Effect of a barley breakfast cereal on blood glucose and insulin response in normal and diabetic patients.

Prowashonupana (Prowash) is a shrunken-endosperm, short awn, waxy starch, hulless barley with low starch, high fiber, high protein, and a relatively high concentration of free sugars. The study was designed to compare equivalent breakfast meals (w/w) of Prowash and oatmeal for glycemic response in diabetic and non-diabetic subjects. A commercial liquid meal replacer (LMR) was included as a reference standard. A substantial reduction of the post-prandial glycemic peak following ingestion of Prowash was observed as compared to LMR or oatmeal. In the non-diabetic subjects, the maximal rise in glucose from baseline was 26.3 +/- 3.9 mg/dL after LMR, 41.3 +/- 3.9 mg/dL after oatmeal and 6.4 +/- 2.7 mg/dL after Prowash (p < 0.01). The maximal increase in glucose in the diabetic patients was 69.9 +/- 4.5 mg/dL after LMR, 80.8 +/- 8.8 mg/dL after oatmeal and 28.4 +/- 3.5 mg/dL after Prowash (p < 0.01). The maximal increase in insulin post-LMR was 33.9 +/- 3.6 mIU/ml in the diabetic patients and 54.0 +/- 9.8 mIU/ml in the non-diabetic controls. Oatmeal elicited a maximal insulin increase of 29.9 +/- 4.2 mIU/ml in the control subjects and 21.4 +/- 2.5 mIU/ml in the diabetic patients. In contrast, the maximal insulin increase after Prowash was 8.6 +/- 1.5 mIU/ml in the non-diabetic controls and 6.8 +/- 1.2 mIU/ml in the diabetic patients (p < 0.01).

Membrane lipids and protein-bound carbohydrates status during the maturation of reticulocytes to erythrocytes in type 2 diabetics.

BACKGROUND: The reticulocyte maturation process is an ideal model for the study of biochemical alterations seen during final stage of erythropoiesis under disease conditions. In this study, determined whether type 2 diabetes has any effect on membrane lipids and protein-bound carbohydrates during the maturation of reticulocytes to erythrocytes. SUBJECTS AND METHODS: Lipids (cholesterol and phospholipids) and protein-bound carbohydrates (hexose, hexosamine and sialic acid) were extracted and estimated in plasma, membrane of reticulocytes and erythrocytes from 20 treated but uncontrolled type 2 diabetic volunteers and age matched controls. RESULTS: Plasma, membranes of reticulocytes and erythrocytes of diabetics showed increase in cholesterol (35.7%, 8.7% and 16.4%); phospholipids (43.4%, 18.8% and 8.2%); hexose (34.1%, 19.3% and 8.2%) and decrease in hexosamine (11.9%, 7.3% and 14.7%); and sialic acid (34.1%, 19.3% and 32.0%) compared to controls. As reticulocytes matured to erythrocytes, cholesterol, phospholipids, hexosamine and sialic acid levels were decreased; C/P ratio and hexose levels were increased in both controls and diabetics. However, these alterations were more intensified in diabetics. CONCLUSION: These alterations in diabetic patients may indicate the existence of one or both of the following conditions: acceleration of maturation processes and/or decreased red blood cell life span.

Clostridium difficile-associated diarrhoea in patients with community-acquired lower respiratory infection being treated with levofloxacin compared with beta-lactam-based therapy.

