bluuebunny/crossref_metadata_2025 huggingface dataset:
How much can you drink before driving? The influence of riding with impaired adults and peers on the driving behaviors of urban and rural youth
Authors: Leadbeater Bonnie J. , Foran Kathleen , Grove‐White Aidan
Published: March 2008

Aims  Following an ecological model to specify risks for impaired driving, we assessed the effects of youth attitudes about substance use and their experiences of riding in cars with adults and peers who drove after drinking alcohol or smoking cannabis on the youths' own driving after drinking or using cannabis.

Design and methods  Participants were 2594 students in grades 10 and 12 (mean age = 16 years and 2 months; 50% girls) from public high schools in urban (994) and rural communities (1600) on Vancouver Island in British Columbia, Canada; 1192 of these were new drivers with restricted licenses. Self‐report data were collected in anonymous questionnaires. Regression analyses were used to assess the independent and interacting effects of youth attitudes about substance use and their experiences of riding in cars with adults or peers who drove after drinking alcohol or smoking cannabis on youth driving.

Findings  Youth driving risk behaviors were associated independently with their own high‐risk attitudes and experiences riding with peers who drink alcohol or use cannabis and drive. However, risks were highest for the youth who also report more frequent experiences of riding with adults who drink alcohol or use cannabis and drive.

Conclusions  Prevention efforts should be expanded to include the adults and peers who are role models for new drivers and to increase youths' awareness of their own responsibilities for their personal safety as passengers.
Long‐term effectiveness of computer‐generated tailored patient education on benzodiazepines: a randomized controlled trial
Authors: Ten Wolde Geeske Brecht , Dijkstra Arie , Van Empelen Pepijn , Van Den Hout Wilbert , Knuistingh Neven Arie , Zitman Frans
Published: March 2008

Aims  Chronic benzodiazepine use is highly prevalent and is associated with a variety of negative health consequences. The present study examined the long‐term effectiveness of a tailored patient education intervention on benzodiazepine use.

Design  A randomized controlled trial was conducted comprising three arms, comparing (i) a single tailored intervention; (ii) a multiple tailored intervention and (iii) a general practitioner letter. The post‐test took place after 12 months.

Participants  Five hundred and eight patients using benzodiazepines were recruited by their general practitioners and assigned randomly to one of the three groups.

Intervention  Two tailored interventions, the single tailored intervention (patients received one tailored letter) and the multiple tailored intervention (patients received three sequential tailored letters at intervals of 1 month), were compared to a short general practitioner letter that modelled usual care. The tailored interventions not only provided different and more information than the general practitioner letter; they were also personalized and adapted to individual baseline characteristics. The information in both tailored interventions was the same, but in the multiple tailored intervention the information was provided to the participants spread over three occasions. In the multiple tailored intervention, the second and the third tailored letters were based on short and standardized telephone interviews.

Measurements  Benzodiazepine cessation at post‐test was the outcome measure.

Findings  The results showed that participants receiving the tailored interventions were twice as likely to have quit benzodiazepine use compared to the general practitioner letter. Particularly among participants with the intention to discontinue usage at baseline, both tailored interventions led to high percentages of those who actually discontinued usage (single tailored intervention 51.7%; multiple tailored intervention 35.6%; general practitioner letter 14.5%).

Conclusions  It was concluded that tailored patient education can be an effective tool for reducing benzodiazepine use, and can be implemented easily.
The case for the plain packaging of tobacco products
Authors: Freeman Becky , Chapman Simon , Rimmer Matthew
Published: March 2008

Aims  The Framework Convention on Tobacco Control (FCTC) requires nations that have ratified the convention to ban all tobacco advertising and promotion. In the face of these restrictions, tobacco packaging has become the key promotional vehicle for the tobacco industry to interest smokers and potential smokers in tobacco products. This paper reviews available research into the probable impact of mandatory plain packaging and internal tobacco industry statements about the importance of packs as promotional vehicles. It critiques legal objections raised by the industry about plain packaging violating laws and international trade agreements.

Methods  Searches for available evidence were conducted within the internal tobacco industry documents through the online document archives; tobacco industry trade publications; research literature through the Medline and Business Source Premier databases; and grey literature including government documents, research reports and non‐governmental organization papers via the Google internet search engine.

Results  Plain packaging of all tobacco products would remove a key remaining means for the industry to promote its products to billions of the world's smokers and future smokers. Governments have required large surface areas of tobacco packs to be used exclusively for health warnings without legal impediment or need to compensate tobacco companies.

