Can acetaminophen/dimethyl sulfoxide formulation prevent accidental and intentional acetaminophen hepatotoxicity?

An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human. We hypothesized that a less hepatotoxic APAP if co-formulated with DMSO. To test this hypothesis, C57BL/6 mice were given toxic dose of APAP (250 mg kg⁻¹, i.p.) mixed with different doses of DMSO (25, 50, 100, and 200 μl kg⁻¹). Six hours after APAP treatment, blood and lives were collected for analysis. In DMSO treated groups, there was dose-dependent decrease in markers of liver injury, alanine aminotransferase, and aspartate aminotransferase. Maximum protection was obtained with 200 μl DMSO kg⁻¹. DMSO was shown to inhibit the activation step by decreasing the rate of GSH depletion in vivo and inhibiting cytochrome P450 system in vitro. Also the levels of lipid peroxides, nitrate/nitrite, tumor necrosis factor-alpha, and interleukin 1β were decreased significantly. In conclusion, DMSO exerts its protective action by inhibiting the metabolic activation of APAP and thus alleviating the downstream, oxidative stress, nitrosative stress, and inflammation via indirect inhibition. Our findings suggest that replacing the current APAP with APAP/DMSO formulation could prevent accidental and intentional APAP toxicity.     

KCNQ1 SNPS and susceptibility to diabetic nephropathy in East Asians with type 2 diabetes

Aims/hypothesis

A Japanese study had earlier reported that KCNQ1 single-nucleotide polymorphisms (SNPs) may be associated with diabetic nephropathy. To further investigate this finding, we analysed three SNPs, rs2237895, rs2237897 and rs2283228, within the KCNQ1 locus for association with albuminuria among Chinese type 2 diabetic patients residing in Singapore. Albuminuria was analysed as both categorical (micro- and macroalbuminuria) and continuous traits (log _e albumin/creatinine ratio [ACR]).

Methods

A total of 752 Chinese patients with type 2 diabetes were included in the study. Albuminuria was determined by ACR using spot urine samples, and renal function was approximated using estimated GFR. Genotyping was performed using invader and Taqman assays as appropriate. Multivariate regression analyses were used to analyse the associations between SNPs and renal traits.

Results

Significant associations were detected between rs2283228 and macroalbuminuria (p?p? e ACR (p?=?0.004, corrected p?=?0.036) after multiple hypothesis testing and adjustment for potential confounding. A trend of increasing OR was observed with increasing severity of diabetic nephropathy (low and high microalbuminuria, macroalbuminuria). rs2237897, previously implicated in the earlier Japanese study, was also associated with macroalbuminuria, but this finding did not remain significant after correction for multiple testing. Meta-analyses of the Chinese and Japanese studies revealed both SNPs to be significantly associated with macroalbuminuria.

Conclusions/interpretation

Together with the previous Japanese study, our findings support the hypothesis that, in addition to KCNQ1 being an established type 2 diabetes gene, genetic variation in this gene may contribute to susceptibility to diabetic nephropathy in East Asians.     

A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies

ObjectiveMultiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs).MethodsSNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS.ResultsThe GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ = 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest.ConclusionAddition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.     

Clinical outcomes of percutaneous interventions in saphenous vein grafts using drug-eluting stents compared to bare-metal stents: a comprehensive meta-analysisof all randomized clinical trials

Background:

Clinical outcomes of percutaneous coronary intervention (PCI) in patients with saphenous vein grafts (SVGs) remain poor despite the use of drug‐eluting stents (DES). There is a disparity in clinical outcomes in SVG PCI based on various registries, and randomized clinical data remain scant. We conducted a meta‐analysis of all existing randomized controlled trials (RCTS) comparing bare‐metal stents (BMS) and DES in SVGPCIs.

Hypothesis:

PCI in patients with SVG disease using DES may reduce need for repeat revascularization without an excess mortality when compared to BMS.

Methods:

An aggregate data meta‐analysis of clinical outcomes in RCTs comparing PCI with DES vs BMS for SVGs reporting at least 12 months of follow‐up was performed. A literature search between Janurary 1, 2003 and September 30, 2011 identified 4 RCTs (812 patients; DES = 416, BMS = 396). Summary odds ratio (OR) and 95% confidence interval (CI) were calculated using the random‐effects model. The primary endpoint was all‐cause mortality. Secondary outcomes included nonfatal myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). These outcomes were assessed in a cumulative fashion at 30 days, 18 months, and 36 months.

Results:

There were no intergroup differences in baseline clinical and sociodemographic characteristics. At a median follow‐up of 25 months, patients in the DES and BMS group had similar rates of death (OR: 1.63, 95% CI: 0.45–5.92), MI (OR; 0.83, 95% CI: 0.27‐2.60), and MACE (OR: 0.58, 95% CI: 0.25–1.32). Patients treated with DES had lower rates of repeat revascularization (OR: 0.40, 95% CI: 0.22–0.75).

Conclusions:

In this comprehensive meta‐analysis of all RCTs comparing clinical outcomes of PCI using DES vs BMS in patients with SVG disease, use of DES was associated with a reduction in rate of repeat revascularization and no difference in rates of all‐cause death and MI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21984 Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (CDA‐09‐028), and has research support from Merck and National Football League Charities (all grants to the institution and not individual). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose.