bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of nifedipine therapy in patients with sphincter of Oddi dysfunction: a prospective, double‐blind, randomized, placebo‐ controlled, cross over trial.
Authors: Khuroo MS , Zargar SA , Yattoo GN
Published: July 2012

1. Twenty‐eight patients who fulfilled entry criteria for sphincter of Oddi dysfunction were randomly allocated to receive nifedipine and placebo in a cross over design with 12 week treatment periods separated by a 2 week wash‐out. 2. All patients had episodic pain resembling biliary pain, had previously undergone cholecystectomy, had elevated alkaline phosphatase during episodes of pain and had elevated basal pressure on sphincter of Oddi manometry. 3. Compared with placebo, significant decreases in cumulative pain score, number of pain episodes, oral analgesic tablets consumed and emergency room visits were observed during nifedipine treatment. 4. Overall 21 patients improved during nifedipine therapy while seven patients did not. None of the following predicted response to nifedipine therapy: enzyme levels, morphine‐Prostigmine test, fatty meal sonography, common duct diameter and pressure, sphincter of Oddi phasic pressure, frequency and duration of phasic waves and maximal fall in the basal pressure at sphincter of Oddi manometry after sublingual administration of nifedipine. However patients with predominant antegrade propagation of phasic contractions of sphincter of Oddi did significantly better on nifedipine than those with abnormal propagation of phasic contractions. 5. Nifedipine therapy orally in maximal tolerated doses relieves pain in patients with sphincter of Oddi dysfunction who have elevated basal pressure and sphincter of Oddi phasic contractions of predominantly antegrade nature.
Sodium valproate acutely inhibits lamotrigine metabolism.
Authors: Yuen AW , Land G , Weatherley BC , Peck AW
Published: July 2012

Concomitant administration of sodium valproate (VPA) reduced lamotrigine (LTG) total clearance by approximately 21% and increased elimination half‐life and AUC. Reduced elimination occurred acutely within the first hour. Renal elimination of LTG was not impaired. The most probable explanation for this effect is hepatic competition between VPA and LTG for glucuronidation. Volume of distribution and parameters related to absorption, Cmax and tmax were unchanged.
In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum.
Authors: Basco LK , Gillotin C , Gimenez F , Farinotti R , Le Bras J
Published: July 2012

The in vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline was compared against chloroquine‐resistant and ‐ susceptible strains of Plasmodium falciparum using a semi‐micro drug susceptibility test. For each strain, the corresponding enantiomers exhibited similar activities. The enantiomers of halofantrine were the most active against both susceptible and resistant strains, followed by the enantiomers of mefloquine and enpiroline.
Recombinant hirudin, a new anticoagulant, has no effect on faecal blood loss.
Authors: Meyer BH , Luus HG , Muller FO , Badenhorst PN , Lotter MG , Rothig HJ , Grotsch H , Rosenkranz B
Published: July 2012

Hirudin is a selective thrombin inhibitor with strong anticoagulant properties which could elicit gastro‐intestinal bleeding. A double‐ blind cross‐over study of the effects of hirudin on gastro‐intestinal bleeding was therefore conducted on 12 healthy, consenting males. After labelling erythrocytes with 51Cr and returning them intravenously, stools were collected for 2 days to measure radioactivity and hence baseline faecal blood loss. After injection of hirudin or placebo stools were collected for 3 days. Partial thromboplastin time was measured sequentially after medication with hirudin or placebo. This procedure was repeated after injection of the alternate medication 1 week later. Hirudin was tolerated well. Mean faecal blood loss associated with hirudin was slightly higher than with placebo (1.63 ml vs 1.15 ml over 3 days; 95% confidence interval for the difference between hirudin and placebo was ‐0.68 to 1.63) but these differences are clinically irrelevant. After hirudin injection PTT was elevated to about twice the baseline values but returned to baseline within 12 h after the last hirudin injection.
Scintigraphic studies on the corneal residence of a New Ophthalmic Delivery System (NODS): rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine.
Authors: Greaves JL , Wilson CG , Birmingham AT , Richardson MC , Bentley PH
Published: July 2012

