bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of preincubation with cimetidine on the N‐hydroxylation of dapsone by human liver microsomes.
Authors: Tingle MD , Coleman MD , Park BK
Published: July 2012

We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon chambers are separated by a semi‐ permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/‐ NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0‐1000 microM) and NADPH prior to the addition of dapsone (100 microM) and NADPH (1 mM) resulted in a concentration‐dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/‐ 47 to 40 +/‐ 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration‐dependent reduction in methaemoglobin measured (from 7.1 +/‐ 0.7 to 3.5 +/‐ 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone‐dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.
Lack of effect of flosequinan on the pharmacokinetics of theophylline.
Authors: Kamali F. , Edwards C. , Rawlins MD
Published: July 2012

The pharmacokinetics of theophylline (240 mg) p.o. were studied before and after the administration of oral flosequinan for 14 days in 21 healthy volunteers using a randomised cross‐over design. Comparisons of Cmax, tmax, AUC, CL of theophylline and urinary recovery of the parent drug and metabolites showed that flosequinan had no significant effect on the disposition of theophylline.
COMT inhibition with nitecapone does not affect the tyramine pressor response.
Authors: Sundberg S. , Gordin A.
Published: July 2012

Nitecapone (OR‐462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine‐induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20‐32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine‐induced catecholamine release.
Effects of age, sex and the oral contraceptive on the platelet membrane fibrinogen binding site (glycoprotein IIb/IIIa).
Authors: Cahill M , Mistry R , Chapman C , Wood JK , Barnett DB
Published: July 2012

1. We have studied the effects of age, sex and the oral contraceptive pill on platelet fibrinogen ‘receptor’ density (Bmax) and affinity (Kd). 2. [125I]‐fibrinogen binding to gel‐filtered platelets was assessed after stimulation with adenosine 5‐diphosphate (ADP) and thrombin in 60 normal subjects; 37 females and 23 males. 3. For both agonists there was no significant difference in Bmax or Kd between the sexes. A trend towards increasing affinity (reduced Kd) with age was noted in the female group following ADP stimulation. This was not considered to be physiologically relevant. In the group as a whole no significant relationship of Bmax and Kd with age was demonstrated. 4. A further group of eight women taking low dose oestrogen combined oral contraceptive pill were studied on days 7, 14, 21 and 28 of the treatment cycle and compared with eight women with regular ovulatory cycles. No significant variations in Bmax or Kd were detected within or between cycles in these two groups.
Gastrointestinal blood loss after non‐steroidal anti‐inflammatory drugs. Measurement by selective determination of faecal porphyrins.
Authors: Cohen A , Boeijinga JK , van Haard PM , Schoemaker RC , van Vliet‐Verbeek A
Published: July 2012

1. A method for the detection of gastrointestinal blood loss based upon the selective measurement of faecal porphyrins was tested in two studies in healthy volunteers. 2. In the first study subjects (n = 6) received intragastric autologous blood (saline, 2 and 6 ml as a single dose) resulting in a dose dependent increase in faecal porphyrins. 3. In a subsequent placebo controlled cross over study in 12 subjects acetylsalicylic acid (ASA), nabumetone (a new NSAID) or placebo were administered for 5 days with a washout period of 9 days. They were no dietary restrictions. 4. All faeces were collected during the treatment period and both the full faecal homogenate and a random faecal sample were analyzed for deutero‐ and pemptoporphyrin content by h.p.l.c. Additionally a benzidine reaction was performed. 5. There was a highly significant correlation (r = 0.95) between the values obtained from random samples and the full homogenate. ASA increased the faecal porphyrin excretion (P less than 0.001) compared with placebo in contrast to nabumetone. Complaints of dyspepsia were most common after ASA. 6. Measurement of faecal porphyrins is useful for monitoring NSAID induced upper gastrointestinal blood loss and lacks some of the practical constraints of other methods.
Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.
Authors: Quiding H , Olsson GL , Boreus LO , Bondesson U
Published: July 2012

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6‐10 months old) received a 4 mg suppository and four children (3‐4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l‐1 in the younger and 309, 251 and 169 nmol l‐1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l‐1 and 6.8, 5.5 and 2.8 nmol l‐1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6‐hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half‐lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half‐lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O‐demethylating codeine to morphine.
The influence of an academic representative on prescribing by general practitioners.
Authors: Newton‐Syms FA , Dawson PH , Cooke J , Feely M , Booth TG , Jerwood D , Calvert RT
Published: July 2012

1. The effect of providing information about medicines by a short ‘sales’ interview between individual general practitioners and an ‘academic representative’ on prescribing was investigated. 2. The promotional campaign was designed to encourage a rational approach to prescribing of non‐steroidal anti‐inflammatory agents in an intervention group of 101 general practitioners selected at random from the Leeds Family Practitioner Committee (FPC). The remaining general practitioners in the Leeds FPC acted as a reference group. 3. The prescribing data for each group for 5 months immediately prior to and 5 months following intervention were compared. 4. Intervention produced a significant increase (P less than 0.005) in the prescribing cost of ibuprofen, the non‐steroidal promoted as first choice agent, which was sustained for at least 5 months. 5. Prescribing of the second choice agent, piroxicam, decreased in the reference group but not in the intervention group. 6. There was a decrease in the average prescribing cost of pounds 6.60 per doctor per month in the intervention group compared with the reference group.
Increases in plasma beta‐endorphin concentrations during exercise do not contribute to increases in heart rate following autonomic blockade in man.
Authors: Shen A , Chin J , Fullerton M , Jennings G , Dart A
Published: July 2012

