bluuebunny/crossref_metadata_2025 huggingface dataset:
Unimodal distribution of the metabolic ratio for debrisoquine in Cuna Amerindians of Panama.
Authors: Jorge LF , Arias TD , Inaba T , Jackson PR
Published: July 2012

1. The metabolic oxidation of debrisoquine (DB) was studied in 89 non‐ related Cuna Amerindian subjects. 2. Means and standard deviations for urinary recoveries of the intact drug and its 4‐hydroxy metabolite (4‐ HD) were: %DB: 6.8 +/− 4.5; %4‐HD: 16.0 +/− 9.1; %sum: 22.8 +/− 12.0. The log10 metabolic ratios for DB (LMRDB) were distributed within a single mode of insignificant skewness (‐0.01, P greater than 0.10), which was unimodal (log kernel density and maximum likelihood methods) and normal (chi 2 = 22.5; d.f. = 15; P greater than 0.09; power of the test greater than 80%). 3. Therefore, no poor metabolizers (95% C.I.: 0.1%, 5.2%) were detected in the population sample studied.
A comparison of a short half‐life marker (low‐dose isoniazid), a long half‐life pharmacological indicator (low‐dose phenobarbitone) and measurements of a controlled release ‘therapeutic drug’ (metoprolol, Metoros) in reflecting incomplete compliance by volunteers.
Authors: Hardy E , Kumar S , Peaker S , Feely M , Pullar T
Published: July 2012

1. Although, long half‐life compounds appear to be more appropriate pharmacological indicators of compliance with treatment, short half‐ life markers or measurements of short half‐life therapeutic drugs are frequently used. 2. We have compared the usefulness of low‐dose phenobarbitone (a long half‐life indicator), low dose isoniazid (a short half‐life marker) and controlled release metoprolol (Metros) (a controlled release formulation of a short half‐life ‘therapeutic’ drug) in seven volunteers with simulated partial (two thirds) compliance. 3. Detection of isoniazid metabolites in urine had an 83% sensitivity and 94% specificity for detecting ingestion within the previous 24 h and 100% sensitivity and 82% specificity for detecting ingestion within the past 6 h but gave no indication of the longer term pattern of compliance. 4. At 28 days (a time when steady‐state would be obtained for all three drugs) phenobarbitone plasma levels were 70% (66‐76%)‐ median and interquartile range‐of the expected steady‐state level if compliance had been complete. Corresponding figures for metoprolol were 82% (37‐100%). 5. Measurement of phenobarbitone was much superior to isoniazid or metoprolol measurements in reflecting partial compliance over the previous 1 to 4 weeks.
Effects of non‐steroidal anti‐inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension.
Authors: Minuz P , Barrow SE , Cockcroft JR , Ritter JM
Published: July 2012

1. The effects of non‐steroidal anti‐inflammatory drugs (NSAID) on prostacyclin and thromboxane biosynthesis and on blood pressure were determined in 46 patients with mild essential hypertension. Patients who had abstained from antihypertensive therapy for 2 weeks before study were treated with either aspirin, ibuprofen, sulindac or placebo for 7 days. 2. Excretion rates of 2,3‐dinor‐6‐oxo‐prostaglandin (PG) F1 alpha, 6‐oxo‐PGF1 alpha, 2,3‐dinorthromboxane (TX) B2 and TXB2 were measured as indices of prostacyclin and TXA2 biosynthesis. Samples were assayed using immunoaffinity chromatography and gas chromatography/electron capture chemical ionisation mass spectrometry. 3. Aspirin and ibuprofen reduced urinary excretion of all prostacyclin‐ and thromboxane‐derived products. Sulindac inhibited excretion of 2,3‐ dinor‐6‐oxo‐PGF1 alpha, 6‐oxo‐PGF1 alpha and 2,3‐dinor‐TXB2, but had no significant effect on TXB2. 4. Systolic blood pressure increased in the ibuprofen‐treated group when compared with the placebo group. There were no other significant changes in systolic or diastolic pressure in any of the treatment groups. Among the patients as a whole, there was a significant negative correlation between change in blood pressure and change in excretion of the prostacyclin‐derived but not of the thromboxane‐derived products. 5. We conclude that, in patients with mild essential hypertension, neither sulindac nor aspirin (in the doses used) selectively spares prostacyclin biosynthesis by the kidney. The significant relationship between increase in blood pressure and reduction in prostacyclin biosynthesis favours the possibility that in individuals who become hypertensive, prostacyclin biosynthesis determines, in part, the severity of the hypertensive state.
Pharmacokinetics and pharmacodynamics of oxazepam and metabolism of paracetamol in severe hypothyroidism.
Authors: Sonne J , Boesgaard S , Poulsen HE , Loft S , Hansen JM , Dossing M , Andreasen F
Published: July 2012

