reduction in dose compared to younger subjects is recommended in elderly patients with osteoarthritis.
The effects of age on carbamazepine pharmacokinetics and adverse effects.
Authors: Hockings N , Pall A , Moody J , Davidson AV , Davidson DL
Published: July 2012

The pharmacokinetics and effect of single oral doses of carbamazepine (400 mg) were compared in a group of six young volunteers aged between 20 and 25 years, and a second group of five elderly volunteers aged between 66 and 84 years. No age related changes in salivary or plasma pharmacokinetics or in psychomotor function were detected.
Oxicams: relative safety and anti‐injury effects in rats.
Authors: Whitehouse MW
Published: July 2012

1 Oxicams have certain distinctive properties, which distinguish them from other arylalkanoic (carboxylic) acids that show anti‐ inflammatory/analgesic/antipyretic activities. These include: (i) slow rates of metabolism (ii) lesser gastro‐irritancy/ulcerogenicity (iii) preventing fever development (iv) some effect on the adaptive responses of the liver to severe inflammation or trauma that compromise normal hormone/xenobiotic metabolism (detoxification). 2 Isoxicam was notably less gastrotoxic than either piroxicam or tenoxicam, when given either orally or parenterally, at equipotent doses in rats.
A comparison of isoxicam pharmacokinetics in young and elderly subjects.
Authors: George CF , Renwick AG , Darragh AS , Hosie J , Blake D , Van Marle W , Frank GJ
Published: July 2012

1 The pharmacokinetics of isoxicam have been compared in 57 volunteers with an average age of 31.3 years and 48 elderly subjects with an average age of 71.9 years. 2 Isoxicam was given in a single daily dose of 200 mg for up to 22 days. Similar plasma concentrations were obtained in the two age groups, average maximum concentrations being 39.7 mg l‐1 in those under 65 and 38.1 mg l‐1 in the elderly. There were no significant differences in the half‐life which averaged 30.4 and 32.1 h respectively. 3 Approximately 9% of all those studied had half‐life values in excess of 50 h. The results are consistent with the possibility of genetic polymorphism of isoxicam hydroxylation. 4 It is concluded that isoxicam is suitable for use in once daily dosage and that there are no clinically significant differences in its pharmacokinetics between young and elderly subjects.
Pharmacokinetics of isoxicam following intravenous, intramuscular, oral and rectal administration in healthy volunteers.
Authors: Kolle EU , Vollmer KO
Published: July 2012

1 The pharmacokinetic characteristics and bioavailability of isoxicam were investigated in healthy male volunteers following various routes of administration. Plasma concentrations were determined up to 96 or 120 h following each administration using a selective h.p.l.c. method. 2 Twelve subjects received an i.v. and an i.m. injection of 150 mg and an oral dose of 200 mg (two capsules) in a three‐way crossover design. 3 The plasma concentration‐time curves after intravenous administration followed two compartmental characteristics with a rapid initial distribution phase and a predominant terminal elimination phase. The area under the distribution phase contributed only 0.4% to the total AUC. Mean disposition parameters were: t1/2, lambda 1 = 3.3 min t1/2, lambda z = 28 h, Vc = 5.61, Vdarea = 12.71, CL = 5.1 ml min‐1. 4 Following other routes of administration, the isoxicam plasma profile could be adequately described by a one compartment model. 5 After the i.m. dose, isoxicam was rapidly and completely absorbed: within 15 min 40% of the peak concentrations were attained. Maximum plasma concentrations of 11.7 micrograms ml‐1 were reached after an average of 3 h. 6 After oral administration isoxicam was completely bioavailable. Mean peak concentrations of 12.3 micrograms ml‐1 were obtained within 10 h. 7 The bioavailability of suppositories containing 200 mg of active substance was investigated in another 10 volunteers relative to capsules (2 × 100 mg). The formulations tested were bioequivalent with respect to the amount absorbed. 8 Comparison of AUCs (normalized for dose and body weight) resulting from all treatments, did not show significant differences among the various formulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of the efficacy and tolerance of isoxicam and piroxicam following surgery for skiing accidents.
Authors: Massart P , Bezes H
Published: July 2012

