bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortisol does not inhibit prednisolone clearance.
Authors: Meffin PJ , Sallustio BC , Purdie YJ , Robson RA , Wing LM , Brooks PM
Published: July 2012

The disposition of prednisolone has been studied in eight male subjects with and without the concomitant administration of cortisol which produced plasma cortisol concentrations 10‐fold higher than endogenous levels. The clearance and steady‐state distribution volume of total prednisolone were increased as was the prednisolone free fraction but the clearance of unbound prednisolone was unaltered by cortisol co‐ administration.
No effect of ethanol ingestion on beta‐adrenoceptor‐mediated circulatory responses to isoprenaline in man.
Authors: Eisenhofer G. , Lambie DG , Johnson RH
Published: July 2012

The acute effects of ethanol on circulatory responses to isoprenaline and atropine were investigated in 21 and 15 normal male subjects respectively. Each subject acted as his own control by participating twice, once after consumption of ethanol (1.0 ml kg‐1, 20% v/v in orange juice) and once after orange juice. Ethanol increased baseline heart rate and forearm blood flow, but had no effect on heart rate and forearm blood flow responses to isoprenaline, or on heart rate responses to atropine. Baseline blood pressure and blood pressure responses to isoprenaline were also unaffected by ethanol. It is concluded that acute ethanol ingestion has no physiologically significant effect on beta‐adrenoceptor responsiveness as assessed by the cardiovascular responses to bolus doses of isoprenaline.
Pharmacokinetics of flestolol in man: preliminary data.
Authors: Achari R. , Hulse JD , Drissel D. , Matier WL
Published: July 2012

The steady state pharmacokinetics of flestolol, a short acting beta‐ adrenoceptor blocking agent, were studied in six healthy subjects following intravenous infusion of six different doses; 18, 24, 35, 50, 75 and 100 micrograms kg‐1 min‐1, for 60 min. Steady state blood levels increased linearly with dose for all six subjects. The overall mean half‐life was 6.5 min. The total body clearance averaged 208 ml min‐1 kg‐1 indicating significant extrahepatic metabolism of the drug. There were no significant changes in the half‐lives or the total body clearances after the six doses, suggesting that the kinetics of flestolol are linear over the dose range studied.
The effect of nicardipine on glucose and drug‐stimulated insulin secretion in normal volunteers.
Authors: Dow RJ , Baty J. , Isles TE
Published: July 2012

The effect of nicardipine on insulin secretion was examined in two double‐blind, randomised, cross‐over, placebo‐controlled studies in normal volunteers. In the first study, the effect of acute dosing (via an intravenous infusion of 5 mg h‐1 for 3 h) on the glucose, insulin, hormonal, and intermediary metabolite responses to an intravenous glucose tolerance test was determined in six healthy male volunteers. In the second study, the glucose, insulin, and C‐peptide responses to intravenous tolbutamide (200 mg) was determined in another six male volunteers after oral dosing with nicardipine 30 mg three times daily for 1 week. A relative increase in insulin secretion was the principal finding of the first study. No other response was affected significantly. No significant differences between the nicardipine‐ and placebo‐treated groups were noted in the insulin, glucose, and C‐ peptide measurements of the second study. In conclusion, treatment with nicardipine does not appear to impair insulin secretion in response either to an intravenous glucose load or intravenously administered tolbutamide.
The effect of nicardipine on pituitary hormone release in normal volunteers.
Authors: Isles TE , Baty J. , Dow RJ
Published: July 2012

In a double‐blind, placebo‐controlled, randomised, cross‐over study of six healthy male subjects, the effect of nicardipine (5 mg h‐1 for 3 h) on basal and stimulated pituitary hormone release was examined. Statistically significant differences between nicardipine and placebo were seen occasionally for follicle‐stimulating hormone, luteinising hormone and prolactin, but not for thyroid‐stimulating hormone. These differences were always within the between‐batch coefficient of variation of the assay. The overall differences in both basal and stimulated results for all four pituitary hormones were not statistically significantly different. It is concluded, therefore, that nicardipine has no significant effect on either basal or stimulated pituitary hormone release in healthy male subjects.
A comparison of the gastric and central nervous system effects of two substituted benzamides in normal volunteers.
Authors: McClelland GR , Sutton JA
Published: July 2012

Eight healthy male volunteers participated in a single‐blind, random allocation, crossover, comparison of intravenous metoclopramide (10 mg), the peripherally acting, gastrointestinal stimulant BRL 20627 (10 mg) and saline. The central nervous system effects were assessed by quantitative electroencephalography (EEG) and by visual analogue scales. Gastric motility and emptying were assessed by epigastric impedance. Metoclopramide increased the EEG amplitude by 10.4% (a statistically significant, P less than 0.05, effect) and increased frequencies above 22 Hz, whereas both BRL 20627 and placebo had only minor effect on the EEG frequencies and slightly decreased the EEG amplitude. Ratings on visual analogue scales showed that metoclopramide caused statistically significant (P less than 0.01 difference from placebo) restlessness and slight but significantly less (P less than 0.05 difference from placebo) feeling of happiness. Epigastic impedance changes indicated that both metoclopramide and BRL 20627 increased gastric contractile activity, but the rate of gastric emptying was not significantly altered by either drug although it tended to be shortened following metoclopramide but not BRL 20627 treatment. It is concluded that since the published animal data show that BRL 20627 has only weak dopamine antagonistic properties this study further implicates dopamine receptor blockade in the akathisia but not in the gastric effect of metoclopramide.
Pharmacokinetics of antipyrine in epileptic patients.
Authors: Rimmer EM , Routledge PA , Tsanaclis LM , Richens A
Published: July 2012

