bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices.
Authors: Jackson PR , Tucker GT , Lennard MS , Woods HF
Published: July 2012

The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined. Pharmacokinetic determinants in addition to partial metabolic clearance down the polymorphic route were identified in each index. The ability of the various indices to discriminate bimodality in population data was assessed using a computer simulation. With the exception of the AUC data, bimodality was apparent to varying extents in all of the frequency distributions and, in general, logarithmic transformation allowed clearer visualisation of the two phenotypic groups. Simulated distributions were compared with those observed experimentally for metoprolol and its alpha‐hydroxy metabolite. Detailed pharmacokinetic data from controlled studies in small numbers of volunteers can form the basis of the input to the simulation programme. Inspection of the output may help in the design of further studies in larger numbers of subjects in whom only limited data collection is possible.
The effects of food and posture on the pharmacokinetics of a biphasic release preparation of nifedipine.
Authors: Challenor V , Waller DG , Gruchy BS , Renwick AG , George CF , McMurdo ET , McEwen J
Published: July 2012

The pharmacokinetics of a novel 20 mg biphasic release tablet of nifedipine were compared with the conventional 10 mg capsule and 20 mg sustained release preparations in healthy volunteers. The influence of food and posture on the pharmacokinetics of the biphasic tablet were studied. In the fasting state, the time to peak concentration of nifedipine was not significantly different between the 20 mg biphasic and 20 mg sustained release tablets, but plasma concentrations were higher between 2 and 4 h after the biphasic tablet. The terminal elimination half‐lives of the two formulations were similar. In subjects who fed prior to nifedipine administration there was no significant difference between either the peak plasma concentration or terminal half‐life of the biphasic tablet and two 10 mg capsules of nifedipine. When the biphasic preparation was given after a standard breakfast, the time to peak plasma concentration was significantly longer and the terminal half‐life shorter than when given in the fasting state. The dissolution characteristics of the biphasic tablet were influenced by prior administration of food to an extent which may be of clinical significance during twice daily administration.
Salivary concentrations of pirmenol as a possible cause of unpleasant taste.
Authors: Johnson BF , Shekar V , Woodman T , Canada AT
Published: July 2012

Salivary concentrations of the anti‐arrhythmic, pirmenol, were compared with plasma concentrations in six patients. Group mean salivary values tended to be higher despite high plasma protein binding, suggesting the possibility of an active transport process. The observed salivary concentrations are reasonably close to those detectable in healthy volunteers as tasting unpleasant.
Comparative haemodynamic effects of intravenous lignocaine, disopyramide and flecainide in uncomplicated acute myocardial infarction.
Authors: Silke B , Frais MA , Verma SP , Reynolds GW , Hafizullah M , Kalra PA , Jackson NC , Taylor SH
Published: July 2012

A prospective study evaluated the comparative haemodynamic effects of three Class I antiarrhythmics (lignocaine Class 1B, disopyramide Class 1A and flecainide Class 1C) in 30 patients with uncomplicated acute myocardial infarction. Three groups, each of 10 patients, were allocated to lignocaine (Group I) 1.5 mg kg‐1 i.v. loading dose over 10 min followed by infusion at 3 mg kg‐1 h‐1, disopyramide (Group II) or flecainide (Group III), both administered as a 1.0 mg kg‐1 i.v. loading bolus over 10 min followed by a 1.6 mg kg‐1 h‐1 infusion for 120 min. The plasma levels of each drug were in the described therapeutic range. Lignocaine decreased cardiac index (‐0.3 l min‐1 m‐2 (9%); P less than 0.05) and stroke volume index (‐5 ml m‐2 (11%); P less than 0.01). Systemic blood pressure, heart rate and systemic vascular resistance index were unchanged. There was a small increase (+3 mm Hg (30%); P less than 0.01) in pulmonary artery occluded pressure (PAOP). Both disopyramide and flecainide increased systemic blood pressure; the maximum increases for mean blood pressure were +10 mm Hg (11%) and +4 mm Hg (4%) respectively. Both drugs reduced cardiac index (‐0.5 l min‐1 m‐2 (16%): −0.4 l min‐1 m‐2 (11%)) and stroke volume index (‐11 ml m‐2 (25%): −5 ml m‐2 (11%)). There were increases in heart rate (+13: +5 beats min‐1) pulmonary artery occluded pressure (+2: +3 mm Hg) and systemic vascular resistance index (+696: +275 dyn s cm‐5 m2).(ABSTRACT TRUNCATED AT 250 WORDS)
Excretion of chloroquine, dapsone and pyrimethamine in human milk.
Authors: Edstein MD , Veenendaal JR , Newman K , Hyslop R
Published: July 2012

The concentration of chloroquine (CQ), dapsone (DDS) and pyrimethamine (PYR) in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration‐time curve (AUC) ratio ranged from 1.96 to 4.26 for CQ, 0.22 to 0.45 for DDS and 0.46 to 0.66 for PYR. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for CQ, DDS and PYR in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.
Peripheral neutrophil inclusions in amiodarone treated patients.
Authors: Adams PC , Sloan P , Morley AR , Holt DW
Published: July 2012

