Obesity and weight gain as risk factors for erosive oesophagitis in men

Background  Although obesity and weight gain increase the risk for symptoms of gastro-oesophageal reflux disease, their association with erosive oesophagitis is still unclear in the male population.
Aim  To evaluate, in men, the association of body mass index (BMI) and weight gain with endoscopically proven erosive oesophagitis.
Methods  A total of 8571 Korean men in a comprehensive screening cohort were enrolled. Effects of BMI and abdominal obesity on erosive oesophagitis were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analysis. We also evaluated the association between erosive oesophagitis and BMI change after 1–3 years.
Results  The prevalence of erosive oesophagitis was 6.4% (552/8571). In univariate analysis, the ORs for erosive oesophagitis increased as BMI or waist circumference increased ( P for trend <0.001, both). In multivariate analysis, OR for erosive oesophagitis increased as BMI increased ( P for trend = 0.002), while the significance of waist circumference was attenuated ( P for trend = 0.13). Increase in BMI (≥1 kg/m²) was associated with persistence of erosive oesophagitis (OR = 2.83, 95% CI: 1.01–7.92, P  = 0.04) and new development of the disease (OR = 2.13, 95% CI: 1.38–3.28, P  = 0.001) compared with BMI change less than 1 kg/m².
Conclusions  Elevated BMI and weight gain have a significant association with erosive oesophagitis.     

Epidemiological study of gastro-oesophageal reflux disease: reflux in spouse as a risk factor

Background  Gastro-oesophageal reflux disease (GERD) is a growing health-care problem with variable distribution.
Aim  To assess GERD prevalence and risk factors and their possible correlation with pathophysiology in a population-based study.
Methods  Individuals aged 18–65 years were enrolled through random cluster sampling in Tehran. Previously validated self-administered questionnaires were used.
Results  Of the 2500 questionnaires, 2057 were analysed (mean age: 34.8 ± 13.0 years, 55.1% female). Frequent GERD was seen in 18.2%. Minor symptoms increased prevalence. Female gender (OR: 1.55, 95% CI: 1.01–2.41), BMI >30 kg/m² (OR: 1.79, 95% CI: 1.03–3.12), less education (OR: 1.52, 95% CI: 1.02–2.27), smoking (OR: 1.83, 95% CI: 1.12–2.99), NSAID use (OR: 4.23, 95% CI: 1.66–10.74) and GERD in spouse (OR: 1.82, 95% CI: 1.18–2.82) were associated with frequent GERD on multivariable analysis. GERD in first-degree relatives (OR: 1.73, 95% CI: 1.23–2.43) and asthma (OR: 4.09, 95% CI: 1.27–13.15) correlated with infrequent GERD. Minor symptoms correlated with GERD history in first-degree relatives, coffee consumption and NSAID use. Prevalence in the past 3 months was similar to that in the past 12 months ( P  < 0.05).
Conclusions  Gastro-oesophageal reflux disease is common in Tehran. The association of 'infrequent symptoms' with GERD history in first-degree relatives and 'frequent symptoms' with GERD history in spouse may point to the presence of yet unknown precipitating environmental factors inducing GERD in a genetically susceptible host. Minor GERD symptoms seem to have independent contribution to GERD. Assessing GERD in the past 3 months predicts prevalence in the past year.     

Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

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 ( t _max ) 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 ( k _a ) 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 t _max of 2.12 (0.89–3.28) h, the sotalol/cisapride oral solution gave a smaller t _max (p=0.009) [95% CI: −1.64, −0.36]. The k _a of the sotalol/cisapride solution was significanty ( P =0.010) larger than the k _a 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.     

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme

Aims Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug.
Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20–80  mg (0.3–1.14  mg  kg⁻¹ ). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms.
Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24–0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15  l  kg⁻¹  day⁻¹ and a bioavailability of 100% was 17.4 (10.8–24)  μg  kg⁻¹  day⁻¹. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07–3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5  μg  l⁻¹ . Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen.
Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.     

Transplacental distribution of salbutamol enantiomers at Caesarian section

Aims To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section.
Methods Five women about to undergo elective Caesarian section were administered a single 0.25  mg bolus intravenous dose of (R,S)-salbutamol. The time from drug administration to delivery was different for each woman (27–105  min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography.
Results The concentrations (mean±  s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46±0.35 and 0.89±0.50  ng  ml⁻¹, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12–0.74  ng  ml⁻¹ ). The corresponding concentrations of the (S) enantiomer of 0.92±0.45 and 1.11±0.67  ng  ml⁻¹, respectively, were not significantly different (95% CI of the difference −0.08–0.48  ng  ml⁻¹ ). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma ( P =0.016).
Conclusions Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental-foetal metabolism.     