The aim of the study was to compare the incidence of Clostridium difficile-associated diarrhoea (CDAD) following treatment of community-acquired lower respiratory tract infection (LRTI) in hospitalized patients with levofloxacin or a beta-lactam-based therapy. Nine hundred and thirty-eight patients were included in the prospective open-labelled "randomized" trial. This included 490 patients treated with levofloxacin and 448 patients treated with beta-lactams such as cefuroxime or amoxicillin. The overall incidence of CDAD was 3.8%. There was a lower incidence of CDAD (P < 0.01) in the patients treated with levofloxacin (levofloxacin group) (11/490; 2.2%) compared with patients treated with beta-lactams (beta-lactam group) (25/448; 5.6%), particularly with cefuroxime (cefuroxime group) (21/229; 9.2%; P < 0.0001). There was no significant difference (P = 0.6) in the incidence of CDAD between patients treated with levofloxacin or amoxicillin (amoxicillin group) (4/219; 1.8%). Patients in the cefuroxime and amoxicillin groups had a significantly longer duration of treatment than patients in the levofloxacin group. Although previous antibiotic therapy was a significant risk factor for CDAD in each of the groups, previous antibiotic therapy or admission to specific wards in the hospital were not confounding factors when comparing the groups. The levofloxacin group had a significantly shorter duration of hospitalization (mean 11.7 days; P < 0.01) compared with the beta-lactam group (mean 13.3 days), especially compared with the cefuroxime group (mean 16 days; P < 0.0000001). The amoxicillin group (mean 10.5 days) had a shorter duration of stay compared with the levofloxacin group, but this was not found to be statistically significant. Patients with CDAD had a longer duration of hospital stay than those without CDAD (CDAD +ve 25.8 days; CDAD -ve 11.9 days; P < 0.0000001). In conclusion, levofloxacin is less likely to be the cause of CDAD and is associated with a shorter duration of hospital stay compared with beta-lactam-based therapy for LRTI.

PMT13, a pyrimidone analogue of thiazolidinedione improves insulin resistance-associated disorders in animal models of type 2 diabetes.

AIM: To evaluate the antidiabetic and hypolipidaemic potential of a novel thiazolidinedione, PMT13, in different animal models of insulin resistance. METHODS: PPAR transactivation study was performed in HEK293T cells using ligand binding domains of PPARalpha, gamma and delta. Insulin-resistant db/db and ob/ob mice were treated orally with different doses of PMT13 at 0.3-10 mg/kg/day for 15 and 14 days respectively. Zucker fa/fa rats were treated with 3 mg/kg (p.o.) dose of the compound. Plasma glucose, triglyceride, free fatty acid and insulin levels were measured. Liver glucose 6-phosphatase (G6-Ptase) and adipose lipoprotein lipase activity was measured in treated mice. Isolated rat aortic preparations preconstricted with phenylephrine were used to study the vascular relaxation potential of PMT13 in presence of insulin. A 28-day oral toxicity study was performed in Wistar rats. RESULTS: PMT13 showed similar PPARgamma activation as rosiglitazone, but failed to show any activity against PPARalpha or PPARdelta. In obese and diabetic db/db and ob/ob mice, PMT13 showed better reduction in plasma glucose, triglyceride and insulin levels than rosiglitazone and an improvement in glucose tolerance. In insulin-resistant Zucker fa/fa rat model, PMT13 treatment showed better reduction in plasma triglyceride, free fatty acid and insulin levels than that of rosiglitazone. Treated mice showed decreased G6-Ptase activity in liver. The LPL activity was increased in post-heparin plasma and epididymal fat of treated db/db mice. In an isolated, precontracted rat aortic preparation, PMT13 treatment significantly increased insulin-induced relaxation. A 28-day oral toxicity study in rats showed no treatment-related adverse effects. CONCLUSION: Our studies indicate that PMT13 is a potent activator of PPARgamma with antidiabetic, hypolipidaemic and insulin-sensitizing properties. Additionally, PMT13 inhibited liver G6-Ptase activity and increased lipoprotein lipase activity. It showed improvement in insulin-induced vasorelaxation. The compound also showed a good safety margin. Therefore, PMT13 can be a potential drug candidate for future development.

Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Euglycemic and hypolipidemic activity of PAT5A: a unique thiazolidinedione with weak peroxisome proliferator activated receptor gamma activity.

The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine analog of thiazolidinedione, have been evaluated in different animal models. Administration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of troglitazone and comparable to that of rosiglitazone. In addition, PAT5A showed better lipid-lowering activity than troglitazone or rosiglitazone. A similar profile was seen in ob/ob mice. In high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. An in vitro peroxisome proliferator activated receptor gamma (PPARgamma) transactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPARalpha- or PPARdelta-activating properties. Ex vivo study in db/db mice treated with PAT5A showed decreased activity of liver glucose 6-phosphatase, a key enzyme in gluconeogenesis. A 28-day probe toxicity study in Wistar rats did not show any treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas rosiglitazone treatment increased liver and heart weights. Our results indicate that PAT5A is a potent insulin sensitizer and hypolipidemic compound with a weak PPARgamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mechanisms not related to PPAR activation.

