bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis of 16 Colorado human NL63 coronaviruses identifies a new genotype, high sequence diversity in the N-terminal domain of the spike gene and evidence of recombination
Authors: Dominguez Samuel R. , Sims Gregory E. , Wentworth David E. , Halpin Rebecca A. , Robinson Christine C. , Town Christopher D. , Holmes Kathryn V.
Published: July 2012

This study compared the complete genome sequences of 16 NL63 strain human coronaviruses (hCoVs) from respiratory specimens of paediatric patients with respiratory disease in Colorado, USA, and characterized the epidemiology and clinical characteristics associated with circulating NL63 viruses over a 3-year period. From 1 January 2009 to 31 December 2011, 92 of 9380 respiratory specimens were found to be positive for NL63 RNA by PCR, an overall prevalence of 1 %. NL63 viruses were circulating during all 3 years, but there was considerable yearly variation in prevalence and the month of peak incidence. Phylogenetic analysis comparing the genome sequences of the 16 Colorado NL63 viruses with those of the prototypical hCoV-NL63 and three other NL63 viruses from the Netherlands demonstrated that there were three genotypes (A, B and C) circulating in Colorado from 2005 to 2010, and evidence of recombination between virus strains was found. Genotypes B and C co-circulated in Colorado in 2005, 2009 and 2010, but genotype A circulated only in 2005 when it was the predominant NL63 strain. Genotype C represents a new lineage that has not been described previously. The greatest variability in the NL63 virus genomes was found in the N-terminal domain (NTD) of the spike gene (nt 1–600, aa 1–200). Ten different amino acid sequences were found in the NTD of the spike protein among these NL63 strains and the 75 partial published sequences of NTDs from strains found at different times throughout the world.
Dissecting Functions of KATANIN and WRINKLED1 in Cotton Fiber Development by Virus-Induced Gene Silencing
Authors: Qu Jing , Ye Jian , Geng Yun-Feng , Sun Yan-Wei , Gao Shi-Qiang , Zhang Bi-Pei , Chen Wen , Chua Nam-Hai
Published: July 2012

Most of the world’s natural fiber comes from cotton (Gossypium spp.), which is an important crop worldwide. Characterizing genes that regulate cotton yield and fiber quality is expected to benefit the sustainable production of natural fiber. Although a huge number of expressed sequence tag sequences are now available in the public database, large-scale gene function analysis has been hampered by the low-efficiency process of generating transgenic cotton plants. Tobacco rattle virus (TRV) has recently been reported to trigger virus-induced gene silencing (VIGS) in cotton leaves. Here, we extended the utility of this method by showing that TRV-VIGS can operate in reproductive organs as well. We used this method to investigate the function of KATANIN and WRINKLED1 in cotton plant development. Cotton plants with suppressed KATANIN expression produced shorter fibers and elevated weight ratio of seed oil to endosperm. By contrast, silencing of WRINKLED1 expression resulted in increased fiber length but reduced oil seed content, suggesting the possibility to increase fiber length by repartitioning carbon flow. Our results provide evidence that the TRV-VIGS system can be used for rapid functional analysis of genes involved in cotton fiber development.
Profiling oxidative DNA damage: Effects of antioxidants
Authors: Box Harold C. , Patrzyc Helen B. , Budzinski Edwin E. , Dawidzik Jean B. , Freund Harold G. , Zeitouni Nathalie C. , Mahoney Martin C.
Published: July 2012

The goal of this research was to determine whether antioxidant usage could be correlated with changes in DNA damage levels. Liquid Chromatography‐tandem Mass Spectrometry (LC‐MS/MS) was used to simultaneously measure five different oxidatively‐induced base modifications in the DNA of WBC. Measurements of the five modifications were made before and after an 8‐week trial during which participants took the SU.VI.MAX supplement. Levels of the five DNA modifications were compared among different groupings: users versus non‐users of antioxidant supplements, before versus after the supplement intervention and men versus women. The statistical significance of differences between groups was most significant for pyrimidine base modifications and the observed trends reflect trends reported in epidemiological studies of antioxidant usage. A combination of modifications derived from pyrimidine bases is suggested as a superior indicator of oxidative stress.
Mianserin and doxepin in the treatment of outpatient depression with anxiety.
Authors: Khan MC , Bennie EH , Stulemeijer SM , Ravens MA
Published: July 2012

1 A double‐blind group comparative trial was performed comparing mianserin (Bolvidon‐Organon) and doxepin (Sinequan‐Pfizer) in the treatment of depression with anxiety. 2 Sixty outpatients from two centres were divided into ‘high’ and ‘low’ severity groups, based on initial HRS scores, and treated for four weeks. 3 Standard rating scales for depression and anxiety demonstrated a substantial improvement with both drugs. However, no consistent difference in efficacy was found although the ‘low severity’ group appeared to respond better to mianserin. 4 There was a greater incidence of drug‐ related side‐effects with doxepin treatment.
Antidepressant drugs, convulsions and epilepsy.
Authors: Richens A. , Nawishy S. , Trimble M.
Published: July 2012

