Relative Risk and Clinical Severity Assessment in Patients with Non-Oral Route Organophosphate Poisoning Compared with Oral Route Poisoning.

PURPOSE: Organophosphates, commonly used in agricultural pesticides, pose high risks and incidences of poisoning. In the present study, we investigated the relative risk and clinical severity, including laboratory results, of non-oral route poisoning (NORP) patients, compared to oral route poisoning (ORP) patients. MATERIALS AND METHODS: A single institutional toxicology database registry was utilized to gain information on clinical laboratory results on organophosphate poisoning patients who visited the emergency department (ED) between January 2000 and October 2016. Clinical outcomes, such as mortality and complication rates, were compared using 1:2 propensity score matching in the total cohort. RESULTS: Among a total of 273 patients in our study, 34 experienced NORP. After 1:2 propensity score matching, rates of respiratory complications and mortality were higher in the ORP group than in the NORP group. However, there was no difference in hospitalization time and time spent in the intensive care unit between the two groups. Compared with ORP patients after matching, the relative risk of mortality in NORP patients was 0.34, and the risk of respiratory distress was 0.47. The mean level of pseudocholinesterase was significantly higher in the NORP group than in the ORP group, while recovery rates were similar between the two groups. CONCLUSION: Although the majority of NORP patients were admitted to the ED with unintentional poisoning and the relative risk of NORP was lower than that for ORP, we concluded that NORP is as critical as ORP. Considerable medical observation and intensive therapeutic approaches are also needed for NORP patients.

In vivo assessment of the vascular disrupting effect of M410 by DCE-MRI biomarker in a rabbit model of liver tumor.

The present study aimed to prospectively monitor the vascular disrupting effect of M410 by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rabbits with VX2 liver tumors. Twenty-eight rabbits bearing VX2 tumors in the left lobe of the liver were established and randomly divided into treatment and control groups, intravenously injected with 25 mg/kg M410 or sterile saline, respectively. Conventional and DCE-MRI data were acquired on a 3.0-T MR unit at pretreatment, 4 h, 1, 4, 7 and 14 days post-treatment. Histopathological examinations [hematoxylin and eosin (H&E) and CD34 immunohistochemisty staining] were performed at each time point. The dynamic changes in tumor volume, kinetic DCE-MRI parameter [volume transfer constant (Ktrans)] and histological data were evaluated. Tumors grew slower in the M410 group 4-14 days following treatment, compared with rapidly growing tumors in the control group (P<0.05). At 4 h, 1 and 4 days, Ktrans significantly decreased in the M410 group compared with that in the control group (P<0.05). However, Ktrans values were similar in the two groups for the other time points studied. The changes in DCE-MRI parameters were consistent with the results obtained from H&E and CD34 staining of the tumor tissues. DCE-MRI parameter Ktrans may be used as a non-invasive imaging biomarker to monitor the dynamic histological changes in tumors following treatment with the vascular targeting agent M410.

Acetylcholinesterase inhibitors as pretreatment before acute exposure to organophosphates: assessment using methyl-paraoxon.

Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of organophosphorus compounds (OPCs). The usefulness of pyridostigmine, the only compound approved by the Food and Drug Administration (FDA) for such pretreatment, has been questioned. In search for more efficacious alternatives, we have examined in vivo the efficacy of a group of ten compounds with known anti-AChE activity (pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7- methoxytacrine and K-27) to reduce mortality induced by the OPC methyl-paraoxon. AChE inhibitors were given intraperitoneally in equitoxic dosage (25% of LD01) 30 min before OPC exposure. Protection was quantified in rats by determining the relative risk of death (RR) by Cox analysis, with RR=1 for animals given only methyl-paraoxon, but no pretreatment. Only physostigmine (RR=0.39), K-27 (RR=0.40) and tacrine (RR=0.48) significantly (p≤ 0.05) reduced methylparaoxon- induced mortality, when given prophylactically. Pretreatment with pyridostigmine, ranitidine, tiapride, amiloride, metoclopramide and methylene blue did not significantly protect against the lethal effects of methyl-paraoxon. 7-methoxytacrine (7-MEOTA) significantly (p≤ 0.05) increased the relative risk of methyl-paraoxon-induced death (RR=1.31). These results indicate that pretreatment with pyridostigmine cannot be considered a broad-spectrum approach against OPC exposure. K-27 may be a suitable alternative if passage into the brain is contraindicated.

