bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel method for culturing sweat gland epithelia: comparison of normal and cystic fibrosis tissues.
Authors: Brayden DJ , Cuthbert AW
Published: July 2012

A new method is described to produce epithelial sheets by direct explantation of human sweat glands onto matrigel‐coated millipore filters. The method is applicable to whole glands, separated coils or ducts and to normal and CF tissues. Electrogenic transport studies show that epithelia develop sodium transporting capability, even when explants are derived from secretory coils.
Disposition of pravastatin sodium, a tissue‐selective HMG‐CoA reductase inhibitor, in healthy subjects.
Authors: Singhvi SM , Pan HY , Morrison RA , Willard DA
Published: July 2012

Pravastatin sodium, a competitive inhibitor of HMG‐CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two‐way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]‐pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first‐pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half‐life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min‐ 1 kg‐1, respectively, and the steady‐state volume of distribution averaged 0.51 kg‐1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.
The effect of autonomic blockers on heart rate: a comparison between two ethnic groups.
Authors: Meyer EC , Sommers DK , Schoeman HS , Avenant JC
Published: July 2012

The influence of autonomic blockers on the heart rate of ten Bushmen and eight White volunteers was studied. There were significant differences in heart rate response to atropine alone between the White's and Bushmen. However, after prior beta‐adrenoceptor blockade, these differences were no longer significant. It is postulated that a varying pharmacogenetic sensitivity to autonomic blockers may result from inequality of vagal or sympathetic tone.
Cimetidine as modulator of the cell‐mediated immune response in vivo using the tuberculin skin test as parameter.
Authors: Snyman JR , Meyer EC , Schoeman HS
Published: July 2012

The in vivo pharmacological effects of cimetidine on delayed hypersensitivity reactions in healthy volunteers were studied using the tuberculin skin test as parameter. Cimetidine clearly enhanced this reaction when it was administered well before antigenic stimulation.
The effect of propranolol on paracetamol metabolism in man.
Authors: Baraka OZ , Truman CA , Ford JM , Roberts CJ
Published: July 2012

Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half‐life of antipyrine by 11 +/‐ 5% (mean +/‐ s.e. mean) and lowered its clearance by 14 +/‐ 3% (P less than 0.05). Propranolol increased the half‐life of paracetamol by 25 +/‐ 12% (P less than 0.05) and lowered its clearance by 14 +/‐ 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/‐ 3% (P less than 0.05) and 32 +/‐ 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/‐ 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.
Lack of effect of atenolol and nadolol on the metabolism of theophylline.
Authors: Corsi CM , Nafziger AN , Pieper JA , Bertino JS
Published: July 2012

The effects of 7 days of pretreatment with atenolol, 150 mg day‐1, or nadolol, 80 mg day‐1, on the pharmacokinetics and metabolism of theophylline were determined in six male smokers. Theophylline clearance, volume of distribution, half‐life and the urinary excretion of theophylline and its metabolites were unchanged during either treatment compared with control.
Safety of vancomycin in acute porphyria.
Authors: Hift R , Sohnius U , Meissner PN
Published: July 2012

A 27‐year‐old female with acute intermittent porphyria presented in a life‐threatening acute attack. She developed a Staphylococcus aureus septicaemia and was treated with intravenous vancomycin for 4 weeks. Porphyrins and their precursors were monitored and declined during the course of therapy. The safety of vancomycin in people with the acute porphyrias has not previously been documented, and we conclude that, in this case, the use of vancomycin was without ill‐effect.
The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.
Authors: Hasselstrom J , Eriksson S , Persson A , Rane A , Svensson JO , Sawe J
Published: July 2012

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine‐3 (M3G) and morphine‐6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half‐life of morphine was 4.2 h (95% CI 3.6‐4.8) the mean volume of distribution was 4.1 l kg‐1 (95% CI 2.9‐5.4) and the mean plasma clearance was 11.4 ml min‐1 kg‐1 (95% CI 8.1‐14.7). The mean oral bioavailability was 101% (95% CI 56‐147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half‐life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half‐life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.
A dose‐effect study of the in vivo inhibitory effect of quinidine on sparteine oxidation in man.
Authors: Nielsen MD , Brosen K , Gram LF
Published: July 2012

1. Twelve healthy extensive metabolisers of sparteine were sparteine tested daily for 6 days (19.00 h to 07.00 h). A small but statistically significant rise in sparteine metabolic ratio (MR) was observed. 2. Following 100 mg quinidine sulphate given to four of the subjects at 16.00 h, sparteine tests were carried out 19.00 h to 07.00 h on the same day and then daily for 6 days. Quinidine caused an immediate twenty‐fold increase in sparteine‐MR which then gradually returned to normal over the following 4‐6 days. Quinidine concentrations in plasma were measurable only up to 20 h after the quinidine test dose. 3. At weekly intervals, all 12 subjects received single doses of quinidine sulphate of 5, 10, 20, 40 and 80 mg at 16.00 h, each time followed by a sparteine test 19.00 h to 07.00 h on the same day. A clear dose‐effect relationship was found with a significant rise in the sparteine‐MR even after 5 mg quinidine. After 80 mg quinidine, 8 of 12 subjects became phenotypically poor metabolisers (MR greater than 20).
Effects of acetylsalicylic acid and paracetamol alone and in combination on prostanoid synthesis in man.
Authors: Bippi H , Frolich JC
Published: July 2012