1. A gamma scintigraphic study has been carried out on the precorneal residence and pharmacodynamic action of a radiolabelled New Ophthalmic Delivery System (NODS) containing pilocarpine nitrate in 12 healthy volunteers. 2. The NODS was radiolabelled with the soluble marker technetium‐99m labelled diethylenetriaminepentaacetic acid, to mark the release characteristics of soluble drugs contained within the matrix. 3. The relationship between the precorneal residence time of the marker and the duration of drug effect on intraocular pressure and pupil diameter was monitored. Results obtained following administration of the NODS were compared with those obtained after administration of a 25 microliters drop of a 2% w/v pilocarpine nitrate solution. Each formulation was administered to one eye only, the other eye acting as a control. 4. Dissolution of the radiolabel from the NODS in vivo showed considerable intersubject variation with half‐times of dissolution ranging from 46 s to 833 s (mean +/‐ s.d. ‐280 +/‐ 217 s), the mean (+/‐ s.d.) half‐time of clearance of the radiolabel from the NODS and corneal region of interest was 406 +/‐ 214 s whereas the radiolabelled solution had a mean (+/‐ s.d.) ocular surface residence time of 2.9 +/‐ 1.5 s. 5. Pupil diameter and intraocular pressure were measured for 5 h post‐administration of the NODS and the solution. After both treatments pupil diameter was significantly constricted in the test eye when compared with the control eye (P less than 0.001; Student's paired t‐ test). Pupil diameter was constricted by 52% after administration of the NODS and by 35% after administration of the solution.(ABSTRACT TRUNCATED AT 250 WORDS)
Autoinduction and steady‐state pharmacokinetics of carbamazepine and its major metabolites.
Authors: Kudriakova TB , Sirota LA , Rozova GI , Gorkov VA
Published: July 2012

1. The effect of carbamazepine (CBZ) dose change on mean plasma concentrations of CBZ, its two metabolites and apparent steady‐state clearance was studied in 77 affectively ill patients receiving CBZ at doses of 100‐1200 mg day‐1. 2. Autoinduction of CBZ metabolism appeared to be complete within 1 week of starting CBZ therapy or dose change, and its degree was linearly related to CBZ daily dose. 3. Curvilinear plots were obtained for steady‐state concentrations of CBZ and its ‐ 10,11‐epoxide metabolite, and for the ratio of CBZ‐10,11‐epoxide to CBZ level, versus daily dose of CBZ. 4. On the contrary, steady‐state concentration of CBZ‐10,11‐diol increased proportionately with the dose. This indicates that there is no dose dependency in absorption of CBZ, and that dose‐dependent autoinduction of CBZ metabolism is the main cause of the curvilinear relationship between dose and steady‐ state concentration of CBZ and its intermediary metabolite, CBZ‐10,11‐ epoxide.
The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.
Authors: Poyhia R , Seppala T , Olkkola KT , Kalso E
Published: July 2012

1. The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross‐over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg‐1) and twice orally (0.28 mg kg‐1) at intervals of 2 weeks. A double‐blind randomized pretreatment with amitriptyline (10‐50 mg a day) or placebo was given prior to oral oxycodone. 2. The concentrations of oxycodone, noroxycodone and oxymorphone in plasma and the 24 h urine recoveries of their conjugated and unconjugated forms were measured by gas chromatography. 3. No differences were found between treatments in mean Cmax and AUC values of oxycodone which varied from 34 to 38 ng ml‐1 and from 208 to 245 ng ml‐1 h, respectively. The median tmax of oxycodone was 1 h in all groups. The bioavailability of oral relative to i.m. oxycodone was 60%. The mean renal clearance of oxycodone was 0.07‐0.08 l min‐1. The kinetics of oxycodone were unaffected by amitriptyline. 4. The mean ratio of the AUC(0.24 h) values of unconjugated noroxycodone to oxycodone was 0.45 after i.m. oxycodone and 0.6‐0.8 after oral oxycodone. Plasma oxymorphone concentrations were below the limit of the assay. Eight to 14% of the dose of oxycodone was excreted in the urine as unconjugated and conjugated oxycodone over 24 h. Oxymorphone was excreted mainly as a conjugate whereas noroxycodone was recovered mostly in an unconjugated form.
Inhaled budesonide fails to inhibit the PAF‐induced increase in plasma leukotriene B4 in man.
Authors: Nieminen MM , Moilanen EK , Koskinen MO , Karvonen JI , Tuomisto L , Metsa‐Ketela TJ , Vapaatalo H
Published: July 2012

1. We studied the ability of inhaled budesonide to modulate PAF‐induced acute effects in nine healthy nonsmoking volunteers. Responses in inflammatory cells and mediators in peripheral blood as well as in pulmonary function and circulation were monitored. 2. Inhalation of increasing doses of PAF (total cumulative dose of 500 micrograms) caused a rapid and profound decrease in circulating white blood cells, especially in granulocytes (P less than 0.01), which was turned to an increased number of these cells (P less than 0.05, P less than 0.025, respectively) in the blood samples taken 8 min after completion of the PAF challenge. No changes in the circulating platelets or their thromboxane production were found. Plasma concentrations of histamine or methylhistamine remained unchanged during PAF‐inhalation, while plasma LTB4 tripled from the baseline level at 10 min (P less than 0.0005) and was returned to the pre‐PAF value at 60 min. 3. PAF inhalation induced a bronchial obstruction (P less than 0.025), but no bronchial hyperresponsiveness to methacholine was found in any of our subjects when measured 24 h after the PAF challenge. Furthermore, PAF caused a decrease in systolic blood pressure (P less than 0.05). 4. Budesonide pretreatment of 400 micrograms twice daily during the preceding 5 days had no effect on any PAF‐induced events measured in our study. That fact may also contradict the role of bronchial resident or alveolar cells as a source of the PAF‐induced LTB4 burst in plasma. 5. We conclude that in healthy volunteers inhaled PAF induces a marked increase in plasma LTB4, which is not inhibited by inhaled budesonide.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of a protein meal on zidovudine pharmacokinetics in HIV‐ infected patients.
Authors: Sahai J , Gallicano K , Garber G , McGilveray I , Hawley‐Foss N , Turgeon N , Cameron DW
Published: July 2012

