Safety profile of methotrexate used off-label in ectopic pregnancy: an active monitoring study based on a Chinese hospital pharmacovigilance system

Methotrexate (MTX) is characterized as first-line therapy although its indication of ectopic pregnancy is off-label use. We aimed to conduct a retrospective cohort study to investigate the incidence, characteristics of adverse drug reactions (ADRs) of MTX, provide valuable insights for medical workers. Basing on China Hospital Pharmacovigilance System (CHPS), a retrospective analysis was performed to evaluate the safety of MTX (n = 672). An active monitoring model was set to detect ADR signals from the hospital information system. Frequency, Common Terminology Criteria for Adverse Events (CTCAE) grade proportion and association of dose exposure with ADRs were presented as outcomes. The total incidence of ADRs was 54.0%. Anaemia (37.6%) was the most frequent ADR, followed by hepatic function abnormal (11.3%), hyperuricemia (6.1%), neutropenia (4.6%), leukopenia (4.0%), and dyslipidaemia (2.5%). For the composition of all ADRs, CTCAE grade one, two and three dominated for 86.3%, 12.1% and 1.6%, respectively. The severity of hepatic function abnormal was more serious in the two-dose exposed group (p = .021), while other types of ADRs had no statistical or clinical differences. Logistic regression analysis showed the incidence of any ADRs (OR 1.87 [1.31–2.64]; p = .001), hepatic function abnormal (OR 2.75 [1.69–4.48]; p p = .001) were significantly higher in the two-dose exposed group. After adjusted, the positive associations were still maintained. MTX is quite safe in ectopic pregnancy, despite its mild to moderate hematotoxicity, hepatotoxicity and nephrotoxicity. Taking CHPS can present the accurate denominator of the incidence of adverse drug reactions into account, our study advocates that it may have great potential to be used as an active monitoring tool for off-label drug use risk management.</p

Characteristics of literatures included in the meta-analysis.

<p>EC: Esophageal Cancer; HCC: Hepatocellular Carcinoma; SCCHN: Squamous Cell Carcinoma of the Head and Neck; PCR-RFLP: Polymerase Chain Reaction-restriction Fragment Length Polymorphism; PCR–LDR: Polymerase Chain Reaction–Ligation Detection Reaction; Fuorescence: Labeled Hybridization Probes; PB, Population Based; HB, Hospital Based.</p

Begg's funnel plot for publication bias test (CC versus TC/TT).

<p>Each point represents a separate study for the indicated association. Log[or], natural logarithm of OR. Horizontal line, mean effect size.</p

Studies identified with criteria for inclusion and exclusion.

<p>Studies identified with criteria for inclusion and exclusion.</p

A Genetic Variant in <em>pre-miR-27a</em> Is Associated with a Reduced Renal Cell Cancer Risk in a Chinese Population

<div><h3>Background</h3><p>MicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of <em>pre-miR-27a</em>. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population.</p> <h3>Methods</h3><p>In this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors.</p> <h3>Results</h3><p>Compared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56–0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55–0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55–0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28–0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC.</p> <h3>Conclusion</h3><p>Our results suggest that the <em>pre-miR-27a</em> rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.</p> </div

Distribution of selected variables between the RCC cases and control subjects.

a<p>Student's t-test for age and BMI distributions between cases and controls; two-sided χ² test for other selected variables between cases and controls.</p><p>SD, standard deviation; BMI, body mass index.</p

DNA sequencing chromatograms of three different samples of PCR products confirmed rs895819 polymorphism.

<p>(A) Double peaks labeled with an arrow represented the heterozygous genotype TC (AG). (B) Single peak labeled with an arrow represented the homozygous genotype TT (AA). (C) Single peak labeled with an arrow represented the homozygous genotype CC (GG).</p

Associations between rs895819 polymorphism and clinical characteristics of RCC.

a<p>Adjusted for age, sex, smoking, drinking status, diabetes and hypertension in logistic regression model.</p

Genetic Variation in <i>DROSHA</i> 3’UTR Regulated by hsa-miR-27b Is Associated with Bladder Cancer Risk

<div><p>Purpose</p><p>miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk.</p> <p>Experimental Design</p><p>We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of <i>DICER</i> and <i>DROSHA</i> genes and bladder cancer risk. We then evaluated the functionality of the important SNPs.</p> <p>Results</p><p>We found that rs10719T>C polymorphism located in 3’ untranslated region (UTR) of <i>DROSHA</i> gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, <i>P</i> = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, <i>DROSHA</i> rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein.</p> <p>Conclusions</p><p>Taken together, these findings suggested that <i>DROSHA</i> rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3’UTR.</p> </div

Stratification analyses between the genotypes of rs895819 polymorphism and RCC risk.

a<p>Adjusted for age, sex, smoking, drinking status, diabetes and hypertension in logistic regression model. CI, confidence interval; OR, odds ratio.</p