bluuebunny/crossref_metadata_2025 huggingface dataset:
Concentration‐time profiles of ethanol and acetaldehyde in human volunteers treated with the alcohol‐sensitizing drug, calcium carbimide.
Authors: Jones AW , Neiman J , Hillbom M
Published: July 2012

1. The disposition kinetics of ethanol and its toxic metabolite acetaldehyde were investigated in 10 healthy male volunteers who ingested 0.25 g kg‐1 ethanol after an overnight fast. This dose of ethanol was given 2 h after they swallowed a tablet of either calcium carbimide CC (50 mg), a potent inhibitor of low Km aldehyde dehydrogenase (ALDH), or placebo according to a single‐blind crossover design. 2. The pulmonary blood concentrations of ethanol and acetaldehyde were estimated indirectly by means of a gas chromatographic method modified for analysis of end‐expired breath. This non‐invasive sampling technique allowed replicate determinations at 15 min intervals. 3. The distribution volume of ethanol (V) was 0.64 +/‐ 0.023 1 kg‐1 after CC and 0.68 +/‐ 0.026 l kg‐1 after placebo treatment (P greater than 0.05). The zero order slope of the blood‐ ethanol decay profile (ko) decreased by about 5% when low Km ALDH was inhibited. The elimination of ethanol from the body (V X ko) was 1.9 +/‐ 0.051 mmol kg‐1 h‐1 after CC compared with 2.11 +/‐ 0.056 mmol kg‐1 h‐1 in placebo control experiments (P less than 0.001). The area under the ethanol concentration time curve (0–180 min) increased after CC treatment implying a change in clearance. 4. The disposition of acetaldehyde was markedly different in subjects pretreated with CC. The peak blood‐concentrations, estimated by analysis of breath, ranged from 40‐242 mumol l‐1 compared with 1.7‐6.5 mumol l‐1 after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine.
Authors: Jamaludin A , Mohamad M , Navaratnam V , Selliah K , Tan SC , Wernsdorfer WH , Yuen KH
Published: July 2012

The hydrochloride, sulphate and ethylcarbonate salts of quinine were given in single oral doses (600 mg base equivalent) to nine healthy male subjects according to a cross‐over design. No statistically significant differences were noted in the plasma drug concentration‐ time profiles although inter‐ and intra‐subject variation in AUC, Cmax and tmax values was appreciable. The ethylcarbonate salt may be preferred for use in paediatric patients because of its neutral taste.
The effect of ageing on the disposition of nifedipine and atenolol.
Authors: Scott M , Castleden CM , Adam HK , Smith RP , Fitzsimons TJ
Published: July 2012

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half‐life in the elderly was significantly longer (8.8 +/‐ 0.9 h) compared with that in the young (5.8 +/‐ 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post‐dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.
Lisinopril and nifedipine: no acute interaction in normotensives.
Authors: Lees KR , Reid JL
Published: July 2012

1. A double‐blind, four period crossover study was undertaken to test for an interaction between single oral doses of nifedipine retard (20 mg) and lisinopril (20 mg) in normal subjects. 2. Side effects with both drugs were mild and the incidence was additive. 3. Blood pressure (BP) was lowered by nifedipine for 4 h, by lisinopril for 48 h and the combination showed simply additive effects. Standing heart rate was higher after the combination than after single treatment. 4. Plasma angiotensin converting enzyme (ACE) and renin activity (PRA), aldosterone, noradrenaline and adrenaline levels showed no evidence of an interaction. 5. The pharmacokinetics of lisinopril were unaltered by nifedipine and vice versa. 6. There is no evidence of a pharmacokinetic or pharmacodynamic interaction between single oral doses of nifedipine and lisinopril.
Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.
Authors: Ferry N , Geoffroy J , Pozet N , Cuisinaud G , Benzoni D , Zech PY , Sassard J
Published: July 2012

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half‐life established around 7 h, and both its renal clearance (0.4 ml min‐1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half‐life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration‐effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6‐keto‐ prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
A survey of the prevalence of penicillin‐specific IgG, IgM and IgE antibodies detected by ELISA and defined by hapten inhibition, in patients with suspected penicillin allergy and in healthy volunteers.
Authors: Christie G , Coleman JW , Newby S , McDiarmaid‐Gordon A , Hampson JP , Breckenridge AM , Park BK
Published: July 2012

1. IgG, IgM and IgE anti‐benzylpenicilloyl (BPO) antibody activities were determined by enzyme‐linked immunosorbent assay (ELISA) in sera from 100 patients who claimed to be allergic to penicillin, and from 50 healthy volunteers. Continuous frequency distributions for all three classes of anti‐BPO antibody, defined as differential binding (delta OD) to BPO‐human serum albumin (HSA) and HSA, were obtained for both groups. 2. For IgM and IgE classes the anti‐BPO activities were slightly but statistically significantly higher in the patient group compared with the volunteer group. 3. Hapten inhibition ELISAs were performed to confirm specificity for the BPO determinant. On the basis of antibody activities (delta OD values) greater than or equal to 0.3 and 50% inhibition of binding in the presence of 100 micrograms ml‐1 BPO‐caproate, BPO‐specific IgG antibody was identified in 4/100 of the patients' sera and in 1/50 of the volunteers' sera; BPO‐specific IgM was identified in 7/100 patients' sera and 1/50 volunteers' sera; and BPO‐specific IgE in 5/100 patients' sera and 1/50 volunteers' sera. 4. Not all sera with differential antibody binding to BPO‐HSA/HSA were inhibited by the BPO hapten. Hence, hapten inhibition assays are essential for the unambiguous demonstration of drug specific antibodies.
Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive‐drug interactions with anticonvulsants and antibiotics.
Authors: Back DJ , Grimmer SF , Orme ML , Proudlove C , Mann RD , Breckenridge AM
Published: July 2012