In 14 patients receiving chronic amiodarone therapy the appearance of multilamellar inclusion bodies in peripheral blood neutrophils was related to both plasma concentrations of amiodarone and its desethyl metabolite and unwanted effects of the drug. Seven of the patients had well defined inclusion bodies. In this group mean amiodarone and desethylamiodarone concentrations were significantly higher than in the remaining seven patients and all but one had unwanted effects of the drug. Of the seven patients without inclusion bodies only one, with high plasma amiodarone and desethylamiodarone concentrations, had unwanted effects of the drug. It is concluded that the appearance of multilamellar bodies in the blood neutrophils of amiodarone‐treated patients may help to distinguish those patients at risk of long‐term amiodarone toxicity.
In vitro immunosuppressive potency of deflazacort, a new bone‐sparing corticosteroid on T lymphocytes, NK and K cells.
Authors: Langhoff E. , Olgaard K.
Published: July 2012

The in vitro immunosuppressive effect of deflazacort, a new bone‐ sparing glucocorticoid, and its biologically active metabolite, 21‐ deacetyl‐deflazacort, was examined on phytohaemagglutinin (PHA) stimulated human peripheral blood lymphocytes (PBL) as well as on natural killer (NK) and killer (K) cell activity. Deflazacort and the 21‐deacetyl metabolite were as potent as prednisolone and hydrocortisone in suppressing PHA stimulated lymphocytes in a dose dependent way, but all were less potent than methylprednisolone. The physiological metabolites of hydrocortisone, dihydrocortisol and tetrahydrocortisol were without any immunosuppressive effects in vitro. Deflazacort, 21‐deacetyl‐deflazacort, and methylprednisolone suppressed NK cell activity, while hydrocortisone and aldosterone had no effect on NK cells. K cell activity was resistent to all tested glucocorticoids except methylprednisolone at high concentrations. The present results indicate that deflazacort and 21‐deacetyl‐deflazacort are potent immunosuppressive drugs in vitro and, on a molar basis, equally as potent as prednisolone.
Inability of ibuprofen to alter single dose phenytoin disposition.
Authors: Bachmann KA , Schwartz JI , Forney RB , Jauregui L. , Sullivan TJ
Published: July 2012

The effect of ibuprofen treatment (1600 mg day‐1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/‐ s.d.) value of 6.9 (+/‐ 0.7)% to 7.8 (+/‐ 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/‐ 0.009) 1 h‐1 kg‐ 1 to 0.032 (+/‐ 0.014) 1 h‐1 kg‐1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day‐1 are not likely to produce important changes in DPH dispositional parameters.
The cardiovascular effects of xamoterol, a beta 1‐adrenoceptor partial agonist, in healthy volunteers at rest.
Authors: Hashimoto T. , Shiina A. , Toyo‐Oka T. , Hosoda S. , Kondo K.
Published: July 2012

The cardiovascular effects of three single intravenous doses of a beta 1‐adrenoceptor partial agonist, xamoterol (0.025, 0.05 and 0.1 mg kg‐1) and placebo were studied in six healthy volunteers at rest using a single‐blind design. In addition to heart rate and blood pressure measurements, cardiac contractility was measured by means of M‐mode echocardiography and systolic time intervals. Ambulatory 24 h Holter‐ monitoring of the electrocardiogram was performed. Plasma concentrations of xamoterol were measured. Compared to baseline, xamoterol (0.025 mg kg‐1) increased heart rate (61 +/‐ 3‐68 +/‐ 3 beats min‐1, means and SEM) and systolic blood pressure (119 +/‐ 3‐138 +/‐ 5 mm Hg) but decreased pre‐ejection period (100 +/‐ 4‐76 +/‐ 5 msec). Stroke volume (88 +/‐ 6‐104 +/‐ 10 ml), cardiac output (4.8 +/‐ 0.4‐6.6 +/‐ 0.61 min‐1), velocity of circumferential fibre shortening (1.15 +/‐ 0.06‐1.50 +/‐ 0.06 circ s‐1) were increased by xamoterol. No significant changes were produced by placebo. No dose‐dependent effects were seen and maximum effects were produced by 0.025 mg kg‐1 xamoterol. Significant effects were observed for 2 h. The areas under the plasma concentration curves (AUC0‐12) showed a linear dose response. No adverse effects attributable to xamoterol were seen in haematological, biochemical, urinalysis or electrocardiographic tests. Four volunteers were aware of a more forceful heart beat after xamoterol, but this was mild and transient. It is concluded that xamoterol has a positive inotropic action.
Stereoselective interaction between the R enantiomer of warfarin and cimetidine.
Authors: Choonara IA , Cholerton S. , Haynes BP , Breckenridge AM , Park BK
Published: July 2012

The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day‐1). Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma half‐life of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h‐1 kg‐1) (P less than 0.02). Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3‐epoxide concentrations, which were similar in each case.
Pharmacokinetics of ranitidine in critically ill patients.
Authors: Ilett KF , Nation RL , Tjokrosetio R. , Thompson WR , Oh TE , Cameron PD
Published: July 2012

