bluuebunny/crossref_metadata_2025 huggingface dataset:
Adequacy of twice daily dosing with potassium chloride and spironolactone in thiazide treated hypertensive patients.
Authors: Toner JM , Brawn LA , Yeo WW , Ramsay LE
Published: July 2012

1. The effects of 4‐6 weeks treatment with placebo, potassium chloride 32 mmol 12 hourly, and spironolactone 25 mg 12 hourly upon the plasma potassium concentration‐time profile were examined in hypertensive patients taking bendrofluazide 5 mg daily. 2. When compared with placebo, potassium chloride increased peak plasma potassium concentration (P less than 0.05), 12 h AUC for plasma potassium (P less than 0.1), and 12 h urine potassium excretion (P = 0.002). Spironolactone increased peak plasma potassium concentration (P less than 0.05), and 12 h AUC for plasma potassium (P less than 0.05), compared with placebo values. 3. Potassium chloride and spironolactone did not differ significantly in any respect other than 12 h urine potassium excretion. The 12 h AUC for plasma potassium was 35% larger with spironolactone than potassium chloride (not significant). 4. With both active drugs peak plasma potassium was observed 2‐3 h after dosing, and efficacy tended to wane towards 12 h. However, variability of plasma potassium within the dose interval was not increased markedly, and 12 hourly dosing is probably satisfactory for both potassium chloride and spironolactone at the doses studied.
Analysis of the natriuretic action of a loop diuretic, piretanide, in man.
Authors: Noormohamed FH , Lant AF
Published: July 2012

1. The renal responses to a loop diuretic, piretanide, were investigated in a group of fourteen healthy volunteers. The effect of fluid replacement on the drug‐response relationship was evaluated in the absence and in the presence of probenecid pretreatment following both oral and intravenous administration of piretanide. 2. Urinary excretion of piretanide was greater when volume losses were replaced than in the absence of volume replacement (i.v. dose: 3.32 +/‐ 0.15 vs 2.55 +/‐ 0.23 mg 6 h‐1, P less than 0.01; oral dose: 2.57 +/‐ 0.09 vs 1.87 +/‐ 0.27 mg 6 h‐1, P less than 0.01). With intravenous piretanide urinary excretion of sodium was likewise greater in the fluid replaced group (198 +/‐ 4 vs 141 +/‐ 10 mmol 6 h‐1, P less than 0.01); these differences caused by fluid replacement did not however occur after oral dosing of piretanide (181 +/‐ 12 vs 167 +/‐ 14 mmol 6 h‐1). 3. Probenecid pretreatment significantly decreased the renal excretion of piretanide in all subjects and consistently decreased the natriuretic response with the exception of intravenous piretanide challenge in subjects not undergoing fluid replacement. In this situation, despite probenecid causing a decrease in the amount of drug excreted (2.55 +/‐ 0.23 vs 1.63 +/‐ 0.15 mg 6 h‐1, P less than 0.05) the sodium output was unaltered (141 +/‐ 10 vs 152 +/‐ 16 mmol 6 h‐1, NS). 4. Complete replacement of the induced fluid losses resulted in the enhancement of the renal response, without affecting the shape of the diuretic response curve, of either the intravenous or orally administered piretanide.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of cimetidine and ranitidine on the pharmacokinetics of cifenline.
Authors: Massarella JW , Defeo TM , Liguori J. , Passe S. , Aogaichi K.
Published: July 2012

Twelve healthy subjects completed an open single dose study to evaluate the effect of co‐administration of cimetidine and ranitidine on the pharmacokinetics of cifenline. Each subject received a single 160 mg dose of cifenline alone, in combination with cimetidine (300 mg four times daily), and with ranitidine (150 mg twice daily). The H2‐receptor antagonists were given with breakfast 1 h prior to cifenline dosing and continuing for 48 h. Co‐administration of cimetidine significantly increased Cmax (27%) and AUC (44%) and prolonged the half‐life (30%) of cifenline. There were no differences in these parameters when ranitidine was co‐administered with cifenline. The results of this study suggest that cimetidine, but not ranitidine, lowers the clearance of cifenline by inhibition of hepatic oxidative metabolism.
The effect of intra‐arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man.
Authors: Cockcroft J.R. , Clarke JG , Webb DJ
Published: July 2012