1. The present study was designed to investigate the effects of acetylsalicylic acid and paracetamol given separately and in combination on total body and renal PGE2 synthesis in healthy volunteers. 2. In a randomized four‐way cross‐over study eleven female volunteers received for two consecutive days 3 g day‐1 acetylsalicylic acid or 3 g day‐1 paracetamol or a combination of 1.5 g day‐1 acetylsalicylic acid and 1.5 g day‐1 paracetamol, or 1.5 g day‐1 acetylsalicylic acid separated by washout phases of at least 5 days. Urinary excretion of the major urinary metabolite of PGE2 (PGE‐MUM), PGE2 and creatinine clearance were measured before and on day 2 of each treatment period. Compliance was tested by measuring metabolites of the two drugs in urine. 3. Paracetamol did not reduce urinary excretion of PGE2 whereas both dosages of acetylsalicylic acid caused a significant reduction. 4. The combination of both drugs did not reduce PGE2 excretion more than acetylsalicylic acid alone. 5. All four drug schedules reduced urinary excretion of PGE‐MUM significantly.
Effect of formoterol, a long‐lasting beta 2‐adrenoceptor agonist, against methacholine‐induced bronchoconstriction.
Authors: Nix A , Nichol GM , Robson A , Barnes PJ , Chung KF
Published: July 2012

1. The effects of a new long‐acting inhaled beta 2‐adrenoceptor agonist aerosol formoterol (12 micrograms), on FEV1, and on methacholine‐ induced bronchoconstriction, were compared with those of terbutaline (250 micrograms) and placebo in 12 midly asthmatic subjects. 2. PC20, the concentration of methacholine needed to cause a 20% fall in baseline FEV1, was determined 2 and 5 h after formoterol, terbutaline and placebo on separate days. Baseline PC20 was determined on a different day. 3. Compared with terbutaline and placebo, formoterol hastened recovery from methacholine‐induced bronchoconstriction, and significantly increased mean PC20 (by 2.2‐ and 2.9‐fold at 2 and 5 h respectively). 4. Thus, formoterol has a protective effect against methacholine‐induced bronchoconstriction which lasts for at least 5 h.
Investigation of intravascular haemolysis during treatment of acute stroke with intravenous glycerol.
Authors: Kumana CR , Chan GT , Yu YL , Lauder IJ , Chan TK , Kou M
Published: July 2012

1. In patients with acute strokes entering a large ongoing randomised double‐blind controlled trial of intravenous glycerol therapy, the extent and pathogenesis of any ensuing haemolysis were evaluated using standard clinical investigations and in vitro techniques. 2. Twenty patients received 10% glycerol in saline (500 ml over 4 h on 6 consecutive days) and 15 received corresponding control treatment with saline. 3. Intravascular haemolysis was evident after the first infusion; compared with the controls the glycerol group had i) a greater mean reduction in serum haptoglobin concentration (P less than .05), and ii) a greater proportion exhibiting haemoglobinaemia (P = 0.03). 4. After 6 days of glycerol treatment, the mean reduction in haemoglobin concentration was only 0.8 g more than in controls; this difference being neither clinically nor statistically significant. 5. Glycerol therapy was not associated with haemoglobinuria, renal insufficiency or disseminated intravascular coagulation. 6. Exposure of red blood cells to 1‐10% glycerol in vitro did not induce haemolysis per se; on re‐exposure to lower concentrations lysis ensued provided a minimum osmotic gradient was present. 7. Whilst taking standard dosage regimes of glycerol, the stroke patients we studied manifested a degree of intravascular haemolysis but its consequences were not clinically significant; lysis probably ensued after venous blood acquiring high glycerol concentrations mixed with blood containing little or no glycerol.
Single doses of ritodrine delay orocaecal transit in patients with irritable bowel syndrome.
Authors: Basilisco G , Camboni MG , Bozzani A , Molgora M , Bianchi PA
Published: July 2012

The lactulose hydrogen breath test was used to assess the effect of a single dose of the beta 2‐adrenoceptor agonist ritodrine on orocaecal transit time in 11 patients (three men) with irritable bowel syndrome. Transit time (median values, range) was significantly longer (P less than 0.01) after ritodrine than after placebo (120, 50‐200 vs 75, 40‐ 100 min). Median heart rate was similar before treatments whereas the maximal increase in heart rate was significantly greater (P less than 0.01) after ritodrine than after placebo.
The effect of sulindac on dermal responses to bradykinin in normal subjects given an angiotensin converting enzyme inhibitor.
Authors: Ferner RE , Kamali F , Rawlins MD
Published: July 2012

