bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.
Authors: Rasmussen BB , Maenpaa J , Pelkonen O , Loft S , Poulsen HE , Lykkesfeldt J , Brosen K
Published: July 2012

1. Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2. None of the drugs showed potent inhibition of CYP2A6 (coumarin 7‐hydroxylase) or CYP2E1 (chlorzoxazone 6‐hydroxylase), while norfluoxetine was the only potent inhibitor of CYP3A having IC50 values of 11 microM and 19 microM for testosterone 6 beta‐hydroxylase and cortisol 6 beta‐hydroxylase, respectively. 3. Norfluoxetine, sertraline and fluvoxamine inhibited CYP1A1 (7‐ ethoxyresorufin O‐deethylase) in microsomes from human placenta (IC50 values 29 microM, 35 microM and 80 microM, respectively). Fluvoxamine was a potent inhibitor of CYP1A2‐mediated 7‐ethoxyresorufin O‐ deethylase activity (IC50 = 0.3 microM) in human liver. 4. In microsomes from three human livers fluvoxamine potently inhibited all pathways of theophylline biotransformation, the apparent inhibitor constant, Ki, was 0.07‐0.13 microM, 0.05‐0.10 microM and 0.16‐0.29 microM for inhibition of 1‐methylxanthine, 3‐methylxanthine and 1,3‐ dimethyluric acid formation, respectively. Seven other SSRIs showed either weak or no inhibition of theophylline metabolism. 5. Ethanol inhibited the formation of 1,3‐dimethyluric acid with K(i) value of 300 microM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8‐hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3‐dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8‐hydroxylation of theophylline. 6. It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.
The effect of fasting on total serum bilirubin concentrations.
Authors: Meyer BH , Scholtz HE , Schall R , Muller FO , Hundt HK , Maree JS
Published: July 2012

Thirty‐seven healthy volunteers, 19 of whom had consistently elevated total serum bilirubin (TSB) concentrations, took part in an open, randomised cross‐over study to determine the effect of fasting on TSB concentrations. The study comprised of two treatments. During one treatment period volunteers ate a standard supper but fasted for 24 h thereafter. During the other treatment period volunteers ate a standard supper, snacks, breakfast and lunch. TSB concentrations were measured at regular intervals. In both the normal and high bilirubin groups, minimum TSB values were recorded 4 h after the supper. A 24 h fast more than doubled TSB concentration from baseline values in both the normal and high bilirubin groups. A clinically relevant rise in TSB took place after 12 h into the fasting period (TSB of 17.3 mumol l‐1 in the fasted group vs 14.0 mumol l‐1 in the non‐fasted group). When designing a clinical trial, selecting volunteers, or judging the tolerance of a new drug, the rise in TSB caused by fasting must therefore be taken into account, particularly in trials where volunteers or patients fast before entering the study.
Relative bioavailability of a new oral form of cyclosporin A in patients with rheumatoid arthritis.
Authors: Van den Borne BE , Landewe RB , Goei The HS , Mattie H , Breedveld FC , Dijkmans BA
Published: July 2012

The relative bioavailability of cyclosporin A (CsA) from a new microemulsion oral formulation (NEO) and the currently used soft gelatine capsule (SGC) was determined at steady state in 12 patients with rheumatoid arthritis. The AUC(0,12 h) values of cyclosporin A were significantly greater after NEO than SGC (2873 +/‐ 848 ng ml‐1 h (mean +/‐ s.d.) vs 2355 +/‐ 1128 ng ml‐1 h; P = 0.02, 95% CI (confidence interval of the difference: 81 to 955 ng ml‐1 h). Cmax values were significantly higher after NEO than after SGC (811 +/‐ 244 ng ml‐1 vs 495 +/‐ 291 ng ml‐1, P < 0.0001, 95% CI of the difference: 209 to 422 ng ml‐1).
Methylprednisolone‐hemisuccinate and its metabolites in serum, urine and bile from two patients with acute graft rejection.
Authors: Lawson GJ , Chakraborty J , Tredger JM , Baylis EM
Published: July 2012

Methylprednisolone‐hemisuccinate (MPHS), methylprednisolone (MP), 20‐ alpha‐hydroxy‐ (20 alpha HMP) and 20‐beta‐hydroxymethyl‐prednisolone (20 beta HMP) concentrations were measured in serum, urine and bile from two liver transplant recipients who had received 1 g MPHS by a 1 h intravenous infusion for treatment of an acute rejection episode. These patients excreted similar total amounts of the dose in urine as patients with rheumatoid arthritis (historical controls) who had normal liver function. The transplant patients showed a ratio in urine of 'total metabolites'/MPHS that was one third that of patients with rheumatoid arthritis. Less than 0.2% of the administered MPHS appeared in bile as MPHS, MP, 20 alpha HMP and 20 beta HMP during the 24 h following infusion. Liver transplantation did not affect the overall elimination of drug in urine. However, the impaired liver function following transplantation resulted in reduced conversion of MPHS to its active form (MP).
Pharmacokinetics of piroximone after oral and intravenous administration to patients with renal insufficiency.
Authors: Fauvel JP , Bernard N , Laville M , Pozet N , Sassard J , Zech PY
Published: July 2012