1. The hypothesis that endothelin (ET) influences sympathetically mediated vasoconstriction was investigated in 13 healthy, male subjects. 2. ET (1 pmol min‐1) was infused for 60 min into the left brachial arteries of seven healthy male subjects. Resting forearm blood flow, and sympathetic vasoconstriction produced by lower body negative pressure (LBNP; 15 mm Hg), was measured in both arms by strain gauge plethysmography. In a further six subjects, noradrenaline (NA) was infused intra‐arterially at doses of 150‐600 pmol min‐1, with and without co‐infusion of ET (1 pmol min‐1), with blood flow measured in both forearms. 3. ET produced a small but significant reduction of blood flow in the infused forearm from 3.9 +/‐ 0.6 ml 100 ml‐1 min‐1 during infusion of saline, to 3.3 +/‐ 0.7 ml 100 ml‐1 min‐1 during infusion of ET at 60 min (P less than 0.05). Blood flow in the non‐ infused forearm was not altered by ET infusion. 4. NA produced a significant and dose‐dependent reduction of blood flow in the infused forearm from 3.13 +/‐ 0.5 ml 100 ml‐1 min‐1 during saline infusion, to 1.49 +/‐ 0.2 ml 100 ml‐1 min‐1 with NA at 600 pmol min‐1 (P less than 0.001). During co‐infusion of ET, blood flow was reduced similarly in the infused arm from 3.15 +/‐ 0.7 ml 100 ml‐1 min‐1 during saline infusion to 1.55 +/‐ 0.2 ml 100 ml‐1 min‐1 with NA at 600 pmol min‐1. Blood flow in the non‐infused arm was not altered by ET and NA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diflunisal and its conjugates in patients with renal failure.
Authors: Dickinson RG , Verbeeck RK , King AR , Restifo AC , Pond SM
Published: July 2012

Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated diflunisal clearance (by overestimation of plasma diflunisal concentrations through unrecognized acidic hydrolysis of diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.
A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine.
Authors: Yue QY , Svensson JO , Sjoqvist F. , Sawe J.
Published: July 2012

1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l‐1) and AUC (1660 nmol l‐1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l‐1 and 1010 nmol l‐1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half‐life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/‐ 0.14 s.d. vs 1.42 +/‐ 0.48 s.d. 1 h‐1 kg‐1) in Chinese than in Caucasians. 4. The total urinary recovery of drug‐related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6‐glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.
A screening test for slow metabolisers of tolbutamide.
Authors: Page MA , Boutagy JS , Shenfield GM
Published: July 2012

1. Six subjects participated in a detailed pharmacokinetic study of tolbutamide (pilot study). Using parameters based on these data, sixty‐ three non‐diabetic volunteers underwent a simple screening test designed to identify slow metabolisers of tolbutamide. 2. The screening test was an estimate of tolbutamide plasma elimination half‐life from plasma concentrations at 8 and 24 h after 500 mg tolbutamide orally, and urinary recovery of the hydroxy‐ and carboxytolbutamide metabolites over the 4‐8 h post‐dose period. 3. The mean tolbutamide half‐life for 61 of the screened subjects was 7.5 +/‐ 1.5 h (range 5.2‐12.2 h). Two subjects had half‐lives of 21.6 and 16.1 h. Their urinary metabolite recoveries were within the range of those in the screening test but lower than those in the pilot study. 4. The subject with the 21.6 h half‐life was restudied with intensive serial sampling for 72 h post‐ dose. She was confirmed as a ‘slow’ metaboliser of tolbutamide since her terminal half‐life was 25.9 h but plasma Cmax and tmax were within the range of those in the detailed study. This subject's 24 h urinary recoveries of both hydroxytolbutamide and carboxytolbutamide were clearly different from the mean values for the pilot study subjects implicating hydroxylation of tolbutamide as the metabolic defect. 5. The two point plasma half‐life is therefore a discriminatory screening test but a 4‐8 h urinary recovery is not. 6. A partial family study did not provide conclusive evidence of the inheritance of slow tolbutamide metabolism but the screening test should allow simple identification of slow metabolisers for further study.
Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase).
Authors: Tyndale RF , Kalow W. , Inaba T.
Published: July 2012

1. The conversion of haloperidol (HAL) to reduced haloperidol (RHAL) and then back to HAL has been established in vivo and observed in psychiatric patients. The reduction of HAL to RHAL is known to be catalysed by a ketone reductase, while the nature of oxidation back to HAL is the subject of the present study. 2. We examined the in vitro oxidation of RHAL to HAL in human livers. The activity was microsomal and evidence is presented to suggest that the sparteine/debrisoquine metabolizing isoenzyme P450IID6 contributes to this oxidation. 3. Reciprocal inhibition studies between RHAL and sparteine, a specific substrate for cytochrome P450IID6, indicated that both compounds compete for the same binding site. Quinidine, the most specific inhibitor for this cytochrome P450 potently inhibited the oxidative conversion of reduced haloperidol to haloperidol. A significant correlation (rs = 0.62, P less than 0.01) was found between RHAL oxidation and sparteine oxidation in a study involving 17 human liver samples.
Pharmacokinetic interaction between propranolol and the HMG‐CoA reductase inhibitors pravastatin and lovastatin.
Authors: Pan HY , Triscari J. , DeVault AR , Smith SA , Wang‐Iverson D. , Swanson BN , Willard DA
Published: July 2012

1. Single oral 20 mg doses of the HMG‐CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four‐way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration‐time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first‐pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.
Pharmacokinetics and pharmacodynamics of a new transdermal delivery system for bopindolol.
Authors: Drewe J. , Meier R. , Timonen U. , Thumshirn M. , Munzer J. , Kissel T. , Gyr K.
Published: July 2012

1. In two separate studies, each with 12 healthy male volunteers, the pharmacokinetic and dynamic properties of a transdermal delivery system for bopindolol were evaluated. 2. In study I it was shown that bopindolol absorption from a 14 mg patch occurred over the whole 7‐day application period. No signs of a significant skin depot were found. 3. In study II, a linear pharmacokinetic behaviour but a non‐linear kinetic/dynamic relationship was established for the patches over a dose range from 7 to 21 mg. Comparable peak effects of reduction in exercise‐induced tachycardia were observed after different patch doses and an i.v. injection. However, the effect was significantly prolonged with the patches compared with the injection and was maintained over 7 days. 4. The patches showed a good local and systemic tolerability in both studies over a dosing interval of up to 7 days.
Metabolism of verapamil in a family pedigree with deficient N‐oxidation of trimethylamine.
Authors: Ayesh R. , Kroemer H. , Eichelbaum M. , Smith RL
Published: July 2012

The oxidative N‐dealkylation of verapamil has been studied in a family of five members with two propositi with an inherited deficiency of trimethylamine N‐oxidation (fish‐odour syndrome). The results were assessed for possible co‐segregation of the trimethylamine N‐oxidation phenotype and any observed deficiency in oxidative N‐dealkylation. The general pattern of metabolism of verapamil in the five subjects studied was similar to that reported in earlier investigations. Moreover, there were no differences between the two affected subjects and other family members with respect to the metabolic pattern. It is concluded that there is no functional segregation with respect to the mechanisms controlling trimethylamine N‐oxidation and verapamil N‐dealkylation.
Lithium does not alter the renal response to a pressor dose of tyramine in man.
Authors: Lang CC , Rahman AR , Struthers AD
Published: July 2012

Renal clearance of lithium has been used as a marker of proximal tubular function in man. Recently, lithium pre‐treatment has been shown to interfere with the natriuretic actions of some natriuretic agents in man. We have therefore investigated the effects of oral lithium carbonate (500 mg) on the natriuretic response to a pressor dose of tyramine (15 micrograms kg‐1 min‐1) in six normal volunteers. Lithium had no effect on baseline sodium excretion, nor did it affect the tyramine‐induced increase in blood pressure and subsequent natriuresis. These results show that oral lithium carbonate (500 mg) does not appear to interfere with the pressure natriuretic response to tyramine in man.
Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.
Authors: Bonde J. , Pedersen LE , Nygaard E. , Ramsing T. , Angelo HR , Kampmann JP
Published: July 2012

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross‐over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R‐(‐) enantiomer than the S‐(+) enantiomer (7.9 vs 4.6 l h‐1 and 89 vs 50 l, respectively), whereas no significant difference in half‐life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S‐(+) enantiomer than that of the R‐(‐) enantiomer (34.6 +/‐ 5.4 l h‐1 vs 27.2 +/‐ 5.6 l h‐ 1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/‐ 38 l vs 226 +/‐ 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration‐ or time‐ related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.
Single dose pharmacokinetics and pharmacodynamics of oral oxazepam in very elderly institutionalised subjects.
Authors: Sonne J. , Loft S. , Dossing M. , Boesgaard S. , Andreasen F.
Published: July 2012

The effect of extreme old age on the pharmacokinetics and pharmacodynamics of orally administered oxazepam 15 mg was studied in 10 healthy elderly (age 80‐94 years) institutionalised subjects and 10 healthy young controls (age 26‐42 years). The total oxazepam clearance was 1.24 (0.91‐1.80) ml min‐1 kg‐1 (median and range) and 1.44 (0.88‐ 2.13) ml min‐1 kg‐1 in the elderly and young, respectively (NS), and the elimination half‐lives were 8.1 (5.5‐10.8) h and 5.7 (4.9‐6.2) h. respectively (P less than 0.01). The percent of unbound oxazepam was greater in the elderly; 9.8 (8.1‐13.3)% as opposed to 5.1 (3.7‐5.9)% in the young (P less than 0.0001). Clearance of unbound oxazepam was lower in the elderly, median values being 13.8 (7.1‐21.1) ml min‐1 kg‐1 compared with 30.3 (18.3‐41.5) ml min‐1 kg‐1 in the young (P less than 0.0001). A single 15 mg dose oxazepam decreased the ability of the elderly to perform a finger tapping test at 3 h but not 8 h after drug administration, whereas placebo had no effect at either times. No effect was observed in the young subjects.
The influence of Org 10172, a low molecular weight heparinoid, on antipyrine metabolism and the effect of enzyme induction on the response to Org 10172.
Authors: De Boer A. , Stiekema JC , Danhof M. , Breimer DD
Published: July 2012

1. We have investigated the effect of repeated s.c. Org 10172 (a low molecular weight heparinoid; Lomoparan) treatment (1000 anti‐Xa units twice daily for 5 days) on antipyrine (500 mg orally) metabolism, and the effect of enzyme induction by pentobarbitone (100 mg for 12 days) on the pharmacokinetics and pharmacodynamics of Org 10172 following an intravenous bolus injection of 3250 anti‐Xa units. 2. Org 10172 treatment caused a small increase in the formation rates of all antipyrine metabolites (P less than 0.05), while the overall kinetics of antipyrine did not change significantly. 3. Oxidative enzyme induction by pentobarbitone, as demonstrated by an increased clearance of antipyrine, was associated with an increase in the area under the anti‐thrombin activity vs time curve (P less than 0.05). No influence was seen on the kinetics of plasma anti‐Xa and thrombin generation inhibiting (TGI) activity. 4. The pharmacodynamics of Org 10172, as determined by clotting tests, was not influenced by enzyme induction. 5. The clinical relevance of these observations is likely to be limited.
The effect of infinitesimal drug dilutions on the pharmacokinetics of nalidixic acid and atenolol.
Authors: Ferry N. , Bernard N. , Pozet N. , Gardes E. , Bruguier M. , Cuisinaud G. , Sassard J.
Published: July 2012

1. Ten healthy subjects received two treatments: a single 1 g oral dose of nalidixic acid (NA) followed 1 h later by either an infinitesimal dilution of the drug (NA 7CH) or by succussed water which served as placebo. The study was repeated 18 months later in 10 different subjects. 2. A further 10 healthy subjects received three treatments: a single 100 mg oral dose of atenolol (AT) followed 3 h later by either placebo or a dilution of AT (AT 7CH) or of bisoprolol (BI 7CH). The homoeopathic preparations were administered by the sublingual route. 3. In the first NA experiment NA 7CH significantly shortened the elimination half‐life of NA from 8.6 +/‐ 2.2 (placebo) to 6.4 +/‐ 1.6 h (NA 7CH). In the second NA experiment none of the pharmacokinetic parameters was modified significantly by the administration of NA 7CH. Neither AT 7CH nor BI 7CH modified the pharmacokinetics of AT.
Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine.
Authors: Ahmed JH , Grant AC , Rodger RS , Murray GR , Elliott HL
Published: July 2012

1. The principal aim of this study was to investigate the effect of renal impairment on the pharmacokinetics of nicardipine following intravenous and oral dosing. 2. The plasma clearance of nicardipine was significantly lower at 6.5 ml min‐1 kg‐1 in patients with impaired renal function, compared with a mean value of 10.4 in patients with normal renal function and with 12.5 ml min‐1 kg‐1 in patients on regular haemodialysis treatment. 3. In comparison to the patients with normal renal function, there were significant increases in AUC and Cmax in the patients with renal impairment. These increases were particularly marked during chronic dosing ‐ AUC was increased by 163%, Cmax by 127% and apparent oral bioavailability by 90%. There were no such increases in the dialysis group whose values were similar to those for normal renal function. 4. There were no significant differences in volume of distribution or protein binding, nor in the measured indices of hepatic function to account for the reduction in drug clearance in the patients with renal impairment. 5. The results of this study indicate that renal impairment may have a significant and potentially important impact on the disposition of a drug which, under normal circumstances, is highly extracted by the liver. Accumulation of a metabolic 'inhibitor' substance is a possible explanation.
Aspirin‐induced gastric mucosal damage: prevention by enteric‐coating and relation to prostaglandin synthesis.
Authors: Hawthorne AB , Mahida YR , Cole AT , Hawkey CJ
Published: July 2012

1. Gastric damage induced by low‐dose aspirin and the protective effect of enteric‐coating was assessed in healthy volunteers in a double‐blind placebo‐controlled cross‐over trial using Latin square design. Each was administered placebo, plain aspirin 300 mg daily, plain aspirin 600 mg four times daily, enteric‐coated aspirin 300 mg daily, or enteric‐ coated aspirin 600 mg four times daily for 5 days. Gastric damage was assessed endoscopically, and gastric mucosal bleeding measured. 2. Aspirin 300 mg daily and 600 mg four times daily caused significant increases in gastric injury compared with placebo. Gastric mucosal bleeding was significantly more with the high dose, with a trend towards increased gastric erosions, compared with the low dose. 3. Enteric‐coating of aspirin eliminated the injury caused by low dose aspirin and substantially reduced that caused by the higher dose. 4. All dosages and formulations caused similar inhibition of gastric mucosal prostaglandin E2 synthesis. 5. Serum thromboxane levels were suppressed equally with plain and enteric‐coated aspirin. 6. In this short‐term study in healthy volunteers, gastric toxicity from aspirin was largely topical, independent of inhibition of prostaglandin synthesis, and could be virtually eliminated by the use of an enteric‐ coated preparation.
Reduction of LDL cholesterol by pravastatin does not influence platelet activation in patients with mild hypercholesterolaemia at risk of coronary heart disease.
Authors: Barrow SE , Stratton PD , Benjamin N. , Brassfield T. , Ritter JM
Published: July 2012

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20‐40 mg day‐1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3‐ dinor‐thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.
Interindividual variability in the N‐sulphation of desipramine in human liver and platelets.
Authors: Romiti P , Giuliani L , Pacifici GM
Published: July 2012

