Treatment with angiotensin converting enzyme inhibitors, angiotensin-II-antagonists and beta-blockers in an unselected group of patients with chronic heart failure

Objectives Modern diagnostics of chronic heart failure (CHF) is based on echocardiography. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II-antagonists (AIIAs) in case of ACEI intolerance, and beta-blockers are recommended as first-line drugs in patients with CHF and left ventricular systolic dysfunction. The aims of this study were to analyse the diagnostics and treatment of patients with CHF and to identify the optimal drug profile (target level) with regard to ACEI/AIIA- and beta-blocker treatment.Methods The medical records of all patients (n=635) from a part of a Swedish county who had a diagnosis of CHF in the year 2000 were analysed retrospectively.Results The prevalence of CHF increased with age, from 0.9% and 1.6% in the age group 60–64 years in women and men, respectively, to 8.8% and 11.5%, respectively, in the age group 80–84 years. Only 17.6% of the patients had been examined by means of echocardiography. Of the patients without any contra-indication for the drugs, 45.9% received treatment with ACEI/AIIAs and 41.8% with beta-blockers. Treatment with ACEI/AIIAs and beta-blockers was given to 21.3%. The corresponding proportions for treatment of patients with CHF verified by echocardiography were 88.0% (ACEI/AIIA), 52.0% (beta-blocker) and 46.7% (the combination). The target level of the combination treatment was estimated to be about 70% in a group of unselected patients with CHF.Conclusions CHF was not optimally diagnosed in this cohort of patients. Correct diagnosing seems to be associated with more adequate treatment.     

Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia

Summary Sixteen patients with primary hypercholesterolaemia received double-blind either fenofibrate (n=8; 200 mg bid) or the HMG-CoA reductase inhibitor simvastatin (n=8; 20 mg qid or 40 mg qid if LDL-cholesterol did not fall below 3.6 mmol·l^–1 after 4 weeks of treatment).Simvastatin reduced total cholesterol from 9.7 to 7.0 mmol·l^–1 after 10 weeks (–28%), and fenofibrate reduced it from 9.2 to 7.7 mmol·l^–1 (–15%). The decrease was less during fenofibrate than during simvastatin treatment (time × drug:p=0.02).Serum LDL-cholesterol fell from 8.3 to 5.3 mmol·l^–1 (–36%) during simvastatin and from 7.2 to 6.0 mmol·l^–1 (–16%) during fenofibrate administration. Again, the effect of simvastatin was more pronounced than that of fenofibrate (time × drug:p=0.03).HDL-cholesterol increased significantly from 1.1 to 1.2 mmol·l^–1 (+13%) during fenofibrate administration and it did not change significantly during simvastatin.Serum triglycerides fell from 1.3 to 1.1 mmol·l^–1 (–16%) during simvastatin, and even more significantly from 2.2 to 1.1 mmol·l^–1 (–51%) during fenofibrate (time × drug:p=0.002).Apolipoprotein B fell on simvastatin from 1.9 to 1.4 g·l^–1 (–24%) and from 1.8 to 1.4 g·l^–1 (–22%) during fenofibrate.Both drugs were well tolerated and had no significant adverse effects.Simvastatin lowered total and LDL-cholesterol concentrations more than fenofibrate, while the latter had more effect on triglycerides, suggesting specific indications for the two drugs in the treatment of hyperlipoproteinaemias.     

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine

We have assesed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzodiazepine.Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1–3, 100 mg on days 4–10) (n=20), 1 mg of alprazolam four times daily for four days (days 7–10 of the study period) (n=20), or a combination of the two (n=20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10.Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration.The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam.The dosage of alprazolam should be reduced during co-administration with fluvoxamine.     

Anti-asthmatic drugs dosage forms in children: a cross-sectional study

Objective: To describe the choice of drugs as well as the dosage forms of anti-asthmatic drugs in children with regard to different age groups.Methods: Cross-sectional study based on computerized pharmacy dispensing records of 1999 for children aged 0–16 years in the north of the Netherlands. All children were selected and divided in the following age groups: 0–1, 2–5, 6–11 and 12–16-year-olds.Results: Inhaled beta2-agonists and inhaled corticosteroids were the most widely used anti-asthmatic drugs in all age groups (respectively 59 and 58 users per 100 anti-asthmatic using 0–16 year-olds). Cromones were rarely used. Up to four years of age the use of treatment with aerosol inhalers increased simultaneously with a decrease of oral dosage forms. The use of dry powder inhalers started at the age of approximately 4 years old and increased to about 85% of the users at the age of 11, with the strongest increase around the age of 6 and 7.Conclusion: The choice of drugs and dosage forms corresponds with what might be expected based on guidelines for the treatment of asthma in children, except for the high use of deptropine in the youngest age group. Anti-asthmatic drugs for preventive treatment are used so frequently without beta2-agonists that questions about possible overtreatment need to be raised.     

