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Aim:The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an opportunity to combat multidrug resistance. Methods:We investigated the activity of RBx 10080758 against Gram-positive bacteria in vitroand in vivo. Results:RBx 10080758 showed a potent 50% inhibitory concentration of 0.13 μM and 0.25 μM against gyrase B and topoisomerase IV, respectively, and exhibited strong whole-cell in vitroactivity with MIC ranges of 0.015–0.06 and 0.015–0.03 μg/ml against Staphylococcus aureusand Streptococcus pneumoniae, respectively. In a rat thigh infection model with methicillin-resistant S. aureus, RBx 10080758 at 45 mg/kg exhibited a >3 log10CFU reduction in thigh muscles. Conclusion:RBx 10080758 displayed potent activity against multiple multidrug-resistant Gram-positive bacteria with a dual-targeting mechanism of action.

Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the presence of isoniazid. Although isoniazid also degrades partially, its degradation is reversible. Objective: Presently, we provide a proof of the fact that the simultaneous oral administration of rifampicin (RIF), upon incorporation into solid lipid nanoparticles (RIF-SLNs), with isoniazid (INH) overcomes its INH-induced degradation and improves its oral bioavailability in rats. Methods: Solid lipid nanoparticles of RIF (RIF-SLNs) were prepared using a novel and patented method. The effect of INH was investigated on in vivo bioavailability of RIF both in its free and encapsulated (RIF-SLNs) form, after oral administration to rats. Results: Cmax and AUC0-∞ of RIF increased 158 % and 125 %, respectively, upon incorporation into SLNs versus free RIF when combined with INH. The Tmax decreased from 5.67 h to 3.3 h, and the plasma concentration of RIF remained above its MIC (8 μg/ml) at all the tested time points starting with 15 min, when administered as RIF-SLNs in combination with INH. Conclusion: The results confirm the scope of combining RIF-SLNs with INH to overcome the bioavailability of free RIF when combined with INH, especially in fixed dose combinations.

Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the presence of isoniazid. Although isoniazid also degrades partially, its degradation is reversible. Objective: Presently, we provide a proof of the fact that the simultaneous oral administration of rifampicin (RIF), upon incorporation into solid lipid nanoparticles (RIF-SLNs), with isoniazid (INH) overcomes its INH-induced degradation and improves its oral bioavailability in rats. Methods: Solid lipid nanoparticles of RIF (RIF-SLNs) were prepared using a novel and patented method. The effect of INH was investigated on in vivo bioavailability of RIF both in its free and encapsulated (RIF-SLNs) form, after oral administration to rats. Results: Cmax and AUC0-∞ of RIF increased 158 % and 125 %, respectively, upon incorporation into SLNs versus free RIF when combined with INH. The Tmax decreased from 5.67 h to 3.3 h, and the plasma concentration of RIF remained above its MIC (8 μg/ml) at all the tested time points starting with 15 min, when administered as RIF-SLNs in combination with INH. Conclusion: The results confirm the scope of combining RIF-SLNs with INH to overcome the bioavailability of free RIF when combined with INH, especially in fixed dose combinations.

ABSTRACTWe present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitroand in vivoactivities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitroactivity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivoefficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniaeATCC 6303 and systemic infection with S. pneumoniae3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniaeATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

ABSTRACTThe MIC90of RBx 14255, a novel ketolide, against Clostridium difficilewas 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An in vitrotime-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile. Furthermore, in the hamster model of C. difficileinfection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficiletreatment.

The paper deals with regional policies towards temporary labour migration (or the movement of natural persons) with specific reference to the liberalization of trade in services. The paper deals with policies towards labour migration, and progress in related Mode 4 negotiations within the GATS framework, among the Association of Southeast Asian Nations, or ASEAN. It finds that unilateral, national policies rather than regional or multilateral commitments dominate in policies towards temporary foreign workers. Despite advances on administrative issues, little progress has been made towards achieving ‘GATS-Plus’ outcomes, partly because of the lack of a strong political commitment among member countries to liberalizing the entry of foreign workers and partly because of real or imagined shortcomings in the ‘architecture’ for Mode 4 negotiations. Weak political will has led to relatively shallow commitments with a focus on skilled workers over unskilled migrants. With regard to architectural issues, we draw attention to the weaknesses of the ‘positive list’ approach in services trade negotiations, specifically with regard to the case of labour migration. However, the interpretation of the relationship between different modes of supply has also tended to inhibit regional negotiations for Mode 4. In particular, we point to the neglect of the potential importance of independent suppliers of services. It is concluded that the ASEAN countries need to place more emphasis on regional priorities and problems in seeking more open worker flows within the region.

