Psychopathology in patients with severe asthma is associated with increased health care utilization.

Severe asthma accounts for the majority of health costs for this disease, which is mainly related to the treatment of failed control. Several psychosocial factors have been associated with poor asthma control, but the question remains whether psychiatric disorder in patients with severe asthma predisposes for increased health care utilization. In the present study we compared outpatients with severe asthma with and without psychological dysfunctioning with respect to health care utilization. All patients used high dose inhaled corticosteroids and long-acting bronchodilators for more than 1 yr, and had difficult-to-control asthma, requiring one or more courses of corticosteroids during the past year or maintenance therapy with prednisone. Medical history was taken and health care utilization questionnaires were completed. The General Health Questionnaire (GHQ) was used to identify psychiatric cases (GHQ-12 score of > or = 6). There were no differences between the psychiatric cases (n = 21) and the noncases (n = 77) with respect to demographic and objective disease characteristics. However, the psychiatric cases had increased odds ratios (OR) for frequent visits to GP (OR = 5.9), frequent emergency visits (OR = 5.3), frequent exacerbations (OR = 12.4), and frequent hospitalizations (OR = 4.8) as compared with the nonpsychiatric patients. The present findings suggest that the morbidity and costs of asthma might be related to the level of psychological dysfunctioning in patients with severe asthma rather than to asthma severity per se, thereby identifying an area of potential intervention.

Similar psychological characteristics in mild and severe asthma.

OBJECTIVE: Psychological factors have been implicated as potentially contributing to asthma severity. In the present study, we investigated whether patients with mild and severe asthma differ with regard to several psychological characteristics. METHODS: Ninety outpatients with severe asthma (74% female, mean [S.D.] age: 46.5 [13.7] years) and 37 outpatients with mild asthma (73% female, age: 39.4 [13.9] years) were compared with respect to general psychological health, anxiety sensitivity, hyperventilation symptoms, personality, and locus-of-control orientation, all measured by well-validated self-report questionnaires. Analysis of (co)variance (ANCOVA) was used to assess between-groups differences. RESULTS: No significant differences in psychological characteristics were found between patients with mild and severe asthma. Only on the subscale for external locus-of-control orientation, severe asthmatic patients differed from those with mild disease (P=.005) in showing less trust in physicians and medication with regard to influencing their asthma. CONCLUSION: The results suggest that mild and severe asthmatic patients cannot be differentiated on the basis of psychopathology or personality. Whether or not the observed lack of confidence in the influence of physicians or medication on asthma course is cause or consequence of disease severity, remains to be established.

Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects.

The objectives of this study were to assess the tolerability, safety, pharmacodynamics and pharmacokinetics of high-dose moclobemide in healthy subjects. Two sequential groups of six male and six female subjects (eight on active treatment, four on placebo) received for 8 days moclobemide 450 mg b.i.d. and 600 mg b.i.d., respectively. Intravenous tyramine pressor tests were conducted at baseline, at the beginning of treatment and at steady state. Oral tyramine pressor tests with 50, 100 and 150 mg tyramine were conducted under steady-state conditions. Pharmacokinetic parameters of moclobemide and two of its metabolites in plasma and urine were determined after the first and last dose of moclobemide. The incidence and intensity of adverse events was dose-dependent. The most frequently reported adverse events were insomnia, headache, dizziness and dry mouth. The i.v. tyramine pressor sensitivity during both moclobemide dosing regimens was enhanced 3 to 4-fold. Intake of tyramine 50 mg did not result in systolic blood pressure increases greater than 30 mmHg. With regard to blood pressure increases, tyramine 100 mg is still compatible with moclobemide 450 mg b.i.d. but not with 600 mg b.i.d. The clearance of moclobemide decreased by about 60% on multiple dosing, but no differences were found between both dosing regimens. The urinary excretion of the N-oxide metabolite doubled during multiple dosing. In conclusion, the maximum tolerated dose of moclobemide in healthy subjects is 600 mg b.i.d. provided the tyramine content in a meal is not higher than 50 mg.

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy subjects.

A multiple-dose study was performed to assess the pharmacokinetic profile of a new levodopa/benserazide dual-release formulation (DRF) in comparison with a conventional slow-release formulation (SRF). The study was of an open label, randomized, two-way cross-over design and was conducted in 18 subjects. Assessment of the two formulations was at day 1 (single-dose) and at day 7 after a 5-day t. i.d. pre-treatment (100 mg levodopa and 25 mg benserazide) in fasting state. The pharmacokinetic parameters reflecting bioavailability, accumulation and metabolism of levodopa were determined. The levodopa pharmacokinetics of the new DRF showed rapid absorption (tmax=1.1 h), followed by sustained levodopa plasma concentrations, similar to the SRF. Following multi-dose administration, the peak plasma concentration of the new DRF was 90% higher compared to the SFR (Cmax=2.1 and 1.1 microg/ml, respectively). The bioavailability was significantly increased by 40% (AUC0-infinity=6.1 and 4.3 microg x h/ml, respectively). The new DFR was well tolerated as shown by the low incidence of mild side effects. In conclusion, the results of this study confirmed the levodopa dual-release properties of this new levodopa/benserazide formulation.

Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function.

OBJECTIVE: The influence of liver disease on the pharmacokinetics of candesartan, a long-acting selective AT1 subtype angiotensin II receptor antagonist was studied. METHODS: Twelve healthy subjects and 12 patients with mild to moderate liver impairment received a single oral dose of 12 mg of candesartan cilexetil on day 1 and once-daily doses of 12 mg on days 3-7. The drug was taken before breakfast. Serial blood samples were collected for 48 h after the first and last administration on days 1 and 7. Serum was analyzed for unchanged candesartan by HPLC with UV detection. RESULTS: The pharmacokinetic parameters on days 1 and 7 revealed no statistically significant influence of liver impairment on the pharmacokinetics of candesartan. Following single dose administration on day 1, the mean Cmax was 95.2 ng.ml-1 in healthy subjects and 109 ng.ml-1 in the patients. The AUC0-infinity was 909 ng.h.ml-1 in healthy volunteers and 1107 ng.h.ml-1 in patients and the elimination half-life was 9.3 h in healthy volunteers and 12 h in the patients. At steady state on day 7, mean Cmax values were similar in both groups (112 vs 116 ng.ml-1); the AUC tau was 880 ng.h.ml-1 in healthy subjects and 1080 ng.h.ml-1 in patients while the elimination half-life was 10 h in healthy subjects and 12 h in the patients with liver impairment. The ACU0-infinity on day 1 was almost identical to the AUC tau on day 7. A moderate drug accumulation of 20%, which does not require a dose adjustment, was observed following once-daily dosing in both groups. No serious or severe adverse events were reported. CONCLUSION: Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients.

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure.

OBJECTIVE: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL(CR)) 64 ml x min(-1); range 42-77 ml x min(-1)], eight patients with severe chronic renal failure (mean CL(CR), 18 ml x min(-1); range 11-29 ml x min(-1)) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. RESULTS: No statistical differences of either maximum concentration (Cmax) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, Cmax and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. CONCLUSION: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency.

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with impaired liver function.

OBJECTIVE: The possible influence of impaired liver function on the pharmacokinetic disposition of imidapril, a novel prodrug type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite, imidaprilat, was investigated. METHODS: Eight subjects with normal liver function and eight patients with liver dysfunction received an oral dose of 10 mg imidapril once daily for 7 days. RESULTS: Plasma imidapril concentrations after single and, although less pronounced, after repeated dosing were higher in the liver disease patients, whereas imidaprilat concentrations were lower. This suggests that the conversion of imidapril into imidaprilat in the liver is delayed in patients with impaired liver function. However, the slower biotransformation did not result in statistically significant differences in Cmax and AUC for either imidapril or its active metabolite following repeated administration. Moreover, no relevant accumulation of either imidapril or imidaprilat occurred after repeated dosing. CONCLUSIONS: Imidapril is regarded as an ACE inhibitor of which the pharmacokinetic disposition is only slightly affected in patients with impaired liver function.

Pharmacokinetics and bioavailability of percutaneous ibuprofen.

The absorption, pharmacokinetics and bioavailability of ibuprofen (CAS 15687-27-1) were investigated for an ibuprofen gel preparation (ibugel) for percutaneous application, and compared to a standard oral ibuprofen tablet preparation. The monocentric, randomised, 2-way cross-over study with 7-day wash-out period was performed on 18 healthy female volunteers with an average age of 26.3 +/- 4.8 years (range: 20-38 years), average weight 60.4 +/- 7.6 kg, and average height 164.7 +/- 5.9 cm. Blood samples were taken from the volunteers before administration of the tablet or gel, and periodically during 24 h after administration. The ibuprofen content in these samples was determined using a validated HPLC method. Main pharmacokinetic parameters derived from individual plasma concentration-time courses included: Cmax, tmax, AUCO-->24, AUCO-->infinity, MRTO-->infinity, t1/2 and Frel. For percutaneous application of 500 mg ibuprofen (10 g 5% gel on the back, area of 20 x 20 cm) with occlusion for 2 h, a Cmax of 7.1 +/- 4.4 micrograms/ml (95% confidence interval (CI): 5.0-9.1) was obtained at 2.4 +/- 0.8 h (95% CI: 2.0-2.8). For oral administration of 400 mg, Cmax was 36.7 +/- 7.5 micrograms/ml (95% CI: 33.2-40.1) at 1.1 +/- 0.8 h (95% CI: 0.7-1.5). The (dose-corrected) relative bioavailability of the topical ibuprofen was found to be 22 +/- 12% (95% CI: 14-30%) of that after oral administration. The plasma elimination half-life was 2.5 +/- 1.4 h (95% CI: 1.9-3.2) for topical administration, and 1.8 +/- 0.5 h (95% CI: 1.6-2.1) after oral administration (not significant, p > 0.05). The surprisingly high levels of ibuprofen found in the plasma after percutaneous application are still below the threshold where systemic side effects might be expected (10 micrograms/ml). The high peak plasma concentration and relative bioavailability of percutaneous ibuprofen are likely due to the galenical formation of the gel preparation, which contains isopropyl alcohol and propylene glycol as co-solvents and is adjusted to pH 5, and to the use of occlusion.