[Health care costs of multiple sclerosis in Austria. Cross-sectional study including consideration of quality of life]. / Krankheitskosten der multiplen Sklerose in Osterreich. Querschnittstudie unter Berücksichtigung der Lebensqualität.

A retrospective, cross-sectional study was performed to evaluate direct and indirect costs related to multiple sclerosis (MS) in Austria in a representative cohort of patients ( n=895) with typical symptoms. Demographic, socioeconomic, and disease-related data including degree of disability and health-related quality of life as well as consumption of medical and nonmedical resources were recorded and mean total costs per patient and year were calculated (based on 1999 figures). Total direct costs borne by public sources were 15,684 euro per MS patient per year. Overall societal costs increased disproportionately with the progression of the disease, from 12,990 euro per year in patients with mild disability to 69,554 euro per year in patients with severe disability. Increasing disability was reflected by substantial deterioration of health status-related quality of life. Direct costs of MS in Austria are similar to those in other countries.

Prevalence of multiple sclerosis in Austria. Results of a nationwide survey.

The epidemiology of multiple sclerosis (MS) in Austria is almost unknown. We evaluated the prevalence of MS in Austria using data from questionnaires completed by neurologists, comprising information on a total of 1,006 MS patients who attended 30 out-patient specialized clinics nationwide. Additional data were collected from 2,414 MS patients, who received questionnaires from the Austrian MS Society or their doctor. A novel extrapolation model, based on frequencies of patients visits at MS clinics, was used to estimate the overall prevalence of MS. Considering either disability or the course of the disease, the prevalence of MS patients in Austria was estimated to be 98.5 per 100,000 people. The prevalence of MS in Austria was found to be similar to that of other countries in Central Europe. Epidemiological studies, such as this, provide a unique source of data from which key features of a disease and its impact on patients may be examined.

[Prospective study of determining the value of D-dimer in diagnosing pulmonary embolism]. / Prospektive Untersuchung zur Erfassung der Wertigkeit von D-Dimer in der Pulmonalembolie-(PE)-Diagnostik.

Pulmonary embolism (PE) is still misdiagnosed in a high proportion of cases. 107 patients admitted for suspected pulmonary embolism were studied prospectively to shed light on the value of ELISA-D-dimer and Latex-D-dimer. Pulmonary embolism was ruled out by negative perfusion scans in 66 patients (61.7%) and by angiography in 24 patients. 58% of the scans suggesting a high probability of PE were confirmed by angiography, but only 18% of the scans suggesting a low or intermediate probability of PE. Sensitivity and specificity were 88% and 79%, respectively for the D-dimer ELISA, versus 94% and 90% for the Latex agglutination test. The Latex test increased the positive predictive value of lung scanning suggesting low to intermediate probability of PE (group B) from 18% to 75% and that of lung scanning suggesting high probability of PE (group C) from 58% to 93%. The positive predictive value was improved by ELISA-D-dimer in both groups to 75%. In order to augment the diagnostic efficacy in clinical practice the determination of Latex-D-dimer simultaneously with lung scanning is recommended.

[Reducing blood pressure and modification of coronary risk factors by therapy with doxazosin]. / Blutdrucksenkung und Modifikation koronarer Risikofaktoren unter Therapie mit Doxazosin.

In an open, non-comparative, multicenter trail performed by general practitioners, the efficacy and safety of doxazosin, an inhibitor of postsynaptic alpha 1-adrenoceptors, were studied in 924 patients with mild to moderate hypertension. Under treatment with doxazosin both systolic and diastolic blood pressure decreased significantly from 178.4 +/- 18.2/103.1 +/- 8.6 to 149.1 +/- 12.0/85.6 +/- 7.3 mm Hg; the mean daily dose at the end of the 12 weeks' treatment period was 3.3 +/- 2.6 mg. Heart rate decreased by 5% and body weight by 6%. As compared with baseline values, total cholesterol (255.7 +/- 45.4 vs 232.7 +/- 37.3 mg%), triglycerides (206.3 +/- 97.6 vs 175.2 +/- 70.9 mg%) and blood glucose (101.9 +/- 31.0 vs 97.9 +/- 25.5 mg%) decreased significantly, whilst HDL-cholesterol (47.7 +/- 13.0 vs 51.5 +/- 12.4 mg%) increased. Overall, doxazosin was very well tolerated; only 16% of all patients reported adverse drug reactions. The results of this study confirm the effectiveness of doxazosin as first-line medication in the treatment of hypertension, especially in patients with concomitant metabolic disorders such as hyperlipidemia and diabetes mellitus. Moreover, the patients who appear to benefit most from doxazosin treatment are those who show the highest metabolism-related coronary risk, as calculated according to the Framingham Study equation.

