On pharmaceutical risk minimization.

Current regulatory guidelines related to pharmaceutical risk minimization put most emphasis on risk communication and control of the use of drugs. Little, if any, consideration is given to those aspects of an adverse drug reaction that ultimately determine whether the risk can be minimized. However, this limited scope is unfortunate and could prevent risk minimization activities from improving drug use safety. This article attempts to present an overview of possible elements of pharmaceutical risk minimization and to place these in a framework. The promotion of drug safety through risk communication and control of use should be advanced, with more attention to actionable and evidence-based guidance relating to the 'pretreatment evaluation', and in particular the 'on-treatment management' of the patient.     

Der Einfluß von Schilddrüse und Hypophysis auf die Chlorverteilung

Zusammenfassung Vom intravenös bei Hunden eingespritzten Kochsalz findet sich bei normalen Tieren nach 5 Stunden ein bedeutender Teil in der Haut, während die Muskeln chlorarmer geworden sind.Unter Einfluß von Hypophysenhinterlappenextrakt findet eine relative Verschiebung von der Haut nach den Muskeln statt.Unter Einfluß von Thyroxin findet eine gleichsinnige Verschiebung statt.     

Increasing rate of lymph node invasion in patients with prostate cancer treated with radical prostatectomy and lymph node dissection

Objectives

To investigate lymph node invasion (LNI) rates in prostate cancer (PCa) patients. Recent studies demonstrated an inverse stage migration in PCa patients toward more advanced and unfavorable diseases. We hypothesized that this trend is also evident in LNI rates, in PCa patients treated with radical prostatectomy (RP) and pelvic lymph node dissection (PLND).

Sonographische Funktionsbeurteilung von H?modialysefisteln

Zusammenfassung Hintergrund und Ziel:   Für die Hämodialyse und verwandte Verfahren wird ein stabiler Gefäßzugang benötigt, wobei die Brescia-Cimino-Fistel am nicht dominierenden Unterarm die beste Form darstellt. Die apparative Diagnostik von Fisteldysfunktionen erfolgt heute in erster Linie mit der farbkodierten Duplexsonographie. Der Wert der dopplersonographischen Widerstandsindex-( RI-)Messung am zuführenden Gefäß für die Vorhersage des Stromzeitvolumens der Fistel sollte beurteilt werden. Patienten und Methodik:   Bei 47 Patienten mit Dialysefisteln wurden morphologische und funktionelle Untersuchungen des Fistelarms einschließlich Stromzeitvolumenbestimmung mittels farbkodierter Duplexsonographie durchgeführt. Es erfolgten RI-Messungen proximal und distal der Fistel sowie am kontralateralen Arm an den gleichen Ableitorten mit Hilfe der bidirektionalen CW-Doppler-Sonographie. Die systolischen Fingerarteriendrücke am zweiten und dritten Finger beider Hände wurden dopplersonographisch ermittelt. Es wurden Untersuchungen zur Feststellung eines Zusammenhangs zwischen dem proximalen RI und dem Stromzeitvolumen durchgeführt. Ergebnisse:   Am Fistelarm lagen proximal und distal niedrigere RI-Werte vor als am kontralateralen Arm. Die systolischen Fingerarteriendrücke waren am Fistelarm niedriger. Die Stromzeitvolumina waren bei Oberarmfisteln höher als bei Unterarmfisteln, bedingt durch die größeren Gefäßdurchmesser. Eine lineare Korrelation zwischen dem proximalen RI und dem Stromzeitvolumen der Fistel ließ sich nicht belegen. 50% der Unterarmfisteln mit einem proximalen RI 0,53 wiesen ein Stromzeitvolumen < 400 ml/min auf. Schlussfolgerung:   Die Bestimmung des RI an der fistelspeisenden Arterie bei Unterarmfisteln eignet sich zur Identifizierung von Unterarmfisteln mit für eine effektive Hämodialyse zu geringen Stromzeitvolumina. In diesen Fällen ist eine weitere Untersuchung der betreffenden Fisteln indiziert. Viele Einflüsse, vor allem auf die Bestimmung der Stromzeitvolumina, sind zu beachten. Empfehlenswert sind intraindividuelle Längsschnittuntersuchungen mit der CW-Doppler-Sonographie zur Evaluation der Dynamik der Dialysefisteln, um bessere Möglichkeiten für die Überwachung der funktionstüchtigen Fisteln zur Verfügung zu haben.     

Enriched Flavonoid Fraction from <Emphasis Type="Italic">Cecropia pachystachya</Emphasis> Trécul Leaves Exerts Antidepressant-like Behavior and Protects Brain Against Oxidative Stress in Rats Subjected to Chronic Mild Stress

The purpose of this study was to assess the effect of an enriched C-glycosyl flavonoids fraction (EFF-Cp) from Cecropia Pachystachya leaves on behavior, mitochondrial chain function, and oxidative balance in the brain of rats subjected to chronic mild stress. Male Wistar rats were divided into experimental groups (saline/no stress, saline/stress, EFF-Cp/no stress, and EFF-Cp/stress). ECM groups were submitted to stress for 40 days. On the 35th ECM day, EFF-Cp (50 mg/kg) or saline was administrated and the treatments lasted until the 42nd day. On the 41st and 42nd days, the animals were submitted to the splash test and the forced swim test. After these behavioral tests, the enzymatic activity of mitochondrial chain complexes and oxidative stress were analyzed. EFF-Cp reversed the depressive-like behavior induced by ECM. It also reversed the increase in thiobarbituric acid reactive species, myeloperoxidase activity, and nitrite/nitrate concentrations in some brain regions. The reduced activities of the antioxidants superoxide dismutase and catalase in some brain regions were also reversed by EFF-Cp. The most pronounced effect of EFF-Cp on mitochondrial complexes was an increase in complex IV activity in all studied regions. Thus, it is can be concluded that EFF-Cp exerts an antidepressant-like effect and that oxidative balance may be an important physiological process underlying these effects.     

