Association between thyroid hormones and diabetic kidney disease in Chinese adults.

OBJECTIVE: We aimed to explore the association between thyroid hormones and different stages of diabetic kidney disease (DKD) in Chinese adults. METHODS: This is a retrospective study involving 2,832 participants. DKD was diagnosed and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: After propensity score matching (PSM) on age, gender, hypertension, hemoglobin A1c(HbA1c), total cholesterol (TC), serum triglyceride (TG) and duration of diabetes, per 0.2 pg/mL increment in serum free triiodothyronine (FT3) was significantly associated with 13%, 22% and 37% reduced risk of moderate-risk (OR, 95% CI, P: 0.87, 0.70-0.87, < 0.001), high-risk (0.78, 0.70-0.87, < 0.001) and very-high-risk (0.63, 0.55-0.72, < 0.001) DKD stages relative to the low-risk DKD stage, respectively. After PSM analyses, serum FT4 and TSH showed no statistical significance in risk estimates for all DKD stages. To facilitate clinical application, a nomogram prediction model was established for the moderate-risk, high-risk and very-high-risk DKD stages, with decent accuracy. CONCLUSION: Our results indicate that high concentrations of serum FT3 were associated with the significantly reduced risk of having moderate-risk to very-high-risk DKD stages.

Is serum hemoglobin level an independent prognostic factor for IgA nephropathy?: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Decreased serum hemoglobin (Hb) level is associated with Immunoglobulin A nephropathy (IgAN) progression. However, whether serum Hb level is an independent prognostic factor of IgAN remains controversial. Herein, we aimed to investigate the prognostic value of serum Hb level in IgAN. METHODS: The Cochrane Library, Embase, PubMed and Open Grey databases were systematically searched and reviewed. Kidney disease progression of IgAN was defined as a doubling of serum creatinine (SCr), a 30% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), or death. We evaluated the hazard ratio (HR) between serum Hb level and the incidence of kidney disease progression in IgAN before and after adjusting for relevant covariates. RESULTS: We included nine studies with 10006 patients in the meta-analysis. As a continuous variable, we found that serum Hb was an independent prognostic factor of IgAN [unadjusted HR = 0.89, 95% confidence interval (CI) = 0.84-0.95, I2 = 98%; adjusted HR = 0.85, 95% CI = 0.79-0.91, I2 = 0%]. The sensitivity analysis confirmed the stability of these results. Consistently, as a dichotomous variable defined as the below/above cutoff for anemia, we observed a positive correlation between serum Hb and kidney disease progression in IgAN (unadjusted HR = 2.12, 95% CI = 1.44-3.12, I2 = 79%; adjusted HR = 1.65, 95% CI = 1.20-2.27, I2 = 0%). CONCLUSION: Serum Hb level was independently correlated with the incidence of kidney disease progression in IgAN.

Is hyperuricemia an independent prognostic factor for IgA nephropathy: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Hyperuricemia has been reported to be correlated with IgA nephropathy (IgAN). However, whether hyperuricemia or elevated serum uric acid (SUA) is an independent prognostic factor of IgAN remains unknown. Therefore, this systematic review and meta-analysis evaluated the prognostic value of hyperuricemia and elevated SUA in IgAN. METHODS: Databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Open Gray were reviewed systematically. The kidney failure events of IgAN were defined as a doubling of serum creatinine, halving of eGFR, end-stage renal disease (ESRD), or death. The risk ratio (RR) between hyperuricemia and IgAN-caused kidney failure was evaluated before and after adjustment for relevant covariates. The RR between elevated SUA and IgAN-caused kidney failure was evaluated after adjustment for relevant covariates. RESULTS: A total of 11 548 patients from 14 studies were included in this meta-analysis. Hyperuricemia was found to be an independent prognostic factor of IgAN (unadjusted RR = 2.79, 95% CI = 1.93-4.03, p for heterogeneity <0.00001, I2 = 91%; adjusted RR = 2.12, 95% CI = 1.64-2.73, p for heterogeneity = 0.86, I2 = 0%). Subgroup and sensitivity analyses confirmed the stability of these results. Similarly, elevated SUA was positively correlated with kidney failure events of IgAN (adjusted RR = 1.25, 95% CI = 1.19-1.31, p for heterogeneity = 0.6, I2 = 0%). CONCLUSION: Our meta-analysis showed that hyperuricemia and elevated SUA were both independently associated with an increased incidence of kidney failure events in IgAN patients.

