A case study of acute human chlorpyrifos poisoning: novel aspects on metabolism and toxicokinetics derived from liquid chromatography-tandem mass spectrometry analysis of urine samples

The metabolic fate of the organophosphorothioate-type insecticide chlorpyrifos (CP) in an acutely intoxicated 59 years old female was investigated by liquid chromatography-electrospray ionisation-tandem mass spectrometry (LC-ESI-MS/MS) analysis of urine samples. Fifteen metabolites of CP and its bioactivated intermediate chlorpyrifos-oxon (CPO), respectively, of which only three have been described in man so far, were identified on the basis of characteristic MS/MS transitions, precursor/product ion and/or neutral loss scans, chlorine isotopomer patterns, and partly by synthesis of reference compounds and subsequent structure confirmation. Three distinct biotransformation routes of CP are proposed: (1) cleavage reactions at the aromatic phosphoester bond, (2) cleavage reactions at the alkyl phosphoester bonds, and (3) glutathione (GSH) dependent nucleophilic substitution of the 6-chlorine at the aromatic moiety. Route (2) has not been reported in humans before and (3) is a hitherto completely unknown scheme of CP metabolism. Urinary markers of the latter were chiefly cysteine S-conjugates of mono-dechlorinated CP, CPO, mono-O-deethyl CP, and mono-O-deethyl CPO as well as the 6-mercapturic acid conjugate of 3,5-dichloro-2-pyridinol. The presence of 3,5-dichloro-6-methylthio-2-pyridinol as well as its O-glucuronide suggests further a cysteine S-conjugate beta-lyase mediated degradation. In addition to the qualitative LC-MS/MS screening the renal elimination profiles of the primary products of scheme (1), i.e. diethyl thiophosphate (DETP), diethyl phosphate (DEP), and 3,5,6-trichloro-2-pyridinol (TCP), were monitored over 14 days (n=21). A biphasic first-order excretion mechanism with half-lives of 21.5h (initial fast excretion phase) and 119.5h (terminal phase) for the sum of free DETP and DEP was found. TCP was hardly eliminated in its free form (O-glucuronide identified as phase II conjugate) and half-lives calculated for the total amount of TCP (acidic hydrolysis of urine samples) were 40.8 and 150.7h. The present study gives a more detailed view on the biotransformation of CP and together with the obtained kinetic data adds novel aspects to the limited knowledge of human metabolism of this xenobiotic, in particular at high dosage.     

Cardiac troponin T and creatine kinase MB mass concentrations in children receiving anthracycline chemotherapy

Anthracyclines (doxorubicin, daunorubicin, and derivatives) are among the most effective antineoplastic drugs for pediatric cancer with dose-limiting acute and longterm cardiotoxicity. The exact mechanism of the development of cardiomyopathy is still not clear. Anthracyclines may induce subclinical acute myocardial injury leading to lysis of a limited number of myocytes. Alternatively, myocytes may experience a transient loss of cytoplasmic membrane integrity. Both conditions may lead to a transient efflux of small amounts of cytoplasmic enzymes and other proteins specific to the heart muscle fibers. To test these hypotheses we assayed plasma creatine kinase (CK) MB mass and cardiac specific troponin T (TnT). CKMB may be released even in case of reversible cell membrane injury, while prolonged elevation of TnT is the most sensitive and specific marker of limited myocardial necrosis. Thirty-five anthracycline-containing chemotherapy courses in 22 children with cancer were analyzed. CKMB mass and TnT concentrations were within the normal range in all children before anthracycline therapy. Within 72 hours from anthracycline therapy no increment of one of these two marker proteins was detected (ANOVA for repeated measures, P = 0.94 [TnT] and 0.25 [CKMB]). We conclude that only minimal if any acute necroses of cardiac myocytes occur after anthracycline therapy. Even membrane integrity appears to be maintained within the first 3 days after anthracycline therapy, in the absence of electrocardiographic or echocardiographic signs of acute cardiotoxicity. © 1995 Wiley-Liss, Inc.     

High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients

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Exercise-induced increase in plasma concentrations of calcitonin gene-related peptide in patients with coronary heart disease and healthy controls

Calcitonin gene-related peptide is a potent regulator of vascular tone. In the present study the authors investigated plasma levels of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) during maximum bicycle exercise in 8 patients with coronary heart disease (CHD) and in a control group of 11 healthy volunteers. There was no significant difference in CGRP-LI baseline concentrations between patients with CHD and controls. During exercise a significant increase in CGRP-LI was observed in both groups, as compared with baseline values. Although maximum CGRP-LI values did not differ significantly between the two groups, the increase in CGRP-LI was found at a much-lower work load (p=0.0006) in patients with CHD.The results suggest that CGRP-LI is involved in the regulation of vascular tone during physical exercise in humans.     

Association of myeloperoxidase with total and cardiovascular mortality in individuals undergoing coronary angiography—The LURIC study

Background

The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography.