Glutathione synthetase deficient human fibroblasts in culture

Cultured skin fibroblasts from patients with 5-oxoprolinuria caused by hereditary deficiency of glutathione synthetase have decreased levels of the corresponding enzyme as well as of glutathione. Fibroblasts from the same patients accumulated gamma-glutamyl cysteine, but the levels were lower than those of glutathione in control fibroblasts. The uptake of [35S]cystine was equally rapid in control and patient fibroblasts. In the acid-soluble fraction gamma-glutamyl-[35S]cysteine accumulated in fibroblasts from patients but not from controls. Appreciable turnover of gamma-glutamyl cysteine and glutathione in the respective cell strains was observed, the half-lives of these pools being approximately 5 hours. The growth rate of mutant fibroblasts in culture was significantly slower than that of control fibroblasts. There was no significant accumulation of 5-oxoproline in the culture medium.     

Urine measurement indicates the plasma brain natriuretic peptide concentration during optimization of heart failure treatment

Aim: To assess the correlation between the amino-terminal pro-hormone brain natriuretic peptide (NT-proBNP) concentration in blood and urine during a period when actively adjusting the treatment of heart failure (HF). Methods: Plasma and urine analyses of NT-proBNP were compared in 51 patients on admission to and discharge from a nurse-led outpatient clinic where HF treatment was optimized. The median time between the two measurements was 42 days. Correlations were analyzed using linear regression, where R² is the degree of variability in the plasma NT-proBNP concentration that can be accounted for by the urinary NT-proBNP. Results: There was a statistically significant linear relationship between the urine and plasma concentrations of NT-proBNP on both occasions, but R² varied greatly depending on how the data were presented. The correlation between the raw data showed an R² of only 30%, and it almost doubled upon logarithm transformation, which shows that the variability (error) was concentration-dependent. Correction of the urinary NT-proBNP for urinary creatinine further increased R² for the logarithm-transformed correlation to 68% on admission and 76% on discharge. The highest R² (77%) was obtained when the relative changes in urinary NT-proBNP/creatinine between admission and discharge were compared with the corresponding relative changes in the plasma concentration. The sensitivity and specificity of the urine in indicating plasma concentration changes?>?10% were 82% and 86%, respectively. Conclusion: Relative changes in plasma NT-proBNP could be reliably estimated from urine samples during a period of optimization of HF treatment.     

Adverse events and problems in therapeutic hemapheresis. A report from the Swedish registry.

BACKGROUND: Since 1996 adverse events (AE) in therapeutic apheresis (TA) have been more extensively registered in Sweden. This report analyzes the extent and relation of AEs to procedures and diagnoses. MATERIALS AND METHODS: Reporting of TA performed in Sweden was centralized. A separate system for the registration of AE in TA was established and the data received were entered into a central database for registration and analyses. Fifteen of all 35 apheresis units reported both TA and AE during 1996-1999. These centers performed 75% of all TA procedures. Adverse events included medical symptoms, vascular access problems, technical and other problems. RESULTS: More than 14,000 procedures were registered during the observation period. No fatalities occurred. AEs occurred in 3.7% (1996), 4.6% (1997), 4.2% (1998) and 4.4% (1999) of procedures. Interventions during the adverse event were performed in about 65% of the events. Apheresis procedures were interrupted due to an adverse event in about 1%. Adverse events occurred in 5.6% of plasma exchanges, 1.9% of plasma modulations and 6.8% of cytapheresis procedures. Paresthesia was registered in 22% and hypotensive events in 20.5%. Other more frequent symptoms were urticaria (14.4%), shivering (7.4%) and nausea (7.4%). AEs were most frequent in patients with Goodpasture's syndrome (12.5%), TTP/HUS (10.5%) and GuillainBarré syndrome (11.0%). CONCLUSION: AEs are few, often mild and less common in plasma modulation than plasma exchange. AEs are more frequent during TA of patients with certain diagnoses such as TTP/HUS.     

Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats

Several studies have supported the idea that ionotropic glutamate N-methyl-d-aspartate receptor (NMDA) is an important player in the etiology of psychopathologies, such as anxiety disorders and major depression. Additionally, studies have shown that ketamine induces antidepressant effects in humans as well as in rodents subjected to animal models of depression. In this context, the present study was aimed to evaluate behavioral and physiological effects of acute and chronic administration of ketamine, a NMDA receptor antagonist, in rats exposed to chronic mild stress (CMS). After 40 days of CMS, rats were treated with ketamine (15 mg/kg) and sweet food consumption, body and adrenal gland weight, corticosterone and adrenocorticotropic (ACTH) hormone levels, and hippocampal BDNF protein levels were assessed. Our findings demonstrated that CMS evoked anhedonia, induced hypertrophy of adrenal gland, impaired gain of body weight and increased corticosterone and ACTH circulating levels in rats. Acute and chronic treatment with ketamine reversed the increase in adrenal gland weight, promoted regain of body weight, and normalized corticosterone and ACTH circulating levels. Repeated, but not acute, administration of ketamine reversed anhedonia-like behavior, although the treatment with ketamine per se increased sweet food consumption in non-stressed rats. Finally, acute and chronic ketamine treatment did not alter hippocampal BDNF protein levels in stressed rats. In conclusion, these findings support the idea of a putative role of NMDA receptors in mood-related symptoms, and rapid and robust effects of ketamine in reverting mainly physiological alterations induced by chronic mild stressful situations in rats.