1 Evidence concerning the convulsant effects of non‐monoamine oxidase inhibitor antidepressant drugs has been reviewed. 2 Mianserin is convulsant in therapeutic doses but seizures have not been reported following overdose. 3 The convulsant effects of mianserin are probably no greater than for other non‐monoamine oxidase inhibitor antidepressant drugs. 4 Enzyme‐inducing anti‐epileptic drugs can reduce the peak plasma concentration of mianserin and shorten its elimination half‐life, probably by inducing its metabolism.
Chemical design of cilazapril.
Authors: Attwood MR
Published: July 2012

1. The three dimensional requirements for inhibition of ACE (angiotensin converting enzyme) were investigated in order to facilitate design of a more potent and selective antihypertensive agent. 2. All compounds designed possessed a bicyclic unit incorporating carboxylate and amidic carbonyl groups together with a thiol‐bearing side chain. 3. NMR spectroscopy of the bicyclic units and molecular mechanics calculations enabled the possible positions of the thiol group to be studied. 4. Determination of the positions of the thiol group conferring best inhibition in the active site of ACE permitted the probable location of the active site zinc ion to be identified. The intention was to replace the thiol side chain with a homophenylalanine unit to bind to the zinc ion and also to occupy the S1 site which fits the Phe8 side chain of angiotensin I. 5. Examination of a torsional angle psi in a compound possessing poor inhibitory potency indicated correspondence to a high energy conformation of alanylproline. The bicyclic unit was modified to incorporate a seven‐ instead of a six‐membered ring to bring psi into the range of an accessible conformation of alanylproline. The corresponding IC50 resulting indicated that psi was closer to that of the active conformations of enalaprilat and captopril. 6. Removal of one carbonyl improved the ACE inhibitory potency further. 7. The postulated active conformation of cilazaprilat is presented.
The pharmacokinetics and dose proportionality of cilazapril.
Authors: Massarella J , DeFeo T , Lin A , Limjuco R , Brown A
Published: July 2012

1. The pharmacokinetics and dose proportionality of cilazapril, an orally active angiotensin‐converting enzyme (ACE) inhibitor, were investigated in a four‐way randomized crossover study in 24 volunteers, over the 0.5 to 5 mg dose range intended for therapeutic use. 2. Plasma concentrations of cilazapril and of the active metabolite cilazaprilat together with plasma ACE activity were determined by radio‐enzymatic assay. 3. Plasma concentrations of both cilazapril and cilazaprilat increased in proportion to dose over the range studied. All doses produced substantial inhibition of ACE. Higher doses were associated with earlier onset and longer duration of maximal effect.
The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.
Authors: Meredith PA , Elliott HL , Reid JL , Francis RJ
Published: July 2012

1. In a double‐blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril. 2. Peak plasma levels of cilazaprilat and the 24 h areas under curve were directly proportional to dose. 3. The elimination half‐ life during the first 8 h was about 1.7 h. 4. From 24 h onwards there was a prolonged terminal elimination phase with a half‐life of about 40 h, and strict dose proportionality of plasma concentrations was not maintained. 5. The pharmacokinetics of cilazaprilat and the pharmacodynamics of plasma ACE inhibition were well described by a one compartment model with saturable binding to ACE. 6. The coefficients of the model which related to plasma ACE and its interaction with cilazaprilat were in good agreement with model independent observations. 7. The values for kinetic and dynamic parameters in hypertensive patients were comparable with those reported for healthy volunteers.
A pharmacokinetic study of cilazapril in patients with congestive heart failure.
Authors: Rosenthal E , Francis RJ , Brown AN , Rajaguru S , Williams PE , Steiner J , Curry PV
Published: July 2012

1. The pharmacokinetics of cilazapril and the inhibition of angiotensin converting enzyme (ACE) were investigated in 10 patients with congestive heart failure, NYHA class II‐III, receiving diuretics with or without digoxin. 2. Patients received 0.5 mg and 1 mg cilazapril on the first 2 days, followed by 0.5 mg or 1 mg daily for the next 8 weeks, in a single‐blind study. Plasma cilazaprilat concentrations and plasma ACE activities were measured by radioenzymatic methods up to 24 h after the first and last doses. 3. After the initial 0.5 mg dose of cilazapril, a mean maximum plasma concentration of cilazaprilat of 6.8 ng ml‐1 was observed at 2.3 h. Concentrations declined up to 8 h with a mean half‐life of 5.8 h, followed by slower decrease to 24 h. Total clearance, based on data to 24 h, was estimated at 8.5 l h‐1, with three‐fold inter‐individual variation. Mean maximum plasma ACE inhibition was 87%, decreasing to 65% at 24 h. 4. In the multiple dose phase of the study, four patients received cilazapril 0.5 mg daily, and six patients 1 mg daily. Cilazapril accumulation for the 0.5 mg group averaged 77%, but steady state concentrations for the 1 mg group were less than double those of the 0.5 mg group. ACE inhibition profiles at steady state were similar for both groups, and they differed from first dose data only in a somewhat lower inhibition at 24 h. 5. Historical comparison of the first‐dose data with those for healthy young volunteers at identical dosage revealed only minor differences in kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of cilazapril in patients with renal failure.
Authors: Fillastre JP , Moulin B , Godin M , Williams PE , Brown AN , Francis RJ , Pinta P , Manfredi R
Published: July 2012