1 A 10 day double‐blind study was carried out comparing isoxicam (300 mg day‐1) and piroxicam (40 mg day‐1 for the first two days and 20 mg day‐1 for the remaining days) following surgery in patients who had sustained skiing accidents. There were 20 patients in each group. The isoxicam‐treated group had a slightly greater mean pain score prior to treatment. 2 Both isoxicam and piroxicam reduced pain and nocturnal awakening at days 5 and 10, but isoxicam was significantly superior to piroxicam in producing improvement in pain (at day 5, P less than 0.05) and in nocturnal awakenings (at day 10, P less than 0.05). 3 Both agents facilitated rehabilitation and there was no significant difference between them in this regard. 4 All patients in both groups considered themselves ‘better’ or ‘much better’ on day 5 of treatment. 5 Both agents were well tolerated by most patients but one patient in each group left the trial because of abdominal pain. One patient stopped isoxicam when she was found to be pregnant.
Haemodynamic effects of vasodilating drugs on the common carotid and brachial circulations of patients with essential hypertension.
Authors: Bouthier JD , Safar ME , Benetos A. , Simon AC , Levenson JA , Hugues CM
Published: July 2012

The haemodynamic pattern of the common carotid artery was studied in men with sustained essential hypertension using pulsed Doppler methods before and after administration of vasodilating drugs. Captopril produced both a fall in vascular resistance and an increase in arterial diameter of the common carotid artery. Isosorbide dinitrate increased markedly the arterial diameter but did not change vascular resistance. Nitrendipine decreased vascular resistance with no change in the arterial diameter. In the common carotid circulation of patients with essential hypertension, vasodilating drugs may either dilate small arteries (nitrendipine), large arteries (isosorbide dinitrate), or both (captopril).
The pharmacokinetics of R‐ and S‐tocainide in patients with acute ventricular arrhythmias.
Authors: Thomson AH , Murdoch G. , Pottage A. , Kelman AW , Whiting B. , Hillis WS
Published: July 2012

The pharmacokinetics of R(‐) and S(+)‐ tocainide were studied in twelve patients requiring intravenous tocainide. In all patients, a progressive increase in the S(+):R(‐) ratio was observed during the infusion. Mean +/‐ s.d. ratios increased from 1.03 +/‐ 0.05 at 2 min to 1.76 +/‐ 0.35 at 48.5 h. Data from eight patients were fitted to a two‐ compartment model and there was a significant difference (Wilcoxon matched‐pairs test P less than 0.01) in the clearance estimates for the two enantiomers. The median values were: S(+)‐tocainide = 6.25 l h‐1 and R(−)−tocainide = 9.31 l h‐1. There was no differences in V1 or Vss.
Kinetic and dynamic interaction of brotizolam and ethanol.
Authors: Scavone JM , Greenblatt DJ , Harmatz JS , Shader RI
Published: July 2012

Thirteen healthy male volunteers ingested a single 0.25 mg dose of the thienodiazepine hypnotic, brotizolam, on two occasions: once with a typical social cocktail (containing 60 ml of vodka), and in a second trial with an 'ethanol‐placebo' cocktail. Brotizolam kinetics were determined from multiple plasma concentrations measured during the 24 h after dosage. Coadministration of brotizolam with ethanol, as opposed to the placebo cocktail, slightly imparied brotizolam clearance (1.85 vs 2.19 ml min‐1 kg‐1 P less than 0.005), increased peak plasma concentrations (5.3 vs 4.3 ng ml‐1, P less than 0.05), and prolonged elimination half‐life (5.2 vs 4.4 h, P less than 0.05). There was evidence of impairment of performance, although not statistically significant, for the first 4‐6 h after brotizolam dosage in the reaction time test, the digit‐symbol substitution test, and a tracking task. None of these was enhanced by ethanol. In both trials, brotizolam produced significant increases in self‐rated perceptions of sedation, fatigue, feeling 'spaced‐out', and thinking slowed down. These effects were more intense during the brotizolam‐ethanol as compared to brotizolam‐placebo. In both trials, recovery was essentially complete by 6‐8 h after dosage. Coadministration of brotizolam with ethanol produces a small but significant impairment of brotizolam clearance. Brotizolam produced self‐rated perceptions of sedation and fatigue during 4‐6 h after dosage, but objective impairment of psychomotor performance was minimal. Subjective perceptions of sedation were enhanced by ethanol coadministration, but the effects on psychomotor performance were not.
Subclinical impairment of colour vision in patients receiving ethambutol.
Authors: Joubert PH , Strobele JG , Ogle CW , van der Merwe CA
Published: July 2012

Colour discrimination was assessed by means of the Farnsworth‐Munsell 100‐Hue test in 54 patients being treated for tuberculosis with ethambutol and 50 patients who were treated for tuberculosis by drugs other than ethambutol. The ethambutol group showed significantly more errors than controls along the deuteran axis. The sub‐group of ethambutol treated patients who had been taking the drug for more than 2 months showed significantly more errors along the tritan axis. It is concluded that subclinical colour discrimination impairment is relatively common in patients receiving ethambutol and that a deuteran type of defect is an early and a tritan type of defect is a later manifestation of ethambutol toxicity.
Effects of ICI 141,292 on exercise tachycardia and isoprenaline‐induced beta‐adrenoceptor responses in man.
Authors: Pringle TH , O'Connor PC , McNeill AJ , Finch MB , Riddell JG , Shanks RG
Published: July 2012

