Fatal overdose with a combination of SNRIs venlafaxine and duloxetine.

Drugs for the treatment of depressive disorders, including SNRIs (serotonin noradrenaline reuptake inhibitors) venlafaxine and duloxetine, are widely prescribed as they have a high therapeutic to toxicity ratio. In rare cases, adverse effects may be severe, usually due to iatrogenic, accidental or intentional self-overdose that cause the excessive accumulation of serotonin and noradrenaline in synaptic clefts. Lethal intoxication with a combination of venlafaxine and duloxetine (postmortem blood concentrations 24 mg/L and 0.97 mg/L, respectively) without co-ingested substances, comorbidities or injuries that could have an unknown contribution to a fatal outcome is presented for the first time in the following case report, with a comprehensive clinical history, and complete results of the performed analyses. The cause of death was a serotonin syndrome that progressed to death in approximately six hours and 15 min after the suicidal ingestion of venlafaxine and duloxetine. Despite the high therapeutic to toxicity ratio SNRIs, which are reserved for patients with severe forms of depressive disorders and a higher suicidal tendency, they should be cautiously prescribed and handed over in smaller packages to make them easier to follow, and thus avoid accumulation within the patient's reach.

Endothelin-1 Gene Polymorphisms rs5370, rs1476046, and rs3087459 are not Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus.

BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Several lines of evidence implicate the endothelin (ET) system in the pathophysiology of DN. The aim of the present study was to analyze if genetic polymorphisms of the ET-1 (EDN1) gene affect susceptibility to DN in Caucasians with T2DM. MATERIALS AND METHODS: The study population consisted of 651 Caucasian subjects with T2DM of more than 10 years' duration: 276 patients with DN (cases) and 375 patients without evidence of DN (controls). Polymorphisms in ET-1 (EDN1) gene, rs5370, rs1476046, and rs3087459, were studied. RESULTS: Genotype distributions of the studied polymorphisms showed no significant difference between cases and controls. CONCLUSIONS: We provide evidence that the rs5370, rs1476046, and rs3087459 polymorphisms of EDN1 gene are not risk factors for DN in Caucasians with T2DM.

PECAM-1 Leu125Val (rs688) Polymorphism and Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus.

Objectives. Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays a key role in the transendothelial migration of circulating leukocytes during inflammation and in the maintenance of vascular endothelial integrity. We hypothesized that genetic variation in PECAM-1 gene could be associated with diabetic nephropathy (DN) and with the level of soluble PECAM-1 in Caucasians with type 2 diabetes mellitus (T2DM). Design and Methods. We analyzed the rs688 single nucleotide polymorphism of PECAM-1 gene C373G (Leu125Val) at exon 3, which encodes the first extracellular Ig-like domain that mediates the homophilic binding of PECAM-1, in 276 T2DM subjects with documented DN (cases) and 375 T2DM subjects without DN (controls), using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. Level of plasma soluble PECAM-1 (sPECAM-1) was measured by ELISA in a subpopulation of 120 diabetics with DN. Results. We found no association between the Leu125Val polymorphism and DN in subjects with T2DM. Likewise, the Leu125Val polymorphism was not associated with serum sPECAM-1 levels in a subpopulation of 120 diabetics with DN. Conclusion. The Leu125Val polymorphism of PECAM-1 and the level of sPECAM-1 are not associated with DN in T2DM subjects of Slovenian origin.

Association of thioredoxin reductase 2 (TXNRD2) gene polymorphisms with myocardial infarction in Slovene patients with type 2 diabetes mellitus.

OBJECTIVES: The aim of our study was to investigate the relationship between genetic polymorphisms in the mitochondrial thioredoxin reductase 2 (TrxR2) and myocardial infarction (MI) in subjects with type 2 diabetes mellitus (T2DM) of Slovenian origin. METHODS: The study population consisted of 972 Caucasian subjects with T2DM of more than 10 years' duration: 161 patients with MI and 811 patients with no history of coronary artery disease. Polymorphisms in thioredoxin reductase 2 (TXNRD2) gene, rs1548357, rs4485648, and rs5748469, were studied. RESULTS: Individuals carrying CC+CT genotypes of rs1548357 TXNRD2 polymorphism had lower prevalence of MI compared with TT genotype group (41.6% vs 52.8%, OR=0.589, 95% CI=0.368-0.942, P=0.027). CONCLUSIONS: The TXNRD2 rs 1548357 polymorphism might be a genetic risk factor for MI in subjects with T2DM of Slovenian origin.

