bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK–PD modelling analysis
Authors: Webb James A. , Rostami‐Hodjegan, Amin , Abdul‐Manap Roslina , Hofmann Ute , Mikus Gerd , Kamali Farhad 
Published: March 2003

Aims  It is not clear whether the analgesic effect following dihydrocodeine (DHC) administration is due to either DHC itself or its metabolite, dihydromorphine (DHM). We examined the relative contribution of DHC and DHM to analgesia following DHC administration in a group of healthy volunteers using a PK‐PD link modelling approach.Methods  A single oral dose of DHC (90 mg) was administered to 10 healthy volunteers in a randomised, double‐blind, placebo‐controlled study. A computerized cold pressor test (CPT) was used to measure analgesia. On each study day, the volunteers performed the CPT before study medication and at 1.25, 2.75, 4.25 and 5.75 h postdose. Blood samples were taken at 0.25 h (predose) and then at half hourly intervals for 5.75 h postdose. PK‐PD link modelling was used to describe the relationships between DHC, DHM and analgesic effect.Results  Mean pain AUCs following DHC administration were significantly different to those following placebo administration (P = 0.001). Mean pain AUC changes were 91 score. s−1 for DHC and −17 score. s−1 for placebo (95% CI = ± 36.5 for both treatments). The assumption of a simple linear relationship between DHC concentration and effect provided a significantly better fit than the model containing DHM as the active moiety (AIC = 4.431 vs 4.668, respectively). The more complex models did not improve the likelihood of model fits significantly.Conclusions  The findings suggest that the analgesic effect following DHC ingestion is mainly attributed to the parent drug rather than its DHM metabolite. It can thus be inferred that polymorphic differences in DHC metabolism to DHM have little or no effect on the analgesic affect.
The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: The Fremantle Diabetes Study
Authors: Davis Timothy M. E. , Jackson Denise , Davis Wendy A. , Bruce David G. , Chubb Paul 
Published: March 2003

Aims  To determine (i) which factors, including metformin, are associated with the fasting plasma lactate concentration in type 2 diabetes, and (ii) whether plasma lactate is associated with haemodynamic and metabolic effects.Methods  We measured fasting plasma lactate in 272 well‐characterized diabetic patients from a community‐based sample, 181 (67%) of whom were taking metformin with or without other therapies. Linear regression analysis was used to identify predictors, including metformin therapy, of the plasma lactate, and to investigate associations between plasma lactate and resting pulse rate and serum bicarbonate. Factor analysis assessed independent relationships between groups of cosegregating variables.
Results Metformin‐treated patients had higher plasma lactate concentrations than nonmetformin‐treated subjects (geometric mean [s.d. range] 1.86 [1.34–2.59]vs 1.58 [1.09–2.30] mmol l−1, respectively; P < 0.001). In a linear regression model, plasma glucose, BMI and metformin use (but not dose) were independently associated with plasma lactate (P ≤ 0.028); after adjustment for the former two variables, metformin‐treated patients had a mean plasma lactate 0.16 mmol l−1 greater than in subjects not taking the drug. Factor analysis revealed that plasma lactate, plasma glucose, BMI and pulse rate cosegregated but serum bicarbonate was not in this grouping.Conclusions The present results show that metformin therapy increases the fasting plasma lactate in ambulant patients with type 2 diabetes from a community‐based cohort. From associations in the data we hypothesize that this increase reflects (i) increased sympathetic activity in patients with the metabolic syndrome (ii) increased substrate (glucose) availability and (iii) a direct metformin effect.
Cigarette smoking in men and vascular responsiveness
Authors: Butler R. , Morris A. D. , Struthers A. D. 
Published: March 2003

