bluuebunny/crossref_metadata_2025 huggingface dataset:
Metronidazole excretion in human milk and its effect on the suckling neonate.
Authors: Passmore CM , McElnay JC , Rainey EA , D'Arcy PF
Published: July 2012

1. Milk and plasma metronidazole and hydroxymetronidazole concentrations were measured in 12 breast‐feeding patients following multiple doses of metronidazole (400 mg three times daily). All patients received metronidazole in combination with other broad spectrum antibiotics. 2. Plasma concentrations of both parent drug and metabolite were measured in seven suckling infants. Thirty‐five infants were monitored for adverse reactions to maternal metronidazole therapy and two further groups of suckling infants, those whose mothers received either ampicillin alone or no drug therapy, were recruited as controls. 3. The mean milk to plasma ratio (M/P) was 0.9 for metronidazole and 0.76 for hydroxymetronidazole while the mean milk metronidazole concentrations (around Cmax) were 15.5 micrograms ml‐1. The mean milk hydroxymetronidazole concentration was 5.7 micrograms ml‐ 1. 4. Infant plasma metronidazole concentrations ranged from 1.27 micrograms ml‐1 to 2.41 micrograms ml‐1, and the corresponding hydroxymetronidazole concentrations from 1.1 to 2.4 micrograms ml‐1. 5. There were no significant increases in adverse effects in infants which could be attributable to maternal metronidazole therapy. 6. Metronidazole was excreted in milk at concentrations which caused no serious reactions in the infants studied. The drug may therefore be administered at doses of 400 mg three times daily to mothers wishing to breast‐feed their infants.
The influence of diazepam on the plasma concentrations of bupivacaine and lignocaine after caudal injection of a mixture of the local anaesthetics in children.
Authors: Giaufre E , Bruguerolle B , Morisson‐Lacombe G , Rousset‐Rouviere B
Published: July 2012

Twenty‐one children undergoing surgery received a caudal block using 1 ml kg‐1 of a mixture of 50% lignocaine (1%) and 50% bupivacaine (0.25%). They were randomized into two groups, one of which received diazepam 10 mg rectally as premedication. Diazepam administration resulted in significantly higher Cmax and AUC values for bupivacaine but did not influence the plasma concentrations of lignocaine.
Central effects of beta‐adrenoceptor antagonists. II‐ Electroencephalogram and body sway.
Authors: Nicholson AN , Wright NA , Zetlein MB , Currie D , McDevitt DG
Published: July 2012

1. Effects of the beta‐adrenoceptor antagonists, propranolol (40, 80 and 160 mg) and atenolol (50 and 100 mg) on the electroencephalogram and on body sway, were studied in 12 healthy male subjects. The study was double‐blind, and included two placebos and an active control, oxazepam (15 mg). Medication was ingested at 11.00 h, and assessments were made before, and at 2 h and 4 h after ingestion. 2. All doses of both beta‐adrenoceptor antagonists modified the electroencephalogram, and the changes reported were statistically significant at probability levels of less than 5%. The circadian rise in alpha activity was reduced by both beta‐adrenoceptor antagonists as well as by oxazepam. Atenolol also decreased beta activity. 3. Body sway was modified by atenolol and oxazepam (P less than 0.05). The increase with oxazepam was most marked in the low frequency component (0.05‐2.25 Hz) of the spectrum, while atenolol modified only the component of higher frequency (2.25‐4.0 Hz). 4. These observations suggest that propranolol and atenolol have a sedative effect, and that hydrophilic antagonists are unlikely to be free of central activity. The changes in body sway could imply that peripheral mechanisms may be modified at least with atenolol.
Predicting the ciprofloxacin‐theophylline interaction from single plasma theophylline measurements.
Authors: Bachmann KA , Schwartz JI , Jauregui L
Published: July 2012

The effect of ciprofloxacin treatment on theophylline clearance was evaluated with a theophylline multiple dose, multiple sample protocol and with a single dose, single sample protocol. The object was to determine whether a single dose, single sample protocol for estimating theophylline clearance could be used as a screening strategy for evaluating host factor influences on theophylline clearance. Ciprofloxacin (750 mg per os) was administered every 12 h for nine doses in the multidose study and every 12 h for seven doses in the single dose protocol. Subjects were sixteen healthy, non‐smoking young adult males. The oral clearance of theophylline at steady state, (CL/F)ss, decreased from a mean (+/‐ s.d.) value of 0.035 (+/‐ 0.008) 1 h‐1 kg‐1 to 0.024 (+/‐ 0.004) 1 h‐1 kg‐1 during ciprofloxacin treatment. Single sample estimates of theophylline clearance, CL/F, similarly decreased from 0.040 (+/‐ 0.014) 1 h‐1 kg‐1 to 0.018 (+/‐ 0.008) 1 h‐1 kg‐1. Mean theophylline clearances were significantly different when comparing control with ciprofloxacin treatment means (P less than 0.01), but were not different when comparing single sample vs multiple sample clearances for a given treatment (i.e. control or ciprofloxacin). It is concluded that a single dose, single sample strategy may be used in screening for host‐factor influences on theophylline clearance.
Pharmacokinetics of amoxycillin and clavulanic acid in haemodialysis patients following intravenous administration of Augmentin.
Authors: Davies BE , Boon R , Horton R , Reubi FC , Descoeudres CE
Published: July 2012