Eleven HIV‐infected men participated in a randomized, two‐treatment, two‐period crossover study to determine the effect of a 25 g protein meal on zidovudine pharmacokinetics. On two separate occasions, 1 week apart, each patient received 200 mg zidovudine in a fasting state or immediately following the protein meal. A protein meal significantly decreased Cmax [532 (228 s.d.) vs 802 (452 s.d.) ng ml‐1, P = 0.004] and increased mean residence time (138 (26 s.d.) vs 114 (26 s.d.) min, corrected for lag times, P = 0.001). However, AUC, tmax, terminal half‐ life and renal clearance were not significantly altered (P greater than 0.05). The power to detect a 20% change in AUC was 98% at the 5% significance level. In contrast to fat‐containing foods, protein‐based meals may not alter the extent of zidovudine absorption.
Medical management of hypercalcaemia.
Authors: Ralston SH
Published: July 2012

1. Hypercalcaemia is a common disorder, which frequently requires specific treatment either to control symptoms, or to prevent the development of irreversible organ damage or death. Although the best and most effective way of controlling hypercalcaemia in the long‐term is to treat the underlying cause, medical antihypercalcaemic therapy is often required in clinical practice, either as a holding measure, or because the primary disease cannot itself be treated. 2. The mainstays of medical antihypercalcaemic therapy are firstly, to promote calcium excretion by the kidney by restoring extracellular volume with intravenous saline and secondly, to administer pharmacological agents which inhibit bone resorption. Measures which seek to reduce intestinal calcium absorption are seldom effective. 3. Intravenous bisphosphonates are the treatment of first choice for the initial management of hypercalcaemia, followed by continued oral, or repeated intravenous bisphosphonates to prevent relapse. These drugs have a relatively slow onset of action (1‐3 days) but have potent and sustained inhibitory effects on bone resorption, resulting in a long duration of action (12‐ 30 days). 4. Of the other agents available, calcitonin has an important place in the management of severe hypercalcaemia where a rapid effect is desirable; calcitonin is best used in conjunction with a bisphosphonate however, because of its short duration of action. Intravenous phosphate also has a place in the emergency management of severe hypercalcaemia, but is probably best reserved for patients in whom other less toxic therapies have failed. Corticosteroids are generally ineffective except in certain specific instances and are best avoided in the routine treatment of undiagnosed hypercalcaemia.
Captopril augments both basal and frusemide‐induced natriuresis in normal man by suppression of circulating angiotensin II.
Authors: Motwani JG , Struthers AD
Published: July 2012

1. We studied the renal effects of reinfusing low dose angiotensin II (1 ng kg‐1 min‐1) into seven salt‐replete healthy volunteers after pretreatment with the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg) to establish whether the natriuretic and renal haemodynamic responses to ACE inhibition in normal man result from suppression of circulating angiotensin II. In the same subjects we also studied the effect of captopril (25 mg) with and without exogenous angiotensin II (1 ng kg‐1 min‐1) on the natriuretic response to intravenous frusemide (20 mg). 2. In the pre‐frusemide study captopril increased absolute and fractional excretion of sodium and paraaminohippurate clearance but had no effect on inulin clearance. 3. Reinfusion of angiotensin II after captopril pretreatment completely suppressed the renal effects of ACE inhibition, yielding renal vasoconstrictor and antinatriuretic effects equivalent to those produced by infused angiotensin II in the absence of captopril. 4. Frusemide increased renal sodium excretion without affecting paraaminohippurate or inulin clearance. Captopril augmented frusemide‐ induced natriuresis and again this effect was reversed by angiotensin II reinfusion. 5. We conclude that captopril augments both basal and frusemide‐induced renal sodium excretion in normal man. Our findings suggest that these renal responses to ACE inhibition may be mediated by inhibition of circulating angiotensin II, specifically its renal tubular salt‐retaining actions, rather than via effects on other neurohumoral systems.
Effects of granisetron and haloperidol, alone and in combination, on psychometric performance and the EEG.
Authors: Leigh TJ , Link CG , Fell GL
Published: July 2012