Conclusions  Requiring plain packaging is consistent with the intention to ban all tobacco promotions. There is no impediment in the FCTC to interpreting tobacco advertising and promotion to include tobacco packs.
Predictors of 4‐year outcome of community residential treatment for patients with substance use disorders
Authors: Laffaye Charlene , McKellar John D. , Ilgen Mark A. , Moos Rudolf H.
Published: March 2008

Aims This study examined systematically how predictors of substance use disorder (SUD) treatment outcome worked together over time and identified mediators and moderators of outcome.

Design The MacArthur model was applied in this naturalistic study to identify how baseline, discharge and 1‐year follow‐up factors worked together to predict 4‐year improvement in substance‐related problems.

Setting Eighty‐eight community residential facilities were selected based on geographic representativeness, number of patient referrals and type of treatment orientation.

Participants Of 2796 male patients who completed intake assessments, 2324 were assessed at the 1‐year follow‐up and 2023 at the 4‐year follow‐up.

Measurements Self‐report measures of symptom severity, functioning, social resources and coping, treatment and involvement in Alcoholics Anonymous (AA) were collected at baseline and at 1‐ and 4‐year follow‐ups. Provider‐rated treatment participation measures were obtained at discharge.

Findings Greater substance use severity, more psychiatric symptoms, more prior arrests and stronger belief in AA‐related philosophy at treatment entry predicted improvement significantly in substance‐related problems 4 years later. At the 1‐year follow‐up, being employed and greater use of AA‐related coping predicted outcome significantly. AA‐related coping at 1 year mediated the relationship partially between belief in AA philosophy at treatment entry and 4‐year outcome.

Conclusions The findings highlight the unique and positive impact of AA involvement on long‐term SUD treatment outcome and extend understanding of why AA is beneficial for patients.
Preliminary evidence for gender‐specific effects of topiramate as a potential aid to smoking cessation
Authors: Anthenelli Robert M. , Blom Thomas J. , McElroy Susan L. , Keck Paul E.
Published: March 2008

Aims  Study aims were threefold: (i) to determine the feasibility, potential efficacy and safety of topiramate as an aid to smoking cessation; (ii) to examine potential predictors of abstinence including gender; and (iii) to explore topiramate's effects on tobacco withdrawal and post‐cessation weight gain.

Design  Randomized, double‐blind, placebo‐controlled, 11‐week clinical trial with a 6‐week dosage titration period and 5 weeks of maintenance treatment.

Setting  Single‐site, out‐patient, randomized clinical trial.

Participants  Thirty‐eight adult male and 49 female chronic smokers who smoked an average of > 10 cigarettes per day and who were motivated to try to quit smoking.

Intervention  Random assignment to receive either topiramate (n = 43) up to 200 mg daily in divided doses or placebo (n = 44) orally combined with brief counseling over an 11‐week period.

Measurements  Carbon monoxide (CO)‐confirmed 4‐week prolonged abstinence rate during weeks 8–11. Changes in tobacco withdrawal, body weight and safety parameters were also assessed.

Findings  Overall, no significant increase in the prolonged abstinence rate was detected, but logistic regression analysis indicated significant gender‐specific differences. Men treated with topiramate were nearly 16 times more likely to quit smoking than women on topiramate [37.5% versus 3.7%; odds ratio (OR) = 15.6; P = 0.016] and were roughly four times more likely to quit smoking than placebo‐treated men (37.5% versus 13.6%; OR = 3.8; P = 0.098). Topiramate‐treated men reported significantly lower tobacco withdrawal scores than both women taking topiramate and men on placebo. On average, male cessators on placebo gained 3.30 kg, whereas topiramate led to a 0.72 kg weight loss (P = 0.03). Study discontinuation rates due to adverse events (AEs) were significantly higher in the topiramate group (topiramate 23% versus placebo 2%). The most commonly reported AEs in the topiramate arm were paraesthesia, fatigue, difficulty with concentration/attention and nervousness.

Conclusions  Topiramate produced gender‐specific effects on smoking cessation. Male smokers had markedly greater quit rates than female smokers and men were roughly four times more likely to quit smoking when treated with topiramate as compared to placebo. Topiramate was fairly well tolerated, although higher discontinuation rates were seen. Topiramate's triple effects aiding smoking abstinence, attenuating nicotine withdrawal and preventing post‐cessation weight gain might make it a promising agent for treating tobacco addiction, at least in men.
Sexual orientation and adolescent substance use: a meta‐analysis and methodological review*
Authors: Marshal Michael P. , Friedman Mark S. , Stall Ron , King Kevin M. , Miles Jonathan , Gold Melanie A. , Bukstein Oscar G. , Morse Jennifer Q.
Published: March 2008

Aims Several decades of research have shown that lesbian, gay and bisexual (LGB) adults are at high risk for substance use and substance use disorders (SUDs). These problems may often start prior to young adulthood; however, relatively little is known about risk for substance use in LGB adolescents. The primary aims of this paper were to conduct a meta‐analysis of the relationship between sexual orientation and adolescent substance use and a systematic review and critique of the methodological characteristics of this literature.

Methods Medical and social science journals were searched using Medline and PsychInfo. Studies were included if they tested the relationship between sexual orientation and adolescent substance use. Eighteen published studies were identified. Data analysis procedures followed expert guidelines, and used National Institutes of Health (NIH)‐sponsored meta‐analysis software.

Results LGB adolescents reported higher rates of substance use compared to heterosexual youth (overall odds ratio = 2.89, Cohen's d = 0.59). Effect sizes varied by gender, bisexuality status, sexual orientation definition and recruitment source. None of the studies tested mediation and only one tested moderation. One employed a matched comparison group design, one used a longitudinal design, and very few controlled for possible confounding variables.

Conclusions The odds of substance use for LGB youth were, on average, 190% higher than for heterosexual youth and substantially higher within some subpopulations of LGB youth (340% higher for bisexual youth, 400% higher for females). Causal mechanisms, protective factors and alternative explanations for this effect, as well as long‐term substance use outcomes in LGB youth, remain largely unknown.
Human pharmacology of a performance‐enhancing dietary supplement under resting and exercise conditions
Authors: Haller Christine A. , Duan Minjing , Jacob Peyton , Benowitz Neal
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Performance‐enhancing dietary supplements have not been clinically tested for safety or efficacy.

• In clinical trials performed under resting conditions, performance‐enhancing supplements raise blood pressure and affect glucose homeostasis.

• The effect of exercise on the pharmacokinetics and pharmacodynamics of stimulant herbals is unknown.

WHAT THIS STUDY ADDS

• Supplement‐induced effects on blood pressure and glucose levels are not ameliorated by exercise.

• Exercise does not affect the kinetics of stimulant ingredients, caffeine and synephrine.

• Performance‐enhancing supplement use modestly improves exercise tolerance.

AIMS

Dietary supplements (DS) promoted to enhance athletic performance often contain herbal sympathomimetics such as Citrus aurantium (synephrine) and caffeine. We aimed to characterize the pharmacology of a performance‐enhancing DS in the setting of exercise.

METHODS

Ten healthy adults (three women) aged 20–31 years participated in a three‐arm, double‐blind, placebo‐controlled, crossover study. Subjects ingested one dose of DS (Ripped Fuel Extreme Cut® with 21 mg synephrine and 304 mg caffeine by analysis) under resting conditions and 1 h prior to moderately intense exercise (30 min on cycle ergometer at 75–80% HRmax), with a placebo (PLC)/exercise control. Plasma synephrine and caffeine concentrations were measured over 12 h, and vital signs, serum electrolytes, oxygen consumption and perceived exercise exertion were monitored.

RESULTS

No significant adverse events occurred. Synephrine and caffeine pharmacokinetics were unaffected by exercise. Post‐exercise diastolic blood pressure was higher after DS (peak mean 71.7 ± 8.7 mmHg) than PLC (63.0 ± 4.9 mmHg) (p = 0.007). There were no substantial treatment‐related differences in post‐exercise HR, systolic blood pressure, or temperature. Postprandial plasma glucose increased to 121.0 ± 31.6 mg dl−1 with DS and exercise vs. 103.7 ± 25.5 mg dl−1 with PLC and exercise (P = 0.004). No treatment differences in exercise‐related oxygen consumption, serum lactate, or insulin were observed. Exercise was rated less difficult with DS than PLC (P = 0.001).

CONCLUSIONS

Blood pressure and plasma glucose increased post‐exercise with DS use, which could be detrimental in some people. Exercise was perceived as less strenuous after DS, presumably due to the stimulant effects of caffeine.
Clinically informative measures of the effect of drugs or other interventions
Authors: Salmi L. Rachid , Suissa Samy , Chêne Geneviève , Salamon Roger
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Several comparative measures (ratios, differences, or the number needed to treat) are used to express the effect of a drug or another intervention.

• These measures can vary in the way they are affected by the background risk measured from the reference group.

WHAT THIS STUDY ADDS?

• This paper reviews the formulation, interpretation and limitations of measures of effect.

• We describe a little‐known parameter, the attained effect or clinical result ratio, a positive reformulation of the relative risk difference, and suggest how available parameters can be best used to summarize results of studies of the effect of drugs.

AIMS

Measures to compare two drugs are often affected by the background risk in the reference group; a ceiling effect results when the background risk is small. We review measures of the effect of drugs, including a special formulation of the relative risk difference, the attained effect or clinical result ratio, that addresses background risk and ceiling effect.

METHODS

Existing measures are the risk and odds ratios, the absolute and relative risk differences, and the number needed to treat. The attained effect is defined as the observed gain in success (the difference of proportion of success between the two interventions), divided by the maximum attainable gain, the maximum proportion of success one can expect. We illustrate the relationship between these measures with published results of two meta‐analyses.

RESULTS

In studies of the effectiveness of cell salvage, the baseline risk ranged between 8 and 95%. This variability affected the risk difference and number needed to treat, while the attained effect, with a ceiling residual risk of 2%, showed that the gain in success was half the maximum attainable gain. In studies of the effectiveness of therapy in patients infected by the human immunodeficiency virus, where the baseline risk was less variable, and there was no ceiling effect, the maximum attained effect indicated that the gain could be much smaller.

CONCLUSION

The attained effect, interpreted as the proportion of effectiveness that remains to gain for future interventions, can usefully complete the number needed to treat as a clinically informative effect measure.
Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment
Authors: Currie Graeme P. , Butler Claire A. , Anderson Wendy J. , Skinner Chris
Published: March 2008

Chronic obstructive pulmonary disease represents a major global health care burden for both primary and secondary care providers and is the most common respiratory condition necessitating hospital admission. Short‐acting bronchodilators play a vital role in immediate relief of symptoms, while inhaled long‐acting bronchodilators and inhaled corticosteroids are advocated for regular use in individuals with persistent symptoms and exacerbations. Theophylline is a nonspecific phosphodiesterase inhibitor and is usually reserved for patients with ongoing symptoms despite optimum inhaled bronchodilator treatment or when difficulty is encountered with inhaler devices. However, it is often not widely used mainly due to frequency of dose‐related adverse effects, numerous drug interactions and narrow therapeutic index. This in turn has lead to the development of more selective phosphodiesterase inhibitors in an attempt to create a drug which patients can use with beneficial effects but without the problems associated with theophylline. Current data do indicate that phosphodiesterase 4 inhibitors confer some benefits in chronic obstructive pulmonary disease when compared to placebo in terms of lung function, quality of life and exacerbations. They are also generally well tolerated. Further studies are required to determine fully their long‐term beneficial and adverse effect profiles and ultimately where they might comfortably sit in management algorithms.
The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men
Authors: Rolan Paul , Sargentini‐Maier Maria Laura , Pigeolet Etienne , Stockis Armel
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.

• Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy.

WHAT THIS STUDY ADDS

• We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.

AIMS

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.

METHODS

Three successive panels of 12 healthy male subjects received double‐blind brivaracetam 200, 400 or 800 mg day−1 (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.

RESULTS

Brivaracetam was rapidly absorbed (tmax∼2 h) and eliminated (t1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6‐β‐hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system‐related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose‐related sedation and decreased alertness that only persisted at 800 mg daily.

CONCLUSIONS

Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single‐compartment elimination and dose proportionality.
Candidate mechanisms for capecitabine‐related hand–foot syndrome
Authors: Milano Gérard , Etienne‐Grimaldi Marie‐Christine , Mari Mireille , Lassalle Sandra , Formento Jean‐Louis , Francoual Mireille , Lacour Jean‐Philippe , Hofman Paul
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Hand–foot syndrome (HFS) is a limiting toxicity of the widely used fluorouracil (5FU) prodrug capecitabine.

• The pharmacological origin of HFS has not been elucidated.

• The expression of capecitabine‐metabolizing enzymes thymidine phosphorylase (TP, activating pathway) and dihydropyrimidine dehydrogenase (DPD, catabolic pathway) in the skin of the palm (target tissue for HFS) is unknown.

WHAT THIS STUDY ADDS

• This pilot study, conducted in healthy volunteers, clearly demonstrated that TP expression is significantly greater in the palm compared with the lower back (control area).

• This suggests TP‐facilitated enhanced production of 5FU in the palm that could explain the occurrence of HFS.

• This result may support strategies to prevent HFS.

AIMS

The oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand–foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue‐specific expression of drug‐metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area).

METHODS

Two paired 4‐mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues.

RESULTS

Proliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm.

CONCLUSIONS

The high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP‐facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.
Absence of respiratory effects with ivabradine in patients with asthma
Authors: Babu K. Suresh , Gadzik Frantisek , Holgate Stephen T.
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ivabradine is a new heart rate‐lowering agent that acts specifically on the sinoatrial node via the If pacemaker channels.

• Ivabradine has demonstrated similar efficacy to β‐blockers.

• As β‐blockers are contraindicated in patients with obstructive airway disease, this study was conducted to assess the safety of ivabradine in patients with asthma.

WHAT THIS STUDY ADDS

• This study demonstrates that ivabradine has no effect on the pulmonary functions in patients with asthma and can be safely used a heart rate‐lowering agent in patients with angina and coexistent airflow obstruction.

AIM

β‐Blockers are commonly prescribed for stable angina and are recommended as initial therapy. However, β‐blockers are contraindicated in patients with obstructive airway disease because of a risk of bronchoconstriction. Ivabradine is a specific heart rate‐lowering agent that acts via If pacemaker channels in the sinoatrial node with no β‐adrenoreceptor activity. Ivabradine has been recently approved for the treatment of stable angina. This study assessed the effects of repeated administration of ivabradine on lung function in patients with asthma.

METHODS

In this double‐blind, placebo‐controlled, crossover study, 20 subjects with asthma received either oral ivabradine 10 mg b.i.d. or placebo for 4.5 days. Forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate (PEFR) were designated as the main outcome variable. Diary cards were used to monitor asthma symptoms on a five‐point scale, rescue medication usage, and adverse events.

RESULTS

There were no significant differences in mean variation of FEV1 (ivabradine P = 0.664; placebo P = 0.652) or PEFR (ivabradine P = 0.153; placebo P = 0.356) from baseline following administration of ivabradine. There was also no significant difference in maximum percent variation in FEV1 or PEF between treatment groups (P = 0.994; FEV1 and P = 0.704; PEF). On a similar note, there was no significant difference in asthma symptoms or rescue medication usage reported between the two groups. Adverse events were generally mild‐to‐moderate in intensity and no cardiovascular or serious adverse events were recorded.

CONCLUSIONS

This study confirms that ivabradine does not affect respiratory function or symptoms in patients with asthma and therefore represents a valuable therapeutic alternative to β‐blockers for treating patients with stable angina and asthma.
Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients
Authors: Nath Christa E. , Earl John W. , Pati Nalini , Stephen Katherine , Shaw Peter J.
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetics of oral busulphan given four times daily has been extensively studied.

• Large inter‐ and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring.

• However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6‐h dosing interval, due to late absorption in some patients.

• Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose.

WHAT THIS STUDY ADDS

• Inter‐ and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable.

• Children with immune deficiencies, in particular, have widely variable exposure.

AIM

To examine inter‐ and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease.

METHODS

Busulphan (120 mg m−2, 130 mg m−2 or 3.2 mg kg−1) was administered over median 2.1 h. Blood samples (4–10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration–time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m−2 dose in 13 children who had busulphan pharmacokinetic monitoring.

RESULTS

Clearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h−1 (% CV 61%), 0.23 ± 0.08 l h−1 kg−1 (% CV 35%) and 5.79 ± 1.59 l h−1 m−2 (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h−1) and CL (l h−1 kg−1), but not with CL (l h−1 m−2). AUC normalized to the 130 mg m−2 dose ranged from 14.1 to 56.3 mg l−1.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h−1 m−2) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children.

CONCLUSIONS

There is considerable inter‐ and intrapatient variability in i.v. busulphan CL (l h−1 m−2) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.
The effect of anti‐CD40 ligand in immune thrombocytopenic purpura
Authors: Patel Vivek L. , Schwartz Joseph , Bussel James B.
Published: March 2008

Immune thrombocytopenic purpura (ITP) is mediated by antiplatelet autoantibodies possibly involving CD40:CD40L co‐stimulation. Two humanized anti‐CD40L monoclonal antibodies, hu5c8 and IDEC‐131, were evaluated in 46 patients with chronic refractory ITP. Fifteen patients were treated with 20 mg/kg of hu5c8: four (27%) had complete responses (CR) and two (13%) had partial responses (PR). Three responders to hu5c8 were successfully retreated with IDEC‐131, demonstrating its efficacy. Thirty‐one subsequent patients were treated with 5–20 mg/kg per infusion of IDEC‐131: five (16%) responded (one CR and four PR). The 24% (11/46) overall response rate demonstrates the potential role of CD40‐CD40L in the pathogenesis of ITP.
Mutated and non‐mutated TP53 as targets in the treatment of leukaemia
Authors: Nahi H. , Selivanova G. , Lehmann S. , Möllgård L. , Bengtzen S. , Concha H. , Svensson A. , Wiman K. G. , Merup M. , Paul C.
Published: March 2008

TP53 is mutated in 10–20% of cases of chronic lymphocytic leukaemia (CLL) and 3–8% of cases of acute myeloid leukaemia (AML). Recently, two classes of compounds that restore the function of p53 in tumours have been described. PRIMA‐1 (p53‐dependent reactivation and induction of massive apoptosis) restores the wild‐type conformation of mutant TP53, whereas RITA (reactivation of p53 and induction of tumour cell apoptosis) increases intracellular levels of p53. We evaluated the effects of RITA alone and in combination with PRIMA‐1 or conventional cytostatics on leukaemic cells isolated from AML and CLL patients. AML samples with −17, which are more resistant to daunorubicin and cytarabine compared with samples without −17, were effectively killed by PRIMA‐1. RITA, which stabilizes the function of wild‐type p53, induced apoptosis in AML cells. In contrast to that seen with PRIMA‐1, AML patient samples without −17 were significantly more sensitive to RITA. Similarly, RITA exerted dose‐dependent apoptosis and cytotoxicity in CLL cells, which was significantly more pronounced in samples without hemizygous TP53 deletion. Notably, a synergistic effect was observed in all CLL samples with RITA and fludarabine in combination. In both AML and CLL cells exposure to RITA resulted in induction of intracellular p53. We conclude that small molecules targeting p53 might be of clinical importance in the future for treating drug‐resistant leukaemia.
The insulin‐like growth factor‐I receptor inhibitor NVP‐AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells
Authors: Maiso Patricia , Ocio Enrique M. , Garayoa Mercedes , Montero Juan C. , Hofmann Francesco , García‐Echeverría Carlos , Zimmermann Johann , Pandiella Atanasio , San Miguel Jesús F.
Published: March 2008

Multiple myeloma (MM) is a B‐cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP‐AEW541, a small molecule that belongs to the pyrrolo[2,3‐d]pyrimidine class, identified as a selective inhibitor of the insulin‐like growth factor‐I receptor (IGF‐IR) in vitro kinase activity. NVP‐AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP‐AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP‐AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP‐AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP‐AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP‐AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP‐AEW541 induced cell death through caspase‐dependent and ‐independent mechanisms. All these data, suggest the potential effect of IGF‐IR kinase inhibitors as therapeutic agents for MM patients.
Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis
Authors: Ricart José M. , Ramón Luis A. , Vayá Amparo , España Francisco , Santaolaria Maria‐Luisa , Todolí José , Castelló Remedios , Fontcuberta Jordi , Estellés Amparo
Published: March 2008

This study aimed to assess the fibrinolytic inhibitors and their association with thrombosis in Behçet disease. Thrombin activatable fibrinolysis inhibitor (TAFI) (P < 0·001) and plasminogen activator inhibitor‐1 (PAI‐1) levels (P = 0·022) were significantly higher in 79 patients than in 84 controls. No significant differences were observed in CPB2 (TAFI) Thr325Ile and SERPINE1 (PAI1) 4G/5G polymorphism distribution between patients and controls. TAFI activity levels were significantly higher in patients with thrombosis than in those without thrombosis (P = 0·024). In conclusion, the increased TAFI levels in Behçet disease could contribute to the increased risk of thrombosis observed in these patients.
Disorders of red cell membrane
Authors: An Xiuli , Mohandas Narla
Published: March 2008

Studies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red cell membrane disorders. This review highlights our current understanding of molecular and mechanistic insights into various inherited red cell membrane disorders involving either altered membrane structural organization (hereditary spherocytosis, hereditary elliptocytosis and hereditary ovalocytosis) or altered membrane transport function (hereditary stomatocytosis). The molecular basis for the vast majority of cases of hereditary spherocytosis, elliptocytosis and ovalocytosis have been fully defined while little progress has been made in defining the molecular basis for hereditary stomatocytosis. Mutations in a number of distinct genes account for hereditary spherocytosis and elliptocytosis, while a single genetic defect accounts for all cases of hereditary ovalocytosis. Based on these molecular insights, a comprehensive understanding of the structural basis for altered membrane function has been developed. Loss of vertical linkage between membrane skeleton and lipid bilayer leads to membrane loss in hereditary spherocytosis, while weakening of lateral linkages between skeletal proteins leads to membrane fragmentation and surface area loss in hereditary elliptocytosis. Importantly, the severity of anaemia in both these disorders is directly related to extent of membrane surface area loss. Splenectomy results in amelioration of anaemia.
Novel melanocortin 4 receptor gene mutations in severely obese children
Authors: Lee Yung Seng , Poh Larry Kok Seng , Kek Betty Lay Kee , Loke Kah Yin
Published: March 2008

Objective  Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children.

Design  We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing.

Results  We identified three mutations in three subjects: 4 bp deletion from nucleotides 631–634 (c.631–634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1·32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non‐obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early‐onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity.

Conclusion  MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.
Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo–pituitary–adrenal axis
Authors: Finucane Francis M. , Liew Aaron , Thornton Evan , Rogers Barbara , Tormey William , Agha Amar
Published: March 2008

Objective  The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol production in pituitary disease. However, areas of uncertainty remain regarding its safety in older people, the optimal duration of the test and its performance in insulin resistant states. Whether basal cortisol concentration can reliably predict an adequate adrenal response to hypoglycaemia remains to be determined.

Patients and design  We performed a cross‐sectional retrospective examination of 197 consecutive patients (mean age 41·8 ± 16·4, range 13–76 years) with pituitary disease who underwent the ITT over 18 months. The standard intravenous insulin dose administered was 0·15 units/kg body weight. Patients with acromegaly or with type 2 diabetes received 0·2 units/kg; those with basal cortisol < 100 nmol/l received 0·1 units/kg.

Results  Adequate hypoglycaemia (nadir glucose < 2·2 mmol/l) was achieved in 87% of patients, amongst whom 17% did not achieve peak cortisol until 120 min. There were no significant adverse events, even in those ≥ 65 years. Of the 18 patients who had basal cortisol < 100 nmol/l, 78% achieved adequate hypoglycaemia; 29% of those had an adequate peak cortisol response ≥ 500 nmol/l. A receiver operating characteristics curve identified a basal cortisol of ≥ 393 nmol/l to predict a normal peak cortisol response to hypoglycaemia.

Conclusions  In specialized units, the ITT is safe even in elderly patients and those with hypocortisolaemia. The standard 90‐min. cut‐off for the ITT misses one in six peak cortisol responses. Some patients with basal cortisol < 100 nmol/l had a normal cortisol response to hypoglycaemia.
Glucose turnover and intima media thickness of internal carotid artery in type 2 diabetes offspring
Authors: Anderwald C. , Pfeiler G. , Nowotny P. , Anderwald‐Stadler M. , Krebs M. , Bischof M. G. , Kozakova M. , Luger A. , Pacini G. , Roden M. , Waldhäusl W.
Published: March 2008

Background  First‐degree offspring (OFF) of type 2 diabetic (T2DM) patients bear a ~40% lifetime risk of developing T2DM. They are insulin resistant and carry a risk of premature atherosclerosis, the extent of which can be estimated by intima media thickness (IMT) of the carotid artery (CA). Thus, this study examines parameters of glucose and lipid metabolism, insulin sensitivity, beta cell function (BCF) and IMT with their interrelationships in middle‐aged OFF.

Materials and methods  T2DM‐OFF (n = 18, 14f/4m, 45·6 ± 2·1 years, BMI: 26 ± 1 kg m−2) were compared with 18 matching humans without a family history of diabetes (CON; 14f/4m, 44·5 ± 2·1 years, BMI: 24 ± 1 kg m−2; each P > 0·30), all with normal glucose tolerance as tested by three‐hour (75 g) oral glucose tolerance tests (OGTT). Two‐hour hyperinsulinaemic (40 mU min−1·m−2)isoglycaemic clamp tests were performed with simultaneous measurement of endogenous glucose (D‐[6,6‐2H2]glucose) production (EGP). IMT [internal (ICA), common CA, and bulb] were measured sonographically. BCF was assessed by Adaptation Index (AI).

Results  Before and during OGTT, both groups were similar in plasma glucose, insulin, C‐peptide and free fatty acids (FFA), whereas OFF showed ~30% lower (P < 0·03) fasting plasma triglycerides before OGTT. During hyperinsulinaemic clamps, insulin sensitivity was ~38% lower (P < 0·03) in OFF who showed higher plasma FFA (44 ± 9 µmol L−1) than CON (26 ± 3 µmol L−1, P < 0·05) after 90 min. EGP was similar in both groups. OFF had 38% (P < 0·007) reduced AI. ICA‐IMT was ~18% higher in OFF (P < 0·002), but did not correlate with insulin sensitivity.

Conclusion  The data obtained show middle‐aged T2DM‐OFF with normal glucose tolerance displaying reduced total insulin sensitivity and impaired beta cell function, which relates to impaired insulin‐dependent suppression of plasma FFA and increased ICA‐IMT.
Secretory type II phospholipase A2 in culprit coronary lesions is associated with myocardial infarction
Authors: Nijmeijer R. , Meuwissen M. , Krijnen P. A. J. , Van Der Wal A. , Piek J. J. , Visser C. A. , Hack C. E. , Niessen H. W. M.
Published: March 2008

Background  Secretory type‐II phospholipase A2 (sPLA2‐II) is a cardiovascular risk marker since higher levels of this acute phase protein imply an increased risk for coronary artery disease. Moreover, it is hypothesized that local activity of sPLA2‐II in the atherosclerotic plaque facilitates an inflammatory response to induce plaque instability or rupture. We have studied the presence of sPLA2‐II in culprit lesions in the coronary arteries of patients with acute myocardial infarction (AMI) or angina pectoris.

Materials and methods  We performed a histological examination of culprit lesions in 41 patients with stable (SAP) or unstable angina pectoris (UAP), or AMI using directed coronary atherectomy (DCA). Frozen slides were analysed immuno‐histochemically for the presence of sPLA2‐II, macrophages and smooth muscle cells. Immunopositive areas were calculated as a percentage of the total tissue area using image analysis software.

Results  Intracellular sPLA2‐II was found in atherosclerotic lesions in the macrophages of the intima as well as in vascular smooth muscle cells. Next to this, extracellular sPLA2‐II depositions were also found. These depositions were significantly more extensive in patients with AMI, i.e. 26%median[6%25th(percentile)–44%75th(percentile)] of the intima area, than in patients with SAP 0%median (0%25th–10%75th; P = 0·013) or UAP 0%median (0%25th–0%75th; P = 0·04).

Conclusions  Extracellular sPLA2‐II is more abundantly present in atherosclerotic culprit lesions that have led to myocardial infarction. This suggests a role for extracellular sPLA2‐II in the development of complications of atherosclerotic lesions in coronary arteries.
Severe aseptic inflammation caused by long distance running (246 km) does not increase procalcitonin
Authors: Papassotiriou I. , Alexiou V. G. , Tsironi M. , Skenderi K. , Spanos A. , Falagas M. E.
Published: March 2008

Background  The Spartathlon ultra distance running race (246 kilometres) is an exhausting physical exercise leading to a state of systemic inflammation associated with dramatic elevation of interleukin‐6 and acute‐phase reactants to levels seen only in critically ill or patients near death. We sought to study the effect of this severe inflammatory response on the levels of serum procalcitonin.

Materials and methods  Fifteen healthy endurance‐trained runners who participated in the 2006 Spartathlon were studied. Blood samples were taken the day before the race, within 15min after the end of the race and 48 h after the end of the race. Serum interleukin‐6, serum amyloid A protein, C‐reactive protein, tumour necrosis factor‐alpha and procalcitonin concentrations were determined.

Results  Serum interleukin‐6, serum amyloid A protein and C‐reactive protein were dramatically increased after the end of the race (150‐, 116‐ and 10 470‐ fold increase of the mean values, respectively). Procalcitonin levels remained within normal range (mean ± standard error of mean, 0·27 ± 0·02 µg L−1, 0·26 ± 0·02 µg L−1 and 0·27 ± 0·02 µg L−1 before, at the end, and 48 h after the race, respectively). Tumour necrosis factor‐alpha measurements revealed no significant changes.

Conclusions  This study provides strong evidence that Spartathlon, a prolonged endurance exercise resulting in severe stimulation of inflammatory mediators followed by muscle and liver damage, does not induce procalcitonin secretion. The findings cannot directly be applied to other causes of aseptic inflammation.
Metabolic and anti‐inflammatory benefits of eccentric endurance exercise – a pilot study
Authors: Drexel H. , Saely C. H. , Langer P. , Loruenser G. , Marte T. , Risch L. , Hoefle G. , Aczel S.
Published: March 2008

Background  Eccentric endurance exercise (e.g. hiking downwards) is less strenuous than concentric exercise (e.g. hiking upwards) but its potential to reduce cardiovascular risk is unknown.

Materials and methods  We randomly allocated 45 healthy sedentary individuals (16 men and 29 women, mean age 48 years) to one of two groups, one beginning with two months of hiking upwards, the other with two months of hiking downwards the same route, with a crossover for a further two months. For the opposite way, a cable car was used where compliance was recorded electronically. The difference in altitude was 540 metres; the distance was covered three to five times a week. Fasting and postprandial metabolic profiles were obtained at baseline and after the two month periods of eccentric and concentric exercise, respectively.

Results  Forty‐two of the 45 participants completed the study; the compliance rate was therefore 93%. Compared with baseline, eccentric exercise lowered total cholesterol (by 4·1%; P = 0·026), low‐density lipoprotein (LDL) cholesterol (by 8·4%, P = 0·001), Apolipoprotein B/Apolipoprotein A1 ratio (by 10·9%, P < 0·001), homeostasis model assessment of insulin resistance scores (by 26·2%, P = 0·017) and C‐reactive protein (by 30·0%; P = 0·007); the magnitude of these changes was comparable to that of concentric exercise. Eccentric exercise improved glucose tolerance (by 6·2%, P = 0·023), whereas concentric exercise improved triglyceride tolerance (by 14·9%, P = 0·022).

Conclusions  Eccentric endurance exercise is a promising new exercise modality with favourable metabolic and anti‐inflammatory effects and is well applicable to sedentary individuals.