Aims  Smoking is a major risk factor for developing atherosclerosis. In order to understand the vascular abnormalities observed in smokers, we investigated vascular responsiveness in cigarette smokers.Methods  We performed two consecutive matched group comparative studies to investigate vascular responsiveness using venous occlusion plethysmography. The mean effects of three incremental doses of each vasoactive agent are presented. Both studies compared smokers with nonsmokers.Results  The first investigated 68 subjects (smokers = 29; mean ± s.d. ages; 24 ± 6 vs 25 ± 5 years; P = NS) and found smoking was associated with a significant blunting of the flow ratio between treated and untreated arms to endothelium‐dependent vasodilatation to acetylcholine (mean ± s.d., nonsmokers vs smokers) 4.07 ± 2.18 vs 3.42 ± 1.79 (P = 0.04, 95% CI 0.02, 1.12). By contrast, there was no significant difference in the responses to the endothelium‐independent vasodilators sodium nitroprusside and verapamil. Smoking was also associated with a significant impairment in endothelium‐dependent vasoconstriction induced by monomethyl‐l‐arginine (L‐NMMA) 0.78 ± 0.22 vs 0.87 ± 0.21 (P = 0.006, 95% CI −0.14, −0.02) and a trend to blunted endothelium‐independent vasoconstrictor responses to noradrenaline. In the second study we investigated the response to angiotensin I and II in 23 subjects (smokers=12; mean ± s.d. ages; 34 ± 10 vs 32 ± 11 years). There was significant impairment in smokers of the mean vasoconstrictor response to angiotensin I 0.51 ± 0.15 vs 0.59 ± 0.16 (nonsmokers vs smokers; P = 0.003, 95% CI −0.13, −0.03) and a nonsignificant trend towards impairment of the response to angiotensin II.Conclusions  Cigarette smoking in male volunteers is associated with blunted basal and stimulated nitric oxide bioactivity. Endothelial independent vasodilator responses (to nitroprusside and verapamil) were unaltered in smokers. A defect in the vasoconstrictor response to angiotensin I was also seen.
Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers
Authors: Zhang Shu‐Qiu , Hai Trinh Ngoc , Ilett Kenneth F. , Huong Dinh Xuan , Davis Timothy M. E. , Ashton Michael 
Published: March 2003

Aims  To investigate whether coadministration of the antimalarials artesunate and artemisinin alters the clearance of either drug.Methods  Ten healthy Vietnamese males (Group AS) were randomized to receive a single dose of 100 mg oral artesunate (pro‐drug of dihydroartemisinin) on day −5 and then once daily for 5 consecutive days (days 1–5). Oral artemisinin (500 mg) was coadministered on days 1 and 5. Another 10 subjects (Group AM) were given 500 mg oral artemisinin on day −5 and then further doses on days 1–5. Artesunate 100 mg was given on days 1 and 5. Artemisinin and dihydroartemisinin plasma concentrations on days −5, 1 and 5 were quantified by h.p.l.c. with on‐line postcolumn derivatization and u.v. detection.Results  In Group AS, dihydroartemisinin oral clearance values (mean (95% CI)) were similar on day 1 (32 (22, 47)) l h−1 and day 5 (38 (28, 51)) l h−1 of daily artesunate administration but these mean values were approximately three fold higher compared with day −5 after a single dose (95 (56, 159)). In this group, artemisinin oral clearance increased from 196 (165, 232) l h−1 on day 1–315 (241, 410) l h−1 on day 5. In Group AM, dihydroartemisinin oral clearance on day 1 was 39 (34, 46) l h−1 and increased 1.6 fold to 64 (48, 85) l h−1 on day 5. In this group, artemisinin oral clearance increased sequentially (1.5 and 4.7 fold, respectively) from 207 (151, 285) l h−1 on day −5–308 (257, 368) l h−1 on day 1 and to 981 (678, 1420) l h−1 on day 5. The increase in artemisinin oral clearance between days −5 and 1 (in the absence of artesunate) was similar to that between days 1 and 5 in Group AS subjects who took daily artesunate. Dihydroartemisinin was not a significant metabolite of artemisinin.Conclusions  Artesunate (dihydroartemisinin) did not alter the elimination of artemisinin. However, dihydroartemisinin elimination was inhibited by artemisinin. Artemisinin induced its own elimination even 5 days after a single oral dose. There was no evidence for the formation of dihydroartemisinin from artemisinin.
In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)
Authors: Wen Xia , Wang Jun‐Sheng , Kivistö Kari T. , Neuvonen Pertti J. , Backman Janne T. 
Published: March 2003