1. We have searched the adverse reactions register for the years 1968‐ 84 in an attempt to evaluate data relating to reported pregnancies in women on oral contraceptive steroids (OCS) who concurrently received either an antiepileptic drug or an antibiotic. 2. A total of 43 pregnancies were reported in women on OC therapy who concurrently received antiepileptic drugs and 63 pregnancies in women receiving antibiotics. In addition the number of prescriptions for both antiepileptics and antibiotics in England are reported for the years 1973‐84.
Concentration‐effect relationships for oxprenolol in patients with essential hypertension.
Authors: McInnes GT , Brodie MJ
Published: July 2012

1. Plasma drug concentrations, and heart rate and blood pressure responses to exercise at a predetermined load were examined in twelve hypertensive patients following single and repeated doses of oxprenolol administered once daily as oral osmotic drug delivery systems (10/170 and 16/260 oxprenolol OROS). 2. Plasma oxprenolol concentration profiles after each preparation were consistent with the criteria for sustained drug release. Levels immediately after exercise were significantly higher than those prior to exercise (P less than 0.001), but differences were slight. 3. Both OROS drug forms reduced exercise heart rate for 24 h after single and repeated doses; effects were greater for 16/260 OROS than for 10/170 OROS. Significant reductions in post‐exercise systolic BP were observed 24 h after drug administration and after repeated doses there was little difference between the preparations. Effects on diastolic BP after exercise were slight. 4. The relationship between plasma oxprenolol concentrations and exercise heart rates fitted an exponential mathematical model which makes allowance for inter‐individual variability. No such kinetic‐dynamic relationship could be defined for post‐exercise systolic or diastolic BP.
Comparison of the effects of dopamine, dobutamine, and dopexamine upon renal blood flow: a study in normal healthy volunteers.
Authors: Mousdale S , Clyburn PA , Mackie AM , Groves ND , Rosen M
Published: July 2012

1. We compared the effects of dopexamine, dopamine and dobutamine on the heart rate, blood pressure and renal blood flow of six healthy volunteers in an open triple crossover trial. 2. The results suggest that at the dose ranges investigated dopamine was the most effective agent for increasing renal blood flow.
Effect of a PAF antagonist, BN52063, on PAF‐induced bronchoconstriction in normal subjects.
Authors: Roberts NM , McCusker M , Chung KF , Barnes PJ
Published: July 2012

1. The effects of an oral platelet activating factor (PAF) antagonist, BN52063, or matched placebo on inhaled PAF challenge were assessed in a double‐blind study in eight normal subjects. 2. PAF (24 micrograms) induced an immediate bronchoconstriction, with a maximum fall in flow at 30% of vital capacity from a partial flow volume manoeuvre (Vp30) of 47.1 +/‐ 7% (mean +/‐ s.e. mean) 5 min after inhalation following placebo treatment. Repeated PAF challenges at 15 min intervals resulted in tachyphylaxis of the bronchoconstrictor response. 3. Two hours after the ingestion of BN52063 (120 mg) the maximum bronchoconstriction induced by inhaled PAF was attenuated (35.9 +/‐ 9% fall at 5 min) with a significant reduction (P less than 0.05) in response after the first and second inhalations. 4. Inhaled PAF induced an immediate neutropenia (73.2 +/‐ 9% fall 5 min after inhalation) followed by a rebound neutrophilia, which were unaffected by pretreatment with BN52063. 5. Oral ingestion of a dose of BN52063 which is effective in reducing skin responses to PAF gave partial protection against the bronchoconstrictor effect of inhaled PAF in normal subjects.
Effect of cicloprolol in intraocular pressure in healthy volunteers.
Authors: Mekki QA , Turner P
Published: July 2012

Two oral doses of cicloprolol (50 mg and 100 mg), a beta 1‐adrenoceptor partial agonist, were administered to nine healthy volunteers in a double‐blind placebo‐controlled study. Intraocular pressure (IOP) and exercise heart rate were reduced while the resting heart rate and blood pressure remained unchanged. The responses to the two different doses of cicloprolol were similar.
Effects of H2‐receptor antagonists on ethanol metabolism in Japanese volunteers.
Authors: Tanaka E , Nakamura K
Published: July 2012