The plasma pharmacokinetics of ranitidine (50 mg i.v.) have been studied in 17 critically ill patients in an intensive care unit. Measurements of gastric aspirate pH were also made in 16 of these patients. Ranitidine therapy was part of the patients' normal drug regimen. Ranitidine plasma concentration was measured by high performance liquid chromatography and appropriate polyexponential equations were fitted to concentration‐time data to enable calculation of relevant pharmacokinetic parameters. Values of the volume of the initial dilution space (median = 89 ml kg‐1) and volume of distribution at steady state (median = 1.54 l kg‐1) were about 60% of corresponding mean literature values for healthy controls. Plasma clearance (median = 4.22 ml min‐1 kg‐1) and terminal half‐life (median = 4.7 h) were about 2‐3 fold less and 2‐3 fold greater, respectively, than values for healthy controls. There was wide interpatient variation in all the pharmacokinetic parameters. Renal impairment was considered to be largely responsible for the low plasma clearance. Gastric aspirate pH was measured at 0, 1 and 7 h after ranitidine administration and 58% of samples were found to be above pH 4. Four patients had gastric pH values which were consistently below pH 4 despite average trough plasma ranitidine concentrations equal to or greater than those required for a 50% suppression of gastric acid secretion in normal volunteers.
Gastrointestinal side effects after intravenous erythromycin lactobionate.
Authors: Downey KM , Chaput de Saintonge DM
Published: July 2012

Ten healthy normal volunteers received an intravenous infusion of erythromycin lactobionate over 60 min to a total dose of 800 mg (n = 9), and 524 mg (n = 1). Blood samples were collected at 10 min intervals for 100 min and gastric contents aspirated, via a nasogastric tube, from pre‐dose to 105 min after start of infusion. Incidence and severity of three gastrointestinal symptoms (nausea, stomach discomfort and feelings of hunger), two CNS symptoms (dizziness and faintness) and a 'control' symptom (back pain) were measured using 100 mm visual analogue scales. Rate of infusion and plasma erythromycin concentration correlated with nausea (P less than 0.001) and stomach discomfort (P less than 0.001); plasma erythromycin concentration was also correlated with dizziness (P less than 0.05). Concentrations of active erythromycin in the aspirate were pH dependent. In one subject the concentration of erythromycin in the aspirate exceeded that in the plasma by 100 fold. Bile staining of samples containing the highest levels of microbiologically active erythromycin makes the origin of the erythromycin in these samples uncertain.
The effect of intra‐articular steroids on plasma salicylate concentrations.
Authors: Edelman J. , Potter JM , Hackett LP
Published: July 2012

Plasma salicylate concentrations and salicylate clearances were evaluated in 10 patients before and then 3 days after the intra‐ articular administration of glucocorticoid steroids. All patients were on chronic salicylate treatment, the dosage varying from 1.3‐4.6 g day‐ 1 of enteric‐coated aspirin. The mean steady state plasma concentration (+/‐ s.e. mean) of salicylate decreased significantly after intra‐ articular steroid (90.9 +/‐ 14.8 mg l‐1‐64.7 +/‐ 8.9, P less than 0.05), whilst the mean clearance increased significantly (87.3 +/‐ 20.6 ml min‐1‐120.6 +/‐ 28.3, P less than 0.05). In these paired studies, the intra‐articular administration of steroids lead to a significant decrease in plasma salicylate levels in patients taking enteric‐coated aspirin.
The effect of chloroquine on paracetamol disposition and kinetics.
Authors: Adjepon‐Yamoah KK , Woolhouse NM , Prescott LF
Published: July 2012

The effect of chloroquine on paracetamol kinetics and disposition was investigated in six healthy male Ghanaian volunteers. Chloroquine administration shortened the time taken to reach peak plasma paracetamol concentration (tmax) in five of the volunteers. Peak plasma paracetamol concentration (Cmax) was significantly increased by chloroquine administration. The area under the plasma paracetamol concentration‐time curve was also significantly increased by chloroquine administration. There was, however, no effect of chloroquine on paracetamol metabolism.
Inhibition of human liver cytochrome P‐450 by omeprazole.
Authors: Jensen JC , Gugler R.
Published: July 2012

The effects of omeprazole on cytochrome P‐450 mediated 7‐ethoxycoumarin deethylation were studied in human liver microsomes. Omeprazole inhibited both the high and low affinity components of deethylation, with an estimated Ki of 0.03 mM for the high affinity component. The results are further evidence that the previously reported prolongation of the half‐life of diazepam by omeprazole in vivo is due to inhibition of cytochrome P‐450 monooxygenases.
Plasma levels of nitroglycerin generated by three nitroglycerin patch preparations, Nitradisc, Transiderm‐Nitro and Nitro‐Dur and one ointment formulation, Nitrobid.
Authors: McAllister A. , Mosberg H. , Settlage JA , Steiner JA
Published: July 2012