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.
Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6  mg) and histamine (0.03 to 30.69  g  l⁻¹ ) in normal subjects. Benazepril 20  mg, salbutamol 8  mg, propranolol 160  mg, and placebo were given orally once daily over 10 days.
Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P >0.05), propranolol shifted the curves to the right ( P <0.05). On day 10, histamine challenge resulted in following P D ₃₅sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09)  g  l⁻¹ , benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).
Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.     

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application

Aims The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×10⁶  IU  m⁻² once daily and group B 10×10⁶ IU  m⁻² twice daily (every 12  h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated.
Results The mean area under the serum concentration-time curve to 24  h (AUC(0,24  h)) was 627  IU  ml⁻¹  h in treatment group A and 1130  IU  ml⁻¹  h ( P =0.029) in treatment group B. In both study groups C _max and AUC(0,12  h) were not significantly different. Seventy-two  hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly ( P =0.016), and sIL-2R levels over 1200  pmol  l⁻¹ seemed to reduce the AUC.
Conclusions In patients with metastatic renal cell cancer administration of 20×10⁶  IU  m⁻² of rhIL-2  s.c. in two daily doses (10×10⁶  IU  m⁻² every 12  h) provides better bioavailability and is preferable to the single dose administration.     

Bradykinin-induced venodilation is not different in blacks

Aims The aim of this study was to determine whether young, normotensive blacks who have been recently demonstrated to have a venodilator response to isoprenaline decreased compared with whites, also have an decreased vasodilatory response to bradykinin.
Methods Eleven black and 11 white subjects were studied. Full dose-response curves to bradykinin (dosing range 0.5–500  ng min⁻¹ ) were generated in hand veins preconstricted with phenylephrine (dosing range 20–6800  ng min⁻¹ ).
Results The groups had a similar maximal response to bradykinin (57.6±32.2% vs 67.8±49.3%, P =NS 95% confidence interval for the difference (CI): −47.3, 26.8). Also, the log of the dose that produced half maximal response to bradykinin was similar for the two groups (0.89±0.58 vs 0.78±0.61  ng min⁻¹, P =NS, 95% CI: −0.42, 0.64). There was no difference between the two groups in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein.
Conclusion Diminished vasodilatory response to endothelium-derived relaxing factor (EDRF) does not seem to be associated with the increased prevalence of hypertension in blacks.     

Attenuation by ACE inhibitor drugs of α-adrenoceptor sensitivity in human vessels: possible differences related to drug lipophilicity

Aims We investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) on postsynaptic adrenoceptor sensitivity and compared the effect of the lipophilic ACEI, quinapril, and that of hydrophilic agent, enalapril in human vessels.
Methods α-adrenoceptor sensitivity was evaluated using the dorsal hand vein compliance technique. The dose–response curves of vasoconstriction to phenylephrine and prostaglandin F_2α were obtained in healthy male volunteers.
Results The ACEIs shifted the dose–response curve of phenylephrine to the right and raised the median effective dose (E D ₅₀; 189.3 (57.6  ng  min⁻¹ ) of phenylephrine. Following quinapril administration, E D ₅₀ increased to 481.1 (101.8  ng  min⁻¹ compared with 266.8 (55.8  ng  min⁻¹ after enalapril (95% CI for differences; 31.1–397.5  ng  min⁻¹ ). Quinapril administration had no effect on the dose–response curve of PGF_2α .
Conclusions ACE inhibition attenuates α-adrenoceptor sensitivity in human vessels. The effect of quinapril, a lipophilic ACEI, was greater than that of enalapril, a hydrophilic ACEI. Lipophilic ACEIs may be more potent in vasodilating effect than hydrophilic ACEIs. Angiotensin II concentration in tissue rather than that in plasma may contribute to the α-adrenoceptor sensitivity of the vessels.     

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250  mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/ F was 6.5±1.8 l  h⁻¹, V _ss/ F 815±165  l, and k 0.0081± 0.0023  h⁻¹. The kinetics of (−)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h⁻¹, 95% CI for the difference 0.86–1.60 l h⁻¹ ) and a longer half-life (345 vs 185  h, 95% CI for the difference 47–291  h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (−)SR-MQ was significantly correlated within subjects ( r =0.69, P <0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (−)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.     

