Prediction of the Hiestand bonding indices of binary powder mixtures from single-component bonding indices

A priori predictions of the bonding indices of binary powder mixtures from the single-component indices were attempted. The binary mixtures were classified according to the mechanism of deformation of the single-components as plastic-plastic, brittle-brittle, and plastic-brittle. When the components of a binary mixture consolidated by the same mechanism (plastic-plastic and brittle-brittle mixtures), a straight line could be fit to a plot of bonding index versus composition. This linearity indicates that the bonding index can be reliably estimated by interpolation between the two single-component bonding indices. When the mixtures were such that one component was brittle while the other was plastic, a linear function did not fit the data. For these cases, a second-degree polynomial equation could be fit to a plot of bonding index versus composition. A combination of multiple linear regression and trial and error was used to generate a single generalized equation. For pairs of compounds wherein each compound has a different compaction mechanism, this new equation appears to allow satisfactory predictions of the bonding indices of mixtures with varying compositions using only the single-component bonding indices.     

Pharmacodynamics of insulin in polyethylene glycol-coated liposomes

To reduce the injection frequency and toxicity of intravenously administered protein drugs, it is necessary to develop safe and sustained injectable delivery systems. In this study, to evaluate liposomes as safe and sustained injectable delivery systems of proteins, we chose insulin as a model protein drug and tested its incorporation efficiency and pharmacodynamics in various liposomes with and without polyethylene glycol (PEG)-derivatized phospholipid. The liposomes coated with PEG showed 3-fold higher efficiency of insulin incorporation than did the liposomes without PEG. Moreover, among the liposomes coated with PEG, dipalmitoylphosphocholine (DPPC) liposomes showed higher incorporation efficiency than did dimyristoylphosphocholine (DMPC) liposomes. For pharmacodynamic study, insulin (2 IU/kg) was administered in various formulations, such as insulin alone in phosphate-buffered saline and insulin in the DPPC liposomes with and without PEG, to streptozotocin-treated diabetic rats. The pharmacodynamics of insulin alone, however, could not be measured due to the immediate death of rats caused by hypoglycemic shock. In contrast, all the rats treated with liposomal insulin survived, probably by the sustained release of insulin from liposomes. Pharmacodynamics of liposomal insulin showed that PEG-coated liposomes induced the lowest level of blood glucose-the nadir-1 h later than did the liposomes without PEG. These results indicate that PEG-coated liposomes could be developed as a relatively safe and sustained injectable delivery system for insulin with improved incorporation efficiency. Moreover, it is suggested that the liposomes coated with PEG might have a potential as safe injectable delivery systems for other protein and peptide drugs.     

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.     

Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers

Chromosome 8p21-22 is a frequent site of allelic deletions in many types of human tumors, including non-small cell lung cancer (NSCLC). Tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) is a cell-surface receptor involved in cell death signaling. The TRAIL-R2 gene recently has been mapped to chromosome 8p21-22. To explore the possibility that the TRAIL-R2 gene might be the relevant gene to the frequent deletion of 8p21-22 in NSCLC, we have analyzed the entire coding region and all splice sites of TRAIL-R2 for the detection of the somatic mutations in a series of 104 NSCLCs. Overall, 11 tumors (10.6%) were found to have TRAIL-R2 gene mutations in the death domain known to be involved in the transduction of an apoptotic signal. Our data indicate that somatic mutation of TRAIL-R2 may play a role in the pathogenesis of some NSCLCs and that the TRAIL-R2 gene is one of the genes relevant to the frequent loss of chromosome 8p21-22 in NSCLC.     

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.