The pharmacokinetics of antipyrine were examined after oral and intravenous administration to 20 epileptic subjects receiving antiepileptic drug therapy. Bioavailability was essentially complete (mean bioavailability 101.2% +/‐ 14.4 (s.d.] indicating that even in enzyme induced subjects, antipyrine behaves as a restrictively eliminated compound with negligible presystemic elimination in the gut or liver. Of the generally used measures of enzyme induction (oral clearance, oral half‐life and intravenous half‐life) oral clearance was the most closely related to the intravenous clearance of antipyrine (r = 0.919, P less than 0.001). Oral antipyrine administration is an alternative to intravenous administration in epileptic subjects who are enzyme‐induced.
Is biliary excretion of paracetamol significant in man?
Authors: Jayasinghe KS , Roberts CJ , Read AE
Published: July 2012

The extent of biliary excretion of paracetamol and its principal metabolites was studied in 10 healthy adults. Duodenal intubation was performed approximately 12 h after an oral dose of 1 g paracetamol. Duodenal fluid was aspirated following intravenous cholecystokinin, and urine was collected for 12 h after dosing. The mean concentration of the cysteine and glucuronide conjugates in the bile was 253.7 +/‐ 39.0 micrograms ml‐1 (s.e. mean) and 69.3 +/‐ 15.3 micrograms ml‐1, respectively. The mean recoveries of the cysteine and glucuronide conjugates in the bile were 6.0 +/‐ 1.5 mg and 1.2 +/‐ 0.41 mg, respectively. The bile is an important route of elimination for the cysteine conjugate and accounts for 19.4 +/‐ 4.4% of the total excretion of the metabolite. The fate of the biliary excreted conjugates is not known, and needs further investigation.
Food induced changes in theophylline absorption from a once‐a‐day theophylline product.
Authors: Steffensen G , Pedersen S
Published: July 2012

Bioavailability and the absorption pattern of theophylline from the sustained release theophylline (SRT) product, Uniphyllin, were studied in eight adults and eight children under fasting conditions in the morning, after a standardised breakfast in the morning, and under fasting conditions in the evening (adults only). Theophylline given intravenously was used as a reference. The extent of absorption of theophylline was complete for all administrations of SRT both in adults and children. In adults the absorption profiles after the three administrations of SRT were very similar and at no time point was there any difference in serum theophylline concentration or fraction absorbed between the three regimens. In addition, inter and intra individual variations in absorption were small. In children food caused a substantial change in the absorption pattern of theophylline so that the profiles became rather unpredictable with delays in absorption and periods of rapidly increasing serum drug concentrations. In three of the patients the dose dumping phenomenon resulted in toxic serum drug concentrations. Dumping of the dose could take place at any time interval between 3 and 15 h post dosing. Cmax was about 50% higher after fed than after fasting medication (P less than 0.01). It is concluded that children should not take SRT in large doses in combination with food.
The effect of isoxicam‐aspirin combinations on the polyurethane sponge implantation model in the rat.
Authors: Garrett R , Manthey B , Vernon‐Roberts B , Brooks PM
Published: July 2012

1 Anti‐inflammatory effects of isoxicam alone and in combination with aspirin were studied in rats using the polyurethane sponge implantation model of acute inflammation. 2 Dose‐response studies were performed to delineate a suppressive (high) and non‐suppressive (low) dose of isoxicam prior to studying these doses in combination with aspirin. 3 The results indicate that a combination of aspirin with isoxicam does not have an additive anti‐inflammatory effect. 4 The interference demonstrated by aspirin with the anti‐inflammatory effects of other NSAIDs such as indomethacin is also demonstrated with aspirin/isoxicam combinations.
Adimolol, a long acting beta‐adrenoceptor blocker in man.
Authors: Elliott HL , Jones CR , Deighton NM , Meredith PA , Reid JL
Published: July 2012

A comparative study in eight healthy normotensive males of the effects on blood pressure, heart rate and beta‐adrenoceptor function following single oral doses of adimolol (600 mg), propranolol (240 mg) and placebo. Both active treatments produced small but significant reductions in blood pressure and heart rate, supine and erect. These effects persisted for up to 7 days after adimolol. The heart rate increases following both dynamic exercise and intravenous isoprenaline were attenuated by both propranolol and adimolol. With adimolol evidence of functional beta‐adrenoceptor antagonism was sustained for up to 7 days. Lymphocyte beta‐adrenoceptor binding studies showed that both adimolol and propranolol significantly reduced affinity for beta‐ adrenoceptors. In addition, adimolol significantly reduced receptor number and even by 3 days after dosing Bmax had only returned to half the control value. In a small sub‐group of subjects there was no evidence to suggest that adimolol had additional alpha‐adrenoceptor antagonist properties. Adimolol was detected in plasma for up to 3 days after dosing. The mean terminal elimination half‐life was 14 h, compared to 3 h for propranolol. This study confirms that adimolol has prolonged beta‐adrenoceptor antagonist activity with effects persisting for up to 7 days after a single dose. The reduction in beta‐ adrenoceptor number following adimolol suggests that this prolonged effect may not be solely due to competitive antagonism but may additionally depend upon non‐competitive antagonism at beta‐ adrenoceptors.
Responses to mental stress and physical provocations before and during long term treatment of hypertensive patients with beta‐adrenoceptor blockers or hydrochlorothiazide.
Authors: Eliasson K , Kahan T , Hylander B , Hjemdahl P
Published: July 2012