The beta‐adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/‐ 3.7%) and 400 mg (24.3 +/‐ 5.2%) were similar to atenolol 50 mg (27.3 +/‐ 4.7%) but less than atenolol 100 mg (30.8 +/‐ 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min‐1. Dose‐response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min‐1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta‐adrenoceptor antagonist with partial agonist activity.
Dose independent pharmacokinetics of mexiletine in healthy volunteers.
Authors: Pringle T. , Fox J. , McNeill JA , Kinney CD , Liddle J. , Harron DW , Shanks RG
Published: July 2012

In 12 healthy volunteers who received orally 100, 200, 300, 400 and 600 mg mexiletine at weekly intervals, the maximum plasma concentration of mexiletine and AUC increased linearly with the dose of mexiletine. Between doses there were no significant differences in the values for clearance and volume of distribution of mexiletine but there were for plasma elimination half‐life. These results indicate that the kinetics of mexiletine are linear.
The plasma protein binding of metoclopramide in health and renal disease.
Authors: Webb D. , Buss DC , Fifield R. , Bateman DN , Routledge PA
Published: July 2012

The plasma protein binding of metoclopramide was measured after addition of the drug (60 ng ml‐1) to plasma from 18 patients with renal disease and 18 age and sex matched healthy individuals. The mean free fraction in renal disease (0.59 range 0.41‐0.71) was not significantly different from controls (mean 0.6 range 0.56‐0.69). In both groups the binding ratio of metoclopramide was significantly related to plasma alpha 1‐acid glycoprotein (AAG) concentration but not to albumin or plasma non‐esterified fatty acids concentration. Metoclopramide bound to human serum albumin (HSA) to a limited extent and to human AAG to a greater extent indicating that AAG is the major binding protein for the drug in plasma.
Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.
Authors: Hockings N. , Ajayi AA , Reid JL
Published: July 2012

The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22‐30 years and nine sex matched elderly subjects aged 65‐73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration‐time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/‐ 0.16) and elderly subjects (0.61 +/‐ 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.
Age and the pharmacodynamics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.
Authors: Ajayi AA , Hockings N. , Reid JL
Published: July 2012

The effect of age on the pharmacodynamic responses to converting enzyme inhibitors, enalapril and enalaprilat was investigated in nine young (22‐30 years) and nine sex‐matched elderly (65‐73 years), healthy volunteers. The groups differed in baseline blood pressure, young 121/64 mmHg, elderly 142/75 mmHg (P less than 0.01), but not in sodium intake or body weight. Both enalapril and enalprilat produced significant falls in blood pressure in both groups but no increase in heart rate in the supine or erect posture. The blood pressure fall was significantly greater in the elderly on both treatments and in both erect and supine posture. The greater fall in blood pressure in the elderly was associated with a more prolonged inhibition of plasma angiotensin converting enzyme activity. The apparent age‐related difference in response appears to be due to the difference in baseline blood pressures between the groups. Further study of the usefulness of chronic dosing with angiotensin converting enzyme inhibitors in hypertension in the elderly is indicated.
The haemodynamic and myocardial effects of dopexamine: a new beta 2‐ adrenoceptor and dopaminergic agonist.
Authors: Jaski BE , Wijns W. , Foulds R. , Serruys PW
Published: July 2012

Dopexamine increases inotropic state and rate of relaxation independent of changes in heart rate. Dopexamine has a chronotropic effect and results in a decrease in systemic vascular resistance. Dopexamine has a spectrum of action that should be useful in patients with severe heart failure.
Racial differences in drug responses‐a comparative study of trimazosin and alpha 1‐adrenoceptor responses in normotensive Caucasians and West Africans.
Authors: Vincent J. , Elliott HL , Meredith PA , Reid JL
Published: July 2012

The possible racial differences in alpha 1‐adrenoceptor responsiveness and the blood pressure and heart rate responses following alpha 1‐ adrenoceptor antagonism with trimazosin have been investigated in matched groups of six Caucasians and six Nigerians. There were no significant differences between the racial groups in the blood pressure and heart rate responses to oral (200 mg) and intravenous (100 mg) trimazosin. alpha 1‐adrenoceptor responsiveness was similar in both groups after placebo and following both active treatments. There were only minor pharmacokinetic differences with the Caucasians having a larger volume of distribution, and a longer terminal elimination half‐ life for the metabolite, 1‐hydroxy‐trimazosin. These results suggest a similarity in peripheral vascular alpha 1‐adrenoceptor mechanisms and show no major significant racial differences in the pharmacokinetics and pharmacodynamics of trimazosin.
Prolonged midazolam elimination half‐life.
Authors: Dundee JW , Collier PS , Carlisle RJ , Harper KW
Published: July 2012