The pharmacokinetics of piroximone (PI) were determined in patients with renal failure (inulin clearance less than 50 ml min‐1 per 1.73 m2) using two protocols: (a) 10 patients received a single i.v. infusion of 0.5 mg kg‐1 PI and the data were compared with those from seven healthy subjects receiving the same regimen; (b), a single oral dose of either 25 or 50 mg PI was given to 20 patients. PI concentrations were assayed by h.p.l.c. in plasma and urine over 48 h. After i.v. administration to healthy subjects PI was distributed rapidly and eliminated with a mean half‐life of 1.3 +/‐ 0.2 h. The urinary recovery of unchanged PI was 64% of the dose. In the patients the extent of renal elimination of PI was decreased (‐78%) in relation to the degree of renal insufficiency as assessed by inulin clearance (r = 0.97, P < 0.0001). Mean Cmax, AUC and t1/2,z values after i.v. infusion were increased by 47%, 127% and 77%, respectively, in comparison with healthy subjects. Similar results were obtained after oral administration. Until chronic dosing studies are undertaken, PI dosage should be adapted in relation to renal function.
Patient knowledge and prescription of ulcer healing drugs in medical inpatients.
Authors: Tham TC , Johnston S , Watson RG
Published: July 2012

If patients on ulcer healing drugs are ill‐informed about their medication or diagnosis their lack of knowledge may prejudice them from receiving potentially beneficial treatment, such as thrombolytic therapy, because of concern about upper gastrointestinal side effects. Furthermore because ulcer healing drugs are safe and effective there is a tendency to prescribe these drugs inappropriately. We therefore assessed patients' knowledge about their ulcer healing drugs and whether the prescriptions were appropriate or not. Consecutive patients on ulcer healing drugs admitted as emergencies to the general medical take‐in underwent a structured interview designed to assess knowledge of drugs prescribed prior to admission. Patient responses (fully correct, partially correct or incorrect) and appropriateness (appropriate, possibly appropriate or inappropriate) of the prescriptions were graded by reference to information obtained from hospital notes and/or general practitioner. Seventy‐nine out of a total of 537 patients (15%) were on ulcer healing drugs. Mean age was 64 years (range 26‐91). Fifty‐five (70%) of these patients could be analysed for correctness and 62 (78%) for the appropriateness. Patients gave an incorrect indication for 18% of ulcer healing drugs but only for 10% of non‐ulcer healing drugs (P < 0.05). Factors associated with a poorer knowledge of drugs overall, were increasing age and impaired mental test score but not the number of drugs the patient was taking. The trends were similar for ulcer healing drugs alone. Sixteen out of 62 (26%, 95% CI 16‐39%) prescriptions for ulcer healing drugs were deemed inappropriate. Our findings demonstrate a need for greater attention to patient education about drugs, especially ulcer healing drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of the behaviour pattern on the nocebo response of healthy volunteers.
Authors: Drici MD , Raybaud F , de Lunardo C , Iacono P , Gustovic P
Published: July 2012

The occurrence of a nocebo effect after placebo administration to healthy volunteers in a Phase I trial was analysed according to their type of personality (Bortner Rating Scale). More subjects with a behaviour pattern A (competitive and aggressive) (50%) described subjective side effects of the placebo than type B subjects (17%, P = 0.03). The volunteers who had nocebo effect had a higher Bortner score (BS) than did placebo non‐responsive subjects (P = 0.05). The BS was 205 for paramedical staff, 189 for medical and dentistry students, 173 for non‐science students and 161 for science students (P < 0.04). The nocebo response was not statistically correlated with professional status. These results suggest that volunteer's type of personality might influence the reporting of subjective symptoms after placebo, and therefore impair the evaluation of new drugs in Phase I clinical trials.
Attitudinal survey of adverse drug reaction reporting by medical practitioners in the United Kingdom [see comments]
Authors: Belton KJ , Lewis SC , Payne S , Rawlins MD , Wood SM
Published: July 2012

1. Attitudes of doctors to the Committee on Safety of Medicines' (CSM) adverse drug reaction (ADR) reporting scheme were investigated in order to assess their understanding of the purposes of the scheme and to identify reasons for failing to report suspected adverse drug reactions. 2. A postal questionnaire and letter of invitation were sent to 500 doctors who were randomly selected from the 1992 Medical Directory. A reminder letter and a second copy of the questionnaire were sent to non‐responders after 4 weeks. 3. 284 (57%) responded to the questionnaire. Of these, 179 (63%) stated that they had previously reported an ADR to the CSM or a pharmaceutical manufacturer. 77% of general practitioners stated that they had reported one or more ADRs compared with 55% of hospital doctors. 4. Reasons for under‐reporting included lack of time, lack of report forms and the misconception that absolute confidence in the diagnosis of an adverse reaction was important in the decision to send in a report. 5. An investigation of seven commonly proposed reasons for under‐reporting showed that on the whole they did not apply. 6. Most doctors knew the types of reactions that the Committee on Safety of Medicines seeks reports for but only 38% knew the precise meaning of the Committee on Safety of Medicines' black triangle symbol. There also seemed to be confusion about some of the purposes of the adverse drug reaction reporting scheme. 7. The number of reporting doctors is much higher than has previously been estimated.(ABSTRACT TRUNCATED AT 250 WORDS)
Psychoactive medication use, sensori‐motor function and falls in older women.
Authors: Lord SR , Anstey KJ , Williams P , Ward JA
Published: July 2012