1. The pharmacokinetics of a single 1 mg dose of cilazapril were determined in six subjects with normal renal function and in 19 uraemic patients with various degrees of renal impairment. 2. Significant decreases in systolic and diastolic blood pressure were noted in all groups of subjects between 2 and 8 h after administration of 1 mg cilazapril. 3. There was a significant correlation between ACE inhibition at 24 h and creatinine clearance (CrCL). 4. For cilazapril, Cmax and tmax were independent of creatinine clearance. AUC(24) was inversely related to CrCL and apparent plasma clearance (CL/F) was directly related to CrCL. 5. For cilazaprilat, Cmax and tmax were related to creatinine clearance. AUC(24) was inversely related to CrCl and apparent plasma clearance (CL/F) was directly related to CrCL. 6. Dialysis clearance was approximately 2 l h‐1 for cilazapril and for cilazaprilat. 7. The effects of renal impairment on cilazapril and cilazaprilat kinetics were similar to those observed for other inhibitors of angiotensin‐converting enzyme such as captopril, enalapril and lisinopril. 8. It may be necessary to modify doses of cilazapril for the treatment of essential hypertension in uraemic patients. When creatinine clearance was below 15 ml min‐1 cilazaprilat concentrations were increased, half‐lives were prolonged and ACE inhibition remained above 90% for at least 24 h. A reduced dosage is indicated for these patients. 9. In patients requiring haemodialysis, maintenance doses of 0.5 mg given after each haemodialysis session are sufficient.
The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.
Authors: Tsai HH , Lees KR , Howden CW , Reid JL
Published: July 2012

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double‐blind randomised crossover study in a group of patients with compensated biopsy‐proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/‐ 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/‐ 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.
Adverse drug reactions: a hospital pharmacy‐based reporting scheme.
Authors: Winstanley PA , Irvin LE , Smith JC , Orme ML , Breckenridge AM
Published: July 2012

A pharmacy‐based adverse drug reaction (ADR) reporting scheme, using pharmacists, nurses and medical practitioners as initiators of reports, was set up at the end of 1984 in the Royal Liverpool Hospital in order to encourage reporting. New reports were inspected at weekly intervals by a staff pharmacist, and a clinical pharmacologist. Reports were forwarded to the Committee on Safety of Medicines if the reaction was considered to be serious by the clinicians, or the ADR team or involved 'black triangle' drugs. The total number of ADR reports was increased eightfold by the introduction of the scheme (from 14 in 1984 to 76, 102 and 94 in 1985, 1986 and 1987 respectively), and this rate of reporting has been sustained.
The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia (Gilbert's syndrome).
Authors: Posner J , Cohen AF , Land G , Winton C , Peck AW
Published: July 2012

A single oral dose of lamotrigine was administered to seven volunteers with Gilbert's Syndrome (unconjugated hyperbilirubinaemia). Plasma samples were assayed by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were compared with those of a group of nine normal volunteers. In the subjects with Gilbert's Syndrome mean oral clearance (CLpo) was 32% lower (P less than 0.01) and the plasma elimination half‐life (t1/2) was 37% lower (P less than 0.02) than in the normal controls. The amount of unchanged lamotrigine excreted in the urine was 30% greater in the Gilbert's subjects (P less than 0.01) although this only amounted to 9.5% of the administered dose. Subjects with Gilbert's Syndrome have some impairment of lamotrigine elimination but this is unlikely to be clinically important.
N‐acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.
Authors: Hogan JC , Lewis MJ , Henderson AH
Published: July 2012

1. The effects of chronic dosing with N‐acetylcysteine (NAC), on nitrate‐induced haemodynamic changes during the acute and chronic treatment of healthy volunteers with glyceryl trinitrate (GTN) patches (Transiderm nitro) has been investigated. 2. Seven volunteers were treated in a double‐blind randomised crossover manner for two periods of 4 days with 20 mg of transdermal GTN/24 h together with NAC (200 mg three times daily) or matching placebo. There was a washout period of greater than 3 days between treatment periods. 3. Haemodynamic measurements (blood pressure (BP); heart rate (HR] at rest and following maximal treadmill exercise were performed before treatment and 4 h after starting treatment on days 1 and 4. 4. Significant haemodynamic changes as evidenced by a fall in BP and rise in HR, were seen on day 1 in both the NAC and placebo phases. By day 4 the haemodynamic changes had returned towards the pre‐treatment values during both the NAC and placebo phases suggesting the development of tolerance in both treatment groups. 5. These findings suggest that concurrent administration of NAC fails to prevent the development of tolerance to GTN.
Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism‐hypothesis testing.
Authors: Jackson PR , Tucker GT , Woods HF
Published: July 2012