The pharmacokinetics of a fixed dose of midazolam (0.3 mg kg‐1 i.v.) were studied in detail in 115 healthy patients or volunteers and nine were found with a prolonged elimination half‐life. A further 102 patients had an abbreviated pharmacokinetic study, of whom five showed a similar abnormality. Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug.
Disposition of metronidazole and its effects on sulphasalazine metabolism in patients with inflammatory bowel disease.
Authors: Shaffer JL , Kershaw A. , Houston JB
Published: July 2012

The pharmacokinetics of metronidazole were studied after oral and intravenous administration to seven patients with Crohn's disease and five patients with ulcerative colitis. The oral/intravenous availability ratio was 0.97 +/‐ 0.2 in the Crohn's patients and 0.90 +/‐ 0.1 in the colitics (mean +/‐ s.e. mean). Plasma clearance was 3.24 +/‐ 0.2 l h‐1 and 4.1 +/‐ 0.5 l h‐1, respectively. These differences were not statistically significant. Ten of the patients on long term sulphasalazine were studied to observe the effect of 2 weeks metronidazole therapy on plasma sulphapyridine concentration. The sulphapyridine concentration changed from 22.1 +/‐ 2.0 micrograms ml‐1 to 15.95 +/‐ 4.5 micrograms ml‐1 in the Crohn's patients and 26.0 +/‐ 6.0 micrograms ml‐1 to 36.4 +/‐ 8.5 micrograms ml‐1 in the colitis group, pre‐ and post‐metronidazole. These differences were not statistically significant. These results suggest that metronidazole does not interfere with diazo‐link splitting of sulphasalazine and that patients with Crohn's disease handle metronidazole in a similar manner to patients with colitis.
Protective effect of theophylline on histamine‐induced bronchoconstriction in asthmatic children.
Authors: Levene S. , McKenzie SA
Published: July 2012

The bronchial responsiveness of a group of asthmatic children was studied using histamine stimulation after a single dose of theophylline and after placebo. Theophylline, when levels were greater than 10 micrograms ml‐1 significantly reduced responsiveness but only by just over one doubling concentration of histamine (P less than 0.001).
Potentiation of the adverse effects of intravenous terbutaline by oral theophylline.
Authors: Smith SR , Kendall MJ
Published: July 2012

We have studied the influence of therapeutic plasma concentrations of theophylline on some of the unwanted responses to intravenous terbutaline in normal subjects. There was a significantly greater fall in serum potassium and rise in plasma glucose, pulse rate and systolic blood pressure in response to an intravenous infusion of terbutaline when theophylline was present compared with when terbutaline was given alone. These drugs are commonly used together in the treatment of acute asthma and potentiation of side effects may be hazardous. We suggest monitoring of the serum potassium when these drugs are used together during acute exacerbations of asthma.
Effect of allopurinol on caffeine disposition in man.
Authors: Grant DM , Tang BK , Campbell ME , Kalow W.
Published: July 2012

Caffeine (5 mg kg‐1) was administered orally to two healthy, non‐ smoking subjects on three separate occasions‐before, and during therapy with the xanthine oxidase inhibitor allopurinol at doses of either 300 or 600 mg daily. Plasma and urinary levels of methylxanthines, endogenous oxypurines and allopurinol and its metabolite oxypurinol were measured using h.p.l.c. analyses. Allopurinol treatment caused a specific, dose‐dependent inhibition of the conversion of the caffeine metabolite 1‐methylxanthine (1X) to 1‐ methyluric acid (1U). A good correlation was observed in both subjects between the urinary 1U/1X molar ratio and the ratio of endogenous urate to hypoxanthine + xanthine at the different allopurinol doses, supporting the proposal that the 1U/1X molar ratio after caffeine intake provides an in vivo index of xanthine oxidase activity in man.
Human gastrointestinal absorption of acyclovir from tablet duodenal infusion and sipped solution.
Authors: Lewis LD , Fowle AS , Bittiner SB , Bye A. , Isaacs PE
Published: July 2012