1. Serum concentrations of amoxycillin and clavulanic acid were measured in patients with end‐stage renal disease (ESRD) following intravenous administration of 1.2 g Augmentin. Augmentin was administered on a non‐dialysis day and 2 h prior to a 4 h dialysis session. 2. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half‐life for amoxycillin on the non‐dialysis day were 14.4 ml min‐1, 19.2 h, 14.9 l and 13.6 h, respectively. 3. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half‐life during dialysis for amoxycillin were 77.1 ml min‐1, 91.5 ml min‐1, 0.64 and 2.30 h, respectively. 4. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half‐life for clavulanic acid on the non‐dialysis day were 43.6 ml min‐ 1, 4.4 h, 11.0 l and 3.05 h, respectively. 5. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half‐life during dialysis for clavulanic acid were 92.8 ml min‐1, 136 ml min‐1, 0.65 and 1.19 h, respectively. 6. The total serum clearance on the non‐dialysis day, which represents non‐renal clearance, was lower than that in normal subjects for both amoxycillin and clavulanic acid. These data would suggest some degree of hepatic impairment in patients with ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)
Relationship between plasma oxipurinol concentrations and xanthine oxidase activity in volunteers dosed with allopurinol.
Authors: Day RO , Miners J , Birkett DJ , Graham GG , Whitehead A
Published: July 2012

1. 1‐methyl xanthine (1‐MX) is metabolized exclusively to 1‐methyl uric acid (1‐MU) by the enzyme xanthine oxidase. 2. The ratio of 1‐MU to 1‐ MX in the urine, following a dose of 50 mg of 1‐MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase induced by different doses of allopurinol. 3. Normal volunteers (n = 8) were given allopurinol 50, 100, 300 and 600 mg daily for 1 week each, in random order and 1 week separated each treatment. Inhibition of xanthine oxidase was assessed twice, on the last 2 days of each treatment week. 4. Steady‐state oxipurinol concentrations increased linearly with increasing dose of allopurinol. 5. There was a hyperbolic relationship between the 1‐MU/1‐MX ratio and plasma oxipurinol concentrations, with an initial steep decline in the ratio which plateaued when plasma oxipurinol was around 4‐6 mg l‐1. This reduction in the ratio was quickly reversible upon cessation of allopurinol. 6. The 50% and 90% effective inhibitory oxipurinol concentrations, in relation to the 1‐MU‐/1‐MX ratio were 1.4 +/‐ 0.46 and 4.08 +/‐ 2.03 mg l‐1 respectively. 7. The concentration of oxipurinol required for almost complete inhibition of the enzyme was substantially less than those often observed in clinical practice.
Effects of diazepam and chlormethiazole on ventilatory control in normal subjects.
Authors: Gilmartin JJ , Corris PA , Stone TN , Veale D. , Gibson GJ
Published: July 2012

We have studied the effects of chlormethiazole and diazepam given orally on the ventilatory and mouth occlusion pressure (P0.1) responses to CO2 in a placebo controlled study in 10 healthy volunteers. Diazepam 10 mg produced a significant reduction in both the ventilatory and P0.1 responses to CO2, and this was not associated with any effect on respiratory muscle power. Chlormethiazole 250 mg produced less drowsiness than diazepam 10 mg. Therefore in a subsequent study chlormethiazole 500 mg was compared with placebo. Chlormethiazole in either dose had no effect on CO2 responses or on maximum static respiratory pressures. We conclude that diazepam has a direct depressant effect on chemoreceptors and its effects on indices of ventilatory control are not due to impaired muscle function; chlormethiazole in the doses used has no such effects despite producing drowsiness.
A study of the clinical efficacy of azelastine in patients with extrinsic asthma, and its effect on airway responsiveness.
Authors: Gould CA , Ollier S. , Aurich R. , Davies RJ
Published: July 2012

1. The effect of 4.4 mg azelastine administered orally on airway responsiveness, skin prick testing, daily peak expiratory flow rates and symptoms of asthma was compared with placebo in a 7 week double‐ blind, parallel group study of 24 patients with extrinsic asthma. The study was in two parts: a 2 week assessment period, during which all patients received placebo tablets but recorded daily peak flow rates (PEFRs) and symptoms, preceding the 7 week double‐blind comparison. 2. Azelastine, 4.4 mg, significantly decreased airway responsiveness to histamine compared with placebo both after a single dose (P less than 0.001), and following 7 weeks continuous treatment (P less than 0.02). Airway responsiveness to methacholine was not altered by administration of azelastine compared with placebo. 3. Skin prick test weal diameters to both allergen and histamine were significantly reduced after both a single dose and following 7 weeks continuous therapy treatment with azelastine. 4. There was a significant improvement in both the mean of the morning and the evening peak flow rates recorded during the last week compared with the first week of the study in the group receiving 4.4 mg of azelastine twice daily compared with placebo. Scores for wheeze were significantly reduced during the final 3 weeks of the study in patients receiving azelastine compared both with those receiving placebo and with the first week of the study (P less than 0.05, P less than 0.01). Consumption of inhaled bronchodilators fell significantly during the study in the group receiving azelastine therapy (P less than 0.05); no such fall occurred in the placebo treated patients. 5. A bitter metallic taste was reported by 58% of patients who received azelastine therapy.
Review of yellow cards (1986): report to the Committee on the Safety of Medicines.
Authors: Bem JL , Breckenridge AM , Mann RD , Rawlins MD
Published: July 2012