The ability of sulindac to modify the weal response to four doses of intradermal bradykinin in subjects given enalapril was tested in a double‐blind cross‐over study in normal volunteers. The dose‐dependent increase in skin thickness after bradykinin was significantly reduced by prior administration of sulindac. Certain of the actions and adverse effects of angiotensin converting enzyme inhibitors may be due to the interaction of prostaglandins and bradykinin.
Comparative haemodynamic effects of intravenous nisoldipine and hydralazine in congestive heart failure.
Authors: Haitas B , Meyer TE , Angel ME , Reef E
Published: July 2012

The acute haemodynamic effects of intravenous nisoldipine and hydralazine were compared in nine patients with heart failure. Both agents caused qualitatively similar effects, reducing both left ventricular preload and afterload, with reductions in systemic vascular resistance and increases in cardiac output. However, the effect of hydralazine was significantly greater and of longer duration than nisoldipine, and was associated with side effects in four patients. This, and previously reported data, suggests that nisoldipine may be useful in patients with ischaemia and concomitant heart failure.
The effect of multiple dosage on the kinetics of glucuronidation and sulphation of diflunisal in man.
Authors: Verbeeck RK , Loewen GR , MacDonald JI , Herman RJ
Published: July 2012

1. The single (250 and 500 mg) and multiple dose (250 and 500 mg twice daily for 15 days) pharmacokinetics of diflunisal were compared in young volunteers. 2. The plasma clearance of diflunisal was lowered significantly after multiple dose administration (5.2 +/− 1.2 and 4.2 +/− 0.7 ml min‐1 for the 250 and 500 mg twice daily regimens, respectively) as compared with single dose administration 11.4 +/− 3.1 and 9.9 +/− 2.0 ml min‐1 for the 250 and 500 mg single doses, respectively). 3. The partial metabolic clearances of diflunisal by acyl and phenolic glucuronide formation were lowered significantly (greater than 50%) after multiple dose administration. 4. The urinary recovery of diflunisal sulphate increased as a function of dose: 6.1 +/− 2.8 and 9.1 +/− 3.5% following the 250 and 500 mg single dose, respectively, and 10.9 +/− 3.1 and 15.9 +/− 3.6% following the 250 and 500 mg twice daily regimens. The partial metabolic clearance of diflunisal by sulphate conjugation was unchanged following multiple dose administration. 5. The plasma protein binding of diflunisal was concentration‐dependent. Analysis of unbound plasma clearances of diflunisal showed that its total plasma clearance following 500 mg twice daily was affected by both saturable glucuronidation and concentration‐dependent plasma binding.
Plasma and urine aluminium concentrations in healthy subjects after administration of sucralfate [see comments]
Authors: Allain P , Mauras Y , Krari N , Duchier J , Cournot A , Larcheveque J
Published: July 2012

1. Sucralfate (basic sucrose aluminium sulphate), a topical intestinal agent, was administered in suspension or granule form to 25 healthy subjects at a total dose of 4 g day‐1 for 21 days. Aluminium in plasma and 24 h urine samples was assayed before, during and after administration of sucralfate by inductively coupled plasma optical emission spectrometry. 2. Sucralfate produced significant increases in plasma and urine aluminium concentrations. On average, plasma aluminium increased from about 2 micrograms 1‐1 to more than 5 micrograms 1‐1 and 24 h urine aluminium increased from less than 5 micrograms to more than 30 micrograms. Both plasma and urine aluminium concentrations decreased rapidly after sucralfate was stopped. However, urinary aluminium concentrations remained higher than normal 5 and 10 days after discontinuation of sucralfate administration. Moreover subjects receiving sucralfate granules had significantly higher average urinary excretion of aluminium than subjects receiving the suspension. 3. The small but significant increase in plasma and urine aluminium following sucralfate administration in therapeutic doses may reflect intestinal absorption of aluminium. Although such absorption would appear to be moderate in healthy subjects, it is suggested that aluminium‐based treatments should be used only intermittently, especially in patients with renal disorders.
The comparative effects of paracetamol and indomethacin on renal function in healthy female volunteers.
Authors: Prescott LF , Mattison P , Menzies DG , Manson LM
Published: July 2012

1. Renal function was assessed in 10 healthy female volunteers during administration of placebo, paracetamol (acetaminophen) (4.0 g daily) and indomethacin (150 mg daily) for 3 days under conditions of controlled sodium and fluid intake. 2. Paracetamol and indomethacin had no significant effect on the glomerular filtration rate and effective renal plasma flow as measured by the renal clearances of inulin, creatinine and p‐aminohippurate (PAH). 3. Compared with placebo, paracetamol reduced the mean urinary excretion of prostaglandin E2 by 43% on the second day and 58% on the third treatment day (P less than 0.01). With indomethacin the corresponding reductions were 73 and 80%. Paracetamol and indomethacin had much less effect on the excretion of prostaglandin 6‐keto F1 alpha, and a significant decrease was observed only on the third day. 4. The decreased urinary excretion of prostaglandin E2, produced by paracetamol was associated with a reduction in sodium excretion of more than 50% (P less than 0.01) and delay in the onset of diuresis following an acute water load. 5. The renal effects of paracetamol and indomethacin appear to differ. Although indomethacin reduced prostaglandin excretion more than paracetamol it had a similar effect on sodium excretion and less initial antidiuretic action. Unlike paracetamol, indomethacin also reduced basal plasma renin activity. 6. Paracetamol reduced the total body clearance of PAH and increased its plasma half‐life. This effect could be attributed to inhibition of the acetylation of PAH by paracetamol. 7. In normal use paracetamol does not appear to have the adverse renal effects associated with the non‐steroidal anti‐ inflammatory analgesics and further studies are required to establish the clinical significance of these findings.
Lack of effect of lithium on the renal response to DA1‐dopamine receptor stimulation by fenoldopam in normal man [see comments]
Authors: Girbes AR , Smit AJ , Meijer S , Reitsma WD
Published: July 2012