On two occasions at least 1 week apart, nine healthy male volunteers were administered in random order either 2 X 200 mg (1.8 mmol) acyclovir tablets or 400 mg of acyclovir in 500 ml of 5% dextrose solution which was infused at constant rate into the duodenum over 4 h. Six of the subjects subsequently sipped the same solution at the rate of 10.4 ml in each 5 min period for 4 h. Blood and urine were sampled over 24 h for each mode of administration. Acyclovir was assayed by radioimmunoassay. Mean areas under the plasma concentration‐time curves (AUCs) +/‐ s.d. for tablet (T), intraduodenal infusion (I) and sipping (S) were, respectively: T = 14.7 +/‐ 5.1; I = 24.6 +/‐ 5.1; S = 28.4 +/‐ 9.5 (n = 6) mumol l‐1 h. AUCs for I and S were significantly greater than that for T (2P less than 0.05). Mean apparent maximum plasma concentrations (Cmax) +/‐ s.d. were T = 3.8 +/‐ 1.5; I = 4.8 +/‐ 0.9; S = 5.1 +/‐ 1.5 mumol l‐1. This trend to higher values for I and S was not significant. Mean apparent plasma disappearance half‐lives (t1/2) +/‐ s.d. were respectively T = 2.3 +/‐ 0.4; I = 2.7 +/‐ 0.5; S = 3.0 +/‐ 0.2 h, I being significantly greater than T (2P less than 0.05), as was S greater than T (2P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.
Authors: Griffiths AN , Jones DM , Richens A.
Published: July 2012

The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo. The performance tests selected (stroop task, five choice serial reaction time, memory span, logical reasoning, mood and saccadic eye movement analysis) were thought to reflect aspects of normal daily activity. The tests demonstrated a clear reduction of performance for all active treatments. No drug emerged as the most potent sedative overall, as each of the tests was affected to a different degree by each drug. Drug effects were not qualitatively different between active treatments so that zopiclone was indistinguishable from the three benzodiazepines with which it was compared.
Sparteine oxidation polymorphism: a family study.
Authors: Brosen K. , Otton SV , Gram LF
Published: July 2012

Polymorphic oxidation of the pharmacogenetic probe drug sparteine was investigated in 35 parents and 29 siblings of 20 unrelated poor metabolizer (PM) probands. Phenotyping was carried out on the basis of metabolic ratio (MR) = sparteine/dehydrosparteines in the 12 h urine. The distribution of MR was bimodal: 47 relatives (20 siblings and 27 parents) had MR ranging from 0.22‐12 and were defined as extensive metabolizers (EM) whereas MR ranged from 20‐340 in nine siblings and eight parents thus defined as PM. The 20 pedigrees confirmed that poor metabolism of sparteine is inherited as an autosomal recessive character. The mean recovery of dehydrosparteines (% of dose) was 27% in 23 positively identified drug free heterozygotes compared with 37% in unrelated EM (both genotypes) (P less than 0.05) previously phenotyped. Degrees of dominance of 73% and 77% were calculated on basis of log excretion of dehydrosparteines (% of dose in 12 h urine) and log MR, respectively.
Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria.
Authors: Phillips RE , Looareesuwan S. , White NJ , Silamut K. , Kietinun S. , Warrell DA
Published: July 2012

Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg‐1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/‐ 0.27 l kg‐1 (+/‐ s.d.), elimination half‐ time (t1/2,z), 11.3 +/‐ 4.3 h, total clearance, 1.22 +/‐ 0.77 ml min‐1 kg‐1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l‐1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/‐ s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/‐ 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l‐1; simultaneous maternal plasma quinine was 7.1 mg l‐1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5‐ 3.6 mg l‐1 (mean 2.6) and 0.11‐0.53 (mean 0.31) in twenty‐five women who were breast‐feeding and had taken oral quinine sulphate for 1‐10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l‐1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of diabetes mellitus, exercise, and single doses of biguanides upon lactate metabolism in man.
Authors: Fletcher P. , Hirji MR , Kuhn S. , Alexander L. , Mucklow JC
Published: July 2012

The polymorphism of phenformin oxidation has been investigated in 103 non‐insulin‐dependent (Type II) diabetics. The frequency distribution was clearly bimodal and 14 poor metabolisers were identified. The frequency of the recessive allele (0.369) was not significantly different from that found previously in non‐diabetics. Six of the extensive metabolisers of phenformin were matched for age, sex and oxidizer phenotype with non‐diabetic controls. All subjects underwent a standard 3‐min exercise test, using a bicycle ergometer, after which plasma lactate concentration was monitored for 90 min. There was no significant difference between groups in lactate accumulation or elimination. Ten extensive metabolisers, ten poor metabolisers and seven non‐diabetics (matched for age, sex and phenotype with seven of the diabetic extensive metabolisers) were challenged with a fasting oral dose of phenformin (50 mg), after which plasma lactate, and blood pyruvate and glucose concentrations were monitored for 4 h. A further ten diabetics (five extensive and five poor metabolisers of phenformin) received a single dose of metformin (1 g) following an identical protocol. No significant changes were observed in any group.
Effect of nadolol on liver haemodynamics and function in patients with cirrhosis.
Authors: Merkel C. , Sacerdoti D. , Finucci GF , Zuin R. , Bazzerla G. , Bolognesi M. , Gatta A.
Published: July 2012