1. Intrinsic heart rate (IHR: heart rate following autonomic blockade with atropine and propranolol) increases with exercise. The opioid antagonist naloxone has been shown to decrease IHR at rest, raising the possibility that increases in IHR with exercise are beta‐endorphin related, since beta‐endorphin concentrations have also been shown to rise during exercise. 2. We examined the effects of naloxone (10 mg) on IHR and plasma beta‐endorphin levels during aerobic exercise in eight healthy, male subjects in a single blind, crossover study. 3. IHR increased with 25 min bicycling from 97.1 +/‐ 1.4 to 129.7 +/‐ 1.2 beats min‐1 (mean +/‐ s.e. mean). This rise was not affected by administration of naloxone. 4. Plasma beta‐endorphin concentration rose from 31.1 +/‐ 3.8 to 94.9 +/‐ 23.9 pg ml‐1 after 25 min exercise. This exercise‐induced rise in beta‐endorphin concentration was further increased (P less than 0.05) in the presence of naloxone. 5. Our results confirm a rise in IHR and beta‐endorphin concentrations with acute exercise but indicate that the changes in IHR are not endorphin‐ related.
Norfloxacin interaction with antacids and minerals.
Authors: Campbell NR , Kara M , Hasinoff BB , Haddara WM , McKay DW
Published: July 2012

The urinary excretion of norfloxacin was measured in eight healthy volunteers after its co‐administration with a variety of over‐the‐ counter preparations, each containing a different metal ion. Commonly used doses of ferrous sulphate, zinc sulphate, aluminium hydroxide and magnesium hydroxide reduced the 24 h urinary excretion of norfloxacin by 50 to 90%. Bismuth subsalicylate had no significant effect. In vitro experiments demonstrated the formation of complexes between norfloxacin and iron, zinc, aluminium, and magnesium ions, respectively. Many pharmaceuticals contain the same metal ions that caused significant interactions with norfloxacin. The efficacy of norfloxacin treatment may be compromised when it is taken concurrently with preparations containing these metal ions.
Lack of effect of ageing on the stereochemical disposition of propranolol.
Authors: Zhou HH , Whelan E , Wood AJ
Published: July 2012

The elderly are more resistant to the effects of propranolol than the young. To determine whether the decreased sensitivity in the elderly could be due to stereoselective alteration in propranolol metabolism, we investigated the effect of age on the oral clearance of (‐)‐ and (+)‐ propranolol. Six young (aged 24‐32, mean 27.3 +/‐ 1.3 years) and six elderly (65‐80, mean 71.3 +/‐ 2.7 years) white male volunteers were given a single 80 mg oral dose of racemic propranolol. The mean peak plasma concentrations of both (+)‐ and (‐)‐propranolol were significantly higher (P less than 0.05) in the elderly (105.7 +/‐ 19.7 and 165.0 +/‐ 29.7 nmol l‐1) compared with the young subjects (68.6 +/‐ 10.1 and 115.7 +/‐ 18.1 nmol l‐1). The oral clearances of both (+)‐ and (‐)‐propranolol were significantly higher (P less than 0.05) in the young (6933 +/‐ 598 and 4554 +/‐ 372 ml min‐1) than in the elderly (4548 +/‐ 712 and 2941 +/‐ 473 ml min‐1). Age had no effect on the relative concentration of the two isomers. Thus, the ratio of (+)‐ propranolol to (‐)‐propranolol was 0.67 +/‐ 0.05 in the young compared with 0.65 +/‐ 0.02 in the elderly.
The disposition of oral and intramuscular pyrimethamine/sulphadoxine in Kenyan children with high parasitaemia but clinically non‐severe falciparum malaria.
Authors: Winstanley PA , Watkins WM , Newton CR , Nevill C , Mberu E , Warn PA , Waruiru CM , Mwangi IN , Warrell DA , Marsh K
Published: July 2012

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg‐1, sulphadoxine 25 mg kg‐1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine‐resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration‐time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.
Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects.
Authors: Winstanley PA , Newton CR , Pasvol G , Kirkham FJ , Mberu E , Peshu N , Ward SA , Were JB , Warrell DA , Marsh K
Published: July 2012

1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l‐1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l‐1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/‐ 24 h (mean +/‐ s.d.), and 33 +/‐ 21 h, respectively. 4. In an open, dose‐finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg‐1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg‐1 should be studied.
Lisinopril and nifedipine administration inhibits the ex vivo uptake of [45Ca2+] by platelets from hypertensive diabetic patients.
Authors: Gill J , Fonseca V , Dandona P , Jeremy JY
Published: July 2012