1. The effects of granisetron (160 micrograms kg‐1 body weight) and haloperidol (3 mg) on psychometric performance and the EEG were investigated in a randomised, single‐blind, crossover, placebo controlled study of 12 healthy male volunteers. 2. There was evidence that haloperidol impaired psychometric performance; however its effects on the EEG were not clear cut. In contrast there was very little evidence to suggest that granisetron had any impact on performance or the EEG. 3. The findings from this study suggest that granisetron does not impair daytime function and that it can be co‐administered with haloperidol without producing unwanted synergistic effects.
Inhibition of inhaled metabisulphite‐induced bronchoconstriction by inhaled frusemide and ipratropium bromide.
Authors: Bellingan GJ , Dixon CM , Ind PW
Published: July 2012

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double‐blind fashion, prior to construction of a dose‐response curve to metabisulphite (2.5‐100 mg ml‐1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4‐ 36 mumol) compared with 36 (16‐78) mumol after ipratropium bromide and 45 (22‐94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40‐57)% after placebo, 11 (0‐22)% after frusemide and ‐1 (‐25‐22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.
Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol.
Authors: Bannwarth B , Netter P , Lapicque F , Gillet P , Pere P , Boccard E , Royer RJ , Gaucher A
Published: July 2012

Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve‐root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half‐life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time‐course of paracetamol in CSF may parallel that of analgesic effect.
Lack of effect of flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan in healthy volunteers.
Authors: van Hecken AM , Depre M , De Schepper PJ , Fowler PA , Lacey LF , Durham JM
Published: July 2012

Twenty‐four healthy subjects completed a double‐blind, placebo controlled, parallel group study to evaluate the effect of treatment with flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan, a 5HT1‐like agonist. Subjects received a single oral 200 mg dose of sumatriptan on the eighth day of a once daily treatment with either flunarizine 10 mg or matching placebo. There were no significant differences between treatments in relation to Cmax (82.3 ng ml‐1 in the absence and 81.4 ng ml‐1 in the presence of flunarizine), AUC (368 ng ml‐1 h in the absence and 360 ng ml‐1 in the presence) and elimination half‐life (2.2 h in the absence and 2.4 h in the presence of flunarizine) of sumatriptan. Similarly pretreatment with flunarizine was not found to have any clinically significant effect on the pharmacodynamics of sumatriptan as measured by pulse rate, blood pressure and ECG.
Agreement and reproducibility of the estimates of cardiovascular function by impedance cardiography and M‐mode echocardiography in healthy subjects.
Authors: De Mey C , Matthews J , Butzer R , Schroeter V , Belz GG
Published: July 2012

The reproducibility and agreement of the estimates of stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) by transthoracic impedance cardiography (ZCG) and M‐mode echocardiography (ECHO) were analyzed before and after the placebo‐controlled administration of ascending doses of isosorbide dinitrate and nicorandil in 12 healthy subjects. There was no biostatistical agreement between the two methods in estimating cardiovascular function either before or after dosing (ZCG estimated substantially larger SV, CO and lower TPR). But, ZCG and ECHO estimated about similar overall treatment related changes (across treatments and periods) and reached substantially better agreement when the values were expressed as ratio of the baseline before dosing. Such improvement did not occur when the data were expressed as arithmetic difference from baseline. In spite of the improvement of agreement by expressing the data as ratio of baseline, the coefficients of reproducibility between the two methods (circa 25% of baseline) remained too large to judge the methods interchangeable.
Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.
Authors: McCulloch J
Published: July 2012

1. A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2. The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N‐methyl‐D‐aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3. The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4. NMDA receptor antagonists have marked effects on brain function in normal animals. The balance between these potential adverse effects and the anti‐ ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5. The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.
Assessment of bronchial effects following topical administration of butylamino‐phenoxy‐propanol‐acetate, an oculoselective beta‐ adrenoceptor blocker in asthmatic subjects.
Authors: Bauer KG , Brunner‐Ferber F , Distlerath LM , Lippa EA , Binkowitz B , Till P , Kaik GA
Published: July 2012