Beta‐adrenoceptor blockers used in the medical management of portal hypertension decrease liver blood flow. The sporadic onset of hepatic encephalopathy during propranolol treatment was ascribed to this decrease. The aim of the present study was to evaluate the effect of chronic treatment with nadolol on liver blood flow and liver function. Nadolol, a non‐cardioselective beta‐adrenoceptor blocker, has been reported to be as powerful as propranolol in decreasing portal pressure. Before and after 1 month of treatment with nadolol at a dose reducing heart rate by 25%, in 15 cirrhotic patients with portal hypertension, the following parameters were determined: hepatic venous pressure gradient, hepatic blood flow, galactose eliminating capacity, aminopyrine metabolic activity, ICG clearance and intrinsic hepatic clearance. Hepatic venous pressure gradient and hepatic blood flow were decreased by nadolol. However liver function was not affected by the drug. We conclude that, despite a lowered hepatic blood flow, liver function is not affected by 1 month of nadolol treatment.
A comparison of the ventilatory, cardiovascular and metabolic effects of salbutamol, aminophylline and vasoactive intestinal peptide in normal subjects.
Authors: Morice AH , Schofield P. , Keal EE , Sever PS
Published: July 2012

Intravenous infusion of placebo for 30 min followed by either salbutamol 10 micrograms min‐1, aminophylline 0.2 mg kg‐1 min‐1 or vasoactive intestinal peptide (VIP) 6 pmol kg‐1 min‐1 for 30 min was performed in a single blind fashion in six normal volunteers. Both salbutamol and aminophylline increased minute ventilation, (P less than 0.05) the mean increase being 26% and 19% respectively. Aminophylline also increased the ventilatory response to carbon dioxide by 47% (P less than 0.05) when measured by hyperoxic rebreathing, whereas salbutamol and VIP were without significant effect. All three drugs caused a tachycardia, mean increase in the pulse being 16, 8 and 2 beats min‐1 for salbutamol, aminophylline and VIP respectively, and aminophylline also increased both systolic and diastolic blood pressure, mean arterial pressure increasing by 14 mmHg. VIP caused haemoconcentration and salbutamol the expected changes in plasma biochemistry. Plasma catecholamines increased slightly during drug infusion, although this effect is unlikely to be important.
Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.
Authors: Lelo A. , Birkett DJ , Robson RA , Miners JO
Published: July 2012

The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml min‐1 kg‐1, respectively) as were those for TP and TB (0.93 and 1.20 ml min‐1 kg‐1, respectively). The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min‐1 kg‐1, respectively) as were those of TP and TB (1.61 and 1.39 ml min‐1 kg‐1, respectively). The half‐lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively). The volume of distribution at steady state of TP (0.44 l kg‐1) was lower than that of the other methylxanthines (0.63‐ 0.72 l kg‐1). The unbound volume of distribution of TP (0.77 l kg‐1) was however the same as that of TB (0.79 l kg‐1) whereas the unbound volume of distribution of PX (1.18 l kg‐1) was similar to that of CA (1.06 l kg‐1).
Sparteine oxidation is practically abolished in quinidine‐treated patients.
Authors: Brinn R. , Brosen K. , Gram LF , Haghfelt T. , Otton SV
Published: July 2012

In eight patients a sparteine‐test was carried out immediately before and after 1 week of treatment with quinidine 600‐800 mg day‐1. Before treatment one patient was classified as a poor metaboliser (metabolic ratio: greater than or equal to 20), and seven patients as extensive metabolisers. During quinidine treatment, the formation of sparteine metabolites (2‐ and 5‐dehydrosparteine) was practically abolished. Patients initially classified as extensive metabolisers thus exhibited the phenotype of poor metabolisers during quinidine treatment.
The acute haemodynamic effects of intravenous enalaprilic acid (MK422) in patients with left ventricular dysfunction.
Authors: Hornung RS , Hillis WS
Published: July 2012

Intravenous enalaprilic acid (2.5 mg) was given to 11 patients with stable cardiac failure (NYHA functional class II‐IV). Reductions in mean right atrial, pulmonary artery and pulmonary capillary wedge pressure of 25%, 18% and 30% respectively (P less than 0.01), were observed. Cardiac output rose by 13% (NS) and mean blood pressure fell by 20% (P less than 0.01) with a decrease in systemic vascular resistance of 24% (P less than 0.01). Heart rate was unaltered. The haemodynamic effects correlated with control plasma renin activity (r = 0.78, P less than 0.01). Marked hypotension occurred in several subjects but no other side‐effects were noted. The rapid onset of action and mixed venous and arteriolar dilating activity of intravenous enalaprilic acid may be an advantage in some clinical situations where parenteral vasodilating therapy is required.
The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man.
Authors: Dixey JJ , Noormohamed FH , Lant AF , Brewerton DA
Published: July 2012