1. The activity of N‐sulphotransferase (N‐ST) with desipramine (DMI) as substrate was measured in 118 human liver specimens, in platelets obtained from 105 subjects, in 12 specimens of human ileum and colon mucosa and in five specimens of human kidney and lung. 2. N‐ST activity ranged between 5.71 and 157 pmol min‐1 mg‐1 protein in human liver and between 0.27 and 17.3 pmol min‐1 mg‐1 protein in human platelets. 3. Probit analysis was compatible with a unimodal distribution of the data from both liver and platelets. 4. The frequency distribution histograms of N‐ST were asymmetric, with a positive skew in data from both liver and platelets. The mode, median and mean of N‐ST were 16.4, 30.2 and 40.4 pmol min‐1 mg‐1 protein in liver, and 2.12, 3.61 and 3.82 pmol min‐ 1 mg‐1 protein in platelets, respectively. After logarithmic transformation of N‐ST activity, the frequency distribution histogram was symmetric for data from both liver and platelets. 5. In extrahepatic tissues, the average (+/‐ s.d.) N‐ST activity (pmol min‐1 mg‐1 protein) was 22.2 +/‐ 22.8 (ileum), 20.9 +/‐ 26.9 (colon), 12.4 +/‐ 5.5 (renal cortex), 9.3 +/‐ 2.8 (renal medulla) and 4.2 +/‐ 1.1 (lung). N‐ST is widely distributed in the body and the intestine is the extrahepatic tissue with the highest N‐ST activity.
The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid.
Authors: Taylor ML , Misso NL , Stewart GA , Thompson PJ
Published: July 2012

1. The effect of increasing doses of orally administered aspirin (30‐ 900 mg) on platelet aggregation and ATP release induced by arachidonic acid (AA), collagen and platelet activating factor (PAF) was assessed in 12 normal volunteers. 2. Aspirin ingestion was associated with a significant increase in EC50 for AA (P less than 0.0001) and collagen (P less than 0.0001) but not for PAF (P greater than 0.495) although the normal biphasic aggregation response for the latter was abolished. Maximum ATP release was reduced by aspirin for all three agonists. 3. The mean maximum degrees of inhibition of platelet aggregation induced by aspirin for AA, collagen and PAF were 100%, 48% and 21% of baseline, respectively. The corresponding mean maximum inhibition of ATP release was 100%, 63% and 57%. The minimum cumulative doses of aspirin producing these effects were 240, 240 and 90 mg for AA, collagen and PAF respectively. For collagen alone, there was a significant decrease in the degree of inhibition of aggregation between the last dose on day 1 (150 mg) and the baseline measurement on day 2. 4. Platelets from female subjects were more sensitive to collagen (P less than 0.05) and AA (P less than 0.01) stimulation compared with males. However, prior to aspirin ingestion, PAF produced a greater maximum response in platelets from females (P less than 0.02) while following aspirin ingestion PAF‐induced activation was inhibited to a greater degree in females (P less than 0.02). 5. These results indicate that collagen‐ and PAF‐induced platelet activation are only partially dependent on cyclo‐oxygenase and for PAF this seems related only to the second phase of aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)
Drug related admissions to medical wards: a population based survey.
Authors: Hallas J , Gram LF , Grodum E , Damsbo N , Brosen K , Haghfelt T , Harvald B , Beck‐ Nielsen J , Worm J , Jensen KB , et al
Published: July 2012

1. In total 1999 consecutive admissions to six medical wards were subjected to a prospective high‐intensity drug event monitoring scheme to assess the extent and pattern of admissions caused by adverse drug reactions (ADRs) or dose related therapeutic failures (TF), in a population‐based design. The wards were sub‐specialised in general medicine, geriatrics, endocrinology, cardiology, respiratory medicine and gastroenterology. 2. Considering definite, probable and possible drug events, the prevalence of drug related hospital admissions was 11.4% of which 8.4% were caused by ADRs and 3.0% by TFs. There were large inter‐department differences. 3. The six classes of drugs most frequently involved in admissions caused by ADRs were anti‐rheumatics and analgesics (27%), cardiovascular drugs (23%), psychotropic drugs (14%), anti‐diabetics (12%), antibiotics (7%), and corticosteroids (5%). Noncompliance accounted for 66% of the TFs with diuretics and anti‐asthmatics most frequently involved. 4. The pattern of drugs involved in ADRs was compared with the regional drug sales statistics. Drugs with a particularly high rate of ADR related admissions per unit dispensed were nitrofurantoin and insulin (617 and 182 admissions per 1,000,000 defined daily doses), while low rates were seen for diuretics and benzodiazepines (10 and 7 admissions per 1,000,000 defined daily doses). Confidence intervals were wide. 5. Patients who had their therapy prescribed by a hospital doctor had a slightly higher prevalence of drug events than those who were treated by a general practitioner (12.6% vs 11.8%). The reverse applied for drug events assessed as avoidable (3.3% vs 4.6%). Although these differences were not statistically significant, it may suggest general practitioners as the appropriate target for interventive measures.(ABSTRACT TRUNCATED AT 250 WORDS)
Age‐related changes in adenosine and beta‐adrenoceptor responsiveness of vascular smooth muscle in man.
Authors: Ford GA , Hoffman BB , Vestal RE , Blaschke TF
Published: July 2012