1. Butylamino‐phenoxy‐propanol‐acetate (BPPA) is a new topical oculoselective beta‐adrenoceptor blocker for the reduction of intraocular pressure (IOP) in man. Its potency on the airways of normal subjects was identical with that of placebo. A study was carried out to determine the potential of BPPA to cause bronchoconstriction in mild asthmatics (FEV1 greater than or equal to 60% predicted) with normal IOP. 2. Twelve nonsmoking outpatients who bronchoconstricted to 0.25 or 0.50% of timolol eye drops (fall in FEV1 23.33 +/‐ 1.20% (mean +/‐ s.e. mean), range 16‐30) were investigated in this double‐masked, randomized, 3‐period, crossover study. On three different occasions six incremental concentrations of BPPA (range: 0.1‐2%; maximum cumulative concentration 4%), timolol (0.1‐1%; 2%), and placebo were administered bilaterally until bronchoconstriction (decrease in FEV1 greater than or equal to 20% and in specific airway conductance (sGaw) greater than or equal to 35% simultaneously) or the maximum cumulative concentration was reached. 3. Airway response was measured as change in FEV1 and sGaw and dose‐response curves to timolol, BPPA and placebo were performed. IOP was measured 3 h after the highest concentration of each study day. 4. Timolol caused dose‐dependent falls in FEV1 and sGaw as well as clinical symptoms of respiratory distress in all subjects. The median cumulative concentrations of timolol required to decrease FEV1 by 20% and sGaw by 35% were 0.98% and 1.53%. Neither placebo (P greater than 0.05) nor BPPA (P greater than 0.05) caused a significant change in sGaw. A fall in FEV1 by 20% not accompanied by a simultaneous fall in sGaw by 35% was found in four subjects following BPPA and in five subjects following placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
Passage of S(+) and R(‐) gamma‐vinyl‐GABA across the human isolated perfused placenta.
Authors: Challier JC , Rey E , Bintein T , Olive G
Published: July 2012

1. The maternal to foetal transfers of S(+)‐ and R(‐)‐gamma‐vinyl‐GABA (VGB) across the human isolated perfused placenta were low and comparable with those of acidic alpha‐amino acids. 2. The placental uptake of the active S(+)‐isomer from the maternal circulation exceeded that of the R(‐)‐isomer and this was reflected by a corresponding difference in placental tissue concentrations. 3. During perfusion with recirculation of the foetal medium, the two enantiomers were present at a similar concentration and did not concentrate in foetal perfusate, indicating that the excess amount of S(+)‐VGB cleared from the maternal circulation was not accessible to the foetal perfusate. Furthermore, stable concentrations of both isomers in the foetal perfusate suggested a lack of placental metabolism. 4. Possible explanations of these findings include the operation of a stereoselective sodium‐dependent‐ GABA placental uptake system on the maternal side, similar to that observed in neuronal tissue, or stereoselective binding to a placental GABA transaminase.
Postmarketing surveillance of captopril for hypertension.
Authors: Chalmers D , Whitehead A , Lawson DH
Published: July 2012

1. A scheme for augmented spontaneous reporting of adverse drug events using advanced view data systems was developed and applied to study 67,698 consecutive patients prescribed captopril in general practice for the treatment of hypertension. 2. Captopril was an effective hypotensive agent in this population, as only 1.9% of patients were withdrawn because of apparent inefficacy. 3. Adverse effects of captopril resulted in withdrawal of treatment in 8.9% of recipients, and such effects were more frequent in elderly and female recipients. 4. Skin reactions‐usually maculopapular rashes‐tended to occur early during therapy whereas cough occurred much later and was reported more frequently in non‐smokers. 5. Some 1.1% of recipients died during follow‐up. There was no evidence of any unusual or unexpected causes of death which might be partially or totally captopril‐related in the study cohort. 6. The study confirms the feasibility of large scale postmarketing surveillance studied in general practice and allowed risk benefit assessments to be made on the use of captopril for treating hypertension.
Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off
Authors: Demolis P , Chalon S , Annane D , Duhaze P , Giudicelli JF
Published: July 2012

1. The effects of a single oral dose (10 mg) of ramipril on (a) systemic haemodynamics (arterial pressure, cardiac output), (b) carotid artery haemodynamics (blood flow and diameter, pulsed Doppler technique), (c) intracranial haemodynamics (middle cerebral artery mean blood velocity, transcranial Doppler technique), and (d) renin‐ angiotensin system (plasma converting enzyme and renin activities) have been investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double‐blind and cross‐ over study performed in six healthy volunteers. 2. Ramipril induced a strong and sustained inhibition of plasma converting enzyme activity (‐ 96% at 4 h, ‐63% at 24 h) and an increase in plasma renin activity (+993% at 8 h). 3. As compared with placebo, ramipril did not significantly affect arterial blood pressure, heart rate, cardiac output and total peripheral resistance. 4. Ramipril significantly increased carotid blood flow (by 27% at 8 h) without significantly changing carotid artery diameter, indicating, given the unchanged arterial pressure, an arteriolar vasodilation in the carotid territory. 5. The middle cerebral artery mean blood flow velocity underwent spontaneous modifications during the placebo period but these changes were not affected by ramipril. This lack of influence of ramipril on intracranial haemodynamics suggests that the drug‐induced arteriolar vasodilation and increase in carotid blood flow only concern the extracranial, musculo‐cutaneous part of the carotid territory.
N‐demethylation of ethylmorphine in pregnant and non‐pregnant women and in men: an evaluation of the effects of sex steroids.
Authors: Gerdin E , Rane A
Published: July 2012