Effects of Alendronate and Calcitonin on Bone Mineral Density in Postmenopausal Osteoporotic Women. An Observational Study

Objective: Alendronate and calcitonin are antiresorptive drugs that were used for the treatment of postmenopausal osteoporosis and were shown to increase bone mineral density (BMD). However, the effect of both drugs in daily clinical practice may differ from that observed in clinical trials.Method: About 50 postmenopausal osteoporotic women were observed during their first year of treatment. Among them, 32 patients used alendronate and 18 used calcitonin. Lumbar spine and femoral neck BMD were measured by dual energy X-ray absorptiometry (DXA) at baseline and after 1 year of therapy. Biochemical markers (B-ALP – bone-specific alkaline phosphatase, OTC – osteocalcin and DPD/UCr – deoxypyridinoline/creatinine ratio) of bone metabolism were measured at baseline and 6 months later. Patient compliance was assumed by tablet counting and verified at interview. Each patient was further questioned about her attitude towards the treatment, as well as her dairy product intake, physical activity, use of other medications, smoking and social status.Main outcome measure: (1) Annual percent change in BMD in lumbar spine and femoral neck after the one-year treatment with either alendronate or calcitonin. (2) The change in biochemical markers of bone turnover.Results: The lumbar spine BMD significantly increased by 7.0% (P < 0.001), the femoral neck BMD by 4.3% (P < 0.01). OTC, B-ALP and DPD/UCr decreased significantly during the therapy with alendronate. Compliance with therapy was 79% (95% CI 68–90%). In the calcitonin-treated group, the lumbar spine BMD significantly increased by 3.1 % (P < 0.05), while the femoral neck BMD remained unchanged. OTC, B-ALP and DPD/UCr did not change significantly during the treatment with calcitonin. Compliance with calcitonin therapy was 87% (95% CI 63–110%). The annual change of BMD in both treatment groups was independent on all questioned factors.Conclusion: In daily practice, alendronate enhanced significantly BMD both in lumbar spine and femoral neck. Calcitonin showed increase only in the lumbar spine BMD.     

Pharmacokinetics of nicorandil in patients with normal and impaired renal function

Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CL_Cr): GROUP I (n=6) > 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) < 20 ml/min.After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h^–1 in Group I, 44 l·h^–1 in Group II and 56 l·h^–1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment.The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.     

Red cell folate levels in pregnant epileptic women

Red cell folate concentrations were determined in 74 epileptic women in early pregnancy in a prospective study. All patients were treated continuously with antiepileptic drugs since before conception. The most frequently used drugs were carbamazepine (n–39) and phenytoin (n–26). Sixty-four patients (86%) were on monotherapy. Blood samples for red cell folate and antiepileptic drug concentrations were drawn before folate supplementation. Red cell folate levels in patients, 468 nmol·l^–1, did not differ from those in non-epileptic, drug-free, pregnant women, 416 nmol·l^–1 or from those in non-pregnant age-matched healthy controls, 412 nmol·l^–1. No correlation was found between red cell folate concentrations and doses or plasma levels of phenytoin or carbamazepine.     

An assessment of DDT and other chlorinated compounds and the reproductive success of American robins (Turdus migratonrius) breeding in fruit orchards

Although DDT was banned in the 1970s, American robins (Turdus migratorius) breeding in fruit orchards of the Okanagan Valley, British Columbia, continue to be contaminated with DDT and its metabolites. The objectives of our study were (1) to assess organochlorine (OC) contamination in robins breeding in Okanagan orchards (1993–1995, 1997–1998) and (2) to determine if exposure affected reproductive success when compared to robins from non-orchard habitat (lower mainland, British Columbia). Robins in orchards had total DDT egg residues of 48.64 mg/kg (geometric mean; n=92) while those in non-orchard habitat had 1.10 mg/kg (geometric mean; n=26), wet weight. The probability of nest survival during the incubation period was 96.7% (confidence interval: 95.7–97.5%; n=165) in orchard habitat and 96.7% (confidence interval: 94.6–98.1%; n=28) in non-orchard habitat. During the nestling period the probability of nest survival was 98.2% (confidence interval: 97.2–98.9%; n=123) in orchard habitat and 96.2% (confidence interval: 92.8–98.0%; n=34) in non-orchard habitat. Clutch (p<0.0001) and brood size (p=0.0133) were larger in orchards (n=150 and n=93, respectively) compared to non-orchard nests (n=42 and n=23, respectively) with no difference in fledge rate. DDE (r ²=0.11, p=0.0030, n=68) and dieldrin (r ²=0.29, p<0.0001, n=68) were negatively correlated with fledge rate in robin eggs collected from orchard habitat, however, low r ² values signify minimal biological significance. Although American robins nesting in Okanagan orchards are exposed to high OC levels, reproductive success does not appear to be negatively impacted.     

Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate

Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t _1/2 a) averaged 24 min. Neither peak time nor t _1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t _1/2 ) of 82 h (range 27–219 h). t _1/2 became prolonged with age in men but not in women Likewise, clearance of total (free plus bound) DMDZ declined with age in male subjects (r=–0.47, P<0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0–4.3%), and increased significantly with declining plasma albumin concentrations (r=–0.57, P<0.001). Partly due to a decline in plasma albumin with age (r=–0.47, P<0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=–0.62, P<0.01), but actually was slightly higher, in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.