1 Cardiovascular and sympatho‐adrenal responsiveness to mental stress (CWT; a colour word test), orthostatic testing (ORT) and a cold pressor test (CPT) were examined in three groups of hypertensive patients (n = 14‐16) before and after 6 months treatment with metoprolol (243 +/‐ 26 mg daily), propranolol (149 +/‐ 16 mg daily) or hydrochlorothiazide (50 +/‐ 8 mg daily) in an open trial design. 2 Treatment reduced outpatient blood pressures in the three groups similarly (from approximately 155/102 to 135/90 mm Hg). During treatment resting blood pressures in the laboratory were clearly reduced by beta‐adrenoceptor blockade but not by thiazide treatment. Metoprolol and propranolol caused similar reductions of basal heart rates and plasma glycerol levels, whereas only propranolol reduced cyclic AMP concentrations in plasma. 3 Before treatment CWT and CPT increased systolic and diastolic blood pressures by about 30%. Heart rate increased by about 30 beats min‐1 during CWT and 10‐15 beats min‐1 during CPT and ORT. Small venous plasma adrenaline responses were evoked by all tests, whereas noradrenaline was elevated mainly by CPT and ORT. Dopamine levels did not change. 4 Heart rate responses to all stressors were markedly and similarly reduced, whereas blood pressure responses were essentially unchanged during metoprolol or propranolol treatment. In the thiazide group circulatory responses to CWT were slightly attenuated, whereas responses to ORT and CPT were unchanged. 5 The systolic blood pressure levels were reduced throughout the test session in all three groups, although less so in the hydrochlorothiazide group. Both beta‐ adrenoceptor antagonists clearly reduced diastolic blood pressure and heart rate levels at rest and during stress, whereas thiazide treatment caused no significant changes in these respects. 6 The rate pressure product, which increased by 80‐100% in response to CWT before treatment, was more markedly reduced by beta‐adrenoceptor blockade than by thiazide treatment both at rest and during stress. 7 Self ratings (visual analogue scales) of stress and irritation were increased by CWT in a similar fashion before and during treatment in all groups. beta‐ adrenoceptor blockade was associated with higher subjective ratings of tiredness at rest, but not after CWT. Performance in the CWT increased slightly more in the thiazide group. The physiological responses to CWT were not correlated to the subjective responses.(ABSTRACT TRUNCATED AT 400 WORDS)
Immediate effects of bumetanide on systemic haemodynamics and left ventricular volume in acute and chronic heart failure.
Authors: Verma SP , Silke B , Reynolds G , Muller P , Frais MA , Taylor SH
Published: July 2012

1 The haemodynamic and radionuclide effects of i.v. bumetanide (25 micrograms kg‐1) were prospectively studied in 24 patients with angiographically documented coronary artery disease and either acute exercise‐induced (Group I, n = 12) or chronic (Group II, n = 12) heart failure. 2 Bumetanide at rest increased systemic arterial blood pressure and vascular resistance index; cardiac index and pulmonary artery occluded pressure (PAOP) were reduced at an unchanged heart rate in all patients. The left ventricular ejection fraction fell in patients with normal resting left ventricular filling pressure without change in those with chronic heart failure. The cardiac volumes were unchanged in either group. 3 During constant‐load supine bicycle exercise, there were similar effects on systemic arterial pressures, vascular resistance index and PAOP; however the cardiac index was maintained at a reduced left ventricular filling pressure and unchanged ejection fraction and volumes. 4 These data demonstrate immediate mild pressor and vasoconstrictor actions of bumetanide which appear independent of the state of cardiac function; they suggest that any immediate improvement in patient symptomatology following bumetanide may be consequent on the reduction in PAOP; short‐term reductions in volume may not occur.
Pharmacokinetics and metabolism of salbutamol in premature labour.
Authors: Hutchings MJ , Paull JD , Wilson‐Evered E , Morgan DJ
Published: July 2012

1 The pharmacokinetics of salbutamol and its sulphate conjugate were examined during intravenous and steady‐state oral administration in nine patients receiving the drug for the prevention or treatment of premature labour. 2 Uterine contractions were inhibited by plasma salbutamol concentrations in the range 8‐33 ng ml‐1 in six of the seven patients who were receiving intravenous drug. 3 By comparison with our previous study in a control group of healthy males and nonpregnant females, the total clearance of salbutamol in premature labour (501; s.d. 185 ml min‐1) was similar to that in the control group (480; s.d. 123 ml min‐1). Renal salbutamol clearance (208; s.d. 51 ml min‐1), however, was significantly less than that in the control group (283; s.d. 51 ml min‐1). 4 The systemic availability (n = 3), urinary recovery of unchanged oral salbutamol and area under the plasma curve during the oral dosage interval (n = 5) were all only slightly lower (10‐20%) than control values, suggesting slightly lower oral absorption. 5 Formation and elimination of the sulphate conjugate were similar to those observed in control subjects suggesting that first‐ pass sulphation in the gut wall is unchanged in pregnancy. Overall there were only minor differences in salbutamol pharmacokinetics between control subjects and patients in premature labour.
Pharmacokinetics of pentopril in the elderly.
Authors: Rakhit A , Kochak GM , Tipnis V , Radensky P , Hurley ME , Williams R
Published: July 2012