1. A 1 year prospective study was undertaken to identify possible mediating physiological mechanisms for the association between psychoactive medication use and falls in 414 women aged 65 to 99 years (mean age 73.7 years, s.d. = 6.3) who were randomly selected from the community. 2. Women taking certain psychoactive medications showed impaired performance in a number of sensori‐motor measures, including tactile sensitivity, lower limb muscle strength, reaction time and balance control compared with women not taking these medications. Those using psychoactive medications were also comparatively inactive—taking part in only 1.1 h of planned exercise per week compared with 2.6 h for non‐users (F = 12.44, df = 1,412, P < 0.01). 3. Multiple logistic regression analysis revealed that use of long‐acting benzodiazepines (OR = 7.03, 95% CI = 2.12‐23.28) and antidepressants (OR = 2.84, 95% CI = 1.00‐8.02) was significantly associated with multiple falls, whilst adjusting for age, other drug category use, frequency of alcohol use, and number of medical conditions. Use of any two psychoactive medications was also significantly associated with falling frequency (Chi‐square = 13.91, df = 1, P < 0.01). 4. Path analysis revealed a significant direct association (P < 0.001) between psychoactive medication use and falls, and a significant indirect association mediated via reduced physiological functioning (P < 0.001). Postural hypotension was not significantly associated with falls (RR = 1.37, 95% CI = 0.84‐2.22). 5. The findings suggest that psychoactive medication use may predispose older people to falling by impairing important sensori‐motor systems that contribute to postural stability.
The opiate addiction test: a clinical evaluation of a quick test for physical dependence on opiate drugs.
Authors: Ghodse H , Taylor DR , Greaves JL , Britten AJ , Lynch D
Published: July 2012

1. Mydriasis (pupil dilation) in response to conjunctivally applied naloxone hydrochloride has been demonstrated using an innovative electronic binocular pupillometer in 40 opiate dependent patients, on maintenance methadone treatment. 2. No pupillary response to naloxone was seen when an identical procedure was carried out in a control population of 12 healthy volunteers. 3. After a baseline measurement of pupil size, two drops of naloxone hydrochloride were instilled into the conjunctival sac of one eye. Serial binocular pupillometry was then carried out at 5, 10, 15, 20, 25, 30, 35, 40 and 45 min post‐ instillation. 4. Discriminant analysis between the control and patient groups showed that the false negative rate (error of misclassification to the wrong population) was lowest (20%) at 40 min post‐eyedrop instillation, with no false positives in the control group. 5. The study has therefore shown an improvement in the previously reported false negative rate (25%) [1,2], of the conjunctival naloxone test of opiate dependence, with the use of our innovative electronic binocular pupillometer.
The effect of inhaled and oral dextromethorphan on citric acid induced cough in man.
Authors: Grattan TJ , Marshall AE , Higgins KS , Morice AH
Published: July 2012

1. Dextromethorphan is a widely used antitussive agent which is a non‐ narcotic codeine analogue. We have investigated whether inhaled administration of dextromethorphan provides antitussive activity in a citric acid induced cough model. 2. Twenty normal subjects underwent repeated cough challenge with 5% citric acid. Subjects were studied on six occasions. Study medication consisted of oral dextromethorphan 30 mg or oral matched placebo or 1, 3 and 30 mg inhaled dextromethorphan or matched inhaled placebo. Cough challenge was administered 10 min after study medication and hourly thereafter up to 250 min. 3. No significant differences were seen between baseline cough responses. Oral dextromethorphan (30 mg) produced a mean percentage reduction in cough of 38% (P < 0.002), which remained significant at 250 min. Inhaled dextromethorphan had no clinically significant effect although activity at later time points was not excluded. The antitussive effect of oral dextromethorphan is confirmed with prolonged inhibition of induced cough. It is possible that dextromethorphan or its active metabolites act centrally to inhibit the cough reflex.
Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study.
Authors: Wood R
Published: July 2012

1. We report a controlled retrospective cohort study of respiratory adverse reactions to ACE inhibitors. Bronchospasm and cough occurred at a higher rate in patients treated with ACE inhibitors, no links with sex, past history of bronchospasm, drug type or dose were found. 2. Cohorts of 1013 patients on angiotensin converting enzyme (ACE) inhibitors and 1017 patients on lipid lowering drugs (LLDs) were compared for the occurrence of new bronchospasm, relapse of previous bronchospasm, increase of current bronchospasm, and cough. 3. The prevalence of bronchospasm was 5.5% for patients on ACE inhibitors and 2.3% for patients on LLDs, P < 0.001. The relative risk of a bronchospasm adverse reaction for a patient on an ACE inhibitor compared with a patient on a LLD was 2.39, 95% confidence interval 1.47 to 3.90. 4. No ACE inhibitor specificity, or significant sex differences were found in the prevalence of bronchospasm or cough after correcting for bias implicit in the original cohorts. The bronchospastic reactions were not dose dependent. 5. The prevalence of a past history of bronchospasm in patients reporting ACE inhibitor‐ induced bronchospasm (16%) was not significantly different from the prevalence in patients on ACE inhibitors without an adverse reaction (13%), P = 0.447. 6. The prevalence of ACE inhibitor cohort cough was 12.3% and 2.7% in the patients on LLDs, P < 0.0001. Cough did not occur more commonly in patients on ACE inhibitors who had experienced any bronchospasm (28%) than in patients on LLDs with bronchospasm (27%).
Effect of dose adjustment on enalapril‐induced cough and the response to inhaled capsaicin.
Authors: Yeo WW , Higgins KS , Foster G , Jackson PR , Ramsay LE
Published: July 2012