1. The effect of severe hypothyroidism on the pharmacokinetics and pharmacodynamics of oxazepam 15 mg given orally (n = 10) and the metabolism of paracetamol 750 mg given intravenously (n = 8) was investigated before and after treatment with levothyroxine. 2. The median total and unbound clearance of oxazepam increased significantly during the study period from 0.78 ml min‐1 kg‐1 (0.40‐1.25) to 1.22 ml min‐1 kg‐1 (0.66‐1.94) and from 9.3 ml min‐1 kg‐1 (5.2‐14.2) to 15.9 ml min‐1 kg‐1 (7.8‐21.8), respectively (P less than 0.01). 3. The elimination half‐life of oxazepam was prolonged by hypothyroidism to a median (range) value of 9.3 h (5.4‐21.9) compared with 7.5 h (4.8‐10.5) in the euthyroid state (P less than 0.05). 4. Hypothyroidism did not affect the protein binding of oxazepam; median values of the free percentage being 8.2% as compared with 7.7% when euthyroid. 5. The median (range) clearance of paracetamol under hypothyroid conditions was 3.12 ml min‐1 kg‐1 (1.64‐4.40) and 4.70 ml min‐1 kg‐1 (3.18‐5.70) following replacement therapy (P less than 0.01). This increase was associated with a comparable increase in the partial clearance to the glucuronide metabolite: 1.86 ml min‐1 kg‐1 to 2.70 ml min‐1 kg‐1. 6. Hypothyroidism was associated with decreased performance in a finger tapping test that was exacerbated by oxazepam. When the patients were euthyroid oxazepam did not produce any effect.
A comparison of the central nervous system effects of haloperidol, chlorpromazine and sulpiride in normal volunteers.
Authors: McClelland GR , Cooper SM , Pilgrim AJ
Published: July 2012

1. Twelve healthy male volunteers participated in four experimental occasions during each of which they were dosed with one of the following anti‐psychotic drugs: chlorpromazine (50 mg), haloperidol (3 mg), sulpiride (400 mg) and placebo. Drugs were allocated to subjects in a double‐blind, crossover fashion. 2. The subject's mood state, psychometric performance and electroencephalogram (EEG) were assessed pre‐dose, and at 2, 4, 6, 8, 24 and 48 h post‐dose. Mood states were assessed using 16 visual analogue scales and psychomotor performance was measured using the following tests: elapsed time estimation, tapping rate, choice reaction times, a rapid information processing task, flash fusion threshold, a manipulative motor task, digit span, body sway and tremor. 3. Chlorpromazine and haloperidol significantly reduced subjective ratings of ‘alertness’ and ‘contentedness’, and haloperidol significantly reduced feelings of ‘calmness’. Sulpiride did not significantly affect any of the visual analogue scales. 4. All three anti‐psychotic drugs had similar EEG effects with peak effect 2 to 4 h postdose. The profile was characterised by an increase in the proportion of slow wave activity (delta and theta) as well as decreased alpha (8‐14 Hz) and faster (beta) wave activity. 5. Chlorpromazine reduced tapping rate and increased choice reaction movement times. Haloperidol reduced the flash fusion threshold frequency at 6 h post‐ dose. Sulpiride prolonged the duration of the manipulative motor task, particularly at 48 h post‐dose. 6. All three anti‐psychotic drugs impaired performance on the rapid information processing task. Chlorpromazine significantly reduced the number of correct letter pair identifications at 2, 4 and 6 h post‐dose, haloperidol at 4, 6, 8, 24 and 48 h post‐dose, and sulpiride at 24 h post‐dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Fat preload delays gastric emptying: reversal by cisapride.
Authors: Stacher G. , Bergmann H. , Gaupmann G. , Schneider C. , Kugi A. , Hobart J. , Binder A. , Mittelbach‐Steiner G.
Published: July 2012

1. Meals empty more slowly when they contain fat. 2. This study investigated whether an intragastric fat preload in comparison with a water preload affected gastric emptying of a semisolid meal and antral motor activity, and whether cisapride reversed such effects. 3. Twelve healthy subjects were studied under three conditions each: (A), preload of 50 ml water orally; (B) and (C), preload of 50 ml cream (20 g fat). After preloads, subjects reclined right sided for 20 min. Thereafter, placebo in conditions (A) and (B) and 10 mg cisapride in (C) were administered i.v. in a random double‐blind fashion and subjects ingested a semisolid radiolabelled 1150 kJ meal. Gastric emptying and antral motor activity were recorded scintigraphically for 50 min using a dual‐headed gamma camera. 4. Gastric emptying was significantly slower (P less than 0.005) after fat preload and placebo than after water preload and placebo. Cisapride administered after fat preload abolished the delaying effect of the fat preload (P less than 0.001). 5. Antral contraction amplitudes after fat preload and placebo were higher (P less than 0.01) than after water preload and placebo as well as fat preload and cisapride at the start of recording and decreased slightly thereafter, whereas slight increases occurred in the other conditions. Frequency and propagation velocity of contractions were not differently affected. 6 Gastric emptying is delayed after prior fat ingestion and this effect is abolished by cisapride.
Cutaneous blood flow responses in the forearms of Raynaud's patients induced by local cooling and intradermal injections of CGRP and histamine.
Authors: Brain SD , Petty RG , Lewis JD , Williams TJ
Published: July 2012

