A toxicokinetic model of malathion and its metabolites as a tool to assess human exposure and risk through measurements of urinary biomarkers.

A toxicokinetic model is proposed to predict the time evolution of malathion and its metabolites, mono- and dicarboxylic acids (MCA, DCA) and phosphoric derivatives (dimethyl dithiophosphate [DMDTP], dimethyl thiophosphate [DMTP], and dimethyl phosphate [DMP]) in the human body and excreta, under a variety of exposure routes and scenarios. The biological determinants of the kinetics were established from published data on the in vivo time profiles of malathion and its metabolites in the blood and urine of human volunteers exposed by intravenous, oral, or dermal routes. In the model, body and excreta compartments were used to represent the time varying amounts of each of the following: malathion, MCA, DCA, DMDTP, DMTP, and DMP. The dynamic of intercompartment exchanges was described mathematically by a differential equation system that ensured conservation of mass at all times. The model parameters were determined by statistically adjusting the explicit solution of the differential equations to the experimental human data. Simulations provide a close approximation to kinetic data available in the published literature. When simulating a dermal exposure to malathion, the main route of entry for workers, the model predicts that it takes an average of 11.8 h to recover half of the absorbed dose of malathion eventually excreted in urine as metabolites, compared to 3.2 h following an intravenous injection and 4.0 h after oral administration. This shows that following a dermal exposure, the absorption rate governs the urinary excretion rate of malathion metabolites because the dermal absorption rate is much slower than biotransformation and renal clearance processes. The model served to establish biological reference values for malathion metabolites in urine since it allows links to be made between the absorbed dose of malathion and the time course of cumulative amounts of metabolites excreted in urine. From the no-observed-effect level (NOEL) of 0.61 micromol/kg/day derived from the data of Moeller and Rider (1962), the model predicts corresponding biological reference values for MCA, DCA, and phosphoric derivatives of 44, 13, and 62 nmol/kg, respectively, in 24-h urine samples. The latter were used to assess the health risk of workers exposed to malathion in botanical greenhouses, starting from urinary measurements of MCA and DCA metabolites.     

Ministernotomy for aortic valve replacement: a study of the preliminary experience.

Objective

The aim of the study was to evaluate the technical feasibility and the postoperative course of aortic valve replacement through a ministernotomy.

Setting

The Montreal Heart Institute and the Hôpital Lariboisière, Paris, France.

Design

A case series from 2 institutions.

Patients

Fifty-one patients who underwent aortic valve replacement through a ministernotomy. The sternal incision was started at the level of the sternal notch extending down to the third or fourth intercostal space with a transverse section of the sternum at this level on both sides or limited to the right side (inverted T or L incision). Thirty-nine patients had aortic stenoses, 6 patients were operated for aortic insufficiency and 6 had mixed disease. The mean (and standard deviation) preoperative left ventricular ejection fraction was 0.56 (0.17).

Main outcome measures

Cardiac bypass time, complications and outcome.

Results

The patients received Carbomedics and St. Jude mechanical valves, Hancock and Carpentier–Edwards bioprostheses. Thirty-eight patients were administered antegrade and retrograde cardioplegia, 10 patients ante-grade and 3 retrograde blood cardioplegia only. The mean (and standard error) cardiopulmonary bypass time and aortic cross-clamp time were 104 (38) minutes and 72 (16) minutes respectively. Two patients (4%) died and 2 patients (4%) showed evidence of a stroke after the procedure. Hospital stay averaged 8 (5) days.

Conclusion

We conclude that aortic valve replacement can be done through a ministernotomy approach with perioperative results similar to those obtained through a conventional sternotomy.     

Troponin levels in patients with myocardial infarction after coronary artery bypass grafting

BACKGROUND: The objective of this study was to evaluate serum cardiac troponin T and I levels in patients in whom electrocardiogram, myocardial scan, and serum CK-MB levels of the MB isoenzyme of creatine kinase indicated perioperative myocardial infarction (MI) after coronary artery bypass grafting (CABG). METHODS: We studied 590 patients who underwent CABG at the Montreal Heart Institute between 1992 and 1996. Postoperative cardiac troponin T levels (493 patients), troponin I levels (97 patients), and activity of the MB isoenzyme of creatine kinase, electrocardiograms, clinical data, and clinical events were recorded prospectively. The diagnosis of perioperative PMI was defined by a new Q wave on the electrocardiogram, by serum levels of the MB isoenzyme of creatine kinase higher than 100 IU/L within 48 hours after operation, or both. RESULTS: After CABG, 22 patients in whom troponin T levels (22/493, 4.5%) and 6 patients in whom troponin I levels (6/97, 6.2%) were measured had sustained a perioperative MI according to current diagnostic criteria. In these patients, troponin T levels higher than 3.4 microg/L 48 hours after CABG best detected the presence of perioperative MI, with an area under the receiver operating characteristic curve of 0.95, a sensitivity of 90%, a specificity of 94%, a positive predictive value of 41%, a negative predictive value of 99%, and a likelihood ratio of 15. Serum troponin I levels higher than 3.9 microg/L 24 hours after CABG confirmed the perioperative MI with an area under the receiver operating curve of 0.86, a sensitivity of 80%, a specificity of 85%, a positive predictive value of 24%, a negative predictive value of 99%, and a likelihood ratio of 5. CONCLUSIONS: Serum troponin T levels higher than 3.4 microg/L 48 hours after CABG correlated best with the diagnosis of perioperative MI. Serum troponin T levels greater than 3.9 microg/L 24 hours after CABG also correlated with the diagnosis of perioperative MI, although a larger experience is needed to confirm the validity of the chosen cutoff value.     