We have studied the effect of a single dose challenge of naproxen (500 mg) and sulindac (200 mg) on renal function in five volunteers, and the effect of a single dose challenge of the thiazide, hydrochlorothiazide (100 mg), and loop diuretic, piretanide (6 mg) on renal function when the diuretics were given alone or when superimposed on chronic therapy of either naproxen or sulindac. None of the nonsteroidal anti‐ inflammatory drug (NSAID) or diuretic exposures significantly influenced glomerular filtration rate, as measured by creatinine clearance. Over the first 4 h of the study, both naproxen and sulindac reduced fractional excretion of sodium by approximately 50%. Sulindac also caused a significant uricosuria whilst naproxen promoted urate retention. Similar changes were observed over 8 h. Superimposition of either hydrochlorothiazide or piretanide on top of chronic sulindac therapy resulted in a blunting of the natriuresis by approximately 30% compared to when these diuretics were given alone: the action of the diuretics was unchanged by naproxen. Sulindac pretreatment did not alter the urinary excretion of either hydrochlorothiazide or piretanide; naproxen did not alter hydrochlorothiazide excretion. On the basis of these findings, it is concluded that NSAIDs exert direct tubular effects that do not necessarily interfere with the delivery of diuretics to their sites of action within the nephron.
Conclusiveness of rechallenge in the interpretation of adverse drug reactions.
Authors: Girard M
Published: July 2012

We here consider the extent to which the presumed correlation between an adverse event and the administration of a particular drug can be reinforced by rechallenge. At first question of terminology is: what is a rechallenge? Rechallenge is often accepted too readily as proof of a causal relationship and clinical examples give illustrations of common misinterpretations. Definitions are proposed to characterize: the outcome of rechallenge; the conditions under which rechallenge is performed. In discussing causality, a sharp distinction is drawn between the outcome per se and the establishment of a causal relationship. Finally, the simple concepts proposed here should permit to establish a typology of rechallenge and to assess, by further experimental or retrospective research, the conclusiveness of rechallenge in interpreting adverse drug reactions.
Absence of a pharmacokinetic interaction between enalapril and frusemide.
Authors: Van Hecken AM , Verbesselt R , Buntinx A , Cirillo VJ , de Schepper PJ
Published: July 2012

Single doses of enalapril maleate 10 mg and frusemide 80 mg do not significantly affect the pharmacokinetics of each other when taken concomitantly. Their concomitant use may be associated with more adverse effects than with the individual entities.
Antihypertensive effect of single doses of enalapril in hypertensive patients treated with bendrofluazide.
Authors: Webster J , Newnham D , Robb OJ , Petrie JC
Published: July 2012

This study was designed to investigate the validity of the then current recommendations for initiation of therapy with enalapril in hypertensive patients on treatment with a diuretic. Enalapril in single doses of 10 and 20 mg was given to 13 hypertensive patients on treatment with bendrofluazide 5 mg daily in a randomised, crossover, placebo controlled study. The mean maximal reduction in blood pressure was similar with both doses (35/20 mmHg supine, 38/20 mmHg standing), occurred on average within 6 h of tablet ingestion, and was not accompanied by any significant change in heart rate. Three patients experienced symptomatic hypotension. In one patient this was incapacitating after 10 mg and precluded exposure to 20 mg. This study shows that in hypertensive patients receiving treatment with diuretics, the addition of enalapril should be undertaken with caution. An optimal starting dose of enalapril in such patients remains to be confirmed.
A haemodynamic and radionuclide assessment of diltiazem in coronary heart disease.
Authors: Silke B , Sharma SK , Verma SP , Midtbo KA , Reynolds G , Taylor SH
Published: July 2012

To obtain multiple dose‐response haemodynamic and radionuclide data on i.v. diltiazem, 12 ischaemic patients were studied during routine catheterization. At rest, following a 20 min stable control period, the effects of four doses (0.0625, 0.0625, 0.125 and 0.25 mg kg‐1 diltiazem at 5 min intervals) were measured in the 3‐5 min following i.v. injection. The exercise effects of the cumulative 0.5 mg kg‐1 dosage were assessed by comparing a control and post drug period of supine bicycle exercise. The increase in plasma diltiazem levels correlated linearly with the administered dose and achieved therapeutic levels. There were significant dose‐related reductions in systemic arterial blood pressure and vascular resistance index; the heart rate fell and cardiac stroke index increased. The calculated double‐product (heart rate X systolic blood pressure) was significantly reduced. The left ventricular filling pressures, ejection fraction and cardiac volumes were unaltered. During supine bicycle exercise, the systemic diastolic blood pressure, heart rate and calculated double‐product were reduced without change in other parameters. Over the dose range 0.0625‐0.5 mg kg‐1, diltiazem acutely increased cardiac stroke index and reduced resting heart rate. These haemodynamic data, taken together with its described coronary vasodilator activity suggest that its role in acute vasospastic angina and during angiographic procedures ought to be explored further.
Relationships between heart rate and PR interval during physiological and pharmacological interventions.
Authors: Carruthers SG , McCall B , Cordell BA , Wu R
Published: July 2012