The effects of H2‐receptor antagonists (cimetidine, ranitidine, and famotidine) on ethanol metabolism were investigated. Neither in aldehyde dehydrogenase (ALDH)‐1 deficient subjects nor in those with normal ALDH‐1, did the three H2‐receptor antagonists and placebo differ in their effects on the pharmacokinetic parameters of ethanol (i.e. peak time (tmax), metabolic rate (k0), peak serum concentration (Cmax), volume of distribution (V) and area under the concentration‐time curve (AUC). The AUC of acetaldehyde was slightly but significantly (P less than 0.05) larger only after treatment with cimetidine. Cmax and tmax of acetaldehyde were unchanged.
Nonlinear accumulation of propranolol enantiomers.
Authors: Lalonde RL , Bottorff MB , Straka RJ , Tenero DM , Pieper JA , Wainer IW
Published: July 2012

The accumulation of (+)‐ and (‐)‐propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)‐ propranolol AUC increased from 412 +/‐ 223 ng ml‐1 h after single doses (0‐infinity) to 584 +/‐ 279 ng ml‐1 h at steady‐state (0‐24 h) (P less than 0.05). Similarly, (‐)‐propranolol AUC increased from 609 +/‐ 304 to 777 +/‐ 370 ng ml‐1 h (P less than 0.05). The AUC ratio (‐)/(+) was 1.52 +/‐ 0.36 and 1.32 +/‐ 0.17 after single doses and steady‐state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (‐)/(+) ratio to decrease at steady‐state.
The effect of thyrotoxicosis on isoniazid acetylation.
Authors: Littley MD , Hutchings A , Spragg BP , Routledge PA , Lazarus JH
Published: July 2012

Isoniazid acetylation was assessed in 10 thyrotoxic patients before and after standard antithyroid therapy. The group contained five fast and five slow acetylators and all remained within the same phenotypic classification when rendered euthyroid. There was no significant change in the elimination half‐life of isoniazid between thyrotoxicosis and euthyroidism for the group as a whole or for fast and slow acetylators considered separately. Thyrotoxicosis does not appear to be an important determinant of isoniazid acetylation in man.
Bradykinin induced wheal and flare is not mediated by histamine release or cyclooxygenase products.
Authors: Crossman DC , Fuller RW
Published: July 2012

The wheal and flare response to intradermal bradykinin was studied in man. The possibility that histamine and cyclooxygenase products are involved in the response to bradykinin was examined. Terfenadine given by mouth significantly inhibited the cutaneous response to histamine but the effect of bradykinin was unaltered. Similarly the cutaneous response to bradykinin was unchanged by aspirin.
Correction of systolic time intervals for heart rate: a comparison of individual with population derived regression equations.
Authors: Warrington SJ , Weerasuriya K , Burgess CD
Published: July 2012

1. We have examined the problem of how systolic time intervals (STI) should be corrected for heart rate in clinical pharmacological studies. 2. 'Individual' linear regression equations describing the relationship between STI and heart rate were derived for each of 43 healthy young adults (30 men and 13 women) by measuring STI at different heart rates produced by incremental doses of intravenous atropine. 'Population' equations for each sex were obtained by taking the mean of the 'individual' regression coefficients. 3. In order to assess which method more effectively reduced variability of the STI, 'individual' regression coefficients were derived for eight men who had previously participated in a placebo‐controlled study which had used STI to test the cardiovascular effects of calcium antagonists alone and in combination with propranolol. 4. Within‐subject variability in rate‐ corrected STI was similar after application of 'individual' and 'population' regression equations. Between‐subject variability tended to be less after the use of 'population' equations. 5. 'Population' regression equations were more effective than 'individual' regression equations in allowing detection of differences between treatments, as judged by F values from ANOVA. 6. In clinical pharmacological studies including measurements of STI in healthy young subjects, 'individual' regression equations appear to have no advantage over 'population' equations derived in a group of subjects of similar age and sex.
Suspected adverse drug reactions in elderly patients reported to the Committee on Safety of Medicines.
Authors: Castleden CM , Pickles H
Published: July 2012

1. Spontaneous reports of suspected adverse drug reactions (ADRs) reported to the Committee on Safety of Medicines (CSM) have been studied in relation to patient age. 2. The proportion of reports received for the elderly increased between 1965 and 1983. 3. There was a correlation between the use of drugs and the number of ADR reports. Thus age‐related prescription figures for two non‐steroidal anti‐ inflammatory drugs (NSAI) and co‐trimoxazole matched ADR reports for each drug in each age group. 4. The reported ADR was more likely to be serious or fatal in the elderly. 5. The commonest ADRs reported for the elderly affected the gastrointestinal (GIT) and haemopoietic systems, where more reports were received than would be expected from prescription figures. 6. The drug suspected of causing a GIT reaction was a NSAI in 75% of the reports. 7. Ninety‐one per cent of fatal reports of GIT bleeds and perforations associated with NSAI drugs were in patients over 60 years of age.
An evaluation of different doses of soluble aspirin and aspirin tablets in postoperative dental pain.
Authors: Holland IS , Seymour RA , Ward‐Booth RP , Ord RA , Lim KL , Hoare RC
Published: July 2012