1. The effect of administration of the angiotensin converting enzyme inhibitor (ACEI), lisinopril (Carace; 10‐40 mg twice daily) and the calcium channel blocker, nifedipine (Adalat Retard; 20‐40 mg twice daily) on ex vivo [45Ca2+] uptake by platelets from hypertensive diabetic (type 1 and 2) patients was investigated. 2. At the end of at least 3 months treatment, blood was collected prior to the patient taking the morning dose of medication and washed platelets prepared. [45Ca2+] uptake was monitored following the addition of adrenaline, isoprenaline and dibutyryl cAMP (dbcAMP), as well as in unstimulated (zero) platelets. 3. Both nifedipine and lisinopril significantly inhibited the ex vivo uptake of [45Ca2+] by platelets when this process was stimulated by adrenaline, isoprenaline and dibutyryl cAMP. Basal uptake was also inhibited in both groups. 4. These data consolidate the hypothesis that ACE inhibitors may possess calcium channel/calcium mobilisation blocking properties. Apart from its hypertensive action, lisinopril may also reduce platelet activity via modulation of calcium dynamics, thereby reducing the incidence of vascular complications associated with diabetes mellitus.
Effect of captopril on functional, physiological and biochemical outcome criteria in aged heart failure patients.
Authors: O'Neill CJ , Charlett A , Dobbs RJ , Deshmukh AA , Bowes SG , Weller C , Nicholson PW , Milledge JS , Dobbs SM
Published: July 2012

1. Captopril was evaluated as an adjuvant to diuretic and digoxin therapy in heart failure in old age, using walking ability, minute ventilation and oxygen consumption and plasma atrial natriuretic factor (ANF) concentration as measures of outcome. 2. Twenty patients, mean (s.d.) age 81 (6) years, entered a double‐blind, randomised, crossover study of three treatments, a twice daily regimen of captopril (AA), at a dosage established by titration against serum angiotensin converting enzyme (ACE) activity, the same dosage in the morning with placebo at night (AP), and twice daily placebo (PP). Each treatment lasted 3 weeks. A 2 week run‐in period on triple therapy, with AA captopril, was used to assess stability and compliance. Seventeen completed all treatments: three completed two. 3. Any benefit of captopril was modest and there was deterioration in gait on the titrated dosage 3 months afterwards (P = 0.04). Efficacy in the old may be greatest when the titrated dose (25 or 50 mg) is given once daily: the multiple daily doses recommended may be unnecessarily demanding. 4. Walking performance was measured by gait analysis (GA) at free walking speed and by a simple walking test (SWT), in which patients stopped at the first relevant symptom. There was a consistent tendency for four measures of performance (GA: speed, stride length and double support time; SWT distance) to be best on the AP treatment, next best on AA, and worst on PP but for the fifth, SWT speed, AP and AA were similar. The trend appeared most marked for SWT distance, mean (s.e. mean) values for AP, AA and PP being 123 (15), 94 (16) and 75 (16) m, respectively. However, the treatment effect did not reach statistical significance at the 0.05 level. 5. There was no significant difference between treatments in minute ventilation, minute oxygen consumption, or their ratio, either at rest or on exercise. 6. Resting ANF concentrations were nearly four times higher (P = 0.0001) in the patients than those, mean (s.e. mean) 66 (5) pmol l‐1, in eleven healthy volunteers of mean age 80 (6) years, and the increase on exercise, seen in the controls (P less than 0.01), was absent. In the patients the resting plasma ANF concentration was significantly affected by treatment (P = 0.03), being less on both AP, 245 (9), and AA, 214 (9) than on PP, 264 (10) pmol l‐1 (P = 0.02 and 0.03, respectively). 7. Baseline serum ACE activity was induced on active treatment. The change in ACE activity at 3 h post an active dose was significantly greater on AP than AA (P = 0.005). The increased sensitivity to inhibition during once daily administration was reflected in mean arterial pressure. The pre‐dose standing pressure was less on AP than on PP (P less than 0.05), and the change in postural fall (pre‐dose minus 2 h post), was greater (P = 0.004), but AA and PP were similar in these respects.(ABSTRACT TRUNCATED AT 400 WORDS)
The distribution of cis‐ and trans‐acitretin in human epidermis.
Authors: Meyer E , Lambert W , De Leenheer A , De Bersaques J , Kint A
Published: July 2012

The concentrations of trans‐acitretin and its principal metabolite, cis‐ acitretin, were measured by h.p.l.c. after single and multiple dosing (50 mg orally for 13 days) in plasma, blister fluid and epidermal samples from four healthy male volunteers. Within‐day epidermal concentrations of trans‐acitretin exceeded those of the cis‐form which were at the limit of assay sensitivity. No accumulation of trans‐ acitretin was observed in plasma or blister fluid but AUC values for the drug in blister roof cells tended to be higher after multiple dosing.
Extrahepatic metabolism of zidovudine.
Authors: Howe JL , Back DJ , Colbert J
Published: July 2012

The metabolism of zidovudine (3′‐azido‐3′‐deoxythymidine; AZT) has been studied in human renal, gut and hepatic microsomes. Metabolism of AZT to the ether glucuronide (3'azido‐3'‐deoxy‐5'‐beta‐D‐glucopyranosyl thymidine; GAZT) occurred in the kidney with Km and Vmax values of 1.50 +/‐ 0.49 mM and 14.5 +/‐ 2.6 nmol h‐1 mg‐1 respectively (mean +/‐ s.d.; n = 3 batches of microsomes from a single kidney). Comparative values obtained in liver were 2.19 +/‐ 0.6 mM and 43.0 +/‐ 9.5 nmol h‐1 mg‐1, respectively. Morphine caused inhibition of AZT conjugation in kidney microsomes. Metabolism of AZT by the kidney could contribute significantly to the overall elimination of AZT. In contrast to the kidney findings, AZT was not metabolised to GAZT by either non‐ activated (Brij‐58) or activated gut microsomes.
The importance of general practitioner information in selection of volunteers for clinical trials.
Authors: Watson N , Wyld PJ
Published: July 2012