1. The theory of methods of hypothesis testing in relation to the detection of bimodality in density distributions is discussed. 2. Practical problems arising from these methods are outlined. 3. The power of three methods of hypothesis testing was compared using simulated data from bimodal distributions with varying separation between components. None of the methods could determine bimodality until the separation between components was 2 standard deviation units and could only do so reliably (greater than 90%) when the separation was as great as 4‐6 standard deviation units. 4. The robustness of a parametric and a non‐parametric method of hypothesis testing was compared using simulated unimodal distributions known to deviate markedly from normality. Both methods had a high frequency of falsely indicating bimodality with distributions where the components had markedly differing variances. 5. A further test of robustness using power transformation of data from a normal distribution showed that the algorithms could accurately determine unimodality only when the skew of the distribution was in the range 0‐1.45.
Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).
Authors: Cushman DW , Wang FL , Fung WC , Grover GJ , Harvey CM , Scalese RJ , Mitch SL , DeForrest JM
Published: July 2012

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin‐converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose‐response and time‐course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized ‘equiactive’ oral doses employed for time‐course studies were: SQ 29,852 (1.0), 100 mg kg‐1; captopril (3.5), 30 mg kg‐1; enalapril (12), 20 mg kg‐1; fosinopril (13), 25 mg kg‐1; zofenopril (20), 10 mg kg‐1; lisinopril (24), 10 mg kg‐1; and ramipril (51), 5 mg kg‐1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short‐lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long‐lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.
Effects of antihypertensive agents on endothelium‐dependent and endothelium‐independent relaxations.
Authors: Shultz PJ , Raij L
Published: July 2012

1. Antihypertensive agents normalize blood pressure and restore depressed endothelium‐dependent relaxations in experimental models of hypertension, but little is known regarding whether antihypertensive agents themselves can directly modulate responses to agonists of endothelium‐dependent or independent relaxations, or contractions. 2. Normal rats were treated with either tap water, captopril, hydralazine or enalapril in their drinking water for 2 weeks, following which endothelium‐dependent and endothelium‐independent relaxations were tested with acetylcholine and sodium nitroprusside, respectively, in aortic rings suspended in organ chambers. 3. All antihypertensive agents caused slight but similar potentiation of sodium nitroprusside‐ induced relaxations. However, their effects on acetylcholine‐induced relaxations were quite different: captopril had a marked potentiating effect, hydrazaline a slight potentiating effect, and enalapril had no significant effect on these relaxations. 4. The relaxations induced by acetylcholine and potentiated by captopril were not altered when indomethacin was included in the tissue bath. However, pyrogallol, an inhibitor of endothelium‐derived relaxing factor (EDRF), markedly inhibited these relaxations suggesting that captopril's effect may involve EDRF. 5. SQ 14,534, a stereoisomer of captopril which is 100 fold less potent in inhibiting angiotensin converting enzyme, also significantly enhanced acetylcholine induced relaxations. Thus the effects of both captopril and SQ 14,534 upon EDRF appear independent of the effects of these compounds on the angiotensin converting enzyme. 6. We conclude that certain antihypertensive agents may modulate endothelium‐dependent relaxations in response to agonists, and that these properties may be of therapeutic importance in cardiovascular diseases.
Lack of effect of cimetidine on the pharmacokinetics of R(−)− and S(+)‐ ibuprofen.
Authors: Evans AM , Nation RL , Sansom LN
Published: July 2012

1. To investigate the effect of cimetidine on the pharmacokinetics of R(−)− and S(+)‐ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug‐free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross‐over manner. 2. The plasma concentrations of R(−)− and S(+)‐ibuprofen were measured by high‐performance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3. There was no difference (P greater than 0.05, two‐tailed Student's t‐test; data expressed as mean +/‐ s.d.) between C and T phases in the total area under the plasma concentration‐time curve of R(−)−ibuprofen (C 4514 +/‐ 1063 mg 1(‐1) min vs T 4665 +/‐ 1435 mg 1(‐1) min) and S(+)‐ ibuprofen (C 6460 +/‐ 1063 mg 1(‐1) min vs T 6886 +/‐ 1207 mg 1(‐1) min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half‐life, the maximum plasma concentration or the time of its occurrence. 4. Cimetidine treatment had no effect (P greater than 0.05) on the time‐averaged percent unbound in plasma of R(−)−ibuprofen (C 0.419 +/‐ 0.051% vs T 0.435 +/‐ 0.060%) and S(+)‐ibuprofen (C 0.643 +/‐ 0.093% vs T 0.633 +/‐ 0.053%). (ABSTRACT TRUNCATED AT 250 WORDS)
Stereoselectivity in the urinary excretion of the mercapturates of (R‐) and (S‐) alpha‐bromoisovalerylurea in man.
Authors: te Koppele JM , Schipper C. , Breimer DD , Mulder GJ
Published: July 2012