Twenty‐four healthy male subjects participated in a study comparing plasma concentrations of nitroglycerin generated by single applications of Nitradisc 32 mg, Transiderm‐Nitro 50 mg and Nitro‐Dur 104 mg patches and from one inch of Nitrobid 2% ointment. The three patch preparations are designed to release 10 mg nitroglycerin systemically over a 24 h period. Nitrobid ointment is intended to deliver 15 mg nitroglycerin per inch of ointment, and to be reapplied at least every 8 h. Blood was taken for nitroglycerin assay up to and including 24 h after each application. Assay for nitroglycerin was performed using a gas chromatography‐mass spectrometry technique. Plasma concentrations of nitroglycerin were sustained up to the 24 h mark with all three patch preparations, but not with application of Nitrobid ointment. Nitrobid was associated with a rapid rise in nitroglycerin plasma concentrations maximal 1 h after application. Plasma concentrations of nitroglycerin absorbed from Nitrobid ointment fell below those absorbed from all three patch preparations after 8 h. Clinically, all four formulations were similar with respect to side effects, with headache and dizziness being the most common.
The interaction between i.v. theophylline and chronic oral dosing with slow release nifedipine in volunteers.
Authors: Jackson SH , Shah K. , Debbas NM , Johnston A. , Peverel‐Cooper CA , Turner P.
Published: July 2012

Eight healthy volunteers received a 5 min i.v. infusion of lysine theophylline, equivalent to 197 mg anhydrous theophylline, both before (day 1) and during (day 5) steady state chronic oral dosing with slow release nifedipine 20 mg 12 hourly. A theophylline pharmacokinetic profile was performed on day 1 and day 5 and a nifedipine pharmacokinetic profile was performed on day 4 and day 5. The greatest difference in serum theophylline concentrations was seen at the first sampling time (5 min after completion of the infusion) with a mean concentration of 9.9 mg l‐1 during nifedipine administration and 14.6 mg l‐1 with theophylline alone. Thereafter, the difference fell to approximately 1 mg l‐1 until 6 h when they became almost identical. Repeated measures analysis of variance using the theophylline serum concentrations at each of ten time points over 8 h as the repeated measures showed a small but significant effect of nifedipine (F(1,151) = 7.0, P less than 0.01) on serum theophylline concentrations. Mean volume of distribution (V) rose from 0.33 +/‐ 0.07 to 0.39 +/‐ 0.06 1 kg‐1 corrected body weight (CBW) in the presence of nifedipine (t = 2.23, P = 0.052). Theophylline clearance, area under the curve to 8 h AUC (0‐8), area under the curve to infinity AUC (0‐infinity) and elimination half‐life (t1/2) did not change appreciably. No statistically significant changes in nifedipine pharmacokinetics occurred in the presence of theophylline.
Felodipine vs hydralazine: a controlled trial as third line therapy in hypertension. Cooperative Study Group.
Authors: Halperin JL , Mindich BP , Rothlauf EB , Reder RF , Litwak RS , Kupersmith J.
Published: July 2012

In a placebo‐controlled, double‐blind, randomized, parallel group study one hundred and one patients with supine diastolic blood pressure greater than or equal to 100 mm Hg phase V, despite treatment with atenolol 100 mg plus chlorthalidone 25 mg once daily also received either felodipine 5‐20 mg twice daily or hydralazine 25‐100 mg twice daily for 6 weeks. Felodipine achieved a lower supine blood pressure (mean +/‐ s.d. 177/108 +/‐ 29/8‐138/82 +/‐ 19/8 mm Hg) than hydralazine (174/109 +/‐ 25/8‐149/92 +/‐ 26/11 mm Hg), (P less than 0.05/P less than 0.001). Felodipine also lowered supine diastolic blood pressure to less than 90 mm Hg more often than hydralazine (42 vs 22 patients, P less than 0.001). The incidence of unwanted effects was similar in both groups. The felodipine treated patients experienced more ankle swelling and flushing than those in the hydralazine group who experienced more headache and minor gastro‐intestinal upset.
The effect of cigarette smoking on 7‐ethoxyresorufin O‐deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.
Authors: Pelkonen O. , Pasanen M. , Kuha H. , Gachalyi B. , Kairaluoma M. , Sotaniemi EA , Park SS , Friedman FK , Gelboin HV
Published: July 2012

Four cytochrome P‐450 enzyme activities, 7‐ethoxyresorufin O‐deethylase (ERDE), coumarin 7‐hydroxylase (CH), 7‐ethoxycoumarin O‐deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non‐smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels. Enzyme inhibitory monoclonal antibodies (MAb) to a 3‐ methylcholanthrene‐induced (MAb 1‐7‐1) and phenobarbitone‐induced (MAb 2‐66‐3) rat hepatic cytochrome P‐450 were used to measure the contribution of MAb‐defined, epitope‐specific cytochromes P‐450 to the total reaction measured for each of the above activities. ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. MAb 1‐7‐1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1‐7‐1 on ERDE activity was greater than 50% in the non‐smokers. MAb 2‐66‐3 had no inhibitory effect on any of the enzyme activities studied. In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1‐7‐1. The MAb 2‐66‐3 was without effect. Cigarette smoking induces a form of P‐450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1‐7‐1. This form of cytochrome P‐450 is insensitive to MAb 2‐66‐3 and is not contributing to AHH, CH or ECDE activities of human liver.
Drug‐specific antibodies in patients receiving captopril.
Authors: Coleman JW , Yeung JH , Roberts DH , Breckenridge AM , Park BK
Published: July 2012