1 The pharmacokinetics of pentopril in elderly subjects aged 70 to 75 years were compared with those of healthy young subjects aged 22 to 26 years. 2 There were no appreciable differences between the two groups in any of the pharmacokinetic parameters for pentopril derived from its plasma data (Cmax, tmax, AUC and t1/2). 3 In contrast, the active metabolite CGS 13934 exhibited an increase in mean values of AUC by 56% in elderly compared to young. However, the difference was not statistically significant (0.1 greater than P greater than 0.05). The variability was, however, significantly higher (P less than 0.05) in the elderly group compared with young. The peak time for metabolite was also significantly delayed in elderly (3.9 vs 2.5 h). The mean half‐ life for metabolite however, was comparable for the two groups (3.6 vs 3.9 h). 4 Urinary analysis showed a significant decrease in renal clearance (CLR) with age for both pentopril (107 vs 203 ml min‐1) and its active metabolite (116 vs 205 ml min‐1). 5 Pharmacodynamic measurements of the renin‐angiotensin system, in general, demonstrated a drug effect at 2 h with recovery almost to the basal value at 24 h except for plasma ACE activity at 24 h in the elderly. 6 Because of large variability and an increase in the mean AUC of active metabolite in elderly, greater caution may be necessary for dose selection in this group. However, no substantial difference in extent of drug accumulation is anticipated in elderly compared with young people based on the similarity in t1/2 values.
Determinants of free theophylline clearance in asthma.
Authors: Williams PE , Alwazir YA , Littley M , Buss DC , John R , Campbell IA , Routledge PA , Lazarus JH
Published: July 2012

1. The free and total plasma and saliva concentrations of theophylline were measured during a dosing interval at steady state in nineteen asthmatic subjects receiving a once‐daily theophylline preparation (Riker TCR‐1). 2. Saliva theophylline clearance (mean +/‐ s.d. 5.8 +/‐ 2.1l h‐1) was closely related to total plasma theophylline clearance (mean 3.6 +/‐ 1.2l h‐1) (r = 0.958, n = 19, P less than 0.001). 3. Saliva theophylline clearance was closely related (r = 0.967, n = 19, P less than 0.001) and numerically very similar to the free plasma theophylline clearance (mean 5.8 +/‐ 1.9l h‐1) (mean difference = 0.06 +/‐ 0.12 s.e. mean). 4. Free plasma theophylline clearance was significantly, although weakly, related to body weight and to the plasma free thyroxine concentration which together accounted for over 40 per cent of the variability in free clearance. 5. Theophylline administered for 2 weeks did not affect plasma free thyroxine (FT4) free tri‐iodothyronine (FT3) or reverse tri‐iodothyronine (rT3) concentrations compared with placebo.
Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.
Authors: Imbimbo BP , Urso R , Thieme G , Sturn B , Ueckert B , Vidi A , Ladinsky H , Daniotti S
Published: July 2012

1. The pharmacokinetics of mifentidine, a new long acting histamine H2‐ receptor antagonist, were studied using two protocols. 2. In one study, on 5 different days six normal male subjects were given 2.5, 5, 10, or 20 mg mifentidine or placebo orally 60 min before starting a 3 h continuous gastric aspiration during which time blood samples were taken for measurement of mifentidine concentration. 3. The area under the curves of mifentidine plasma levels (AUC) vs time for the four doses was linearly related to the dose for each individual subject (r = 0.972, P less than 0.001). After doses of 2.5, 5, 10 and 20 mg, mifentidine reduced hydrogen ion output by respectively 36, 37, 60 and 75% and secretory volume by 1, 17, 40, and 47%. The effects at the two highest doses were statistically significant. AUC was correlated positively with the percentage reduction in hydrogen ion output (r = 0.802, P less than 0.001) and volume (r = 0.834, P less than 0.001) over a 3 h period. 4. In the second study, the pharmacokinetics were evaluated after once‐daily treatment for 14 days in seven subjects given 10 mg and in seven others subjects given 20 mg. 5. After multiple dosing, renal clearance was similar for the two doses (11.6 +/‐ 2.11 l h‐1 for the low dose and 17.0 +/‐ 2.0 l h‐1 for the high dose). Plasma half‐life (t1/2 lambda 2) was 16.0 +/‐ 3.0 h after the 10 mg dose and 11.9 +/‐ 1.2 h after 20 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of oral activated charcoal on quinine elimination.
Authors: Lockey D. , Bateman DN
Published: July 2012

The effect of repeated dose oral activated charcoal on quinine elimination has been studied following a therapeutic (600 mg) dose of quinine bisulphate to seven normal volunteers. Activated charcoal lowered quinine half‐life from 8.23 +/‐ 0.57 s.d. h to 4.55 +/‐ 0.15 s.d. h (P less than 0.001) and increased its oral clearance by 56%. Activated charcoal may have a role in the management of quinine poisoning.
Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose.
Authors: Passmore AP , Whitehead EM , Johnston GD
Published: July 2012