1. In nine hypertensive patients with enalapril‐induced cough the effect of altering the dose of enalapril on subjective cough and the cough response to inhaled capsaicin was examined in a random single‐ blind balanced cross‐over study. They received three doses of enalapril, each for 3 weeks; the dose at entry (mean 10 mg daily); double this dose (mean 20 mg daily); and half this dose (mean 5 mg daily). 2. The cough response to inhaled capsaicin was also measured in two control groups: hypertensive patients on long‐term enalapril treatment with no cough (n = 18), and hypertensive patients taking nifedipine (n = 17). 3. In patients with enalapril‐induced cough there were significant dose‐responses for enalapril as regards severity of cough (P < 0.05) and night time waking by cough (P < 0.05), but not for frequency of cough. Although the cough was less severe (P < 0.02) and caused less night time waking (P < 0.03) on the lowest dose of enalapril (mean 5 mg daily) it did not disappear completely in any patient. 4. The sensitivity to inhaled capsaicin did not differ significantly on the three doses of enalapril. The relative potency of capsaicin on enalapril 20 mg compared with enalapril 5 mg was 1.0 (95% CI 0.4‐2.2). The wide confidence limits indicate that an important dose‐ dependent shift in capsaicin sensitivity is not excluded. 5. The sensitivity to inhaled capsaicin differed significantly between patients with enalapril‐induced cough and both control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.
Authors: Setiabudy R , Kusaka M , Chiba K , Darmansjah I , Ishizaki T
Published: July 2012

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4‐chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S‐mephenytoin of Indonesian origin. 2. The mean (+/‐ s.d.) values of the elimination half‐life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/‐ 3.1 vs 14.6 +/‐ 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/‐ 1.89 vs 3.68 +/‐ 0.83 (0.58 to 2.91) micrograms ml‐1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time‐ course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/‐ 0.13 vs 0.88 +/‐ 0.50 (‐0.14 to 0.96) micrograms ml‐ 1 h). 4. Log10 percentage urinary recovery of 4'‐hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = ‐0.661) and AUC (rs = ‐0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'‐ hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = ‐0.876), PG/CPB (rs = ‐0.833) and PG/(CG + CPB) (rs = ‐ 0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)
Population pharmacodynamics of romazarit.
Authors: Holford NH , Williams PE , Muirhead GJ , Mitchell A , York A
Published: July 2012

1. The response to romazarit, a disease modifying anti‐rheumatoid agent, was observed in patients with rheumatoid arthritis (RA) in a double‐blind placebo controlled study. 2. Two hundred and twenty‐four patients were recruited from 11 centres and treated with placebo or romazarit at a dose of 200 mg or 450 mg every 12 h for up to 24 weeks. Disease activity was measured using the Ritchie Index (RI). Plasma concentrations of romazarit were measured at each of up to eight assessments of RI. 3. The effect of romazarit was examined using analysis of variance (ANOVA) in 164 patients who contributed 61% of observations of disease activity. Observations after 12 weeks of treatment were excluded from ANOVA. 4. A population pharmacokinetic‐ dynamic model for the time course of disease progress and the response to placebo and romazarit was used to describe observations from all patients. 5. The population model suggested that the effect of romazarit was on the rate of progress of the disease and was describable by an Emax model. Concentration was a better predictor of response than dose. 6. Romazarit was significantly better than placebo in improving the RI in patients with RA. The placebo efficacy of romazarit treatment was similar to that associated with placebo treatment. 7. The population model provided a more complete description and explanation of the clinical pharmacology and therapeutic potential of romazarit than ANOVA.
The potentiation of adrenaline‐induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.
Authors: Alarayyed NA , Graham BR , Prichard BN , Smith CC
Published: July 2012

1. Aggregation in platelet‐rich plasma from normotensive men was induced by adrenaline (0.25‐16 microM), ADP (0.25‐16 microM), collagen (0.25‐8 micrograms ml‐1) or serotonin (10 microM) alone, or by previously sub‐threshold concentrations of adrenaline (0.03‐1 microM) in combination with sub‐threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml‐1). The effects of the alpha 1‐adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose‐response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin‐induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose‐response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline‐induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose‐ dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of oral sumatriptan, a 5‐HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man.
Authors: Entwisle SJ , Fowler PA , Thomas M , Eckland DJ , Lettis S , York M , Freedman PS
Published: July 2012

