bluuebunny/crossref_metadata_2025 huggingface dataset:
Biopharmaceutical characterisation of a low‐dose (75 mg) controlled‐release aspirin formulation
Authors: CHARMAN WILLIAM N. , CHARMAN SUSAN A. , MONKHOUSE DONALD C. , FRISBEE STEVEN E. , LOCKHART EARLE A. , WEISMAN STEVEN , FITZGERALD GARRET A.
Published: July 2012

The release of aspirin from a 75 mg controlled‐release formulation, designed to inhibit maximally thromboxane A2 production while sparing stimulated prostacyclin biosynthesis, was characterised in healthy subjects. The calculated in vivo release rate of aspirin matched the design goal of approximately 10 mg h−1. The Cmax of aspirin associated with the controlled‐release formulation was lowered 15‐fold relative to a solution formulation of the same dose. The bioavailability of aspirin (based on salicylate concentrations) from the controlled‐release formulation was approximately 90% relative to the solution, and drug release was not affected by co‐administration of a standard breakfast.
Stress responses after treatment of hypercholesterolaemia with simvastatin
Authors: NUGENT A.‐M. , NEELY D. , YOUNG I. , McDOWELL I. , O'KANE M. , BELL N. , STANFORD C. F. , NICHOLLS D. P.
Published: July 2012

In order to determine whether treatment of hyperlipidaemia with simvastatin impairs exercise stress responses and so may contribute to an excess of suicides and violent deaths, the effects of simvastatin 20 mg daily and placebo on exercise physiology were compared in 19 patients. After 6 weeks of treatment there was no evidence of reduced exercise capacity, or of reduced cortisol or catecholamine responses. It is concluded that treatment of hyperlipidaemia with an inhibitor of HMG‐CoA reductase does not significantly modify stress responses, and so the explanation for a possible increase in non‐cardiac mortality must be sought elsewhere.
A clinical pharmacological assessment of doxazosin and enalapril in combination
Authors: BAINBRIDGE A. D. , MEREDITH P. A. , ELLIOTT H. L.
Published: July 2012

This study in 12 normotensive males investigated potential pharmacokinetic and pharmacodynamic interaction mechanisms resulting from the combination of enalapril and doxazosin. Blood pressure reductions were consistently greater with the combination but there was no evidence of a significant pharmacodynamic interaction (as determined by heart rate changes, renal function tests or by pressor responsiveness indices) and there was no evidence of a pharmacokinetic interaction with either drug. Responsiveness to each drug i.e. blood pressure reduction per unit drug concentration was not significantly altered in the combination regimen. In conclusion, these results suggest that the combination of enalapril and doxazosin produces a usefully additive hypotensive effect but there was no evidence of synergism i.e an effect which was more than additive.
Responsiveness of human isolated bronchial segments and its relationship to epithelial loss.
Authors: Omari TI , Sparrow MP , Mitchell HW
Published: July 2012

1. The responsiveness of human and bovine bronchi was examined by comparing the magnitude of responses to agonists applied to the adventitial (outside) and to the luminal (inside) surfaces. The development of smooth muscle tone was measured as both an increase in pressure in isovolumic bronchial segments and narrowing in perfused segments. 2. In both closed and perfused human segments, ACh added to the adventitial surface produced highly homogeneous responses while responses to ACh added to the luminal side were extremely variable. 3. Histological examination of the human segments showed that they possessed variable degrees of pre‐existing epithelial loss from the mucosal circumference, ranging from 0 to 82%. 4. Denuded human isovolumic segments (exhibiting > 30% epithelial loss) were 40 fold more sensitive to ACh inside than intact segments (< 30%). Denuded segments were also equally responsive to KCl inside or outside while KCl inside produced a contraction that was 50% of that to KCl outside in intact segments. 5. A strong and highly significant relationship was determined between the proportion of epithelial loss and both the responsiveness and rate of contraction of human segments to ACh and KCl introduced onto the lumen. No relationship was observed between epithelial denudation and responsiveness or contractility to agonists added to the adventitial surface. 6. Mechanical denudation of the epithelium from bovine segments had no effect on responsiveness to ACh or KCl added to the outside while significantly augmenting the sensitivity to ACh (9 fold) and reactivity to KCl introduced into the lumen to the extent that it became the same as outside.(ABSTRACT TRUNCATED AT 250 WORDS)
A population based case‐cohort study of drug‐induced anaphylaxis.
Authors: Van der Klauw MM , Stricker BH , Herings RM , Cost WS , Valkenburg HA , Wilson JH
Published: July 2012