The safe conduct of phase I volunteer studies requires careful selection and screening of volunteers. We have reviewed the results of the selection procedure in our clinic. The information received from the volunteer's general practitioner revealed clinical problems which had not been disclosed during medical history or examination.
Is ondansetron a less effective antiemetic against moderately emetic as compared with highly emetic chemotherapy? [see comments]
Authors: Dundee JW , McMillan CM , Yang J , Wright PM
Published: July 2012

The severity of sickness in the first 5 days after cancer chemotherapy was compared in patients who had or had not received ondansetron 8 mg three times daily. Patients were divided into those having highly emetic chemotherapy, irrespective of gender and women having moderately emetic drugs. Ondansetron appeared to be more effective in the former group.
A comparison of the haemodynamic and behavioural effects of moxonidine and clonidine in normotensive subjects.
Authors: Macphee GJ , Howie CA , Elliott HL , Reid JL
Published: July 2012

1. This randomised double‐blind placebo controlled crossover study in healthy normotensive males compared the haemodynamic and behavioural responses following single oral doses of moxonidine (200 micrograms), clonidine (200 micrograms) and placebo. 2. Both active drugs significantly reduced blood pressure as compared with placebo: on average (over the study day) by ‐5.6/‐0.8 with moxonidine and by ‐13.3/‐ 5.3 mm Hg with clonidine. The hypotensive effect of clonidine was significantly greater (95% CI 3.2‐12.2). Heart rate was unchanged by either drug. 3. Psychomotor testing, salivary flow and side effect reporting showed a consistent treatment rank order similar to that of the hypotensive response: clonidine greater than moxonidine greater than placebo. 4. Although moxonidine produced less adverse effects than clonidine, an equivalent hypotensive response was not demonstrated in normal subjects. Further study at comparable antihypertensive doses is required to clarify the relative side effect profile of these agents.
Lack of effect of chronic calcium antagonist treatment on beta 1‐ and beta 2‐adrenoceptors in right atria from patients with or without heart failure.
Authors: Brodde OE , Hundhausen HJ , Zerkowski HR , Michel MC
Published: July 2012

1. We studied the effects of chronic calcium antagonist (calcium entry blocker, CEB; nifedipine, verapamil, diltiazem) treatment on beta‐ adrenoceptor density (assessed by (‐)‐[125I]‐iodocyanopindolol [ICYP] binding) and subtype distribution in right atria from 65 patients without apparent heart failure undergoing elective coronary artery bypass grafting (CAD‐patients) and from 13 patients with moderate heart failure (NYHA class III to class III‐IV) undergoing mitral valve replacement (MVD‐patients). 2. In CAD‐patients atrial beta‐adrenoceptor density was 79.3 +/‐ 7.9 fmol ICYP bound mg‐1 protein (n = 18), the beta 1:beta 2‐adrenoceptor ratio 69:31%. Chronic CEB‐treatment did not affect either atrial beta‐adrenoceptor density or beta 1:beta 2‐ adrenoceptor ratio. 3. In contrast, in CAD‐patients chronically treated with beta 1‐adrenoceptor antagonists (atenolol, bisoprolol, metoprolol) and CEB, atrial beta‐adrenoceptor density was significantly increased (108.6 +/‐ 10.5 fmol ICYP bound mg‐1 protein, n = 21); this increase was due to a selective increase in beta 1‐adrenoceptors. 4. In MVD‐ patients atrial beta‐adrenoceptor density (55.5 +/‐ 8.7 fmol ICYP bound mg‐1 protein, n = 7) was significantly lower (P less than 0.05) than in CAD‐patients; beta 1:beta 2‐adrenoceptor ratio, however, was not changed (67:33%). Chronic CEB‐treatment of MVD‐patients did not prevent the decrease in atrial beta‐adrenoceptors. 5. We conclude that chronic CEB‐treatment does not affect human right atrial beta‐adrenoceptor density, either in patients without apparent heart failure or in patients with moderate heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Stereoselective genetically‐determined interaction between chronic flecainide and quinidine in patients with arrhythmias.
Authors: Birgersdotter UM , Wong W , Turgeon J , Roden DM
Published: July 2012

1. Recent reports have indicated a role for the P450IID6 polymorphism in the stereoselective disposition of single doses of the antiarrhythmic flecainide. 2. In this study, we evaluated the effects of adding low dose quinidine, a potent inhibitor of P450IID6, to chronic flecainide therapy in patients with arrhythmias. 3. In five extensive metabolizer patients, quinidine significantly reduced the clearance of R‐(‐)‐flecainide, from 395 +/‐ 121 (s.d.) to 335 +/‐ 88 ml min‐1. This change was attributable to a decrease in metabolic clearance, was accompanied by decreased formation of the two major metabolites of flecainide and was not observed in a poor metabolizer subject. The renal clearance of R‐(‐)‐flecainide rose significantly. 4. Quinidine did not alter the clearance of S‐(+)‐flecainide. 5. The pharmacologic effects of flecainide therapy (QRS widening, % arrhythmia suppression) were slightly, but not significantly, increased. 6. In extensive metabolizer patients receiving chronic flecainide, increased plasma concentrations will develop if P450IID6 is inhibited.
A placebo‐controlled study of effects of oral progesterone on performance and mood.
Authors: Freeman EW , Weinstock L , Rickels K , Sondheimer SJ , Coutifaris C
Published: July 2012

