bluuebunny/crossref_metadata_2025_split huggingface dataset:
Valproate overdose: a comparative cohort study of self poisonings
Authors: Isbister Geoffrey K. , Balit Corrine R. , Whyte Ian M. , Dawson Andrew 
Published: December 2004

Aims  Based on individual case reports of massive overdoses, valproate is often regarded as having significant toxicity. This study aimed to describe the epidemiology of valproate poisoning and the spectrum of its clinical effects.Methods  Consecutive valproate poisonings were identified and compared with other anticonvulsant overdoses and all other poisonings, from a prospective database of poisoning admissions presenting to a regional toxicology service. National prescription data for the same period were obtained.Results  There were 79 patients with valproate poisoning from January 1991 to November 2001, 15 cases with valproate alone. Of the 15 cases, drowsiness occurred in two patients (both taking> 200 mg kg−1), vomiting occurred in four and tachycardia in five. In patients co‐ingesting other medications, moderate to severe effects were consistent with the co‐ingestants. There was one death not directly related to valproate. One patient had metabolic acidosis and thrombocytopaenia consistent with severe valproate toxicity. Comparison of valproate, carbamazepine, phenytoin and control groups showed that length of stay for both phenytoin and carbamazepine was significantly longer than for valproate (P < 0.0001), and there was a significantly increased risk of intensive care unit admission for carbamazepine vs valproate (OR 2.73; 95% CI 1.22, 6.28; P = 0.015). Although valproate prescriptions increased over the 10 years, there was relatively greater increase in the incidence of valproate poisoning. The odds of a valproate overdose in 1992 compared with carbamazepine were 0.29 (95% CI 0.07, 1.28; P = 0.141), but in 2001 were 2.73 (95% CI 1.38, 5.39; P = 0.004).Conclusions  Valproate causes mild toxicity in the majority of cases. Massive overdoses of greater than 400 mg kg−1 can cause severe toxicity, but these are uncommon. The older anticonvulsants phenytoin and carbamazepine remain a greater problem than valproate in overdose.
An evaluation of short‐term corticosteroid response in perennial allergic rhinitis using histamine and adenosine monophosphate nasal challenge
Authors: Wilson Andrew M. , Sims Erika J. , Orr Linda C. , Robb Fiona , Lipworth Brian J. 
Published: December 2004

Aims  To evaluate the role of AMP nasal challenge as a measure of short‐term treatment response in patients receiving intranasal corticosteroids. Adenosine monophosphate (AMP) challenge has been shown to be a good inflammatory surrogate in the lower airways, but it has not been properly evaluated as a nasal challenge test.Methods  Fourteen patients with perennial allergic rhinitis (PAR) were randomized to receive 2 weeks treatment with placebo (PL) or 200 µg intranasal mometasone furoate (MF) once daily in a randomized single‐blind crossover study. AMP (25–800 mg ml−1) and histamine (0.25–8 mg ml−1) nasal challenge testing were performed after each treatment period with 30% decrease in minimal cross‐sectional area (MCA). Domiciliary symptom data were collected.Results  There was a significant (P < 0.05) improvement in PC30 MCA and nasal volume with AMP but not with histamine comparing MF vs PL. This amounted to a 2.8 (95% CI 1.5, 4.0) and 0.7 (95% CI −0.5, 1.9) doubling‐dose change for AMP and histamine challenges, respectively. There were significant (P < 0.05) improvements in nasal symptoms and quality of life.Conclusions  AMP nasal challenge using acoustic rhinometry may be a useful test to assess short‐term treatment response in patient with PAR.
A randomized, double‐blind crossover trial of paracetamol 1000 mg four times daily vs ibuprofen 600 mg: effect on swelling and other postoperative events after third molar surgery
Authors: Bjørnsson G. A. , Haanæs H. R. , Skoglund L. A. 
Published: December 2004