Establishment and characterization of a paclitaxel-resistant human non-small cell lung cancer cell line.

We have established a paclitaxel-resistant mutant cell line called H460/TAX which was derived from human non-small cell lung cancer (NSCLC) H460. A 64-fold greater resistant was shown in our assay as compared with the parental cells. High specificity of drug resistance was also observed since this mutant was not cross-resistant to several other anticancer drugs. Drug accumulation in H460/TAX was significantly less than that in H460. Many endogenous protein profiles were intact, including the expression level of P-glycoprotein, multidrug resistance-associated protein, the 70 kDa heat shock proteins as well as the phosphorylation of Bcl-2 in H460/TAX cells, except that the total amount of alpha- and beta- tubulins was higher in H460/TAX than in H460 cells. Higher drug concentration and longer treatment for paclitaxel were required in H460/TAX to exert the phosphorylation of keratin 19 which was then accompanied by reorganization of the intermediate filament and the microtubule networks. Since all of the aforementioned factors involved in paclitaxel-resistance in other systems were not found to be significantly altered in H460/TAX, there must be other paclitaxel-resistance mechanisms(s) which remains to be identified in human lung cancers.

Antinociceptive and anti-inflammatory activity of a flavonoid isolated from Caralluma attenuata.

Luteolin-4'-O-neohesperidoside, i.e. luteolin-4'-O-[alpha-(L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside)] has significant anti-inflammatory action. It is more potent than ibuprofen. Its antinociceptive activity is less pronounced when compared with its anti-inflammatory activity.

Synthesis and evaluation of [14C]-labelled and fluorescent-tagged paclitaxel derivatives as new biological probes.

Our present report deals with the preparation of hitherto unreported 7-([carbonyl-14C]-acetyl)paclitaxel 4 and two new bioactive 7-substituted fluorescent taxoids (FITC 9 and rhodamine 11), as well as evaluation towards their applications as biological probes. The results in this report demonstrate that (a) the new paclitaxel derivatives 4, 9, 11 could be prepared with good yields starting from paclitaxel; (b) the [14C]acetylation step was found to be better by using [14C]acetic anhydride rather than [14C]sodium acetate; (c) the radiochemical purity of 4 was 96% and its specific activity was 48 mCi/mmol; (d) the cytotoxicity of 4 was close to that of paclitaxel whereas 9, 11 were far less active than paclitaxel, but these cytotoxic levels were good enough for their biological applications; (e) the drug-quantitation by flow cytometric analysis using 9 and 11 was proved to be equally efficient with respect to the radioactivity-based determination employing 4; (f) the intracellular fluorescence mapping by 9 and 11 was found to be effective and the microtubule network pattern was visible in both the cases; (g) the overall fluorescence imaging efficiency was better with 11 while the intensity of fluorescence was higher with 9; (h) staining of nucleolus was observed in fluorescence studies of both 9 and 11. Based on these results, the newly prepared paclitaxel derivatives can be considered as efficient biological probes and should find further use in relevant applications.

Synthesis and biological activity of novel thiazolidinediones.

Novel compounds having a dual pharmacophore were synthesised and evaluated for their insulin sensitiser and anti-inflammatory properties in different animal models.

Prognosis in intra-abdominal sepsis.

Peritonitis is a common surgical problem with a high mortality rate. Recent advances have not brought down the mortality rate. Eighty six patients with intra-abdominal sepsis were studied for factors affecting prognosis. The factors which significantly affected prognosis were: duration of illness, source of infection and APACHE-II score. Further, among the factors contributing to APACHE II score, statistical analysis using logistic regression identified some factors which individually affect outcome. Our results indicate that mortality rate is high in patients with long duration of illness, postoperative peritonitis and organ system insufficiency.

IDPH-8261--a new nonsteroidal antiinflammatory agent.