1. In 1986 the CSM received 15,527 yellow cards. This was the highest number received in any one year since the scheme started in 1964. Much of the increase was due to the use by doctors of the yellow cards now included in the British National Formulary and NHS prescription pads. 2. The overall profile of reports of serious reaction, in 1986, was broadly similar to that of the previous years. The most commonly reported serious suspected adverse reactions involved the gastro‐ intestinal tract (801 reports), the skin (539 reports), the central nervous system (535 reports), and the blood (505 reports). 3. Of the drugs introduced between 1984 and 1986 appreciable numbers of reports of serious reactions were received in association with the use of diltiazem (33 reports), mitozantrone (30 reports), enalapril (173 reports) and etodolac (27 reports).
Consensual pupillary responses to mydriatic and miotic drugs.
Authors: Theofilopoulos N. , Longmore J. , Kerr FA , Szabadi E. , Bradshaw CM
Published: July 2012

1. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated fellow eye, in healthy volunteers. 2. In Experiment 1, the effects of four subjects, using photography in an illuminated room to assess pupil diameter. The drug evoked a dose‐ dependent mydriasis in the index eye which was accompanied by a simultaneous dose‐dependent miosis in the fellow eye. 3. In Experiment 2, the same method was used to assess pupil diameter as in Experiment 1. The effects of mydriatic (methoxamine and tyramine) and of miotic (pilocarpine) drugs instilled into the fellow eye, were studied on the sizes of pupillary responses to the same drugs instilled into the index eye. The presence of a mydriatic drug in the fellow eye resulted in a decrease in the size of the mydriatic responses in the index eye. 4. In Experiment 3, the effects of three concentrations of phenylephrine hydrochloride (0.15‐0.60 M) and of three concentrations of pilocarpine hydrochloride (0.002‐0.008 M), were studied in darkness using an infra‐ red binocular television pupillometer, in seven subjects. Phenylephrine evoked dose‐dependent mydriasis and pilocarpine evoked dose‐dependent miosis. The pupillary responses of the index eye were not accompanied by any changes in the diameter of the pupil of the fellow eye. 5. It is concluded that drug‐induced mydriasis in the index eye is accompanied by a consensual miosis in the fellow eye.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative effects of rilmenidine and clonidine on bronchial responses to histamine in asthmatic subjects.
Authors: Dinh Xuan AT , Matran R. , Regnard J. , Vitou P. , Advenier C. , Lockhart A.
Published: July 2012

1. The effects of pretreatment with clonidine and rilmenidine, a new alpha 2‐adrenoceptor agonist, on the bronchial responses to inhaled histamine were studied on 3 different days in a controlled, double‐ blind, randomized study in 12 asymptomatic asthmatic subjects. Clonidine and rilmenidine were orally administered as single and equipotent doses of 150 micrograms and 1 mg, respectively. All the subjects were non‐smokers with normal lung function tests (forced expiratory volume in one second (FEV1) = 97 +/‐ 10% predicted FEV1). 2. Histamine (first dose = 543 nmol) was delivered by a breath activated dosimeter (DeVilbiss no. 646 nebulizer) every 5 min; FEV1 was measured in triplicate after each dose and the largest value was analyse. The three dose‐response curves were compared by analysis of variance. 3. Both clonidine and rilmenidine decreased arterial blood pressure in all subjects. There was no difference in baseline values and pre‐challenge values of FEV1 after placebo, clonidine and rilmenidine on the 3 study days. Compared with placebo, both rilmenidine and clonidine significantly increased the bronchial responses to histamine (P less than 0.05 and P less than 0.01 respectively) an effect which was significantly more marked with clonidine than rilmenidine (P less than 0.05). 4. We suggest that the enhancement of bronchial responsiveness to histamine by clonidine and rilmenidine may result from their effects on both central and peripheral alpha 2‐adrenoceptors, and that the lesser aggravation of histamine‐induced bronchial obstruction in asthmatic subjects on rilmenidine might be explained by its lesser central and/or greater peripheral effects than clonidine.
The importance of bradykinin and histamine in the skin response to antigen.
Authors: Warren JB , Newman CM , Pixley FJ , Fuller RW , Dollery CT
Published: July 2012