1. The cutaneous responses of the forearm to local cold exposure and intradermal injection of CGRP and other vasoactive mediators were compared in primary Raynaud's sufferers and normal volunteers. 2. Skin responses in the forearm were measured in terms of erythema reddening and skin blood flow. Visual responses were recorded by tracing and then area calculated by computerised planimetry. Skin blood flow was measured using a laser Doppler blood flow meter. 3. Cooling (5‐6 degrees C for 2 min) of a 1 cm2 area of the forearm caused a localised reactive hyperaemia response in normal volunteers, measured using the last Doppler blood flow meter. The peak response in Raynaud's patients was significantly smaller than that of normal volunteers. 4. The cutaneous responses of Raynaud's patients and normal volunteers to intradermal injections of CGRP, histamine and PGE2 were not significantly different. 5. The results suggest that Raynaud's sufferers do not exhibit a diminished response to CGRP in the cutaneous microvasculature and can respond normally to histamine with an axon reflex mediated flare.
Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.
Authors: Raghoebar M. , Mak M. , Cournot A. , Pistorius MC , Van Harten J. , Roseboom H.
Published: July 2012

The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross‐over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/‐ 148 (3 mg dose) and 471 +/‐ 56 (8 mg dose) ml kg‐1 h‐1, while CLR was 226 +/‐ 124 (3 mg dose) and 189 +/‐ 38 (8 mg dose) ml kg‐1 h‐1. The Vss was 3.3 +/‐ 0.7 (3 mg dose) and 3.8 +/‐ 0.5 (8 mg dose) 1 kg‐1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3‐8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml‐1 after an oral dose of 8 mg. The plasma elimination half‐life after oral administration was 9.8 +/‐ 3.9 h. Absolute oral bioavailability was 110 +/‐ 32%. Dose‐dependent somnolence was observed.
Mitigation of beta 1‐ and/or beta 2‐adrenoceptor function in human heart failure.
Authors: Michel MC , Maisel AS , Brodde OE
Published: July 2012

1. Patients with congestive heart failure (CHF) have an elevated activity of the sympatho‐adrenal system. We have investigated several aspects of beta‐adrenoceptor desensitization in such patients. 2. The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2‐values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF. 3. We then studied the density of cardiac beta 1‐ and beta 2‐adrenoceptors in order to understand the mechanism of beta‐adrenoceptor desensitization in these patients. Our data show that cardiac beta 1‐adrenoceptors are down‐ regulated in all forms of severe CHF, but that cardiac beta 2‐ adrenoceptor density decreases only in some forms of CHF including ischaemic cardiomyopathy and mitral valve disease. 4. In circulating mononuclear leucocytes (MNL) obtained from CHF patients at rest, isoprenaline‐ and prostaglandin E1‐stimulated cAMP generation as well as cholera toxin and pertussis toxin catalyzed ADP ribosylation were similar to those in MNL from control patients. However, pretreatment of intact MNL with pertussis toxin enhanced cAMP generation in CHF patients but not in healthy control subjects, suggesting a tonic inhibitory effect of Gi in such patients. 5. We conclude that alterations of adrenoceptors and of their signal transduction might contribute to the desensitization of beta‐adrenergic responses in CHF.
Membrane proteins of the myocytes in cardiac overload.
Authors: Mansier P. , Chevalier B. , Mayoux E. , Charlemagne D. , Ollivier L. , Callens‐el Amrani F. , Swynghedauw B.
Published: July 2012

1. Hypertrophy of the cardiac myocytes resulting from a mechanical overload may be responsible for major membraneous modifications, either at the sarcolemmal or at the sarcoplasmic level. In this study several sarcolemmal markers such as beta‐adrenoceptors, muscarinic receptors or (Na+, K+)‐ATPase were investigated in an experimental model of cardiac hypertrophy, the chronic aortic stenosis in adult rats. 2. Left ventricular beta‐adrenoceptor density (expressed in fmol mg‐1 protein) was decreased in the aortic stenosis group by about 30%; however, when expressed in number of receptors per cardiac cell beta‐adrenoceptor number in the hypertrophied myocytes was unchanged. 3. Similarly, the number of muscarinic receptors in the hypertrophied cells, expressed as number of receptors per cardiac cell, was unchanged. 4. The number of (Na+, K+)‐ATPase molecules with high affinity for ouabain was markedly increased in the hypertrophied myocytes, while those with low affinity for ouabain were not. 5. These results indicate the necessity in chronic hypertrophy to calculate receptors not only in density (fmol mg‐ 1 protein) but also in number per cardiac cell. The unchanged number of beta‐adrenergic and muscarinic receptors present on the hypertrophied myocytes suggests a non‐regulation for the genes coding for these receptors.
The beta‐adrenoceptor antagonist carteolol and its metabolite 8‐ hydroxycarteolol have different intrinsic sympathomimetic activities.
Authors: Jasper J.R. , Michel MC , Insel PA
Published: July 2012

We have tested the effects of carteolol and 8‐hydroxycarteolol on cAMP generation in S49 lymphoma and BC3H1 smooth muscle‐like cells. Carteolol was a high affinity beta‐adrenoceptor antagonist in both systems but did not stimulate cAMP accumulation. The metabolite 8‐ hydroxycarteolol also was a high affinity antagonist. In contrast to its parent compound, however, it possessed an agonistic component which was considerably stronger than that of other beta‐adrenoceptor blockers with intrinsic sympathomimetic activity, e.g. dichloroisoprenaline, pindolol, or celiprolol. These results suggest that metabolites can possess different pharmacodynamic properties in terms of beta‐ adrenoceptor interaction relative to parent compounds.
Phorbol‐12,13‐dibutyrate antagonizes the alpha 1‐adrenoceptor‐mediated positive inotropic effect in the rabbit ventricular myocardium.
Authors: Endoh M. , Otomo J. , Norota I.
Published: July 2012