1. The effect of oral lithium (300 mg) on the renal response to the selective DA1‐dopamine receptor agonist fenoldopam was investigated in seven normal men. Lithium had no influence on sodium excretion and renal haemodynamics during fenoldopam infusion. The fenoldopam‐induced rise in PRA was enhanced in the presence of lithium. We conclude that a previously described interaction between lithium and the dopamine agonist gludopa is not mediated by DA1‐dopamine receptors or is confined to higher doses of lithium.
Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers.
Authors: Echizen H , Nakura M , Saotome T , Minoura S , Ishizaki T
Published: July 2012

1. The protein binding of disopyramide was measured in plasma obtained from nonpregnant women, pregnant women in the first, second, and third trimesters, matched pairs of mothers and neonates (cord plasma), and 1 month postpartum women (n = 6 or 8 of each). 2. Plasma samples spiked with 0.2‐12.0 micrograms ml‐1 of the drug were ultrafiltered and the free fractions were measured with a fluorescent polarization immunoassay. 3. The mean (+/− s.d.) percentages of free drug at a total concentration of 3.0 micrograms ml‐1 observed in the third trimester (46 +/− 9%) and neonate (79 +/− 5%) groups were greater (P less than 0.05 or 0.01) than that in the non‐pregnant group (34 +/− 7%). In contrast, the corresponding value observed in the postpartum group (23 +/− 8%) was less (P less than 0.05) than that in the non‐pregnant group. In addition, there was a significant (P less than 0.01) difference in the mean percentage of free drug at 3.0 micrograms ml‐1 in plasma from mothers (43 +/− 9%) and neonates (79 +/− 5%). 4. A multiple regression analysis indicated that alpha 1‐acid glycoprotein (r = ‐0.88, P less than 0.01), rather than albumin (r = ‐0.008), dominated the binding of disopyramide within the therapeutic range of drug concentration. An analysis of the binding parameters of disopyramide suggested that alterations in binding were attributable to changes in the capacity rather than the affinity of binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Haemodynamic and radionuclide effects of amlodipine in coronary artery disease.
Authors: Silke B , Verma SP , Zezulka AV , Sharma S , Reynolds G , Jackson NC , Guy S , Taylor SH
Published: July 2012

1. The haemodynamic and radionuclide effects of a new long‐acting slow‐ calcium channel blocking agent, amlodipine, were evaluated in 32 patients with coronary artery disease. 2. Haemodynamic measurements in 24 patients were made at rest and 10 to 15 min after 20 mg i.v. amlodipine. Amlodipine significantly reduced systemic arterial blood pressure and vascular resistance index with an increased heart rate and augmented cardiac index. Cardiac stroke volume index rose and stroke work fell without change in pulmonary artery occluded pressure (PAOP). 3. The exercise effects were determined by comparison of measurements during 4 min of supine bicycle exercise at a fixed workload before and after drug treatment. During dynamic exercise, amlodipine reduced systemic arterial pressure and vascular resistance index. Exercise cardiac index, stroke volume index and heart rate were higher. The left ventricular filling pressure was significantly reduced. 4. Radionuclide parameters were studied in 16 patients at rest and on exercise; ejection fraction was unaltered following amlodipine. 5. Pre‐therapy haemodynamic values correlated with response following amlodipine for resting mean blood pressure, systemic vascular resistance and exercise PAOP. 6. Thus, the immediate impact of amlodipine in stable coronary artery disease was to reduce left ventricular afterload and thereby improve cardiac pumping performance.
Clofibrate raises human 24 h intragastric acidity but does not affect plasma gastrin concentration.
Authors: Gavey CJ , Smith JT , Nwokolo CU , Pounder RE
Published: July 2012

1. We studied the effects of acute oral dosing with clofibrate (500 mg four times daily) on 24 h intragastric acidity and plasma gastrin concentration in 12 healthy female subjects. 2. The 24 h integrated intragastric acidity rose from 429 mmol l‐1 h (95% CI 296‐479) before dosing to 527 mmol l‐1 h (95% CI 385‐664) on the day of dosing (+23%; P = 0.041), but no change was observed in the 24 h integrated plasma gastrin concentration: 420 pmol l‐1 h (95% CI 282‐499) before and 389 pmol l‐1 h (95% CI 249‐489) during dosing (P = 0.182). 3. We conclude that clofibrate has no acute antisecretory effect on the human stomach, and that human gastrin‐induced enterochromaffin‐like cell proliferation is unlikely with this drug.
Comparative effects of ciprofloxacin and lomefloxacin on the oxidative metabolism of theophylline.
Authors: Robson RA , Begg EJ , Atkinson HC , Saunders DA , Frampton CM
Published: July 2012

