Elevation of liver enzymes in multiple dose trials during placebo treatment: are they predictable?

The present study examined the increase in transaminases, especially in ALT in young healthy males during placebo treatment in phase I multiple dose trials. The primary objective was to investigate whether volunteers showing increasing ALT levels also present characteristic patterns of demographic data, laboratory parameters, and vital signs. The secondary objective was to determine whether there is a possibility to predict increases of ALT during a trial by analyzing demographic data and baseline levels of routine safety laboratory parameters and vital signs. In a meta-analysis of 13 placebo-controlled multiple dose phase I studies, volunteers showing elevations of ALT during placebo treatment were compared with those presenting no clinically significant changes of ALT levels. Demographic data as well as routine safety laboratory values and vital signs measured at screening and on the first day of the in-house stay were subject to the analysis. Using Wilcoxon's rank sum test, significant differences between ALT-susceptibles and ALT-nonsusceptibles were found for baseline values (mean values of screening and the first day of the in-house stay) of ALT, gamma GT, AST/ALT, and AST/ gamma GT. Differences found for the screening values of the heart rate were statistically rather than clinically significant. Cut-off values were found for baseline levels of ALT and AST/ALT ratio. Their use resulted in a sensitivity of 73% and a specificity of 74% with regard to predictability of ALT levels increasing during the trial.

Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS)

OBJECTIVE: To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. SETTING: A total of 75 hospitals in 14 European countries. PATIENTS: A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT). INTERVENTION: Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms. OUTCOME MEASURES: Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage. RESULTS: The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA-treated patients (P = .035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA-treated patients in both analyses (P < .001). Neurologic recovery at 90 days was significantly better for rt-PA-treated patients in the TP (P = .03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA-treated patients. CONCLUSIONS: Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.

[Effect of acarbose on postprandial increase in blood glucose. Additive acute effect of once daily administration in insulin treated diabetes]. / Wirkung von Acarbose auf den postprandialen Blutzuckeranstieg. Additiver Akuteffekt der einmal täglichen Gabe bei insulinbehandelten Diabetikern.

UNLABELLED: Only few controlled studies have been conducted on the influence of additive treatment with the glucosidase inhibitor acarbose on post-prandial blood sugar levels in insulin-dependent diabetics. To date, the behavior of blood sugar levels under treatment with acarbose has not been studied in insulin-dependent, type II diabetics. METHOD: Forty-six diabetics--36 insulin-dependent type II, and 10 type I--were enrolled in a double-blind, placebo-controlled randomized parallel group study with the aim of investigating the influence of acarbose on the primary variable maximum blood glucose increase following a standard breakfast eaten after 7 days of treatment. The patients were to have an HbA1 value of > 9%, and a post-prandial increase in blood glucose 90 minutes after a standardised breakfast (3 white bread units) of at least 50 mg/dl as compared with the fasting blood sugar during a one-week run-in period. INTERVENTION: The patients were randomized to treatment consisting of either one tablet of 100 mg acarbose or a single placebo tablet taken daily with breakfast. RESULTS: While the placebo group showed a mean further rise in maximum blood glucose levels after 7 days of treatment from 76.1 +/- 13.1 mg/dl to 84.3 +/- 17.8 mg/dl over the baseline value, there was a decrease in the acarbose group from 80.5 +/- 12.8 to 46.3 +/- 12.8 mg/dl. The difference between the two groups was statistically significant (p = 0.0001). No significant correlation was found between the treatment and type of diabetes. Mild adverse events such as meteorism, flatulence and diarrhea did not lead to any interruption of the study, and had cleared up by the end of the trial in all patients. CONCLUSION: The use of a single dose of 100 mg acarbose at breakfast time can result in a marked flattening of elevated post-prandial morning blood glucose profiles in both insulin-dependent type II and type I diabetics.

[Comparative study of the pharmacokinetics of amitriptyline oxide and trimipramine after single administration in healthy male probands and patients with renal failure]. / Vergleichende Untersuchung zur Pharmakokinetik von Amitriptylinoxid und Trimipramin nach Einmalgabe bei gesunden männlichen Probanden und Patienten mit Niereninsuffizienz.

The pharmacokinetics of the antidepressants amitriptyline oxide and trimipramine and their major metabolites amitriptyline, nor-triptyline and desmethyltrimipramine, were studied in twelve healthy male subjects (aged from 22 to 62 years) and twelve patients (aged from 25 to 73 years) with severe renal impairment (glomerular filtration rate < 10 ml/min). Oral single doses of 60 mg amitriptyline oxide and 50 mg trimipramine, separated by a washout period, were administered to all study participants. Blood and urine samples were collected up to 120 hours after administration. For trimipramine and desmethyltrimipramine, a new HPLC method was developed. The "Fischer Somatic and Undesired Effects Check List" was used for the assessment of adverse events. The mean plasma half-life and AUC of amitriptyline oxide and its metabolites were significantly higher in patients than in healthy adults. For trimipramine the AUC was significantly higher in patients. The plasma half-life of trimipramine was longer in patients, but statistically not significant. The maximum plasma concentrations for both drugs and metabolites were at an average distinctly higher in patients. Clearance rate of amitroptylinoxide and trimipramine also differed between the two groups. Correlating with these results a high incidence and a longer persistence (in most cases > 12 hours) and more pronounced adverse effects were noted in the patient group, whereas in volunteers adverse events were only observed up to approximately eight hours.

Determinacoa cinetica da haptoglobina serica em portadores de anemias hemoliticas. / Kinectic determination of serum haptoglobin in patients with haemolytic anaemia

Avaliou-se um metodo cinetico para determinacao da haptoglobina serica em 101 individuos normais e 20 pacientes com anemias hemoliticas de etiologia variada. O metodo cinetico provou ser util para ser empregado na rotina laboratorial, apresentando boa precisao, exatidao e sensibilidade. A media dos niveis sericos de haptoglobina no grupo de anemias hemoliticas foi significantemente inferior a media do grupo de controle. Houve correlacao estatisticamente significante entre haptoglobina, porcentagem de reticulocitos e numero total de eritrocitos, no grupo de anemias hemoliticas

Suggested isosbestic wavelength calibration in clinical analyses.

I recommend the use of isosbestic points for conveniently checking the wavelength scale of spectrophotometers in the ultraviolet and visible regions. Colorimetric pH indicators, hemoglobin derivatives, and other radiation-absorbing substances that are convertible into stable isomers of different absorption spectra provide a means for calibrating many different wavelengths by comparing the absorptivities of these isomers in equimolar solutions. The method requires no special precautions and results are independent of substance concentration and temperature between 4 and 45 degrees C. Isosbestic calibration may be important for (e.g.) coenzyme-dependent dehydrogenase activity determinations and in quality assurance programs.