cis MZ 1 - CAS 1797406-72-4

Hyponatremia, defined as a nonartifactual serum sodium level <135 mmol/L, is the most common fluid and electrolyte abnormality in clinical practice. Traditional managements (fluid restriction, hypertonic saline and loop diuretics, etc.) are difficult to maintain or ineffective. Recently, vasopressin receptor antagonists (VRAs) have shown promise for the treatment of hyponatremia. We aimed to conduct a meta-analysis to evaluate the efficacy and safety of VRAs in patients with euvolemic or hypervolemic hyponatremia. We searched Pubmed, Cochrane Library, Web of Science and Springer, etc. (latest search on June 4, 2015) for English publications with randomized controlled trials. Two authors independently screened the citations and extracted data. We calculated pooled relative risk (RR), risk difference (RD), weighted mean difference (WMD) or standard mean difference (SMD), and 95% confidence intervals (CIs) by using random and fixed effect models. We collected data from 18 trials involving 1806 patients. Both random and fixed effect meta-analyses showed that VRAs significantly increased the net change of serum sodium concentration (WMD(random) = 4.89 mEq/L, 95%CIs = 4.35-5.43 and WMD(fixed) = 4.70 mEq/L, 95%CIs = 4.45-4.95), response rate (RR(random )= 2.77, 95%CIs = 2.29-3.36 and RR(fixed) = 2.95, 95%CIs = 2.56-3.41), and 24-hour urine output (SMD(random) = 0.82, 95%CIs = 0.65-1.00 and SMD(fixed) = 0.79, 95%CIs = 0.66-0.93) compared to placebo. Furthermore, VRAs significantly decreased body weight (WMD(random) = -0.87 kg, 95%CIs = -1.24 to -0.49 and WMD(fixed) = -0.91 kg, 95%CIs = -1.22 to -0.59). In terms of safety, rates of drug-related adverse events (AEs), rapid sodium level correction, constipation, dry mouth, thirst, and phlebitis in the VRA-treated group were greater than those in control group. However, there was no difference in the total number of AEs, discontinuations due to AEs, serious AEs, death, headache, hypotension, nausea, anemia, hypernatremia, urinary tract infection, renal failure, pyrexia, upper gastrointestinal bleeding, diarrhea, vomiting, peripheral edema, and dizziness between the 2 groups. Random effect meta-analyses showed that post treatment urine osmolality, supine systolic blood pressure, and diastolic blood pressure were lowered (WMD(random) = -233.07 mOsmol/kg, 95%CIs = -298.20-147.94; WMD(random) = -6.11 mmHg, 95%CIs = -9.810 to -2.41; WMD(random )= -2.59 mmHg, 95%CIs = -4.06 to -1.11, respectively), but serum osmolality was increased (WMD(random) = 9.29 mOsmol/kg, 95%CIs = 5.56-13.03). There was no significant change from baseline in serum potassium concentration between the 2 groups (WMD(fixed) = 0.00 mmHg, 95%CIs = -0.07-0.06). VRAs are relatively effective and safe for the treatment of hypervolemic and euvolemic hyponatremia.

Objective:To assess the association between exposure to monotherapy with 10 different antiepileptic drugs (AEDs) during the first 2 months of pregnancy and the risk of 23 major congenital malformations (MCMs). Methods:This nationwide cohort study, based on the French health care databases, included all pregnancies ≥20 weeks and ending between January 2011 and March 2015. Women were considered to be exposed when an AED had been dispensed between 1 month before and 2 months after the beginning of pregnancy. The reference group included pregnant women with no reimbursement for AEDs. MCMs were detected up to 12 months after birth (24 months for microcephaly, hypospadias, and epispadias). Odds ratios (ORs) were adjusted for potential confounders for MCMs with at least 5 cases. Otherwise, we calculated crude ORs with exact confidence intervals (CIs). Results:The cohort included 1,886,825 pregnancies, 2,997 of which were exposed to lamotrigine, 1,671 to pregabalin, 980 to clonazepam, 913 to valproic acid, 579 to levetiracetam, 517 to topiramate, 512 to carbamazepine, 365 to gabapentin, 139 to oxcarbazepine, and 80 to phenobarbital. Exposure to valproic acid was associated with 8 specific types of MCMs (e.g., spina bifida, OR 19.4, 95% CI 8.6-43.5), and exposure to topiramate was associated with an increased risk of cleft lip (6.8, 95% CI 1.4-20.0). We identified 3 other signals. We found no significant association for lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and gabapentin.Conclusions:These results confirm the teratogenicity of valproic acid and topiramate. Because of the small numbers of cases and possible confounding, the other 3 signals should be interpreted with appropriate caution.

Rationale:Previous studies on the relationship between diabetes and arterial stiffness were mostly cross-sectional. A few longitudinal studies focused on one single direction. Whether the association between arterial stiffness and diabetes is bidirectional remains unclear to date. Objective:To explore the temporal relationship between arterial stiffness and fasting blood glucose (FBG) status.Methods and results:Included were 14 159 participants of the Kailuan study with assessment of brachial-ankle pulse wave velocity (baPWV) from 2010 to 2015, and free of diabetes, cardiovascular and cerebrovascular diseases, and chronic kidney disease at baseline. FBG and baPWV were repeatedly measured at baseline and follow-ups. Cox proportional hazard regression model was used to estimate hazard ratios and 95% confidence intervals (CIs) of incident diabetes across baseline baPWV groups: <1400 cm/s (ref), 1400≤ baPWV <1800 cm/s, and ≥1800 cm/s. Path analysis was used to analyze the possible temporal causal relationship between baPWV and FBG, among 8956 participants with repeated assessment of baPWV and FBG twice in 2010 to 2017. The mean baseline age of the observed population was 48.3±12.0 years. During mean 3.72 years of follow-up, 979 incident diabetes cases were identified. After adjusting for potential confounders, the hazard ratio (95% CI) for risk of diabetes was 1.59 (1.34-1.88) for the borderline arterial stiffness group and 2.11 (1.71-2.61) for the elevated arterial stiffness group, compared with the normal ideal arterial stiffness group. In the path analysis, baseline baPWV was associated with follow-up FBG (the standard regression coefficient was 0.09 [95% CI, 0.05-0.10]). In contrast, the standard regression coefficient of baseline FBG for follow-up baPWV (β=0.00 [95% CI, -0.02 to 0.02]) was not significant.Conclusions:Arterial stiffness, as measured by baPWV, was associated with risk of developing diabetes. Arterial stiffness appeared to precede the increase in FBG.