1. In order to determine the risk of anaphylaxis as an adverse reaction to drugs, a case‐cohort study was performed. Cases consisted of all admissions in 1987 and 1988 to all Dutch hospitals with anaphylaxis as the principal diagnosis, and a random sample of admissions with related symptoms. Hospital discharge summaries were classified according to probability to anaphylaxis by a blinded Audit Committee. Of admissions classified as probable or possible anaphylaxis, the causative agent was assessed. The reference cohort consisted of all persons in the catchment area of a sample of pharmacies in The Netherlands, in the period between January 1, 1987 and December 31, 1988. 2. Out of 934 admissions, discharge summaries on 811 admissions were received, of which 727 contained enough clinical details. Out of 727, 391 were classified as probable or possible anaphylaxis. In 336 of these 391, anaphylaxis was reason for admission. This group consisted of 158 men and 178 women. Drug‐induced anaphylaxis occurred in 107 patients. 3. Drug‐induced anaphylaxis was most frequently caused by penicillins, analgesics and non‐steroidal antiinflammatory drugs (NSAID) with the highest point estimate of the risk relative to all other drugs of 10.7, 6.9 and 3.7 respectively. 4. In the cases of probable anaphylaxis, the risk of anaphylaxis to glafenine relative to all other drugs was 167.7 in 1987 (95%‐CI: 63.0‐446.4) and 128.6 in 1988 (95%‐CI: 50.4‐328.5), to amoxycillin 15.2 in 1987 (95%‐CI: 5.0‐46.0) and 4.4 in 1988 (95%‐CI: 1.03‐18.9) and to diclofenac 6.1 in 1988 (95%‐CI: 1.4‐26.1).(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of methotrexate and its 7‐hydroxy metabolite in patients with rheumatoid arthritis.
Authors: Seideman P , Beck O , Eksborg S , Wennberg M
Published: July 2012

1. The pharmacokinetics of MTX and its 7‐hydroxy metabolite (7‐OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross‐over design. The plasma concentrations of MTX and 7‐OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7‐OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half‐lives of MTX and 7‐OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration‐time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7‐OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7‐OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7‐OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non‐responders or patients with increased risk of side‐effects.
The metabolism of aprindine in relation to the sparteine/debrisoquine polymorphism.
Authors: Ebner T , Eichelbaum M
Published: July 2012

1. Incubation of the class I antiarrhythmic drug aprindine (AP) with human liver microsomes resulted in the formation of two hydroxylated metabolites (HA1 and HA2) and desethylaprindine which were identified by GC‐mass spectrometry. In liver microsomes isolated from a poor metaboliser (PM) of sparteine no hydroxylated metabolites of AP were detected whereas AP N‐dealkylation was unimpaired. Thus hydroxylation of AP is mediated by cytochrome P450 2D6 (CYP2D6). 2. AP was found to be a competitive inhibitor of CYP2D6 as indicated by its ability to impair the formation of (2S)‐hydroxysparteine, 5,6‐didehydrosparteine and 5‐hydroxypropafenone by human liver microsomes. 3. These in vitro findings are consistent with a major role of CYP2D6 in the clearance of AP in vivo, with its ability to impair the metabolism of other CYP2D6 substrates in vivo, and an ability to cause phenocopying (conversion of extensive metaboliser phenotypes for sparteine/debrisoquine to apparent 'poor metabolisers).
The effect of tocainide on theophylline metabolism.
Authors: Loi CM , Wei X , Parker BM , Korrapati MR , Vestal RE
Published: July 2012

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg‐1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 +/‐ 6.9 (mean +/‐ s.d.) to 33.7 +/‐ 5.0 ml kg‐1 h‐1 (difference ‐3.8, 95% CI, ‐1.7 to ‐5.9; P = 0.004) and increased its terminal elimination half‐life from 9.7 +/‐ 2.5 to 10.4 +/‐ 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3‐methylxanthine and 1‐methyluric acid, but the formation clearance of 1,3‐dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.
The pharmacokinetics of quinine in patients with hepatitis.
Authors: Karbwang J , Thanavibul A , Molunto P , Na Bangchang K
Published: July 2012

The pharmacokinetics of quinine were studied in six patients with hepatitis B infection (during acute and convalescent periods) and six healthy subjects. A single 10 mg kg‐1 dose of quinine was given intravenously over 2 h. Pharmacokinetic parameters of quinine during the acute phase of the infection were not different from those during the recovery phase. However, when compared with those obtained from healthy subjects, significant changes were found. The terminal elimination half‐life was prolonged (17 and 15 vs 10 h) and clearance was lower (2.9 and 2.3 vs 3.5 ml min‐1 kg‐1). Unbound quinine concentration in plasma at 2 h was approximately 10% of the total concentration in all subjects in the three study groups. A prolonged QTc interval (< 25%) was observed in all groups. The present data suggest that current dosage regimens of quinine used in the treatment of falciparum malaria may not be suitable for malaria patients with acute hepatitis or those who have had hepatitis within the past 3 months.
Dose‐dependent heart rate reducing effect of nizatidine, a histamine H2‐ receptor antagonist.
Authors: Hinrichsen H , Halabi A , Fuhrmann G , Kirch W
Published: July 2012

1. Twelve healthy subjects were treated in a randomised placebo‐ controlled crossover study with placebo, 150 mg, 300 mg, and 600 mg nizatidine, 100 mg pirenzepine, and 300 mg nizatidine plus 100 mg pirenzepine for 1 week each. 2. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, impedance cardiographic and Doppler ultrasound variables were measured. 3. Stroke volume and blood pressure were not altered by nizatidine and/or pirenzepine. By contrast, heart rate and cardiac output significantly (P < 0.05) decreased in a dose‐dependent manner 1.5 and 3 h after administration of 300 and 600 mg nizatidine. Treatment with 150 mg nizatidine led to similar though non‐significant trends. 4. While a slightly insignificant rise in heart rate was detected with pirenzepine alone, heart rate and cardiac output remained unchanged upon combined nizatidine and pirenzepine treatment as compared with placebo and baseline values. 5. In conclusion, nizatidine reduced heart rate and cardiac output in a dose‐dependent manner, whereas this negative chronotropic effect was counteracted by concurrent administration of the anti‐cholinergic drug pirenzepine.
The pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.
Authors: Vree TB , Van den Biggelaar‐Martea M , Verwey‐Van Wissen CP , Vree ML , Guelen PJ
Published: July 2012