1. The efficacy of three different single doses (600, 900 and 1200 mg of soluble aspirin and aspirin tablets) was determined in a randomized placebo‐controlled parallel study in 140 patients (70 females) with postoperative pain after removal of impacted third molars. 2. Patients treated with soluble aspirin 600 mg, 900 mg, 1200 mg and aspirin tablet 1200 mg reported significantly less pain (P less than 0.01) throughout the investigation period than those treated with placebo. 3. Overall pain scores after treatment with aspirin tablets 600 and 900 mg did not differ significantly from those after treatment with placebo (P greater than 0.05). 4. On a comparative dose basis, soluble aspirin was significantly more potent (P less than 0.05) than aspirin tablets.
Quinapril and blood lipids.
Authors: Koskinen P , Manninen V , Eisalo A
Published: July 2012

To assess the effects of angiotensin‐converting enzyme inhibition with quinapril on blood lipid profile, serum total cholesterol and triglycerides, together with high‐density and low‐density lipoprotein cholesterol were analysed in 23 hypertensive patients receiving either placebo (7 patients) or quinapril hydrochloride (16 patients). After 12 weeks of therapy there were no significant changes in blood lipids in either group. No unfavourable changes in blood lipid profile were observed even after 1 year of therapy with quinapril hydrochloride in 13 patients.
Comparative study of the bronchodilating effects of (−)− and (+)‐ oxyphenonium bromide.
Authors: Feitsma KG , Postma DS , Koeter GH , Nossent GD , Brenth BF , de Zeeuw RA
Published: July 2012

1. Racemic oxyphenonium bromide, its enantiomers and placebo were inhaled by eight adult patients with chronic airflow obstruction, in a four‐way double‐blind cross‐over study. 2. Forced expiratory volume in one second (FEV1) and slow inspiratory vital capacity (VC) were measured during the first 6 h after inhalation. 3. (+)‐Oxyphenonium was found to be the active enantiomer (eutomer), providing better bronchodilation than (+/‐)‐oxyphenonium. 4. The distomer, (−)− oxyphenonium, showed only a slight effect on FEV1 and VC as compared with placebo.
Sustained haemodynamic effects of felodipine in patients with chronic cardiac failure.
Authors: Tweddel AC , Martin W. , McGhie AI , Hutton I.
Published: July 2012

1. The efficacy of felodipine a new calcium channel blocker with selective vasodilator activity in the management of severe low output cardiac failure, secondary to coronary heart disease, was determined in 10 patients. 2. Haemodynamic measurements were made at rest and during dynamic exercise and left ventricular function was assessed by radionuclide ventriculography. 3. Significant increases in cardiac index, stroke volume index and ejection fraction were found particularly during exercise, both acutely and following 4 weeks administration of felodipine therapy. 4. Felodipine could well have a significant role in the long term management of the patient with chronic cardiac failure.
The pharmacokinetics of oral nifedipine‐a population study.
Authors: Renwick AG , Robertson DR , Macklin B. , Challenor V. , Waller DG , George CF
Published: July 2012

1. The pharmacokinetics and metabolism of nifedipine have been studied in a population of 59 young male volunteers following administration of a 10 mg capsule. 2. The area under the plasma concentration‐time curves (AUC) for nifedipine demonstrated a skewed but not a bimodal distribution (mean 154 ng ml‐1 h; range 54‐306 ng ml‐1h). 3. Calculation of the ratio of the AUC of nifedipine to the AUC of its nitropyridine metabolite did not separate those individuals with high AUC values of nifedipine from the remainder of the population. 4. Similarly there was no evidence for bimodality in the excretion of the major urinary metabolite. Those subjects with high plasma AUC values for nifedipine excreted similar amounts to the remainder of the population. 5. In contrast to a previous study using a 20 mg oral dose, there was no evidence of polymorphism in the pharmacokinetics or metabolism of nifedipine following a single 10 mg oral dose.
Lisinopril pharmacokinetics in chronic renal failure.
Authors: Jackson B. , Cubela RB , Conway EL , Johnston CI
Published: July 2012

1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h‐1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s‐1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = ‐0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = ‐0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = ‐ 0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml‐1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml‐1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1‐1 in four patients, without adverse clinical effect.
Pharmacokinetics of intraperitoneal teicoplanin in patients with chronic renal failure on continuous ambulatory peritoneal dialysis.
Authors: Bonati M. , Traina GL , Gentile MG , Fellin G. , Rosina R. , Cavenaghi L. , Buniva G.
Published: July 2012

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram‐positive aerobic and anaerobic bacteria, is described in five patients with end‐stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). A single 3 mg kg‐1 dose was given intraperitoneally in the dialysate during a 6 h dwell time. The drug appeared in the plasma within 15 min at 1.00‐0.28 mg l‐1 (mean +/‐ s.d. = 0.70 +/‐ 0.45) in all five subjects, and peak serum concentrations ranged from 5.53 to 2.80 mg l‐1 (4.84 +/‐ 1.43) at 6 h. Approximately 70% (71 +/‐ 12) of teicoplanin was absorbed from the peritoneal dialysis fluid during a single 6 h dwell time. The rate constant for peritoneal transfer (lambda d) averaged 0.318 h‐1 and the half‐life (t1/2 lambda d) was 2.18 h. Further values were serum elimination half‐life 114‐173 h; total body clearance 263‐532 ml h‐1; steady‐state volume of distribution 68‐93 l. This drug profile closely agrees with data reported after intravenous injection in patients on CAPD and suggests that teicoplanin has bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid is consistently low. Instillation of teicoplanin in CAPD fluid may be a useful route of administration for treatment of peritonitis and exit site infections in CAPD patients.
An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin.
Authors: Riley RJ , Maggs JL , Lambert C. , Kitteringham NR , Park BK
Published: July 2012