Nine healthy male volunteers were studied to assess the interaction between theophylline and ciprofloxacin and to assess whether a similar interaction occurred with lomefloxacin, using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without lomefloxacin 400 mg 12 hourly or ciprofloxacin 500 mg 12 hourly for 7 days. Ciprofloxacin treatment lowered total theophylline clearance by 27%, owing to a decreased clearance via 1‐, 3‐demethylation and 8‐ hydroxylation. Lomefloxacin treatment did not alter theophylline clearance. Ciprofloxacin, at usual clinical doses, could cause a clinically significant interaction when co‐administered with theophylline.
Lowering of theophylline clearance by isoniazid in slow and rapid acetylators [see comments]
Authors: Samigun  , Mulyono  , Santoso B
Published: July 2012

The effect of isoniazid (INH) pretreatment (400 mg daily for 2 weeks) on the elimination kinetics of theophylline (given intravenously as aminophylline equivalent to 151.2 mg theophylline) was investigated in 13 healthy male non‐smokers. Amongst the 13 subjects studied, seven were rapid and six were slow acetylators. The mean clearance of theophylline was significantly lowered after INH (2.20 +/− 0.24 l h‐1) (mean +/− s.e. mean) compared with the baseline value (2.80 +/− 0.24 l h‐1). The volume of distribution at steady state was also lowered significantly after INH (0.42 +/− 0.01 l kg‐1 vs 0.47 +/− 0.02 l kg‐1). Consequently, there was no significant prolongation of theophylline half‐life after INH (7.0 +/− 0.3 h vs 6.7 +/− 0.4 h control). The lowering of theophylline clearance by INH may be related to acetylator status since slow acetylators showed a greater interaction than rapid acetylators. However, this difference was not statistically significant.
A comparative pharmacokinetic study of conventional and chewable carbamazepine in epileptic patients.
Authors: Patsalos PN
Published: July 2012

Using an open substitution study design, conventional carbamazepine (Tegretol, CBZ‐C and a chewable carbamazepine formulation (Tegretol Chewtabs, CBZ‐CHEW) were compared in 12 patients with severe intractable epilepsy. During a dosing interval, no significant differences were observed with respect to trough or peak serum concentrations of CBZ and CBZ‐10,11‐epoxide (CBZ‐E), the active metabolite. The area under the serum CBZ concentration‐time curve for a dosing interval was (mean +/− s.e. mean) 146 +/− 10 mumols l‐1 h on CBZ‐ C and 143 +/− 9 mumols l‐1 h on CBZ‐CHEW. The two formulations, therefore, have a similar pharmacokinetic profile and could be used interchangeably in the management of patients with epilepsy.
Clinical and pharmacological study of a novel controlled release preparation of salbutamol.
Authors: Milroy R , Carter R , Carlyle D , Boyd G
Published: July 2012

This study compared the efficacy of 8 mg controlled release (CR) salbutamol tablets twice daily with standard 4 mg salbutamol tablets four times daily in patients with chronic obstructive airways disease. There was significant bronchodilation in both treatment groups as measured by standard spirometry (P less than 0.05). With the CR preparation there was significantly less wheeze (P less than 0.05) and significantly reduced requirement for rescue bronchodilator (P less than 0.05). Salbutamol levels measured hourly on the final day of each treatment period showed that the drug profile in the CR group was smoother, without the troughs and peaks seen with standard tablets.
The disposition of amodiaquine in Zambians and Nigerians with malaria.
Authors: Winstanley PA , Simooya O , Kofi‐Ekue JM , Walker O , Salako LA , Edwards G , Orme ML , Breckenridge AM
Published: July 2012

1. Oral amodiaquine (AQ) has been used to treat patients with symptomatic malaria in Zambia (n = 14) and Nigeria (n = 5). Clinical cure was obtained in all patients and no serious adverse drug reactions were seen. 2. As in healthy subjects, AQ achieved low plasma concentrations. Plasma concentration vs time profiles of desethylamodiaquine (AQm) from the present study did not differ from those obtained from healthy subjects. 3. In contrast to previous results from healthy subjects, the mean ratio of red cell (RBC): plasma AQm concentration in the present study was 0.80: 1 at the start of the study and rose in a linear manner (r = 0.873; P less than 0.01) to 3.04: 1 by the end (n = 10; P less than 0.01). The final mean value was similar to that seen in healthy subjects. 4. These data show that there are differences in the disposition of orally administered AQ between healthy subjects and patients with clinical malaria. The relevance of this observation to the frequency of adverse reactions to AQ in these two groups is not established.
Cardiovascular responses to upright tilting in hypertensive patients, with and without renal impairment and before and following nisoldipine treatment.
Authors: Wahbha MM , Wilson J , Hainsworth R
Published: July 2012