1. The pharmacokinetics of 500 mg naproxen given orally were described in 10 subjects using a direct h.p.l.c. analysis of the acyl glucuronide conjugates of naproxen and its metabolite O‐desmethylnaproxen. 2. The mean elimination half‐life of naproxen was 24.7 +/‐ 6.4 h (range 7 to 36 h). 3. Naproxen acyl glucuronide accounted for 50.8 +/‐ 7.3% of the dose recovered in the urine, its isomerised conjugate isoglucuronide for 6.5 +/‐ 2.0%, O‐desmethylnaproxen acyl glucuronide for 14.3 +/‐ 3.4%, and its isoglucuronide for 5.5 +/‐ 1.3%. Naproxen and O‐ desmethylnaproxen were excreted in negligible amounts (< 1%). 4. Even though the urine pH of the subjects was kept acid in order to stabilize the acyl glucuronides, isomerisation took place in blood. 5. The extents of plasma binding of the unconjugated compounds were 98% (naproxen) and 100% (O‐desmethylnaproxen), while naproxen acyl glucuronide binding was 92%; that of its isomer isoglucuronide 66%. O‐ desmethylnaproxen acyl glucuronide was 72% bound and its isoglucuronide was 42% bound. 6. Cimetidine (400 mg twice daily) decreased the t1/2 of naproxen by 39‐60% (mean 47.3 +/‐ 11.5%; P = 0.0014) from 24.7 +/‐ 6.4 h to 13.2 +/‐ 1.0 h. It increased (10%) the urinary recovery of naproxen acyl glucuronide (P = 0.0492). The urinary recoveries of naproxen isoglucuronide and O‐desmethylnaproxen acyl glucuronide remained unchanged.
The effects of 5‐HT and m‐chlorophenylpiperazine (m‐CPP) on the efflux of [3H]‐5‐HT from human perfused platelets.
Authors: Carver JG , Grahame‐Smith DG , Johnson ES , Madgwick Z
Published: July 2012

1. m‐Chlorophenylpiperazine (m‐CPP), a 5‐HT1c‐receptor agonist, induces migraine‐like headaches when taken orally by migraine sufferers. The present study was undertaken to see what effects m‐CPP had on 5‐HT function in platelets. 2. Platelets from healthy male volunteers were loaded with [3H]‐5‐HT and continuously perfused in vitro with carboxygenated Krebs solution at 37 degrees C. After 30 min washout the effects of m‐CPP, thrombin, 5‐HT and ADP on the efflux of [3H]‐5‐HT were recorded. 3. m‐CPP (0.5‐500 microM) did not evoke an increase in the efflux of [3H]‐5‐HT over that occurring spontaneously whereas thrombin, unlabelled 5‐HT and ADP did. The effects of 5‐HT were potentiated by ADP. The results were identical whether or not the 5‐HT reuptake blocker paroxetine (1 microM) was present. 4. m‐CPP inhibited the increase in the efflux of [3H]‐5‐HT evoked by different concentrations of unlabelled 5‐HT in the presence of ADP (2.5 microM) and displaced the 5‐HT log concentration response curve to the right. A similar result was obtained with the 5‐HT2‐receptor antagonist ketanserin. 5. We conclude that m‐CPP is a 5‐HT2‐receptor antagonist on human platelets, which is unlikely to account for its headache‐inducing property, as many drugs effective in migraine prophylaxis have this action.
Neutrophils and mononuclear cells from patients with chronic granulomatous disease release nitric oxide.
Authors: Condino‐Neto A , Muscara MN , Grumach AS , Carneiro‐Sampaio MM , de Nucci G
Published: July 2012

1. Chronic granulomatous disease (CGD) is a group of genetic disorders characterised by recurrent severe suppurative infections due to impaired microbial killing. The principal biochemical defect is an impairment in the production of reactive oxygen intermediates by phagocytes. 2. Nitric oxide (NO) is synthesised from the guanidino nitrogen atom(s) of L‐arginine and has recently been proposed to be involved in defence mechanisms. The aim of this study was to investigate the involvement of the oxidative burst in the biosynthesis of NO by neutrophils and mononuclear cells from patients with CGD. 3. NO synthesis was assayed by the ability of neutrophils and mononuclear cells to inhibit thrombin‐induced washed platelet aggregation while superoxide anion (O2‐) production was measured spectrophotometrically by the superoxide dismutase inhibitable reduction of cytochrome c. 4. Neutrophils and mononuclear cells from patients with CGD released NO. This release was inhibited by nitro‐L‐arginine methyl ester but could be reversed by L‐arginine. Zymosan‐ and PMA‐induced O2‐ production was less than 10% as compared with healthy controls. 5. These results indicate that O2‐ production is not essential for NO synthesis in human leucocytes.
A comparison of amlodipine with enalapril in the treatment of moderate/severe hypertension.
Authors: Fowler G , Webster J , Lyons D , Witte K , Crichton WA , Jeffers TA , Wickham EA , Sanghera SS , Cornish R , Petrie JC
Published: July 2012

