Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance.

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.

Effects of acarbose treatment in Type 2 diabetic patients under dietary training: a multicentre, double-blind, placebo-controlled, 2-year study.

This 24-months, placebo-controlled, double-blind, randomised, group comparison study investigated the effect of acarbose vs placebo for improving metabolic control in patients with Type 2 diabetes under dietary training insufficiently controlled by diet alone. Patients randomised to acarbose had their dose increased in a stepwise manner to week 5. From week 5 onwards, they received 100 mg three times daily. This incremental dosing scheme was matched in the placebo group. All patients received specialist, intensive, continuous dietary training and counselling throughout the 2 yr of the study. Of the 74 patients randomised, 60 were included in the per-protocol analysis (28 receiving acarbose; 32 receiving placebo). HbA1c was the primary target variable. Per-protocol analysis found that, after 24 months, the mean difference in HbA1c relative to baseline value was -1.71+/-1.6% in the acarbose group and -0.82+/-1.1% in the placebo group. End-point values were 6.85+/-1.7% in the acarbose group and 7.41+/-1.1% in the placebo group. This difference between acarbose and placebo was statistically significant (p=0.02). Patients were defined as responders if they did not require additional treatment with an antidiabetic agent during the study. The responder rate under acarbose therapy was 89%, compared with 47% for placebo (p=0.0005). Acarbose-treated responders improved their HbA1c level to 6.45+/-0.82% after 24 months. The efficacy of acarbose was consistent throughout the study; decreasing efficacy was not evident. The results demonstrate the efficacy of acarbose for improving metabolic control in patients with Type 2 diabetes, even when such patients receive good dietary treatment and counselling.

The effect of acarbose on insulin sensitivity and proinsulin in overweight subjects with impaired glucose tolerance.

Insulin sensitivity is impaired in overweight subjects with IGT and is accompanied by hyperinsulinemia, a condition, that might promote early B-cell exhaustion. Twelve subjects were recruited for a double-blind trial using either 100 mg of acarbose or placebo for three months. Insulin sensitivity was measured by hyperglycemic clamp and with the minimal model. Baseline characteristics such as body weight, BMI, blood glucose, HB-A1c and serum lipids did not change throughout the study period. The steady state glucose infusion rate (SSGIR) improved significantly following acarbose. The insulin sensitivity as measured by clamp (MI) or minimal model, (SI), however, increased only descriptively (p = 0.08). The fasting proinsulin was raised in all subjects during pretreatment. Following acarbose, the proinsulin dropped from 20.3 +/- 12.9 to 13.6 +/- 7.1 ng/ml, but remained unchanged in the placebo group. Due to the high variability of values and the low number of subjects in this study, differences were only descriptive and did not reach significance (p = 0.08). The proinsulin/insulin ratio, however, significantly decreased after 3 months of acarbose treatment. Acarbose might therefore be considered recommendable for the protection of the B-cell function and for delaying the transition of IGT to overt NIDDM.

Cerebellar herniation in syringomyelia: relation between tonsillar herniation and the dimensions of the syrinx and the remaining spinal cord. A quantitative MRI study.

The dimensions of the syrinx, the remaining spinal cord and the degree of cerebellar herniation were analyzed by one- and two-dimensional MRI studies in 22 patients with syringomyelia. A deep and/or broad cyst tends to be a long one. The dimensions of the syrinx and the spinal cord have an inverse relationship. The degree of cerebellar herniation is not related to the longitudinal or transverse extension of the cyst or the ratio cyst/cord or the remaining spinal cord (neither for diameters nor for cross-sectional areas). The dimensions of cysts are not significantly greater in patients with tonsillar herniation than in patients without. We conclude that cerebellar herniation is not a major prognostic factor and should not be overestimated for the development and progression of the disease.

Albuminuria in HIV-infected patients.