Population pharmacokinetics of fluconazole after administration of fosfluconazole and fluconazole in critically ill patients.

WHAT IS KNOWN AND OBJECTIVE: Fluconazole is an antifungal agent that is commonly used to treat patients with serious systemic fungal infections in intensive care units. Fosfluconazole is a phosphate prodrug of fluconazole, which was developed to reduce the volume of fluid required to administer fluconazole by intravenous injection. The objective of this study was to characterize the pharmacokinetics of the antifungal fluconazole after the intravenous administration of the prodrug fosfluconazole or fluconazole in critically ill patients with serious systemic fungal infections, by population pharmacokinetic analysis using the nonmem software package. METHODS: Clinical biochemical data including serum fluconazole levels were obtained from 57 patients treated in the intensive care unit along with two naïve pooled patients gleaned from previous reports. The pharmacokinetic model of fluconazole was estimated using a one-compartment model. The probability that the area under the concentration-time curve is higher than 800 µg h/mL was determined by simulation. RESULTS: It was assumed that all the administered fosfluconazole was converted to fluconazole with an estimated fosfluconazole-fluconazole conversion rate constant of 2·05/h. The significant covariates for clearance for fluconazole (CL) and volume of distribution for fluconazole (Vd) were resulted in creatinine clearance (CLcr) and body weight (BW), respectively, in the final pharmacokinetic model equations: CL (L/h) = 0·799 × [CLcr (mL/min)/92·7](0·685) and Vd (L) = 48·1 × [BW (kg)/65](1·40) , where the interpatient variabilities in CL and Vd and the intrapatient variability were 44·8%, 79·7% and 19·8%, respectively. On the basis of the results of the Monte Carlo simulation, the probabilities of target attainment were 60%, 26% and 11% for 400 mg/day administration as fluconazole equivalent at CLcr values of 40, 70 and 100 mL/min, respectively. WHAT IS NEW AND CONCLUSION: The present population pharmacokinetic analysis strongly indicates that fosfluconazole (and fluconazole) dosage should be optimized in terms of CLcr in critically ill patients.

Assessment of acetylcholinesterase activity in Clarias gariepinus as a biomarker of organophosphate and carbamate exposure.

The objective of this study was to investigate the response of acetylcholinesterase (AChE) activities in Clarias gariepinus in response to Organophosphates (Ops) and carbamate exposure. The AChE activities were determined in plasma, and eye and brain homogenates of unexposed and exposed fish using Ellman's method and 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) chromophore. The baseline AChE activities in plasma, eyes and brain tissues in unexposed fish were comparable between males and females (P > 0.05). Concentrations of pesticides that inhibited 50% (IC(50)) of AChE activities in brain homogenates following in vitro exposures were 0.003, 0.03, 0.15, 190, 0.2, 0.003 and 0.002 microM for carbaryl, chlorfenvinphos, diazinon, dimethoate, fenitrothion, pirimiphosmethyl and profenofos, respectively. The in vivo dose-effect relationships were assessed using chlorfenvinphos and carbaryl at different concentrations that ranged from 0.0003 to 0.06 microM and 0.0005 to 0.05 microM, respectively. Acetylcholinesterase activities were comparable in plasma, and eye and brain homogenates from control and carbaryl-exposed fish. Following exposure of fish to chlorfenvinphos at concentrations above 0.03 microM, a significant inhibition of AChE activities in plasma (84%) and eye homogenate (50%) was observed. The AChE activities in brain homogenate were comparable between chlorfenvinphos-exposed fish and controls. Because carbaryl cause reversible inhibition of AChE activities was found to be more potent than chlorfenvinphos that cause irreversible inhibition following in vitro exposure. Contrary, carbaryl was less potent than chlorfenvinphos after in vivo exposure possibly due to more rapid biotransformation of carbaryl than chlorfenvinphos. Findings from this study have demonstrated that inhibition of AChE activity in C. gariepinus is a useful biomarker in assessing aquatic environment contaminated by anticholinesterases.