Despite the discovery of many ions and molecules that activate the Ca2+receptor, there are no known ligands that block this receptor. Reported here are the pharmacodynamic properties of a small molecule, NPS 2143, which acts as an antagonist at the Ca2+receptor. This compound blocked (IC50of 43 nM) increases in cytoplasmic Ca2+concentrations [Ca2+]ielicited by activating the Ca2+receptor in HEK 293 cells expressing the human Ca2+receptor. NPS 2143, even when tested at much higher concentrations (3 μM), did not affect the activity of a number of other G protein-coupled receptors, including those most structurally homologous to the Ca2+receptor. NPS 2143 stimulated parathyroid hormone (PTH) secretion from bovine parathyroid cells (EC50of 41 nM) over a range of extracellular Ca2+concentrations and reversed the effects of the calcimimetic compound NPS R-467 on [Ca2+]iand on secretion of PTH. When infused intravenously in normal rats, NPS 2143 caused a rapid and large increase in plasma levels of PTH. Ca2+receptor antagonists are termed calcilytics and NPS 2143 is the first substance (either atomic or molecular) shown to possess such activity. The pharmacodynamic properties of NPS 2143 together with the recently demonstrated effects of this compound on bone formation support the view that orally active calcilytic compounds might provide a novel anabolic therapy for osteoporosis.

The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure–activity relationships of a peptide SK&F 107647 (1Figure 1Structure of SK&F 107647 (1).), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.

The synthesis of a 1,3,5-trisubstituted pyridinium salt combinatorial array containing two variable groups was accomplished in good yields. This entailed the incorporation of 5-bromonicotinic acid onto the resin, followed by Pd(0) catalyzed Suzuki coupling, then alkylation of the pyridine nitrogen and finally cleavage from the resin. A mix and split scheme was also carried out.

Tentoxin, a cyclic tetrapeptide, induces chlorosis in certain plant species. It inactivated photophosphorylation and coupling factor 1 (CF1) ATPase in lettuce, a sensitive species. This effect was due to binding of tentoxin with CF1at a single site (affinity constant 1.3 to 20 × 107M-1). Neither AMP nor adenyl-5′-yl imidodiphosphate appeared to bind to this site. In radish, an insensitive species, 20 times more tentoxin was required for 50% inhibition of photophosphorylation. In this species CF1ATPase was unaffected by tentoxin, and its CF1bound tentoxin only weakly (affinity constant less than 1 × 104M-1). Sensitivity of photophosphorylation to tentoxin was correlated with chlorosis sensitivity in six other species examined.

SK&F 107647, a novel synthetic dimetric pentapeptide, has been shown to be a potent hematoregulatory agent. The potential for the hematoregulatory factors elicited by SK&F 107647 to confer protection in experimental models of systemic Candida albicansinfection was evaluated in immunosuppressed and immunocompetent mice. Prophylactic treatment with recombinant human interleukin-1 (rhIL-1), recombinant human granulocyte colony stimulating factor (rhG-CSF), or the hematoregulatory peptide SK&F 107647 significantly increased survival times in γ irradiated immunosuppressed as well as non-irradiated immunocompetent mice challenged with a lethal dose of C. albicans. Protection was also observed in athymic nu/nu “nude” mice. Additionally, significant increases in survival in non-irradiated immunocompetent mice dosed by oral gavage were observed. These results indicate that SK&F 107647 can significantly enhance natural host resistance to experimental C. albicansinfections both in immunosuppressed and immunocompetent mice.)

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SK&F 107647,a novel synthetic low-molecular-weight peptide, has demonstrated potent antiinfective activities in murine models of fungal and viral infection. To determine if the hematoregulatory activities of SK&F 107647 could offer protection over conventional antibiotic therapy or as a single agent in animal models of bacterial sepsis, rats were implanted intraperitoneally with a live bacteria-containing fibrin-thrombin clot. Rats pretreated subcutaneously or orally with SK&F 107647 and then infected with either a gram-negative (Escherichia coli) or a gram-positive (Staphylococcus aureus) bacteria-containing clot demonstrated significantly improved survival over control formulation-treated animals. Treated animals showed increased effector cell activation, measured by CD11b expression on neutrophils and monocytes, and up to lO00-fold reduction in the number of E. coli recovered from blood. Thus, the hematoregulatory activities of SK&F 107647 can increase natural host resistance to infections caused by both gram-negative and gram-positive bacteria.

A simple, accurate, and specific liquid chromatographic procedure is described for the determination of gentamicin in 50 µL of serum. Gentamicin and sisomicin (IS) were converted into their trinitrophenyl derivatives by reaction with a water soluble derivatizing agent at 70°C for 30 minutes. The derivatives were extracted from the crude mixture with chloroform, which was separated, evaporated, and the residue reconstituted in acetonitrlle. Gentamicin was separated Into three major isomers (C1, C2, and C1) on a reversed-phase octyl column by eluting with a mobile phase. The eluted compounds were detected at 340 nm and quantified from their peak heights or peak areas. Chromatography was complete in ◂11.0 minutes. The lower limit of detection for gentamicin was ◂0.5 mg/L, analytical recoveries varied from 96.6% to 99.3%, linearity extended to 15.0 rag/L, and day-to-day precision was between 2.2% to 2.9%.