Minor association of kinase insert domain-containing receptor gene polymorphism (rs2071559) with myocardial infarction in Caucasians with type 2 diabetes mellitus: case-control cross-sectional study.

OBJECTIVE: Vascular endothelial growth factor A (VEGF) and its receptor KDR play central roles in angiogenesis and vascular repair, which occur in diabetic vascular complications, such as MI. The aim of our study was to investigate if polymorphisms rs2071559 and rs2305948 in the kinase insert domain-containing receptor (KDR) gene are associated with myocardial infarction (MI) in Caucasians with type 2 diabetes (T2DM). DESIGN AND METHODS: The association of KDR -604T>C (rs2071559) and 1192G>A (rs2305948) polymorphisms was tested in a case-control cross-sectional study including 171 subjects with T2DM and MI compared to 855 subjects with T2DM without coronary artery disease (CAD). In addition, VEGF serum levels were analyzed in 98 subjects with type 2 diabetes without CAD. RESULTS: A significantly higher frequency of the CC genotype of the KDR -604T>C (rs2071559) polymorphism was found in diabetic patients with MI compared to diabetic patients without CAD (27.5% vs. 21.1%, p=0.04). On the other hand, the 1192G>A (rs2305948) polymorphism was not associated with MI in subjects with type 2 diabetes. Significantly higher VEGF serum levels were found in subjects with the -604CC genotype compared to those with other (CT+TT) genotypes (73.8 ± 22.1 ng/l vs. 58.1 ± 18.5 ng/l; p<0.01). Multiple logistic regression analysis adjusted for age, arterial hypertension, LDL cholesterol, HDL cholesterol and hsCRP revealed that carriers of the -604CC genotype (rs2071559) had a 1.6-fold higher risk for MI (OR=1.6; 95% CI=1.1-2.1; p=0.022). CONCLUSION: The present study demonstrates that the CC genotype of the KDR -604T>C polymorphism (rs2071559) is a possible risk factor for MI in Caucasians with T2DM.

Association of manganese superoxide dismutase and glutathione S-transferases genotypes with myocardial infarction in patients with type 2 diabetes mellitus.

AIM: In the present study we investigated the association between genetic polymorphisms with functional effects on redox regulation: Val16Ala of manganese superoxide dismutase (MnSOD), polymorphic deletions of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and Ile105Val of glutathione S-transferase P1 (GSTP1) and myocardial infarction (MI) in a group of patients with type 2 diabetes mellitus. METHODS: The study population consisted of 463 Caucasian subjects with type 2 diabetes mellitus of more than 10 years' duration: 206 patients with MI and 257 patients with no history of coronary artery disease (CAD). Genotypes were determined by polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) and with multiplex PCR. RESULTS: The genotype distributions of tested single nucleotide polymorphisms did not show significant difference between cases and controls. After adjustment for age, gender, smoking, BMI, duration of diabetes and lipid parameters carriers of GSTM1/GSTT1-null haplotype showed an increased risk for MI (OR=3.22, 95% CI 1.37-5.04, p=0.03). CONCLUSIONS: The GSTM1/GSTT1 haplotype might be a genetic risk factor for MI in patients with type 2 diabetes mellitus.

The interleukin-1 receptor antagonist gene and the inhibitor of kappa B-like protein gene polymorphisms are not associated with myocardial infarction in Slovene population with type 2 diabetes.

In this study we investigated the association of the interleukin-1 receptor antagonist gene variable number tandem repeat (IL1RN VNTR) polymorphism and of the inhibitor of kappa B-like protein (IKBL) gene polymorphism with myocardial infarction (MI) in a group of patients with type 2 diabetes. The IL1RN VNTR and the IKBL+ 738T > C gene polymorphisms were tested in 374 Caucasians: 151 cases with MI and 223 subjects with no history of coronary artery disease. The IL1RN VNTR polymorphism was not a risk factor for MI in Caucasians with type 2 diabetes (genotype 22 vs. the rest: odds ratio (OR) 1.6; 95% confidence interval (CI) = 0.8-3.5; p = 0.2). We also failed to demonstrate that IKBL+ 738T > C gene polymorphism was associated with MI in patients with type 2 diabetes (OR = 0.9; 95% CI = 0.3-2.6; p = 0.9). We provide evidence that the IL1RN VNTR and the IKBL + 738T > C gene polymorphisms are not risk factors for MI in Caucasians with type 2 diabetes.