1. The effects of oestrogens, testosterone, progesterone and medroxyprogesterone acetate (MPA) on the rate of N‐demethylation of ethylmorphine (EM) to norethylmorphine (NEM) were studied in human adult liver microsomes. 2. N‐Demethylase activity was found to be inhibited by progesterone and MPA to a similar extent while oestrogens and testosterone had no or negligible effects. 3. These findings prompted us to measure the N‐demethylation of EM in relation to serum progesterone concentration in vivo in three groups of volunteers with large physiological differences in their endogenous levels of progesterone, i.e. i) pregnant women, ii) non‐pregnant ovulating women and iii) men. 4. The metabolic ratio (MRP) of EM to NEM in plasma 60 min after dosage and the corresponding ratio in urine sampled for 6 h (MRU,1), measured on two occasions 14 days apart were used to reflect intraindividual variation in the rate of N‐demethylation. 5. The average difference in MRP and MRU,1 between the two occasions was similar in all groups. However, the variability in MRP between individuals within a group was significantly higher in ovulating women than in men, but this had no relation to the serum concentrations of progesterone or oestradiol. 6. The cumulative 12 h urinary excretion of EM, NEM and morphine (MO) after hydrolysis with beta‐glucuronidase was about 46%. There was no difference in the metabolic ratio of EM to NEM and its conjugate(s) in the urine between the luteal and the follicular phases. Our findings suggest that the menstrual cycle does not influence the rate of N‐demethylation of EM.
The effect of selective serotonin re‐uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes.
Authors: Crewe HK , Lennard MS , Tucker GT , Woods FR , Haddock RE
Published: July 2012

Inhibition of human cytochrome P4502D6 (CYP2D6)‐catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6‐catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.
Beta‐adrenoceptor antagonists enhance white blood cell aggregation in patients with ischaemic heart disease.
Authors: Bridges AB , Pringle TH , McNeill GP , Tavendale R , Belch JJ
Published: July 2012

The effects of beta‐adrenoceptor antagonists, calcium channel blockers and long acting nitrates on white blood cell (WBC) aggregation were studied in patients with ischaemic heart disease. WBC aggregation was significantly increased by beta‐adrenoceptor antagonists (P = 0.011) but was unaffected by either calcium channel blockers or long acting nitrates. Enhanced WBC aggregation promotes microvascular occlusion and damage.
Diffusion of cloxacillin into synovial tissue.
Authors: Mattie H , De Marie S , Slaghuis G , Rozing PM , van Strijen E
Published: July 2012

After a 30 min i.v. infusion of 1 g cloxacillin, the concentrations of this antibiotic were measured in plasma and synovial tissue samples from 11 patients undergoing total hip replacement. Assuming passive distribution between plasma and tissue the rate constants of distribution were estimated. The mean half‐life of distribution was 22 min. The concentration of free drug in synovial tissue was estimated to be 77% of the total tissue concentration. The maximum tissue drug concentration after an i.v. bolus dose is predicted to occur at about 37 min.
Do nitrates differ?
Authors: Fung HL
Published: July 2012

1. The organic nitrates all share a common biochemical and physiological mechanism of action. 2. The organic nitrates differ substantially in their pharmacologic potency and pharmacokinetics. In vitro potency differences appear larger than the corresponding in vivo activities. 3. The duration of action of organic nitrates, after a single immediate‐release dose, is governed by the pharmacokinetics of the drug. However, the duration of action of available sustained‐ release preparations, whatever the nitrate or formulation, is limited to about 12 h, due to the development of pharmacologic tolerance. 4. Nitrates do not appear to differ in their production of undesirable effects.
Prophylactic nitrate therapy in angina pectoris‐is there an optimal treatment regimen?
Authors: Olsson G , Allgen J
Published: July 2012

1. Nitrates have a place in the prophylactic treatment of patients with angina pectoris. Their efficacy is not in doubt. 2. However, there may be some practical problems associated with their use, such as unreliable absorption, short duration of action, treatment‐induced headache, development of nitrate tolerance and a suggested rebound phenomenon observed during intermittent dosing. Furthermore, patient convenience with treatment schedule and patient compliance have to be considered during prophylactic treatment. The present article discusses how many of these problems may be solved by selection of formulation as well as nitrate compound. 3. The development of controlled‐release formulations producing sufficiently high nitrate plasma concentration during part of the day followed by nitrate‐poor rather than nitrate‐ free interval, have the potential to prevent both nitrate tolerance and rebound phenomenon, and produce a sufficiently long duration of action with a convenient once daily regimen.
Effects of nitrates on mortality in acute myocardial infarction and in heart failure.
Authors: Held P
Published: July 2012