The phorbol ester phorbol‐12,13‐dibutyrate (PDBu) elicited a slight but significant positive inotropic effect (PIE) (10‐100 nM) in the presence of a beta‐adrenoceptor antagonist (+/‐)‐bupranolol (300 nM). PDBu (10‐ 1000 nM) inhibited the alpha 1‐adrenoceptor mediated PIE in a concentration‐dependent manner, while beta‐adrenoceptor‐mediated PIE was not decreased by PDBu up to 300 nM. Thus, PDBu exerted a differential effect on alpha‐ and beta‐adrenoceptor‐mediated PIE, and was much more effective than 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in antagonizing the alpha‐adrenoceptor‐mediated PIE. These findings imply that (1) certain subcellular process of myocardial alpha‐ adrenoceptor stimulation may be specifically antagonized by an activation of protein kinase C induced by PDBu or TPA; (2) there may be species difference in the response to activation of protein kinase C, which results in differential modulation of myocardial alpha 1‐ adrenoceptor‐mediated regulation of contractility among different mammalian species.
The effect of reserpine, desipramine and thyroid hormone on alpha 1a‐ and alpha 1b‐adrenoceptor binding sites: evidence for a subtype‐ specific regulation.
Authors: Hanft G. , Gross G.
Published: July 2012

Using radioligand binding techniques we studied whether alpha 1a‐ and alpha 1b‐adrenoceptor recognition sites can be regulated independently by drugs and hormones. In rat cerebral cortex subchronic treatment with reserpine enhanced the number of [3H]‐prazosin binding sites and the proportion of alpha 1b binding sites. Desipramine treatment which did not alter Bmax values, increased the proportion of alpha 1a and decreased alpha 1b binding sites. In rat myocardium hypothyroidism decreased alpha 1b‐adrenoceptor binding sites. These results suggest that alpha 1‐adrenoceptors are regulated in a subtype‐selective manner.
Arterial vasodilating profile and biological effects of pinacidil in healthy volunteers.
Authors: Thuillez C , Pussard E , Bellissant E , Richer C , Kechrid R , Giudicelli JF
Published: July 2012

1. The effects of pinacidil (25 mg, sustained release formulation) a) on systemic (arterial pressure, cardiac output) and regional (brachial and carotid arteries' diameters and flows) haemodynamics (pulsed Doppler techniques), b) on sympathetic (plasma noradrenaline) and renin‐ angiotensin (plasma renin activity) systems, and c) on atrial natriuretic factor have been investigated and compared with those of a placebo during the 12 h period following oral administration in a randomized, double‐blind and cross‐over study performed in six healthy volunteers. Simultaneously, the plasma levels of pinacidil and of its active metabolite, pinacidil N‐oxide, were determined. 2. As compared with placebo, pinacidil decreased systemic vascular resistance and arterial blood pressure but cardiac output was not modified. 3. Pinacidil significantly increased brachial and carotid arteries' diameters (by 7 and 8% respectively) and flows (by 60 and 17% respectively) and decreased forearm vascular resistance (by 43%). Thus, pinacidil dilates both large and small arteries, increases large vessels' compliance and redistributes blood flow towards the muscular vascular bed. These effects peaked at 4 h and their duration at the brachial level was 8 h. 4. Pinacidil administration resulted in a stimulation of both sympathetic (increases in heart rate and plasma noradrenaline) and renin‐angiotensin systems, and induced a transient increase in atrial natriuretic factor. 5. The duration of pinacidil haemodynamic effects at the brachial level is consistent with the pharmacokinetic data which show that pinacidil and pinacidil N‐oxide plasma levels almost plateaued between 3 and 8, and 2 and 8 h respectively after oral administration of the sustained release formulation used.
Backtracking booze with Bayes‐the retrospective interpretation of blood alcohol data.
Authors: Jackson PR , Tucker GT , Woods HF
Published: July 2012

1. A Bayesian method is described which allows the explicit estimation of errors produced in estimating drug concentrations at times for which samples are not available for analysis. 2. This method was applied to the problem of ‘backtracking’ alcohol concentrations for medico‐legal purposes. 3. Computer simulation allowed the effect of continuing alcohol absorption on the position and range of estimates of alcohol concentrations to be studied.
A new, sensitive graphical method for detecting deviations from the normal distribution of drug responses: the NTV plot.
Authors: Endrenyi L , Patel M
Published: July 2012

1. A new graphical method was developed for the detection of deviations from the normal distribution. The approach took advantage of the similarity of graphical features of a graded dose‐response relationship and a cumulative normal distribution. 2. The behaviour of the new normal test variable (NTV) plot was evaluated, in comparison with that of the probit plot and probability density functions (the generalization of histograms), for various assumed distributions. These included skewed distributions and composites of normal distributions with a variety of separations, ratios of peak sizes and widths. 3. The NTV approach generally detected deviations from the normal distribution more sensitively than the probit plot. 4. The NTV and probit plots may be able to identify biomadality by complementary approaches. 5. The characteristics of the three graphical representations were illustrated by a simulated sample from a composite of normal distributions and by an example of sparteine metabolism in 142 Cuna Amerindians.
Transpulmonary pharmacokinetics of an ACE inhibitor (perindoprilat) in man.
Authors: MacFadyen RJ , Lees KR , Gemmill JD , Hillis WS , Reid JL
Published: July 2012