1. Ageing is associated with a decline in beta‐adrenergic responsiveness in several tissues. Reduced beta‐adrenoceptor mediated smooth muscle relaxation in aged man has been demonstrated using the dorsal hand vein technique. Isoprenaline and adenosine activate adenylate cyclase through separate membrane bound receptors to induce vasodilatation. 2. To determine the specificity of reduced beta‐ adrenergic responsiveness in smooth muscle of aged man, and possible sites of the defect responsible, venodilatory responses to isoprenaline, a beta‐adrenoceptor agonist and adenosine were determined in nine young (age 26 +/‐ 3 years: mean +/‐ s.d.) and eight elderly (age 70 +/‐ 5 years), healthy male volunteers. Veins were partially constricted with the alpha 1‐adrenoceptor agonist phenylephrine and increasing doses of adenosine (5 to 1220 micrograms min‐1) or isoprenaline (271 ng min‐1) were infused. 3. Maximal dilatation induced by isoprenaline was 83 +/‐ 26% in the young and 51 +/‐ 34% in the elderly, P = 0.02. Maximal dilatation induced at the highest dose of adenosine (1220 micrograms min‐1) was similar in young and elderly: 79 +/‐ 25% vs 88 +/‐ 28%, P = 0.26. 4. Adenosine venodilatation was measured before and after infusions of theophylline (6.8 to 135 micrograms min‐1) for 30 min in six subjects. Adenosine responsiveness was unchanged following theophylline: 48 +/‐ 16% to 49 +/‐ 40%, P = 0.44. 5. The results suggest that the age‐associated reduced responsiveness of the beta‐adrenergic system in human vascular smooth muscle is not shared by venodilatation mediated by adenosine.
The pharmacokinetics of perindopril and its effects on serum angiotensin converting enzyme activity in hypertensive patients with chronic renal failure.
Authors: Sennesael J , Ali A , Sweny P , Vandenburg M , Slovic D , Dratwa M , Resplandy G , Genissel P , Desche P
Published: July 2012

1. Perindopril, an orally active angiotensin converting enzyme inhibitor, was given to 23 hypertensive patients with stable chronic renal failure for 15 days. The dose of perindopril was 2 or 4 mg once a day according to the degree of renal failure. The creatinine clearance of the patients ranged from 6 to 67 ml min‐1 1.73 m‐2. The pharmacokinetics of perindopril and perindoprilat, its active metabolite, were studied after acute and chronic administration of perindopril. 2. The drug was well tolerated and creatinine clearance was unaltered by treatment. 3. In both groups, steady‐state was reached within 3 days of chronic treatment. 4. After both acute and chronic drug administration renal impairment had no effect on perindopril pharmacokinetics but the pharmacokinetics of perindoprilat were altered significantly. After chronic administration the serum accumulation ratio was 1.81 in patients with mild renal failure and 5.35 in patients with severe renal failure. Chronic administration did not modify the renal clearance of perindoprilat nor its elimination half‐life. 5. A significant correlation between the renal clearance of perindoprilat and creatinine clearance was observed (r = 0.87 first dose, r = 0.83 last chronic dose). 6. A non‐linear relationship between serum perindoprilat concentration and inhibition of angiotensin converting enzyme was described by a modified Hill equation. Values of IC50 were 1.11 +/‐ 0.07 micrograms I‐1 (mean +/‐ s.d.) in patients with severe renal failure and 1.81 +/‐ 0.20 micrograms l‐1 in patients with moderate renal failure. Chronic administration increased maximal inhibition and decreased the time to maximal inhibition only in patients with severe renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of personality factors and suggestion in placebo effect during mental stress test.
Authors: McCann CC , Goldfarb B , Frisk M , Quera‐Salva MA , Meyer P
Published: July 2012

The aims of this study were first of all to document a placebo effect on systolic blood pressure and heart rate during mental arithmetic induced stress and secondly to assess the role of suggestion in producing this effect. Two types of placebo were used, a simple placebo and a placebo with an implied therapeutic action. Both were compared with alprazolam. A placebo response was seen in just over half of the volunteers when the cardiovascular changes to mental arithmetic induced stress in healthy volunteers were measured. This response appeared to be unaffected by the suggested therapeutic effect. Dominant, independent subjects, identified using the Cattell 16 PF personality test were less likely to respond to placebo. Alprazolam (0.5 mg) did not prevent, to a significantly greater degree than placebo, the systolic blood pressure or heart rate increases provoked by the mental stress.
Rapid tolerance to acute psychomotor impairment with carbamazepine in epileptic patients.
Authors: Larkin JG , McKee PJ , Brodie MJ
Published: July 2012