Aims To evaluate the effect of a 3‐day regimen of ibuprofen 600 mg × 4 on acute postoperative swelling and pain and other inflammatory events after third molar surgery compared with a traditional regimen of paracetamol 1000 mg × 4.Methods A controlled, randomized, double‐blind, cross‐over study where 36 patients (26 females, 10 males) with mean age 23 (range 19–27) years acted as their own controls. All patients were subjected to surgical removal of bilateral third molars. After one operation the patients received tablets of ibuprofen 600 mg × 4 for 3 days. After the other operation they received an identical regimen of paracetamol 1000 mg tablets. Swelling was objectively measured (mm) with a standardized face bow and the patients scored their pain intensity (PI) on a 100‐mm visual analogue scale.Results There was no statistically significant difference between paracetamol and ibuprofen treatment with respect to effect on acute postoperative swelling. Swelling after paracetamol on the third postoperative day was 1.8% less than that after ibuprofen. Mean (95% CI) difference between treatments was −0.3 (−4.7, 4.1) mm. On the sixth postoperative day swelling after ibuprofen was 2.3% less than that after paracetamol. Mean (95% CI) between treatments was 0.2 (−2.4, 2.8) mm. There was   no   statistically   significant   difference   in   pain   intensity   between the paracetamol and the ibuprofen  regimen on the day of surgery.  The mean (95% CI) difference between the treatments for summed pain intensity on the day of surgery (SUMPI3.5−11) was 3.31 (−47.7, 54.3) mm. Two patients developed fibrinolysis of the blood clot (dry socket) after receiving ibuprofen while none did this after paracetamol treatment. There was no noticeable difference between treatments with respect to appearance of haematomas/ecchymoses or adverse effects which all were classified as mild to moderate.Conclusions A 3‐day regimen of ibuprofen 600 mg × 4 daily does not offer any clinical advantages compared with a traditional paracetamol regimen 1000 mg × 4 daily with respect to alleviation of acute postoperative swelling and pain after third molar surgery.
Pharmacokinetics of ribavirin in combined interferon‐alpha 2b and ribavirin therapy for chronic hepatitis C virus infection
Authors: Tsubota Akihito , Hirose Yuichi , Izumi Namiki , Kumada Hiromitsu 
Published: December 2004

Aims The aim of this study was to clarify the pharmacokinetics of ribavirin and interferon‐alpha (IFN‐α) 2b when administered in combination for 24 weeks and effects of pharmacokinetics of both on treatment outcome in chronic hepatitis C with genotype 1b and high viral load.Methods In this multicentre open study, 27 patients received 2‐week daily induction therapy followed by 22‐week, three‐times‐a‐week maintenance therapy of intramuscular IFN‐α 2b at a dose of 6 million units and oral ribavirin at 400 mg twice daily for 24 weeks, and followed up for 24 weeks post‐treatment. Single‐ and multiple‐dose pharmacokinetic studies were assessed by serial measurements of serum concentrations of both compounds at weeks 1 and 24.Results Five patients attained sustained virological response. Serum ribavirin concentrations asymptoted after 4–8 weeks of treatment in all patients. The steady‐state concentration correlated significantly with serum ribavirin clearance after multiple dosing (r = −0.875; 95% CI −0.932, −0.721; P < 0.001). Serum concentrations at weeks 4 and 8, Cmax and AUC(0,12 h) after multiple dosing and AUC(0,28 weeks) of ribavirin were significantly higher in sustained virological responders than in virological responders or nonresponders (P < 0.05, each). Increased Cmax and accumulation index of AUC(0,12 h) (median 10.5; 95% CI 6.4, 12.4), and prolonged washout half‐life after multiple dosing reflected accumulation and slow clearance of ribavirin from the tissue compartments.Conclusions Continuous exposure and accumulation of ribavirin may be necessary for sustained virological response to combination therapy in chronic hepatitis C with genotype 1b and high viral load.
Olanzapine pharmacokinetics are similar in Chinese and Caucasian subjects
Authors: Sathirakul Korbtham , Chan Clark , Teng Leyan , Bergstrom Richard F. , Yeo Kwee Poo , Wise Stephen D. 
Published: December 2004

Aim  To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects.Methods  Randomized, three‐period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived.Results  No statistically significant racial differences in the weight‐normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5‐ and 10‐mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups.Conclusion  The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.
Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine
Authors: El‐Eraky Hala , Thomas Simon H. L. 
Published: December 2004

Aims   To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization.Methods   Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg−1) and compared between 27 male and 21 female healthy volunteers.Results   There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997 ± 56 and 871 ± 57 ng ml−1, respectively (mean difference (−125, 95% confidence intervals (CI) −239, 11 ng ml−1, P = NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P < 0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33 ± 16 vs 24 ± 17 ms, mean difference 9 ± 20 ms, 95% CI 3, 15, P = 0.037). At this time mean differences (95% CI) were 1.0 min−1 (−2.5, 4.4, P = NS) for heart rate, 5.5 ms (3.5, 7.6, P = 0.05) for the QRS and 3.4 ms (−2.5, 9.3, P = NS) for the JTc intervals.Conclusions   Quinidine‐induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.
Effects of passive smoking on blood pressure and aortic pressure waveform in healthy young adults – influence of gender
Authors: Mahmud Azra , Feely John 
Published: December 2004

Aims  Passive smoking impairs the elasticity of the aorta in patients with coronary heart disease. We therefore studied the effect of passive smoking on wave reflection in the aorta, a marker of arterial stiffness, in healthy subjects.Method  We examined the effects of acute exposure to passive smoking on blood pressure and the aortic pressure waveform in healthy young men (n = 10) and women (n = 11), aged 26 ± 5 years (mean ± SEM) compared with 12 healthy controls, aged 24 ± 2 years (six female) who were exposed to room air. The aortic pressure waveform was derived with radial applanation tonometry (SphygmoCor, AtCor Medical, version 6.2) and the augmentation index, a measure of arterial wave reflection in the aorta, calculated. Blood pressure (Omron Model HEM‐705 CP, Omron Corporation, Tokyo, Japan) and augmentation index were measured at baseline, 15, 30 and 60 min after exposure to environmental tobacco smoke (carbon monoxide 25–30 p.p.m. for 60 min) or room air.Results  Passive smoking was associated with an increase in brachial (124 ± 4–137 ± 3 mmHg, P < 0.01) and aortic systolic blood pressure (110 ± 3–123 ± 4 mmHg, P < 0.01) at 60 min in the male subjects only. The augmentation index increased from −1.7 ± 5 to 14 ± 5 at 60 min (P < 0.001) only in the male subjects. The transit time of the pulse did not change significantly. The change in augmentation index was independent of the increase in blood pressure. Brachial and aortic diastolic blood pressure and heart rate did not change significantly in either male or female subjects. No haemodynamic changes were observed in the control group.Conclusions  Acute exposure to passive smoking has a deleterious effect on the arterial pressure waveform in healthy young males but not in females, suggesting a possible protection of female gender from functional changes in arteries.
Sildenafil does not improve nitric oxide‐mediated endothelium‐dependent vascular responses in smokers
Authors: Dishy Victor , Harris Paul A. , Pierce Rosanna , Prasad Harish C. , Sofowora Gbenga , Bonar Holly L. , Wood Alastair J. J. , Stein C. Michael 
Published: December 2004

Aims  To examine the hypothesis that sildenafil, a phosphodiesterase type 5 inhibitor that inhibits cGMP breakdown, could enhance nitric oxide‐mediated vasodilation and reverse endothelial dysfunction in chronic smokers.Methods  Flow‐mediated dilation of the brachial artery and forearm postischemic reactive hyperemia (both nitric oxide‐mediated responses) were measured before and after sildenafil 50 mg and placebo in a double‐blind, randomized, crossover study in 9 men who were chronic smokers (21 ± 3 pack years).Results  There was no significant change in flow‐mediated dilation after either sildenafil (0.18%, 95%CI −1.7–2%) or placebo (0.24%, 95%CI −2.8–3.3%) (P = 0.88 and 0.8, respectively). Sildenafil had no significant effect on resting forearm blood flow or postischemic reactive hyperemia (P = 0.39 and 0.7, respectively). Resting heart rate and blood pressure were unaffected by sildenafil.Conclusions  Acute sildenafil administration did not improve endothelial function in chronic smoking men.
Protective role of glutathione S‐transferase P1 (GSTP1) Val105Val genotype in patients with bronchial asthma
Authors: Aynacioglu A. Sükrü , Nacak Muradiye , Filiz Ayten , Ekinci Erhan , Roots Ivar 
Published: December 2004

Background  GlutathioneS‐transferase P1 (GSTP1), the abundant isoform of glutathione S‐transferases (GSTs) in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. It has been suggested that polymorphisms in the GSTP1 gene are associated with asthma and related phenotypes. As significant interindividual and interethnic differences exist in the distribution of xenobiotic‐metabolizing enzymes, we have studied the GSTP1 Ile105Val polymorphism in patients with asthma in a Turkish sample.Methods  GSTP1 Ile105Val polymorphism in exon 5 was determined in 210 patients with asthma (112 extrinsic and 108 intrinsic) and 265 control individuals without lung diseases and without history of allergy or atopy, using polymerase chain reaction (PCR)‐restriction fragment length polymorphism (RFLP) techniques.Results  The proportion of GSTP1 Val105 homozygotes was significantly lower in the patients with asthma than in the control individuals (3.8% vs 12.1%). The odds ratio for GSTP1 Val105 homozygotes vs all other genotypes was 0.29 (95%CL 0.13–0.64, p = 0.01) for asthmatics. The distribution of GSTP1 Ile105Val genotypes and the frequency of GSTP1 Val105Val homozygotes (3.7% vs 3.9%) was not significantly different between extrinsic and intrinsic asthmatics.Conclusion  These results suggest a significant association between GSTP1 Ile105Val polymorphism and susceptibility to asthma and that the GSTP1 Val105Val genotype may be protective against developing this disease.
Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults
Authors: Courtney Rachel , Wexler David , Radwanski Elaine , Lim Josephine , Laughlin Mark 
Published: December 2004

Aims   This randomized, crossover, single‐dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal.Methods   This was a randomized, open‐label, four‐way crossover, single‐dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high‐fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 × 100 mg) administered with a high‐fat meal.Results   The posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h) = 137% (90% confidence interval (CI) 119%, 156% and Cmax = 123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and Cmax values were about 400% when administered with a high‐fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; Cmax 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in Cmax of 296% (90% CI 250%, 350%) relative to the fasted state.Conclusions   The suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.
Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria
Authors: Hung Te‐Yu , Davis Timothy M. E. , Ilett Kenneth F. , Karunajeewa Harin , Hewitt Sean , Denis Mey Bouth , Lim Chiv , Socheat Doung 
Published: December 2004

Aims To study the population pharmacokinetics of piperaquine after co‐administration with dihydroartemisinin in uncomplicated malaria.Methods The disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine‐dihydroartemisinin coformulation Artekin®. All patients were given Artekin® orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32–35 mg base kg−1. Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17–19 samples) or sparse (2–5 samples) blood sampling schedules over 35 days and clinical/parasitological follow‐up over > 28 days. Piperaquine in plasma was quantified by high performance liquid chromatography.Results All patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28‐day cure rate was 97% in adults and 98% in children. A covariate‐free two‐compartment population model with first‐order absorption and elimination gave the most robust representation of the plasma concentration‐time data in both adults and children. In adults (n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/F, Vss/F and t1/2,z were 0.9 l h−1 kg−1 (0.79–1.02 l h−1 kg−1), 574 l kg−1(371–711 l kg−1) and 23 days (19–28 days), respectively. In children (n = 47), corresponding values were 1.8 l h−1 kg−1 (1.29–2.3 l h−1 kg−1), 614 l kg−1 (332–1205 l kg−1) and 14 days (10–18 days), respectively.Conclusions Piperaquine is a highly lipid‐soluble drug with a large Vss/F, long t1/2,z and a clearance that is markedly higher in children than in adults.
Retrospective population pharmacokinetic analysis of cetirizine in children aged 6 months to 12 years
Authors: Pitsiu Maria , Hussein Ziad , Majid Oneeb , Aarons Leon , De Longueville Marc , Stockis Armel 
Published: December 2004

Aims  To evaluate retrospectively the population pharmacokinetics of cetirizine, a second‐generation antihistamine, in children.Methods  Data were pooled from six clinical trials, in which cetirizine was administered orally in various formulations and in single and multiple dosage regimens. The population consisted of 112 children (33 female and 79 male) aged 6 months to 12 years. A one‐compartment open model with first‐order absorption and elimination was fitted to the plasma concentration‐time profiles using nonlinear mixed effects modelling with first‐order estimation.Results  A linear association was found between apparent clearance (CL/F) and age with the former increasing by 0.12 l h−1 per year. The intercept of the relationship was slightly lower for female children (0.59 vs. 0.77 l h−1 in male). The population estimate of CL/F for an average age of 7 years was 1.61 and 1.43 l h−1 for male and female children, respectively. A linear association was found between apparent volume of distribution (V/F) and age with the former increasing by 1.4 l year−1, with an intercept of 4.0 l. The population estimate of V/F for an average age of 7 years was 13.9 l. The magnitudes of interpatient variability were 35.6% for CL/F and 19.7% for V/F. The magnitude of residual variability in cetirizine concentrations was 26.9%.Conclusions  Population  analysis  predicts  a  linear  increase  in  cetirizine  CL/F  and V/F with age, with CL/F being slightly lower in female children, relative to males of the same age. However, this gender difference probably has no clinical consequences. Since V/F increased more rapidly with age than CL/F, a nonlinear increase in half‐life was seen, from < 4 h in infants to near the adult value at 12 years of age. The current recommended dosing regimens that younger children should receive lower but more frequent doses, are confirmed by the present analysis.