IgG anti‐captopril (CP) antibody activity was detected by enzyme‐linked immunosorbent assay (ELISA) in serum from two out of 45 patients receiving the drug (25‐75 mg day‐1). Five of the 45 patients, including one whose serum was antibody‐positive, suffered skin rashes which were thought to be drug‐induced. The specificity of the antibody for the disulphide‐conjugated form of captopril was established as follows: serum IgG bound to disulphide‐linked captopril‐human albumin (CP‐S‐S‐ HSA) conjugate but not to HSA; binding of IgG to CP‐S‐S‐HSA was inhibited by disulphide‐linked captopril‐ovalbumin (CP‐S‐S‐OVA) conjugate and captopril disulphide (CP‐S‐S‐CP). The structurally related drug D‐penicillamine (PA) in disulphide‐linked form (PA‐S‐S‐OVA and PA‐S‐S‐PA) was without inhibitory activity. The inhibitory preparations of CP‐S‐S‐OVA and CP‐S‐S‐CP were shown to be inactive in an ELISA for human IgG directed against the unrelated benzylpenicilloyl antigen. Since disulphide‐linked CP‐plasma protein conjugates are formed extensively in vivo, and since the antibodies we describe are directed against CP in disulphide‐linked form, it appears that CP may be immunogenic in some patients receiving the drug.
The pharmacodynamics and dose‐response relationships of the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.
Authors: Ajayi AA , Elliott HL , Reid JL
Published: July 2012

In a double‐blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94‐96% at 2‐3 h. At 24 h residual inhibition of ACE was 49‐54%. Plasma renin activity increased in a dose‐dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.
The effect of lamotrigine, a novel anticonvulsant, on interictal spikes in patients with epilepsy.
Authors: Jawad S. , Oxley J. , Yuen WC , Richens A.
Published: July 2012

Lamotrigine, a novel anticonvulsant, has been evaluated in patients with epilepsy using the method of interictal EEG spike counting. In a randomised double‐blind trial it was found that oral lamotrigine (240 mg) was more effective than placebo, but less effective than diazepam (20 mg) in suppressing interictal spikes. Further clinical evaluation of lamotrigine is recommended in patients with epilepsy.
Estimating the clearance of amylobarbitone from a single plasma measurement.
Authors: Bachmann K
Published: July 2012

Amylobarbitone sodium (200 mg) was given by intravenous injection to nine healthy, young adults (four males). Subjects were drug‐free and nonsmokers. Serial blood samples were drawn for 48 h following the infusion, and multiple sample and single sample estimates of clearance were calculated. The mean (+/‐ s.d.) values for clearance (CL) and apparent volume of distribution (V) were 0.032 (+/‐ 0.007) 1 h‐1 kg‐1 and 1.08 (+/‐ 0.16) 1 kg‐1, respectively. The mean (+/‐ s.d.) single sample estimate of clearance, CL, based on just the 48 h plasma concentrations of amylobarbitone was 0.033 (+/‐ 0.006) 1 h‐1 kg‐1. The 48 h single sample CL value was shown to reliably reflect the value of CL with little bias and good precision. Values of the 48 h CL when compared to CL exhibited a mean prediction error (mpe) of 1.2% with 95% confidence limits of −6.3% to 9.4%, and a root mean squared error (rmse) of 9.4%. It is concluded that amylobarbitone's clearance can be estimated in a single dose, single sample protocol permitting its use as a single dose, single sample probe for studying host factor influences on drug metabolism.
Nefopam excretion in human milk.
Authors: Liu DT , Savage JM , Donnell D
Published: July 2012

Human milk and plasma samples were obtained from five healthy nursing mothers who were taking nefopam hydrochloride (60 mg four‐hourly) for post‐episiotomy pain. Concentrations of nefopam were quantified in milk and plasma paired samples, taken daily from birth for 5 days, by a specific paired‐ion reverse phase h.p.l.c. method. Although nefopam was present in human milk in an equivalent concentration to plasma (milk: plasma ratio 1.2 +/‐ 0.7, mean +/‐ s.d.), the likely infant exposure was less than 0.05 mg kg‐1 day‐1 which, on a body weight basis, would be less than 3% of the maternal dose.
Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.
Authors: Lees KR , Reid JL
Published: July 2012

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.
Differential effects of the anxiolytic drugs, diazepam and buspirone, on memory function.
Authors: Lucki I , Rickels K , Giesecke MA , Geller A
Published: July 2012

The effects of the anxiolytic drugs diazepam (5 mg) or buspirone (5 or 10 mg) were studied in comparison with placebo on memory function in 39 subjects diagnosed with generalized anxiety disorder. Neither drug altered the immediate recall of a list of 16 nouns or impaired digit span, a second test of immediate memory. Diazepam selectively impaired the recall of nouns after a 20 min delay when compared with placebo. In contrast, neither dose of buspirone altered the delayed recall of the word list. The implications of such different effects of anxiolytic drugs on memory function for the clinical treatment of anxiety are discussed.
The effects of intrathecal midazolam on sympathetic nervous system reflexes in man‐a pilot study.
Authors: Goodchild CS , Noble J
Published: July 2012