1. Cardiovascular responses to upright tilting were determined before and after treatment with the calcium antagonist, nisoldipine, in patients with essential hypertension and in patients of similar ages and similar degrees of hypertension complicated by renal impairment. 2. Cardiac output was determined by a single breath respiratory method and heart rate and blood pressure by an automatic sphygmomanometer. 3. During placebo treatment, the supine values of heart rate and blood pressure were similar in the two groups, but the renal patients had significantly higher cardiac outputs. Following nisoldipine treatment blood pressure was lower in both groups due to decreased vascular resistance; cardiac output was unchanged. 4. Upright tilting lowered cardiac output in both groups, but the fall in the patients with renal disease was greater. There were similar increases in heart rate, diastolic blood pressure and vascular resistance in both groups. After nisoldipine, in the renal patients the fall in cardiac output was again greater and there was also a fall in systolic blood pressure. 5. These results indicate that patients with hypertension complicated by renal impairment may have reduced orthostatic tolerance particularly after treatment with nisoldipine.
Pharmacodynamic monitoring during acute intervention in ischaemic heart disease using a new echo‐Doppler device.
Authors: Silke B , Verma SP , Taylor SH
Published: July 2012

1. We have utilised a new non‐imaging echo‐Doppler cardiac output device, using the principle of attenuated compensated volume flow (ACVF), to assess the cardiovascular effects of atenolol and buccal nitroglycerin (NTG) in a placebo‐controlled study of 30 patients with coronary disease. 2. Atenolol (4 mg i.v.) reduced heart rate, cardiac output and time‐averaged mean aortic velocity (P less than 0.01) and increased systemic vascular resistance (P less than 0.01). 3. Buccal NTG (5 mg) reduced systemic mean arterial pressure (P less than 0.01), cardiac stroke volume (P less than 0.05) and stroke length (P less than 0.01). 4. Thus although both drugs reduced time‐averaged aortic velocity (an index of cardiac performance), the concomitant reduction in cardiac stroke length and tachycardia suggested sub‐optimal cardiac filling for buccal NTG, whereas for atenolol (with the associated increased systemic vascular resistance but unchanged stroke length) attenuation of sympathetic stimulation at cardiac beta‐adrenoceptors. 5. The ACVF method of cardiovascular monitoring should prove useful in human pharmacodynamic studies.
A comparison of the CNS effects of enprofylline and theophylline in healthy subjects assessed by performance testing and subjective measures.
Authors: Tiplady B , Fagan D , Lamont M , Brockway M , Scott DB
Published: July 2012

1. The effects of intravenous infusions of enprofylline, theophylline, and placebo on subjective ratings and on psychological test performance were studied in a double‐blind crossover experiment in 12 healthy subjects who abstained from caffeine throughout the experimental procedures. 2. Mean plasma concentrations of enprofylline were: mean 2.9 mg l‐1 (range 1.9‐3.4). Those for theophylline were: mean 12.1 mg l‐ 1 (range 9.0‐14.4). 3. Performance on the auditory vigilance task showed a significant improvement with theophylline compared with both enprofylline and placebo. The correct detection rates (out of 90) were 50.3, 43.4 and 39.1 respectively. A similar effect was seen with finger tapping rates: 404, 394 and 390 taps min‐1 respectively. Other measures showed no significant effects, although choice reaction time showed a trend towards faster responses with theophylline. 4. Subjective ratings showed that subjects were significantly more alert with theophylline than with enprofylline. Subjects reported themselves as significantly more dizzy and ill with both active drugs compared with placebo. 5. These results suggest that emprofylline largely lacks the CNS stimulant effects of theophylline, but that the incidence of other unwanted effects of the drugs may be similar.
The effects of dopexamine, a new dopamine analogue, on platelet function in stress.
Authors: Wagaine‐Twabwe D , Hendra TJ , Smith CC , Yudkin JS
Published: July 2012

1. Dopexamine is a novel analogue of dopamine which is free of alpha‐ adrenoceptor activity and is of therapeutic value in chronic heart failure. The effects of dopexamine on the in vitro function of platelets from 10 healthy subjects at rest, after exercise and after in vitro addition of adrenaline and noradrenaline were investigated. 2. Dopexamine in a wide range of concentrations (10(‐9)M‐10(‐3)M) did not appear to function as an agonist on platelets either in whole blood or in PRP preparations. 3. Dopexamine caused a dose‐dependent inhibition of agonist‐induced platelet aggregation in both whole blood and PRP. The inhibitory effect of dopexamine was significantly greater in PRP than in whole blood, and significantly greater to adrenaline than to collagen or ADP as agonists in whole blood. 4. After exercise or after in vitro addition of adrenaline and noradrenaline at concentrations commonly seen in myocardial infarction, dopexamine produced similar levels of inhibition seen with platelets from resting subjects. 5. Dopexamine did not affect plasma catecholamine levels but caused an increase in intraplatelet noradrenaline levels. 6. This study suggests that dopexamine is unlikely adversely to affect the hyperaggregable state found in patients with cardiogenic shock after myocardial infarction.
Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2‐adrenoceptor antagonist‐a randomized, double‐blind cross‐over study in healthy male volunteers.
Authors: Karhuvaara S , Kallio A , Scheinin M , Anttila M , Salonen JS , Scheinin H
Published: July 2012