On three separate occasions 12 atopic subjects were injected intradermally with two doses of antigen and one of saline as control. Pretreatment with terfenadine 60 mg orally significantly inhibited the flare response to both the lower dose of antigen and to saline (P less than 0.05). Ingestion of enalapril 5 mg orally 3 h before increased the flare response to both doses of antigen. Neither enalapril nor terfenadine affected the weal response when compared with placebo. Both endogenous histamine and bradykinin appear to be released during the intradermal flare response but are not important in the weal reaction to antigen.
A comparison of the effects of flosequinan, a new vasodilator, and propranolol on sub‐maximal exercise in healthy volunteers.
Authors: Lewis HM , Kendall MJ , Smith SR , Bratty JR
Published: July 2012

1. The effects of steady state flosequinan, a new vasodilator, and propranolol, on glucose mobilisation, lipolysis and plasma potassium concentration during sub‐maximal exercise testing were investigated in a double‐blind, randomised, three‐way crossover study in 12 healthy volunteers. 2. Plasma glucose, potassium and free fatty acid concentration during and after exercise on flosequinan were similar to those on placebo. Exercise heart rates were 7% (+9.2 beats min‐1) higher on flosequinan compared with placebo (P less than 0.05). During exercise on propranolol plasma glucose concentrations were comparable with those on placebo but plasma potassium concentrations were higher (mean increase 0.26 mmol l‐1, P less than 0.01) whereas free fatty acid concentrations were lower (mean decrease 0.10 mmol 1‐1, P less than 0.01). As expected the heart rate on exercise was 25% less (‐35 beats min‐1) on propranolol (P less than 0.05). 3. These data suggest that, in contrast to propranolol, flosequinan does not adversely affect the mobilisation of the two major sources of energy during sub‐maximal exercise.
Effect of CGP 17/582, a selective beta‐adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.
Authors: Whyte KF , de Vane PJ , Whitesmith R , Kelman A , Reid JL
Published: July 2012

1. CGP 17/582B is a new beta‐adrenoceptor antagonist which on experimental studies appears to combine selective beta 1‐adrenoceptor blockade with partial agonist activity (ISA). Assessing beta‐ adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double‐blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non‐selective beta‐adrenoceptor blocker with no ISA) and metoprolol (selective beta‐ adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta‐adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (‐)‐adrenaline to determine the degree of beta 2‐adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (‐)‐adrenaline (0.06 microgram kg‐1 min‐1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (‐)‐adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of the efficacy and acceptability of nicardipine and propranolol, alone and in combination, in mild to moderate hypertension.
Authors: Maclean D , Mitchell ET , Laing EM , Macdonald FC , Gough KJ , Dow RJ , McDevitt DG
Published: July 2012

1. We evaluated the relative efficacies and tolerability of various low‐ dose combinations of nicardipine and propranolol in patients with mild‐ moderate essential hypertension (DBP Phase V of greater than 90‐125 mmHg; WHO Grades I and II) in order to select the best one. 2. Sixty patients completed the double‐blind, balanced, randomised three‐way cross‐over protocol, with each phase lasting 4 weeks, and in which twice daily nicardipine 40 mg or propranolol 80 mg was compared with four twice daily combinations of nicardipine (20 or 30 mg) plus propranolol (40 or 80 mg). 3. At 'peak' effect time (i.e., 2 h post‐ dosing) all four treatment combinations were significantly more effective than propranolol, with effects ranging from 9‐23 mmHg (systolic) and 5‐15 mmHg (diastolic). Only the two 30 mg nicardipine combinations with propranolol were more effective than nicardipine monotherapy, further reducing BP by 8‐13 mmHg (systolic) and 5‐7 mmHg (diastolic); there were no significant differences between them. 4. 'Trough' diastolic pressures were not different between treatments and 'trough' BP control was sub‐optimal on all treatments. 5. 70% of patients on nicardipine monotherapy, 33% of those on propranolol monotherapy and 30% of patients during the placebo run‐in complained of symptoms. In terms of complaint rates, there was little to choose between the four combinations (27‐33%). Serum potassium and creatinine levels were elevated following propranolol monotherapy by 0.19 mmol 1‐1 and 6.5 mumol 1‐1 respectively (P less than 0.01 for both) and following the nicardipine 30 mg/propranolol 80 mg combination. Nicardipine monotherapy elevated serum T4 levels by an average of 0.57 ng dl‐1 (P less than 0.05). 6. The twice daily combination of nicardipine 30 mg plus propranolol 40 mg was therefore the optimum one in terms of its efficacy and tolerability. Further studies need to be performed to test the hypothesis that a higher dose of propranolol might ameliorate troublesome vasodilator side effects. However, none of the treatments studied was ideal for clinical use in the twice daily dosage used in this study.
The benefits of prescription information leaflets (1).
Authors: Gibbs S , Waters WE , George CF
Published: July 2012