Albumin excretion, Analysis of urinary proteins by polyacrylamide gel electrophoresis (PAGE), and clinical evaluation were performed in 90 HIV-infected patients to assess subclinical renal involvement in HIV infection. Thirteen percent of all patients showed an albumin excretion > 20 mg/liter. Seven of four homosexual patients had albuminuria. Albuminuria occurred exclusively with T4 cell counts below 200/mm3. Polyacrylamide gel electrophoresis indicated glomerular lesions and showed no tubular proteinuria in patients with increased albumin excretion. It is concluded that subclinical renal involvement is not uncommon in HIV infection with T4 cell counts > 200/mm3. HIV-associated nephropathy and heroin-associated nephropathy may not be the main causes of renal involvement. In some cases, opportunistic viral infections may be the cause of microalbuminuria.

The relation between functional deficits, motor and sensory conduction times and MRI findings in syringomyelia.

Opinions about the relation between the dimensions of the syrinx and the severity and distribution of symptoms in patients with syringomyelia are controversial. Therefore, this study investigates the relation of clinical symptoms, a disability score, quantified (1- and 2-dimensional) radiological findings (magnetic resonance imaging, MRI) and electrophysiological data (somatosensory and motor evoked potentials) in 22 patients with syringomyelia. There was a close relation between clinical symptoms and electrophysiological data. By both electrophysiological methods subclinical deficits could be detected. Furthermore, the results disclosed that the clinical symptoms, the degree of disability and the duration of the disease are not related to the dimensions of the syrinx or the electrophysiological results obtained by investigating the long ascending and descending spinal tracts of the lower limbs. Our findings suggest that, besides the syrinx, other factors not directly visible in the MRI are responsible for the development and progress of clinical symptoms.

Acute myelogenous leukaemia in children under 2 years--experiences of the West German AML studies BFM-78, -83 and -87. AML-BFM Study Group.

Clinical, morphological, immunological, cytogenetical and prognostic features of 84 children under 2 years of age with AML in studies AML-BFM-78, -83 and -87 were retrospectively analysed. There was a high incidence of acute monoblastic leukaemia (FAB M5) (41 patients--49%) and acute megakaryoblastic leukaemia (FAB M7) (study AML-BFM-87: five patients--13%) in this age group. Acute monoblastic leukaemia was associated with hepatosplenomegaly, extramedullary organ manifestations and chromosomal abnormalities involving 11q23. The probability of an 11-year event-free survival of all patients under 2 years of the three studies combined was 39% (SD 6%). While the event-free survival rates of patients aged 2 years and older could be improved in studies AML-BFM-83 and -87 compared with study AML-BFM-78, overall prognosis in children under 2 years in the three consecutive studies remained unchanged. The event-free survival rate of children with acute monoblastic leukaemia in both age groups was comparable (7 yr-EFS (AML-BFM-83 and -87): much less than 2 years--43% (SD 9%), =/much greater than 2 years--33% (SD 9%); P much greater than 0.5). This also applied to other risk groups. In conclusion, taking the high incidence of acute monoblastic and megakaryoblastic leukaemia in children under 2 years into account, no significant differences between children under 2 years or older children concerning response to therapy and overall prognosis could be evaluated.

[Comparison of chemotherapy alone with allogeneic bone marrow transplantation in first full remission in children with acute myeloid leukemia in the AML-BFM-83 and AML-BFM-87 studies--matched pair analysis]. / Vergleich der alleinigen Chemotherapie mit der allogenen Knochenmarktransplantation in erster Vollremission bei Kindern mit akuter myeloischer Leukämie in den Studien AML-BFM-83 und AML-BFM-87--Matched-Pair-Analyse.

16 patients of studies AML-BFM-83 and -87 with allogeneic bone marrow transplantation (BMT) in first complete remission (CR) were compared with matched controls with postremission chemotherapy (CT-MC). CT-MC were selected from 250 non-grafted patients with a minimum of remission duration corresponding to the median interval between remission and allogeneic BMT (7.3 and 3.6 months in studies BFM-83 and BFM-87). Matched pair criteria according to prognostic significance were: blast cell reduction day 15 in bone marrow, FAB subtypes, white blood cell count, age, and time to CR. Therapy results in BMT and CT-MC groups were comparable: 2 relapses and 2 treatment-related deaths after BMT vs. 5 relapses. The probability for event-free interval of 9 years was: .73 (SD .12) in the BMT group vs. .67 (SD .12) in the CT-MC group. Early and late toxicity was higher in the BMT group. 3 children of the BMT group had tolerable or severe sequelae (convulsive seizures, hemiparesis). Currently, there is no advantage for allogeneic BMT in first CR according to our results. Only high risk patients should be grafted as soon as possible after achieving CR.

[Effect of cranial irradiation on rate of recurrence in children with acute myeloid leukemia. Initial results of the AML-BFM-87 study. The AML-BFM Study Group]. / Einfluss der Schädelbestrahlung auf die Rezidivrate bei Kindern mit akuter myeloischer Leukämie. Erste Ergebnisse der Studie AML-BFM-87. AML-BFM-Studiengruppe.

Study AML-BFM-87 compared prospectively if cranial irradiation could be abandoned by adding two blocks of intensification with high dose ARA-C and VP-16 after consolidation and furthermore, improve prognosis compared to study -83. 210 children were enrolled in study AML-BFM-87 until March 31, 1991. 164 (78%) achieved complete remission. Probabilities for event-free survival (EFS) and event-free interval (EFI) of 5 years were: .45 (SD .04) and .57 (SD .05). In the first 2.5 years of the study irradiation was randomized (n = 31), selected or refused (n = 24). However, during this period irradiation was mandatory in patients with leukocyte count greater than 70,000/mm3, and also in children with initial CNS involvement. Since July 1989 prophylactic cranial irradiation was abandoned. Patients of the group with mandatory irradiation (n = 39) presented with more unfavourable risk parameters than the group of non-irradiated children, who were enrolled in the study after randomisation had been stopped. Nevertheless, results showed in randomized and selected patient groups as well as in the total cohort a longer relapse-free interval (RFI) in irradiated (n = 66) compared to non-irradiated (n = 94) patients (RFI of 5 years: .70, SD .04 vs. .51, SD .07, p less than .05). Relapses in non-irradiated children occurred mainly in the bone marrow and less often in the CNS. The increase in relapse rate was seen especially in non-irradiated patients of the low risk group as defined in study AML-BFM-83 (RFI: .40, SD .14 vs. .79, SD .09 with irradiation, p less than .01). In the high risk group, however, the differences were not significant. Our results suggest that cranial irradiation is an important part of therapy in childhood AML, and that the good prognosis of the low risk group in study AML-BFM-83 was probably based on the combination of intensive chemotherapy and cranial irradiation.

[Serum prolactin after cerebral and psychogenic seizures in childhood and adolescence--an additional useful method for differentiating the two forms of seizure]. / Prolaktin im Serum nach zerebralen und psychogenen Krampfanfällen im Kindes- und Jugendlichenalter--eine nützliche Zusatzmethode zur Unterscheidung zwischen beiden Anfallsformen.

Prolactin levels were measured immediately after the seizure in some, and 15 to 20 minutes later in all of 67 children aged between 6 months and 17 years. Values were determined after grand mal, complex partial and petit mal seizures and psychogen seizures. A more than 2 to 3 fold prolactin increase over the baseline value occurred almost always after grand mal and regularly after complex partial seizures. No hyperprolactinaemia was observed after petit mal seizures. Also after psychogenic seizures a rise in serum prolactin failed. The neurophysiological basis underlying this phenomenon is a decrease of gaba- und dopaminergic systems associated with the seizure. The described method is useful in the differential diagnosis of epileptogenic versus psychogenic seizures.

[Effect of etamsylate on hemorrhagic diathesis of children with oncologic diseases. Retrospective matched-pair analysis of 64 patients in a study of 100 patients of the Münster University Pediatric Clinic]. / Einfluss von Etamsylat auf die Blutungsneigung von Kindern mit onkologischen Erkrankungen. Retrospektive Matched-pair-Analyse von 64 Patienten bei Untersuchung von 100 Patienten der Universitätskinderklinik Münster.

The hemostatic efficacy of ethamsylate studied by a matched-pair analysis was not proved to be statistically significant. The appearance of bleeding signs as well as the frequency of platelet transfusions have been examined. An important side-effect was found in patients receiving ethamsylate: severe leucocytopenia (less than 1000 leucocytes/microliters) was noticed more frequently followed by an enhanced susceptibility to infections. The incidence of septic infections was proved to be significantly increased in an extended sample of 100 patients.