Calcium supplementation and ototoxicity in patients receiving cisplatin

We have studied the effect on ototoxicity of maintaining serum calcium concentration by calcium gluconate infusion in cancer patients receiving high-dose cisplatin in a randomized study in two groups: 11 patients received calcium gluconate, 4  mg  kg⁻¹ i.v. infusion during cisplatin therapy; 11 other patients without any calcium supplementation served as controls. All of them received the first course of chemotherapy, based on cisplatin, 120  mg m² with a hydration schedule. An audiogram was performed in each patient just before cisplatin and repeated after 1 day and 3 weeks. Mean total calcium concentration in control patients before and after chemotherapy was 2.2±0.14 (95% confidence interval 1.9–2.5) and 2.0±0.13 (95% CI 1.7–2.24)  mmol l⁻¹ respectively ( P =0.0004) and for ionized calcium 1.22±0.52 (95% CI 0.21–2.23) and 1.11±0.07 (95% CI 0.97–1.25)  mmol l⁻¹ respectively ( P =0.0005). Serum magnesium levels were maintained or increased by magnesium supplementation. Although there was no change in serum total or ionized calcium, or serum magnesium in the calcium infusion group, no differences in hearing loss between the groups were observed. High-dose cisplatin chemotherapy for cancer patients induces an acute decrease of serum total calcium and serum ionized calcium and audiometric changes. Maintenance of calcium serum levels by calcium gluconate infusion did not protect against ototoxicity in those patients.     

Clinical trial: effectiveness of Lactobacillus rhamnosus (strains E/N, Oxy and Pen) in the prevention of antibiotic-associated diarrhoea in children

Background  Convincing evidence that probiotic administration can lower the risk of antibiotic-associated diarrhoea is limited to certain micro-organisms.
Aim  To determine the efficacy of administration of Lactobacillus rhamnosus (strains E/N , Oxy and Pen ) for the prevention of antibiotic-associated diarrhoea in children.
Methods  Children (aged 3 months to 14 years) with common infections were enrolled in a double-blind, randomized, placebo-controlled trial in which they received standard antibiotic treatment plus 2 × 10¹⁰ colony forming units of a probiotic ( n  = 120) or a placebo ( n  = 120), administered orally twice daily throughout antibiotic treatment. Analyses were by intention to treat.
Results  Any diarrhoea (≥3 loose or watery stools/day for ≥48 h occurring during or up to 2 weeks after the antibiotic therapy) occurred in nine (7.5%) patients in the probiotic group and in 20 (17%) patients in the placebo group (relative risk, RR 0.45, 95% confidence interval, CI 0.2–0.9). Three (2.5%) children in the probiotic group developed AAD (diarrhoea caused by Clostridium difficile or otherwise unexplained diarrhoea) compared to nine (7.5%) in the placebo group (RR 0.33, 95% CI 0.1–1.06). No adverse events were observed.
Conclusion  Administration of L. rhamnosus (strains E/N , Oxy and Pen ) to children receiving antibiotics reduced the risk of any diarrhoea, as defined in this study.     

Systematic review: primary and secondary prevention of gastrointestinal cancers with antioxidant supplements

Background  The evidence on whether antioxidant supplements prevent gastrointestinal cancers is contradictory.
Aim  To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.
Methods  Using the Cochrane Collaboration methodology, we reviewed the randomized trials comparing antioxidant supplements with placebo or no intervention on the occurrence of gastrointestinal cancers. We searched electronic databases and reference lists until October, 2007. Our outcome measures were gastrointestinal cancers, overall mortality and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence intervals (CI) based on random-effects and fixed-effect models meta-analyses.
Results  We identified 20 randomized trials (211 818 participants) assessing beta-carotene, vitamin A, vitamin C, vitamin E, and selenium. The trial quality was generally high. The antioxidant supplements were without a significant effect on the occurrence of gastrointestinal cancers (RR 0.94, 95% CI 0.83–1.06, I ²  = 54.0%). The heterogeneity seemed to be explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96–1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43–0.80, test of interaction P  < 0.0005) and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). Antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97–1.07, I ²  = 53.5%) but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02–1.07).
Conclusions  We could not find evidence that the studied antioxidant supplements prevented gastrointestinal cancers. On the contrary, they seem to increase overall mortality.     