1. The safety and efficacy of amlodipine vs enalapril as monotherapy was evaluated in patients with moderate/severe hypertension (supine DBP 105‐125 mm Hg, SBP 140‐220 mm Hg). 2. After 2 weeks placebo treatment 31 patients were randomised by the technique of minimisation in an observer‐blind study to receive once daily treatment with either amlodipine (15 patients) 5‐10 mg, or enalapril (16 patients) 5‐20 mg for 8 weeks. The study design concluded with 2 weeks placebo treatment. In addition to clinic measurements, home blood pressure monitoring (Copal UA‐251) was performed during the study. 3. Clinic supine systolic blood pressure was reduced from 177 to 152 mm Hg (amlodipine) and 183 to 169 mm Hg (enalapril) (95% CI for the intergroup difference ‐ 22.1, 0.3, P = 0.06) after 8 weeks treatment. 4. Clinic supine diastolic blood pressure was reduced from 110 to 93 mm Hg (amlodipine) and 109‐102 mm Hg (enalapril) (95% CI for the intergroup difference ‐ 17.7, ‐2.7, P < 0.01) after 8 weeks treatment. 5. Home blood pressure recordings confirmed these reductions in blood pressure. Although the reduction in blood pressure was greater for the amlodipine treated group, the differences between treatments were not statistically significant. 6. Both drugs were reasonably well tolerated. The adverse events occurring most frequently in the amlodipine group were headache (5), peripheral oedema (3), upper respiratory infection (3) and anxiety (2). The adverse events occurring most frequently in the enalapril treated patients were headache (6), dizziness (3) and upper respiratory infection (2).
A comparison of amlodipine with enalapril in the treatment of isolated systolic hypertension.
Authors: Webster I , Fowler G , Jeffers TA , Lyons D , Witte K , Crichton WA , Wickham EA , Sanghera SS , Cornish R , Petrie JC
Published: July 2012

1. The safety and efficacy of amlodipine and enalapril were compared in patients with isolated systolic hypertension (supine DBP < 95 mm Hg and supine SBP 160‐200 mm Hg). 2. After 2 weeks treatment with placebo 31 patients were randomised by the technique of minimisation in an observer‐blind study to receive once daily treatment with either amlodipine (16 patients) or enalapril (15 patients) for 8 weeks. The study design concluded with 2 weeks placebo treatment. In addition to clinic measurements, home blood pressure monitoring (Copal UA‐251) was performed during the study. 3. Mean supine systolic blood pressure was reduced from 185 to 164 mm Hg (amlodipine) and 183 to 159 mm Hg (enalapril) (95% CI for the difference between the drugs ‐10.5, 15.3) after 8 weeks treatment. 4. Mean supine diastolic blood pressure was reduced from 86 to 80 mm Hg (amlodipine) and 88 to 80 mm Hg (enalapril) (95% CI for the difference between the drugs ‐4.9, 7.6) after 8 weeks treatment. 5. Home blood pressure recordings confirmed these reductions in blood pressure, although there was no significant difference between treatments for the reductions in blood pressure. 6. Both drugs were reasonably well tolerated. The adverse events occurring most frequently in the amlodipine group were headache (2), peripheral oedema (5) and palpitations (2). The adverse events occurring most frequently in the enalapril group were headache (2), peripheral oedema (2), palpitations (2) and dizziness (3).
Lack of effect of enalaprilat on the action of vasoactive intestinal polypeptide in the human forearm.
Authors: Cockcroft JR , Chowienczyk P , Elliott TG , Ritter JM
Published: July 2012

It has been proposed that angiotensin converting enzyme (ACE) may play a role in the metabolism of the vasodilator peptide vasoactive intestinal polypeptide (VIP). Reduced metabolism following treatment with ACE inhibitors may cause accumulation of VIP which in turn may mediate some of the beneficial haemodynamic effects of ACE inhibition observed in patients with heart failure. This study has shown that inhibition of local vascular ACE does not interfere with the vascular effects of VIP on forearm resistance vessels when this peptide is infused into the brachial artery of normal volunteers. These results suggest that endothelial ACE plays little part in the metabolism of intravascular VIP.
Presenting clinical pharmacology and therapeutics: the course in pharmacotherapeutics.
Authors: De Vries TP
Published: July 2012

To aid the rational choice and prescribing of drugs a normative (ideal) problem‐solving model was developed, and based on this model a course in pharmacotherapeutics for small groups of fifth year medical students was developed. The general objective is that students will learn the skills required to choose and prescribe drugs rationally. The program consists of about 10 plenary sessions and the principle role of the teacher is to guide the process. The main teaching methods are: Modified Essay Questions (MEQ), explanatory exercises and practical training sessions. Special teaching materials have been developed. For the examination the Objective Structured Clinical Exam (OSCE) is used.
Presenting clinical pharmacology and therapeutics: evaluation of a problem based approach for choosing drug treatments.
Authors: De Vries TP
Published: July 2012