1. The transpulmonary pharmacokinetics of the intravenous diacid ACE inhibitor perindoprilat were studied in 10 male patients undergoing diagnostic cardiac catheterisation for the management of ischaemic heart disease. 2. Following successful completion of diagnostic cardiac catheterisation and ventriculography, subjects received a low dose (1 mg) constant rate infusion of perindoprilat over 20 min with co‐ infusion of the intravenous marker dye indocyanine green (0.5 mg kg‐1). Simultaneous transpulmonary blood sampling was conducted for 1 h and subsequent peripheral venous blood samples were collected for 20 h. 3. No acute changes in blood pressure or heart rate were noted despite rapid and marked inhibition of central circulation plasma ACE activity persisting in peripheral venous blood for 20 h. A delayed rise in plasma renin activity was noted. 4. Transpulmonary passage during early accumulation of the drug was seen to incorporate an early delay. Concurrent ICG measurements suggested that this was entirely due to circulatory delay and not to binding of the drug. Thus, despite the suggested high concentration of tissue ACE activity in the pulmonary circulation, transpulmonary passage of perindoprilat was not measurably influenced by binding at this site under the conditions studied.
Metabolism of the aldose reductase inhibitor ALO1567 in man.
Authors: Park YH , Hudson JE , Barker RC , York BM , Brazzell RK
Published: July 2012

1. The metabolism of the aldose reductase inhibitor, ALO1567, was studied in man. The major biotransformation pathway was aromatic hydroxylation followed by glucuronide conjugation. 2. Hydroxylation occurred at several positions on the fluorene ring. The major metabolite was identified as the 7‐hydroxy analogue of ALO1567 and three minor metabolites were characterized as positional isomers of the 7‐hydroxy metabolite. 3. Oxidative defluorination and metabolism on the hydantoin ring were also indicated as minor pathways. 4. The capacity of normal subjects to oxidize ALO1567 was indicated by the urinary ratio of the parent drug to the 7‐hydroxy metabolite after daily oral administration of 100 mg and 200 mg of ALO1567. Most subjects having higher ALO1567 plasma concentrations showed higher ratios.
Pharmacokinetics of trospectomycin sulphate in healthy subjects after single intravenous and intramuscular doses.
Authors: Nichols DJ , Bye A , Novak E
Published: July 2012

The pharmacokinetics of trospectomycin (75‐1000 mg free base equivalents) were studied in 128 healthy males (eight per dose group), after a 20 min intravenous (i.v.) infusion and intramuscular (i.m.) injection of trospectomycin sulphate. The concentrations of trospectomycin in serum were described by bi‐ or tri‐exponential disposition functions indicating an initial half‐life of 1.1‐1.4 h for the i.v. dose and 1.6‐2.1 h for the i.m. dose and terminal half‐lives of over 15 h. Most of the drug was eliminated rapidly (mean residence time 5‐12 h). The distribution volume was 59‐112% of body weight and clearance was 112‐152 ml min‐1. The absorption into blood after i.m. dosing was rapid. The area under the concentration‐time curve and maximum concentration values were linearly related to dose. Serum drug concentrations fell below the minimum inhibitory concentration values for a variety of organisms by 8‐12 h, which indicates that two or three times daily dosing would be appropriate. However, the long terminal half‐life suggests that significant accumulation is likely in some tissues with an 8 h dose interval and this may prolong the action of trospectomycin.
The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.
Authors: Schwinghammer TL , Przepiorka D , Venkataramanan R , Wang CP , Burckart GJ , Rosenfeld CS , Shadduck RK
Published: July 2012

1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/‐ 1.7 ml min‐1 kg‐1 to 2.0 +/‐ 0.6 ml min‐1 kg‐1 after 14 days of treatment. The mean +/‐ s.d. absolute oral bioavailability of cyclosporine was 17 +/‐ 11%. 4. Hydroxylated CsA (M‐17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.
Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.
Authors: Tartara A , Galimberti CA , Manni R , Parietti L , Zucca C , Baasch H , Caresia L , Muck W , Barzaghi N , Gatti G , et al
Published: July 2012

1. The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme‐inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2. Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven‐fold (P less than 0.01) in patients taking enzyme‐inducing anticonvulsants and increased by about 50% (P less than 0.05) in patients taking sodium valproate. 3. Nimodipine half‐lives were shorter in enzyme‐induced patients than in controls (3.9 +/‐ 2.0 h vs 9.1 +/‐ 3.4 h, means +/‐ s.d., P less than 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate‐treated patients, half‐lives (8.2 +/‐ 1.8 h) were similar to those found in controls.
The basis of the histamine assay in skin.
Authors: Byrom H , Clark M , White V , Vere DW
Published: July 2012

1. The assay of wheal response to histamine injected sub‐epidermally has been reviewed. Several discrepant claims were found in earlier work. 2. The saline control injection may evoke a wheal, which if present should be allowed for in the assay procedure. 3. There was no evidence for a limb dominance effect. 4. Using a 3.26 mM (1 mg ml‐1) standard solution of histamine acid phosphate (1.18 mM as free base) and 0.1 ml injections, the straight central portion of the assay curve was found to be between 0.3 and 2.3 × 10(‐3) mM, as free base, with an ED50 of about 0.018 mM histamine base.
The pharmacokinetics of oxycodone after intravenous injection in adults.
Authors: Poyhia R , Olkkola KT , Seppala T , Kalso E
Published: July 2012