1. Seven randomized controlled trials of intravenous nitroglycerin in a total of about 850 patients have been reported. Overall, there were 51 deaths (12.5%) in the nitroglycerin group and 87 (20%) in the control group. This indicates a 48% reduction in the odds of death (P less than 0.001, 95% confidence limits (25% to 64%)). 2. There are five randomized trials of oral nitrates after acute myocardial infarction. In these trials, 11.8% of the patients in the nitrate group compared with 13.3% in the control group died. This indicates a nonsignificant 12% reduction in the odds of death but the 95% confidence interval overlaps widely with the i.v. trials. If all trials of i.v. or oral nitrates are considered the reduction in the odds of death is 32% (P less than 0.01). 3. Nitrates have a beneficial effect on haemodynamics in heart failure but the data on mortality effects are sparse. In combination with hydralazine, however, long‐term mortality was reduced in the V‐HEFT trial of chronic heart failure.
Clinical relevance of endothelium‐derived relaxing factor (EDRF).
Authors: Bassenge E
Published: July 2012

1. In addition to metabolic and neurohumoral factors endothelium‐ derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L‐arginine by a Ca2+/calmodulin‐ dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium‐dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L‐arginine supplementation is effective in a few instances.
Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO‐5334 after ascending single doses in post menopausal women
Authors: Nagase Shinichi , Hashimoto Yoshitaka , Small Maria , Ohyama Michiyo , Kuwayama Tomohiro , Deacon Steve
Published: July 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Cathepsin K plays a critical role in bone resorption where it degrades the major organic components of bone and cartilage.

• Therefore inhibitors of cathepsin K may offer clinical benefit in metabolic bone diseases characterized by accelerated bone resorption including osteoporosis.

WHAT THIS STUDY ADDS

• This phase I study in post menopausal women provides the first safety, tolerability, pharmacokinetic and pharmacodynamic data for single doses of the cathepsin K inhibitor, ONO‐5334.

• Morning administration of ONO‐5334 showed rapid and dose‐dependent suppression in bone resorption.

• This study shows that ONO‐5334 is safe, well tolerated and suppresses bone resorption and therefore shows potential as a new treatment for osteoporosis.

AIMS

To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO‐5334.

METHODS

A double‐blind, placebo‐controlled, randomized studywas carried out in 52 healthy post menopausal females. Single ascending doses of ONO‐5334 (3–600 mg) were evaluated in six cohorts. The effect of food was studied at ONO‐5334 100 mg.

RESULTS

Across the doses tested, mean ONO‐5334 Cmax occurred 0.5–1.0 h after dosing and the the t1/2 ranged from 9.1 to 22 h. Linear increases in Cmax and AUC(0,∞) were observed in the 3–300 mg and 3–600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) Cmax and AUC(0,∞) for ONO‐5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)‐fold greater than fasted, respectively. ONO‐5334 significantly reduced serum bone resorption markers within 4 h vs. placebo. Statistical significance was achieved for ONO‐5334 doses ≥30 mg for C‐terminal telopeptide of type 1 collagen (CTX) and ≥300 mg for N‐terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO‐5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of −32%, −59%, −60% and −66% for 30, 100, 300 and 600 mg ONO‐5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs. placebo. ONO‐5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship.

CONCLUSIONS

ONO‐5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3–300 mg, with clear suppression of urinary bone resorption markers at doses ≥100 mg for serum markers at 24 h. ONO‐5334 was well tolerated up to 600 mg day–1 when administered to healthy post menopausal women.
Post‐secondary transitions of youth emancipated from foster care
Authors: Batsche Catherine , Hart Sarah , Ort Rhonda , Armstrong Mary , Strozier Anne , Hummer Victoria
Published: July 2012

This study investigated the extent to which KnowHow2Go (KH2Go), a national college access campaign developed for first‐generation students in the USA, would resonate with youth who had aged out of foster care. Interviews were conducted with 27 youth who were enrolled in a post‐secondary programme following emancipation from foster care. We found KH2Go to have a close fit with the experiences of youth who had been in foster care. Four topics emerged as particularly important for youth in our study: money management, work, parenting and transportation. Finally, the study identified attributes these youth demonstrated that contributed to their resilience during the transition process. This study and the data presented pertain to youth living in the south‐eastern USA.
Evaluating the relationship between basin‐scale fish species richness and ecologically relevant flow characteristics in rivers worldwide
Authors: IWASAKI YUICHI , RYO MASAHIRO , SUI PENGZHE , YOSHIMURA CHIHIRO
Published: July 2012

1. River flow alterations due to climate change and increasing water usage affect freshwater biodiversity including fish species richness. Here, we statistically explored the relationships of fish species richness to 14 ecologically relevant flow metrics as well as basin area and latitude in 72 rivers worldwide.

2. The statistical models best supported by the data included three variables with positive coefficients (mean river discharge, basin area and the maximum proportion of no‐flooding period) and three variables with negative coefficients (latitude, coefficients of variation in the frequency of low flow and the Julian date of annual minimum flow).

3. The model outputs have provided the first empirical indication that specific low‐ and high‐flow characteristics may be important in explaining variations in basin‐scale fish species richness. Our findings can be useful in identifying high‐risk basins for conservation of fish species diversity.