1. Prescription information leaflets (PILs) giving information about non‐steroidal anti‐inflammatory drugs (NSAIDs), beta‐adrenoceptor antagonists and inhaled bronchodilators were evaluated in three small Hampshire towns, while a fourth, in which no leaflets were distributed, acted as a control. 2. Seven hundred and nineteen (82%) patients prescribed one of these medicines agreed to be interviewed in their homes, 1 to 2 weeks after the medicine had been prescribed. Four hundred and nineteen of them had received leaflets, while 300 received no written information. Two hundred and sixty patients received their leaflets from a pharmacist while 159 were given them by their general practitioner. 3. Patients who received leaflets were better informed about every item of knowledge tested, except for the name of the medicine. Awareness of the side effects showed the greatest improvement, but there was no evidence that these leaflets produced spurious side effects. 4. Much improved levels of satisfaction were recorded amongst patients who received leaflets, especially those for NSAIDs (P less than 0.001) and for beta‐adrenoceptor antagonists (P less than 0.01). 5. Subsequently, three hundred and fifty‐eight (77%) of the patients prescribed either a NSAID or a beta‐adrenoceptor antagonist 1 year earlier responded to a postal questionnaire. The benefits in terms of knowledge and satisfaction were still apparent, although less marked than previously. Of the patients still taking beta‐ adrenoceptor antagonists 70% had retained their leaflets over the intervening 12 months. 6. Ninety‐seven per cent of patients read their leaflet regardless of whether it was distributed by a general practitioner or pharmacist. However, those who obtained it from a pharmacist tended to be more knowledgeable and satisfied. 7. We conclude that patients welcome the idea of receiving PILs. They improve patients' knowledge of how to take their medicines correctly and their awareness of potential side effects. Importantly, patients who receive leaflets are more satisfied than those who do not. These overall benefits justify the use of leaflets on a routine basis.
The effect of angiotensin II and noradrenaline alone and in combination on renal sodium excretion in man.
Authors: Seidelin PH , McMurray JJ , Brown RA , Struthers AD
Published: July 2012

1. The renin‐angiotensin‐aldosterone‐system is important for the maintenance of sodium balance in man. Recent animal evidence suggests the angiotensin II can modulate the effect of the renal sympathetic nervous system on renal function. We have investigated the possible interaction of physiological doses of angiotensin II and noradrenaline on sodium excretion in man. 2. Seven normal volunteers were studied on four occasions during maximum water diuresis sustained by oral hydration. Samples were obtained during a baseline and four subsequent 20 min periods (A‐E). Placebo or noradrenaline was infused over periods B‐E, and angiotensin II infused over period C. 3. There was no change in systemic blood pressure, heart rate or creatinine clearance caused by infusion of either angiotensin II, noradrenaline or both in combination. 4. Noradrenaline alone caused a significant fall in absolute and fractional sodium excretion. Angiotensin II when infused with placebo caused a 37% fall in absolute sodium excretion and a 32% fall when infused with noradrenaline (no significant difference between the 2 days). Similar changes were seen for urinary flow and fractional sodium excretion. 5. We have therefore found no evidence to support a postsynaptic interaction of low doses of angiotensin II and noradrenaline on renal sodium excretion in man.
Metabolic effects of low‐dose fluconazole in healthy female users and non‐users of oral contraceptives.
Authors: Devenport MH , Crook D , Wynn V , Lees LJ
Published: July 2012

1. Azole antifungal agents such as ketoconazole act by inhibiting cytochrome P‐450 mediated sterol synthesis in the fungal cell membrane and thus have the potential to interfere with mammalian steroidogenesis. Fluconazole is a novel orally‐effective antifungal triazole which has been reported to have more specific effects on the cytochrome P‐450 enzymes involved in fungal sterol synthesis. 2. Due to the potential value of systemic antifungal agents in the treatment of infections commonly occurring in women, we assessed the effect of oral fluconazole on the metabolic profile of 18 healthy premenopausal women, 10 of whom were taking combined oral contraceptives (OC). Each woman acted as her own control, being studied both before and 21‐28 days after fluconazole therapy (50 mg daily), in the luteal phase of consecutive menstrual cycles. 3. The endocrinological profile included measurement of serum oestradiol, progesterone, testosterone and sex hormone binding globulin (SHBG) concentrations, short tetracosactrin adrenal stimulation test and thyroid function tests. Carbohydrate metabolism was investigated by means of an oral glucose tolerance test with measurement of plasma glucose, insulin and C‐peptide concentrations. Serum lipids, lipoproteins and apolipoproteins were analysed on samples taken after an overnight fast. 4. Minor biochemical changes associated with fluconazole treatment included increases in serum thyroxine and testosterone concentrations (but not in women taking OC as well as fluconazole) and in insulin and apolipoprotein B levels (but only in women taking OC as well as fluconazole). In general, these changes were small and of no clinical significance with the values remaining within the laboratory normal range. There were no adverse side‐effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental studies of the influence of vigabatrin on the GABA system.
Authors: Gram L , Larsson OM , Johnsen A , Schousboe A
Published: July 2012

1. Studies of the influence of clinically relevant concentrations of vigabatrin on GABA‐transaminase and on the release of endogenous GABA were performed in selectively cultured astrocytes and neurons. In addition, the two stereoisomers of vigabatrin were investigated separately. 2. The results indicated a preferential inhibition of neuronal GABA‐transaminase by vigabatrin. 3. Only the (S)‐form of vigabatrin seems to inhibit GABA‐transaminase. This finding corresponds to observations in epileptic animals that the (R)‐form exhibits no anticonvulsant effect. 4. Resynthesis of GABA‐transaminase, following withdrawal of vigabatrin showed that maximum enzyme activity was obtained within 6 days. This finding corresponds to the persistent effect after withdrawal of the drug in patients, observed in clinical trials. 5. At a concentration of 25 microM, vigabatrin caused a significant increase in the release of endogenous GABA from cultured GABAergic neurons. Although no data on brain levels of the drugs are currently available, judging from vigabatrin blood concentrations in man and from information of brain levels in animals, following chronic treatment, it is conceivable that a sufficiently high concentration of the drug in human brain is obtained to augment GABA release.
Clinical pharmacology of vigabatrin.
Authors: Schechter PJ
Published: July 2012