Influence of isosorbide-5-mononitrate on the circadian rhythm of angina pectoris.

Efficacy and safety of two different dose regimens of isosorbide-5-mononitrate (isosorbide mononitrate, ISMN, Mono Mack, CAS 16051-77-7) (40 mg ISMN in the morning, n = 187 vs. 20 mg ISMN b.i.d. morning and early afternoon, n = 195) were evaluated in an open, randomised study in patients with symptomatic myocardial ischemia. Circadian rate, frequency, severity and duration of angina pectoris attacks, as well as the additional need of short-acting nitrates were assessed on 3 consecutive days before and at the end of the first and second weeks of treatment, respectively. In both treatment groups, a statistically significant decrease of frequency and severity of angina pectoris attacks was observed as compared to baseline. Apart from minor variations, no statistically significant differences were found between the two treatment groups.

[Effectiveness and tolerance of amlodipine in treatment of patients with mild to moderate hypertension. Results of a long-term study with a new calcium antagonist]. / Wirksamkeit und Verträglichkeit von Amlodipin in der Behandlung von Patienten mit leichter bis mittelschwerer. Hypertonie Ergebnisse einer Langzeitstudie mit einem neuen Kalziumantagonisten.

The efficacy and safety of amlodipine in the long term treatment of outpatients with mild to moderate hypertension were examined in an open, non-comparative study. 87 patients were enrolled in the study, 62 (71%) of whom were observed for 27 months under controlled conditions. Daily doses of 5-10 mg amlodipine led to a statistically significant decrease in systolic and diastolic blood pressure (-30.5/-20.7 mmHg, p less than 0.01) while there was no substantial influence on heart rate or decrease in efficacy. Amlodipine was tolerated very well; only 17% of the patients reported side effects, most of which were either mild or moderate and were tolerated or disappeared with continued treatment. No clinically significant changes were noted in clinical laboratory or ECG examinations. Based on its special pharmacological and pharmacokinetic properties, amlodipine is a novel calcium antagonist from the dihydropyridine class which has proved to be effective in the treatment of hypertension. The antihypertensive effect, which is sustained for more than 24 hours, parallels the circadian variations in blood pressure and thus induces beneficial pharmacodynamic effects. Due to the low incidence of side effects and the once-daily dosage regimen, an improvement in patient compliance can be expected.

Quantification of tissue distribution of antibiotics by kinetic hysteresis analysis.

Distribution of antibiotics can be described by kinetic hysteresis analysis when concentrations are measured in the serum and an extravascular sampling site. By calculating the area of the hysteresis loop (a simple formula is presented), the relative amount of drug transferred to an extravascular site can be quantified. With this approach, changes in disposition characteristics can be evaluated under various pathophysiological conditions. In addition, a specific distribution coefficient may be derived for any drug when different dose levels are studied under identical conditions. Kinetic hysteresis analysis overcomes the drawback of conventional compartment model pharmacokinetic analysis, since no simultaneous fitting of two different concentration-time courses is feasible.

Pharmacokinetics of an anti-cytomegalovirus hyperimmunoglobulin after single intravenous administration to healthy volunteers.