Nine patients were given intrathecal injections of midazolam (dose 0.3‐ 2 mg dissolved in 3 ml 5% dextrose). No changes in motor power or general sensation were produced. Resting heart rate and blood pressure were unchanged and normal valsalva manoeuvres were elicited 30 min post‐ injection. Cardiovascular responses were provoked at a light plane of anaesthesia by intubation of the trachea and manipulation of peritoneum and bowel but not by surgical incision of the skin. Intrathecal administration of midazolam relieved post‐operative pain of somatic origin but not of visceral origin. It is concluded that intrathecal midazolam in the dosage used interrupts somatic nociceptive afferent pathways but not abdominal visceral nociceptive afferent pathways.
Glyceryl‐1‐nitrate pharmacokinetics in healthy volunteers.
Authors: Laufen H , Leitold M
Published: July 2012

The plasma kinetics and urinary excretion of glyceryl‐1‐nitrate (G‐1‐ N), a metabolite of glyceryl trinitrate with antianginal potential, were investigated in 10 healthy male volunteers, after intravenous infusion and oral administration of 20 mg G‐1‐N. The apparent volume of G‐1‐N distribution was 601 corresponding to 0.761 kg‐1 body weight, on average. It is suggested that total body water is the principal biological correlate of the hydrophilic drug. Mean intravenous clearance was 283 ml min‐1 or 3.61 ml min‐1 kg‐1. The average of elimination half‐lives were 2.50 +/‐ 0.36 (s.d.) h after the intravenous and 2.54 +/‐ 0.40 (s.d.) h after the oral dose. Inter‐ subject variances of pharmacokinetic parameters were low compared to variances reported for glyceryl trinitrate. The coefficient of intra‐ subject variation of the elimination half‐lives was 8.8%. 5.5% (i.v.) and 5.4% (p.o.) of the administered dose were excreted into urine up to 48 h after the administration. 1% (i.v.) and 1.5% (p.o.) were in the conjugated form. The oral dose was rapidly and almost completely absorbed. The oral bioavailability on the basis of areas under the curve amounted to 88.6% on the average. For clinical use, owing to its high oral bioavailability, long residence in the body, inactivation by metabolic conversion, and good predictability of kinetic parameters, G‐ 1‐N offers advantage over glyceryl trinitrate.
The disposition of chloroquine in healthy Nigerians after single intravenous and oral doses.
Authors: Walker O , Salako LA , Alvan G , Ericsson O , Sjoqvist F
Published: July 2012

The pharmacokinetics of chloroquine after single oral (600 mg) and intravenous (2 mg kg‐1) doses were studied in healthy black Nigerian students. The plasma concentrations of chloroquine and its desethylmetabolite were determined using a high performance liquid chromatography technique. Concentrations as low as 3 ng ml‐1 were reproducibly determined. After i.v. dosage, the half‐life ranged between 144 and 298 h; the total plasma clearance was between 282 and 1130 ml min‐1 and the volume of distribution between 142 and 398 1 kg‐ 1. Renal clearance was about 52% of plasma clearance. The estimated total urinary recovery of chloroquine and desethylchloroquine was 77% of the oral dose. There was no significant difference in the pharmacokinetics between the oral and the i.v. administration. The pharmacokinetic properties of chloroquine, in these black subjects did not differ from those previously demonstrated in Caucasians.
The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N‐desmethylclobazam.
Authors: Pullar T , Edwards D , Haigh JR , Peaker S , Feely MP
Published: July 2012

The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N‐desmethylclobazam (NDMC) was studied in volunteers. Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. The increases in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant.
Effect of beta‐adrenoceptor blockade on exercise‐induced plasma catecholamine concentrations and their dissipation profile.
Authors: Ohnishi A , Minegishi A , Sasaki T , Suganuma T , Ishizaki T
Published: July 2012

The time‐course of plasma noradrenaline (NA) and adrenaline (A) concentrations and their dissipation profiles were examined concomitantly with heart rate changes after strenuous exercise in eight normal subjects receiving either placebo or carteolol, a beta‐ adrenoceptor blocker. Post‐exercise NA concentrations declined with time in a biexponential manner, while A disappearance curves were apparently monophasic. Plasma NA concentrations and their peak value attained within 3 min after exercise were higher in the carteolol than in the placebo phase, whereas there were no significant differences in the first and second disappearance t1/2 between the two trials. The monoexponential t1/2 of A in the carteolol trial was significantly longer than in the placebo trial. Our results suggest that the dissipation profiles of catecholamines released by exercise appear to be affected by beta‐adrenoceptor blockade.
Salivary paracetamol elimination kinetics during the menstrual cycle.
Authors: Somaja L , Thangam J
Published: July 2012

Studies were done to examine the influence of the menstrual cycle on the elimination kinetics of paracetamol. Salivary concentrations of paracetamol were determined after oral administration of 1 g of paracetamol on day 3, 10, 14, 20 and 25 of the menstrual cycle in normal healthy women volunteers with regular menstrual cycles. There was no significant difference in elimination half‐life (t 1/2) or metabolic clearance rate (CL) between the various days of the menstrual cycle. The result suggests that paracetamol kinetics are not altered by the hormonal changes occurring during the menstrual cycle.
Antipyrine metabolism in acute hepatic porphyria in relapse and remission.
Authors: Birnie GG , McColl KE , Thompson GG , Moore MR , Goldberg A , Brodie MJ
Published: July 2012