1. Upon oral administration vigabatrin is rapidly absorbed. Plasma elimination half‐life ranges between 5 and 7 h in normal volunteers. Vigabatrin is eliminated primarily via the kidneys with about 65% of the administered dose found unchanged in the urine within 24 h. Kinetics are dose‐linear within the range of usual therapeutic doses. 2. At therapeutic doses in man vigabatrin produces dose‐related increases in CSF concentrations of free and total GABA, homocarnosine (the GABA‐histidine dipeptide) and beta‐alanine. These biochemical changes are consistent with an inhibition of GABA‐transaminase activity in brain. 3. Thus, with systemic availability upon oral administration and biochemical activity in the CNS, the prerequisites for potential uses of vigabatrin in neurological disorders have been demonstrated in clinical pharmacological studies.
Vigabatrin in epilepsy in mentally retarded patients.
Authors: Matilainen R , Pitkanen A , Ruutiainen T , Mervaala E , Riekkinen P
Published: July 2012

1. The anticonvulsant potency of vigabatrin (gamma‐vinyl GABA, GVG) was studied in an open trial in a group of 21 mentally handicapped patients with drug‐resistant epilepsy. 2. With this treatment one third of these patients had more than 50% reduction in seizure frequency. The anticonvulsant effect appeared during the first month of therapy and was maintained during a 7‐month study. The side effects were mild: mainly tiredness, aggressiveness, and ataxia. Other anticonvulsant drugs remained at baseline levels during GVG therapy. GVG was not found to modulate EEG recordings. 3. According to our results, GVG is effective for treating intractable epilepsy in mentally handicapped patients.
Effect of Wy‐45,727 on 24 h intragastric acidity in twenty normal volunteers.
Authors: Merki HS , Kaufmann D. , Kempf M. , Mappes A. , Heim J. , Roehmel J. , Walt RP
Published: July 2012

1. The effects of single daily doses of 20, 50 and 150 mg of WY‐45,727, a novel H2‐receptor antagonist, and placebo were compared using long term pH‐monitoring in 20 male volunteers. 2. Intragastric acidity was measured using combined Ingold glass electrodes. Subjects underwent four studies each under identical dietary conditions. Medication was taken after the evening meal. 3. Median 24 h pH rose from 1.3 (1.2‐1.4 interquartile range) on placebo to 1.9 (1.6‐2.8) on 20 mg WY‐45,727, to 3.1 (2.3‐3.7) on 50 mg WY‐45,727 and to 4.5 (3.7‐4.7) on 150 mg WY‐ 45,727. All three doses increased 24 h and night‐time pH significantly compared with placebo (P less than 0.0001). 4. The PAGE test for order effects confirmed clear dose dependent inhibition of acidity (P less than 0.0001). 5. Highly consistent individual responses were found during the night following 150 mg WY‐45,727.
Adenosine‐induced respiratory and heart rate changes in young and elderly adults.
Authors: Watt AH , Bayer A. , Routledge PA , Swift CG
Published: July 2012

The effects of intravenous boluses of adenosine on respiration and heart rate were compared in young and elderly individuals. Respiratory stimulation and biphasic changes in heart rate were confirmed. The dose‐ response relationship for the effects of adenosine on respiration and heart‐rate did not differ significantly between 10 young (mean age 25.2 +/‐ 4.9 years) and 10 elderly (mean age 66 +/‐ 3.1 years) drug‐free individuals, indicating that age is unlikely to be a major determinant of adenosine responsiveness.
The tubular excretion of benzylpenicillin in patients with cystic fibrosis.
Authors: Bins JW , Mattie H.
Published: July 2012

1. The tubular excretion of benzylpenicillin (BP) was investigated in six volunteers with cystic fibrosis. 2. The volunteers received a continuous infusion of BP at increasing infusion rates in order to maintain constant plasma concentrations at three different levels. Blood and urine samples were taken every 30 min. Sufficient urinary flow was ensured by a saline infusion (500 ml h‐1). 3. The renal clearance of BP was calculated for the non‐protein bound fraction of the drug. 4. Tubular clearance and tubular excretion rate were estimated from the renal clearance of the antibiotic minus the glomerular filtration rate; the latter was considered to be equal to creatinine clearance. 5. The data were analysed according to a Scatchard plot and values for ECu50 and maximal tubular excretion rate were calculated. The mean value of ECu50 was 89 +/‐ 24 (mg l‐1 +/‐ s.d.) and that for the maximal tubular excretion rate was 2603 +/‐ 714 (mg h‐1 +/‐ s.d.). The latter value was significantly less than that found in a previous study of healthy volunteers, but the ECu50 was similar. 6. It is concluded that the tubular excretory capacity for BP is decreased in patients with cystic fibrosis in direct relation to their low body weight.
Comparative effects of zofenopril and hydrochlorothiazide on office and ambulatory blood pressures in mild to moderate essential hypertension.
Authors: Lacourciere Y. , Provencher P.
Published: July 2012