Methods and results

MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09–1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07–1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality.

Conclusions

MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.     

Values of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in cardioversion]

We investigated atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in patients undergoing elective direct current cardioversion (CV group) due to atrial fibrillation (n = 9) or atrial flutter (n = 3). Anesthesia for cardioversion (CV) was induced with propofol 1.5 mg/kg. Conversion was achieved in all patients. Before CV all patients had elevated ANP and cGMP plasma levels. After CV the concentrations of ANP and cGMP decreased significantly within 15 and 30 minutes (p less than 0.01), respectively. Only one patient in the CV group showed increasing ANP and cGMP levels although his heart rate had decreased after CV and his blood pressure remained stable. High concentrations of ANP and cGMP might possibly be a compensatory mechanism of cardiac dysfunction. To study the influence the anesthetic agent on plasma levels of ANP and cGMP, we investigated six patients anesthetized with propofol for high-density radiation (HDR group). The data from this control group showed that propofol did not influence the plasma levels of ANP and cGMP. ANP correlated statistically significantly (p less than 0.05) with cGMP in both groups (r = 0.88 and 0.76 in the HDR and CV groups, respectively). In addition, we found a cGMP release of 149.6 +/- 17.6 per mol ANP in the HDR group, in the CV group the release was 109 +/- 54.2 cGMP per mol ANP. This phenomenon could be due to minor response of target cells to ANP stimulation (receptor down-regulation) in patients with heart disease. In conclusion, ANP and cGMP levels decreased after successful cardioversion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Staple Line Reinforcement During Laparoscopic Sleeve Gastrectomy: Absorbable Monofilament,Barbed Suture,Fibrin Glue,or Nothing? Results of a Prospective Randomized Study

Background

Laparoscopic sleeve gastrectomy (LSG) is associated with serious complications, such as staple line (SL) leaks and bleeding. In order to prevent the occurrence of these complications, surgeons have advocated the need to strengthen the staple line. The aim of this randomized controlled study was to compare the efficacy of three different ways of strengthening of the SL in LSG in preventing surgical post-operative complications.

Methods

Between April 2012 and December 2014, 600 patients (pts) scheduled for LSG were prospectively randomized into groups without SL reinforcement (group A) or with SL reinforcement including fibrin glue coverage (group B), or oversewn SL with imbricating absorbable (Monocryl?; group C) or barbed (V lock®) running suture (group D). Primary endpoints were post-operative leaks, bleeding, and stenosis, while secondary outcomes consisted of the time to perform the staple line reinforcement (SLR) and total operative time.

Results

Mean SLR operative time was lower for group B (3.4?±?1.3 min) compared with that for groups C (26.8?±?8.5 min) and D (21.1?±?8.4 min) (p?<?0.0001). Mean total operative time was 100.7?±?16.4 min (group A), 104.4?±?22.1 min (group B), 126.2?±?18.9 min (group C), and 124.6?±?22.8 (group D) (p?<?0.0001). Post-operative leaks, bleeding, and stenosis were recorded in 14 pts (2.3 %), 5 pts (0.8 %), and 7 pts (1.1 %), respectively, without statistical difference between the groups.

Conclusion

Our study suggests that SLR during LSG, with an imbricating or non-imbricating running suture or with fibrin glue, is an unrewarding surgical act with the sole effect of prolonging the operative time.

     

Rare Neurological Complications After Sleeve Gastrectomy

Background

Bariatric surgery is considered to be the most effective treatment of morbid obesity and improvement of obesity-related comorbidities, such as type II diabetes. However, both peripheral and central neurological complications can occur after bariatric surgery. Such complications tend to occur more frequently after bypass surgery than after sleeve gastrectomy (SG). The objective of this study was to identify the patients that presented post-operative neurological complications after undergoing SG and describe the incidence, presentation, and management of these complications.

Methods

This was a retrospective study of 592 cases of SG performed between 2009 and 2014 with a special focus on patients who presented neurological complications.

Results

Of the 592 SG cases, only seven (1.18 %) patients presented neurological complications. All patients had uneventful post-operative course, but all reported feeding difficulties, accompanied by severe dysphagia, and rapid weight loss, with a mean weight loss of 35 kg (30–40 kg) 3 months after SG. All patients were readmitted owing to neurological symptoms that included paresthesia, abolition of deep tendon reflexes of the lower limbs, muscle pain, and motor and sensitive deficits in some cases. There were two cases of Wernicke’s encephalopathy. All patients were treated for neuropathy secondary to vitamin B1 deficiency and had a significant improvement and/or resolution of their symptoms.

Conclusions

Neurological complications after SG are rare and are often preceded by gastrointestinal symptoms, rapid weight loss, and lack of post-operative vitamin supplementation. Re-hospitalization and multidisciplinary team management are crucial to establish the diagnosis and initiate treatment.