Acute and chronic effects of troglitazone (CS-045) on isolated rat ventricular cardiomyocytes.

Freshly isolated and primary cultured adult rat cardiomyocytes were used to elucidate the mechanism of action of the new oral antidiabetic agent (+/-)-5-[4-(6-hydroxy-2, 5, 7, 8-tetramethyl-chroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione (troglitazone) on the heart. Interaction with protein kinase C (PKC) and regulation of glucose transport were evaluated as possible sites of drug action. Acute treatment (30 min) of cardiomyocytes with troglitazone did not affect the phorbolester-induced membrane association of PKC-delta and PKC-epsilon, which represent the major isoforms present in these cells. However, under these conditions the phorbolester-mediated increase in membrane associated PKC activity was inhibited by 43 +/- 4% (n = 4) without affecting the basal distribution of PKC activity. In contrast to these findings, troglitazone had no acute effect on basal or insulin-stimulated glucose transport in freshly isolated cardiomyocytes; even after 120 min treatment an unaltered release of lactate was determine in the presence of the drug. After 20 h in serum-free culture troglitazone induced a dose-dependent increase in 2-deoxyglucose uptake reaching a 40-fold stimulation at 5 mumol/l. This was paralleled by a dose-dependent increase of glucose transporter-1 (GLUT1) and GLUT4 protein expression to 320 +/- 80 and 156 +/- 15% of control, respectively. In addition, chronic exposure to troglitazone increased the GLUT4 abundance in a plasma membrane fraction about twofold. These data show that troglitazone exerts multiple effects on cardiomyocytes involving inhibition of PKC and regulation of glucose transporter expression and distribution. We suggest that an increased glucose supply may be beneficial for the diabetic heart and that modulation of PKC-activity could be relevant for improving insulin action in muscle tissue.

Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts.

Troglitazone (CS045), a compound belonging to the thiazolidine diones, is being tested as a new oral antidiabetic agent. Evidence exists from animal studies and clinical trials with non-insulin-dependent diabetes mellitus patients that Troglitazone might reduce insulin resistance. The molecular mechanism of this effect is not understood. In this study, we investigated whether Troglitazone might interfere with the mechanism of glucose-induced insulin resistance. Several studies indicate that hyperglycemia reduces the kinase activity of the insulin receptor in different cell types. This effect is paralleled by translocation of several protein kinase C (PKC) isoforms, and it can be prevented by PKC inhibitors, which suggests that glucose-induced receptor desensitization is mediated by activation of PKC. We studied the effect of hyperglycemia on the insulin receptor kinase activity and its modulation by Troglitazone in rat-1 fibroblasts that stably overexpress the human insulin receptor. Before stimulation with insulin (10(-7) M), cells were acutely exposed to hyperglycemic conditions in the absence or presence of Troglitazone (0.01-2 micrograms/ml). The insulin receptor was solubilized from a plasma membrane fraction or whole cell lysates, and proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted against antiphosphotyrosine and anti-insulin receptor beta-subunit (CT 104) antibodies. Acute hyperglycemia (25 mM glucose) induced a significant inhibition of the insulin receptor kinase (IRK) activity within 30 min (inhibition to 30 +/- 12.5% of maximal insulin-stimulated beta-subunit phosphorylation, n = 9, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrations of cefpodoxime in plasma, ejaculate and in prostatic fluid and adenoma tissue.

Twenty-four healthy volunteers and 24 patients undergoing transurethral resection of the prostate received an oral dose of 200 mg of cefpodoxime as proxetil ester in a fasting state. At the same time 3.235 g of iohexol, a renal contrast medium, was injected intravenously to indicate possible urinary contamination of the prostatic fluid. The subjects were divided into three groups each. After 3, 6 and 12 h the cefpodoxime concentrations were measured in plasma, urine, prostatic fluid and ejaculate in volunteers and in plasma, prostatic fluid and prostatic adenoma tissue in patients by a bioassay as well as by an HPLC method. In general, the concentrations measured by bioassay were higher than those by HPLC. The median plasma concentrations (bioassay) in volunteers (patients) after 3, 6 and 12 h were 2.28 (2.34) mg/l, 0.95 (1.17) mg/l and 0.12 (0.28) mg/l, respectively. The median ejaculate concentrations after 6 and 12 h were 0.95 mg/l and 0.19 mg/l, respectively. Only in three volunteers and in one patient prostatic fluid concentration without urinary contamination could be measured after 3 h with a median fluid to plasma ratio of 0.10. The prostatic adenoma tissue concentrations (bioassay) after 3 and 6 h were 0.50 mg/kg and 0.24 mg/kg with tissue to plasma ratios of 0.30 and 0.26, respectively. After 3 h about half of the volunteers and after 12 h about half of the patients showed no detectable concentration in ejaculate (volunteers) and prostatic tissue (patients), respectively. It was concluded that the cefpodoxime should be administered 3 to 6 h prior to surgery if used for perioperative prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

[NAAGA versus disodium cromoglycate in perennial allergic rhinopathy: results of a multicenter study]. / Naaga versus Dinatrium-Cromoglykat bei perennialer allergischer Rhinopathie: Ergebnisse einer Multizenterstudie.

