The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease

We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. In conclusion: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in cushing's syndrome

We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome,n=2; Cushing's disease,n=3; bilateral adrenal adenoma,n=1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n=5) or 0.3 mg/kg/h (n=3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 µg 1–24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4±13.3 to 21.1±5.7 µg/dl after 7 h (P<0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3±5.7 µg/dl (P<0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose non-hypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome. The possibility to dissociate the adrenostatic effect of etomidate from its hypnotic action, the absence of side effects, and the i.v. route suggest that etomidate in a dose of 0.04–0.05 mg/kg/h may become the drug of choice for rapid initial control of hypercortisolism

Membrane potential stabilizes the O intermediate in liposomes containing bacteriorhodopsin

AbstractIn the bacteriorhodopsin-containing proteoliposomes, a laser flash is found to induce formation of a bathointermediate decaying in several seconds, the difference spectrum being similar to the purple–blue transition. Different pH buffers do not affect the intermediate, whereas an uncoupler, gramicidin A, and lipophilic ions accelerate decay of the intermediate or inhibit its formation. In the liposomes containing E204Q bacteriorhodopsin mutant, formation of the intermediate is suppressed. In the wild-type bacteriorhodopsin liposomes, the bathointermediate formation is pH-independent within the pH 5–7 range. The efficiency of the long-lived O intermediate formation increases at a low pH. In the wild-type as well as in the E204Q mutant purple membrane, the O intermediate decay is slowed down at slightly higher pH values than that of the purple–blue transition. It is suggested that the membrane potential affects the equilibrium between the bacteriorhodopsin ground state (Glu-204 is protonated and Asp-85 is deprotonated) and the O intermediate (Asp-85 is protonated and Glu-204 is deprotonated), stabilizing the latter by changing the relative affinity of Asp-85 and Glu-204 to H+. At a low pH, protonation of a proton-releasing group (possibly Glu-194) in the bacteriorhodopsin ground state seems to prevent deprotonation of the Glu-204 during the photocycle. Thus, all protonatable residues of the outward proton pathway should be protonated in the O intermediate. Under such conditions, membrane potential stabilization of the O intermediate in the liposomes can be attributed to the direct effect of the potential on the pK value of Asp-85

Adrenostatische Therapie mit Metyrapon und Aminoglutethimid beim ACTH-abhängigen Cushing-Syndrom

Bei zehn Patienten mit ACTH-abhängigem Cushing-Syndrom, vier mit ektopem Cushing-Syndrom und sechs mit M. Cushing, wurde retrospektiv die Wirksamkeit einer adrenostatischen Therapie mit Metyrapon (Metopiron®) und Aminoglutethimid (Orimeten®) untersucht. Unter Metyrapon allein (n = 5) sowie in Kombination mit Aminoglutethimid (n = 5) kam es bei allen Patienten zu einer dauerhaften Senkung der Serum-Cortisol-Konzentration. Die Beobachtungszeit betrug 2 Wochen bis 4 Jahre. Der angestrebte therapeutische Bereich von < 16 µg/dl wurde bei sieben Patienten erreicht. Im Verlauf der Therapie wurde ein Anstieg der mittleren Plasma-ACTH-Konzentration beobachtet; dabei kam es nicht zu einem »Escape« der Cortisol-Konzentration. Eine Einschränkung erfuhr die adrenostatische Therapie allein durch die Nebenwirkungen, die bei zwei Patienten zu einer Beendigung der Therapie führten. Folgerung: Die adrenostatische Therapie mit Metyrapon und Aminoglutethimid ist wirksam und praktikabel. Sie eignet sich nicht nur zur akuten Behandlung des floriden Cushing-Syndroms, sondern auch zur Langzeittherapie, wenn eine kurative Therapie nicht möglich ist.The adrenostatic effect of metyrapone (Metopiron®) and aminoglutethimide (Orimeten®) was assessed retrospectively in ten patients with ACTH-dependent Cushing's syndrome, four of them with the ectopic form. Five patients received metyrapone only, the other five both metyrapone and aminoglutethimide. Persistent lowering of the serum cortisol level was achieved in all, after an observation period of two weeks to four years. The intended therapeutic level of below 16 µg/100 ml was achieved in seven patients. In the course of treatment there was a rise in mean plasma ACTH concentration, but without an »escape« phenomenon. The adrenostatic treatment had to be limited, if at all, only because of side effects, which in two patients required that the drug administration be terminated. It is concluded that adrenostatic treatment with metyrapone and aminoglutethimide is effective and practical. It is suitable not only in the management of florid Cushing's syndrome, but also for long-term treatment when complete cure is not possible

Diagnostik und Therapie asymptomatischer Nebennierentumoren

Bei 23 Frauen und neun Männern im mittleren Alter von 54 (25-73) Jahren wurde bei der Klärung anderer Beschwerden zufällig ein asymptomatischer Nebennierentumor entdeckt. In allen Fällen ließen sich die Tumoren computertomographisch darstellen. Achtmal waren sie beidseits lokalisiert, in je 12 Fällen rechts- oder linksseitig. Der durchschnittliche Tumordurchmesser betrug 3 (1-9) cm. Vier Tumoren (12,5 %) wiesen eine endokrine Aktivität auf (ein Phäochromozytom, drei cortisolproduzierende Tumoren). Acht Patienten wurden adrenalektomiert, dabei ergaben sich sechs Nebennierenadenome, ein benignes Phäochromozytom und ein Ganglioneurom. Eine Feinnadelbiopsie wurde bei zwei Patienten vorgenommen, der zytologische Befund war benigne. Computertomographische Verlaufskontrollen bei elf (34,4 %) der nicht-operierten Patienten 6-48 Monate (im Mittel 14 Monate) später zeigten bei keinem der Patienten eine Größenzunahme des Tumors. Daher erscheint es bei zufällig diagnostizierten Nebennierentumoren gerechtfertigt, zunächst einmal den Verlauf zu beobachten, da gutartige Prozesse offensichtlich weitaus häufiger sind als maligne. Bei einem Tumordurchmesser von mehr als 6 cm ist jedoch wegen des Malignitätsrisikos eine Adrenalektomie durchzuführen

Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial

PURPOSE: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. EXPERIMENTAL DESIGN: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival.RESULTS: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.CONCLUSIONS: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.</p