1. Thirty‐eight patients with mild to moderate essential hypertension (seated diastolic 95‐110 mm Hg) were randomized double‐blind to treatment with either zofenopril (n = 19) or hydrochlorothiazide (n = 19) over a period of 12 weeks. 2. Office blood pressure, heart rate, side effects and metabolic changes were assessed at the end of the run‐ in period on placebo and after 4, 8, 12 weeks treatment at the same time, 22‐24 h after the last dosing. Ambulatory recordings over 14 h (8 h to 22 h) were performed at the end of placebo period and after active treatment for 12 weeks. 3. The two regimes reduced office blood pressures equally with minimal additional effect seen on increasing the dose. Both zofenopril and hydrochlorothiazide lowered average baseline ambulatory blood pressure, but zofenopril had greater efficacy in reducing BP during some working hours. 4. Adverse reactions were mild and transient with both drugs. There were no significant changes in laboratory values. 5. Thus hydrochlorothiazide and zofenopril given once daily at low dosage both reduce office and ambulatory blood pressures and are well tolerated.
Extensive oxidative metabolism of dextromethorphan in patients with almitrine neuropathy.
Authors: Belec L. , Larrey D. , De Cremoux H. , Tinel M. , Louarn F. , Pessayre D. , Gherardi R.
Published: July 2012

Almitrine bismesylate can induce a stereotypical sensory peripheral neuropathy probably through a toxic mechanism. High plasma concentrations of almitrine have been reported in a patient with neuropathy. Since large inter‐individual variations in plasma drug concentrations are found it is possible that the development of toxicity may be linked to genetically determined polymorphic oxidation of the drug. Oxidation phenotyping was performed in fifteen patients with almitrine neuropathy using dextromethorphan, a test compound subject to oxidative metabolism similar to that of debrisoquine. All patients were of the extensive metaboliser phenotype. This result shows that, in contrast to perhexiline neuropathy, almitrine neuropathy is not related to slow oxidation of the compound with regard to the particular P‐450 iso‐enzyme involved in dextromethorphan and debrisoquine metabolism.
Does a selective 5‐hydroxytryptamine antagonist (ICI 169, 369) lower blood pressure in hypertensive patients?
Authors: Scott AK , Roy‐Chaudhury P. , Webster J. , Petrie JC
Published: July 2012

1. The effect of single doses (10, 30 and 50 mg) of a selective 5‐HT2 receptor antagonist, ICI 169, 369, on blood pressure, heart rate and the electrocardiogram was studied using a double‐blind, placebo‐ controlled, within subject design in hypertensive patients. 2. ICI 169, 369 did not reduce blood pressure or increase QT interval as has been reported with ketanserin. This suggests that it is the other properties of ketanserin which are responsible for its antihypertensive effect. 3. Plasma concentrations of AUC for ICI 169, 369 were low. This is consistent with low bioavailability due to extensive first pass metabolism. 4. ICI 169, 369 was well tolerated and none of the symptoms reported by the patients was thought to be drug related.
The effect of a prostaglandin DP‐receptor partial agonist (192C86) on platelet aggregation and the cardiovascular system in healthy volunteers.
Authors: Gray SJ , Giles H. , Posner J.
Published: July 2012

1. PGD2 (DP)‐receptors mediate inhibition of platelet aggregation and vasodilatation. If receptor reserve were greater on platelets it might be possible to separate these effects. To determine whether such a difference in receptor reserve exists, we have examined the effects of a highly selective DP‐receptor partial agonist 192C86 on platelet aggregation and the cardiovascular system in healthy volunteers. 2. Using an open, dose‐escalating study design, four male volunteers received constant rate intravenous infusions of 192C86 for up to 60 min. Ex vivo platelet aggregation to ADP and collagen in platelet‐rich plasma (PRP) and whole blood (WB) was studied at baseline, after 15, 30 and 60 min of each infusion and at 180 min post‐infusion. Heart rate (HR), systolic and diastolic (DBP) blood pressure were measured at frequent intervals. Adverse experiences were monitored by checklist. Facial flushing was assessed by the volunteer using a visual analogue scale, by an observer using a numerical scale and by full‐face colour photographs. Blood was taken for assay of plasma 192C86 concentrations by radio‐immunoassay (r.i.a.). 3. 192C86 (0.007‐0.058 micrograms kg‐1 min‐1) inhibited platelet aggregation to ADP and collagen both in PRP and WB in a dose‐dependent manner. However, this was always accompanied by a decrease in DBP, increase in HR and facial flushing. Plasma concentrations of 192C86 were at or below the limits of sensitivity of the r.i.a. (0.5 ng ml‐1). 4. The highest infusion rate was stopped after 20 min due to symptomatic hypotension on standing.(ABSTRACT TRUNCATED AT 250 WORDS)
Perturbation of paracetamol urinary metabolic ratios by urine flow rate.
Authors: Miners JO , Osborne NJ , Tonkin AL , Birkett DJ
Published: July 2012