1. alpha‐Bromoisovalerylurea (BIU) is a racemic drug that is metabolized by glutathione conjugation. The urinary excretion of the separate diastereomeric mercapturates formed from (S)‐ and (R)‐BIU in healthy young human volunteers was investigated. 2. A pronounced stereoselectivity was observed: the mercapturate formed from R‐BIU was excreted with a t1/2 of 1.5 +/‐ 0.4 h, while that from S‐BIU showed a t1/2 of 3.1 +/‐ 1.3 h. Moreover, 22.5 +/‐ 4.3 and 5.7 +/‐ 1.6% of the dose, respectively, was excreted as each mercapturate diastereomer in 24 h. 3. This is the first example of stereoselectivity in the elimination of a substrate for glutathione conjugation in man.
The haemodynamic and hormonal responses after clonidine occur independently of sedation in essential hypertension.
Authors: Kooner JS , Peart WS , Mathias CJ
Published: July 2012

1. To investigate the contribution of sedation to the cardiovascular effects induced by clonidine, we studied patients with essential hypertension on two separate occasions when similar levels of sedation were induced by clonidine and nitrazepam. 2. After clonidine, there was a fall in blood pressure, heart rate, digital skin vascular resistance and plasma noradrenaline which is consistent with its ability to reduce sympathetic outflow. Dissociation of the circulatory/neurohormonal and sedative responses after clonidine indicated that sedation alone is not an important factor in the blood pressure lowering effect of clonidine. 3. The absence of a fall in blood pressure, heart rate, digital skin vascular resistance and plasma noradrenaline after nitrazepam further suggest that sedation did not influence the hypotensive response in essential hypertension.
Haemodynamic and pharmacokinetic study of intravenous fenoldopam in patients with hepatic cirrhosis.
Authors: Vlavianos P , Polson RJ , Settin A , Glover J , Westaby D , Williams R
Published: July 2012

1. The effect of intravenous fenoldopam‐an arterial vasodilator‐was assessed in twelve patients with cirrhosis and portal hypertension. Six patients had compensated (Grade A or B Child‐Pugh classification) and six decompensated (Grade C) liver disease. 2. A significant dose dependent reduction in systemic blood pressure with a concomitant fall in systemic vascular resistance and increase in cardiac index was observed. Estimated portal pressure (WHVP‐FHVP) increased (15.4 +/‐ 3.2 to 19.3 +/‐ 3.7 mm Hg, P less than 0.05) due to a rise in wedged hepatic venous pressure (24.6 +/‐ 4.3 to 29.0 +/‐ 5.8 mm Hg, P less than 0.05). Hepatic blood flow did not change significantly. Similar haemodynamic effects were observed in both compensated and decompensated patients. 3. Fenoldopam plasma clearance and ICG clearance were found to decrease with increasing infusion concentration, indicating possible increase of the intrahepatic shunting. 4. With the observed rise in portal pressure there must be some concern with respect to the long‐term use of this drug in patients with previous variceal bleeding.
Moclobemide excretion in human breast milk.
Authors: Pons G , Schoerlin MP , Tam YK , Moran C , Pfefen JP , Francoual C , Pedarriosse AM , Chavinie J , Olive G
Published: July 2012

1. Six lactating white women, aged 24‐36 years, received a single oral dose of 300 mg moclobemide, between 09.00 h and 11.00 h, 3 to 5 days after the delivery of a full term neonate. 2. Complete milk collections were obtained before, 3, 6, 9, 12 and 24 h after drug administration by means of a breast pump. Venous blood samples were drawn before, and 0.5, 1, 3, 4.5, 6, 9, 12, 24 h post‐dosing. 3. Moclobemide, and its major metabolite (Ro 12‐8095) were measured in milk and plasma samples using h.p.l.c. The active metabolite (Ro 12‐5637) could only be detected in plasma. 4. Moclobemide and its metabolites were not detectable in 24 h plasma samples. Cmax, tmax and t1/2 for moclobemide were (mean +/‐ s.d.) 2.70 +/‐ 1.24 mg l‐1, 2.03 +/‐ 1.19 h and 2.26 +/‐ 0.26 h, respectively. 5. The concentrations of moclobemide and Ro 12‐ 8095 in milk were highest at 3 h after drug administration and the drug and metabolite were not detectable after 12 h. Ro 12‐5637 was not detected in any milk sample. The percentages of the dose excreted as moclobemide and Ro 12‐8095 were (mean +/‐ s.d.) 0.057 +/‐ 0.020% and 0.031 +/‐ 0.011%, respectively. An average 3.5 kg breast‐fed neonate would therefore be exposed to only a 0.05 mg kg‐1 moclobemide dose (approximately 1% of the maternal dose on the mg kg‐1 basis). The low amount of moclobemide excreted into breast milk is unlikely to be hazardous to suckling infants.
Effect of temazepam on blood pressure regulation in healthy elderly subjects.
Authors: Ford GA , Hoffman BB , Blaschke TF
Published: July 2012

