Muraminomicins, novel ester derivatives: in vitro and in vivo antistaphylococcal activity.

Novel muraminomicin derivatives with antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) were synthesized by esterification of the hydroxy group on the diazepanone ring of muraminomicin Z1. Compound 1b (DS14450354) possessed a diheptoxybenzyl-ß-Alanyl-ß-Alanyl group and exhibited minimum inhibitory concentrations (MICs) against MRSA comparable to those against methicillin-susceptible S. aureus (MSSA). The MICs that inhibited 50 and 90% of the strains were 1 and 2 µg/mL, respectively. Compound 1a (DS60182922) possessed an aminoethylbenzoyldodecylglycyl moiety and showed bactericidal activity against MSSA Smith. The bactericidal activity of 1a against MRSA 10925 was comparatively lower, whilst 1b exhibited dose-dependent bactericidal activity against MRSA 10925. The mutation frequency of 1b was lower than that of 1a. An amino acid substitution (F226I) was observed in MraY mutants isolated from culture plates containing 1a or 1b. Subcutaneous 1a and 1b administration showed good therapeutic efficacy in murine systemic infection models with MSSA Smith and MRSA 10925, comparable to that of vancomycin, suggesting that the novel muraminomicin derivatives may be effective therapeutic agents against MRSA that warrant further investigation. A scheme for the formulation of the key ester intermediate, requiring no HPLC preparation, was also established.

Research on the Effect of the Foot Bath and Foot Massage on Residual Schizophrenia Patients.

Researchers performed foot baths and massages for residual schizophrenia patients to gauge the effects on psychiatric symptoms. Subjects were six residual schizophrenia patients hospitalized in a psychiatric hospital. Three times a week for 4weeks, they received an 8-minute effleurage massage to their legs after a 10-minute foot bath. The effect of physiological relaxation was identified by a significant decline in heart rate in all cases. The results of the Positive and Negative Symptom Scale are as follows: a mean score of 29.0 was measured before treatment, which lowered to 21.5 after treatment, indicating that foot care improved their negative symptoms (p<0.05).The results of the Quality of Life Scale before the foot care intervention, were 10.5 and increased to 34.0 after the intervention, indicating improvement in their quality of life (p<0.05). The results of the two measurements indicate that foot baths and massages were effective in improving psychiatric symptoms.

Effect of AS2521780, a novel PKCθ selective inhibitor, on T cell-mediated immunity.

T cell-mediated immunity is central to the pathogenesis of autoimmune diseases, and is a target in the development of alternative therapeutic strategies with reduced adverse effects on other cell types and organs. Protein kinase C (PKC) is a family of serine/threonine kinases, with knockout of the PKCθ isoform in mice resulting in defective T cell activation. However, the effects of selective inhibition of PKCθ by small-molecule compounds on T cell signaling are still unknown. Here, we evaluated the effect of the novel PKCθ inhibitor AS2521780 on T cell activation and joint inflammation in a rat model of arthritis. AS2521780 exerted potent inhibition of recombinant human PKCθ enzyme activity (IC50=0.48 nM), which was more than 30-fold higher than that of other PKC isoforms. Further, AS2521780 exerted little or no inhibition on other protein kinases. AS2521780 suppressed CD3/CD28-induced Interleukin-2 (IL-2) gene transcription in Jurkat T cells and proliferation of human primary T cells. AS2521780 also suppressed concanavalin A-induced cytokine production by rat splenocytes and monkey peripheral blood mononuclear cells with similar potency. Moreover, AS2521780 significantly reduced paw swelling in a dose-dependent manner in a rat model of adjuvant-induced arthritis. These results indicate that PKCθ is an attractive drug target and AS2521780 is a potential immunosuppressant for T cell-mediated autoimmune diseases.

Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism.

Cinacalcet, an allosteric modulator of a calcium (Ca)-sensing receptor, significantly suppresses parathyroid hormone (PTH) secretion and bone turnover rate in chronic hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). In this study, bone metabolism after cinacalcet treatment was examined, because hungry bone syndrome is sometimes experienced after parathyroidectomy in severe SHPT. We conducted a prospective observational study in 17 HD patients with SHPT. Cinacalcet was started at 25 mg/day, and the dose was increased step by step based on serum calcium level. A significant decrease in serum Ca and intact PTH concentration was found within 2 weeks. Tartrate-resistant acid phosphatase 5b, a good bone resorption marker, was significantly decreased at week 2 of the study. Serum bone alkaline phosphatase, a marker of bone formation, was increased at week 2 compared with the basal level. It became, however, gradually decreased until week 14. Only one patient whose bone turnover was considerably high had a mild numbness feeling. These results suggest that cinacalcet treatment might transiently accelerate bone formation with rapid suppression of bone resorption. This uncoupling could be involved in a mechanism by which cinacalcet decreases serum Ca level.

The effects of coffee on conjugation reactions in human colon carcinoma cells.

We examined the effect of coffee on conjugation reactions in the human colon carcinoma cell line, Caco-2. After supplementing Caco-2 cultures with both 1-naphthol (200 microM) and various concentrations of coffee, the accumulation of 1-naphthyl sulfate and glucuronide in the growth medium was determined by analytical HPLC over a 24-h period. A strong reduction in sulfo-conjugation (<50% of the control value) was observed in cells treated with coffee (IC50=4.3%), but no effect on glucuronic acid conjugation (glucuronidation) was observed. Coffee was also found to inhibit sulfotransferase (SULT) activity towards 1-naphthol in vitro to a similar extent (IC50=5.1%) as in intact Caco-2 cells, but exhibited no effect upon UDP-glucuronosyl transferase (UGT) activity in vitro. PCR analyses showed no significant changes in the expression of either SULT genes (SULT1A1 and SULT1A3) or UGT genes (UGT1A1 and UGT1A6) following treatment with coffee solutions of up to 5% in concentration. These results suggest that the consumption of coffee can modify sulfo-conjugation reactions within intestinal epithelial cells, which may possibly affect the bioavailability of therapeutic drugs and the toxicity of environmental chemicals.

[Clinical availability of the herbal medicine, SYOUSAIKOTOU, as a gargling agent for prevention and treatment of chemotherapy-induced stomatitis].

The stomatitis accompanying chemotherapy reduces a patient's QOL. Many reports have suggested that some kinds of gargling agents for oral mucositis shorten the duration and severity of symptoms. This study tested the prevention and efficacy against stomatitis of a herbal medicine (Syousaikotou) as a gargling agent for patients receiving chemotherapy. Compared to gargling with providone-iodine and amphotericin B, the Syousaikotou gargle showed a significantly decreased incidence of stomatitis, and a painkilling effect. Stomatitis occurred in about 17.4% among 23 chemotherapy cycles with the Syousaikotou gargle, against about 40.8% among 71 chemotherapy cycles without the Syousaikotou gargle. Among the patients suffering stomatitis pain after 22 chemotherapy cycles, the painkilling effect was seen to be 76.2%, and continues for about 2 hours. Critical side effects were not seen, but in 4 cases there were complaints about foul smells, such as oil and grass smells. Syousaikotou gargle was considered to be one of the useful methods against the stomatitis prevention and sharp pain mitigation from the chemotherapy.