1. The effects of oral sumatriptan (50, 100 and 200 mg), a 5‐HT1 receptor agonist, and placebo, on circulating adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined over 24 h after dosing, in 26 healthy male subjects. ACTH was measured by immunoradiometric assay and cortisol by radioimmunoassay. 2. After sumatriptan all subjects displayed a normal diurnal rhythm for circulating ACTH and cortisol compared with placebo. 3. There was a reduction in the trough circulating ACTH concentration over 0‐4 h which was 18% with 100 mg (P = 0.002), and 25% with 200 mg (P < 0.001). The 5 h, post‐prandial, peak ACTH concentration was reduced by 21% with 100 mg (P = 0.018) and by 20% with 200 mg (P = 0.024). The weighted mean ACTH over 24 h was reduced by 8% with 100 mg (P = 0.029) and by 8% with 200 mg (P = 0.018). The nadir concentration of ACTH over the 24 h and the ACTH concentration 24 h after sumatriptan were not, however, significantly reduced. All results are compared with placebo. 4. There was a reduction in the trough circulating cortisol concentration over 0‐ 4 h which was 15% with 50 mg (P = 0.015), 14% with 100 mg (P = 0.022) and 24% with 200 mg (P < 0.001). The 5 h, post‐prandial, peak cortisol concentration was reduced by 16% with 100 mg (P = 0.012) and by 15% with 200 mg (P = 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)
A comparative study of acute and subchronic effects of dothiepin, fluoxetine and placebo on psychomotor and actual driving performance.
Authors: Ramaekers JG , Muntjewerff ND , O'Hanlon JF
Published: July 2012

1. The acute and subchronic effects of dothiepin 75‐150 mg and fluoxetine 20 mg on critical fusion frequency (CFF), sustained attention and actual driving performance were compared with those of placebo in a double‐blind, cross‐over study involving 18 healthy volunteers. Drugs and placebo were administered for 22 days in evening doses. Fluoxetine doses were constant but dothiepin doses increased on the evening of day 8. Performance was assessed on days 1, 8 and 22 of each treatment series. Subjective sleep parameters and possible side effects were recorded on visual analogue scales on alternate treatment days. 2. Dothiepin reduced sustained attention on day 1 by 6.7% (95% confidence interval (C1): ‐12.0 to ‐1.3%) and CFF on day 22 by 1.1 (CI: ‐2.2 to ‐0.1) Hz. Fluoxetine reduced sustained attention days 1, 8 and 22 of treatment by 7.4, 6.7 and 6.5% respectively (CI: ‐11.3 to ‐3.6; ‐ 14.3 to ‐1.5 and ‐9.5 to ‐3.4). CFF decreased linearly over days during fluoxetine treatment and significantly differed from placebo on day 22 with 1.2 Hz (CI: ‐2.3 to ‐0.2). Neither drug significantly affected driving performance. Whilst receiving dothiepin, subjects complained of drowsiness on days 1‐3 of treatment (mean rank 5.6; CI: 2.0 to 9.2) and slept 43 min longer (CI: 8.2 to 76.2).(ABSTRACT TRUNCATED AT 250 WORDS)
Glutathione S‐transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.
Authors: Green VJ , Pirmohamed M , Kitteringham NR , Knapp MJ , Park BK
Published: July 2012

1. Tacrine (1,2,3,4‐tetrahydro‐9‐aminoacridine) which is used in Alzheimer's disease, causes elevation of liver transaminases ('tacrine transaminitis') in 40‐50% of patients. This may be related to the formation of a chemically reactive metabolite from tacrine, which can be detoxified in vitro by glutathione. 2. Glutathione‐S‐transferase mu (GSTM1), a detoxication enzyme, is polymorphically expressed being absent in about 50% of patients. Its role in the detoxication of the reactive metabolite of tacrine is not known. 3. The frequency of the enzyme deficiency (GSTM1*0) has been investigated in patients with tacrine transaminitis using polymerase chain reaction (PCR) to determine whether the GSTM1 status can be used as an absolute predictive factor for susceptibility to tacrine transaminitis. 4. The frequency of the GSTM1*0 genotype in patients with tacrine transaminitis (n = 33; 45.5%) was not significantly different from that in patients treated with tacrine without liver dysfunction (n = 37; 43%), and when compared with all the controls used in the study (n = 167; 56%). 5. The frequency of the GSTM1*0 genotype in patients with Alzheimer's disease (n = 79; 46%) was not significantly different from that in healthy volunteers (n = 121; 59.5%). 6. Our results indicate that the GSTM1 status cannot be used clinically to predict individual susceptibility to tacrine transaminitis, and that patients with the GSTM1*0 genotype are unlikely to have an increased risk of tacrine‐ induced liver damage. Furthermore, the GSTM1 status was not associated with Alzheimer's disease.
Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms—a population study.
Authors: Madsen H , Nielsen KK , Brosen K
Published: July 2012

1. Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2‐hydroxy‐imipramine and 2‐hydroxy‐ desipramine was assayed by h.p.l.c. 2. The medians of the hydroxylation ratios (i.e. 2‐hydroxy‐metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EMs) as compared with 27 poor metabolizers (PMs), but none of the ratios separated the two phenotypes completely. 3. There were 324 EM of mephenytoin (EMM) and three PM (PMM) in the sample. The demethylation ratios between desipramine, 2‐hydroxy‐desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's rs: ‐ 0.20 and ‐0.27, P < 0.05). 4. The demethylation ratios were higher in 80 smokers than in 245 non‐smokers. This indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N‐demethylation of imipramine. 5. CYP2D6 genotyping was carried out by PCR in 325 of the subjects, and the D6‐wt allele was amplified in 298 EMs, meaning that they were genotyped correctly. One PMs was D6‐wt/D6‐B, another PMs had the genotype D6‐wt/ and hence both were misclassified as EMs. The remaining 25 PMs were D6‐A/D6‐B (n = 5), D6‐B/ (n = 18) or D6‐D/D6‐D (no PCR amplification, n = 2).(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption of clonazepam after intranasal and buccal administration.
Authors: Schols‐Hendriks MW , Lohman JJ , Janknegt R , Korten JJ , Merkus FW , Hooymans PM
Published: July 2012

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross‐over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/‐ 1.0 ng ml‐1 (mean; +/‐ s.d.) was measured 17.5 min (median) (range 15‐20 min) after intranasal administration. A second peak (4.6 +/‐ 1.3 ng ml‐1) caused by oral absorption was seen after 1.7 h (range 0.7‐3.0 h). After buccal administration a Cmax of 6.0 +/‐ 3.0 ng ml‐1 was measured after 50 min (range 30‐90 min) with a second peak of 6.5 +/‐ 2.5 ng ml‐1 after 3.0 h (range 2.0‐4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/‐ 18 ng ml‐1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.
Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma.
Authors: Corlett SA , Parker D , Chrystyn H
Published: July 2012

Ifosfamide is a chiral pro‐drug which is administered clinically in its racemic form. Serum concentrations of rac‐ifosfamide and its enantiomers were measured in 12 patients with lung carcinoma following a mean (+/‐ s.d.) intravenous dose of 4.2 (0.83) g infused over 1 h. The mean (+/‐ s.d.) volumes of distribution (VSS) of rac, (R)‐ and (S)‐ ifosfamide were 0.61 (0.17), 0.60 (0.16) and 0.61 (0.19) l kg‐1, respectively. The mean (+/‐ s.d.) half‐lives and clearances were 6.57 (1.69), 7.12 (1.92) and 5.98 (1.52) h and 0.065 (0.013), 0.060 (0.013) and 0.072 (0.014) l h‐1 kg‐1 for rac, (R)‐ and (S)‐ifosfamide, respectively. The half‐life of (S)‐ifosfamide was significantly (P < 0.001) shorter than that of (R)‐ifosfamide and it had a significantly higher clearance (P < 0.001). There was no significant difference in the volumes of distribution of the enantiomers. The clinical significance of the faster elimination of (S)‐ifosfamide is not known.
Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6‐mercaptopurine and azathioprine.
Authors: Szumlanski CL , Weinshilboum RM
Published: July 2012

Thiopurine drugs are used in the treatment of inflammatory bowel disease—as are sulphasalazine and its metabolite 5‐aminosalicylic acid (ASA). S‐Methylation catalyzed by thiopurine methyltransferase (TPMT) is a major pathway in the metabolism of thiopurines. The hypothesis was tested that TPMT might be inhibited by sulphasalazine or isomers of ASA. Sulphasalazine as well as 3‐, 4‐ and 5‐ASA inhibited recombinant human TPMT, with IC50 values of 78, 99, 2600 and 1240 microM, respectively. Kinetic studies demonstrated that the inhibition of TPMT by sulphasalazine and ASA isomers was non‐competitive with regard to the thiopurine substrate, 6‐MP, and was uncompetitive with regard to the methyl donor for the reaction, S‐adenosyl‐L‐methionine. Our observations raise the possibility of a clinically significant drug‐ drug interaction in patients treated simultaneously with sulphasalazine and thiopurine drugs.
Effects of different antihypertensive drugs on plasma fibrinogen in hypertensive patients.
Authors: Fogari R , Zoppi A , Malamani GD , Marasi G , Vanasia A , Villa G
Published: July 2012

1. In order to evaluate whether treatment with different antihypertensive drugs would affect plasma fibrinogen levels, 118 mild to moderate essential hypertensive subjects, all males, aged 18 to 65 years, were randomly treated with amlodipine 10 mg, atenolol 100 mg, hydrochlorothiazide 25 mg or lisinopril 20 mg, all given once daily for 8 weeks. 2. Before and after 8 weeks' treatment, blood pressure (BP), heart rate (HR), fibrinogen, total cholesterol (TC), HDL‐C, LDL‐C, triglycerides (TG), plasma glucose, plasma uric acid, serum creatinine and serum potassium were evaluated. 3. All four medications significantly reduced BP values, although the BP lowering effect of lisinopril, amlodipine and atenolol was significantly greater compared with that of hydrochlorothiazide. 4. Plasma fibrinogen levels were unaffected by atenolol, hydrochlorothiazide and amlodipine, whereas they were significantly decreased by lisinopril (‐11.2%, P = 0.002). This fibrinogen lowering effect was more evident in smokers (‐17.7%) than in non smokers (‐7.4%). 5. Atenolol and amlodipine did not significantly affect plasma lipids, hydrochlorothiazide increased TC, LDL‐C and TG and reduced HDL‐C; lisinopril increased HDL‐C and decreased TC and LDL‐C. 6. Hydrochlorothiazide increased plasma glucose and uric acid concentrations, which were unaffected by the other drugs. The diuretic also reduced serum potassium. 7. The results of this study indicate that lisinopril reduces levels of plasma fibrinogen and confirm that different antihypertensive drugs may elicit different metabolic effects, which may variously influence the overall risk profile of the hypertensive patients.
Antagonism of the effects of clonidine by the alpha 2‐adrenoceptor antagonist, fluparoxan.
Authors: Johnson MA , Blackwell CP , Smith J
Published: July 2012