1. Blood pressure regulation was studied in 12 healthy elderly subjects after double‐blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose‐dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min‐ 1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min‐1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/‐ s.d.; placebo: ‐23 +/‐ 10 mm Hg, 15 mg temazepam: ‐31 +/‐ 13 mm Hg, 30 mg temazepam: ‐36 +/‐ 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.
The effects of propranolol or atenolol on the cardiovascular responses to central hypovolaemia in Europeans and Bengalees.
Authors: Rahman MA , Bennett T
Published: July 2012

1. The effects of single oral doses of propranolol (80 mg), or atenolol (100 mg) on resting heart rate, blood pressure, forearm blood flow and forearm vascular resistance and on responses to central hypovolaemia, were compared with those of placebo in nine healthy European and nine healthy Bengalee volunteers, in a double‐blind, three‐period, cross‐ over study. 2. Atenolol induced a significant reduction in resting systolic blood pressure (SBP) in Europeans but not in Bengalees, although the bradycardic effects of atenolol were similar in both groups. Atenolol did not have any significant effect on forearm blood flow (FBF) or forearm vascular resistance (FVR) in either group. In the presence of propranolol (80 mg) there were no statistically significant falls in BP but there were significant bradycardias, falls in FBF and rises in FVR that were similar in Europeans and Bengalees. 3. In the presence of placebo Europeans exhibited significant falls in diastolic blood pressure (DBP) during lower body negative pressure (LBNP) of 20 and 30 mm Hg. Bengalees did not show falls in DBP during LBNP. However, there were no significant differences between DBP responses in Europeans and Bengalee subjects. Both Bengalees and European subjects showed similar reductions in FBF and FVR during LBNP of 30 mm Hg. 4. In the presence of propranolol, significant changes in forearm blood flow and forearm vascular resistance were evident in Bengalee subjects during LBNP of 20 mm Hg and 30 mm Hg, whereas in the Europeans significant changes in those variables did not occur at any level. The changes in FBF and FVR during LBNP of 20 and 30 mm Hg in Bengalee and European subjects were significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)
Parkinsonian abnormality of foot strike: a phenomenon of ageing and/or one responsive to levodopa therapy?
Authors: Hughes JR , Bowes SG , Leeman AL , O'Neill CJ , Deshmukh AA , Nicholson PW , Dobbs SM , Dobbs RJ
Published: July 2012

1. Normally during walking, the heel strikes the ground before the forefoot. Abnormalities of foot strike in idiopathic Parkinson's disease may be amenable to therapy: objective measurements may reveal response which is not clinically apparent. Occult changes in foot strike leading to instability may parallel the normal, age‐related loss of striatal dopamine. 2. The nature of foot strike was studied using pedobarography in 160 healthy volunteers, aged 15 to 91 years. Although 16% of strikes were made simultaneously by heel and forefoot, there were no instances of the forefoot preceding the heel. No significant effect of age on an index of normality of foot strikes was detected (P greater than 0.3). 3. The effect on foot strike of substituting placebo for a morning dose of a levodopa/carbidopa combination was studied in a double‐blind, cross‐over trial in 14 patients, aged 64 to 88 years, with no overt fluctuations in control of their idiopathic Parkinson's disease in relation to dosing. On placebo treatment there was a highly significant (P = 0.004) reduction in the number of more normal strikes, i.e. heel strikes plus simultaneous heel and forefoot strikes. The effect appeared unrelated to the corresponding difference between active and placebo treatments in plasma concentration of levodopa or a metabolite of long half‐time, 3‐O‐methyldopa (3OMD). However, it correlated negatively (P less than 0.05) with the mean of the 3OMD concentrations. 4. It appears that some abnormalities of foot strike due to Parkinson's disease are reversible. Employing test conditions, designed to provoke abnormalities of foot strike, might be useful in screening for pre‐clinical Parkinson's disease.
The effect of age on serum concentrations of albumin and alpha 1‐acid glycoprotein.
Authors: Veering BT , Burm AG , Souverijn JH , Serree JM , Spierdijk J
Published: July 2012

1. Human serum albumin (HSA) concentrations and alpha 1‐acid glycoprotein (AAG) concentrations were measured in 68 subjects, 35 males and 33 females, aged 20‐90 years without evidence of acute or chronic inflammatory disease or malignancy. Subjects were drug free for at least 1 month. HSA and AAG concentrations were measured using rate nephelometry. 2. Age had no effect on alpha 1‐acid glycoprotein concentration, whereas plasma albumin levels decreased as a function of age in both sexes. We observed no differences between males and females in the plasma concentrations of HSA and AAG. 3. These data show that in healthy subjects the HSA concentration decreases with increasing age, whereas age, uncomplicated by disease does not influence AAG concentration.
Increased volume of distribution prolongs midazolam half‐life.
Authors: Wills RJ , Khoo KC , Soni PP , Patel IH
Published: July 2012

