Anthrahydroquinone-2-6-disulfonate is a novel, powerful antidote for paraquat poisoning.
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ABSTRACT:
SUBMITTER: Qian J
PROVIDER: S-EPMC8505516 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Accidental or suicidal ingestion of the world's most widely used herbicide, paraquat (PQ), may result in rapid multi-organ failure with a 60% fatality rate due to the absence of an effective detoxification solution. Effective, specific antidotes to PQ poisoning have been highly desired. Methods: The binding constant of PQ and a synthetic receptor, cucurbit[7]uril (CB[7]), was first determined in various pH environments. The antidotal effects of CB[7] on PQ toxicity were firstly evaluated with in-vitro cell lines. With in-vivo mice models, the pharmacokinetics and the biodistribution of PQ in major organs were determined to evaluate the influence of CB[7] on the oral bioavailability of PQ. Major organs' injuries and overall survival rates of the mice were systemically examined to evaluate the therapeutic efficacy of CB[7] on PQ poisoning. Results: We demonstrate that CB[7] may complex PQ strongly under various conditions and significantly reduce its toxicity in vitro and in vivo. Oral administration of PQ in the presence of CB[7] in a mouse model significantly decreased PQ levels in the plasma and major organs and alleviated major organs' injuries, when compared to those of mice administered with PQ alone. Further studies indicated that oral administration of CB[7] within 2 h post PQ ingestion significantly increased the survival rates and extended the survival time of the mice, in contrast to the ineffective treatment by activated charcoal, which is commonly recommended for PQ decontamination. Conclusion: CB[7] may be used as a specific oral antidote for PQ poisoning by strongly binding with PQ and inhibiting its absorption in the gastrointestinal tracts.
| S-EPMC6376464 | biostudies-literature
Project description:To identify risk factors and develop a simple model to predict early prognosis of acute paraquat (PQ) poisoning patients, we performed a retrospective cohort study of acute PQ poisoning patients (n = 1199). Patients (n = 913) with PQ poisoning from 2011 to 2018 were randomly divided into training (n = 609) and test (n = 304) samples. Another two independent cohorts were used as validation samples for a different time (n = 207) and site (n = 79). Risk factors were identified using a logistic model with Markov Chain Monte Carlo (MCMC) simulation and further evaluated using a latent class analysis. The prediction score was developed based on the training sample and was evaluated using the testing and validation samples. Eight factors, including age, ingestion volume, creatine kinase-MB [CK-MB], platelet [PLT], white blood cell [WBC], neutrophil counts [N], gamma-glutamyl transferase [GGT], and serum creatinine [Cr] were identified as independent risk indicators of in-hospital death events. The risk model had C statistics of 0.895 (95% CI 0.855-0.928), 0.891 (95% CI 0.848-0.932), and 0.829 (95% CI 0.455-1.000), and predictive ranges of 4.6-98.2%, 2.3-94.9%, and 0-12.5% for the test, validation_time, and validation_site samples, respectively. In the training sample, the risk model classified 18.4%, 59.9%, and 21.7% of patients into the high-, average-, and low-risk groups, with corresponding probabilities of 0.985, 0.365, and 0.03 for in-hospital death events. We developed and evaluated a simple risk model to predict the prognosis of patients with acute PQ poisoning. This risk scoring system could be helpful for identifying high-risk patients and reducing mortality due to PQ poisoning.