1. The cytotoxicity of metabolites generated from phenytoin, sorbinil and mianserin by human and mouse liver microsomes was assessed by co‐ incubation with human mononuclear leucocytes as target cells. Cytotoxicity was determined by trypan blue dye exclusion. 2. Phenytoin and sorbinil were metabolised by NADPH‐dependent murine microsomal enzymes to cytotoxic metabolites. Cytotoxicity produced by both drugs was significantly enhanced by the epoxide hydrolase inhibitor trichloropropane oxide (TCPO). No significant cytotoxicity was observed in the presence of human liver microsomes. 3. Mianserin was metabolised by both human and mouse liver microsomes to a cytotoxin. Cytotoxicity was greater in the presence of human liver microsomes (13.7 +/‐ 2.2%; mean +/‐ s.d. for four livers, compared with 6.0 +/‐ 2.4%, mean +/‐ s.d., n = 4, with mouse liver microsomes), and was unaffected by pretreatment with TCPO. 4. Stable metabolites were quantified by radiometric high performance liquid chromatography. Phenytoin and sorbinil were metabolised to 5‐(p‐hydroxyphenyl)‐5‐phenyl‐hydantoin (0.3‐0.5% of incubated radioactivity) and 2‐hydroxysorbinil (0.4‐2.7% of incubated radioactivity), respectively, by both human and mouse liver microsomes. 5. Mianserin was metabolised to 8‐hydroxymianserin and desmethylmianserin by both human and mouse liver microsomes. Desmethylmianserin was the major product in incubations with human liver microsomes (32.3 +/‐ 12%, mean +/‐ s.d. for four livers), whereas 8‐hydroxymianserin was the predominant metabolite generated by mouse liver microsomes (25.9 +/‐ 1.5%, mean +/‐ s.d., n = 4). 6. Generation of electrophilic metabolites was assessed by determination of the amount of radiolabelled material which became irreversibly bound to protein. Only mouse liver microsomes activated phenytoin to a chemically reactive metabolite, whereas both mouse and human liver microsomes generated reactive metabolites from sorbinil and mianserin. 7. These studies show that drug cytotoxicity can be mediated by low concentrations (circa microM) of metabolites generated by NADPH‐ dependent hepatic microsomal enzymes; however demonstration of cytotoxicity in vitro has not been established as a means of predicting in vivo toxicity.
Polymorphism of debrisoquine hydroxylation among Finns and Lapps.
Authors: Arvela P. , Kirjarinta M. , Kirjarinta M. , Karki N. , Pelkonen O.
Published: July 2012

Debrisoquine hydroxylation polymorphism was studied in 155 Finns and 70 Lapps. The frequency of the poor metabolizer phenotype was 3.2% among Finns (95% confidence interval 0.4‐6.0%) and 8.6% among Lapps (95% confidence interval 2.0‐15.1%).
Initial blood pressure as a predictor of the response to antihypertensive therapy.
Authors: Sumner DJ , Meredith PA , Howie CA , Elliott HL
Published: July 2012

1. The relationship between fall in systolic blood pressure and initial systolic blood pressure has been investigated in 255 mixed normotensive and hypertensive subjects given placebo or one of five types of antihypertensive drug (ACE inhibitors, calcium antagonists, direct vasodilators, alpha‐adrenoceptor blocker, beta‐adrenoceptor blocker). 2. In all cases there was a significant correlation between the change in blood pressure and initial blood pressure. When Oldham's transformation was used (replacing the initial blood pressure by the mean of the initial and minimum pressures) the correlation coefficients were all reduced, although five out of six were still statistically significant. 3. In a subset of 43 hypertensive subjects given four antihypertensive agents, concentration‐effect analysis was carried out. For three of the agents a linear model was used to relate effect to concentration; for the remaining agent a Langmuir type model was used. 4. For all four sets of data for which concentration‐effect analysis was carried out, there was a significant correlation between the sensitivity of response and the initial blood pressure. 5. The observed relationships between initial blood pressure, change in blood pressure and sensitivity of response can be qualitatively explained by postulating a general form of dose‐response relationship for all antihypertensive agents.
A single dose pharmacokinetic study of Gastrobid Continus and Maxolon in the perioperative period.
Authors: Madej TH , Ellis FR , Tring I.
Published: July 2012