It has recently been shown by several investigators that the half‐life (t1/2) of midazolam is prolonged (greater than 7 h) in a small proportion of the population. One group has inferred that this subpopulation represents a group of slow metabolizers of midazolam to alpha‐OH‐midazolam. Others disagree and postulate that there is an increase in the volume of distribution (V) resulting in a prolonged t1/2. This controversy led us to report experience from 90 subjects and patients where t1/2, V, and clearance (CL) were determined by both model‐dependent and ‐independent pharmacokinetic analysis. We found a 5.6% (5 of 90) incidence of prolonged t1/2, similar to that previously reported. V was clearly increased without a decrease in CL in the five subjects with prolonged t1/2. Thus, the prolonged t1/2 is secondary to an increase in V and not a result of alterations in CL and metabolism.
Beta‐adrenoceptor blockade and hypoglycaemia. A randomised, double‐ blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.
Authors: Kerr D , MacDonald IA , Heller SR , Tattersall RB
Published: July 2012

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross‐over design in 12 healthy volunteers. 2. All three beta‐adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m‐2 min‐1) clamp conditions, at a blood glucose of 2.5 mmol l‐1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre‐ treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta‐adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter‐regulatory hormones during hypoglycaemia was enhanced by beta‐adrenoceptor blockade. 6. We conclude that beta‐adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.
Ketanserin pharmacokinetics in patients with renal failure.
Authors: Barendregt JN , Van Peer A , Van Der Hoeven JG , Van Oene JC , Tjandra YI
Published: July 2012

1. The pharmacokinetics of ketanserin and its major metabolite ketanserin‐ol were investigated after a single oral dose of 40 mg and after chronic oral administration of 20 or 40 mg twice daily for 10 days in 12 patients with chronic renal insufficiency of whom six were on intermittent haemodialysis. Plasma protein binding of ketanserin was measured in these 12 patients and in eight healthy volunteers. 2. In both dialysis and non‐dialysis patients the terminal half‐life of ketanserin (mean +/− s.d.) was prolonged compared with that reported previously for healthy volunteers (28 +/− 4 h vs 18 +/− 4 h). This may be explained by a lowered renal clearance of ketanserin‐ol from which ketanserin is partly regenerated. 3. In patients with chronic renal insufficiency plasma ketanserin concentrations were similar to those found in healthy subjects after the same dose. Plasma ketanserin‐ol concentrations were elevated, resulting in a raised AUC ratio of ketanserin‐ol to ketanserin as compared with healthy individuals (7.3 +/− 4.0 vs 3.2 +/− 0.7). 4. Urinary excretion of ketanserin was negligible in both dialysis and non‐dialysis patients, and ketanserin‐ ol excretion was markedly lowered. 5. The plasma protein binding of ketanserin was slightly reduced in comparison with healthy volunteers (93.7 +/− 1.0% vs 95.0 +/− 0.2%). 6. A dose regimen of 20 mg twice daily appeared to be well tolerated in spite of less plasma binding in renal failure.
The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.
Authors: Munoz JJ , De Salamanca RE , Diaz‐Obregon C , Timoneda FL
Published: July 2012

Steady state metabolite/parent drug plasma ratios were measured in 15 epileptic patients on carbamazepine (CBZ) monotherapy and in seven patients treated with CBZ and clobazam (CLB). CBZ plasma concentrations did not differ between the two groups but patients also treated with CLB exhibited higher concentrations of CBZ‐10,11‐epoxide (CBZ‐E) and trans‐10,11‐dihydro‐10,11‐dihydroxy‐CBZ (CBZ‐T). Ratios between all of the metabolites of CBZ and the parent compound were higher in patients on polytherapy but the ratio between metabolites was not different. CLB comedication causes a moderate increase (about 1.5‐fold) in CBZ metabolism, probably by inducing its epoxidation.
The pharmacokinetics of enalapril in patients with compensated liver cirrhosis.
Authors: Baba T , Murabayashi S , Tomiyama T , Takebe K
Published: July 2012

The possibility of an impaired hepatic de‐esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half‐life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.
Determinants of gait in the elderly parkinsonian on maintenance levodopa/carbidopa therapy.
Authors: Bowes SG , Clark PK , Leeman AL , O'Neill CJ , Weller C , Nicholson PW , Deshmukh AA , Dobbs SM , Dobbs RJ
Published: July 2012