Between 1983 and 1989 three studies were conducted to determine whether the ability of senior medical students to choose drug treatments rationally had improved. This period spanned the implementation of a course in pharmacotherapeutics which trained students to use a systematic problem‐based approach to choosing and prescribing drugs. The results show that in the short‐term students remembered how to choose drugs rationally for cases known to them (retention effect), but had difficulties in transferring what had been learned to similar but different problems (transfer effect). In the medium‐term a retention effect was shown for all three aspects of choice (drug, dosage and duration), and a transfer effect for choosing a dosage and duration when solving almost all types of patient problems used in the study. Transfer of the ability to choose a drug was less easily demonstrable. Compared with control students rational choices of trained students increased significantly for all aspects of drug choice, and almost all patient problems used in the study, whether or not they had been discussed. Possible causes for not finding a full transfer effect are: the intervention (course) may have been too short; there was sufficient knowledge about drugs but a lack of understanding of basic pharmacological concepts; or there was no reinforcement of the problem‐ based approach during clinical clerkships.
United Kingdom Product Licence applications involving new active substances, 1987‐1989: their fate after appeals.
Authors: Rawlins MD , Jefferys DB
Published: July 2012

1. The overall fate of Product Licence applications for new active substances considered by the Committee on the Safety of Medicines between 1987 and 1989 is described. 2. Fifty‐one applications were the subject of appelate procedures and 44 (86%) were successful. In 19 (43%) of the latter, applicants sought either decreased dosage regimens, substantially reduced indications, or (once) topical rather than systemic treatment. 3. Overall 57% of Product Licence applications considered between 1987 and 1989 either do not reach the market (23%) or only with substantial restrictions on dosage or indications (34%). Drug regulation, in the United Kingdom, thus plays a significant role in promoting public health rather than merely delaying the entry of new products to the market. 4. The number of volunteers and patients exposed to new active substances at the time of marketing varied widely within and between therapeutic classes. The median number of patients (1528) available for the assessment of safety underlies the importance of postmarketing safety surveillance.
Studies on the renal excretion of the acyl glucuronide, phenolic glucuronide and sulphate conjugates of diflunisal.
Authors: Dickinson RG , King AR , McKinnon GE , Hooper WD , Eadie MJ , Herkes GK
Published: July 2012

1. In five healthy male volunteers given multiple doses of diflunisal (DF), renal clearances (CLR) of the acyl glucuronide (DAG), phenolic glucuronide (DPG) and sulphate (DS) conjugates were about 42, 25 and 13 ml min‐1, respectively. 2. These relatively low CLR values are probably due largely to the very high plasma protein binding of the conjugates, found in vitro to be 99.0%, 97.8% and 99.45%, respectively. 3. Thus glomerular filtration plays the minor and active tubular secretion the major role in renal excretion of the three conjugates. 4. This conclusion was supported by the effect of probenecid co‐administration, which decreased CLR of DAG and DPG by about 70%. CLR for DS could not be calculated when probenecid was co‐administered (because of interference by probenecid metabolites in the analysis of DS in urine). 5. Water‐induced diuresis had no effect on CLR of the DF conjugates, consistent with tubular reabsorption being negligible.
Effects of dilevalol (R,R‐labetalol) compared with nifedipine on heart rate, blood pressure and muscle blood flow at rest and on exercise in hypertensive patients.
Authors: Walley T , Tsao Y , Scott A , Mackay E , Vandenburg M , Breckenridge A
Published: July 2012

1. Dilevalol (R,R‐labetalol) is a non‐selective beta‐adrenoceptor antagonist with beta 2‐adrenoceptor agonist activity. Its effects after 1 month's administration on heart rate, blood pressure and muscle blood flow were studied in a double‐blind crossover comparison with nifedipine in 16 hypertensive patients. 2. Dilevalol and nifedipine were similarly effective in lowering systolic and diastolic blood pressure at rest, but dilevalol limited the rise in systolic blood pressure induced by exercise more than nifedipine (rise of 27 vs 53 mm Hg respectively, P < 0.01). 3. Dilevalol decreased resting heart rate compared with nifedipine (73 vs 92 beats min‐1 respectively, P < 0.01). Dilevalol limited the exercise induced rise in heart rate more than nifedipine (36 vs 48 beats min‐1 respectively, P < 0.01). 4. Muscle blood flow (measured by strain gauge plethysmography) was not affected by either dilevalol or nifedipine at rest. After exercise, dilevalol caused an increase in excess blood flow compared with placebo (10.8 vs 5.1 ml min‐1 dl‐1 respectively, P < 0.01). The difference between dilevalol and nifedipine did not reach statistical significance (10.8 vs 6.5 ml min‐1 dl‐1 respectively, P > 0.05). 5. On blood pressure and heart rate, dilevalol demonstrated beta‐adrenoceptor blocker activity at rest and on exercise. On muscle blood flow, dilevalol appeared to have no effect at rest, but may have acted as a beta‐adrenoceptor blocker rather than as a beta 2‐adrenoceptor agonist during exercise.
The multiple dose pharmacokinetics of proguanil.
Authors: Helsby NA , Edwards G , Breckenridge AM , Ward SA
Published: July 2012