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter‐treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin‐angiotensin‐ prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.
Effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin in healthy volunteers.
Authors: Apseloff G , Wilner KD , Gerber N
Published: July 2012

1. An open‐label, randomised study was performed to assess the effect of tenidap sodium on the pharmacodynamics and plasma protein binding of warfarin. 2. Fourteen healthy male volunteers received either a single oral dose of 120 mg tenidap sodium or matching placebo capsules from days 11 to 36. A single oral dose of 0.75 mg kg‐1 warfarin was administered on days 1 and 32. 3. The mean prothrombin AUC(1,120h) value between baseline and day 32 increased from 1692.4 +/‐ 234.5 s h to 1769.3 +/‐ 218.0 s h in the group given tenidap, and decreased from 1747.6 +/‐ 289.4 s h to 1708.1 +/‐ 236.8 s h in the placebo group. 4. Tenidap caused a slight delay in the normalisation of prothrombin times following the second dose of warfarin on day 32 compared with the first dose on day 1. This was significant at 36, 48, 72 and 96 h but not at 120 h after administration of warfarin. 5. The mean percentage of unbound warfarin in the tenidap group (0.08% +/‐ 0.09) was significantly different (P = 0.047) from that in the placebo group (‐ 0.03% +/‐ 0.10) but this was not considered to be clinically meaningful. 6. These data indicate that prothrombin times should be monitored during concomitant administration of tenidap and warfarin.
Tenidap sodium does not alter the clearance or plasma protein binding of tolbutamide in healthy male volunteers.
Authors: Wilner KD , Gardner MJ
Published: July 2012

1. This randomised, double‐blind, parallel group study in 12 healthy young men compared the effects of tenidap sodium 120 mg day‐1, at steady state, with placebo on the plasma protein binding and clearance of tolbutamide. 2. Each subject received a 1000 mg intravenous infusion of tolbutamide given over 5 min on day 1 of the study, and again on day 30 following 22 days of successive tenidap or placebo administration. 3. The percentage of unbound tolbutamide in plasma was determined immediately before each infusion. Mean pharmacokinetic parameters (system plasma clearance, terminal phase rate constant, apparent volume of distribution at steady state) of tolbutamide were derived from individual tolbutamide plasma concentration‐time curves generated after infusion. The within group day 30 minus day 1 differences were compared between treatment groups. 4. Tenidap was shown to have no statistically or clinically significant effects on any of the parameters assessed. These results indicate that tenidap does not induce or inhibit the P450IIC9 isozyme which metabolises tolbutamide and that tenidap does not displace tolbutamide from plasma protein binding sites. 5. Both tenidap and tolbutamide were well tolerated. No severe treatment‐ related adverse events were reported, no subject withdrew from the study, and there were no reports of treatment‐related laboratory abnormalities, or significant variations in vital signs.
The effect of tenidap on the anti‐hypertensive efficacy of thiazide diuretics in patients treated for mild to moderate hypertension.
Authors: Rapeport WG , Grimwood VC , Korlipara K , Grillage MG , James I , Anderton JL , Selfridge DI
Published: July 2012

1. This randomised, placebo‐controlled, double‐blind, parallel‐group study was conducted to assess the effect of tenidap sodium 120 mg, a novel anti‐arthritic cytokine modulating drug, on the hypotensive efficacy of the thiazide diuretics hydrochlorothiazide or bendrofluazide. 2. Twenty‐three male and female patients, aged 41‐78 years, with mild to moderate, uncomplicated, essential hypertension controlled with thiazide diuretic therapy, received either a single daily dose of tenidap sodium 120 mg or matched placebo for 22 days in addition to their diuretic therapy. Changes between baseline and endpoint in supine and standing systolic and diastolic pressures and pulse rate were compared between treatment groups. 3. Daily treatment with tenidap reduced the anti‐hypertensive efficacy of the thiazide diuretics. Blood pressure tended to increase marginally and the increase in mean standing diastolic pressure observed with tenidap was significantly greater than the change in the placebo group. All pressures tended to decrease in the placebo group and all endpoint measurements were within 7 mm Hg of baseline in both groups. 4. Treatment‐related side effects of mild to moderate severity were reported in two subjects receiving tenidap, but in neither case was treatment discontinued. Two subjects receiving placebo also experienced side effects considered to be treatment‐related and both were withdrawn from the study. 5. The results of this study suggest that tenidap may be given to patients treated for mild to moderate essential hypertension controlled with thiazide therapy; however, the patient's blood pressure should be regularly monitored.
Phylogeography of the cold‐water barnacle Chthamalus challengeri in the north‐western Pacific: effect of past population expansion and contemporary gene flow
Authors: Cheang Chi Chiu , Tsang Ling Ming , Ng Wai Chuen , Williams Gray A. , Chu Ka Hou , Chan Benny K. K.
Published: July 2012

Aim  Phylogeographical patterns of marine organisms in the north‐western Pacific are shaped by the interaction of past sea‐level fluctuations during glacial maxima and present‐day gene flow. This study examines whether observed population differentiation in the barnacle Chthamalus challengeri, which is endemic to the north‐western Pacific, can be explained by the interactions between historical glacial events and patterns of contemporary gene flow.