1. We have used gait analysis to investigate the efficacy of maintenance therapy with a levodopa/carbidopa combination in patients with idiopathic Parkinsonism, who do not have overt fluctuations in control in relation to administration of medication. 2. Fourteen patients (aged 64 to 88 years) receiving maintenance therapy with levodopa and carbidopa (Sinemet Plus) entered a placebo‐controlled, randomised cross‐over study of the effect of omission of a morning dose of active treatment on distance/time parameters of gait. Measurements made 2, 4 and 6 h after the morning treatment were standardised by taking the pre‐treatment measurement on that day as baseline. 3. The mean increase in stride length (7%) and decrease in double support time (20%) on active treatment were small but statistically significant (P less than 0.0001, in each case), there being no significant placebo effect on either gait parameter (P = 0.69 and 0.08 respectively). Neither active nor placebo treatments had any significant (P greater than 0.45 in each case) effect on the lying, standing or postural fall in mean arterial pressure, measurements being made in the same temporal relation to the treatments as was gait. 4. In a generalised linear model, after allowing for the effect (P less than 0.0001) of intrinsic variability in pre‐treatment speed as well as for structure of the study, nature of treatment had an effect on stride length over the whole walk, significant at P = 0.002. 5. Pre‐treatment postural fall in mean arterial pressure was nearly as significant (P = 0.003) as the nature of treatment in the context of such a model: the greater the fall, the greater the increment in stride length seen following active or placebo treatment. This was probably explained by an acquired tolerance to the fall as the day progressed. 6. The major determinant (P less than 0.0001) of the change in double support time over the whole walk, after allowing for the structure of the study, appeared to be the post treatment mean arterial standing blood pressure. The lower the pressure, the shorter the double support time, and hence, the greater the tendency to a hurried gait. 7. Nature of treatment, when added into the models described in summary points 5 and 6, had no significant effect (P greater than 0.25, in each case).(ABSTRACT TRUNCATED AT 400 WORDS)
Possible interaction of fluoroquinolones with the benzodiazepine‐GABAA‐ receptor complex.
Authors: Unseld E , Ziegler G , Gemeinhardt A , Janssen U , Klotz U
Published: July 2012

1. The possible involvement of the benzodiazepine (BZD)‐GABAA‐receptor complex in mediating CNS stimulatory effects of fluoroquinolones was tested in vitro, in a binding inhibition assay and in vivo, in a clinical drug interaction study using electro‐encephalogram (EEG) monitoring. 2. The specific binding of [3H]‐flunitrazepam to rat synaptic brain membranes was inhibited by various fluoroquinolones in a concentration‐dependent manner. 3. Ofloxacin had CNS‐stimulating effects as revealed by the EEG which were slightly augmented by flumazenil but reversed by coadministration of midazolam. 4. In conclusion, our findings suggest that clinically observed CNS adverse effects of fluoroquinolones could be mediated at least in part through interaction with the BZD‐GABAA‐receptor complex and may be controlled by BZD agonist administration.
Stereoselective sulphate conjugation of racemic terbutaline by human liver cytosol.
Authors: Walle T , Walle UK
Published: July 2012

1. The enantioselectivity of the sulphation of racemic terbutaline by phenolsulphotransferases was examined in vitro using cytosol from human livers (n = 3) and [35S]‐3′‐phosphoadenosine‐5′‐phosphosulphate (PAP35S) as the sulphate donor. 2. The radioactive sulphate conjugate formed was isolated by h.p.l.c. and its enantiomers were separated intact by h.p.l.c. after chiral derivatization. 3. Sulphation of racemic terbutaline occurred with the same apparent Km value for both enantiomers (270 microM). The extent of sulphation of the (+)‐ enantiomer was double that of the (‐)‐enantiomer, solely due to a difference in their apparent Vmax values. 4. Sulphation of racemic prenalterol, a structural analogue of terbutaline, also showed a two‐ fold preference for the (+)‐enantiomer. 5. These findings suggest that enantioselective sulphate conjugation of chiral phenolic sympathomimetic amine drugs may lead to enantioselective pharmacokinetics that should be considered in the clinical use of these drugs.
The effect of age on the pharmacokinetics of ifosfamide.
Authors: Lind MJ , Margison JM , Cerny T , Thatcher N , Wilkinson PM
Published: July 2012

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half‐life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.
Clinical experiences with a novel percutaneous amethocaine preparation: prevention of pain due to venepuncture in children.
Authors: Woolfson AD , McCafferty DF , Boston V
Published: July 2012

1. The efficacy and safety of a novel percutaneous anaesthetic preparation based on amethocaine has been investigated in the paediatric clinical environment. 2. There were 1241 recorded applications on a named patient basis made to patients from infant to age 16 years. Of these, 88.7% had satisfactory anaesthesia to venepuncture challenge, rising to approximately 90% when the infant group was excluded. 3. A 30 min application time was found to be adequate for reliable topical anaesthesia. 4. There were no serious adverse reactions to the preparation. Of the total 6.9% recorded reactions, 6.3% were of a mild, transient erythema later identified as due to the vasodilator action of the drug. 5. A total of 123 patients received more than one application of the preparation. There was no evidence of sensitisation on subsequent exposure to the preparation. 6. The short application time required was found to be advantageous to ward and clinic routines.