The efficacy and tolerability of Naaga (the magnesium salt of N-acetyl-aspartyl-glutamate) and of sodium cromoglycate after intranasal application were tested and compared in 100 patients suffering from chronic allergic rhinitis. The study was conducted according to a randomized, double-blind design in four centers. The intensity and frequency of typical allergic symptoms such as nasal obstruction, sneezing, runny and itching nose, conjunctivitis, ocular itching and tear flow were recorded on a 4-point scale (absent, light, moderate and severe). The intensity of nasal and ocular symptoms was found to be marked for patients in two centers. For the patients in the other two centers the drugs' efficacy was difficult to assess because symptoms were not marked (rated either as absent or light) at the beginning of the study. Thus the assessment of efficacy was based on 60 patients (centers 1 and 2), while the assessment of tolerability was based on the whole patient sample (n = 100). There was no statistically significant difference between the two compounds in terms of efficacy. A total of five patients in each of both groups complained of moderate untoward effects (all patients from the same center).

[Effectiveness and tolerance of the C3 convertase inhibitor, N-acetyl-aspartyl-magnesium glutamate with anti-allergic action. Results of a double-blind study]. / Wirksamkeit und Verträglichkeit des C3-Konvertasehemmers N-Acetyl-Aspartyl-Magnesiumglutamat mit antiallergischer Wirkung. Ergebnisse einer doppelblinden Phase-II-Studie.

N-Acetyl-aspartyl magnesium glutamate (Rhinaaxia, NAAGA) is a topically active antiallergic dipeptide. The compound acts in two different ways. On the one hand NAAGA inhibits the mast cell-degranulation, on the other hand this compound blocks the activation of the C3-convertase, subsequently followed by a blocked cleavage of the fragments C3a and C5a, respectively. 20 patients suffering from pollinosis were treated for 2 weeks according to a randomized double-blind placebo-controlled study. Besides subjective complaints nasal obstruction was objectively documented via rhinomanometria. 9 out of 10 patients under placebo had to use the rescue drug tritoqualine, a histidine decarboxylase inhibitor, compared to none in the verum group (p less than 0.01). After 14 days of treatment with NAAGA the nasal peak flow rate increased by 21.5 l/min and 21.8 l/min in the tritoqualine/placebo group, respectively (not significant). Nasal obstruction improved statistically significantly after 7 and 14 days of treatment in both groups. Tolerance was reported to be good in either group.

[Effectiveness and tolerance of the C3 convertase inhibitor, N-acetyl-aspartyl-magnesium glutamate in perennial rhinitis. Results of a double-blind, placebo-controlled study]. / Wirksamkeit und Verträglichkeit des C3-Konvertasehemmers N-Acetyl-Aspartyl-Magnesiumglutamat bei perennialer Rhinitis. Ergebnis einer doppelblinden, Plazebo-kontrollierten Untersuchung.

N-Acetyl-aspartyl magnesium glutamate (Rhinaaxia, NAAGA) is a new antiallergic substance for topical use. The compound covers a bilateral way of action. There is inhibition of the mast cell-degranulation and blocking of the C3-convertase, subsequently followed by a blocked cleavage of the fragments C3a and C5a, respectively. 20 patients suffering from perennial allergic rhinitis were treated according to a randomized double blind placebo-controlled study design. Apart from a nominal documentation of subjective complaints the degree of nasal obstruction was objectively rated via rhinomanometria. The nasal flow rate improved significantly in patients treated with NAAGA and subjective complaints decreased markedly. NAAGA showed to be well tolerated although 6 of 10 patients observed transient "nasal burning".

The entire nucleotide sequence of the genome of human hepatitis A virus (isolate MBB).

Hepatitis A virus (HAV) is an important human pathogen causing hepatitis, with high incidence in developed as well as in developing countries. No vaccines are available. In order to determine the primary structure of the HAV genome, we have prepared cDNAs from viral RNA and cloned these into plasmid pBR322. These clones were used to determine the entire nucleotide sequence of the HAV RNA by rapid sequencing methods. We have compared this sequence of 7470 bases to known partial sequences, and one complete sequence of HAV RNA which were obtained recently from different strains of HAV. It is hoped that a comparison of sequence data from different isolates will help in the elucidation of the unusual growth pattern of HAV. In addition, it might provide helpful information about the immunological determinants that elicit the antibody response to infection.