Aims  To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes.Methods  Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O‐deethylase (CYP1A2), coumarin 7‐hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S‐mephenytoin 4′‐hydroxylase (CYP2C19), dextromethorphan O‐demethylase (CYP2D6), chlorzoxazone 6‐hydroxylase (CYP2E1) and midazolam 1′‐hydroxylase (CYP3A4).
Results
Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 µm. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 µm, mixed inhibition) and CYP3A4 activity (Ki = 7975 µm, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time‐, concentration‐ and NADPH‐dependent (KI = 9150 µm, Kinact=0.048 min−1), consistent with mechanism‐based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed.
Conclusions
Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co‐administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.
Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers
Authors: Edstein Michael D. , Kocisko David A. , Brewer Thomas G. , Walsh Douglas S. , Eamsila Chirapa , Charles Bruce G. 
Published: March 2003

Aims  To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis.Methods  The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre‐existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re‐treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM.Results  A one‐compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first‐order absorption rate constant (Ka), CL/F and V/F were 0.694 h−1, 3.20 l h−1 and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half‐lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%.Conclusions  The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short‐term radical treatment of vivax malaria.
Effect of bile acids on absorption of nitrendipine in healthy subjects
Authors: Sasaki Masato , Maeda Akira , Sakamoto Ko‐ichi , Fujimura Akio 
Published: March 2003

Aims  To examine whether bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) can influence the absorption of nitrendipine, a highly lipophilic calcium channel blocker.Methods  Six healthy subjects received nitrendipine (10 mg) with and without UDCA (50 mg) and CDCA (200 and 600 mg) with an interval of 1∼2 weeks between study phases.Results  Bile acids decreased the Cmax (ng ml−1) [control 10.9 ± 5.8 (mean± s.d.), UDCA 5.0 ± 4.7 (95% confidence interval for difference; 3.9, 7.8, P = 0.0006), CDCA (600 mg) 5.0 ± 3.9 (2.6, 9.2, P = 0.0059)] and AUC (ng ml−1 h) [(control; 60 ± 36, UDCA 15 ± 13 (20, 73, P = 0.0064), CDCA (600 mg) 19 ± 19 (21, 63, P = 0.0038)] of nitrendipine, while elimination half‐life remained unchanged.Conclusions  These results suggest that the amount of nitrendipine absorbed was decreased when the drug was administered with UDCA and CDCA.
Human thiopurine methyltransferase activity varies with red blood cell age
Authors: Lennard L. , Chew T. S. , Lilleyman J. S. 
Published: March 2003

Aims  Inherited differences in thiopurine methyltransferase (TPMT) activity are an important factor in the wide interindividual variations observed in the clinical response to thiopurine chemotherapy. The aim of this study was to establish a population range for red blood cell (RBC) TPMT activity in children with acute lymphoblastic leukaemia (ALL) at disease diagnosis. An additional aim was to investigate factors that can influence TPMT activity within the RBC.
Methods
Blood samples were collected from children with ALL at disease diagnosis, prior to any blood transfusions, as part of the nationwide UK MRC ALL97 therapeutic trial. RBC TPMT activity was measured by h.p.l.c. RBCs were age‐fractionated on Percoll density gradients.
Results
Pretreatment blood samples were received from 570 children within 3 days of venepuncture. TPMT activities at disease diagnosis ranged from 1.6 to 23.6 units/ml RBCs (median 7.9) compared with 0.654–18.8 units (median 12.9), in 111 healthy control children (median difference 4.5 units, 95% CI 3.9, 5.1 units, P < 0.001). A TPMT quality control sample, aliquots of which were assayed in 60 analytical runs over a 12 month period, contained a median of 11.98 units with a CV of 11.6%. Seven children had their RBCs age‐fractionated on density gradients. TPMT activities in the top gradient (young cells) ranged from 4.2 to 14.1 units (median 7.5) and in the bottom gradient (old cells) 1.5–12.6 units (median 4.7 units), median difference 2.3 units, 95% CI 0.7, 4.1, P = 0.035.
Conclusions
Circulating RBCs do not constitute a homogeneous population. They have a life span of around 120 days and during that time undergo a progressive ageing process. The anaemia of ALL is due to deficient RBC production. The results of this study indicate that RBC TPMT activities are significantly lower in children with ALL at disease diagnosis. This may be due, at least in part, to a relative excess of older RBCs.
Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval
Authors: Allen Michael J. , Oliver Stuart D. , Newgreen Margaret W. , Nichols Donald J. 
Published: March 2003

