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Givosiran is an N-acetylgalactosamine-conjugated RNA interference therapeutic that targets 5'-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t1/2; less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor-mediated uptake, and the t1/2 in the liver was significantly longer (∼1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3' end of antisense strand, AS(N-1)3' givosiran, which was equipotent to givosiran. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran is not a substrate, inhibitor, or inducer of P450 isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, givosiran has a low potential of mediating drug-drug interactions involving P450 isozymes and drug transporters. SIGNIFICANCE STATEMENT: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous administration results in adequate exposure of givosiran to the target organ (liver). These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of acute hepatic porphyria.

To compare the clinical efficacy between acupuncture combined with western medication and simple western medication for ocular myasthenia gravis (OMG), and to explore its possible mechanism.A total of 60 patients of ocular myasthenia gravis were randomized into an acupuncture combined with western medication group (30 cases, 1 case dropped off) and a western medication group (30 cases, 2 cases dropped off). Oral pyridostigmine bromide tablet and prednisone acetate tablet were given in the western medication group. On the basis of the treatment in the western medication group,After treatment, the OMG clinical absolute scores, values of mean jitter, percentages of jitter55 μs, percentages of blocks and serum levels of AChR-Ab, IFN-γ and IL-4 were decreased compared before treatment in both groups (Acupuncture combined with western medication can effectively improve ptosis, palpebra superior fatigability, eye movement disorder and neuromuscular junction dysfunction in patients with ocular myasthenia gravis, the therapeutic effect is superior to simple western medication. Its mechanism may be related to down-regulating serum levels of AChR-Ab, IFN-γ and IL-4 and promoting the recovery of orbicularis oculi function.

Aim: A novel single-stranded deaminated oligonucleotide metabolite resulting from a REVERSIR™ oligonucleotide was discovered and identified in monkey liver after subcutaneous administration. Results & methodology: REVERSIR-A and its metabolites were extracted from biological matrices by solid phase extraction and analyzed using LC coupled with high-resolution MS under negative ionization mode. A novel 9-mer metabolite of REVERSIR-A, resulting from deamination of the 3′ terminal 2′- O-methyl-adenosine nucleotide to 2′- O-methyl-inosine, was discovered at significant levels in monkey liver. The metabolite's identity was confirmed by LC–MS/MS. Conclusion: This report describes the first observation of a long-chain deaminated metabolite of a single-stranded REVERSIR oligonucleotide in vivo in monkey liver.

Cartilage oligomeric matrix protein (COMP) was a protective factor in the cardiovascular system. Previous studies showed that hypoxia led to decreased COMP in rat models of pulmonary hypertension. However, the expression pattern of COMP in the pulmonary hypertension population was unclear. A total of 35 patients newly diagnosed with pulmonary hypertension and 70 controls were enrolled in the study. Circulating COMP concentrations of serum samples were measured by enzyme-linked immunosorbent assay and were analyzed the association with multiple clinical variables. Serum COMP concentrations in the pulmonary hypertension group were significantly declined in comparison with age- and sex-matched normal controls, especially in the female subgroup. No significant difference of COMP concentrations was observed in the etiological classification, heart function classification, and risk stratification. Major hemodynamic parameters, six-minute walk distance, N-terminal pro brain natriuretic peptide, and short-term prognosis were not statistically associated with COMP. However, some echocardiography parameters, like tricuspid annular plane systolic excursion and mean right atrial pressure, were found the negative relation to COMP concentrations. In conclusion, serum COMP levels were decreased in the patients with pulmonary hypertension, which was in accordance with its known biological effects. Its association with long-term prognosis was worth further exploring.

Givosiran is an

Aim: Advancements in RNA interference therapeutics have triggered development of improved bioanalytical methods for oligonucleotide metabolite profiling and high-throughput quantification in biological matrices. Results & methodology: HPLC coupled with high-resolution mass spectrometry (LC-HRMS) methods were developed to investigate the metabolism of a REVERSIR™ molecule in vivo. Plasma and tissue samples were extracted using solid-phase extraction followed by LC-HRMS analysis for metabolite profiling and quantification. The method was qualified from 10 to 5000 ng/ml (plasma) and 100 to 50000 ng/g (liver and kidney). In rat liver, intra and interday accuracy ranged from 80.9 to 118.5% and 88.4 to 111.9%, respectively, with acceptable precision (

