ABSTRACT
BACKGROUND: Serum phosphate levels remain insufficiently controlled in chronic kidney disease (CKD) patients, and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate cotransporter type 2b (NPT2b) holds promise as one such strategy. METHODS: The in vitro cellular potency of DZ1462 was evaluated using a radioactive Pi uptake assay on stable Chinese hamster ovary (CHO) cell clones transfected with human NPT2b (hNPT2b) or rat NPT2b (rNPT2b). The ability of DZ1462 to inhibit phosphate absorption was studied in vivo in an acute model after oral bolus challenge with 33PO4 and in an adenine-induced chronic hyperphosphatemia rat model. PK and minitox was also evaluated. RESULTS: The cellular assays with the hNPT2b-CHO and rNPT2b-CHO clones showed that DZ1462 significantly and potently inhibited phosphate uptake. In vivo, in a chronic Pi-fed rat model, DZ1462 effectively inhibited intestinal Pi uptake. In a hyperphosphatemia rat model, DZ1462 significantly inhibited Pi uptake, and DZ1462 in combination with sevelamer had a synergistic effect. The pharmacokinetics (PK) study confirmed that DZ1462 is a gastrointestinal (GI)-restricted compound that can remain in the intestine for a sufficient duration. In addition, DZ1462 also reduced cardiovascular events and ameliorated osteoporosis in a CKD animal model. CONCLUSIONS: This study revealed that a GI-restricted NPT2b inhibitor DZ1462 potently inhibits NPT2b in vitro and blocks intestinal phosphate uptake in multiple animal models with potential to reduce various cardiovascular events in CKD models. Therefore, DZ1462 may be useful to treat renal disease patients who have shown an unsatisfactory response to phosphate binders.
ABSTRACT
BACKGROUND: Several studies have investigated the immunomodulating properties of zoledronic acid on T lymphocytes, but the causal relationship between the function of T cells and the efficacy of zoledronic acid has not been elucidated. OBJECTIVE: To investigate the causal relationship between the function of zoledronic acid and T cells. METHODS: We conducted an observational perspective study to observe the effect of intravenous zoledronic acid once yearly for 2 years on lymphocyte subsets in patients with primary osteoporosis through observing the blood cells analysis and the level of lymphocyte subpopulations before and on day 1, 2, and 3 after first and second administration of intravenous zoledronic acid and bone mineral destiny 1 year after a single administration of zoledronic acid. RESULTS: White blood cell count and neutrophils increased, whereas lymphocytes and eosinophils decreased after the first and second zoledronic acid infusion. The count of CD3+T cells, CD3+CD4+T cells, and CD16+CD56+ natural killer lymphocytes decreased from day 1 to day 3 after the first and second zoledronic acid infusion, but the results of second infusion showed no significance. CONCLUSIONS: Further, larger size, more in-depth studies are indicated to examine whether the short-term changes in white blood cells and lymphocyte subtypes noted after 2 once-yearly zoledronic acid injections in this small population of adult patients is associated with the stimulation of immune mechanisms. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).
ABSTRACT
Myofascial pain syndrome (MPS) is characterized by myofascial trigger points and fascial constrictions. At present, domestic and foreign scholars have not reached a consensus on the etiology and pathogenesis of MPS. Due to the lack of specific laboratory indicators and imaging evidence, there is no unified diagnostic criteria for MPS, making it easy to confuse with other diseases. The Chinese Association for the Study of Pain organized domestic experts to formulate this Chinese Pain Specialist Consensus on the diagnosis and treatment of MPS. This article reviews relevant domestic and foreign literature on the definition, epidemiology, pathogenesis, clinical manifestation, diagnostic criteria and treatments of MPS. The consensus is intended to normalize the diagnosis and treatment of MPS and be used by first-line doctors, including pain physicians to manage patients with MPS.
ABSTRACT
Cytochromes P450 (CYPs) play key roles in drug metabolism which are widely distributed in kidney in aquatic organisms. CYP(s) mainly catalyzed the N-demethylation reaction of difloxacin (DIF) biotransformation to sarafloxacin (SAR). However, limited information is available about CYP investigation in fish. In order to supply useful information on CYP(s) characterization for DIF N-demethylation, the present study assessed the effects of fish potent CYP inducers and inhibitors on DIF N-demethylation and the inductive and inhibitive enzyme kinetics in kidney of Chinese idle (Ctenopharyngodon idellus) by reversed-phase high-performance liquid chromatography (RP-HPLC). Results demonstrated that the amounts of SAR formation pretreated by ß-naphthoflavone (BNF) increased by 1.1-fold and α-naphthoflavone (ANF) inhibited SAR formation level by 0.6-fold at the third day. Enzymatic parameters V(max) and Cl(int) of DIF N-demethylase were increased by 0.56- and 0.38-fold due to ß-naphthoflavone (BNF) pretreatment. DIF N-demethylation inhibition by varying ANF concentrations represented a mixed-type inhibition with the value of the inhibition constants (K(i)) 12.9mg/kg. BNF and ANF are the separate typical inducer and inhibitor for CYP1A in fish. Thus, we suggest that CYP1A may be responsible for DIF N-demethylation in kidney. This study provides instructive information to ensure treatment success in fisheries medication with two or more drugs.
ABSTRACT
A drug-drug interaction occurs when the effect of one drug is altered by the presence of another drug which is generally associated with the induction of cytochrome P450s (CYPs) activity. Thus, unexpected treatment failures often happen resulting from inappropriate coadministration in fisheries. However, little information is available about CYP induction in fish. The reaction of difloxacin (DIF) biotransformation to sarafloxacin (SAR) belongs to N-demethylation catalyzed mainly by CYP(s). In order to supply useful information on CYP induction, the present study assessed the effects of fish-specific CYP inducers on DIF N-demethylation and enzyme kinetics in kidney cell of Chinese idle (CIK; grass carp (Ctenopharyngodon idellus)) by RP-HPLC. Results demonstrated that the amounts of SAR formation and enzymatic parameters Clint and Vmax were significantly increased due to beta-naphthoflavone (BNF) pretreatment. Therefore, we suggest that CYP1A may be involved in DIF N-demethylation in CIK. This study provides instructive information to ensure treatment success via avoiding CYP induction in fisheries.