IDPH-8261, methyl alpha-methyl-4-(3-thienyl)benzeneacetate, exhibited marked anti-inflammatory activity in acute, subacute and chronic models of inflammation. In rats, IDPH-8261 exhibited a dose related inhibition of carrageenin-induced rat paw edema and the inhibition was greater than ibuprofen, phenylbutazone, but was three times less than indomethacin. It exhibited anti-inflammatory activity in normal and adrenalectomized rats. It also exhibited the activity against various phlogistic agents. IDPH-8261 exhibited AI activity in subacute granuloma tests. In adjuvant-induced established polyarthritis. IDPH-8261 exhibited anti-arthritic effect at a very low dose (ED50 = 4 mg/kg, p.o.). Ulcerogenic liability was the lowest (UD50 = 180 mg/kg, p.o.), when compared to reference standard drugs. Low toxicity and high efficacy may make this compound a potentially useful therapeutic agent.

Immunotherapeutic modification by an ayurvedic formulation Septilin.

Effect of Septilin, an ayurvedic formulation proven to be effective in the therapy of chronic infections, was investigated on the phagocytic system and humoral response in rats and mice. Septilin exhibited significant protection in E. coli-induced abdominal sepsis in normal mice and in Staphylococcus aureus-induced sepsis in neutropenic mice. It significantly reduced the viable E. coli cells when incubated with neutrophils in rats. Septilin stimulated the phagocytic function of the reticuloendothelial system in mice. In normal rats, Septilin enhanced anti-SRBC hemagglutination antibody titre by 5.7-fold and showed significant protection in cyclophosphamide-induced humoral suppression.

Immunostimulatory activity of Picrorhiza kurroa leaf extract.

A 50% ethanolic extract of Picrorhiza kurroa Royle ex Benth. (Scrophulariaceae) leaves (PKLE) was found to stimulate the cell-mediated and humoral components of the immune system as well as phagocytosis in experimental animals. PKLE elicited a dose-related increase in SRBC, induced 4 h (early) and 24 h (delayed) hypersensitivity reactions in mice and rats, and horse serum induced Arthus reaction in guinea pigs. It also enhanced the humoral immune responses in mice and rats and phagocytic function of the cells of the reticuloendothelial system in mice. PKLE exhibited no mitogenic activity but augmented the responsiveness of murine splenocytes to T cell mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A) and B cell mitogen lipopolysaccharide (LPS E. coli).

Spectrophotometric determination of arsenic by molybdenum blue method in zinc-lead concentrates and related smelter products after chloroform extraction of iodide complex.

The most popular and widely applied method for determination of arsenic in ore concentrates is by spectrophotometry of arsenomolybdic acid reduced to molybdenum blue. While applying this method, several authors have developed procedures which varied in the decomposition, separation of arsenic and in the final colour development. Data regarding interference from germanium is inadequate. The present paper describes a procedure, which combines the best features of the previous procedures and is simple, less time consuming and interference-free compared to earlier procedures. This method has been applied to zinc-lead concentrates and related smelter products.

Biopharmaceutical evaluation of ibufenac, ibuprofen, and their hydroxyethoxy analogs in the rabbit eye.