Antipyrine kinetics following a single oral dose were obtained in porphyric patients in attack and in remission and in controls. The clearance of antipyrine was significantly lower during an acute porphyric attack (median: 0.34 ml min‐1 kg‐1; range: 0.1‐0.71, P less than 0.05) than in patients in remission (median: 0.53 ml min‐1 kg‐1; range: 0.28‐0.87) or controls (median: 0.52 ml min‐1 kg‐1; range: 0.32‐ 0.93). There was a significant negative correlation between weight‐ adjusted antipyrine clearance and the urinary excretion of the porphyrin precursors, delta‐aminolaevulinic acid (r = 0.86, P less than 0.001) and porphobilinogen (r = 0.82, P less than 0.002). These data suggest that the more severe the porphyric attack, the greater the impairment of hepatic monooxygenase activity.
Effects of felodipine on haemodynamics and exercise capacity in patients with angina pectoris.
Authors: Sheridan JV , Thomas P , Routledge PA , Sheridan DJ
Published: July 2012

We studied the effects of adding felodipine to beta‐adrenoceptor blockade on haemodynamics and exercise capacity in 14 patients with stable angina pectoris using a placebo controlled double‐blind crossover protocol. Felodipine reduced supine and standing systolic pressure by 13% (P less than 0.01) and 14% (P less than 0.01) respectively and increased supine heart rate 7.4% (P less than 0.05). Felodipine at a plasma concentration of 15.5 +/‐ 3.0 nmol l‐1 increased exercise duration by 16% (P less than 0.01) but failed to attenuate the degree of ST segment depression during exercise. The mean daily number of episodes of angina (0.53 +/‐ 0.16 on placebo vs 0.37 +/‐ 0.11 on felodipine) and mean daily GTN consumption (0.51 +/‐ 0.07 on placebo vs 0.36 +/‐ 0.12 on felodipine) were not significantly reduced (0.1 less than P greater than 0.05). These findings suggest that felodipine may provide useful additional benefits in patients with hypertension or angina pectoris, who are already receiving beta‐adrenoceptor blockers.
Selective and extremely long inhibition of prolactin release in man by 1‐ethyl‐3‐(3′‐dimethylaminopropyl)‐3‐(6′‐allylergoline‐8′‐beta‐ carbonyl)‐urea‐diphosphate (FCE 21336).
Authors: Pontiroli AE , Viberti GC , Mangili R , Cammelli L , Dubini A
Published: July 2012

The effects on anterior pituitary function of FCE 21336 (1‐ethyl‐3‐(3′‐ dimethylaminopropyl)‐3‐(6′‐allylergoline‐8′‐beta‐ca rbonyl)‐urea‐ diphosphate), a synthetic ergoline derivative with selective dopamine agonistic properties, were studied. Circulating PRL, GH, TSH, cortisol and LH levels were determined up to 96 h after single oral doses of 50, 100, 200 and 300 micrograms of the compound to eight healthy males, and up to 168 h after single oral doses of 400 and 600 micrograms to six healthy males, according to double‐blind, within subjects, experimental designs vs placebo. Vital signs, ECG, laboratory tests and the appearance of newly observed signs and symptoms were monitored. A dose‐ related decrease of serum PRL in comparison with both basal and post‐ placebo levels was observed after 200 micrograms and greater doses of the compound, with inhibition of spontaneous circadian rhythm. Maximal inhibition (PRL less than 2 ng ml‐1) was observed in one out of five subjects after 200, three out of seven subjects after 300, four out of six after 400 and five out of six subjects after 600 micrograms. The effect was of rapid onset and long duration; the maximum or nearly maximum decrease was observed within 3 h after dosing as well as up to 96 h (200 and 300 micrograms) and up to 168 h (400 and 600 micrograms). No modifications of GH, TSH, LH and cortisol as well as of vital signs, ECG and laboratory tests were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)
Chromosomal assignment of human cytochrome P‐450 (debrisoquine/sparteine type) to chromosome 22.
Authors: Eichelbaum M , Baur MP , Dengler HJ , Osikowska‐Evers BO , Tieves G , Zekorn C , Rittner C
Published: July 2012

In order to determine on which chromosome the gene controlling human cytochrome P‐450 (debrisoquine/sparteine type) is located a linkage study of polymorphic sparteine oxidation (PSO) to various polymorphic markers was carried out. Positive information for linkage between PSO and the P1 blood group was obtained with a maximal LOD‐score of LOD = 3.35 for both male and female recombination fraction estimates of theta m = theta f = 0.0. The P1 blood group has been recently mapped to the long arm of chromosome 22. Thus it can be concluded that the gene controlling human cytochrome P‐450 (debrisoquine/sparteine) is situated on the long arm of chromosome 22 in close vicinity to P1.
Single dose disposition of chloroquine in kwashiorkor and normal children‐evidence for decreased absorption in kwashiorkor.
Authors: Walker O , Dawodu AH , Salako LA , Alvan G , Johnson AO
Published: July 2012