1. The effects of fluparoxan, an alpha 2‐adrenoceptor antagonist, on the pharmacodynamic changes induced by clonidine were investigated in this placebo‐controlled, double‐blind, two‐period, cross‐over study in 16 healthy male volunteers (aged 19 to 44 years). 2. Subjects received either fluparoxan or placebo, twice‐daily for 5 1/2 days (11 doses). One hour after the first and last dose of each treatment period, clonidine (200 micrograms) was infused intravenously over 5 min. 3. Indices of clonidine‐mediated pharmacodynamic responses (growth hormone secretion, bradycardia, hypotension, xerostomia and sedation) were taken before and after clonidine infusion. Growth hormone secretion was assessed by quantifying serum growth hormone concentrations; sedation was assessed by both visual analogue scales (VAS) and by a visual psychomotor response meter, measuring critical flicker fusion (CFF). 4. The majority of subjects reported minor adverse events such as lethargy, headache and dry mouth following clonidine infusion. All adverse events were likely to be related to clonidine, as they occurred consistently between treatment groups. Fluparoxan has, however, in previous studies been reported to cause headache and light‐headedness. 5. Prior to the clonidine infusion, fluparoxan caused small but statistically significant increases in systolic blood pressure (4 mm Hg) and salivary flow (approximately 30%) after both single and repeated doses. A small increase in heart rate (2 beats min‐1) was seen after a single dose which was also statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
The interaction of the calcium antagonist RO 40‐5967 with digoxin.
Authors: Siepmann M , Kleinbloesem C , Kirch W
Published: July 2012

1. The interaction of the newer calcium antagonist Ro 40‐5967 with digoxin was investigated in 42 healthy subjects under steady state conditions. 2. After an adequate loading dose digoxin 0.375 mg once daily was given alone for 1 week. Afterwards three different doses (50, 100, 150 mg daily) of the calcium antagonist Ro 40‐5967 were administered to three groups of 14 subjects each for 1 week concurrently with digoxin 0.375 mg daily. 3. Ro 40‐5967 led to an increase of mean maximum digoxin plasma concentrations (Cmax) and AUC. For AUC this effect was significantly dose‐dependent. 4. Increasing doses of the calcium antagonist led to a stepwise rise of the PQ‐time in ECG. 5. A slight fall of heart rate was seen after a 7 day treatment of digoxin alone. This effect was more pronounced when Ro 40‐5967 was added to the medication. No significant changes of stroke volume and blood pressure were noted. 6. In conclusion Ro 40‐5967 led to a significant elevation of the plasma concentration‐time curve (AUC) of digoxin. This effect was dose‐dependent.
Influence of the dosing interval on prolactin release after remoxipride.
Authors: Movin‐Osswald G , Hammarlund‐Udenaes M , von Bahr C , Eneroth P , Walton‐Bowen K
Published: July 2012

1. The prolactin response following administration of the D2‐dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of remoxipride. A further aim was to compare the prolactin response following remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.
The negative inotropic and chronotropic effects of intravenous R 56865 during percutaneous transluminal coronary angioplasty.
Authors: Pijl AJ , Van Wezel HB , Koolen JJ , Piek JJ , Koch K , Swaan A , David GK , Visser CA , Van Zwieten PA
Published: July 2012

The present study was designed to evaluate the potential anti‐ischaemic activity of R 56865 in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) was obtained. In addition, left ventricular pressure and contractility parameters were measured. These parameters were also measured before and after additional balloon inflations, preceded by placebo and R 56865 i.v. R 56865 was infused intravenously at three different dosages, namely: 20 mg (n = 8), 30 mg (n = 2), 40 mg (n = 2). No significant differences were observed between placebo and R 56865 (20 mg) concerning time to onset and duration of ST‐segment changes and symptomatic angina pectoris, respectively. The other parameters did not show differences compared with the baseline values when R 56865 (20 and 30 mg) was infused. However, the two patients receiving a dose of 40 mg R 56865 developed a dramatic decrease in systolic and diastolic blood pressure, left ventricular (LV) systolic pressure, peak positive dP/dt and the CSBF (ranging from 30‐50%), while the LV end‐diastolic pressure increased by 100%. The two patients who received this dose became pale and cyanotic and did not respond to verbal commands. In summary, no anti‐ischaemic effects of R 56865 were observed under these conditions, whereas at the highest dose (40 mg) R 56865 induced hypotension and a reduction in cardiac contractile force.
The role of the renin‐angiotensin and natriuretic peptide systems in the pulmonary vasculature.
Authors: Cargill RI , Lipworth BJ
Published: July 2012