Comparative analysis of proteomes between diabetic and normal human sperm: Insights into the effects of diabetes on male reproduction based on the regulation of mitochondria-related proteins.

This study sought to identify sources of the reduced fertility of men with type 2 diabetes mellitus. Significant reductions in semen volume, sperm concentration, and total sperm count were observed in diabetic individuals, while transmission electron microscopy revealed that the structure of mitochondria in the tail of sperm from diabetic patients was damaged. Proteins potentially associated with these sperm defects were identified using proteomics. Isobaric tagging for relative and absolute quantitation labeling and high-performance liquid chromatography-tandem mass spectrometry allowed us to identify 357 proteins significantly differentially expressed in diabetic versus control semen (>1.2 or <0.83). According to gene ontology enrichment and pathway analyses, many of these differentially expressed proteins are associated with sperm function, including binding of sperm to the zona pellucida and proteasome function; of particular interest, half of these proteins were related to mitochondrial metabolism. Protein-interaction networks revealed that a decrease in Cystatin C and Dipeptidyl peptidase 4 in the mitochondria may be sources of the decreased motility of sperm from diabetic patients.

Coagulation Function and Type 2 Diabetic Kidney Disease: A Real-World Observational Study.

Objectives: Type 2 diabetic kidney disease (DKD), a chronic microvascular complication of diabetes, may exhibit a complex interrelation with coagulation function. This study is aimed at elucidating the association between coagulation function and DKD. Methods: This was a real-world observational study conducted in Beijing, involving 2,703 participants. All patients with diabetes were classified into two groups, viz., DKD and non-DKD groups. Effect magnitudes are denoted as odds ratios (OR) with a 95% confidence interval (CI). To mitigate potential bias in group comparisons, we employed propensity score matching (PSM). Results: After adjusting for variables such as age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), triglyceride (TG), c-reactive protein (CRP), platelet (PLT), and serum albumin (sALB), it was discerned that fibrinogen (FIB) (OR, 95% CI, P: 1.565, 1.289-1.901, <0.001) and fibrinogen degradation products (FDP) (1.203, 1.077-1.344, 0.001) were significantly correlated with an increased risk of DKD. To facilitate clinical applications, a nomogram prediction model was established, demonstrating commendable accuracy for DKD prediction. Conclusions: Our findings suggest that elevated levels of FIB and FDP serve as potential risk indicators for DKD, and coagulation function may play an important role in the occurrence and development of DKD.

Association between serum complements and kidney function in patients with diabetic kidney disease.

Objective: We aimed to explore the association between serum complements and kidney function of diabetic kidney disease (DKD) in Chinese patients. Methods: This is a retrospective study involving 2,441 participants. DKD was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) categories. Participants were classified as stages G1-G5 by KDIGO glomerular filtration rate (GFR) categories. Effect sizes are expressed as odds ratio (OR) with 95% confidence interval (CI). Results: After balancing age, gender, systolic blood pressure (SBP), hemoglobin A1c (HbA1C), serum triglyceride (TG), and urinary albumin-to-creatinine ratio (UACR) between the G2-G5 and control groups, per 0.1 g/L increment in serum complement C3 was significantly associated with a 27.8% reduced risk of DKD at G5 stage (OR, 95% CI, P: 0.722, 0.616-0.847, <0.001) relative to the G1 stage. Conversely, per 0.1 g/L increment in serum complement C4 was associated with an 83.0-177.6% increased risk of G2-G5 stage (P<0.001). Serum complement C1q was not statistically significant compared to controls at all stages prior to or after propensity score matching. Conclusions: Our results indicate that high concentrations of serum C4 were associated with the significantly elevated risk of kidney function deterioration across all stages, and reduced serum C3 levels with an increased risk of DKD stage G5.

Aminoguanidine ameliorates ovariectomy-induced neuronal deficits in rats by inhibiting AGE-mediated Aß production.