The single dose disposition of chloroquine was studied in five children with kwashiorkor and six normal control children after an oral dose of 10 mg kg‐1 of chloroquine base. Plasma concentrations of chloroquine and its main metabolite were assayed by high performance liquid chromatography (h.p.l.c.). Chloroquine was detectable for up to 21 days in all the subjects. Chloroquine was detectable in all the subjects within 30 min after giving the drug except in one subject. Peak levels were reached between 0.5 and 8 h in all the subjects (with no significant difference in the tmax between the two groups of children). Peak plasma chloroquine concentrations in the children with kwashiorkor varied from 9 ng ml‐1 to 95 ng ml‐1 (mean 40 +/‐ 34 ng ml‐1). Peak chloroquine concentrations in the controls varied between 69 ng ml‐1 and 330 ng ml‐1 (mean 134 +/‐ 99 ng ml‐1). The mean AUC in the kwashiorkor children was significantly lower than the mean AUC in the control children (P less than 0.001). Peak plasma desethylchloroquine concentrations in the children with kwashiorkor varied between 3 and 13 ng ml‐1 (mean 6 +/‐ 9 ng ml‐1) while in the controls the concentrations varied between 14 and 170 ng ml‐1 (mean 50 +/‐ 61 ng ml‐1). There was no significant difference in the half‐life of chloroquine between the kwashiorkor children and the normal control children. The possible influence of a different binding and distribution pattern of chloroquine in kwashiorkor could not be assessed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)
A pragmatic approach to the pressor dose‐response as an index of vascular reactivity and adrenoceptor function in man.
Authors: Sumner DJ , Elliott HL , Vincent J , Reid JL
Published: July 2012

In clinical pharmacological studies, where it is not possible to describe the full dose‐response curve, the construction of dose‐ response relationships ideally depends upon achieving a reproducible and readily measurable response for each dose administered. This study investigates in normotensive males the technique of dose‐response analysis for the blood pressure and heart rate increases with constant infusions of incremental doses of vasoactive drugs, particularly catecholamines. Steady state responses could be adequately obtained using 5 min infusion periods (at each dose level) for noradrenaline and alpha‐methyl noradrenaline. At least 7 min was required for phenylephrine and 8 min for isoprenaline. There was an approximate correlation between the time to achieve the steady state response and the half‐life of the offset of the agonist effect. For interindividual comparisons it is desirable to compare steady state responses and so the time at each dose level will vary according to which agonist is being used. For intraindividual comparisons it may not be essential that steady state responses are achieved. For example, assessment of the effect of prazosin on the responses to phenylephrine, by calculation of dose ratios, indicated that 5 min dose intervals were adequate.
Effects of indomethacin and (+/‐)‐propranolol on the cardiovascular and renin responses to vasoactive intestinal polypeptide (VIP) infusion in man.
Authors: Unwin RJ , Reed T , Thom S , Calam J , Peart WS
Published: July 2012

The mechanisms of the cardiovascular and renin responses to vasoactive intestinal polypeptide (VIP) are unclear. Rabbit studies suggest that VIP‐induced tachycardia is largely beta‐adrenoceptor mediated, but that the renin response may be partially prostaglandin‐dependent. To examine the relative importance of prostaglandins and reflex sympathetic activation in the haemodynamic and renin responses to VIP infusion in man, we completed two randomised single‐blind crossover studies in two groups of six healthy male volunteers (aged 24‐35 years). We recorded the effects of indomethacin and propranolol pretreatment on VIP‐related changes in heart rate (HR), blood pressure (BP), forearm vascular resistance (FVR), plasma renin activity (PRA), plasma noradrenaline (PNA) and plasma arginine vasopressin (AVP) concentrations. Intravenous VIP (calculated dose: 6 pmol kg‐1 min‐1) produced cutaneous flushing, increased HR and PRA, decreased FVR, but did not alter mean arterial BP or AVP levels. Indomethacin (375 mg over 3 days) lowered basal PRA and propranolol (circa 40 mg i.v. over 60 min) decreased resting HR and increased FVR. Although indomethacin and propranolol reduced the absolute rise in PRA and HR, respectively, during VIP infusion, the percentage changes were no different from control. Neither drug altered the flush response to VIP and propranolol did not affect the fall in FVR. We conclude that the measured cardiovascular responses to VIP infusion in man are probably direct and do not involve a significant contribution from reflex sympathetic stimulation, nor prostaglandin release.
Effect of rifampicin on haem and bilirubin metabolism in man.
Authors: McColl KE , Thompson GG , el Omar E , Moore MR , Park BK , Brodie MJ
Published: July 2012

Haem and bilirubin metabolism was studied in seven healthy volunteers during 4 weeks treatment with rifampicin 600 mg at night. The serum unconjugated bilirubin concentration increased 2‐3 fold in the first 24 h of treatment (P less than 0.01) and subsequently fell to below pretreatment values (P less than 0.05) during the third and fourth weeks of rifampicin therapy. In each subject, the activity in leucocytes of delta‐aminolaevulinic acid (ALA) synthase increased and that of protoporphyrinogen (proto) oxidase decreased during the first week of therapy. The mean ALA synthase activity was most markedly increased on day 4 being seven‐fold its pretreatment value (P less than 0.01), and the mean proto oxidase activity most depressed on day 2 at 50% its pretreatment value (P less than 0.02). There was increased urinary excretion of porphobilinogen (PBG) during the first week of therapy and increased excretion of porphyrins and PBG during the third week of treatment. The increase in ALA synthase activity and haem precursor excretion can be explained by the combination of increased haem demand for haemoprotein induction and partial block in haem synthesis due to reduced proto oxidase activity.