Proguanil, a prophylactic antimalarial agent, is metabolised by the polymorphic isoenzyme CYP2Cmep in man. In this study the multiple dose pharmacokinetics of proguanil were investigated in subjects who were phenotyped previously as extensive (n = 6) or poor (n = 2) metabolisers of the drug. Steady‐state plasma concentrations of proguanil were achieved within 48 h in extensive metaboliser subjects and chronic administration of the drug did not appear to alter the disposition of proguanil or that of its active metabolite, cycloguanil. The currently recommended dosage regimen appears to be appropriate for extensive metabolisers of proguanil. Poor metabolisers of proguanil had significantly lower plasma concentrations of the active metabolite cycloguanil compared with extensive metabolisers. Thus, even on multiple dose administration these subjects may not achieve adequate plasma concentrations of cycloguanil. Deficient metabolism of proguanil to cycloguanil leads to an increased appearance of the N‐dealkylated metabolite p‐chlorphenylbiguanide in the urine of poor metabolisers.
Cimetidine does not influence the metabolism of the H1‐receptor antagonist ebastine to its active metabolite carebastine.
Authors: Van Rooij J , Schoemaker HC , Bruno R , Reinhoudt JF , Breimer DD , Cohen AF
Published: July 2012

Ebastine is an H1‐receptor antagonist with a relative lack of sedating properties. It is almost completely converted to carebastine, and it is this metabolite which is responsible for the antihistaminic effect. Twelve healthy subjects received a single 20 mg dose of ebastine on day 2 of a multiple oral dosing regimen of either cimetidine (400 mg three times daily and 800 mg in the evening on the day preceding ebastine administration and 400 mg four times daily on the 2 following days) or placebo in a randomised cross‐over design. Significant plasma concentrations of ebastine were not detected after either treatment. The AUC of carebastine was not affected by cimetidine coadministration (4049 +/‐ 985 ng ml‐1 h after cimetidine vs 3795 +/‐ 959 ng ml‐1 h after placebo; 95% confidence interval of the difference: ‐412 to 919). Cimetidine coadministration did not induce any effect of ebastine on blood pressure and heart rate or cause sedation.
A clinical trial of a slow‐release formulation of acetylsalicylic acid in patients at risk for preeclampsia.
Authors: Shen J , Wanwimolruk S , Wilson PD , Seddon RJ , Roberts MS
Published: July 2012

The formation of thromboxane A2 (TXA2) in maternal and foetal cord serum was measured at birth in eight control patients and in 13 patients taking 100 mg of a slow‐release formulation of acetylsalicylic acid. The serum concentrations of TXB2 (a stable end product of TXA2 hydrolysis) in both maternal and cord serum from patients who ingested the acetylsalicylic acid formulation were significantly lower (P < 0.01) than those in control subjects. Acetylsalicylic acid was not detected (< 30 ng ml‐1) in maternal plasma from six mothers and in cord plasma from seven foetuses in the acetylsalicylic acid‐treated group. The mean cord to maternal plasma concentration ratios for detectable acetylsalicylic acid and salicylate were 0.62 +/‐ 0.19 (s.d.) (n = 6) and 0.84 +/‐ 0.16 (n = 13), respectively. We conclude that low doses of acetylsalicylic acid given in a slow‐release form to mothers during pregnancy cause depression of TXA2 formation in the foetal blood.
Interaction study between nifedipine and recombinant tissue‐type plasminogen activator in healthy subjects.
Authors: de Boer A , Kluft C , Kasper FJ , Kroon JM , Schoemaker HC , Breimer DD , Soons PA , Cohen AF
Published: July 2012

1. In a previous study it was demonstrated that a decrease in liver blood flow produced a decrease in clearance of recombinant human tissue‐ type plasminogen activator (rt‐PA). 2. The purpose of this randomized, double‐blind, placebo‐controlled, three‐way, cross‐over investigation was to determine the effect of nifedipine (20 mg orally), a compound that increases liver blood flow, on plasma concentrations of steady state endogenous and recombinant tissue‐type plasminogen activator (t‐ PA and rt‐PA) (35 mg of rt‐PA over 2 h) in nine healthy male volunteers. 3. Nifedipine increased liver blood flow by 95% (42‐167%) (mean (95% confidence interval)) as assessed by indocyanine green (ICG, 0.5 mg kg‐1 i.v. bolus injection) clearance. 4. Nifedipine did not influence the plasma concentrations of total rt‐PA antigen and activity as evaluated by the areas under the rt‐PA curves from 30 min (time at which nifedipine was ingested) to 90 min during the rt‐PA infusion (P > 0.05) and by analysis of a possible treatment x time interaction (P > 0.05). In addition, the plasma concentrations of endogenous t‐PA remained unchanged when nifedipine was given alone. 5. In conclusion, by using nifedipine as a model compound it was demonstrated that the combination of rt‐PA and a compound which increases liver blood flow probably does not lead to substantial changes in plasma concentrations of rt‐PA.
Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.
Authors: Brosen K , Skjelbo E , Flachs H
Published: July 2012

1. A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R‐ mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R‐ mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R‐mephenytoin ratios < or = 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2. The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4‐ chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann‐ Whitney U‐test). 3. There was no statistically significant correlation (Spearmans rs) between any index of proguanil metabolism and the sparteine metabolic ratio.
The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.
Authors: Hayball PJ , Nation RL , Bochner F , Sansom LN , Ahern MJ , Smith MD
Published: July 2012

