Bioequivalence of two oseltamivir formulations in healthy Chinese volunteers
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BACKGROUND: The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu® (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. METHODS: This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70 - 143% for Cmax, 80 - 125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Characteristics of the 20 male volunteers included were as follows: mean age 23 (± 0.7, SD) years (range 21 - 24 years); weight 69 (± 7.1) kg (range 60 - 88 kg); height 177 (± 5.9) cm (range 168 - 192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3 - 114.8%) for Cmax, 104.4% (95.7 - 113.9%) for AUC0-t, and 104.4% (95.6 - 113.9%) for AUC0-∞. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3 - 112.8%) for Cmax, 101.7% (96.6 - 107.1%) for AUC0-t, and 101.4% (96.5 - 106.5%) for AUC0-∞. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. CONCLUSIONS: The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers.
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Mild cognitive impairment risk factor survey of the Xinjiang Uyghur and Han elderly.

To understand risk factors of the Xinjiang Uyghur, Han two ethnic elderly with mild cognitive impairment (mild cognitive impairment, MCI), and provide evidence for in-depth study of the causes and prevention of MCI. The MCI epidemiological survey was based on Xinjiang Uyghur and Han residents with 60 years of age or older. The total number of participants is 5398, including 3931 Uyghur residents, and 1467 Han residents. There are 456 participants with MMSE score 2 points above the demarcation points, excluded from the survey for dementia, cerebrovascular disease and other central nervous system disorders, according to case-control study method of random selection in epidemiological survey. In accordance with the clinical diagnostic criteria of MCI, which is from Disorder Diagnostic and Statistical Manual (the revised version of the fourth edition (DSM-IV) from of the American Psychiatric Association, there are 305 cases of MCI, including 159 cases of Han, 146 cases of Uyghur. In the Han groups: univariate analysis showed a correlation (P < 0.05) between sex, age, blood pressure, triglyceride (TG), low density lipoprotein (LDL-ch) and MCI. Multivariate Logistic regression analysis showed: age, hypertension, TG, LDL-ch (increased) may increase the risk of MCI (OR values were: 1.115, 1.981, 1.315, 1.495, with P < 0.05). In the Uyghur groups: univariate analysis showed a correlation (P < 0.05) between age, gender, hypertension, abnormal glucose metabolism, TG, TC, LDL-ch and MCI. Multivariate Logistic regression analysis showed: age, hypertension, abnormal glucose metabolism, TG, TC, LDL-ch (increased), women have a higher risk of MCI (OR values were: 1.063, 2.145, 2.879, 2.078, 1.429, 1.485, 0.462, P < 0.05). Age, hypertension, TG and LDL-ch are risk factors of MCI for Han population, while age, hypertension, abnormal glucose metabolism, TG, TC and LDL-ch are risk factors of MCI for Uyghur population.

The effect of SIRT1 gene polymorphisms on ambulatory blood pressure of hypertensive patients in the Kazakh population.

OBJECTIVE: To investigate the effect of silent information regulator 1 (SIRT1) gene polymorphisms on ambulatory blood pressure in hypertensive patients. METHODS: Three hundred forty hypertensive patients were recruited from January 2013 to January 2015. SIRT1 Tag single-nucleotide polymorphisms (SNPs; rs2273773, rs4746720, and rs7896005) were genotyped using a PCR-direct sequencing method, and the association between the SIRT1 gene SNPs and ambulatory blood pressure was analyzed. RESULTS: After adjusting for confounding factors, patients with the rs2273773/CT+CC genotypes had lower 24-h systolic and diastolic blood pressures; there were no associations between rs4746720 and rs7896005 genotypes and blood pressure. CONCLUSION: The SIRT1 gene polymorphism (rs2273773) is significantly associated with ambulatory blood pressure level in Han Chinese patients with hypertension.

Relationship between vitamin D receptor gene polymorphism and mild cognitive impairment in elderly Uygur people.

To explore the relationship between vitamin D receptor gene (ApaI, BsmI) genotypes and allele frequency and mild cognitive impairment in Xinjiang Uygur population. The polymorphisms of the VDR genotypes (ApaI and BsmI) were analyzed by Snapshot method in 124 MCI patients and 124 controls. A allele of ApaI gene increased the risk of MCI [OR = 1.62, 95% CI (1.13-2.31)]; AA genotype increased the risk of MCI [OR = 3.49, 95% CI (1.57-7.74)]. T allele of BsmI gene increased the risk of MCI [OR = 1.94, 95% CI (1.24-3.05)]. The risk of MCI increased accompanied with higher TG and SBP level. VDR (ApaI) AA genotype, a allele and VDR (BsmI) T allele probably associated with elderly MCI patients in Uygur ethnicity, higher level of TG and SBP were risk factors to elderly people with MCI among Uygurs.

[Association of single nucleotide polymorphism of KCNE1 and KCNE4 gene with atrial fibrillation in Xinjiang Uygur and Han population].