To explore the relationship between serum high-density lipoprotein cholesterol (HDL-C) levels and the presence and severity of pulmonary arterial hypertension (PAH).A total of 177 patients with PAH and 103 patients without pulmonary hypertension (PH) were enrolled in this study. All patients underwent right heart catheterization (RHC) for diagnosing and assessing the severity of PAH. Demographics, comorbidities, and laboratory data including serum HDL-C levels were collected.Plasma HDL-C levels in patients with PAH were significantly lower compared with patients without PH (1.08 ± 0.36 vs 1.49 ± 0.36, p 0.001). HDL-C levels positively correlated with cardiac output (r = 0.360, p 0.001), cardiac index (r = 0.337, p 0.001), and mixed venous oxygen saturation (r = 0.426, p 0.001), and negatively with mean pulmonary arterial pressure (r = - 0.529, p 0.001), right atrial pressure (r = - 0.421, p 0.001), and pulmonary vascular resistance (r = - 0.583, p 0.001). Multivariate logistic regression analysis indicated that HDL-C was a significant independent predictor of PAH (OR 0.042, 95% CI 0.006-0.304, p = 0.002). The receiver operating characteristic curve analysis showed that the optimal cutoff value of the serum HDL-C concentration for predicting PAH was 1.32 mmol/L, with a sensitivity of 83.6% and a specificity of 72.8% (area under the curve 0.803, 95% confidence interval 0.750-0.856, p 0.001).Serum HDL-C is a simple biomarker that might be used for prediction and assessment of PAH in Chinese Han ethnicity, and the mechanism underlying the association needs further study.

Regulator of G protein signaling 3 (RGS3) is a negative regulator of G protein-mediated signaling. RGS3 has previously been shown to be expressed among various cell types within the mature heart. Basic and clinical studies have reported abnormal expressions of RGS3 in hypertrophic hearts and in the failing myocardium. However, the role of RGS3 in cardiac remodeling remains unclear. In this study, we investigated the effect of cardiac overexpression of human RGS3 on cardiac hypertrophy induced by aortic banding (AB) in RGS3 transgenic mice and wild-type littermates. The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. RGS3 overexpression in the heart markedly reduced the extent of cardiac hypertrophy, fibrosis, and left ventricular dysfunction in response to AB. These beneficial effects were associated with the inhibition of MEK-ERK1/2 signaling. In vitro studies performed in cultured neonatal rat cardiomyocytes confirmed that RGS3 overexpression inhibits hypertrophic growth induced by angiotensin II, which was associated with the attenuation of MEK-ERK1/2 signaling. Therefore, cardiac overexpression of RGS3 inhibits maladaptive hypertrophy and fibrosis and improves cardiac function by blocking MEK-ERK1/2 signaling.

CD95 is the first death receptor identified and characterized in recent years, and it plays important roles in the molecular network regulating cell death and survival. CD95 rs1800682 polymorphism is a common genetic polymorphism identified in the CD95 gene. Many publications evaluated the association between CD95 rs1800682 polymorphism and cervical cancer risk, but the association remained inconclusive. To provide a more precise estimate on the association, a meta-analysis was carried out. The association between CD95 rs1800682 polymorphism and cervical cancer risk was assessed by calculating the pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI). On the basis of our inclusion criteria, ten studies with a total of 5,481 individuals were included into the meta-analysis. There was obvious heterogeneity among the included studies. Meta-analysis of the ten studies suggested that there was no association between CD95 rs1800682 polymorphism and cervical cancer risk under all four genetic models (allele model: OR = 1.05, 95 % CI 0.92–1.18, P = 0.478; homozygous model: OR = 1.08, 95 % CI 0.83–1.41, P = 0.550; dominant model: OR = 1.12, 95 % CI 0.88–1.42, P = 0.347; recessive model: OR = 1.00, 95 % CI 0.76–1.31, P = 0.978). Subgroup analysis by ethnicity suggested that there was no association between CD95 rs1800682 polymorphism and cervical cancer risk in Asians, Caucasians, and Africans. Thus, the meta-analysis suggests that CD95 rs1800682 polymorphism is not associated with cervical cancer risk.

Background Pulmonary arterial hypertension (PAH) frequently arises in patients with congenital heart disease (CHD) and can lead to pulmonary vascular disease (PVD). The present study was initiated to distinguish the predisposing effect of bone morphogenetic protein receptor 2 ( BMPR2 ) in CHD by comparing the different mutation features of BMPR2 between CHD patients with or without PVD. Methods and results 294 CHD–PVD and 161 CHD without PVD patients were enrolled. PAH was diagnosed by heart catheterization at rest after CHD was first recognized by echocardiography. PVD was defined as a pulmonary vascular resistance (PVR) more than 3Wood units. BMPR2 gene was screened by direct sequencing. A total of 24 mutations were identified, accounting for 22 of the 294 patients with CHD–PVD (7.5%) and 2 of the 161 CHD patients without PVD (1.2%, P =0.004). Female/male CHD–PVD patient ratio was 1.6:1, while in the BMPR2 mutation carriers female patients were more dominant (4.5:1, P =0.042). A significant higher BMPR2 mutation rate (12.6%) was found in repaired CHD–PVD ( P =0.010). BMPR2 mutations in CHD–PVD patients were identified in different clinical phenotypes. Missense mutation of BMPR2 is the dominant mutation type. Conclusion Genetic predisposing factor may be an important component in the process of development of PVD in CHD patients. Female, repaired patients are more likely to be detected with genetic mutations.