1. The role of vasoactive peptide systems in the pulmonary vasculature has been studied much less extensively than systemic vascular and endocrine effects. The current understanding of the role of the renin‐ angiotensin (RAS) and natriuretic peptide systems (NPS) in the pulmonary circulation is therefore reviewed. 2. Plasma concentrations of angiotensin II, the main vasoactive component of the RAS, are elevated in pulmonary hypertension and may interact with hypoxaemia to cause further pulmonary vasoconstriction. Pharmacological manipulation of angiotensin II can attenuate hypoxic pulmonary vasoconstriction but larger studies are needed to establish the efficacy of this therapeutic strategy in established pulmonary hypertension. 3. Although all the known natriuretic peptides, ANP, BNP and CNP are elevated in cor pulmonale, only ANP and BNP appear to have pulmonary vasorelaxant activity in humans. ANP and BNP can also attenuate hypoxic pulmonary vasoconstriction, suggesting a possible counter‐regulatory role for these peptides. Inhibition of ANP/BNP metabolism by neutral endopeptidase has been shown to attenuate development of hypoxic pulmonary hypertension but this property has not been tested in humans. 4. It is also well established that there are potentially important endocrine and systemic circulatory interactions between the RAS and NPS. This also occurs in the pulmonary circulation and in humans, where at least BNP acts to attenuate angiotensin II induced pulmonary vasoconstriction. This interaction may be particularly relevant as a mechanism to counter‐regulate overactivity of the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)
The dose dependency of the alpha‐ and beta‐adrenoceptor antagonist activity of carvedilol in man.
Authors: Tham TC , Guy S , McDermott BJ , Shanks RG , Riddell JG
Published: July 2012

1. The alpha‐ and beta‐adrenoceptor antagonist activity of carvedilol, a beta‐adrenoceptor antagonist with vasodilating properties, and labetalol were investigated in 10 healthy male subjects. They received infusions with serially increasing concentrations of isoprenaline and phenylephrine before and after single oral doses of carvedilol 6.25, 12.5 and 25 mg, labetalol 400 mg and placebo at weekly intervals in a double‐blind randomised manner. An exercise step test was performed at the end of the infusions. 2. The dose of isoprenaline required to increase heart rate by 25 beats min‐1 (I25) and the dose of phenylephrine required to increase systolic and diastolic blood pressure by 20 mm Hg (PS20 and PD20) were calculated using a quadratic fit to individual dose‐response curves. Comparisons were made with placebo and P < 0.05 was considered significant. 3. The I25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I25 were: carvedilol 6.25 mg 2.1 +/‐ 1.6, carvedilol 12.5 mg 3.1 +/‐ 1.9, carvedilol 25 mg 6.4 +/‐ 4.9 and labetalol 400 mg 8.8 +/‐ 4.4. 4. The PS20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: carvedilol 6.25 mg 1.0 +/‐ 0.2; 12.5 mg, 1.2 +/‐ 0.2; 25 mg, 1.3 +/‐ 0.4 and labetalol 400 mg 2.2 +/‐ 0.8. 5. The PD20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PD20 were: carvedilol 6.25 mg 1.1 +/‐ 0.3; 12.5 mg, 1.3 +/‐ 0.3; carvedilol 25 mg 1.3 +/‐ 0.4 and labetalol 400 mg 2.1 +/‐ 0.8.(ABSTRACT TRUNCATED AT 250 WORDS)
Postextrasystolic potentiation in patients with ischaemic heart disease: influence of inotropic agents.
Authors: Zhang YI , Ritchie RH , Horowitz JD
Published: July 2012

1. The extent of postextrasystolic potentiation (PESP) has been considered a useful parameter for evaluating myocardial contractile reserve in the presence of myocardial stunning or hibernation. Extent of PESP appears to reflect an interaction between myofibrillar calcium concentration and function of the contractile apparatus. However, potential for cardiovascular drugs including agents modifying adenosine 3' 5'‐cyclic monophosphate concentration to influence the extent of PESP in man has not been extensively studied. 2. In 35 patients undergoing diagnostic coronary angiography, we investigated the relationship between the extrasystolic test pulse interval (ETPI) and left ventricular (LV) +dP/dtmax of a postextrasystolic contraction. The influence of three inotropically active agents on this relationship was examined following intravenous bolus injection (metoprolol, 4 mg; sotalol, 20 mg; and milrinone, 1 mg). 3. The patient group examined had predominantly preserved LV function (LVEF 67% with 95% confidence intervals 63%, 71%). In the doses utilized, all agents exerted significant effects on LV+dP/dtmax during atrial pacing: reduction of 12.3% (6.4, 18.2) for metoprolol (P < 0.0005), and 10.9% (4.2, 17.6) for sotalol (P < 0.005); and increase of 11.8% (1.3, 22.3) for milrinone (P < 0.05). 4. With the postextrasystolic interval identical to baseline pacing cycle length, postextrasystolic potentiation of LV+dP/dtmax varied inversely with ETPI. None of the three agents investigated significantly affected this relationship. 5. These results demonstrate that the extent of PESP is unaffected by 'pure' beta‐ adrenoceptor antagonism, (+/‐)‐sotalol or phosphodiesterase inhibition in man. Hence pharmacotherapy with these agents is unlikely to affect assessment of extent of PESP.