Two new structural analogs, 2-(4-hydroxyethoxyphenyl)acetic acid [R3] and 2-(4-hydroxyethoxyphenyl)propionic acid [R4], along with their parent compounds, ibufenac and ibuprofen, were evaluated for their biopharmaceutical properties. The analogs represented substitution of the lipophilic isobutyl side chains of ibufenac and ibuprofen with hydrophilic hydroxyethoxy side chains. Anti-inflammatory activity was evaluated by administering drugs topically to inhibit inflammation induced by using either clove oil or arachidonic acid. The rank order of activity was ibufenac approximately equal to ibuprofen > R3 approximately equal to R4. The new compounds, R3 and R4, were highly water soluble (> 60-fold) and partitioned less (< 1/1500-fold) into the lipid phase when compared to ibufenac and ibuprofen. R3 and R4 each had apparent corneal permeability coefficients of 6 x 10(-6) cm/sec, whereas ibufenac and ibuprofen yielded values of about 22 x 10(-6) cm/sec. In an ocular pharmacokinetic study in the rabbit eye, constant concentrations of each compound were maintained on the cornea in a cylinder or well fixed to the cornea, resulting in a constant input rate. This method circumvented parallel loss routes at the absorption site including nasolacrimal drainage. From area calculations the dispositions of the compounds within the eye were described by mean residence times, steady state volumes of distributions, and clearance rates. R3 and R4 were more slowly absorbed, retained within eye tissues longer, and were cleared more slowly from the eye than ibufenac and ibuprofen. The aqueous humor concentration-time profiles were also computer-fitted to equations representing classical pharmacokinetic models. For ibufenac and ibuprofen, the entire cornea was assumed to be the net barrier for entry into the anterior chamber. Whereas, for R3 and R4, the corneal epithelium and endothelium were presumed to be the diffusional barriers into and out of the stroma, the latter treated as a compartment. Aqueous humor concentrations of each drug fit the models reasonable well and agreed with conclusions made from the use of area calculations. The drop volume method was used to measure the surface tension of each compound. Both ibufenac and ibuprofen were considerably more surface active than R3 or R4. The greater surface tension measured for ibufenac and ibuprofen correlated to the subjective observations of ocular discomfort for these drugs.

Rapid toxicological model for use in assessing ocular drugs.

Nonsteroidal antiinflammatory drugs (NSAIDs) were applied to corneas either by in vitro or in vivo methods. The in vitro method involved excising and mounting corneas in a perfusion system at 37 degrees and exposing drug for 2.5 h. The in vivo methods represent either topical administration to the rabbit eye or topical in vivo infusion using a fixed well which permitted a constant concentration (0.05 per cent) to be applied to the eye of anesthetized rabbits for up to 120 min. An overlay grid procedure using scanning electron microscopy (SEM) showed less per cent endothelial damage with in vivo methods than with the in vitro method of administration, but per cent damage depended on which section was viewed. Damage to the epithelium and endothelium were also assessed by quantitative carboxyfluorescein and Janus green staining and uptake procedures, respectively, following drug exposure by the in vivo infusion method. Results for the epithelium indicated that the more lipophilic NSAIDs damaged the epithelial layer to a greater degree than newly synthesized hydrophilic NSAIDs. Damage to the epithelium correlated to the surface activity of the NSAIDs. Qualitative assessment of epithelial and endothelial toxicity can be performed with SEM and transmission electron microscopy (TEM) while vital staining procedures and the SEM grid procedure can be used to quantitatively assess corneal toxicity. The staining methods, however, possess advantages over SEM and TEM procedures in that they are rapid and do not require laborious preparation. As a result of these characteristics, the vital staining procedures could be used as part of a biopharmaceutical screening technique in evaluating new ophthalmic drugs.

Macromolecular properties that promote mesangial binding and mesangiopathic nephritis.

The hydrodynamic size, electrostatic charge, and specificity are established determinants of the site of glomerular localization of macromolecules. Larger macromolecules or aggregates and anionic charge are associated with mesangial deposits, despite the fact that the mesangial matrix bears a negative charge similar to that of the capillary wall. Antigens such as Sendai virus, a model infectious pathogen, gliadin, a model dietary/environmental agent and fibronectin, a model endogenous macromolecule, bind to mesangial cells in vitro on the basis of cell surface glycoconjugates. Nonantibody immunoglobulin A, which does not bind to cells directly, binds to these elements via different carbohydrate specificities (simple sugar inhibition). Such binding promotes or augments macromolecular deposition in the mesangium. More significantly, mesangial deposits per se are not pathogenic, because normal renal function can be observed with florid deposits. Pathogenic deposits must have properties that alter mesangial cell metabolism or interaction with the matrix. Although complement activation is well recognized, complement-independent mechanisms related to cell surface modulation are being recognized. In vitro, antigen/immunoglobulin A aggregates alter mesangial cell eicosanoid synthesis. In vivo, large-lattice cross-linking by particulate antigen promotes hematuria. We conclude that the binding of macromolecules to cells and the cross-linking of cell surface molecules cause alterations in the mesangial cells and therefore in glomerular function. The mesangial cell, rather than a passive respondent, is an active participant in the genesis of glomerulonephritis.