Advanced glycation end products (AGEs) have been reported to cause neurodegeneration, senile plaque formation and spatial learning and memory deficits. There is much evidence describing the beneficial effects of aminoguanidine (AG) on the central nervous system; AG is able to inhibit the receptor for AGEs and beta-amyloid (Aß) deposition in the brain, thus preventing cognitive decline and neurodegeneration. In this study, we investigated whether AG protects against ovariectomy-induced neuronal deficits and Aß deposition in rats. Animals in the ovariectomy group (OVX) group, and those in the OVX+AG group were treated with AG (100 mg/kg/day) for 8 weeks. Learning and memory were evaluated using the electric Y maze. AGE and Aß1-40 biochemical assessments were performed using enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, evaluations of brain amyloid precursor protein 695 (APP695) mRNA expression by RT-PCR and AGE expression by immunohistochemistry were carried out. Ovariectomized rats exhibited memory impairment and Aß production disorder with upregulated APP695 mRNA and AGE expression levels. AG pretreatment relieved the ovariectomy-induced learning and memory disorder and significantly ameliorated the Aß production disturbance and AGE generation. Additionally, pathological changes in morphology were also significantly recovered. Our data reveal that AG plays a potentially neuroprotective role against ovariectomy-induced learning and cognitive impairment and Aß production disorder.Advanced glycation end products (AGEs) have been reported to cause neurodegeneration, senile plaque formation and spatial learning and memory deficits. There is much evidence describing the beneficial effects of aminoguanidine (AG) on the central nervous system; AG is able to inhibit the receptor for AGEs and beta-amyloid (Aß) deposition in the brain, thus preventing cognitive decline and neurodegeneration. In this study, we investigated whether AG protects against ovariectomy-induced neuronal deficits and Aß deposition in rats. Animals in the ovariectomy group (OVX) group, and those in the OVX+AG group were treated with AG (100 mg/kg/day) for 8 weeks. Learning and memory were evaluated using the electric Y maze. AGE and Aß1-40 biochemical assessments were performed using enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, evaluations of brain amyloid precursor protein 695 (APP695) mRNA expression by RT-PCR and AGE expression by immunohistochemistry were carried out. Ovariectomized rats exhibited memory impairment and Aß production disorder with upregulated APP695 mRNA and AGE expression levels. AG pretreatment relieved the ovariectomy-induced learning and memory disorder and significantly ameliorated the Aß production disturbance and AGE generation. Additionally, pathological changes in morphology were also significantly recovered. Our data reveal that AG plays a potentially neuroprotective role against ovariectomy-induced learning and cognitive impairment and Aß production disorder.

Effect of Tang-Shen-Ning decoction on podocyte epithelial-esenchymal transformation via inhibiting Wnt/ß-catenin pathway in diabetic mice.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Podocyte epithelial-esenchymal transformation (EMT) induced by the activated Wnt/ß-catenin pathway plays a key role in DN. Tang-Shen-Ning (TSN), a Chinese herbal formula, has been shown to decrease proteinuria and protect the renal function in DN. However, the effect of TSN on the Wnt/ß-catenin pathway and podocyte EMT is unclear. METHODS: TSN was orally administrated in KK-Ay mice for 4 weeks, at a daily dose of 20 g/kg body weight in our in vivo study. Rat serum containing TSN was added in podocyte cultured in high glucose for 24 h. The levels of 24 h urine protein, serum creatinine and blood urea nitrogen were detected by ELISA. Nephrin, Synaptopodin, P-cadherin, desmin, FSP-1, and collagen I protein and mRNA expressions were detected by western blot, immunohistochemistry, immunofluorescence, and RT-PCR. Snail, ß-catenin, and TCF/LEF were detected by Western blot, RT-PCR and luciferase. RESULTS: TSN significantly decreased 24-h urine protein, serum creatinine, and blood urea nitrogen in DN mice. Further, TSN also significantly increased the expression of nephrin, synaptopodin, and P-cadherin, while the expression of desmin, fibroblast-specific protein 1 (FSP-1), and collagen I of podocytes was significantly decreased. Moreover, TSN significantly inhibited the activation of the Wnt/ß-catenin pathway in podocytes cultured under high glucose (HG). Notably, the effect of TSN on podocyte EMT was reversed by activation of the Wnt/ß-catenin pathway. CONCLUSIONS: TSN could protect podocytes from injury in DN, partly via inhibiting the activation of the Wnt/ß-catenin pathway and ameliorating podocyte EMT.

[Expression of EphA2 and EphrinA1 in human renal cell carcinoma and its relationship with angiogenesis].