1. Oral micronized progesterone (P) is proposed for the treatment of certain endocrine gynaecological disorders. To examine the effects of P on performance and mood, a randomized, placebo‐controlled study of 24 healthy females ages 18‐24 years on low‐dose oral contraceptives was conducted. 2. Subjects were admitted to the Clinical Research Center on four occasions and received single doses of oral P (300, 600, 1200 mg) or placebo. Blood sampling, psychometric tests and mood scales were administered at baseline and at hourly intervals for 6 h. 3. P doses produced significant dose‐related but highly variable increases in plasma P concentrations. Fatigue increased with P doses, although few subjects were objectively drowsy. Very high peak plasma P concentrations, achieved by some subjects at the 1200 mg dose, were associated with decreased information processing and verbal memory function as well as fatigue. 4. We conclude that oral P can safely be prescribed at higher than previously‐reported doses, based on evidence of transient behavioural effects only at the highest doses in some subjects who achieved high plasma P concentrations.
The influence of codeine, propantheline and metoclopramide on small bowel transit and theophylline absorption from a sustained‐release formulation.
Authors: Sommers DK , Meyer EC , van Wyk M , Moncrieff J , Snyman JR , Grimbeek RJ
Published: July 2012

1. The effects of the anticholinergic agent, propantheline, the opiate, codeine, and the prokinetic agent, metoclopramide, on oral‐caecal transit time and on the absorption of theophylline from a sustained‐ release formulation were examined in six healthy male volunteers. 2. A cross‐over randomised sequence design was followed, allowing at least 2 weeks interval between studies. On each occasion 500 mg theophylline in a sustained‐release formulation was taken simultaneously with 2 g sulphasalazine at zero time. On three of the four occasions one of the following treatments was given concurrently at ‐0.5 h, +3.5 h, and +7.5 h: 30 mg codeine phosphate, 30 mg propantheline bromide, or 10 mg metoclopramide monohydrochloride. 3. The appearance of sulphapyridine in the plasma was used to assess oral‐caecal transit time and the mean fraction absorbed‐time profile of theophylline was calculated from serial serum theophylline concentration measurements using the Wagner‐ Nelson method. 4. Codeine increased the mean (s.d.) oral‐caecal time (h) significantly (5.14 +/‐ 0.94) compared with the control value (3.78 +/‐ 0.34). Propantheline inhibited peristaltic contractions to such an extent that the oral‐caecal transit time in five of the volunteers was between 9 and 25 h, while sulphapyridine appeared in the 9 h serum sample of the sixth. Metoclopramide did not significantly alter the oral‐caecal transit time. 5. Despite the observed changes in oral‐ caecal transit time the rate and extent of theophylline absorption was similar with all regimens.
The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics.
Authors: Kamali F , Edwards C , Rawlins MD
Published: July 2012

1. The effects of pirenzepine on gastric emptying, salivary flow and saliva paracetamol concentrations were investigated in healthy volunteers. 2. Pirenzepine significantly reduced the area under the saliva flow‐time curves (7.29 +/‐ 3.30 g min‐1 h without pirenzepine; 4.19 +/‐ 2.59 g min‐1 h with pirenzepine, P less than 0.01). Pirenzepine had no significant effect on plasma paracetamol Cmax (17.5 +/‐ 7.8 micrograms ml‐1 without pirenzepine; 12.6 +/‐ 7.7 micrograms ml‐ 1 with pirenzepine), plasma tmax (0.2 h (0.2‐0.8 h) without pirenzepine; (0.2 h 0.2‐0.8 h) with pirenzepine) and plasma AUC(0.6 h) (32.3 +/‐ 7.2 micrograms ml‐1 h without pirenzepine; 30.3 +/‐ 6.5 micrograms ml‐1 h with pirenzepine). 3. Mean ratios of saliva:plasma paracetamol AUC (1.06 +/‐ 0.24 without pirenzepine; 1.84 +/‐ 0.48 with pirenzepine, P less than 0.001) and saliva:plasma paracetamol Cmax (1.7 +/‐ 1.0 without pirenzepine; 6.5 +/‐ 2.7 with pirenzepine, P less than 0.01) were significantly increased by pirenzepine pretreatment, but there was a poor correlation between the percentage change in the area under the saliva flow‐time curve and the percentage change in saliva paracetamol AUC (r = 0.47, P = 0.21). 4. The findings suggest that a) pirenzepine is a more selective antagonist of the muscarinic receptors in salivary glands than those in gastric smooth muscle and b) caution is required when using saliva paracetamol concentrations to determine the pharmacokinetics of the drug in the presence of other agents which may influence salivary flow rate.
Human and mouse liver coumarin 7‐hydroxylases do not metabolize warfarin in vitro.
Authors: Honkakoski P , Arvela P , Juvonen R , Lang MA , Kairaluoma M , Pelkonen O
Published: July 2012

