Massarinolins A-C: new bioactive sesquiterpenoids from the aquatic fungus massarina tunicata

Massarinolins A-C (1-3), three new bioactive sesquiterpenoids possessing rare ring systems, have been isolated from liquid cultures of the aquatic fungus Massarina tunicata Shearer & Fallah. The structures were determined primarily by analysis of NMR data. Metabolites 1-3 are the first compounds to be reported from any member of the genus Massarina.     

Phase II Study of Intravenous Doxil® in Malignant Pleural Mesothelioma

Twenty-four patients with pleural mesotheliomareceived 50 mg/m² of Doxil® every four weeks.At follow-up, the disease had stabilized in 43% percent ofpatients and had progressed in 57%. No objective responses wereobserved. Estimated median survival of all patients was 37 weeks.Major toxicities were erythrodysesthesia of hands and feet andmyelosuppression. No cardiac toxicity was observed. We concludedthat Doxil® at this dosage and schedule is inactiveagainst pleural mesothelioma.     

Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5 ,6,5',6'dimethylenedioxybiphenyl-2-carboxylic acid-2'-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure

The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybip henyl-2-carboxylic acid-2'-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-induced acute hepatic failure. To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl4-intoxicated group. DDB-S 50 mg kg(-1) was administered by intravenous bolus injection to both groups of rats. In the CCl4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6-46 vs 3.34 mg min mL(-1)), and the total body (7.74 vs 15.0 mL min(-1) kg(-1)), renal (2.55 vs 5.10 mL min(-1) kg(-1)), nonrenal (5.07 vs 9.65 mL min(-1) kg(-1)), and biliary (1.48 vs 2.69 mL min(-1) kg(-1)) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl4. To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl4-intoxicated rats with or without DDB-S pretreatment (50 mg kg(-1) i.p.). The effects of DDB-S pretreatment on CCl4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicated-only group. In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl4 and various concentrations of DDB-S (10 or 100 microg mL(-1)). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl4-intoxication only. These results indicate that DDB-S has hepatoprotective activity.     

Effect of postnatal age and clinical status of newborn infants on bilirubin-binding capacity

Serial determinations of bilirubin-binding capacity were performed in 61 newborn infants during the first 10 days of life. 27 infants were classified as term (gestational age greater than or equal to 36 weeks) and 34 as preterm (gestational age less than or equal to 33 weeks); 34 were classified as 'sick' and 27 as 'well'. Bilirubin-binding capacity was measured by Sephadex gel filtration. In relation to postnatal age, total bilirubin-binding capacity (TBBC) remained stable in well term and preterm infants, decreased slightly in sick preterm infants, and decreased significantly in sick term infants. TBBC, serum albumin, and molr binding ratio (B/A) were significantly higher in well than in sick infants in both term and preterm groups; there were no significant differences between sick term and sick preterm infants. Clinical recovery in 16 infants was associated with a significant rise in TBBC and in B/A. The data suggest that in healthy infants, the serum bilirubin-binding capacity remains relatively unchanged during the first 10 days of life. Clinically ill infants show wide patient-to-patient variability in TBBC. Because of the tendency of TBBC to decrease with postnatal age in sick infants, repeated determinations of TBBC may be indicated for the management of sick jaudiced newborns.     

Anatomic confirmation of echocardiographic measurements in neonatal hearts.

Significant correlations were demonstrated between echocardiographic measurements of left ventricular wall thickness, right ventricular wall thickness, septal thickness, left ventricular mass, aortic valve excursion, pulmonary valve excursion, mitral valve excursion, and tricuspid valve excursion and the same measurements made directly on the same hearts at autopsy. A new regression formula was derived for the calculation of echocardiographic right ventricular mass in life and was found to correlate significantly with right ventricular mass measured as the sum of right ventricular wall and septal volumes at postmortem examination.     