OBJECTIVE: To investigate the expression of EphA2 and EphrinA1 and its relationship with angiogenesis in renal cell carcinoma and its relevance to clinicopathologic features. METHODS: The expression of the EphA2 and EphrinA1 was detected by immunohistochemistry (IHC) in the tissues samples from 68 renal cell carcinomas and 24 normal kidneys, and quantitatively analyzed. The microvessel density (MVD) was determined by CD34 immunostaining of microvascular endothelial cells. Statistical analysis was performed using the software SPSS (version 13.0). RESULTS: The expression of EphA2, EphrinA1 and MND in the cancerous tissues were significantly higher (P<0.01) than that in the normal ones. Significantly increased expression of EphA2, EphrinA1 and MVD (P<0.01) was detected in cancer tissues with higher grade differentiation, more advanced stage and more lymph node metastasis, respectively (P<0.05 for each group). Expression of the EphA2 and EphrinA1 protein was shown to be positively associated with the MVD assessed by Spearman's correlation and factor analysis (r=0.555, r=0.485, P<0.01). The MVD was also significantly correlated with the diameter of the tumor (P<0.01). CONCLUSION: EphA2 and EphrinA1 are highly expressed in renal cell carcinoma, and positively correlated with histological differentiation, clinical stage and angiogenesis in the cancer.

Medicine in Future and Advantages of Integrated Chinese and Western Medicine.

The history of medical development shows that oriental medicine, or traditional medicine, was born through medical practice during the times when science and technology were immature and underdeveloped, whereas with the development of science and technology, Western medicine, or modern medicine, was born through experimental analysis and research. With the development of medicine, the pros and cons of both medical systems become increasingly evident. How to integrate them and learn from each other will be the direction of future development of medicine. The formation and development of integrated medicine will, inevitably, usher in a new era for medicine.

Effects of BSF on Podocyte Apoptosis via Regulating the ROS-Mediated PI3K/AKT Pathway in DN.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The ROS-mediated PI3K/AKT pathway plays a key role in podocyte apoptosis and DN progression. Our previous study demonstrated that Baoshenfang (BSF) can decrease proteinuria and attenuate podocyte injury. However, the effects of BSF on podocyte apoptosis induced by the ROS-mediated PI3K/AKT pathway remain unclear. Herein, in vivo and in vitro studies have been performed. In our in vivo study, BSF significantly decreased 24-h urinary protein, serum creatinine, and blood urea nitrogen levels in DN mice. Meanwhile, BSF significantly inhibited oxidative stress and podocyte apoptosis in our in vivo and in vitro studies. Moreover, BSF significantly decreased the inhibition of the PI3K/AKT pathway induced by HG in DN. More importantly, the effects of BSF on podocyte apoptosis were reversed by PI3K siRNA transfection. In conclusion, BSF can decrease proteinuria and podocyte apoptosis in DN, in part through regulating the ROS-mediated PI3K/AKT pathway.

Effect of Baoshenfang Formula on Podocyte Injury via Inhibiting the NOX-4/ROS/p38 Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.

Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors.

Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent.

Separation of liposome-entrapped mitoxantrone from nonliposomal mitoxantrone in plasma: pharmacokinetics in mice.

A method is described for quantification of the liposomal and nonliposomal forms of mitoxantrone (MTO) in mouse plasma after intravenous administration of liposome-entrapped MTO Easy-to-Use (LEM-ETU) formulation. This is based on the property of liposome-entrapped MTO (LEM) to pass through reversed-phase C(18) silica gel cartridges, while nonliposomal MTO or free MTO is retained with strong hydrophobicity and later is eluted with acidic methanol. Extraction of LEM and free MTO from plasma is performed in two steps. This technique is rapid and sensitive and can be used for a large series of sample preparation. The plasma samples are found stable after one freeze-thaw cycle. The recovery of MTO, as well as the precision, linearity, and accuracy of the method for both free and liposomal MTO, appears satisfactory for pharmacokinetic studies. The pharmacokinetic results in mice show a sustained release of MTO from LEM-ETU.

Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation.