Location  Eleven locations in the north‐western Pacific.

Methods  Partial sequences of mitochondrial cytochrome c oxidase subunit I (COI), 12S, 16S and nuclear internal transcribed spacer 1 (ITS1) were obtained from 312 individuals. Parsimony haplotype networks and analysis of molecular variance (AMOVA) were used to determine whether the observed genetic structure corresponds to marine provinces (Kuroshio Current and China Sea Coastal Provinces), zoogeographical zones (oriental and Japan warm‐temperate zones) and/or potential refugial areas (Sea of Japan and East China Sea) in the north‐western Pacific. Neutrality tests, mismatch distribution analysis and Bayesian skyline plots were used to infer the demographic history of C. challengeri.

Results  In total, 312, 117, 182 and 250 sequences were obtained for COI, 12S, 16S and ITS1, respectively. A panmictic population was revealed, which did not conform to the ‘isolation by distance’ model. None of the a priori population groupings based on marine provinces, zoogeographical zones or potential refugial areas was associated with observed genetic patterns. Significant negative values from neutrality tests and the unimodal mismatch distribution and expansion patterns in Bayesian skyline plots for the COI and 16S data sets indicate a population expansion in the mid‐Pleistocene (c. 200 ka). Information from the fossil record suggests that there has been a northward range shift of this species from the East China Sea or the Palaeo‐Pacific coast of Japan to the Sea of Japan since the mid‐Pleistocene.

Main conclusions  Chthamalus challengeri has experienced a population expansion and range shift since the mid‐Pleistocene. The observed lack of population differentiation can be explained by this past population expansion and present‐day wide‐scale larval dispersal (owing to the long planktonic larval duration) across marine provinces, which have led to the successful establishment of the species in different zoogeographical zones and habitats.
Perceptions of healthy eating and physical activity in an ethnically diverse sample of young children and their parents: the DEAL prevention of obesity study
Authors: Rawlins E. , Baker G. , Maynard M. , Harding S.
Published: July 2012

Background

Ethnicity is a consistent correlate of obesity; however, little is known about the perceptions and beliefs that may influence engagement with obesity prevention programmes among ethnic minority children. Barriers to (and facilitators of) healthy lifestyles were examined in the qualitative arm of the London (UK) DiEt and Active Living (DEAL) study.

Methods

Children aged 8–13 years and their parents, from diverse ethnic groups, were recruited through schools and through places of worship. Thirteen focus group sessions were held with 70 children (n = 39 girls) and eight focus groups and five interviews with 43 parents (n = 34 mothers).

Results

Across ethnic groups, dislike of school meals, lack of knowledge of physical activity guidelines for children and negativity towards physical education at school among girls, potentially hindered healthy living. Issues relating to families' wider neighbourhoods (e.g. fast food outlets; lack of safety) illustrated child and parental concerns that environments could thwart intentions for healthy eating and activity. By contrast, there was general awareness of key dietary messages and an emphasis on dietary variety and balance. For ethnic minorities, places of worship were key focal points for social support. Discourse around the retention of traditional practices, family roles and responsibilities, and religion highlighted both potential facilitators (e.g. the importance of family meals) and barriers (reliance on convenience stores for traditional foods). Socio‐economic circumstances intersected with key themes, within and between ethnic groups.

Conclusions

Several barriers to (and facilitators of) healthy lifestyles were common across ethnic groups. Diversity of cultural frameworks not only were more nuanced, but also shaped lifestyles for minority children.
Selective Up‐Regulation of JunD Transcript and Protein Expression in Vasopressinergic Supraoptic Nucleus Neurones in Water‐Deprived Rats
Authors: Yao S. T. , Gouraud S. S. , Qiu J. , Cunningham J. T. , Paton J. F. R. , Murphy D.
Published: July 2012

The magnocellular neurones (MCN) of the supraoptic nucleus (SON) undergo reversible changes during dehydration. We hypothesise that alterations in steady‐state transcript levels might be partially responsible for this plasticity. In turn, regulation of transcript abundance might be mediated by transcription factors. We have previously used microarrays to identify changes in the expression of mRNAs encoding transcription factors in response to water deprivation. We observed down‐regulation of 11 and up‐regulation of 31 transcription factor transcripts, including members of the activator protein‐1 gene family, namely c‐fos, c‐jun, fosl1 and junD. Because JunD expression and regulation within the SON has not been previously described, we have used in situ hybridisation and the quantitative reverse transcriptase‐polymerase chain reaction to confirm the array results, demonstrating a significant increase in JunD mRNA levels following 24 and 72 h of water deprivation. Western blot and immunohistochemistry revealed a significant increase in JunD protein expression following dehydration. Double‐staining fluorescence immunohistochemistry with a neurone‐specific marker (NeuN) demonstrated that JunD staining is predominantly neuronal. Additionally, JunD immunoreactivity is observed primarily in vasopressin‐containing neurones with markedly less staining seen in oxytocin‐containing MCNs. Furthermore, JunD is highly co‐expressed with c‐Fos in MCNs of the SON following dehydration. These results suggest that JunD plays a role in the regulation of gene expression within MCNs of the SON in association with other Fos and Jun family members.
Intact Catecholamine Inputs to the Forebrain are Required for Appropriate Regulation of Corticotrophin‐Releasing Hormone and Vasopressin Gene Expression by Corticosterone in the Rat Paraventricular Nucleus
Authors: Kaminski K. L. , Watts A. G.
Published: July 2012