Aims  To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments.Methods  A randomized, single‐blinded, placebo‐controlled, parallel‐group, multiple‐dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups.Results  Continuous administration of dofetilide resulted in the achievement of steady‐state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean± s.e. mean) increased in response to continuous twice‐daily dofetilide from baseline (373 ± 5) to day 2 (453 ± 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 ± 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (± s.e. mean) maximum QTc increased from a baseline of 387 ± 7–467 ± 14, 467 ± 18, 469 ± 14 and 458 ± 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 ± 1.7 ms/ng ml−1) and day 5 (9.1 ± 0.8 ms/ng ml−1) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were 4.4 (1.3, 7.4) on day 5, 4.9 (1.6, 8.2) on day 10, 5.2 (1.1, 9.2) on day 17 and 4.4 (0.4, 8.4) on day 24.Conclusions  With continuous twice‐daily administration the QT interval responsiveness to dofetilide is greater after the first dose than it is at steady state. After day 5 the relationship between dofetilide plasma concentration and its QT interval effect is predictable and stable over time.
Early clinical experience with the novel NMDA receptor antagonist CNS 5161
Authors: Walters M. R. , Bradford A. P. J. , Fischer J. , Lees K. R. 
Published: March 2003

Aims  To investigate the safety, tolerability and pharmacokinetics of the novel NMDA antagonist CNS 5161 in humans. Excessive activation of glutamate receptors, especially of the N‐methyl‐d‐aspartate (NMDA) subtype has been associated with neuropathic pain, and brain damage caused by focal ischaemia in mature brain or hypoxia‐ischaemia (HI) in neonates. CNS 5161 is a novel NMDA ion‐channel antagonist that interacts with the NMDA receptor/ion channel site to produce a noncompetitive blockade of the actions of glutamate. Pre‐clinical studies have demonstrated neuroprotective effects of CNS 5161 in the adult rat model of focal cerebral ischaemia, as well as anticonvulsant and analgesic effects. This study reports the first administration of CNS 5161 to man. Its objectives were to investigate the haemodynamic effects of the compound, to assess its safety and tolerability in healthy male volunteers, and to provide some preliminary human pharmacokinetic data.Methods  We performed a randomized, double‐blind placebo controlled phase 1 dose escalation study of CNS 5161. Volunteers were randomized to receive CNS 5161 or placebo in a ratio of 3 : 1. Twenty‐four of 32 healthy volunteers received intravenous infusion of CNS 5161 over 15 min, followed by serial measurements of plasma drug concentration and haemodynamic observations over 24 h. A dose escalation design was adopted and the volunteers were stratified into eight dosage groups, ranging from 30 µg to 2000 µg.Results  The drug was well tolerated by recipients. Side‐effects were dose‐related, self limiting and comprised minor subjective sensory symptoms. A dose dependent rise in systolic, mean arterial and diastolic blood pressure was seen in subsequent dosage groups, reaching 23/19 mmHg. Maximal effects were seen between 60 and 120 min after commencement of infusion. All subjects returned to baseline haemodynamic values within 24 h. Putative neuroprotective concentrations of CNS 5161 were achieved transiently, although these levels were not sustained. The pharmacokinetic data were best described by a two compartment model. The mean half‐life was 2.95 h (s.d. 0.75). Mean clearance was 106 l h−1 (s.d. 17.8) mean volume of distribution was 296 l (s.d. 69). These parameters were not significantly affected by body weight.Conclusions  This study suggests that CNS 5161 is well tolerated in healthy volunteers within the dose range studied. In addition, information concerning the pharmacokinetics of the compound has been acquired. Studies to investigate the efficacy of the compound in man may now be justified.
Local nitric oxide release does not affect tachyphylaxis to angiotensin II in dorsal hand veins in man in the presence of prostaglandin synthesis inhibition
Authors: de Haas S. L. , Wilkinson I. B. , Boyd J. L. , Webb D. J. 
Published: March 2003