1. The contribution of human P450 2A6 and mouse P450 2a‐5 isoenzymes, both highly active in coumarin 7‐hydroxylation, to the metabolism of warfarin was studied in several in vitro systems with human and mouse liver preparations. 2. The reconstituted P450 2a‐5 purified from DBA/2 mouse liver did not metabolize warfarin. 3. An anti‐P450 2a‐5 antibody did not consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or mouse liver microsomes, although coumarin 7‐hydroxylation was inhibited by over 90%. 4. In some human microsomal samples, 4‐ and 8‐hydroxylations of warfarin were inhibited to some extent by the anti‐P450 2a‐5 antibody. 5. Warfarin (less than 1 mM) did not inhibit coumarin 7‐hydroxylation by human or mouse liver microsomes in vitro. 6. We conclude that mouse and human coumarin 7‐ hydroxylases do not oxidise warfarin.
Metabolism of 2′,3′‐dideoxyinosine (ddI) in human blood.
Authors: Back DJ , Ormesher S , Tjia JF , Macleod R
Published: July 2012

1. 2′,3′‐Dideoxyinosine (ddI) has potent activity against human immunodeficiency virus (HIV). It is converted within target cells to its active form dideoxyadenosine triphosphate(ddA‐TP). 2. In addition to the intracellular formation of ddA‐TP, ddI can be broken down to hypoxanthine, by purine nucleoside phosphorylase (PNP) and to uric acid, by xanthine oxidase. Since PNP is present in red blood cells we have examined the metabolism of [14C]‐ddI by human blood. 3. When incubated with whole blood at 37 degrees C, ddI was extensively metabolised, principally to hypoxanthine (50.4 +/‐ 12.5% formed at 6 h; mean +/‐ s.d.; n = 16). Small amounts of uric acid were formed (3.8 +/‐ 2.4%). 4. ddI breakdown was temperature dependent, being virtually negligible at 4 degrees C. Metabolism to hypoxanthine occurred within red blood cells. 5. The short half‐life of ddI in patients is probably the result of both hepatic and erythrocytic metabolism.
Intracellular free magnesium in lymphocytes from patients with congestive cardiac failure treated with loop diuretics with and without amiloride.
Authors: Ng LL , Garrido MC , Davies JE , Brochwicz‐Lewinski MJ , Tan LB
Published: July 2012

Cellular Mg2+ depletion has been reported in patients on long term diuretic therapy. We therefore measured lymphocyte free Mg2+ concentrations in patients with congestive cardiac failure treated with loop diuretics or a frusemide/amiloride mixture (Frumil) and compared them with control subjects. There was no correlation between lymphocyte free Mg2+ levels and plasma Mg2+ concentrations. Patients treated with loop diuretics did not show lymphocyte intracellular free Mg2+ depletion compared with normal controls, and those on Frumil showed higher intracellular free Mg2+ levels than normal.
Role of vagal activity in the cardiovascular responses to phenylephrine in man.
Authors: Levine MA , Leenen FH
Published: July 2012

The effects of phenylephrine on blood pressure (BP), left ventricular function and total peripheral resistance (TPR) were evaluated in six normotensive male volunteers before and after vagal blockade with atropine. Before atropine, phenylephrine dose‐related increased TPR, systolic and diastolic BP and decreased cardiac output by decreases in both stroke volume and heart rate. Post‐atropine, the BP (but not TPR) responses to phenylephrine were markedly potentiated, related to an increase in stroke volume despite the higher afterload. Thus vagal tone may regulate cardiac output via effects on both heart rate and venous return.
Milk and yoghurt do not impair the absorption of ofloxacin.
Authors: Neuvonen PJ , Kivisto KT
Published: July 2012

The effects of milk and yoghurt on the oral absorption of ofloxacin were studied in seven healthy volunteers in a randomized cross‐over trial. After an overnight fast, 200 mg ofloxacin was given with 300 ml water, milk or yoghurt. Plasma concentrations and urinary excretion of ofloxacin were determined up to 24 h. Values of total plasma AUC and 24 h urinary excretion of ofloxacin were not affected by milk or yoghurt. Plasma ofloxacin concentrations from 0.5 to 1.5 h and the peak concentration were lower (P less than 0.05) after yoghurt than without and the time to peak was prolonged by 1 h (P less than 0.05).
Stereoselective disposition of flurbiprofen in normal volunteers.
Authors: Knadler MP , Brater DC , Hall SD
Published: July 2012

1. The concentrations of the R‐ and S‐enantiomers of flurbiprofen and its metabolites were measured in plasma and urine following the oral administration of 50 mg racemic flurbiprofen to six normal volunteers. 2. The AUC and half‐life of the R‐enantiomer were significantly lower than the corresponding S‐enantiomer values reflecting the greater clearance of R‐flurbiprofen (20.42 +/‐ 4.71 vs 16.12 +/‐ 3.60 ml min‐ 1). 3. Ex vivo protein binding studies indicated that the percent unbound of R‐flurbiprofen was (not significantly) greater than that of the S‐enantiomer (0.055 +/‐ 0.008 vs 0.049 +/‐ 0.009) and the corresponding unbound clearances did not show enantioselectivity. 4. Both enantiomers were cleared primarily by metabolism to an acylglucuronide and 4′‐hydroxyflurbiprofen. There was significant enantioselectivity (R greater than S) in the formation clearances of these metabolites which remained when unbound metabolite formation clearances were considered. 5. In conclusion, the disposition of the enantiomers of flurbiprofen exhibits enantioselectivity at the level of protein binding and metabolite formation.
Effects of flurbiprofen on renal function in patients with moderate renal insufficiency.
Authors: Murray MD , Greene PK , Brater DC , Manatunga AK , Hall SD
Published: July 2012