1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51‐79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min‐1. 2. The fractions unbound of (R)‐ and (S)‐ketoprofen in plasma were determined for each subject after in vitro addition of rac‐ketoprofen (enantiomer range: 1.00‐6.00 micrograms ml‐1) to pre‐dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre‐dose) spiked with rac‐ ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)‐ketoprofen and CLCR. Corresponding relationships were also observed for the (R)‐enantiomer of ketoprofen. In addition, the half‐life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non‐conjugated and conjugated (R)‐ketoprofen and CLCR while that for the (S)‐stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)‐ and (S)‐ ketoprofen for either unbound or total drug. 6. The mean +/‐ s.d. percentage unbound of (S)‐ketoprofen in plasma (0.801 +/‐ 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/‐ 0.149%). The percentage unbound of the (S)‐enantiomer was higher at 6.00 micrograms ml‐1 than that at enantiomer concentrations of 3.50 micrograms ml‐1 and below, where it was invariant. The percentage unbound of (R)‐ketoprofen was independent of plasma concentration up to 6.00 micrograms ml‐1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)‐ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)‐ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/‐ s.d. EC50 was 0.216 +/‐ 0.143 ng ml‐1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)‐ ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl‐glucuronide conjugates. The apparent sensitivity of platelet cyclo‐oxygenase to the inhibitory effect of (S)‐ketoprofen was not influenced by renal function.
Impaired absorption of paracetamol in vegetarians.
Authors: Prescott LF , Yoovathaworn K , Makarananda K , Saivises R , Sriwatanakul K
Published: July 2012

1. The absorption and disposition of paracetamol was investigated in 10 healthy male Thai vegetarians and 10 similar non‐vegetarians following an oral dose of 20 mg kg‐1. 2. The absorption rate of paracetamol was significantly impaired in the vegetarians compared with the non‐ vegetarians as shown by a lower mean Cmax (11.7 +/‐ 1.4 vs 15.6 +/‐ 1.6 mg l‐1; 95% confidence interval of the difference 2.49 to 5.36), increased tmax (median 1.75, range 0.75 to 3 h compared with 0.75 and 0.25 to 2 h) and an increase in the time for input of 50% of the total amount absorbed (0.54 +/‐ 0.38 compared with 0.20 +/‐ 0.10 h; 95% confidence interval of the difference 0.063 to 0.61). 3. A significantly lower total 24 h urinary recovery of paracetamol and metabolites (72.1 +/‐ 5.4 vs 86.4 +/‐ 5.4% of the dose; 95% confidence interval of the difference 8.0 to 20.6) indicated a decrease in the extent of absorption in the vegetarians also, although the total AUC values did not differ significantly between the two groups. 4. The plasma paracetamol half‐life, partial metabolic clearances and fractional urinary excretion of the glucuronide, sulphate, cysteine and mercapturic acid conjugates of paracetamol were similar in the vegetarians and non‐vegetarians.
Evidence for differences in the binding of drugs to the two main genetic variants of human alpha 1‐acid glycoprotein.
Authors: Herve F , Gomas E , Duche JC , Tillement JP
Published: July 2012

1. Human alpha 1‐acid glycoprotein (AAG), a plasma transport protein, has three main genetic variants. F1. S and A. Native commercial AAG (a mixture of almost equal proportions of these three variants) has been separated by chromatography into variants which correspond to the proteins of the two genes which code for AAG in humans: the A variant and a mixture of the F1 and S variants (60% F1 and 40% S). Their binding properties towards imipramine, warfarin and mifepristone were studied by equilibrium dialysis. 2. The F1S variant mixture strongly bound warfarin and mifepristone with an affinity of 1.89 and 2.06 × 10(6) l mol‐1, respectively, but had a low affinity for imipramine. Conversely, the A variant strongly bound imipramine with an affinity of 0.98 × 10(6) l mol‐1. The low degree of binding of warfarin and mifepristone to the A variant sample was explained by the presence of protein contaminants in this sample. These results indicate specific drug transport roles for each variant, with respect to its separate genetic origin. 3. Control binding experiments performed with (unfractionated) commercial AAG and with AAG isolated from individuals with either the F1/A or S/A phenotypes, agreed with these findings. The results for the binding of warfarin and mifepristone by the AAG samples were similar to those obtained with the F1S mixture: the mean high‐ affinity association constant of the AAG samples for each drug was of the same order as that of the F1S mixture: the decrease in the number of binding sites of the AAG samples, as compared with the F1S mixture, was explained by the smaller proportion of variants F1 and/or S in these samples. Conversely, results of the imipramine binding study with the AAG samples concurred with those for the binding of this basic drug by the A variant, with respect to the proportion of the A variant in these samples.
The dose dependency of the alpha‐adrenoceptor antagonist and beta‐ adrenoceptor partial agonist activity of dilevalol and labetalol in man.
Authors: Tham TC , McKaigue JP , Guy S , Shanks RG , Riddell JG
Published: July 2012