Aims  Local prostaglandin (PG) production contributes to tachyphylaxis to angiotensin II (ANGII) in veins. Our aim was to assess the hypothesis that local nitric oxide (NO) generation is also, in part, responsible for tachyphylaxis to ANGII in veins, using the Aellig dorsal hand vein technique.Methods  Eight healthy male volunteers received 600 mg of aspirin (orally) to inhibit PG production. The venoconstrictor effects of ANGII and noradrenaline (NA) were then compared in dorsal hand veins during co‐infusion of the NO synthase inhibitor L‐NMMA or saline, on separate occasions.Results  ANGII and NA produced a similar degree of initial venoconstriction. However, the response to ANGII was significantly attenuated by 12 min compared with NA (AUC 147 ± 38 vs 196 ± 40, respectively; [95% confidence interval for difference: 7, 92], P = 0.02). Infusion of L‐NMMA did not influence the response to ANGII or NA (P = 0.2 and P = 0.3, respectively).Conclusions  Tachyphylaxis to ANGII in dorsal hand veins is not dependent on local NO release.
Comparative activity of cetirizine and mizolastine on histamine‐induced skin wheal and flare responses at 24 h
Authors: Purohit A. , Mélac M. , Pauli G. , Frossard N. 
Published: March 2003

Aims  The aim of our study was to compare the activity of cetirizine 10 mg with that of mizolastine 10 mg vs placebo at 24 h after intake in healthy volunteers.Methods  This was a double‐blind, randomized, placebo controlled, three‐way cross‐over study with a wash‐out period of 7±2 days between each period. The study included 36 healthy volunteers (18–50 years, mean age = 32 years; 9 males). The objective measurement was the cutaneous reactivity to increasing concentrations of histamine (0, 5, 10, 20, 40, 80, 160 mg ml−1) administered by prick tests. The reactivity was evaluated by the wheal and flare areas (mm2). The AUC (area under curves) values of the wheal and flare areas as a function of the log2 transformed histamine concentration were calculated for each subject and treatment, and compared.Results  A highly significant treatment effect was evidenced both for wheal and flare responses (P = 0.0001). This indicates the good activity of both cetirizine 10 mg and mizolastine 10 mg in inhibiting skin wheal and flare reactions to histamine. In addition, the mean AUC values significantly differed between cetirizine and mizolastine (64.8 and 117.8 log2 (mg ml−1) × mm2 for wheal, and 939.4 and 2340.8 for flare, respectively; P = 0.0001), with a superior activity of cetirizine than mizolastine at 24 h after intake both on wheal and flare responses. The tolerance of cetirizine and mizolastine was good. The severity of the adverse events was never more than ‘moderate’, ‘fatigue’ being the most frequent reported symptom [cetirizine (6 subjects), placebo (3), mizolastine (5)], followed by ‘somnolence’[cetirizine (0), placebo (1), mizolastine (3)]. There was no serious adverse event.Conclusions  This study shows that cetirizine (10 mg) suppresses skin reactivity to histamine more effectively than mizolastine (10 mg) 24 h after intake in healthy volunteers.