The relationships between heart rates (HR) and corresponding PR intervals (PR) were studied in 12 healthy young subjects during rest, standing and graduated treadmill exercise to heart rates of 160 to 170 beats min‐1 and during the infusion of isoprenaline to heart rates of 100 to 110 beats min‐1. During exercise, PR diminished with increasing HR. Over the range of HR from 60 to 160 beats min‐1 all 12 individual subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = −0.351 HR (beats min‐1) + 176.7 for composite data. During isoprenaline infusion the PR interval also diminished with increasing heart rate. Over the range of HR from 60 to 110 beats min‐1, 11 of the 12 subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = − 0.582 HR (beats min‐1) + 186.5 for composite data. The exercise model was used to study the indirect (or rate‐dependent) effects and the direct actions on atrioventricular conduction of beta‐adrenoceptor blocking drugs and calcium channel antagonists, alone and in combination, in three groups of healthy subjects. Control and placebo observations on HR and PR at rest, standing and during exercise in these additional subjects also exhibited individual inverse linear relationships between HR and PR. Following the administration of beta‐ adrenoceptor blockers, PR were prolonged more than expected at the HR observed. Rate‐adjusted PR prolongation during exercise exceeded standing which exceeded resting, indicating greater beta‐adrenoceptor blockade in atrioventricular nodal tissue than in sinoatrial nodal tissue at each level of activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Midazolam: kinetics and effects on memory, sensorium, and haemodynamics.
Authors: Langlois S , Kreeft JH , Chouinard G , Ross‐Chouinard A , East S , Ogilvie RI
Published: July 2012

This study aimed not only to compare the pharmacokinetics of oral and intravenous doses of the new water‐soluble benzodiazepine, midazolam, but also to study the effects on haemodynamics, sensorium, and memory performance. Eight normal human volunteers each received a single 15 mg dose of midazolam base orally and intravenously in randomized sequence 2 weeks apart. Serial venous samples were obtained for 12 h after dosing. Vital signs, sensorium testing and memory testing using word lists were also performed. Computerized non‐linear least squares curve‐ fitting of the two‐compartment open model to the oral and intravenous data simultaneously yielded the following estimates: V1, 0.33 1 kg‐1, VdSS, 1.08 1 kg‐1, t1/2,lambda, 0.10 h, t1/2,Z, 1.89 h, ka 1.17 h‐1 and bioavailability, 49%. The intravenous dose decreased the systolic pressure 22 mm Hg during the first half‐hour and the oral dose had 50% less effect. Most subjects became drowsy halfway through the infusion and were only rousable to voice by its end. The sensorium was clear by 2‐3 h. After oral dosing the peak sensorium effects of ataxia‐ dysarthria were seen at 30 min and had cleared by 2 h. Memory testing showed that memory acquisition was markedly impaired for at least 90 min after the intravenous dose and slight recovery was apparent at this time after the oral dose. Memory performance was proportionately more impaired than the sensorium score. We conclude that: midazolam kinetics are characterized by rapid absorption, but incomplete bioavailability and rapid elimination, midazolam intravenously may lower blood pressure significantly, and the level of consciousness correlates poorly with the degree of memory impairment.
Pharmacokinetics of idarubicin (4‐demethoxydaunorubicin; IMI‐30; NSC 256439) following intravenous and oral administration in patients with advanced cancer.
Authors: Gillies HC , Herriott D , Liang R , Ohashi K , Rogers HJ , Harper PG
Published: July 2012

The plasma pharmacokinetics of idarubicin (4‐demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half‐life of 12.9 +/‐ 6.0 h (mean +/‐ s.d.), clearance 98.7 +/‐ 47.3 1 h‐1 m‐2 and volume of distribution 1533 +/‐ 536 1 m‐2. A bi‐exponential equation corresponding to a two compartment open model best fitted the data. Half‐life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/‐ 0.20 (mean +/‐ s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half‐life of idarubicinol was not significantly different after i.v. (63.1 +/‐ 28.2 h) and oral (45.8 +/‐ 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity.