bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physicians’ opinions about medications to treat alcoholism
Authors: Mark Tami L. , Kranzler Henry R. , Song Xue , Bransberger Peace , Poole Virginia H. , Crosse Scott 
Published: May 2003

ABSTRACTAims Medications play a limited role in the treatment of alcoholism. This paper examines physicians’ opinions about and use of two alcoholism medications currently approved in the US—disulfiram and naltrexone—and one alcoholism medication—acamprosate—that might be approved.Design A total of 1388 substance abuse specialist physicians who were members of the American Academy of Addiction Psychiatry or the American Society of Addiction Medicine completed a questionnaire in 2001 (65% response rate).Findings The average percentages of physicians’ patients with alcoholism who were prescribed the following medications were: 13% (naltrexone), 9% (disulfiram), 46% (antidepressants) and 11% (benzodiazepines). Almost all physicians had heard of naltrexone and disulfiram, but their self‐reported level of knowledge about these medications was lower than for antidepressants. Physicians estimated that naltrexone had a small‐to‐medium effect size, which was similar in magnitude to the effect size reported in recent meta‐analyses of randomized clinical trials. Physicians identified the following three courses of action as the most likely to result in greater use of medications to treat alcohol dependence: more research to develop new medications (33%), more education of physicians about existing medications (17%), and increased involvement of physicians in alcoholism treatment (17%).Conclusions Physicians’ low rate of use of naltrexone may reflect its small‐to‐medium effect size.
Effects of reducing contingency management values on heroin and cocaine use for buprenorphine‐ and desipramine‐treated patients
Authors: Kosten Thomas , Poling James , Oliveto Alison 
Published: May 2003

ABSTRACTAims  During 3 months where contingency management (CM) had an escalating value for each consecutive drug‐free urine (escalating CM), cocaine‐ and heroin‐abusing patients significantly increased drug‐free urines. The ‘escalating CM’ was eliminated during months 4–6 to assess any reduction in drug‐free urines.Design  Patients who completed a 3‐month, randomized, double‐blind, trial evaluating CM versus non‐CM and desipramine (DMI) versus placebo, had an ‘escalating CM’ eliminated during months 4–6. The CM and non‐CM groups were compared using thrice‐weekly urine samples.Setting  Out‐patient buprenorphine maintenance for 6 months.Participants  All 75 of the 160 original study patients who completed month 3 of the clinical trial.Intervention  The ‘escalating CM’ was eliminated for all 3 months and during months 5 and 6 the response requirement was also increased to two and then three consecutive drug‐free urines in order to obtain a voucher.Measurements  Urine toxicology for opiates and cocaine.Findings  After eliminating the ‘escalating CM’, the CM group showed a decline in combined opioid‐ and cocaine‐free urines. This decline within the CM group was greater in those treated with DMI than placebo.Conclusions  Buprenorphine with DMI maintained drug abstinence after eliminating the ‘escalating CM’, but not after increasing the response requirement, suggesting the need for more intensive psychosocial interventions during CM.
Education of key personnel in student pubs leads to a decrease in alcohol consumption among the patrons: a randomized controlled trial
Authors: Johnsson Kent O. , Berglund Mats 
Published: May 2003

ABSTRACTAims  To decrease alcohol consumption among patrons in student pubs by server‐training programmes.Design  Randomized controlled trial.Setting  University campus.Participants  A total of 1322 students visiting local student pubs during ordinary pub evenings.Intervention  Educational programmes were given to bartenders (n = 40) in a randomized design in six of 12 pubs on a university campus. Bartenders in control pubs were not given the programme.Measurements  Breath alcohol concentration (BAC), expressed in percentage, among the patrons and the reported social atmosphere in the pub (‘high’, ‘cosy’ and ‘rowdy’) measured on a visual analogue scale in the pub before and after the intervention programme was given.Findings  BACs of patrons in the intervention pubs were reduced by more than those of the patrons in the control pubs at a 1‐month follow‐up. The mean difference in BAC between intervention and control groups was −0.011% (95% confidence interval, 0.022–0.000). The intervention group also decreased more in reported level of ‘rowdy’ social atmosphere than did the control group. The mean difference was −6 points (95% confidence interval −11 to −1). No differences were found in reported ‘cosy’ and ‘high’ atmosphere.Conclusion  Alcohol levels among the patrons were decreased and the ‘rowdy’ social atmosphere reduced in the intervention group. Server‐training programmes for personnel in student pubs could be a component in the prevention of alcohol problems in university student populations.
Pharmacokinetics of bambuterol in healthy subjects
Authors: Nyberg Lars , Rosenborg Johan , Weibull Eva , Jönsson Sven , Kennedy Britt‐Marie , Nilsson Marita 
Published: May 2003

Aims To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects. Methods Eight healthy subjects (four women) received intravenous doses of bambuterol and terbutaline. On a third occasion, they, plus another four subjects, ingested oral bambuterol as a single dose followed by repeated doses once daily for 7 days. Plasma concentrations and urinary excretion of bambuterol and terbutaline were measured. Results After intravenous administration, renal clearances of bambuterol and terbutaline were similar (about 140 ml min−1 ), but there was a five‐fold difference in total clearance (bambuterol 1.25 l min−1, terbutaline 0.23 l min−1 ). Volume of distribution (Vss ) was 1.6 l kg−1 b.w. for both substances. A similar renal clearance of bambuterol was found during oral administration but that of terbutaline decreased (to about 120 ml min−1 ). Mean terminal half‐life of bambuterol was 2.6 h after intravenous and 12 h after oral administration, implying that uptake was rate‐limiting. Mean residence time of terbutaline generated from oral bambuterol was 34 h compared with 8.0 h when terbutaline as such was infused. Generated terbutaline had a bioavailability of 36% (28–46) after intravenous and 10.2% (6.1–13.2) after oral administration of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, was inhibited between 30–60% during repeated oral dosing. It virtually regained original activity within 48 h after the last dose. Conclusions The plasma concentration of terbutaline fluctuated little during repeated oral administration (mean peak:trough ratio 1.9), as a result of prolonged absorption of bambuterol and slow formation of terbutaline. Thus, the pharmacokinetic properties of bambuterol make it suitable for oral once‐daily dosage.
Pharmacokinetics of bambuterol in subjects homozygous for the atypical gene for plasma cholinesterase
Authors: Bang Ulla , Nyberg Lars , Rosenborg Johan , Viby‐Mogensen Jørgen 
Published: May 2003

Aims It has been assumed that both plasma cholinesterase (EC 3.1.1.8) and oxidative enzymes are needed for optimum formation of the bronchodilator terbutaline from its biscarbamate prodrug bambuterol. The present study aimed at investigating the fate of bambuterol in subjects with deficient plasma cholinesterase but with normal oxidative (CYP2D6) capability. Methods The pharmacokinetics of bambuterol and terbutaline were studied in four healthy subjects (two men and two women) being homozygous for the atypical gene for plasma cholinesterase. Their oxidative metabolism was apparently good as they were all rapid metabolizers of debrisoquine. Bambuterol hydrochloride 20 mg was given orally once daily for 10 days, and plasma and urine samples were taken for 1.5 days (plasma) and 4.5 days (urine) after administration of the last dose. Results The pharmacokinetic parameters in the present study were grossly similar to those found in a study of bambuterol in subjects with normal plasma cholinesterase activity (N). However, subjects with atypical cholinesterase had a shorter terminal half‐life of bambuterol (a measure of uptake rate), 4.8–12.6 h vs 8.3–22.3 h in N, and slightly higher plasma concentrations of bambuterol (average concentrations 1.9–3.7 nmol l−1vs 1.5–3.1 nmol l−1 in N). Peak/trough terbutaline plasma concentrations ratios (2.1–3.2) were somewhat increased, but average plasma concentrations (8.3–14.5 nmol l−1 ) and terminal half‐life (16.5–21.8 h) of terbutaline did not differ. Conclusions In Caucasian populations, one subject out of 2500 is homozygous for the atypical gene for plasma cholinesterase. The atypical enzyme has a much lower affinity for bambuterol than the normal enzyme. Nevertheless, the subjects with atypical cholinesterase were able to produce terbutaline as efficiently as normal subjects. This might be explained by an altered uptake and metabolism in the absence of plasma cholinesterase, or the importance of this enzyme for the formation of terbutaline from bambuterol in vivo may have been overestimated.
Endothelin‐1 induces vasodilation in human skin by nociceptor fibres and release of nitric oxide
Authors: Wenzel René R. , Zbinden Stefan , Noll Georg , Meier Bernhard , Lüscher Thomas F. 
Published: May 2003

Aims Endothelin is a peptide produced by endothelial cells with many biological properties. In the human skin microcirculation endothelin induces neurogenic vasodilation associated with burning pruritus. We investigated the mechanisms involved in this response. Methods The effects of prolonged pretreatment with capsaicin, a specific inhibitor of polimodal nociceptor fibres, and of the nitric oxide synthase inhibitor l‐NMMA on endothelin‐1‐induced vasodilation were studied in 15 human subjects. Furthermore, we investigated the effects of the ETA‐selective antagonist PD147953 on bradykinin‐induced vasodilation. Results After local injection, endothelin‐1 caused vasoconstriction at the injection site and a profound vasodilation in the surrounding area (flare reaction, P<0.01). This response was specific and not induced by saline, albumin, acetylcholine or an ET‐antagonist. Prolonged capsaicin pretreatment inhibited endothelin‐1 induced vasodilation in the area surrounding the injection site, but not the central vasoconstriction at the injection site. Bradykinin also induced a marked vasodilation in the area surrounding the injection site; this was not inhibited by an ETA‐selective antagonist, while the flare reaction was. l‐NMMA applied at the site of the flare reaction prevented endothelin‐1‐induced vasodilation. Conclusions Endothelin‐1 in the human skin microcirculation stimulates polimodal nociceptor fibres leading to the release of nitric oxide. This response may play a pathophysiological role in inflammatory processes in the human skin.
Distribution and excretion of sertraline and N‐desmethylsertraline in human milk
Authors: Kristensen  , Ilett  , Dusci  , Hackett  , Yapp  , Wojnar‐Horton  , Roberts  , Paech  
Published: May 2003

Aims To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N‐desmethylsertraline, in breast‐feeding women taking sertraline for the treatment of depression. Methods Eight women (mean age 28 years) taking sertraline (1.05 mg kg−1 day−1 ) and their infants (mean age 5.7 months) were studied. Sertraline and N‐desmethylsertraline in plasma and milk were measured by high‐performance liquid chromatography over a 24 h dose interval at steady‐state. M/P values were estimated from area under the plasma and milk concentration‐time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight‐adjusted maternal dose. Results Mean milk production was 321 ml day−1 (range 34–974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N‐desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight‐adjusted maternal dose for sertraline and N‐desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg−1 day−1 ), infant exposure was significantly greater (P<0.0001) at 0.90% and 1.32% for sertraline and N‐desmethylsertraline respectively. Neither sertraline nor its N‐desmethyl metabolite could be detected in plasma samples from the four infants tested. No adverse effects were observed in any of the eight infants and all had achieved normal developmental milestones. Conclusions Irrespective of the method of calculation of infant exposure, the mean total dose of sertraline and its N‐desmethyl metabolite transmitted to infants via breast‐feeding is low and unlikely to cause any significant adverse effects.
Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects
Authors: Deneer  , Lie‐A‐Huen  , Kingma  , Proost  , Kelder  , Brouwers  
Published: May 2003

Aims To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl). Methods In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20 mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80 mg sotalol, an oral solution containing both 80 mg sotalol and 20 mg cisapride and an 80 mg sotalol tablet, which was taken sublingually. Results The addition of cisapride decreased the time at which maximum serum concentrations were reached (tmax ) from 2.79 (1.85–4.34) h to 1.16 (0.68–2.30) h (P=0.009) [95% CI: ‐2.59, −0.55] and increased the absorption rate constant (ka ) from 0.49 (0.31–0.69) h−1 to 1.26 (0.52–5.61) h−1 (P=0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00±0.15 to 0.70±0.26 (P=0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median tmax of 2.12 (0.89–3.28) h, the sotalol/cisapride oral solution gave a smaller tmax (p=0.009) [95% CI: −1.64, −0.36]. The ka of the sotalol/cisapride solution was significanty (P=0.010) larger than the ka of 0.56 (0.33–0.75) h−1 found after sublingual administration of the tablet. Conclusions The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.
Verapamil SR and trandolapril combination therapy in hypertension—a clinical trial of factorial design
Authors: Scholze Juergen , Zilles Peter , Compagnone Daniele 
Published: May 2003

Aims To investigate the dose‐response relationship and contribution of verapamil SR and trandolapril given in combination once a day for the treatment of essential hypertension. Methods A randomized, double‐blind, placebo controlled, factorial, 12 arm parallel group comparison with placebo, verapamil SR (120, 180 mg), trandolapril (0.5, 1.0, 2.0 mg) covering all combinations of both drugs. A 4 week placebo run‐in period followed by 6 weeks of treatment. Four hundred and fifty‐six patients from office practice (22 centres) with mild to moderate hypertension enrolled and 426 with diastolic pressure ≥100 mm Hg at the end of run‐in period were randomized. Main outcome measures were reduction in sitting systolic (SBP) and sitting diastolic (DBP) blood pressure. Results The combination of verapamil SR and trandolapril, particularly verapamil SR 180 mg and trandolapril 0.5 or 1.0 mg was significantly superior to both monocomponents at the same dose (P<0.05). For these combinations, the adjusted mean reductions in DBP from baseline to last visit were 14.1 and 16.0 mm Hg, respectively. Response surface analysis provided further evidence that these combinations were optimal for antihypertensive efficacy. All treatments were well tolerated. The incidence of adverse events did not differ significantly between treatment groups; the profile of adverse events on combination therapy was mild and consistent with that of each monocomponent. Conclusions All dosage combinations of verapamil SR and trandolapril produced significantly greater reduction of blood pressure than the monotherapy at the same dosage. However, verapamil SR 180 mg in combination with trandolapril 1.0 mg was the dosage with the greatest blood pressure reduction and had the greatest effects compared with the monocomponents.
The influence of nifedipine and captopril on liver blood flow in healthy subjects
Authors: Burggraaf  , Schoemaker  , Kroon  , Cohen  
Published: May 2003

Aims Application of single methods to assess liver blood flow (LBF) yielded conflicting results on the magnitude and duration of effect on LBF of oral nifedipine and captopril. The aim of this study was to investigate the influence of these drugs on LBF by simultaneous use of ICG infusion and echo‐Doppler. Methods The study was performed according to a double‐blind, placebo‐controlled, randomized, cross‐over design in nine healthy male volunteers. After an overnight fast and an equilibration period, subjects received a continuous i.v. indocyanine green (ICG) infusion for 4 h. At presumed ICG steady state (t=45 min), subjects were dosed with oral nifedipine (20 mg), captopril (50 mg) or placebo. During the experiment, blood sampling for ICG assay and measurement of portal venous blood flow (echo‐Doppler) took place regularly. Treatments were compared using analysis of variance. Differences are reported with 95% confidence intervals (CI). Results The area under the curves (AUC) for ICG over 1 h and over 3 h after nifedipine were 15% (difference in AUC: +0.6, +7.0 mg l−1 min) and 22% (+7.0, +28.4 mg l−1 min) lower compared with placebo. After captopril, the AUC values were 8–10% lower compared with placebo but the 95% CIs included zero. Portal venous flow was 15% (+5, +86 ml min−1 ) higher compared to placebo after nifedipine but not after captopril (−3%; −49, +33 ml min−1 ). The duration of effect on liver blood flow lasted approximately 2 h but was variable (range: 40–160 min). The time to maximal blood flow increase and the duration of effect after nifedipine were very similar for both measures of LBF. Changes in ICG concentrations could be reasonably well predicted from the changes in portal blood flow. Conclusions Nifedipine increases LBF for a substantial period of time but the effect is variable between subjects. This effect could be detected by both the ICG method and echo‐Doppler and the findings of both methods were in agreement. In this respect it is likely that captopril does not influence LBF in healthy volunteers as no effect was detected with either method.
Distribution and excretion of venlafaxine and O‐desmethylvenlafaxine in human milk
Authors: Ilett  , Hackett  , Dusci  , Roberts  , Kristensen  , Paech  , Groves  , Yapp  
Published: May 2003

Aims To characterise the transfer of venlafaxine (V) and its O‐desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast‐fed infant. Methods Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady‐state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83 h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk×a milk intake of 0.15 l kg−1 day−1, relative to the weight‐adjusted maternal dose. Results Mean M/P for V was 4.1 (range 2.8–4.8) and 3.1 for ODV (range 2.8–3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7–9.2%) of the maternal weight‐adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100 μg l−1 ) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects. Conclusions These preliminary data show that the total dose of V and ODV ingested by breast‐fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants’ plasma. We recommend that exposed infants should be observed closely.
Assessment of hepatic blood flow using continuous infusion of high clearance drugs
Authors: Schoemaker  , Burggraaf  , Cohen  
Published: May 2003

Aims To provide methods for the translation of the concentration‐time profile of highly cleared marker compounds into the underlying clearance and hepatic blood flow profile. Methods Continuous infusion of indocyanine green or sorbitol was used to assess the effect of the hepatic blood flow modifiers exercise, somatostatin and octreotide. Three distinct methods are described for the translation of concentration into flow:1. assuming successive phases of constant clearance2. point to point estimation of clearance using estimates of concentration change3. using a parametric description of the flow profile in combination with the differential equations describing the change in marker concentrations. Results The marker compound concentration profiles are adequately described using the different methods. Exercise results in a decrease in hepatic blood flow of about 80%. Somatostatin and octreotide elicit an indistinguishable hepatic blood flow decrease from 1.49 to 1.07 l min−1. Return to baseline takes much longer for octreotide (half‐life 126±104 min) than for somatostatin (half‐life 4.29±3.55 min). Conclusions Translation of concentration profiles into clearance profiles is possible making continuous assessment of hepatic blood flow feasible.