1. Renal function was assessed in eight patients with chronic renal insufficiency following the administration of flurbiprofen 50 mg as a single dose and after chronic administration of 50 mg four times daily for 8 and 27 days. Diet and fluid intake were controlled. 2. Inulin and creatinine clearances and urinary excretion of sodium were measured at baseline and every 20 min for at least 3 h after dosing. The time of the mean peak concentration of (S)‐flurbiprofen was used to guide the analysis of the clearances. Creatinine clearance, urinary excretion of sodium, and serum sodium and potassium were also assessed for 24 h after the dose and on a daily basis. Body weight and blood pressure were measured on a daily basis. 3. Decrements in inulin and creatinine clearances were small and reversible within 3 h of an oral dose of flurbiprofen. Comparison of baseline clearances for the three study periods (first dose and at 8 and 27 days of chronic dosing) revealed a lack of chronic effect on glomerular filtration rate. 4. In contrast, flurbiprofen caused a substantial (73 to 86%) and progressive decrease in the urinary excretion of sodium that reached a nadir within 4‐5 h after drug administration. However, comparison of baseline values did not differ, indicating that balance conditions had been re‐established. 5. Results of 24 h assessments were in agreement with the clearance study results. Reduced urinary excretion of sodium appeared to be limited to the first few days of flurbiprofen administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluation of in vivo partial beta 1/beta 2‐agonist activity: a dose‐ ranging study with carteolol.
Authors: Wheeldon NM , McDevitt DG , Lipworth BJ
Published: July 2012

1. The aims of this study were to investigate the partial agonist profile of carteolol and evaluate methodology for differentiating relative beta 1 and beta 2 partial agonist activity (PAA) in vivo. 2. Eight normal subjects received single oral doses of carteolol 10 mg, 30 mg and 60 mg; nadolol 40 mg; pindolol 30 mg and placebo, given in a single‐blind, randomised crossover design. 3. beta 1‐PAA was demonstrated with carteolol by dose‐related increases in resting heart rate and systolic blood pressure, and a plateau in the dose‐response curve for attenuation of exercise tachycardia. beta 2‐PAA with carteolol was evidenced by a dose‐related increase in resting finger tremor and progressive attenuation of exercise‐induced hyperkalaemia. beta 2‐adrenoceptor antagonism was shown by attenuation of terbutaline induced hypokalaemic, chronotropic and finger tremor responses. 4. Carteolol behaved as a non‐selective beta‐adrenoceptor antagonist with both beta 1 and beta 2‐PAA components. In the standard clinical dose range of 10‐30 mg, its in vivo PAA effects were relatively beta 1‐ selective. Thus at low doses, there appeared to be a dissociation between selectivity of antagonist and partial agonist activity. 5. Attenuation of exercise hyperkalaemia appears to be a novel and sensitive method for the evaluation of beta 2‐PAA in vivo.
The effect of orthotopic transplantation on total, beta 1‐ and beta 2‐ adrenoceptors in the human heart.
Authors: Chester MR , Madden B , Barnett D , Yacoub M
Published: July 2012

1. [125I]‐(‐)pindolol binding was used to determine beta‐adrenoceptor density in homogenate preparations of right ventricular endomyocardial biopsies from 43 non‐rejecting patients over the first 13 months following cardiac transplantation. The selective beta 1 subtype antagonist ligand CGP 20712A was used to determine the subtype density in 32 of the patients. Biopsy specimens from 15 donor hearts were used as controls. 2. beta‐adrenoceptor density (expressed in terms of fmol mg‐1 protein) was increased in the group of transplanted hearts as a whole compared with the donor hearts with respect to total (35 +/‐ 2 vs 23 +/‐ 2) and the beta 1 subtype (25 +/‐ 2 vs 16 +/‐ 2) whereas the beta 2 subtype and radioligand dissociation constant did not differ. 3. Non‐parametric analysis of variance of total receptor density over time revealed significant heterogeneity which appears to be due to a discrete increase in beta‐adrenoceptor density during the 4th post operative month. 4. These results indicate that beta‐adrenoceptor density is not constant following transplantation. Furthermore, the increase in receptor density following transplantation is due mainly to an increase in the beta 1 subtype without a significant change in the beta 2 subtype.
Enhanced leukotriene synthesis in leukocytes of atopic and asthmatic subjects.
Authors: Sampson AP , Thomas RU , Costello JF , Piper PJ
Published: July 2012