To study the effect of flavonoids isolated from aerial parts of Scutellaria baicalensis Georgi (SSF) on cerebral damage induced by okadaic acid (OA) in rats.OA was microinjected into the right lateral ventricle of male rats at a dose of 200 ng kg(-1) twice with a 3-day interval between injections to establish a model of Alzheimer's-disease-like cerebral damage. Neuronal morphology was observed with thionin staining and the expressions of glial fibrillary acidic protein (GFAP) and β-amyloid peptide 1-40 (Aβ1-40) were monitored via immunohistochemistry. The level of malondialdehyde (MDA) and the activities of glutathione peroxidase (GSH-Px) and lactate dehydrogenase (LDH) were measured using spectrophotometry.The results showed that OA-treated rats exhibited marked neuronal damage accompanied by increased levels of Aβ1-40 peptide and MDA accumulation, decreased GFAP protein expression and reduced GSH-Px and LDH activity in the brain. SSF at three doses (25, 50 and 100 mg kg(-1)) dramatically reversed the OA-induced changes in the brains of rats.SSF-mediated amelioration of OA-induced neuronal damage in rats provides a rationale for assessing SSF as a means of to reducing tau hyperphosphorylation and Aβ expression in the treatment of Alzheimer's disease.

Regulator of G protein signaling 3 (RGS3) is a negative regulator of G protein-mediated signaling. RGS3 has previously been shown to be expressed among various cell types within the mature heart. Basic and clinical studies have reported abnormal expressions of RGS3 in hypertrophic hearts and in the failing myocardium. However, the role of RGS3 in cardiac remodeling remains unclear. In this study, we investigated the effect of cardiac overexpression of human RGS3 on cardiac hypertrophy induced by aortic banding (AB) in RGS3 transgenic mice and wild-type littermates. The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. RGS3 overexpression in the heart markedly reduced the extent of cardiac hypertrophy, fibrosis, and left ventricular dysfunction in response to AB. These beneficial effects were associated with the inhibition of MEK-ERK1/2 signaling. In vitro studies performed in cultured neonatal rat cardiomyocytes confirmed that RGS3 overexpression inhibits hypertrophic growth induced by angiotensin II, which was associated with the attenuation of MEK-ERK1/2 signaling. Therefore, cardiac overexpression of RGS3 inhibits maladaptive hypertrophy and fibrosis and improves cardiac function by blocking MEK-ERK1/2 signaling.

The role of vitamin D receptor (VDR) BsmI polymorphism in ovarian cancer development has been studied in various populations, but those results are discordant controversial and ambiguous. Thus, we performed a meta-analysis to assess the association between VDR BsmI polymorphism and susceptibility to ovarian cancer more precisely. Odds ratio (OR) and its 95% confidence interval (95% CI) were used for statistical analysis. Nine individual studies with a total 2,331 cases and 3,301 controls were included into this meta-analysis. There was no heterogeneity among those nine studies. Meta-analysis of total nine studies suggested that there was no association between VDR BsmI polymorphism and susceptibility to ovarian cancer (B vs. b, OR = 1.02, 95% CI = 0.94-1.10, P = 0.616, I(2) = 0%; BB vs. bb, OR = 1.02, 95 % CI = 0.87-1.20, P = 0.810, I(2) = 0 %; BB/Bb vs. bb, OR = 1.05, 95% CI = 0.94-1.18, P = 0.391, I(2) = 0 %; BB vs. bb/Bb, OR = 0.99, 95% CI = 0.85-1.14, P = 0.853, I(2) = 0 %). Meta-analysis of seven studies from Caucasians also showed that there was no association between VDR BsmI polymorphism and susceptibility to ovarian cancer. This meta-analysis suggests that there is no association between VDR BsmI polymorphism and susceptibility to ovarian cancer in Caucasians. Future studies from Asians or Africans are needed to further assess the above association.

To evaluate the safety and efficacy and summarize the initial experience of transcatheter aortic valve implantation (TAVI) for treating patients with severe aortic stenosis.From October 2010 to May 2011, TAVI using 18 F Corevalve system was applied in 3 patients with severe calcified aortic valve stenosis at high risk for surgery. The efficacy and complications of the procedure were analyzed and the procedure experiences were summarized.TAVI procedure was successful in all 3 cases. The mean operation time was (109.0 ± 22.6) minutes and X-ray exposure time was (24.0 ± 9.5) minutes. The peak pressure gradients after surgery were significantly reduced [from (84 ± 15) mm Hg (1 mm Hg = 0.133 kPa) to (6 ± 3) mm Hg]. A trivial to mild paravalvular leak was observed in all patients post procedure. Case 1 was free from perioperative complications. Case 2 experienced a transient complete left bundle branch block. Case 3 developed 3 degree atrioventricular block and implanted with a permanent cardiac pacemaker, cardiac tamponade which was relieved through conservative treatment, including pericardial puncture and drainage and acute kidney injury.Our initial experience showed that TAVI using the 18 F Corevalve system is safe and effective for patients with severe calcified aortic valve stenosis at high-risk for surgery, though the procedure may cause some complications. Strict patient selection and proficient surgical techniques may reduce the incidence of complications.