BACKGROUND: SN-38, 7-ethyl-10-hydroxycamptothecin, is a biologically active metabolite of irinotecan. Its poor solubility restricted its development as an anticancer agent. We have developed an easy-to-use liposome-entrapped SN-38 (LE-SN38) and evaluated its toxicology, pharmacokinetics and antitumor efficacy profile. MATERIALS AND METHODS: Toxicity and pharmacokinetics studies were conducted in CD2F1 mice and beagle dogs. Therapeutic efficacy studies were performed in murine leukemia (P388 and P388/ADR) and in a human pancreatic (Capan-1) tumor models. RESULTS: Multiple dose administration (i.v. x 5) of LE-SN38 indicated a maximum tolerated dose (MTD) of 5.0 and 7.5 mg/kg/day for male and female mice, respectively. The MTD of LE-SN38 in dogs was 1.2 mg/kg. The elimination half-life (t1/2) of SN-38 in mouse plasma was 6.38 h with volume of distribution (VdSS) 2.55 L/kg. In dogs, t1/2 and VdSS were 1.38-6.42 h and 1.69-5.01 L/kg; respectively. P388 tumor-bearing mice dosed with LE-SN38 at 5.5 mg/kg (i.v. x 5) showed 100% survival. LE-SN38 at 4 or 8 mg/kg (i. v. x 5) inhibited 65% and 98% tumor growth, respectively, in a human pancreatic tumor model. CONCLUSION: LE-SN38 showed a favorable pharmacokinetics profile and can be administered safely at therapeutically effective doses.

A simple and sensitive LC/MS/MS assay for 7-ethyl-10-hydroxycamptothecin (SN-38) in mouse plasma and tissues: application to pharmacokinetic study of liposome entrapped SN-38 (LE-SN38).

An LC/MS/MS method to quantify SN-38 in mouse plasma and tissue homogenates containing liposome entrapped SN-38 (LE-SN38) was developed. Camptothecin (CPT) was used as the internal standard (IS). Sample preparation consisted of simple protein precipitation by acetonitrile containing 0.5% acetic acid. SN-38 and IS were separated by a C18 HPLC column and detected using a mass spectrometer operating in the multiple reaction monitoring (MRM) mode. The peak area of the m/z 393.3-->349.1 transition of SN-38 and that of the m/z 349.1-->305.2 transition of the IS were measured and a standard curve was generated from their ratios. The method had a LLOQ of 0.5 ng/mL in mouse plasma, which corresponds to 2.5 pg for the 5 microL injection volume. The linear range was 0.5-1000 ng/mL of SN-38 in plasma sample spiked with LE-SN38. The LLOQ in tissue homogenates (5%, w/v) quantitation was 1 ng/mL (20 ng/g tissue) of SN-38 in kidney, liver, lung, and spleen homogenates, and 2 ng/mL (40 ng/g tissue) in heart homogenate containing LE-SN38. The assay was linear up to 400 ng/mL of SN-38 in tissue homogenates, and may be extended to 120 microg/mL by proper dilution of samples over the upper limit of quantitation. Acceptable precision and accuracy were obtained for concentrations over the entire standard curve range, both between-run and within-run for plasma and tissue homogenates. The method was successfully used to quantify SN-38 in plasma and tissues samples for pharmacokinetic and tissue distribution studies of LE-SN38 in mice.

Improved liquid chromatographic method for mitoxantrone quantification in mouse plasma and tissues to study the pharmacokinetics of a liposome entrapped mitoxantrone formulation.

A simple, rapid HPLC method for quantification of mitoxantrone in mouse plasma and tissue homogenates in the presence of a liposome entrapped mitoxantrone formulation (LEM-ETU) is described. Sample preparation is achieved by protein precipitation of 100 microl plasma or 200 microl tissue homogenate with an equal volume of methanol containing 0.5 M hydrochloric acid:acetonitrile (90:10, v/v). Ametantrone is used as the internal standard (i.s.). Mitoxantrone and i.s. are separated on a C18 reversed phase HPLC column, and quantified by their absorbance at 655 nm. In plasma, the standard curve is linear from 5 to 1000 ng/ml, and the precision (%CV) and accuracy (percentage of nominal concentration) are within 10%. In mouse tissue (heart, kidney, liver, lung, and spleen) homogenates (5%, w/v), the standard curve is linear from 25 to 2000 ng/ml, with acceptable precision and accuracy. The method was used to successfully quantify mitoxantrone in mouse plasma and tissue samples to support a pharmacokinetic study of LEM-ETU in mice.

[Effects of tonifying shen recipe on advanced glycation end products, amyloid-beta peptide in telencephalon and hippocampus of ovariectomized rats].