Oxycodone chloride (0.07 mg kg‐1) was given by intravenous bolus to nine young adult surgical patients on the first postoperative day. Plasma was sampled for up to 12 h. Mean values of t1/2z, CL and Vss were 222 min, 0.78 l min‐1 and 2.60 l kg‐1, respectively. The concentrations of the metabolite noroxycodone was also measured. The mean AUC(0,12) ratio of noroxycodone to oxycodone was 0.33. Oxymorphone was not detected.
Sensitivity to angiotensin II of forearm resistance vessels in pregnancy.
Authors: Benjamin N , Rymer J , Todd SD , Thom M , Ritter JM
Published: July 2012

Resistance vessel sensitivity to angiotensin II in vivo was studied in 13 primigravid normotensive women (16‐24 weeks gestation), and in 10 non‐pregnant control women. Angiotensin II was infused into the brachial artery at doses of 10, 100, 1,000 and 10,000 fmol min‐1 and forearm blood flow measured by plethysmography. Reduction in forearm blood flow at all concentrations of angiotensin II was significantly greater in non‐pregnant than in pregnant women. The dose‐response relationships, plotted semi‐logarithmically, were similar in shape in each group but sensitivity to angiotensin II was reduced in pregnant subjects compared with non‐pregnant women. This is most simply explained by an effect of pregnancy on the sensitivity to angiotensin II of vascular smooth muscle in forearm resistance vessels.
Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose.
Authors: Oosterhuis B , Jonkman JH , Andersson T , Zuiderwijk PB , Jedema JN
Published: July 2012

1. The influence of multiple dose administration of omeprazole on the pharmacokinetics of oral digoxin was studied in 10 healthy male volunteers. 2. In a randomized two‐way crossover design a single dose of 1 mg digoxin was administered either alone (control) or on day 8 of an 11 day course of omeprazole 20 mg once daily. 3. Plasma digoxin concentrations were measured over 96 h after digoxin administration with a [125I]‐r.i.a. method. 4. On average, Cmax and AUC values for digoxin were approximately 10% higher and tmax tended to be shorter during the administration of omeprazole, while the elimination rate constant was unaffected. 5. The increase in AUC(0,96 h) was statistically significant (P less than 0.05), but within the accepted range for bioequivalence. In two subjects the increase was approximately 30%. 6. It is concluded that co‐treatment with omeprazole causes a minor increase in the absorption of oral digoxin. The magnitude of this effect is not considered to be clinically relevant for the majority of patients.
Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled‐release system and as a suspension of 15N‐labelled drug to healthy volunteers.
Authors: Wilding IR , Davis SS , Hardy JG , Robertson CS , John VA , Powell ML , Leal M , Lloyd P , Walker SM
Published: July 2012

1. Plasma drug concentrations after a single oral administration of a suspension of carbamazepine (CBZ) and a 20/200 CBZ Oros osmotic pump system were measured in eight healthy male volunteers. The oral suspension contained 100 mg CBZ labelled with the stable isotope nitrogen‐15, whilst the Oros contained 200 mg unlabelled CBZ. Plasma concentrations of [15N]‐CBZ and CBZ were measured simultaneously by gas chromatography‐mass spectrometry. 2. The position of the CBZ Oros (labelled with indium‐111) in the gastrointestinal tract was followed by gamma scintigraphy. Plasma drug concentrations after the two treatments were used to relate pharmacokinetic with transit data. 3. The Oros was taken after breakfast and gastric emptying occurred between 1.1‐ greater than h post‐dosing (median, 5.3 h). Small intestinal transit times ranged from 1.5‐ greater than 3.6 h, with a median of 2.2 h. There were wide individual variations in colonic transit, and the total transit time ranged from 10‐60 h (median, 22 h). 4. Relative systemic bioavailability of CBZ from the Oros was reduced compared with that from the suspension (mean dose normalised AUC ratio = 0.69 +/‐ 0.17; mean dose‐normalised AUC ratio = 0.85 +/‐ 0.13, allowing for actual release from the Oros system). 5. The in vivo absorption of drug into the systemic circulation from the Oros was estimated using the Wagner‐Nelson method. This showed that absorption of CBZ was rapid when the Oros was present in the stomach and small intestine, the rate being determined by the release of drug from the system.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of atropine on left ventricular volumes and ejection and filling rates at rest and during exercise.
Authors: Kelbaek H , Marving J , Hvid‐Jacobsen K , Nielsen SL
Published: July 2012