1. The alpha‐adrenoceptor antagonist, beta 1‐adrenoceptor antagonist and beta 2‐partial agonist activity of dilevalol, a beta‐adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double‐blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/‐ s.d.) were: dilevalol 200 mg 1.1 +/‐ 0.1, labetalol 400 mg 2.2 +/‐ 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double‐blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/‐ 0.2. dilevalol 400 mg 1.1 +/‐ 0.4, dilevalol 800 mg 1.4 +/‐ 0.4 and labetalol 200 mg 2.5 +/‐ 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/‐ 0.4, dilevalol 400 mg 0.9 +/‐ 0.3. dilevalol 800 mg 1.3 +/‐ 0.4 and labetalol 200 mg 2.3 +/‐ 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/‐ 13 beats min‐1), 400 mg (123 +/‐ 12 beats min‐1), 800 mg (125 +/‐ 9 beats min) and labetalol 200 mg (143 +/‐ 12 beats min‐1) vs placebo (161 +/‐ 17 beats min‐1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/‐ 10.51 vs 6.62 +/‐ 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1‐adrenoceptor antagonist activity with no evidence of alpha 1‐adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1‐ and alpha 1‐ antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2‐adrenoceptor agonist activity by increasing finger tremor.
Effect on dietary fat absorption of orlistat, administered at different times relative to meal intake.
Authors: Hartmann D , Hussain Y , Guzelhan C , Odink J
Published: July 2012

Orlistat (O) is a potent and selective inhibitor of gastrointestinal lipases. The effect on dietary fat absorption following dosing of O at different times relative to meals was investigated in a placebo (P) controlled study in 24 hospitalized healthy males. After a 5‐day run‐ in, to accustom the subjects to a diet of 2400 kcal and 77 g fat per day and to establish baseline faecal fat excretion, subjects received, in four parallel groups of 6. over 8 days three times daily doses of 80 mg O.P.P (group A) or P. 80 mg O.P (group B) or P.P. 80 mg O (group C) or P.P.P (group D) at mid‐meal. 1 h and 2 h after mid‐meal respectively. Faeces were collected to measure total fat excretion. The mean (s.d.) of faecal fat in percent of dietary fat, after deduction of pre‐treatment faecal fat, was (%) 32.8 (8.1), 34.0 (8.8), 26.9 (4.0) and ‐1.4 (1.7) in groups A. B. C and D respectively. It was concluded that, within the time period investigated, the pharmacological effect of O is not critically dependent on the time of dosing relative to meals.
The haemodynamic effects of GR 32191, a thromboxane A2 receptor antagonist, in patients with renal artery stenosis and hypertension.
Authors: Lyons D , Fowler G , Petrie JC , Webster J
Published: July 2012

This study was designed to determine if GR 32191 a thromboxane A2 receptor antagonist, would lower blood pressure in patients with hypertension and renal artery stenosis. Eight patients with unilateral atheromatous renal artery stenosis and hypertension were studied in a double‐blind, single dose, placebo controlled, crossover study. The results show that, GR 32191, given orally, in doses of 20 mg and 40 mg, does not reduce the blood pressure to any clinically important degree.
A comparison of the effects of captopril and enalapril on skin responses to intradermal bradykinin and skin blood flow in the human forearm.
Authors: Li Kam Wa TC , Cooke ED , Turner P.
Published: July 2012

1. The effects of captopril and enalapril on skin responses to intradermal injections of bradykinin and skin blood flow in the forearm were investigated in this randomised, double‐blind, placebo‐controlled, cross‐over study. 2. Intradermal injections of 0, 1, 2.5 and 5 micrograms of bradykinin in 0.9% sodium chloride were made into the forearm of twelve healthy volunteers before and at 2, 6 and 24 h after single oral doses of 25 mg captopril, 10 mg enalapril or placebo. Forearm skin blood flow was measured by the technique of laser Doppler flowmetry (LDF) before the injections were made and the skin responses evaluated at 15 min after injections of bradykinin by measurement of cutaneous blood flow outside the induced weal, erythema area and weal volume. 3. The bradykinin‐induced cutaneous responses measured by LDF, erythema area and weal volume increased with incremental bradykinin dose. Compared with placebo, captopril significantly augmented the cutaneous vasodilator effects of bradykinin, measured by LDF and erythema area, at 2 h and the weal responses at 2 and 6 h. Enalapril enhanced the vasodilator responses to bradykinin at 2 and 6 h and the weal responses at 2, 6 and 24 h. Neither captopril nor enalapril significantly affected forearm skin blood flow. 4. This study showed that captopril and enalapril potentiated the effects of intradermal bradykinin both with respect to blood flow changes and weal formation in keeping with effective kininase II inhibition and the time course of these changes are consistent with enalapril being a longer acting drug than captopril. Captopril and enalapril exerted no influence on forearm skin blood flow measured by LDF.
Paracetamol elimination in patients with non‐insulin dependent diabetes mellitus.
Authors: Kamali F. , Thomas SH , Ferner RE
Published: July 2012

The pharmacokinetics and metabolism of an intravenous dose (500 mg) of paracetamol were studied in a group of non‐insulin dependent diabetic patients (n = 10) and in a group of healthy control subjects (n = 9). Paracetamol clearance, half‐life and the partial clearance to paracetamol glucuronide were not significantly different, but the partial clearance to paracetamol sulphate was significantly reduced (62 +/‐ 18 vs 86 +/‐ 17 ml h‐1 kg‐1 (mean +/‐ s.d.)) and the renal clearance of paracetamol was significantly increased (56 +/‐ 20 vs 22 +/‐ 6 ml h‐1 kg‐1 (mean +/‐ s.d.)) in the non‐insulin dependent diabetic patients, compared with the control group.