1. A single dose pharmacokinetic comparison of Gastrobid Continus and Maxolon was carried out perioperatively in two groups of 12 gynaecological patients; each group comprised six patients for major surgery and six patients for minor surgery. 2. The areas under the plasma drug concentration‐time curves were similar after both preparations. 3. In the minor surgery group after Gastrobid Continus the plasma drug concentration‐time curve was wider at half Cmax (P less than 0.01), Cmax was reduced (P less than 0.05) and delayed (median (range) 4 (3‐6) vs 2.5 (2‐4) h) compared with Maxolon, and the log of the metoclopramide concentration did not have a linear relationship with time from 2‐9 h. 4. A flattening of the plasma drug concentration‐ time curve was the only difference between the two preparations in the major surgery groups. 5. The plasma drug concentration‐time curve was wider (P less than 0.05) at at half Cmax in the minor compared with the major surgery groups receiving Gastrobid Continus. 6. Pharmacokinetic parameters were similar for Maxolon in both surgical groups. 7. Sustained release pharmacokinetic characteristics were most pronounced in the minor surgery group which did not receive opiate medication but in which there were more moderately anxious patients prior to induction and in whom anxiety may have delayed gastric emptying.
Haem arginate improves hepatic oxidative metabolism in variegate porphyria.
Authors: Tokola O. , Mustajoki P. , Himberg JJ
Published: July 2012

1. The elimination of antipyrine was investigated before and after intravenous administration of haem arginate (3 mg haem kg‐1 day‐1 on three or four successive days) to six patients with variegate porphyria in remission. 2. Haem arginate decreased the faecal content of protoporphyrin from 557 +/‐ 91 to 118 +/‐ 32 (mean +/‐ s.e. mean) and of coproporphyrin from 144 +/‐ 19 to 19 +/‐ 3 nmol g‐1 dry weight. 3. Before haem treatment antipyrine elimination half‐life was long (30.5 +/‐ 5.6 h), but the treatment decreased it to 6.3 +/‐ 0.8 h. Antipyrine clearance increased from 0.25 +/‐ 0.05 to 1.03 +/‐ 0.11 ml min‐1 kg‐1 (P less than 0.001), being 4.6 times higher after haem arginate infusions. 4. The volume of distribution of antipyrine did not change. 5. The severe impairment of hepatic mixed function oxidase activity even in the symptomless stage of porphyria indicates cautious dosage of drugs primarily eliminated by hepatic oxidative reactions.
Debrisoquine oxidation in a Finnish population: the effect of oral contraceptives on the metabolic ratio.
Authors: Kallio J. , Lindberg R. , Huupponen R. , Iisalo E.
Published: July 2012

1. The debrisoquine hydroxylation phenotype was assessed in 211 healthy subjects of Finnish Caucasian origin. 2. A bimodal distribution was observed in the urinary debrisoquine/4‐hydroxydebrisoquin ratio. Eleven subjects (about 5%) were poor metabolizers of debrisoquine, when a ratio of 12.6 was used as the cut‐off point. 3. The mean metabolic ratio of 35 extensive metabolizers taking oral contraceptives was slightly lower than that of extensive metabolizers not taking contraceptives. This indicates that oral contraceptives may change the phenotyping near the metabolic ratio of 12.6. 4. The metabolic ratios were determined in eight subjects using both 4 h and 6 h urine collection times. The metabolic ratios corresponded well with each other indicating the usefulness of the shorter 4 h collection time.
Lack of effect of atenolol on the pharmacokinetics of theophylline.
Authors: Cerasa LA , Bertino JS , Ludwig EA , Savliwala M. , Middleton E. , Slaughter RL
Published: July 2012

The effects of 3 days of pretreatment with cardioselective doses of atenolol on theophylline pharmacokinetics were determined. Nine healthy nonsmoking male volunteers received 6 mg kg‐1 i.v. aminophylline under baseline conditions and after both 50 mg day‐1 and 100 mg day‐1 atenolol. Theophylline clearance, volume of distribution and half‐life were not influenced by atenolol pretreatment. These data indicate that cardioselective doses of atenolol do not alter the pharmacokinetics of theophylline.
The contribution of nisoldipine‐induced changes in liver blood flow to its pharmacokinetics after oral administration.
Authors: Van Harten J , Burggraaf J , Danhof M , Van Brummelen P , Breimer DD
Published: July 2012

1. The pharmacokinetics of nisoldipine (10 mg) was assessed in 10 healthy subjects after single dose and multiple dose oral administration. Apparent liver blood flow was measured, using ICG before and during the absorption phase of nisoldipine. 2. Apparent liver blood flow was increased both on acute and short‐term administration of nisoldipine, basal flow being lower on multiple dosing than on acute administration (P less than 0.02). 3. A positive relationship was found between the increase in apparent liver blood flow during absorption of nisoldipine and the flow‐dependent part of the total AUC of nisoldipine. 4. The findings of this study indicate that a variable liver blood flow response during the absorption phase of nisoldipine contributes to the pharmacokinetic variability of the drug, both on acute and multiple dose administration.
Pharmacological investigations of a new renin inhibitor in normal sodium‐unrestricted volunteers.
Authors: de Gasparo M , Cumin F , Nussberger J , Guyenne TT , Wood JM , Menard J
Published: July 2012