4. The results not only support the adoption of mean discharge as a predictor, but also suggest the importance of basin area in predicting basin‐scale fish species richness around the world.
Sirius Passet, Greenland and the Cambrian Explosion
Authors: Brooks Kent
Published: July 2012

Throughout Earth history there have been many important milestones: e.g. the emergence of life, the rise of oxygen in the atmosphere, snowball Earth events. One of these major events was the emergence of multicellular life, which, as we are all told in Palaeontology lectures, took place in the Cambrian, when a sudden flowering of life forms emerged, including all of the major groups we have today: the ‘Cambrian explosion’. Two great questions emerge: what happened before this (a problem which worried Darwin as it seemed to threaten his thesis of steady evolution) and how, in detail did this ‘explosion’ take place?
The Dodo: from extinction to the fossil record
Authors: Hume Julian P.
Published: July 2012

The dodo, Raphus cucullatus (Aves, Columbidae), has become one of the most famous birds in the world, a true icon of extinction. Known from a few contemporary illustrations and accounts, probably more has been written about it than any other species, yet we know practically nothing about the bird in life. Recent excavations on Mauritius are now revealing the ecology and habitat of this iconic bird, and providing new information as to why it was so vulnerable to human interference.
Serpentinite
Authors: Pereira Dolores , Peinado Mercedes
Published: July 2012

Serpentinites are metamorphic rocks formed from the alteration of ultramafic igneous rocks. Their precursors largely consist of clinopyroxene, orthopyroxene, olivine and a member of the spinel group, along with other accessory minerals. Serpentinization can be produced through the percolation of fluids of different origins. The transformation gives rise to other rocks, serpentinites, that are characterized by a high‐water content mineralogy (serpentine) and, sometimes, remnants of the original phases. However, serpentinites may also undergo a subsequent carbonation process, transforming most of the mineral phases into carbonates. This is why confusion may arise when dealing with these rocks in the industrial sector, where geologists are not often involved. Serpentinites are often found in natural stone catalogues under the name of ‘green marble’ and this can be misinterpreted by builders and architects, causing misuse of this rock as an ornamental stone.
Security services as coping mechanisms: an investigation into user intention to adopt an email authentication service
Authors: Herath Tejaswini , Chen Rui , Wang Jingguo , Banjara Ketan , Wilbur Jeff , Rao H. Raghav
Published: July 2012

Email plays an important role in the digital economy but is threatened by increasingly sophisticated cybercrimes. A number of security services have been developed, including an email authentication service designed to cope with email threats. It remains unknown how users perceive and evaluate these security services and consequently form their adoption intention. Drawing on the Technology Acceptance Model and Technology Threat Avoidance Theory, this paper investigates the factors that affect user intention to adopt an email authentication service. Our results show that user intention to adopt an email security service is contingent upon users' perception of risk and evaluation of both internal and external coping strategies. This study contributes to research in security service adoption, service success and design, and information security behaviour.
Antimicrobial efficacy of a high‐power diode laser, photo‐activated disinfection, conventional and sonic activated irrigation during root canal treatment
Authors: Bago I. , Plečko V. , Gabrić Pandurić D. , Schauperl Z. , Baraba A. , Anić I.
Published: July 2012

Aim

To evaluate the antimicrobial effect of a diode laser irradiation, photo‐activated disinfection (PAD), conventional and sonic activated irrigation with 2.5% sodium hypochlorite (NaOCl) on Enterococcus faecalis.

Methodology

Root canals of 120 human extracted teeth with single straight canals were prepared with ProTaper files, sterilized, contaminated with an E. faecalis suspension and incubated for 7 days. They were then randomly distributed into six groups: G1, diode laser irradiation (2 W, 3 × 20 s); G2, PAD (100 mW, 60 s); G3, PAD with 3D Endoprobe (100 mW, 60 s); G4, 30‐gauge syringe irrigation with NaOCl (60 s); G5, sonic agitation of NaOCl with the EndoActivator system (60 s); G6, 30‐gauge syringe irrigation with NaCl (60 s). The pattern of colonization was visualized by scanning electron microscopy. The root canals were sampled by flushing with saline solution at baseline and after the treatments. The number of bacteria in each canal was determined by plate count. The presence and the absence of E. faecalis in root canals were also demonstrated by polymerase chain reaction (PCR).

Results

There was a significant reduction in the bacterial population after all treatments (P < 0.001). The PAD, using both laser systems, and the sonic activated NaOCl irrigation were significantly more effective than diode irradiation and single NaOCl irrigation in reducing CFUs (P < 0.05). High‐power diode laser and single NaOCl irrigation had an equal antibacterial effect (P > 0.05).

Conclusions

The PAD and EndoActivator system were more successful in reducing the root canal infection than the diode laser and NaOCl syringe irrigation alone.