| S-EPMC7794476 | biostudies-literature
Project description:BackgroundSeverity index and plasma paraquat (PQ) concentration can predict the prognosis of patients with PQ poisoning. However, the better parameter is yet to be systematically investigated and determined. Thus, we conduct this systematic review and meta-analysis to investigate the prognostic value of severity index and plasma PQ concentration in patients with PQ poisoning.MethodsWe searched PubMed, Embase, Web of Science, ScienceDirect, and Cochrane Library to identify all relevant papers that were published up to March 2019. All diagnostic studies that compared severity index and plasma PQ concentration to predict mortality in patients with PQ poisoning were enrolled in this meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) for individual trials were pooled using a random-effect model. We also aggregated heterogeneity testing, sensitivity analysis, and publication bias analysis.ResultsUltimately, seven studies involving 821 patients were included. The pooled OR with a 95% CI of severity index was 24.12 (95% CI: 9.34-62.34, P?<?.001), with an area under the curve of 0.88 (95% CI: 0.85-0.90), sensitivity of 0.84 (95% CI: 0.74-0.91), and specificity of 0.81 (95% CI: 0.75-0.87). Meanwhile, the pooled OR with 95% CI of plasma PQ concentration was 34.39 (95% CI: 14.69-80.56, P?<?.001), with an area under the curve of 0.94 (95% CI: 0.91-0.96), sensitivity of 0.86 (95% CI: 0.75-0.93), and specificity of 0.89 (95% CI: 0.76-0.95). Sensitivity analysis demonstrated the stability of the results of our meta-analysis. No significant publication bias was observed in this meta-analysis.ConclusionOverall, this study indicated that severity index and plasma PQ concentration have relatively high-prognostic value in patients with PQ poisoning, and that the sensitivity and specificity of plasma PQ concentration are superior to those of severity index.
| S-EPMC7015625 | biostudies-literature
Project description:Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P50 (partial pressure of O2 at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ?200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.
| S-EPMC5206801 | biostudies-literature
Project description:ObjectiveThis study aimed to explore the effects of arterial lactate as a predictor of mortality in patients with paraquat (PQ) poisoning.MethodsThe databases PubMed, EMBase, Web of Science, ScienceDirect, Cochrane library, and studies published until 31 February 2018 were searched. The data were extracted to perform pooled analysis, heterogeneity testing, sensitivity analysis, publication bias analysis, and Fagan plot analysis.ResultsPooled analysis showed that a high arterial lactate was significantly correlated with poor mortality (pooled odds ratio = 16.94, 95% confidence interval [CI]: 7.96-36.08, P < .001). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 77% (95% CI: 0.69-0.84), 84% (95% CI: 0.74-0.90), 4.7 (95% CI: 2.9-7.8), 0.28 (95% CI: 0.20-0.39), and 17 (8-36), respectively. An area under the curve of 0.87 (95% CI: 0.83-0.89) means a high ability for prognostic detection.ConclusionOur findings show that arterial lactate is an effective predictor of mortality in patients with PQ poisoning.
| S-EPMC6112996 | biostudies-literature
Project description:A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a significant drug payload (5.2 ± 0.9 oxime to MOF-808 molar ratio) and shows a sustained oxime release in simulated physiological media, leading to the successful reactivation of OP-inhibited acetylcholinesterase. At the same time, the hybrid system presents an efficient and moderately fast removal rate of a toxic organophosphorus model compound (diisopropylfluorophosphate) from simulated physiological media (t1/2 = 183 min; 95% removal rate after 24 h).
| S-EPMC10074384 | biostudies-literature
Project description:Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN-) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeIIITPPS, F), two methyl-β-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na2S2O4, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN- once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN- mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN- resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN- levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.
| S-EPMC9992825 | biostudies-literature
Project description:The efficacy of hemoperfusion (HP) in patients with acute paraquat poisoning (PQ) remains controversial. We conducted a multi-center retrospective study to include acute PQ-poisoned patients admitted to two tertiary medical centers between 2005 and 2015. We used the Severity Index of Paraquat Poisoning (SIPP) to stratify the severity of PQ-poisoned patients. The indication to start HP was a positive result for the semiquantitative urine PQ test and presentation to the hospital was within 24 h. Early HP was defined as the first session of HP performed within five hours of PQ ingestion. A total of 213 patients (100 HP group, 113 non-HP group) were eligible for the study. The overall 60-day mortality of poisoned patients was 75.6% (161/213). Multivariate Cox regression analysis showed no statistically significant difference in 60-day survival between HP and non-HP groups (95% confidence interval (CI): 0.84-1.63, p = 0.363). Further subgroup analysis in the HP group showed early HP (95%CI: 0.54-1.69, p = 0.880), and multiple secessions of HP (95%CI: 0.56-1.07, p = 0.124) were not significantly related to better survival. Among acute PQ-poisoned patients, this study found that HP was not associated with increased 60-day survival. Furthermore, neither early HP nor multiple secessions of HP were associated with survival.