OBJECTIVE: To investigate the association between the KCNE1 gene G38S and the KCNE4 gene E145D and atrial fibrillation in Uygur and Han populations living in Xinjiang. METHODS: KCNE1 gene G38S and the KCNE4 gene E145D genotype and frequency were determined using PCR restriction fragment length polymorphism (PCR-RFLP) in 488 atrial fibrillation patients (237 Uygur and 251 Han residents) and 488 age-and-gender matched controls (237 Uygur and 251 Han residents). RESULTS: Genotype and allele frequency of KCNE1 gene G38S were similar between atrial fibrillation group and control group in the Han population (P = 0.556, P = 0.946). In the Uygur population, there was a statistical difference between atrial fibrillation group and control group (P = 0.018, P = 0.003). Logistic regression analysis revealed the KCNE1 38 G was one of the independent risk factors for atrial fibrillation in the Uygur population (OR = 1.634, 95%CI: 1.192-2.240, P = 0.002). The KCNE4 gene E145D, genotype and allele frequency were significantly different between atrial fibrillation group and control group in the Uygur population and Han population (P = 0.041, P = 0.015;P = 0.032, P = 0.013) . Logistic regression analysis revealed the KCNE4 145D was one of the independent risk factors for atrial fibrillation in the Uygur population and Han population (OR = 1.636, 95%CI:1.173-2.281, P = 0.004; OR = 1.491, 95%CI:1.076-2.065, P = 0.016) . CONCLUSIONS: KCNE1 G38S is not associated with atrial fibrillation in the Han population while the KCNE1 G38S is associated with atrial fibrillation in the Uygur population. KCNE4 gene E145D is associated with atrial fibrillation in both Uygur population and Han population.

Changes in microRNAs expression are involved in age-related atrial structural remodeling and atrial fibrillation.

BACKGROUND: Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of extracellular matrix proteins. However, their role in age-related cardiac remodeling and atrial fibrillation (AF) was not well understood. The present study was designed to decipher molecular mechanisms underlying age-related atrial structural remodeling and AF. METHODS: Three groups of dogs were studied: adult and aged dogs in sinus rhythm and with persistent AF induced by rapid atrial pacing. The expressions of microRNAs were measured by quantitative real-time polymerase chain reaction. Pathohistological and ultrastructural changes were tested by light and electron microscopy. Apoptosis index of myocytes was detected by TUNEL. RESULTS: Samples of atrial tissue showed the abnormal pathohistological and ultrastructural changes, the accelerated fibrosis, and apoptosis with aging and/or in AF dogs. Compared to the adult group, the expressions of microRNAs-21 and -29 were significantly increased, whereas the expressions of microRNAs-1 and -133 showed obvious downregulation tendency in the aged group. Compared to the aged group, the expressions of microRNAs-1, -21, and -29 was significantly increased in the old group in AF; contrastingly, the expressions of microRNA-133 showed obvious downregulation tendency. CONCLUSION: These multiple aberrantly expressed microRNAs may be responsible for modulating the transition from adaptation to pathological atrial remodeling with aging and/or in AF.

Accelerated fibrosis and apoptosis with ageing and in atrial fibrillation: Adaptive responses with maladaptive consequences.

The aim of this study was to investigate whether abnormal expression of matrix metalloproteinase (MMP)-9/tissue inhibitors of MMPs (TIMP)-1 and B cell lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) are correlated with the characteristic accelerated fibrosis and apoptosis during ageing and in atrial fibrillation (AF). Four groups of dogs were studied: adult dogs in sinus rhythm (SR), aged dogs in SR, adult dogs with AF induced by rapid atrial pacing and aged dogs with AF induced by rapid atrial pacing. The mRNA and protein expression levels of the target gene in the left atrium were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. Pathohistological and ultrastructural changes were assessed by light and electron microscopy. The apoptotic indices of myocytes were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). The mRNA and protein expression levels of MMP-9 and BAX and those of TIMP-1 and BCL-2 were significantly upregulated and down-regulated, respectively, in the aged groups compared with the adult groups. Compared with the control groups, the adult and aged groups with AF exhibited significantly increased mRNA and protein expression levels of MMP-9 and BAX and decreased expression levels of TIMP-1 and BCL-2. Samples of atrial tissue demonstrated abnormal pathohistological and ultrastructural changes, accelerated fibrosis and apoptosis. MMP-9/TIMP-1 and BCL-2/BAX hold potential for use as substrates conducive to AF and their abnormal expression plays a major role in structural remodeling of the atrium.

[Association of the low density lipoprotein receptor-related protein gene 766C/T polymorphism with Alzheimer's disease in Xinjiang Uygurs and Hans].

OBJECTIVE: To investigate the relationship between the low density lipoprotein receptor-related protein gene (LRP) 766C/T polymorphisms and Alzheimer's disease (AD) in Xinjiang Uygurs and Hans populations. METHODS: Those included in the study were > or = 50 years of age and of either Xinjiang Uygur or Han descents. Two hundred and nine individuals had AD and 220 were healthy controls. They were recruited according to ADRDA-NINCDS criteriaîThe polymorphisms of the LRP gene were determined by the PCR-restriction fragment length polymorphism technique. The case-control analysis was adopted to analyze the frequencies of genotypes and alleles. RESULTS: (1) The distribution of genotypes or alleles of LRP gene had significant differences between the AD group and the control group in both the Xinjiang Uygurs and Hans populations (P < 0.05). (2) The frequencies of genotypes and alleles were significantly different between the Han AD and Han control group (P < 0.05). (3) The frequencies of genotypes and alleles in those > or = 65 years were significantly different from that in others (P < 0.05). There was a significant increase of AD in the C allele carriers (OR=1.98, P < 0.05). (4) The frequencies of the CC genotype and C allele in female AD patients were higher than that in female controls (P < 0.05), and the C allele carriers had significant increase of AD (OR=2.927, P < 0.05). CONCLUSION: The LRP 766C/T polymorphisms were significantly different between the Chinese Xinjiang Uygur and Han populations. The LRP 766C/T polymorphisms might be associated with AD in the Han population, in females and those of > or = 65 years old.