Corticotrophin‐releasing hormone (CRH) neuroendocrine neurones in the paraventricular nucleus of the hypothalamus (PVH) drive adrenocorticotrophic hormone (ACTH) and thereby glucocorticoid release from pituitary corticotrophs and the adrenal cortex, respectively. Glucocorticoids suppress the ability of neuroendocrine corticotrophin‐releasing hormone (CRH) neurones to synthesise and release ACTH secretogogues. Despite the importance of glucocorticoids as regulatory signals to CRH neurones in the extended time domain, how and where they act in this capacity is still not fully understood. Ascending catecholamine projections encode important cardiovascular, metabolic and other visceral information to the rat PVH and surrounding hypothalamus. These afferents have previously been implicated as targets for glucocorticoid action, including a role in the feedback regulation of PVH neuroendocrine neurones. To determine the contribution of these neurones to the long‐term actions of corticosterone on CRH and vasopressin (AVP) gene expression in the PVH, we used an immunocytotoxin (a conjugate of the cytotoxin saporin and an antibody against dopamine‐β‐hydroxylase) that specifically ablates adrenergic and noradrenergic neurones. Lesions were administered to intact animals and to adrenalectomised animals with either no corticosterone or corticosterone replacement that provided levels above those required to normalise Crh expression. The ability of elevated levels of corticosterone to suppress Crh expression was abolished in animals lacking catecholaminergic innervation of the PVH. No effect was seen in the absence of corticosterone or in animals with intact adrenals. Furthermore, Avp expression, which is increased in CRH neurones following adrenalectomy, was suppressed in adrenalectomised catecholaminergic‐lesioned animals. Interactions between corticosterone and catecholaminergic projections to the hypothalamus therefore make significant contributions to the regulation of Crh and Avp expression. However, the importance of catecholamine inputs is only apparent when circulating corticosterone concentrations are maintained either below or above those required to maintain the activity of the hypothalamic‐pituitary‐adrenal axis that is seen in intact animals.
Vagal Afferents Mediate Early Satiation and Prevent Flavour Avoidance Learning in Response to Intraperitoneally Infused Exendin‐4
Authors: Labouesse M. A. , Stadlbauer U. , Weber E. , Arnold M. , Langhans W. , Pacheco‐López G.
Published: July 2012

Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists such as exendin‐4 (Ex‐4) affect eating and metabolism and are potential candidates for treating obesity and type II diabetes. In the present study, we tested whether vagal afferents mediate the eating‐inhibitory and avoidance‐inducing effects of Ex‐4. Subdiaphragmatic vagal deafferentation (SDA) blunted the short‐term (< 1 h) but not long‐term eating‐inhibitory effect of i.p.‐infused Ex‐4 (0.1 μg/kg) in rats. A dose of 1 μg/kg Ex‐4 reduced 0.5, 1, 2 and 4 h cumulative food intake in SDA and sham‐operated rats to a similar extent. Paradoxically, SDA but not sham rats developed a conditioned flavour avoidance (CFA) after i.p. Ex‐4 (0.1 μg/kg). SDA completely blunted the induction of c‐Fos expression by Ex‐4 in the hypothalamic paraventricular nucleus. Ex‐4, however, increased the number of c‐Fos expressing cells, independent of intact vagal afferents, in the nucleus accumbens and in the central nucleus of the amygdala, the lateral external parabrachial nucleus, the caudal ventrolateral medulla and the dorsal vagal complex. These data suggest that intact vagal afferents are only necessary for the full expression of the early satiating effect of Ex‐4 but not for later eating‐inhibitory actions, when circulating Ex‐4 might reach the brain via the circulation. Our data also dissociate the satiating and avoidance‐inducing effects of the low Ex‐4 dose tested under our conditions and suggest that vagal afferent signalling may protect against the development of CFA. Taken together, these findings reveal a complex role of vagal afferents in mediating the effects of GLP‐1R activation on ingestive behaviour.
Blackfly vectors of zoonotic onchocerciasis in Japan
Authors: TAKAOKA H. , FUKUDA M. , OTSUKA Y. , AOKI C. , UNI S. , BAIN O.
Published: July 2012