| S-EPMC7711471 | biostudies-literature
Project description:Paraquat (PQ), one of the most widely used herbicides worldwide, causes severe toxic effects in humans and animals. 1-methylhydantoin (MH) is an active ingredient of Ranae Oviductus, which has broad pharmacological activities, e.g., eliminating reactive oxygen species and inhibiting inflammation. This study investigated the effects of MH on lung injury induced by PQ. A PQ poisoning model was established by intragastric infusion of PQ (25 mg/kg), and the control group was simultaneously gavaged with the same dose of saline. The MH group was intraperitoneally injected with 100 mg/kg once per day after intragastric infusion of PQ (25 mg/kg) for five consecutive days. All animals were sacrificed on the sixth day, and the lung tissues were dissected for metabolomics analysis. The lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, TNF-? and malondialdehyde (MDA) content were determined according to the instructions of the detection kit. Compared with that in the control group, the content of LDH, TNF-? and MDA in the lung tissue of the PQ group was significantly higher, and the activity of SOD in the lung tissue was significantly lower (all p<0.05). Compared with that in the control group, the content of LDH, TNF-? and MDA in the MH group was significantly higher, and the activity of SOD was significantly lower (all p<0.05). However, the differences in SOD activity, LDH activity between the PQ and MH groups were not statistically significant (all p > 0.05). There were significant differences in MDA and TNF-? content between the PQ group and MH group (all p<0.05). MH decreased the production of malondialdehyde and TNF-? to protect against the lung injury caused by PQ poisoning, but it had no significant effect on the activity of LDH and SOD. There were significant differences in metabolomics between the MH group and the PQ poisoning group, primarily in bile acid biosynthesis and metabolism of cholesterol, nicotinate, nicotinamide, alanine, aspartate, glutamate, glycine, threonine, serine, phenylalanine and histidine. Therefore, this study highlights that MH has non-invasive mechanisms and may be a promising tool to treat lung injury induced by PQ poisoning.
| S-EPMC6764654 | biostudies-literature
Project description:High-mobility group box 1 (HMGB1) mediates acute lung injury in a mouse model of paraquat poisoning. However, published reports showing a clinically relevant association between HMGB1 and paraquat exposure are lacking. The objective of the present study was to investigate the potential role of serum HMGB1 level as a prognostic marker of mortality in patients with paraquat poisoning in a clinical setting. This retrospective observational cohort study included a convenience sample of 92 patients with acute paraquat poisoning admitted to the emergency room (ER) of The First Hospital of Jilin University between January 2014 and December 2016. Baseline serum HMGB1 levels and other laboratory parameters were measured on admission. Cumulative incidence of mortality during the first 30 days after admission was 50% (n = 46/92). Serum HMGB1 levels were higher in fatalities than survivors (P = 0.015), 30-day mortality increased with increasing baseline serum HMGB1 level (P < 0.001), and higher serum HMGB1 levels were associated with an increase in 30-day mortality on Kaplan-Meier analysis. Multivariate Cox regression analysis identified baseline serum HMGB1 levels, white blood cell count, and serum lactic acid levels as independent prognostic markers of 30-day mortality. These data suggest that serum HMGB1 levels measured on admission to the ER are an independent predictor of 30-day mortality in patients with acute paraquat poisoning.
| S-EPMC6520495 | biostudies-literature