By selecting blood donors with high cytomegalovirus (CMV) antibody titres, a plasma pool was obtained which was used to produce an IgG hyperimmunoglobulin by means of pepsin fractionation. After administration of approximately 100 mg/kg body weight to healthy subjects, the time course both of anti-CMV IgG antibody titres by ELISA and of virus neutralisation (VN) titres was followed for 15 days. Seronegative subjects showed an increase in CMV-IgG antibodies as well as a significant enhancement of VN. The time course of both titres was non-uniform. The decline of both titres was biphasic: CMV-IgG antibodies fell slowly during the first week and remained unchanged thereafter, whereas VN titres decreased markedly faster in the first than in the second week. In seropositive subjects, on the other hand, VN remained unchanged. CMV-IgG antibodies increased by approximately 3 times, followed by a similar biphasic decline as seen in seronegative subjects. Due to the differences between seronegative and seropositive subjects and to the non-uniform time course, no calculations of the elimination rate were feasible.

A placebo-controlled dose response study of the reactogenicity and immunogenicity of a live cold-recombinant influenza B virus vaccine in healthy volunteers.

A live cold-recombinant influenza B virus vaccine (RB77) was given intranasally in a placebo-controlled, double blind study to volunteers in dosages of 10(7.9) EID50/ml, 10(7.25) EID50/ml, 10(5.7) EID50/ml. The tolerability, safety, and immunogenicity of the vaccine were investigated. No revertant virus was found in nasal swabs taken after immunisation. Local reactions were mild and showed a significant increase over the placebo only in the highest dose group. Systemic reactions were not different from the placebo. A significant increase in haemagglutinin inhibition titre was found in the highest dose group against the immunising strain (RB77) and the two wild strains B/TEC and B/Sing.

Tolerability and immunogenicity of a polyvalent Pseudomonas aeruginosa extract vaccine in human volunteers.

A polyvalent 16 serotype Pseudomonas extract vaccine was administered to normal volunteers to ascertain tolerability, immunogenicity and immunisation schedule. Four groups of nine volunteers were immunised with 0.8 X 10(9) bacterial equivalents (BE), 1.2 X 10(9) BE, 1.6 X 10(9) BE or placebo, respectively, on days 0, 14 and 21. A further six volunteers were immunised with 1.6 X 10(9) BE on days 0 and 28. Tolerability was excellent, slight side effects were unrelated to vaccine concentration and decreased with the number of injections. All concentrations of vaccine gave a significantly increased titre 14 days after the first immunisation. Reimmunisation did not increase the titre, which reached a plateau at day 14. Individuals with high pre-immunisation-titres produced very high post-immunisation-titres with a conversion factor of 6.5 whilst those with low pre-immunisation-titres had a higher conversion factor of 13 but produced lower final titres. ELISA titre did not always correlate with biological activity (mouse protection assay) suggesting that effective protective antibodies are only part of the total specific antibody measured by ELISA with the polyvalent whole-cell vaccine antigen.

Alterations of pharmacokinetic properties of gentamicin, penicillin G and two cephalosporins in septicaemic rabbits.

The pharmacokinetics of gentamicin, penicillin G, latamoxef and CPW 86-363, a novel third generation cephalosporin, were studied in healthy and septicaemic rabbits. Elevation of body temperature in infected animals was paralleled by statistically significant decreases in serum drug levels during the early stages of the distribution phase for penicillin G, latamoxef and CPW 86-363 whereas gentamicin showed increased serum drug levels during the early period. No significant differences were seen in tissue fluid levels (STIF) or normal and septicaemic rabbits for the four antibiotics used. Haemodynamic alterations and an increased permeability of blood vessel walls are presumed to contribute to changes in distribution properties of various drugs during experimental septicaemia. The qualitative differences among the antibiotics tested seem to be related to their physico-chemical characteristics.

Pharmacokinetics of ceftazidime and netilmicin in patients with sepsis.