1. The influence of the parasympathetic nervous system on left ventricular function including ejection and filling rates was studied by radionuclide cardiography in eight healthy young men at rest and during upright exercise. 2. After parasympathetic blockade induced by atropine, the mean heart rate (HR) at upright rest increased from 67 to 114 beats min‐1, cardiac output (CO) from 4.05 to 5.17 1 min‐1 (both P less than 0.001), and the diastolic blood pressure by 13 mm Hg (P less than 0.01). 3. Stroke volume (SV), left ventricular end diastolic and end systolic volume all decreased significantly after atropine. The relative ejection time increased from 0.33 to 0.51 of the cardiac cycle length (P less than 0.001), and the appropriate ejection and filling rates increased by 13% (P less than 0.05) and 147% (P less than 0.001), respectively. Haemodynamic changes in the supine position were virtually the same. 4. During exercise atropine increased HR from 115 to 146 beats min‐1 (P less than 0.001) and CO by 12% (P less than 0.05), whereas SV decreased by 12% (P less than 0.05) and the systolic blood pressure by 16 mm Hg (P less than 0.001). Changes in ejection and filling rate of the left ventricle were of the same nature as those found at rest. 5. Thus apart from its HR limiting properties, secondary effects of parasympathetic nervous tone are dilatation of the left ventricle and enhancement of ejection, effects that are counteracted by atropine.
Circadian changes in estimated hepatic blood flow in healthy subjects.
Authors: Lemmer B , Nold G
Published: July 2012

Intravenous injections of indocyanine green (ICG) were given to 10 healthy supine subjects at 02.00, 08.00, 14.00 and 20.00 h. ICG plasma half‐life, plasma clearance and estimated hepatic blood flow (EHBF), but not volume of distribution, varied significantly with time of day with EHBF being greatest at 08.00 h. This circadian rhythm in EHBF should be considered when evaluating the kinetics of high‐clearance drugs at different times of day.
Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.
Authors: Doecke CJ , Veronese ME , Pond SM , Miners JO , Birkett DJ , Sansom LN , McManus ME
Published: July 2012

1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4‐hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM for both reactions. 6. Anti‐rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7. These in vitro studies are consistent with phenytoin 4‐hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.
Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin.
Authors: Hooper WD , Kavanagh MC , Herkes GK , Eadie MJ
Published: July 2012

Twelve subjects received a single oral dose (300 mg) of gabapentin and serial blood and urine samples were collected for drug measurements. Oral phenobarbitone (30‐90 mg/day) was then administered to steady‐ state, and the gabapentin single dose study was repeated on day 42. Gabapentin was administered from days 49 to 52 to achieved steady‐ state, and further blood and urine samples were collected for drug measurements. Trough plasma phenobarbitone concentrations were monitored at frequent intervals. No statistically significant differences were observed in gabapentin Cmax, tmax, AUC, t1/2 or urinary drug recovery following single doses of gabapentin alone or combined with phenobarbitone. Phenobarbitone did not alter the disposition of gabapentin at steady state. Mean trough steady‐state phenobarbitone concentrations were not significantly affected by concomitant gabapentin administration.
Effects of an EDTA infusion on the urinary elimination of several elements in healthy subjects.
Authors: Allain P. , Mauras Y. , Premel‐Cabic A. , Islam S. , Herve JP , Cledes J.
Published: July 2012

Ethylene diamine tetraacetate calcium disodium salt (EDTA Ca Na2), 1 g dissolved in 250 ml of 5% w/v glucose solution, was infused intravenously over 1 h into 10 healthy subjects (eight males and two females). Urines were collected over 24 h, the day before and on the day of the EDTA Ca Na2 infusion test. The elements Al, B, Ba, Cu, Fe, Mn, Si, Sr, Zn, Na, K, Ca, Mg, S and P were measured by inductively coupled plasma optical emission spectrometry. Pb was measured by inductively coupled plasma mass spectrometry. The EDTA Ca Na2 infusion increased the 24 h elimination of Al from 9.8 micrograms to 58 micrograms, of Fe from 66 to 121 micrograms, of Mn from 2.9 to 16.5 micrograms, of Pb from 9.8 to 56 micrograms and of Zn from 623 to 8847 micrograms. The ratio of the increase of urinary elimination induced by EDTA Ca Na2 was about 2 for Fe, 5 for Al, Pb and Mn, and 15 for Zn.
A comparison of the pharmacokinetics of nisoldipine in elderly and young subjects.
Authors: Baksi AK , Edwards JS , Ahr G.
Published: July 2012

Nine young and 12 elderly healthy volunteers received nisoldipine 10 mg once a day for 7 days. Plasma nisoldipine concentrations were measured on Day 1 and on Day 7. Higher plasma drug concentrations were observed in the elderly group than in the young group with the values for AUC being approximately doubled in the elderly group. There was no evidence of significant accumulation in either age group.
Hearing impairment related to plasma quinine concentration in healthy volunteers.
Authors: Alvan G. , Karlsson KK , Hellgren U. , Villen T.
Published: July 2012

1. Hearing impairment was investigated in six healthy volunteers who received oral doses of 5, 10 and 15 mg kg‐1 quinine single‐blind and in random order. 2. The plasma concentration of quinine was followed for 48 h and the time course was fitted by a linear one compartment pharmacokinetic model. 3. Hearing thresholds were measured by pure tone audiometry. There was a delay between impairment in hearing and change in plasma quinine concentration. Thus the method of effect compartment modelling was applied. 4. The effect on hearing (L), measured as a shift in hearing threshold (dB), was used to estimate the rate constant for elimination of drug from the assumed effect compartment (ke0) and two parameters specifying the effect model (gamma and k). The effect model applied was L = 10 (log k + gamma x log Ce) where Ce is the calculated drug concentration in the effect compartment. This model is a logarithmic transform of a power expression equivalent to the Hill equation at the lower end of the effect range. In all experiments where there was a clear effect on hearing, convergence on a set of parameter estimates occurred, but inter‐ and intraindividual variability was large. The mean value of ke0 was 3.32 +/‐ 5.93 h‐1 s.d., for gamma it was 1.73 +/‐ 1.14 s.d. and for k it was 0.59 +/‐ 0.66 s.d.
Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria.
Authors: Karbwang J. , Milton KA , Na Bangchang K. , Ward SA , Edwards G. , Bunnag D.
Published: July 2012

Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbutylhalofantrine (n = 12) were 1192 +/‐ 410 (mean +/‐ s.d.) and 397 +/‐ 160 ng ml‐1 with tmax values of 16 +/‐ 2 and 55 +/‐ 26 h, respectively. AUC was 60.6 +/‐ 23.9 and 48.5 +/‐ 22.2 mg l‐1 h, respectively, for halofantrine and its metabolite. Halofantrine cured 83% of the patients but in two patients a reduction only in asexual parasitaemia was seen and no overall parasite clearance occurred. One of these, however had relatively low plasma concentrations of both halofantrine and its desbutyl metabolite and it appeared to be a case of inadequate treatment rather than true resistance. We suggest that the large intersubject variability in plasma drug concentrations may relate in part to its poor and inconsistent bioavailability and this rather than true resistance might be responsible for some of the treatment failures.
Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.
Authors: Yue QY , Hasselstrom J. , Svensson JO , Sawe J.
Published: July 2012

1. The kinetics of codeine and seven of its metabolites codeine‐6‐ glucuronide (C6G), norcodeine (NC), NC‐glucuronide (NCG), morphine (M), M‐3 (M3G) and 6‐glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2. The mean area under the curve (AUC), half‐life and total plasma clearance of codeine were 1020 +/‐ 340 nmol l‐1 h, 2.58 +/‐ 0.57 h and 2.02 +/‐ 0.73 l h‐1 kg‐1, respectively. There were no significant differences between EM and PM in these aspects. 3. PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P less than 0.0001), and lower partial metabolic clearance by O‐demethylation (P less than 0.0001). In contrast, the PM had higher AUC of NC (P less than 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N‐demethylation and glucuronidation. 4. Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N‐ and O‐demethylations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Faster and more reliable absorption of adrenaline by aerosol inhalation than by subcutaneous injection.
Authors: Mellem H. , Lande K. , Kjeldsen SE , Westheim A. , Eide I. , Ekholt PF , Boye NP
Published: July 2012

1. The aim of the present study was to compare absorption of adrenaline given by aerosol spray inhalation with absorption after subcutaneous injection. 2. Arterial plasma adrenaline was measured in nine healthy volunteers following adrenaline administration by both methods. 3. Following inhalation of 20 puffs of adrenaline aerosol, 0.15 mg/puff, a peak arterial adrenaline concentration after 1 min and a rapid fall to baseline from this peak occurred. 4. When given by subcutaneous injection absorption was slower with a peak arterial adrenaline concentration after 4 min. The fall in arterial adrenaline from this peak level was not statistically significant within 30 min after injection. 5. There was less intersubject variation of arterial adrenaline concentration following inhalation when compared with injection. 6. Heart rate, blood pressure and finger tremor followed the changes in arterial adrenaline concentrations. 7. These results indicate that absorption is more reliable when adrenaline is given by inhalation. The rapid fall in arterial adrenaline following inhalation, suggests that repeated inhalations are necessary when such adrenaline therapy is required.
Atrial natriuretic factor inhibits metoclopramide stimulated aldosterone release in man.
Authors: Lang CC , Rahman AR , Struthers AD
Published: July 2012

1. Atrial natriuretic factor (ANF) has an inhibitory effect on angiotensin II and ACTH stimulated aldosterone secretion in man. The selectivity of this aldosterone suppressing effect of ANF is unclear in man. The present study investigated the effect of ANF on the increase in plasma aldosterone due to metoclopramide in man. 2. Eight normal male volunteers were studied on three occasions. Metoclopramide (10 mg slow i.v.) was given on all study days and each volunteer was randomised to receive 45 min infusion of either 5% D‐glucose (placebo) or ANF (99‐126) 3 or 15 pmol kg‐1 min‐1. 3. Metoclopramide increased plasma aldosterone to approximately 170% of baseline levels (P less than 0.01). Concomitant infusion of ANF 3 pmol kg‐1 min‐1 and 15 pmol kg‐1 min‐1 significantly attenuated this rise in plasma aldosterone to approximately 130% (P less than 0.05) and 110% (P less than 0.01) of baseline values respectively. 4. It is suggested, in the light of previous findings, that the inhibitory effect of ANF represents a non‐ selective action of ANF on aldosterone release.
The absorption site of cyclosporin in the human gastrointestinal tract.
Authors: Drewe J , Beglinger C , Kissel T
Published: July 2012

1. An emulsion preparation of cyclosporin was administered locally to different parts of the small and large intestine by gavage: to the duodenum (opposite to the papilla of Vater), jejunum (150 cm distal to the teeth), ileum (300 cm distal to the teeth), and to the colon descendens (30 cm proximal to the anus). 2. The bioavailability of cyclosporin after these instillations was compared with that after oral administration of a hard gelatine capsule formulation. 3. Cyclosporin was found to be absorbed predominantly in the small intestine. This may have implications for dosage in patients with reduced absorptive surface area.