OBJECTIVE: To explore the effect of Tonifying Shen recipe (TSR) on advanced glycation end products (AGEPs), amyloid-beta peptide (A beta P) in telencephalon and hippocampus of ovariectomized rats. METHODS: Female SD rats, 9 months old, were randomly divided into 3 groups: the sham operation (Sh) group, the ovariectomized (OV) group and the TSR group. Medication via gastrogavage 4 weeks was given after ovariectomy consecutively for 16 weeks. Competitive ELISA and radioimmunoassay (RIA) was used to detect AGEPs and A beta P level in rats' telencephalon and hippocampus; florescent assay was used to determine the serum and urinary soluble AGE-peptide level; and also the rats' behavioral alteration and hippocampal morphological change were observed. RESULTS: Compared with those in the Sh group, the correct escape rate in the OV group was significantly lower (P < 0.05), content of A beta P in telencephalon and serum soluble AGE-peptide levels significantly higher (P < 0.05), contents of AGEPs in telencephalon and hippocampal tissue showed an increased tendency, but without significance (P > 0.05), argyrophil stain showed that nerve fiber thickened, senile plaques appeared in temporal cortex. In the TSR group after treatment, contents of AGEPs in telencephalon, A beta P in telencephalon and hippocampus significantly decreased (P < 0.05), the urinary soluble AGE-peptide level significantly increased (P < 0.05) and with markedly improvement of learning memory capability and above-mentioned pathological changes. CONCLUSION: TSR could reduce the accumulation of AGEPs in telencephalon and the contents of A beta P in telencephalon and hippocampal tissue, and improve the impaired ability of learning and memory caused by lack of estrogen. Its mechanism might be based on the elevation in excretion of AGE-peptide via kidney.

Sustained release subcutaneous delivery of BMS-686117, a GLP-1 receptor peptide agonist, via a zinc adduct.

BMS-686117 is an 11-mer GLP-1 receptor agonist with a short intrinsic pharmacokinetic half-life (t(1/2)) of approximately 2h. In order to develop an extended release formulation for once-daily (QD) subcutaneous administration, a non-covalently bonded Zn/BMS-686117 adduct with very low aqueous solubility was prepared through mixing zinc acetate and BMS-686117 solutions, followed by filtration or spray drying. At pH 6.8, free BMS-686117 concentration decreased continuously with the increase of Zn:BMS-686117 ratio. Furthermore, free BMS-686117 concentration increases in the presence of ethylenediaminetetraacetic acid (EDTA), indicating the reversibility of the zinc-peptide association. As solids, the glass transition temperature of Zn/BMS-686117 adduct increases with the increase of Zn:BMS-686117 ratio. A Zn/BMS-686117 adduct suspension, with a molar ratio of zinc:BMS-686117 of 3:1, was dosed subcutaneously to dogs along with two other solution formulations. The Zn/BMS-686117 adduct showed a prolonged BMS-686117 terminal t(1/2) of 8.5h, a mean residence time (MRT) of 16h, and a C(max) value 6-8 times lower than the solution formulations. Additionally, the Zn/BMS-686117 was encapsulated into poly(lactide-co-glycolide) (PLGA) microspheres. The Zn/BMS-686117 microspheres showed an almost zero-order release profile in vitro for at least 18 days, with minimal initial burst, indicating the potential of using this approach for long-term sustained release.

Pharmacokinetics and metabolism of a COX-2 inhibitor, valdecoxib, in mice.

The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice. Valdecoxib was extensively metabolized after a single 5 mg/kg oral administration of [(14)C]valdecoxib and elimination of unchanged drug was minor (less than 1%) in male and female mice. The total mean percentage of administered radioactive dose recovered was 99.8% in the male mice and 94.7% in the female mice. Sixteen metabolites were identified in mouse plasma, red blood cells, urine, and feces. The main phase I metabolic pathway of valdecoxib in mice involved the oxidation of the 5-methyl group to form the active hydroxymethyl metabolite M1. M1 was further oxidized to the carboxylic acid metabolite M4, which underwent opening of the isoxazole ring to form M6 and M13. Phase II metabolism included glucuronide, glucoside, and methyl sulfone conjugations. M1 was also conjugated with glucuronic acid and glucose to yield M-G and M1-glucose, respectively. Three novel methylsulfone conjugates M20, M21, and M21-G were detected in blood or urine. Valdecoxib and M1 were the major radioactive components in plasma and red blood cells. The plasma area under the curve from zero to infinity (AUC(0-infinity)) values for valdecoxib and M1 were 3.58 and 0.850 microg. h/ml in males and 2.08 and 1.63 microg. h/ml in females, respectively. The RBC AUC(0-infinity) values for valdecoxib and M1 were 12.1 and 22.6 microg. h/g in males and 6.42 and 35.2 microg. h/g in females, respectively.