Thirteen patients with newly diagnosed epilepsy performed a battery of psychomotor function tests before and during the first 12 weeks of carbamazepine (CBZ) therapy. Movement time (P less than 0.025), total choice reaction time (P less than 0.025), finger tapping rate (P less than 0.005) and number cancellation (P less than 0.05) were all significantly impaired after 1 week's treatment, but had returned to baseline by 4 weeks. Mean (+/‐ s.d.) serum CBZ concentrations and those of its active metabolite CBZ 10,11 epoxide (CBZ‐E) were comparable at 1 (CBZ: 8.5 +/‐ 2.1 mg l‐1, CBZ‐E: 1.1 +/‐ 0.68 mg l‐1) and 4 weeks (CBZ: 8.1 +/‐ 4.4 mg l‐1, CBZ‐E: 0.93 +/‐ 0.27 mg l‐1). These results suggest the rapid development of tolerance to the acute deleterious psychomotor effects of CBZ.
Inhaled beta 2‐adrenoceptor agonists in asthma: help or hindrance?
Authors: Lipworth BJ , McDevitt DG
Published: July 2012

Conventional low doses of inhaled beta 2‐adrenoceptor agonists produce effective bronchodilation without systemic effects. Higher doses of inhaled beta 2‐adrenoceptor agonists may produce substantial improvements in bronchodilator response, which may be helpful to patients with more severe airway obstruction. At higher than recommended doses, in asthmatic patients, fenoterol appears to cause greater dose‐related systemic beta 2‐responses compared with salbutamol or terbutaline, although there is no evidence to suggest that fenoterol is any less beta 2‐selective in vivo. Furthermore, tolerance develops to systemic but not to bronchodilator effects during chronic treatment with inhaled beta 2‐adrenoceptor agonists. The link between asthma mortality and systemic adverse effects of inhaled beta 2‐adrenoceptor agonists at present remains unproven. A critical reappraisal of the regular use of inhaled beta 2‐adrenoceptor agonists including long‐ acting drugs is now indicated in the light of their possible adverse effects on disease control. Patients requiring regular use of inhaled beta 2‐adrenoceptor agonists should be given additional anti‐ inflammatory therapy with inhaled corticosteroids.
A comparison of the effect of salmeterol and salbutamol in normal subjects.
Authors: Spring J , Clague J , Ind PW
Published: July 2012

1. The effects of salmeterol hydroxynaphthoate (50 micrograms, 8.3 x 10(‐8) M) and salbutamol (200 micrograms, 3.5 x 10(‐7) M) on sGaw were compared in a double‐blind, placebo‐controlled, randomised study in 10 normal subjects. 2. SGaw increased by 29% (14‐43) (mean (CI)), 5 min after salmeterol and by 35% (19‐51) at 15 min compared with an increase of 32% (14‐51) and 37% (10‐63) after salbutamol and 4% (‐3‐11) and 8% (0‐16) after placebo. 3. The mean area under the sGaw‐time curve (AUC480) after salmeterol inhalation was 22,500 kPa‐1 (10,100‐39,500) compared with 14100 kPa‐1 (8020‐24,500) after salbutamol and 5300 kPa‐1 (1500‐10,400) after placebo. 4. Salmeterol produced a significantly prolonged bronchodilator effect compared with salbutamol in normals.
The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.
Authors: Wade JR , Meredith PA , Hughes DM , Elliott HL
Published: July 2012

1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/‐ 97 and 450 +/‐ 87 ng ml‐1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.
Prandial and diurnal effects on the absorption of orally administered enteric coated 5‐aminosalicylic acid (5‐ASA).
Authors: De Mey C , Meineke I
Published: July 2012

Plasma and urine concentrations of 5‐ASA and its N‐acetyl metabolite 5‐ AcASA were measured over 48 h in 12 young healthy male subjects, who received three doses of three times enteric coated 500 mg 5‐ASA tablets at 7 h interval, on two occasions 14 days apart. On one occasion the doses were given after standard meals; on the other occasion, they were given 1 h before meals. Administration of the tablets after meals delayed systemic drug absorption but did not affect the extent of absorption. There was a sharp rise in the plasma concentrations of 5‐ ASA and 5‐AcASA in the early morning (i.e. circa 24 h after administration of the 1st dose) independent of when the tablets were taken with respect to the meals. This suggests that tablets or tablet fragments remained in the stomach until the later part of the night. Thus, diurnal effects may be more important than prandial effects in the evaluation of the kinetics of 5‐ASA and its metabolites after peroral administration of enteric coated tablets.
Detection of an autoantibody directed against human liver microsomal protein in a patient with carbamazepine hypersensitivity.
Authors: Pirmohamed M , Kitteringham NR , Breckenridge AM , Park BK
Published: July 2012

A 16‐year old patient with carbamazepine‐induced hepatotoxicity, associated with the hypersensitivity manifestations of fever, rash and eosinophilia, is described. Mononuclear leucocytes from the patient were more sensitive to oxidative metabolites of carbamazepine generated by induced murine and human hepatic microsomes, than cells from controls. On immunoblot analysis, serum from the patient recognised a single protein band (94 kDa) on human liver microsomes, but none out of 25 control sera recognised this band. No bands were recognised by the patient serum on human kidney microsomes or on microsomes from mouse and rat liver.
Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.
Authors: Chauveau D , Guyenne TT , Cumin F , Chatellier G , Corvol P , Menard J
Published: July 2012