Acute hepatitis associated with treatment of Peyronie's disease with potassium para-aminobenzoate (Potaba)

IntroductionPotassium para‐aminobenzoate is an agent used in the treatment of sclerotic diseases including Peyronie's disease of the penis. It has been reported that this medication may have been responsible for cases of acute liver injury.AimTo inform clinicians of the possibility of an adverse drug event associated with the oral intake of potassium para‐aminobenzoate by reporting an additional case and compiling information from previous reports.MethodsThe affected patient's medical records were diligently reviewed; all available and relevant information pertaining to this adverse event is reported. Similar case reports were analyzed and compared, and relevant information was compiled in this report.ResultsThe patient enjoyed a full biochemical recovery from his hepatitis 4 months after discontinuation of potassium para‐aminobenzoate.ConclusionTo date, the oral use of potassium para‐aminobenzoate has been reported to be linked to acute liver injury in six individuals. Appropriate management of this adverse drug event is the immediate discontinuation of the offending drug and general patient support measures. Roy J, and Carrier S. Acute hepatitis associated with treatment of Peyronie's disease with potassium para‐aminobenzoate (Potaba). J Sex Med **;**:**–**.     

Three phase contractile response of rabbit pulmonary artery to norepinephrine: influence of ruthenium red and calcium

We recorded isometric contractile force of rabbit pulmonary artery after application of norepinephrine (50 microM), plotted semilogarithmic graphs of force development over time, and calculated rates of force development. The normal contractile response contained three phases: an initial fast, a short intermediate and a final slow. Correlation coefficients for each phase and differences between rates of force development of each phase were significant (P less than 0.05). Ruthenium red (1 mM) removed only the slow phase and significantly reduced the rates of the fast and intermediate phases. A calcium-free solution removed both the slow and intermediate phases and significantly reduced the rate of the fast phase.     

Synergetic effect of testosterone and phophodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review

Testosterone deficiency seems to impair the clinical response to phophodiesterase-5 (PDE-5) inhibitors in patients with erectile dysfunction (ED). In hypogonadal men, testosterone repletion was associated with enhanced sexual function in patients who failed initial treatment with sildenafil or tadalafil. We conducted a systematic review of studies that evaluated combination therapy of testosterone and PDE-5 inhibitors in patients with ED and low, low-normal testosterone levels who failed monotherapy. The studies we examine are heterogeneous with several methodological drawbacks and that, overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone <300 ng/dL (10.4 nmol/L) who failed monotherapy. Further studies, with a randomized placebo-controlled and double blind design, are needed to describe the appropriate target patient group, testosterone cut-off and to define the optimal dose and duration of combination therapy.     

Comparison of the effects of pentagastrin and meal-stimulated gastrin on plasma calcitonin in normal man

We compared the effects of exogenous pentagastrin and meal-stimulated gastrin on plasma immunoreactive calcitonin (iCT) in various studies of 13 normal adult men. Bolus intravenous injection of pentagastrin (0.5 μg/kg) produced increases of iCT in 8 of 9 men. There was a linearly increasing response of iCT concentrations to increasing doses of pentagastrin (0.0625, 0.125, 0.25, and 0.5 μg/kg) and to achieved serum immunoreactive pentagastrin concentrations (r=0.72, P<0.01). To determine the effects of endogenous gastrin upon peripheral iCT concentrations, we measured serum immunoreactive gastrin (iG) and plasma iCT in four men at frequent intervals for 240 min after ingestion of low-(100 mg) and high- (400 mg) calcium meals. Serum iG increased in all subjects, with a peak at ～30 min. However, plasma iCT levels were unchanged from basal throughout the study. The increase of pentagastrin (0.3 pmol/ml) which caused a barely detectable increase of iCT was five-to tenfold greater than the mean maximal increases of gastrin after low- and high-calcium meals (0.04 and 0.06 pmol/ml, respectively). These results suggest that increases of plasma iCT concentrations after administration of pentagastrin in man reflect pharmacologic phenomena and that postprandial gastrin secretion may be insufficient to affect peripheral iCT concentrations.