1. Single doses (10, 30 and 100 mg) of atipamezole (MPV‐1248), a new potent and selective imidazole‐type alpha 2‐adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double‐blind, cross‐over phase I study. Later, 100 mg atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose‐related concentrations of atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half‐life of 1.7‐2.0 h, an apparent volume of distribution of 3.0‐3.5 l kg‐1 and a total plasma clearance of 1.1‐1.5 l h‐1 kg‐1. No atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose‐related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/− 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/− 7/14 +/− 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C‐peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2‐adrenoceptor antagonistic action of atipamezole and are in general concordance with the reported results of other alpha 2‐ adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, atipamezole may prove to be a useful agent in studies of alpha 2‐adrenoceptor function in man.
Pharmacodynamic, pharmacokinetic and humoral effects of oral zabicipril, an angiotensin converting enzyme inhibitor in normotensive man.
Authors: MacDonald NJ , Hughes DM , Lees KR , Reid JL
Published: July 2012

1. Zabicipril, S9650, a new angiotensin converting enzyme inhibitor, was administered to salt‐replete, normotensive males in single doses of up to 10 mg. 2. The safety, tolerance and dose‐response relationship with regard to inhibition of plasma ACE activity were characterised initially in an open, pilot, dose‐finding study in 12 subjects and further explored in a double‐blind, parallel group, placebo controlled study in another 30 subjects. 3. The drug was generally well tolerated and produced no change in routine haematology or serum biochemistry tests. 4. Dose related (0.03 to 10 mg) inhibition of plasma converting‐ enzyme was observed, with 2.5 mg of zabicipril producing over 90% inhibition at 4 h and 60% at 24 h. 5. There were no significant changes in blood pressure or heart rate in normotensive subjects over the dose range studied. 6. A dose related rise in plasma renin activity and angiotensin I was observed. No dose related reduction in plasma aldosterone was observed. 7. These initial studies suggest that zabicipril is a well tolerated inhibitor of converting enzyme with near maximal inhibitory effect occurring at a dose of 2.5 mg. Further exploration of the dose range after single and multiple doses is indicated.
Effect of oral contraceptive steroids on the pharmacokinetics of phenprocoumon.
Authors: Monig H , Baese C , Heidemann HT , Ohnhaus EE , Schulte HM
Published: July 2012

1. The effect of chronic administration of oral contraceptive steroids (OCS) on the pharmacokinetics of the oral anticoagulant phenprocoumon was investigated in seven healthy females. 2. Plasma concentrations of phenprocoumon and the urinary recovery of unchanged as well as conjugated drug were measured following a single oral dose of 0.22 mg kg‐1. A group of seven non‐smoking, drug‐free women matched for age and body weight served as controls. 3. Administration of OCS was associated with a significant increase in the clearance of phenprocoumon from 1.6 +/− 0.7 to 2.0 +/− 0.7 ml min‐1 kg‐1 (P less than 0.05). The urinary recovery of phenprocoumon glucuronide was significantly higher in OCS users (21.0 +/− 16 vs 14.0 +/− 10 (% of dose); P less than 0.05). No difference in plasma protein binding of phenprocoumon was observed, being 99.2 +/− 0.07 in both groups. 4. The accelerated glucuronidation of phenprocoumon in OCS users suggests the need for careful monitoring of the anticoagulatory response in these subjects, especially when the OCS are withdrawn.
Dipyridamole alone or combined with low‐dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo [see comments]
Authors: Muller TH , Su CA , Weisenberger H , Brickl R , Nehmiz G , Eisert WG
Published: July 2012

1. In a randomized, double‐blind trial we compared the inhibition of the platelet‐vessel wall interactions in whole blood ex vivo. There were four groups of 24 healthy volunteers each of whom were treated orally for 3.5 days with either 200 mg dipyridamole (sustained release preparation), 25 mg acetylsalicylic acid, both drugs combined or placebo twice daily. 2. The mean area of all platelets/aggregates was reduced by 6.2% +/− 4.2% (+/− s.e. mean) by placebo (n = 23), 19.8% +/− 6.7% by dipyridamole (n = 22), 53.7% +/− 4.9% by acetylsalicylic acid (n = 23) and 71.4% +/− 3.7% by the combination of both drugs (n = 24), when compared with total inhibition of aggregation by EGTA. Thus, low‐ dose acetylsalicylic acid inhibited aggregation (P less than 0.001). 3. Dipyridamole reduced the size of platelet aggregates (P less than 0.01, two‐fold analysis of variance). The reduction was correlated with the individual dipyridamole plasma levels (P less than 0.05, analysis of covariance). The subgroup of large and very large thrombi being formed was also reduced by dipyridamole (P less than 0.05). 4. This ex vivo study demonstrates that dipyridamole alone inhibits formation of thrombi on subendothelial matrix and enhances the inhibitory effect of low dose acetylsalicylic acid in this model of thrombosis.
High dose eicosapentaenoic acid ethyl ester: effects on lipids and neutrophil leukotriene production in normal volunteers.
Authors: Hawthorne AB , Filipowicz BL , Edwards TJ , Hawkey CJ
Published: July 2012