1. CGP 38 560 A, a low‐molecular‐weight, non‐peptidic renin inhibitor, was well tolerated upon intravenous and oral administration to recumbent healthy volunteers on an unrestricted‐sodium diet. 2. After intravenous infusion over 30 min at a rate of 100 ml h‐1, doses of 50, 125 and 250 micrograms kg‐1 appear to induce a long‐lasting inhibition of plasma renin activity. Plasma angiotensin II was decreased in a dose‐ dependent manner during the infusion and thereafter reverted to the initial level. A concomitant dose‐related increase in active plasma renin was observed. Blood pressure was unaffected. The plasma levels of CGP 38 560 reached during infusion were at least 2000‐fold higher than the theoretical inhibitory concentration based on in vitro results. 3. After oral administration in doses of 50, 100 and 200 mg CGP 38 560 A, inhibition of plasma renin activity was observed, but plasma active renin was unchanged. Blood pressure also remained unaffected. 4. CGP 38 560 was rapidly cleared from plasma with a half‐life of 7.6 min for the first phase and 63 min for the second phase. Plasma levels were 100‐ fold lower after oral administration than after infusion, indicating a low degree of absorption (less than 1% oral bioavailability).
Stereoselective metabolism of metoprolol in Caucasians and Nigerians‐ relationship to debrisoquine oxidation phenotype.
Authors: Lennard MS , Tucker GT , Woods HF , Silas JH , Iyun AO
Published: July 2012

The relationship between debrisoquine oxidation phenotype and the stereoselective metabolism of metoprolol was investigated in populations of British Caucasians (n = 139) and Nigerian subjects (n = 117). The 0‐8 h urinary S/R‐metoprolol (S/R‐M) ratio was related to the ability to metabolise metoprolol and debrisoquine in both ethnic groups. The median S/R‐M ratio was significantly higher in Caucasians (1.27) than in Nigerians (1.10). In the Caucasian population poor metabolisers of debrisoquine had significantly lower S/R‐M ratio (median = 0.84) than extensive metabolisers (median = 1.28). Bimodality in the frequency distribution of the S/R‐M ratio was not apparent in either ethnic group.
The pharmacokinetics of midazolam following orthotopic liver transplantation.
Authors: Shelly MP , Dixon JS , Park GR
Published: July 2012

Seven patients with chronic liver disease received a 10 mg intravenous bolus dose of midazolam immediately following orthotopic liver transplantation. Plasma samples were analysed for midazolam and alpha‐ hydroxymidazolam by gas chromatography with electron capture detection. Data from three patients could not be evaluated. In the remaining four patients the pharmacokinetics of midazolam were essentially normal but the plasma concentrations of alpha‐hydroxy‐midazolam were higher than those found in healthy subjects. All patients required further sedation between 0.5 and 5 h later indicating that the duration of action of midazolam was not prolonged. These results suggest that following liver transplantation, patients have considerable drug metabolising capacity either in the liver or at extrahepatic sites.
Bradykinin‐induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.
Authors: Dixon CM , Barnes PJ
Published: July 2012

1. The effects of inhaled nedocromil sodium and sodium cromoglycate on bradykinin‐induced bronchoconstriction have been studied in a double‐ blind, placebo controlled study, in eight mild asthmatic subjects. 2. The subjects attended on four occasions. Fifteen minutes after drug pre‐ treatment a bradykinin challenge was performed. Increasing concentrations were inhaled until a greater than 40% fall in expiratory flow at 30% of vital capacity from a partial flow volume manoeuvre (V p30) was demonstrated. 3. Inhaled bradykinin (0.06‐8.0 mg ml‐1) caused dose‐related bronchoconstriction with the geometric mean cumulative dose causing a 40% fall in V p30 (PD40) of 0.035 (95% CI: 0.02‐0.07) mumol, after placebo inhalation, which was similar to that measured before the trial (0.04: 0.02‐0.09 mumol). 4. Both nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) gave significant protection (P less than 0.05) against bradykinin‐induced bronchoconstriction (PD40 0.37: 0.19‐0.72 mumol after nedocromil sodium and 0.22: 0.11‐0.49 after sodium cromoglycate). 5. Since bradykinin‐induced bronchoconstriction is probably neurally mediated we conclude that both nedocromil sodium and sodium cromoglycate have an action on neural pathways which may be useful in the control of asthma symptoms.
The effect of indomethacin and enalapril on the cutaneous response to bradykinin.
Authors: McAlpine LG , Thomson NC
Published: July 2012

The angiotensin converting enzyme inhibitors potentiate the wheal response to intradermal bradykinin. Both converting enzyme inhibitors and bradykinin stimulate prostaglandin synthesis and prostaglandins enhance the cutaneous response to bradykinin. We examined the possibility that the increased wheal response to intradermal bradykinin in the presence of enalapril was due to the effect of prostaglandins. Indomethacin did not inhibit the potentiation by enalapril of the wheal response to bradykinin.
Pharmacokinetics of intravenous cilazaprilat in normal volunteers.
Authors: Whitehead EM , Walters GE , Williams PE , Johnston GD
Published: July 2012

The pharmacokinetics of 1 mg, 2 mg and 4 mg of cilazaprilat administered intravenously were determined in a group of eight volunteers. The fall in plasma concentration was polyphasic. Elimination was predominantly by renal excretion of the unchanged drug. The mean renal clearance values following 1 mg, 2 mg and 4 mg doses were 5.3 +/‐ 0.5, 8.1 +/‐ 0.5, and 9.8 +/‐ 0.5 l h‐1 and plasma clearances were 7.8 +/‐ 0.5, 10.4 +/‐ 0.5 and 11.8 +/‐ 0.6 l h‐1, respectively. Thus, plasma and renal clearances were dose dependent. ACE inhibition was greater than 82% for the first 4 h and about 55% at 24 h, after all three doses. There were no significant haemodynamic effects at any dose.
GABAergic mechanisms in the pathogenesis and treatment of epilepsy.
Authors: Meldrum BS
Published: July 2012