Predictors of serious complications due to Clostridium difficile infection

Background  Identifying individuals with severe Clostridium difficile infection (CDI) at risk for major complications has become an important objective. Presence of clinical variables that predict complications from CDI would have the potential to strongly influence management.
Aim  To determine which clinical variables predict complications from CDI.
Methods  Cross-sectional study of all individuals admitted to Temple University Hospital between 12/1/03 and 7/1/08 with the primary discharge diagnosis of CDI were eligible. Only patients experiencing their first episode of CDI were included. Abstracted data included demographic, physiological, laboratory, radiological, endoscopic, pharmacy and outcome data. Response was categorized as none, partial or complete. Complications attributed to CDI were defined as colon resection or death.
Results  Overall 32 of 200 patients (16%) experienced a complication due to CDI including death ( n  = 20) and colectomy ( n  = 12). White blood cell count above 30,000 cells/mm³ (OR = 4.06; 95% CI, 1.28–12.87) and a rise in the creatinine to over 50% above baseline (OR = 7.13; 95% CI, 3.05–16.68) predicted a complication. AROC for percent rise in serum creatinine was 0.73 (95% CI: 0.64–0.85) and 0.62 (95% CI: 0.58–0.80) for white blood cell count.
Conclusions  Severe white blood cell count elevation and a rise in the creatinine to over 50% above baseline are important independent predictors of serious adverse events due to CDI. These patients likely would benefit from more intensive care and early surgical consultation.     

The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium

Aims   To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.
Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day^{− 1}, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day^{− 1}, given as two divided daily doses, on days 9–11 followed by 80 mg day^{− 1}, given as two divided daily doses on days 12–15 ( n  = 12), or placebo twice daily ( n  = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.
Results   Ziprasidone administration was associated with a 0.07 mmol l^{− 1} (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l^{− 1} (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h^{− 1} (5%) in the ziprasidone group and by 0.14 l h^{− 1} (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.
Conclusions   Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.     

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid

Aims  To evaluate the effects of cimetidine and Maalox^® (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone.
Methods   Eleven healthy young subjects aged 18–45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co‐administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co‐administered with oral Maalox^®.
Results   The administration of cimetidine increased the ziprasidone AUC(0,∞) by 6% but there were no statistically significant differences in C _max, t _max or λ_z between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox^® did not produce any statistically significant differences in AUC(0,∞), C _max, t _max or λ_z between the ziprasidone+Maalox^® group and the ziprasidone group.
Conclusions   The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox^®. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.     

Excretion of citalopram in breast milk

Aims The objective of this study was to measure the secretion of the selective serotonin uptake inhibitor citalopram in breast milk.
Methods The excretion of citalopram in breast milk was studied at steady-state conditions in two patients with depression and in one healthy volunteer after ingestion of a single dose citalopram.
Results Milk/serum concentration ratios based on single pairs of samples from the two patients ranged from 1.16 to 1.88. Based on milk concentration data from the patients, the absolute dose ingested by a suckling infant would be 4.3–17.6  μg  kg⁻¹ day⁻¹, and the relative dose 0.7–5.9% of the weight-adjusted maternal dose. Based on area-under-the-time-concentration curves from the healthy volunteer, the milk/serum ratio was 1.00, the absolute dose to the infant during steady-state conditions would be 11.2  μg  kg⁻¹ day⁻¹ and the relative dose 1.8% of the weight-adjusted maternal dose.
Conclusion The study shows that the relative dose to a suckling infant is close to that reported for fluoxetine, and higher than reported for fluvoxamine, paroxetine and sertraline.     

Effect of age and gender on the pharmacokinetics of eprosartan

Aims To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods Twenty-four subjects (eight subjects/group) received a single 200  mg eprosartan oral dose followed by serial blood sampling over 24  h.
Results Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and C _max values were ≈2-fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; C _max 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and C _max values were, on average, ≈2-fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound C _max 95% CI: 1.02, 4.12]. t _max was delayed in the elderly men compared with young men, with a median difference of 2.5  h (95% CI: 1.00, 3.01  h).
Conclusions No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈  two fold higher AUC and C _max values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200  mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.     

Concentrations and effects of buspirone are considerably reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated.
Methods In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600  mg rifampicin or matched placebo once daily for 5 days. On day 6, 30  mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10  h.
Results The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3–14.5%) of that after placebo (1.64±0.35  ng  ml⁻¹ h vs 22.0±15.1  ng  ml⁻¹ h (mean±s.d.); P <0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6±3.7  ng  ml⁻¹ to 0.84±0.23  ng  ml⁻¹ ( P <0.01) and the half-life from 2.8±0.7  h to 1.3±0.5  h ( P <0.01). A significant ( P <0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment.
Conclusions The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.