1. A 93% pure ethyl ester of eicosapentaenoic acid was investigated for tolerability and biochemical effects on neutrophil leukotriene synthesis and plasma lipoproteins when given in high dose. Six healthy volunteers received 6 g eicosapentaenoic acid ethyl ester daily for 6 weeks, followed by a 4 week wash‐out and then 18 g daily for 6 weeks. 2. There was inhibition of neutrophil leukotriene B4 and 5‐ hydroxyeicosatetraenoic acid synthesis, with no significant differences between low and high dose. 3. There was a dose dependent increase in leukotriene B5 and 5‐hydroxyeicosatetraenoic acid acid synthesis. 4. Plasma triglycerides were reduced maximally on 6 g daily, with no greater suppression at 18 g daily. 5. Plasma cholesterol was only suppressed significantly at 18 g daily. 6. The 6 g daily dose was well tolerated but the 18 g daily dose produced diarrhoea and steatorrhoea.
The pharmacokinetics and pharmacodynamics of quinapril and quinaprilat in renal impairment.
Authors: Begg EJ , Robson RA , Bailey RR , Lynn KL , Frank GJ , Olson SC
Published: July 2012

1. The pharmacokinetics and pharmacodynamics of quinapril and its active metabolite quinaprilat were studied in 20 subjects with renal function varying from normal to severe renal failure, during the approach to and at steady‐state, and for 72 h after cessation of quinapril 20 mg orally for 7 days. 2. The apparent oral plasma clearance of quinaprilat (dose of quinapril equivalent/AUC of quinaprilat) was directly related to creatinine clearance (CLCr). The predicted apparent oral clearance of quinaprilat was zero when CLCr was zero, suggesting minimal extrarenal elimination. 3. Peak and trough concentrations of quinaprilat, and its apparent elimination half‐life, varied inversely with CLCr. 4. Trough concentrations of quinaprilat showed no accumulation between 2 and 7 days, even in severe renal impairment. 5. There was a weak relationship between the oral plasma clearance of quinapril and CLCr. 6. ACE inhibition was marked and prolonged in all subjects, with 50% inhibition at 2.7 +/− 1.9% ng ml‐1 of quinaprilat. The time for which ACE inhibition was greater than 90% was related inversely to CLCr. 7. Aldosterone concentrations and plasma renin activity responded in a predictable way, but with no clear relationship To CLCr. 8. Atrial natriuretic peptide concentrations were not affected by quinapril administration. 9. Glomerular filtration rate, as measured by Tc99mDTPA clearance, was not affected by quinapril administration. 10. Blood pressure at steady‐state decreased significantly in the subjects with hypertension. The changes in blood pressure were not related to renal function. 11. These results suggest that the dosage rate of quinapril may have to be altered in renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
Multiple‐dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.
Authors: Edstein MD , Rieckmann KH , Veenendaal JR
Published: July 2012

1. The multiple‐dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim (100 mg DDS plus 12.5 mg PYR). 2. After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml‐1; elimination half‐life (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h‐1 kg‐1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg‐1. The mean t1/2 of MADDS was 22 h. 3. The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4. The drug combination was assessed in vitro by measuring inhibition of re‐ invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)‐ and PYR‐sensitive FC‐27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ‐ and PYR‐resistant K1 strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.
The excretion of zopiclone into breast milk.
Authors: Matheson I , Sande HA , Gaillot J
Published: July 2012

1. The excretion of zopiclone into breast milk was studied in 12 lactating women in the early postpartum period following the oral administration of a single zopiclone tablet (7.5 mg). 2. The milk/plasma AUC ratio of zopiclone was 0.51 +/− 0.09 (mean +/− s.d.). Individual mean milk/plasma concentration ratios of zopiclone showed significant interindividual variation (range 0.41‐0.70). 3. A comparison of pharmacokinetic parameters in the postpartum women with those reported previously in non‐pregnant women, showed significantly higher Cmax values in the lactating mothers; tmax occurred later in milk than in maternal plasma. 4. Assuming a daily milk intake of 0.15 l kg‐1 and 100% absorption the average infant dose of zopiclone in milk would be 1.4% of the weight adjusted dose ingested by the mother.
Influence of exercise on nitroglycerin plasma concentrations after transdermal application.
Authors: Lefebvre RA , Bogaert MG , Teirlynck O , Sioufi A , Dubois JP
Published: July 2012

Nitroglycerin plasma concentrations following transdermal application were measured in nine healthy subjects during supine rest position or during supine rest interrupted by sitting or exercising for 20 min. Sitting led to almost doubling of the average plasma concentrations (0.31 ng ml‐1 before sitting, 0.55 ng ml‐1 at the end of the sitting period), but exercise was accompanied by a much more marked increase in average plasma concentrations, which reached its maximum 5 min after ending exercise (0.22 ng ml‐1 before exercise, 1.26 ng ml‐1 5 min after the exercise period). Changes of bioavailability as well as of systemic clearance might be involved in the exercise‐induced increase in plasma nitroglycerin concentrations.