1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1‐10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml‐1, and the extraction recovery of [125I]‐Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml‐1) of the standard curve. The overall recovery was 98.5 +/‐ 3.5%. The intra‐ and inter‐ assay reproducibility was 10.4% and 9.7% respectively. Cross‐reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2‐10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long‐acting ACE‐inhibitor. During the following 24 h, the renin‐angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three‐way cross‐over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg‐1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of a selective 5‐HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.
Authors: Millson DS , Jessup CL , Swaisland A , Haworth S , Rushton A , Harry JD
Published: July 2012

1. ICI 170,809 (2‐(2‐dimethylamino‐2‐methylpropylthio)‐3‐ phenylquinoline hydrochloride) is a potent 5‐hydroxytryptamine (5‐HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5‐HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5‐HT aggregation response was reduced by ICI 170,809, with depression of the dose‐ response curve to 5‐HT at all concentrations of 5‐HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5‐HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5‐HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml‐1) of ICI 170,809, enabling the assessment of 5‐HT2‐receptor antagonism in man.
Prostaglandin I2 and the nitric oxide donor molsidomine have synergistic effects on thromboresistance in man.
Authors: Sinzinger H , Rauscha F , O'Grady J , Fitscha P
Published: July 2012

1. In vitro synergistic effects of nitric oxide and prostaglandin I2 (PGI2) have been shown. Consequently we examined any potentiating effect of the nitric oxide donor molsidomine on the reduction in thrombogenicity produced by PGI2 in patients with peripheral vascular disease. 2. Thirty‐six patients all with peripheral and also coronary artery disease were randomly allocated to receive PGI2 5 ng kg‐1 min‐1 for 6 h daily, 5 days a week for 5 weeks, alone (12 patients), with molsidomine 12 mg daily (12 patients) or molsidomine 12 mg daily alone (12 patients). 3. The effect of each treatment regimen was measured in terms of femoral artery platelet uptake and platelet survival after autologous 111Indium‐oxine labelling. Molsidomine alone had no effect on platelet uptake or survival but in combination with PGI2 it significantly potentiated the decreased platelet uptake and prolonged platelet survival observed with PGI2 alone.
The effect of ageing on plasma albumin and plasma protein binding of diazepam, salicylic acid and digitoxin in healthy subjects and patients with renal impairment.
Authors: Viani A , Rizzo G , Carrai M , Pacifici GM
Published: July 2012

1. Plasma albumin concentration was measured in 118 healthy subjects (aged between 18 and 87 years), in 95 renal patients with creatinine clearances between 15 and 50 ml min‐1 (aged between 14 and 79 years) and in 101 uraemic patients maintained on chronic haemodialysis (aged between 27 and 83 years). 2. There was a significant (P less than 0.001) negative correlation between albumin concentration and age in healthy subjects, but no correlation in patients with low creatinine clearance or in uraemic patients. 3. The ex vivo plasma binding of diazepam (1 microM), salicylic acid (2 mM) and digitoxin (37 nM) was studied in groups of age‐selected young and aged healthy subjects in patients with low creatinine clearance and in patients with uraemia. The unbound fractions of diazepam and salicylic acid were about double in old compared with young healthy subjects whereas they were similar in young and old patients with lowered creatinine clearance. In uraemic patients, ageing did not affect the binding of salicylic acid whereas the unbound fraction of diazepam was slightly but significantly greater in elderly subjects. The unbound fraction of digitoxin was independent of age in both healthy subjects and in those with renal disease. 4. Decreased plasma binding of diazepam and salicylic acid was partially corrected by extensive dialysis of plasma. The lower plasma binding of diazepam and salicylic acid associated with ageing may be ascribed to the effects of endogenous displacers and to hypoalbuminaemia. The influence of these two factors appears to be drug‐dependent.
Formation of biologically active 13,14‐dihydro‐prostaglandin E1 during intravenous infusion of prostaglandin E1 in newborns with ductus arteriosus‐dependent congenital heart disease.
Authors: Leonhardt A , Schweer H , Wolf D , Seyberth HW
Published: July 2012

Plasma concentrations of prostaglandin (PG) E1 (12‐150, median 25 pg ml‐ 1) and 13,14‐dihydro‐PGE1 (3‐62, median 45.5 pg ml‐1) were measured by gas chromatography‐mass spectrometry in eight newborns with ductus arteriosus‐dependent congenital heart disease during continuous intravenous infusion of PGE1. Formation of 13,14‐dihydro‐PGE1 was demonstrated for the first time in neonates. Since 13,14‐dihydro‐PGE1 has similar biological activities as the parent compound PGE1, pharmacological effects during PGE1 infusion are most likely related to both PGE1 and the generation and action of 13,14‐dihydro‐PGE1.