The effects of high and low urine flow rates on the urinary metabolic ratios for paracetamol glucuronidation, sulphation and oxidation were determined at steady‐state in seven healthy young adult volunteers. Metabolic partial clearances were unaffected by urine flow rate, but individual paracetamol metabolic ratios varied 2.5‐ to 3.2‐fold over a 7.4‐fold range of urine flow rates (0.81‐6.00 ml min‐1). The change in metabolic ratios was due entirely to a 2.5‐fold change in renal clearance of unchanged paracetamol. These data emphasise the limitations of the metabolic ratio as a measure of intrinsic clearance for compounds which undergo some degree of tubular reabsorption.
Effect of angiotensin converting enzyme inhibitors on erythropoietin concentrations in healthy volunteers.
Authors: Pratt MC , Lewis‐Barned NJ , Walker RJ , Bailey RR , Shand BI , Livesey J.
Published: July 2012

The possibility that the ACE inhibitors, enalapril and captopril, may decrease plasma EPO concentrations was studied in a single‐blind, cross‐ over study in 10 healthy volunteers. Plasma EPO concentrations, haemoglobin concentration, red blood cell count, plasma creatinine concentration and mean arterial pressure were measured at baseline and after 28 days treatment with both ACE inhibitors. A significant fall in mean plasma EPO concentration occurred with both ACE inhibitors and returned to baseline after stopping the drugs. It is likely that ACE inhibitors decrease EPO formation, by inhibition of angiotensin‐II production. This effect could be important in patients with renal failure, renal transplantation or other chronic conditions with an associated anaemia. Haematological parameters should be monitored in such patients when they are treated with an ACE inhibitor.
Blood cyclosporin concentrations and the short‐term risk of lung rejection following heart‐lung transplantation.
Authors: Best NG , Trull AK , Tan KK , Hue KL , Spiegelhalter DJ , Gore SM , Wallwork J.
Published: July 2012

1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart‐lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post‐operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post‐transplant and CyACb was found. During weeks 1‐3, the relative risk (RR) of rejection per unit increase in log(e) (5‐day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post‐operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5‐day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of tenidap sodium on the disposition and plasma protein binding of phenytoin in healthy male volunteers.
Authors: Blum RA , Schentag JJ , Gardner MJ , Wilner KD
Published: July 2012

1. The effects of tenidap sodium 120 mg day‐1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this randomised, double‐blind, placebo‐controlled, parallel‐group study, involving 12 healthy young men, conducted over 34 days. 2. Single oral doses of phenytoin 200 mg were given on days 1‐3 and 29‐31, and intravenous phenytoin, 250 mg infused over 20 min, was given on days 4 and 32. Tenidap (120 mg day‐1), or matching placebo, was administered as single oral daily doses from days 8 to 34 inclusive. 3. The plasma protein binding of phenytoin was determined immediately before oral phenytoin administration on days 1 and 29. Pharmacokinetic parameters were estimated from the serum phenytoin concentration‐time curves derived on days 4 and 32 following the phenytoin infusions. The differences between the pre‐ and post‐ treatment mean percentage of unbound plasma phenytoin and mean pharmacokinetic parameters were compared between treatment groups. 4. Tenidap sodium 120 mg day‐1, at steady state, increased the percentage of unbound phenytoin in plasma by approximately 25%, but did not significantly affect AUC(0,48h) or Cmax. 5. Since tenidap increases the percentage of unbound phenytoin in plasma, when monitoring phenytoin plasma concentrations free concentrations of phenytoin should be considered. 6. Tenidap was well tolerated throughout the study.
Herbal hepatotoxicity: a critical review
Authors: Teschke Rolf , Frenzel Christian , Glass Xaver , Schulze Johannes , Eickhoff Axel
Published: July 2012

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumedHILIcases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using theCouncil forInternationalOrganizations ofMedicalSciences scale (CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.
The utilization of solid organs for transplantation in the setting of infection with multidrug‐resistant organisms: an expert opinion
Authors: Bishara Jihad , Goldberg Elad , Lev Shaul , Singer Pierre , Ashkenazi Tamar , Cohen Jonathan
Published: July 2012

Organ transplantation remains the optimal treatment for many patients suffering from end‐stage organ disease. Increasing numbers of patients admitted to intensive care units, among them potential heart‐beating, brain‐dead organ donors, are exposed to infections with multidrug‐resistant organisms, in particular carbapenem‐resistant
Klebsiella pneumoniae (CR‐KP). An extensive literature search failed to reveal any information regarding the eligibility for transplantation of organs from such donors. For this reason, in 2009, the Israel Transplant Center, together with the Israeli Society for Infectious Diseases, established a working group with the intention of developing a national‐specific approach to the use of these organs. In this viewpoint article, we present an algorithm based on expert opinion and our clinical experience with a donor who was found to be an asymptomatic carrier of CR‐KP.