1. We have investigated the capacities of peripheral leukocytes from atopic asthmatic (AA) (n = 7), atopic non‐asthmatic (AN) (n = 7), and normal (N) (n = 7) subjects to generate the bronchoconstrictor and proinflammatory mediators leukotrienes (LTs) B4 and C4. 2. Mixed leukocyte preparations containing 61‐84% neutrophils, 2.4‐15% eosinophils, and 13‐29% mononuclear cells were incubated in vitro at 37 degrees C in the presence of calcium ionophore A23187. Synthesis of LTB4 and LTC4 was quantitated by radioimmunoassay. 3. Both in dose‐ response experiments (0‐10 microM A23187 for 5 min), and in time‐course investigations (2 microM A23187 for 0‐30 min), the mixed leukocytes of the AA and AN subjects generated on average 4‐ to 5‐fold more LTB4 and 3‐ to 5‐fold more LTC4 than the normal leukocytes (P less than 0.01 in all cases; ANOVA). 4. This enhanced LT synthesis by the AN and AA leukocytes was not due to differences in the counts of leukocyte sub‐ types, or to altered rates of LT catabolism between the subject groups. 5. LTB4 synthesis correlated significantly with LTC4 synthesis in the leukocytes of the AN and AA subjects (r = 0.81, n = 14, P less than 0.01), but not in those of the normal subjects (r = 0.19, n = 7, P greater than 0.05). 6. Our results demonstrate an up‐regulation of the leukotriene synthetic pathway in the circulating leukocytes of atopic non‐asthmatic and atopic asthmatic subjects, which may have important implications in the pathophysiology of asthma and allergy.
The effect of respiratory manoeuvres and pharmacological agents on the pharmacokinetics of nedocromil sodium after inhalation.
Authors: Summers QA , Singh S , Honeywell RG , Renwick AG , Holgate ST
Published: July 2012

1. Eight healthy subjects inhaled nedocromil sodium from a metered‐dose inhaler using a standardised inspiratory technique. Blood samples were taken for up to 270 min after inhalation for radioimmunoassay of plasma nedocromil sodium concentrations. 2. To investigate the possibility that respiratory manoeuvres can alter the absorption of the drug from the lungs, on the first (control) study day at 70 min after dosing, subjects performed nine forced expiratory manoeuvres over a 3 min period. At 110 min after dosing, subjects took a slow, full inspiration with a 30 s breath‐hold, and at 150 min after dosing the subjects performed one single forced expiration. 3. On the second study day, subjects inhaled methoxamine, 0.15 mg kg‐1 of a 20 mg ml‐1 solution at 60 min after dosing, and the study continued as above. On the third day, subjects repeated the sequence of respiratory manoeuvres, after having taken phenoxymethyl penicillin and probenecid by mouth for 48 h. 4. Both multiple forced expirations and the deep inspiration with breath‐hold produced significant increases in the absorption of nedocromil sodium. Inhaled methoxamine did not alter airway calibre or the response to the respiratory manoeuvres. Probenecid, but not penicillin, was detected in the subjects' plasma, and had the effect of increasing the rise in plasma nedocromil sodium concentrations after the multiple forced expirations when compared with the control day. 5. These data suggest that disruption of epithelial tight junctions induced by the respiratory manoeuvres leads to enhanced paracellular transport of nedocromil sodium into the draining circulation of the airways and alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes.
Authors: Engel T , Scharling B , Skovsted B , Heinig JH
Published: July 2012

1. The efficacy of a metered dose inhaler (MDI) is highly dependent on the mode of inhalation. The relatively high built‐in resistance in the Turbohaler (TBH), a new dry powder inhaler device for inhalation of terbutaline sulphate and budesonide, reduces the flow during inhalation. We compared five different modes of inhalation using the terbutaline TBH in 10 stable asthmatic subjects, who were tested on 5 consecutive days. 2. Measurement of 10 different parameters of pulmonary function indicated that the full bronchodilatory effect of an inhaled dose was already achieved at 5 min after the inhalation. Inspiratory flows through the TBH varying from 34 to 88 l min‐1 resulted in comparable bronchodilation, and a previous exhalation to residual volume proved of no value. However, if, prior to inhalation, an exhalation through the device was performed, a substantially reduced effect was seen. 3. Reducing the inspiratory flow to approximately 34 l min‐1 produced slightly reduced side effects and lower plasma terbutaline concentrations.
Effect of high ambient temperature on the kinetics of the pupillary light reflex in healthy volunteers.
Authors: Leung NK , Bradshaw CM , Szabadi E
Published: July 2012

Miotic responses to brief light stimuli were studied in healthy volunteers under two ambient temperature conditions, 22 degrees C and 40 degrees C. The latency and amplitude of the light reflex did not differ between the two conditions, but the recovery time of the reflex was significantly shorter under the 40 degrees C condition than under the 22 degrees C condition. The results are consistent with the hypothesis that exposure to high ambient temperature results in an increased sympathetic drive to the iris dilator muscle but does not influence the parasympathetic light reflex.
What have drugs to offer the patient with acute stroke?
Authors: Grosset DG
Published: July 2012

1. Drug treatment for acute stroke is designed to salvage neuronal tissue, and to prevent complications of stroke, which are often non‐ neurological. This review addresses the areas of recent advance in treatment designed to reduce the size of the cerebral infarct. With the exception of cardiac‐source embolism, for which anticoagulation in the acute phase is sometimes considered, prevention of recurrent events is not discussed. 2. It is to be hoped that pharmaceutical developments will improve the current bleak picture in which there are no proven treatments for ischaemic stroke or intracerebral haemorrhage. To meet this challenge will require careful, controlled evaluation of treatment early after acute stroke in large scale clinical studies.