1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically‐ determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound‐induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA‐transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA‐transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.
Effects of vigabatrin on evoked potentials in epileptic patients.
Authors: Cosi V , Callieco R , Galimberti CA , Manni R , Tartara A , Mumford J , Perucca E
Published: July 2012

1. Somatosensory (SEP) brainstem auditory (BAEP) and visual (VEP) evoked potentials were determined before and after add‐on administration of vigabatrin (GVG) in patients with epilepsy. 2. At pre‐ treatment assessment SEP and BAEP parameters were usually found to be within normal limits, while P100 latencies of the VEP were abnormally prolonged in a considerable proportion of patients. 3. In a double‐ blind, placebo‐controlled trial in 22 patients GVG (1‐3 g day‐1 stratified according to body weight) given for 7 weeks did not modify any of the evoked potential parameters evaluated. 4. Eighteen patients were evaluated prospectively at regular intervals during long‐term GVG (2‐4 g day‐1) therapy with a mean follow up of 24 months (range 13‐42 months). SEP, BAEP and especially VEP parameters showed some interindividual variability, but the within patient variation was relatively small. No consistent important changes were seen in association with GVG, although a possible trend towards a shortening of BAEP latencies and P100 latencies was observed. 5. The relevance of these findings with respect to GVG safety is discussed.
Changes in CSF and brain soluble proteins following vigabatrin treatment in rats.
Authors: Persson LI , Ronnback L , Ben‐Menachem E , Eriksson P , Nilsson M
Published: July 2012

1. Following the discovery of vacuoles in the white matter of the brain of small animals treated with vigabatrin (GVG) it was decided to investigate possible reasons for the occurrence of these vacuoles and to explore the possibility of finding CSF markers which could be applicable for monitoring toxicity in humans. 2. An animal model was developed to study the changes of protein synthesis and to assay soluble brain proteins by isoelectric focusing and two‐dimensional electrophoretic techniques. 3. Five groups of rats were treated either with 300 mg kg‐1 day‐1 GVG, 50 mg kg‐1 GVG every other day, 300 mg kg‐1 day‐1 sodium valproate, 100 mg kg‐1 day‐1 sodium valproate or sham treated. 4. All animals were given the drug in a liquid full nutrient diet. The dietary intake of the different groups was adjusted to the group which showed the smallest dietary intake, to compensate for possible differences between groups due to nutritional factors. 5. The rats on 300 mg kg‐1 day‐1 GVG had a 30% reduction of body weight and a 6% reduction of their brain weight, compared with the lower GVG dose group, the two valproate groups and the sham treated group. 6. The synthesis of soluble proteins in the cerebral cortex, hippocampus and cerebellum was decreased in rats given GVG at 300 mg kg‐1 day‐1 and was increased in rats given valproate at 300 mg kg‐1 day‐1.(ABSTRACT TRUNCATED AT 250 WORDS)
Noradrenaline attenuates the natriuretic effect of atrial natriuretic factor in man.
Authors: McMurray JJ , Seidelin PH , Brown RA , Struthers AD
Published: July 2012

1. The effects of noradrenaline (0.025 micrograms kg‐1 min‐1) and atrial natriuretic factor (0.04 micrograms kg‐1 min‐1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.
Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate.
Authors: Borgstrom L. , Nyberg L. , Jonsson S. , Lindberg C. , Paulson J.
Published: July 2012

1. The pharmacokinetics of the two enantiomers of terbutaline, (+)T and (‐)T, and the racemate (+/‐)T, have been evaluated after single intravenous and oral dosage to six healthy volunteers. 2. The mean systemic clearance, CL, was 0.19 and 0.13 l h‐1 kg‐1 for (+)T and (‐)T, respectively. This difference was statistically significant. The mean clearance of (+/‐)T was 0.20 l h‐1 kg‐1. Volumes of distribution were similar (1.9 l kg‐1) after the three intravenous administrations. The differences in CL were reflected in values of the elimination half‐life and MRT. 3. The difference in CL of the isomers could be explained by a corresponding difference in their renal clearance, CLR. Competition for stereoselective active reabsorption in the tubule might explain why (+)T seemed to enhance the CLR of (‐)T when the drug was given as the racemate. 4. Oral bioavailability, calculated from plasma data, of (+)T was 7.5% and that of (‐)T was 14.8%. This difference was statistically significant and was mainly due to a difference in absorption of (+)T and (‐)T, but also to a difference in their subsequent first‐pass metabolism. The bioavailability of (+/‐)T was similar to that of (‐)T. 5. (‐)T appears to govern the absorption properties of the racemate, while (+)T determines its elimination behaviour. Systemic metabolism of the two enantiomers was similar and, therefore, a greater first‐pass metabolism of (+)T would reflect a higher capacity of the gut wall to metabolise this isomer.