Studies of blackfly vectors of Onchocerca dewittei japonica Uni, Bain & Takaoka (Spirurida: Onchocercidae), a parasite of wild boar implicated in the aetiology of zoonotic onchocerciasis in Japan, and six other zoonotic Onchocerca species of this country are reviewed. Molecular identification of infective larvae found in wild‐caught female blackflies showed that Simulium bidentatum (Shiraki) (Diptera: Simuliidae) is a natural vector of O. dewittei japonica, and also Onchocerca sp. sensu Fukuda et al., another parasite of wild boar. Inoculation experiments demonstrated that Simulium arakawae Matsumura and four other Simulium species are putative vectors. Similarly, S. arakawae, S. bidentatum and Simulium oitanum (Shiraki) are putative vectors of Onchocerca eberhardi Uni & Bain and Onchocerca skrjabini Rukhlyadev, parasites of sika deer. Morphometric studies of infective larvae indicated that Onchocerca lienalis Stiles, a bovine species, is transmitted by S. arakawae, Simulium daisense (Takahasi) and Simulium kyushuense Takaoka, and that Onchocerca sp. sensu Takaoka & Bain, another bovine species, is transmitted by S. arakawae, S. bidentatum, S. daisense and S. oitanum. Prosimulium sp. (Diptera: Simuliidae) and Simulium japonicum Matsumura are suspected vectors of Onchocerca suzukii Yagi, Bain & Shoho and O. skrjabini [Twinnia japonensis Rubtsov (Diptera: Simuliidae) may also transmit the latter], parasites of Japanese serow, following detection of the parasites' DNA genes in wild‐caught blackflies.
Phlebotominae of epidemiological importance in cutaneous leishmaniasis in northwestern Argentina: risk maps and ecological niche models
Authors: QUINTANA M. , SALOMÓN O. , GUERRA R. , LIZARRALDE DE GROSSO M. , FUENZALIDA A.
Published: July 2012

In Argentina, 58.2% out of the 8126 Cutaneous Leishmaniasis (CL) incident cases accumulated from 1954 to 2006 were reported in the provinces of Salta and Jujuy. The aim of this study was to develop an exploratory risk map and a potential distribution map of the vector, in order to offer recommendations for CL prevention. A total of 12 079 Phlebotominae (Diptera: Psychodidae) belonging to the species Lutzomyia neivai (Pinto), Lu. migonei (França), Lu. cortelezzii (Brèthes), Lu. shannoni (Dyar), Lu. quinquefer (Dyar) and Brumptomyia spp. (França & Parrot) were captured.

Potential distribution models were created for two species, Lu. neivai (incriminated vector of Leishmania braziliensis) and Lu. migonei, associated with domestic animals in Argentina and that in turn could be involved as a link between zoonotic transmission cycles and anthropozoonotic.

The Maximum Entropy Modeling System (MaxEnt) was used. The Jackknife test was performed, and the ‘rainfall of the driest month’ was the variable that best generalized the models. Accuracy was evaluated by the area under the curve (AUC) and validated by the Cohen's kappa index.

This approximation provides a new analytical resource of high potential for the prevention of the disease, in order to allocate resources properly and to develop the most suitable strategies for action.
Allotetraploid Mimulus sookensis are highly interfertile despite independent origins
Authors: MODLISZEWSKI JENNIFER L. , WILLIS JOHN H.
Published: July 2012

Polyploidy (whole‐genome duplication) has contributed significantly to angiosperm evolution and diversification. To date, it has been found that most polyploids are the result of multiple formation events, which may contribute to genetic diversity and affect interfertility among polyploid lineages of independent origin. A recently discovered allotetraploid derivative of Mimulus guttatus and M. nasutus, Mimulus sookensis, is found throughout the valleys of western Oregon and Vancouver Island. Here, we analyse the patterns of nucleotide diversity at three chloroplast and six nuclear loci in M. guttatus, M. nasutus and M. sookensis, to gain insight into the formation of M. sookensis. By analysing the patterns of genetic variation seen in the diploid progenitors in comparison with the variation seen in M. sookensis, we are able to show that M. sookensis has recurrently formed. We also observed that most M. sookensis individuals are fixed heterozygotes at all of the nuclear loci examined, suggesting that duplicate gene loss is not extensive in M. sookensis. To assess the possibility that hybridization among M. sookensis has contributed to genetic diversity, we conducted crossing experiments within M. sookensis. We found that M. sookensis of independent origin are highly interfertile, suggesting that crossing barriers do not exist within M. sookensis, and that hybridization among M. sookensis may result in new recombinant genotypes. Together, the data suggest that although recurrent origins may be common, they can contribute to genetic diversity without contributing to reproductive isolation among independently arisen polyploid lineages.
You're so vein: bundle sheath physiology, phylogeny and evolution in C3 and C4 plants
Authors: GRIFFITHS HOWARD , WELLER GEORGE , TOY LYDIA F. M. , DENNIS ROSS J.
Published: July 2012

Bundle sheath (BS) anatomy is found in most C4 lineages, associated with low inter‐veinal distances (IVD) and high BS:mesophyll ratio (BS:MC). The origins, function and selective advantages of the BS in C3 lineages are relevant for understanding the environmental, molecular and phylogenetic determinants of C4 evolution. Suggested functions for BS have included structural support, hydraulic isolation, storage for water, ions, and carbohydrates, and photorespiratory carbon metabolism; we propose a central role for cavitation repair, consistent with the BS as a control centre on regulating stem and leaf hydraulic continuity. An analysis of BS traits in the phylogenetic lineages giving rise to C4 grasses (the ‘PACMAD’ clade) shows an initial enhancement in BS:MC ratio in C3 lineages, although IVD is similar to the Pooideae sister group. Using a global database, a well‐developed BS in the C3 PACMAD lineages was associated with higher precipitation and temperatures in the habitat of origin on an annual basis, with the C3 to C4 progression defined by the aridity index (AI). Maintaining leaf hydraulic conductance and cavitation repair are consistent with increased evaporative demand and more seasonal precipitation as drivers, first for the C3 BS, and then C4 diversification, under declining CO2concentrations in the Palaeogene and Neogene.