Autoregulation of brain blood flow in the newborn piglet: regional differences in flow reduction during hypotension

The potential use of a piglet as a model for investigation of brain blood flow was evaluated by assessing the presence of autoregulation in 11 spontaneously breathing newborn piglets. Blood pressure was altered by phlebotomy. When the mean arterial blood pressure was greater than 50 mm Hg, no significant change in brain blood flow (microsphere technique) occurred (r = 0.04), indicating the presence of autoregulation. When the animals became hypotensive a pressure passive relationship exists between brain blood flow and mean arterial blood pressure. However, since the piglets breathed spontaneously and hyperventilated during hypotension, both the mean arterial blood pressure and PaCO2 fell and both correlated with brain blood flow. Thus, it cannot be determined which factor is responsible for the reduction in flow. The blood flow to the specific regions of the brain (cerebrum, cerebellum, brainstem) and mean arterial blood pressure also showed no correlation when the latter was greater than 50 mm Hg. During hypotension, each region demonstrates pressure passive relationships, but the reduction in blood flow is most pronounced in the cerebrum, less in the cerebellum, and least in the brainstem (mean +/- S.E., 64 +/- 8%, 41 +/- 13%, 32 +/- 13% reductions from control respectively, P less than 0.05). The study indicates that a newborn piglet may serve as an appropriate model for the study of brain hemodynamics particularly with regard to autoregulation. Furthermore, during hypotension, preferential protection of vital regions of the brain (cerebellum and brainstem) occur which may have important implications in interpreting the effect of hypotension on the newborn central nervous system.     

Peginterferon alpha and ribavirin combination therapy in patients with hepatitis C virus-related liver cirrhosis

Background/Aims

Pegylated interferon (peginterferon) and ribavirin combination therapy is less effective and associated with a higher frequency of serious complications in chronic hepatitis C patients with cirrhosis than in noncirrhotic patients. This study evaluated the efficacy and tolerability of peginterferon and ribavirin treatment in patients with hepatitis C virus (HCV)-related cirrhosis.

Methods

Eighty-six patients with clinically diagnosed liver cirrhosis were treated with either peginterferon alpha-2a (n=51) or peginterferon alpha-2b (n=35) plus ribavirin. The sustained virologic response (SVR) and adverse effects were analyzed retrospectively.

Results

Of the 86 patients (55 males), 48 patients (55.8%) had HCV genotype 1 infection and 38 (44.2%) had genotype non-1 infection. The overall SVR rate was 34.9% (30/86), and the rates of SVR in the genotype 1 and non-1 patients were 20.8% (10/48) and 52.6% (20/38), respectively. The multivariate analysis revealed that having HCV genotype 1 (P=0.003) and high baseline viral load (>8.0×10⁵ IU/mL, P=0.012) were the independent predictive factors for SVR failure. In 20.9% (18/86) of the patients, treatment was not completed due to adverse events (27.8%), loss to follow-up (50.0%), and other reasons (22.2%).

Conclusions

Peginterferon and ribavirin combination therapy was relatively effective and feasible for clinically diagnosed HCV patients, especially in those with genotype non-1 infection and low baseline viral load.     

Is the GABA System Related to the Social Competence Improvement Effect of Aripiprazole? An 18F-Fluoroflumazenil PET Study

Objective

Patients with schizophrenia who are treated with aripiprazole experience some benefits including an improvement of social competence, but the underlying mechanism of this improvement has not been investigated yet. This study aimed to provide preliminary evidence that the GABA system may be involved in the effect of aripiprazole on social competence.

Methods

Seventeen outpatients with schizophrenia (9 taking aripiprazole and 8 taking risperidone) and 18 healthy controls underwent ¹⁸F-fluoroflumazenil PET, and GABA_A receptor binding potential was compared between the three groups.

Results

Voxelwise one-way ANOVA showed that GABA_A receptor binding potentials in the right medial prefrontal cortex (p=0.04) and right dorsolateral prefrontal cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone group, and those in the left frontopolar cortex (p=0.03) and right premotor cortex (p=0.02) were significantly lower in the aripiprazole group than the risperidone and control groups.

Conclusion

Our results suggest that aripiprazole administration results in increased GABA transmission in the prefrontal regions, and that these increases may be a neural basis of aripiprazole''s clinical benefits on an improvement of social competence.