The pharmacokinetics of ceftazidime and netilmicin were evaluated under septicemic conditions. In a longitudinal study, both drugs were administered simultaneously (ceftazidime 2.0 g 20 min constant i.v. infusion and netilmicin 150 mg i.v. bolus injection) every 12 hours to patients who had a positive blood culture and hyperdynamic circulatory functions. Twenty-four hours after the first period of this pharmacokinetic study, identical parameters were evaluated under dipyrone induced normothermic conditions. The mean residence time and the volume of distribution was significantly altered during septicemia compared to normal conditions. With respect to the relative distribution properties ceftazidime tended to be distributed to a greater extent to the tissue compartment, whereas netilmicin showed an opposite behaviour. Beside significant correlations of absolute values, i.e. blood volume vs. volume of distribution, and relative values, i.e. total peripheral resistance vs. extraction rate, all other attempts failed to show any meaningful correlation. Owing to the heterogenous alterations of metabolic and hemodynamic functions and pharmacokinetic parameters, respectively, the data gained from this study do not allow any statistically validated conclusion regarding the pathophysiological mechanisms involved, although these findings are in accordance with animal experiments.

Distribution properties of cephalosporin in man: pharmacokinetic and experimental approaches.

The distribution properties of cephalosporin derivatives in man were analysed according to a two-compartment model and several pharmacokinetic approaches were followed to calculate disposition parameters. These calculations resulted in different parameters with the dimension of either volume or time or in relative values. These correlate significantly with experimentally derived disposition data, e.g., the volume of distribution of the peripheral compartment vs. the ratio of intravascular and extravascular AUC-values or the mean residence time vs. absolute drug levels at various extravascular sampling sites. Based on calculated disposition parameters, the various cephalosporin derivatives can be assigned to 4 different clusters with specific distribution properties, which correlate significantly with the daily dose recommended for the treatment of moderate to severe infections. This demonstrates the clinical relevance of mathematically derived distribution parameters for the prediction of drug levels in extravascular sites and for the design of therapeutically effective dose regimens. The usefulness of other pharmacokinetic concepts is discussed together with the graphical computation of experimental data according to kinetic hysteresis analysis.

Comparative pharmacokinetic analysis of latamoxef and CPW 86-363, a novel carboxy-pyrazol-cephalosporin and formation of N-methyl-thiotetrazole.

The pharmacokinetics of latamoxef and CPW 86-363, a novel carboxy-pyrazol-cephalosporin, were evaluated in healthy volunteers after intravenous bolus injection of 1 g. Based on concentration-time courses in serum both cephalosporins showed similar distribution properties, although CPW 86-363 was eliminated significantly faster. The route of elimination of latamoxef was mainly via the urine, whereas CPW 86-363 was also excreted into the bile. N-methylthiotetrazole, which is the common side chain in position 3 of both cephalosporins, was found in the serum as well as in the urine. Its rate and extent of formation was higher for latamoxef than for CPW 86-363 and depends rather on the instability of the parent compound than on metabolic transformation. This is supported by studies on the in vitro degradation of both derivatives. The relevance of these findings are discussed in view of secondary coagulopathies, which are associated with cephalosporins having a N-methylthiotetrazole side chain.

The utility of diffusion chambers as models for the description of drug disposition.

Tissue cages were employed to explore the diffusion processes of several cephalosporins into extravascular fluids. Concentrations of cefotaxime in serum and in subcutaneous chambers increased proportionally to the amount of the drug injected. Administration of single equal doses of cephalothin, cephaloridine and cefotaxime resulted in different concentration-time courses in the serum and in diffusion chambers. These observations suggest that diffusion chambers are linked to the tissue at the implantation site. None of the classical compartmental approaches can be applied to evaluate the kinetics of drug diffusion into tissue cages. Correlations of total or non-protein bound drug concentrations in tissue cages to those in the peripheral compartment assumed concentration and time dependent diffusion processes. No specific diffusion constant based on the law of Fick could be derived for the diffusion chambers used in this study. Concentration-time courses in serum and interstitial fluid can be simultaneously evaluated according to pharmacokinetic-pharmacodynamic models. Based on the equation describing the effect site this model can be used to simulate drug concentrations in tissue cages by varying the dose size or the dose interval.