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Science Translational Medicine May 2020Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to...
Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: ) leads to systemic hemorrhage and coagulopathy and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity and low affordability and must be administered in clinical settings because of its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially affects patient outcomes after envenoming. Here, we investigated the value of metal ion chelators as prehospital therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS) were found to potently antagonize the activity of Zn-dependent snake venom metalloproteinases in vitro. Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also considerably extended survival in a "challenge and treat" model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming. Last, the potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that the safe and affordable repurposed metal chelator DMPS can effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the promise of this drug as an early, prehospital, therapeutic intervention for hemotoxic snakebite envenoming.
Topics: Africa; Animals; Asia; Chelating Agents; Humans; Mice; Snake Bites; Viper Venoms
PubMed: 32376771
DOI: 10.1126/scitranslmed.aay8314 -
Biomolecules Feb 2020High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of... (Review)
Review
High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.
Topics: Animals; Antidotes; Arsenic; Arsenic Poisoning; Arsenicals; Chelating Agents; Dimercaprol; Drinking Water; Humans; Models, Molecular; Occupational Exposure; Oxidative Stress; Succimer; Unithiol; Water Pollutants, Chemical
PubMed: 32033229
DOI: 10.3390/biom10020235 -
The Turkish Journal of Pediatrics 2019Çelebi-Tayfur A, Yaradılmış RM, Ulus F, Çaltık-Yılmaz A, Özayar E, Koşar B, Büyükkaragöz B, Horasanlı E. Bismuth intoxication resulting in acute kidney...
Çelebi-Tayfur A, Yaradılmış RM, Ulus F, Çaltık-Yılmaz A, Özayar E, Koşar B, Büyükkaragöz B, Horasanlı E. Bismuth intoxication resulting in acute kidney injury in a pregnant adolescent girl. Turk J Pediatr 2019; 61: 292-296. Bismuth intoxication is a rare cause of acute kidney injury (AKI) and is usually reversible by appropriate therapeutic measures. We present here a case of an adolescent pregnant girl who developed AKI due to an overdose of colloidal bismuth subcitrate (CBS, total amount of 6 g). She received parenteral chelating agent dimercaprol for 14 days. Continuous venovenous hemodiafiltration (CVVHD) with high-flux membrane was carried out in the first 3 days of chelating therapy and intermittent hemodialysis for 11 days, thereafter. The patient recovered clinically and was discharged after 21 days. She gave birth to a healthy term boy. At the last visit, the baby was 6 months old with normal growth and development as well as normal kidney functions. Neither deterioration in renal functions nor emergence of proteinuria was recorded in the patient during follow-up care after hospital discharge. In cases of AKI due to an overdose of CBS, treatment with dimercaprol combined with high flux hemodiafiltration and subsequently hemodialysis appears to be both useful and safe for bismuth elimination.
Topics: Acute Kidney Injury; Adolescent; Bismuth; Drug Overdose; Female; Hemodiafiltration; Humans; Pregnancy; Pregnancy Complications; Renal Dialysis
PubMed: 31951346
DOI: 10.24953/turkjped.2019.02.024 -
BMC Nephrology Oct 2019Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical... (Review)
Review
BACKGROUND
Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered.
CASE PRESENTATION
We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance.
CONCLUSION
Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.
Topics: Adult; Animals; Anuria; Arsenic Poisoning; Chelating Agents; Continuous Renal Replacement Therapy; Dimercaprol; Edetic Acid; Humans; Kidney Failure, Chronic; Lead Poisoning; Male; Renal Dialysis; Succimer; Unithiol
PubMed: 31623560
DOI: 10.1186/s12882-019-1561-1 -
Medicine Dec 2018Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11,...
RATIONALE
Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11, respectively. Here, we report on a patient with coexisting WD and OCA, initially presenting episodes of tremors.
PATIENT CONCERNS
WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. OCA is a disorder of melanin biosynthesis, characterized by a generalized reduction in pigmentation of the eyes (oculo-), skin (-cutaneous), and hair.
DIAGNOSIS
The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Interestingly, the patient also had very light skin color, blond hair and eyebrows, and dark brown eyelashes and irises. Because the association of dermatologic signs in WD has rarely been reported, OCA was highly suspected based on these clinical findings. Genetic analysis was subsequently conducted, and the results revealed the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of the ATP7B gene, confirming the diagnosis of WD; the p. (D456fs) mutation in 1 allele and the p. (R299H) mutation in the other allele of the TYR gene, confirming the diagnosis of OCA. The family history was positive for WD with a 14-year-old younger brother also being diagnosed with it. Her parents are negative for OCA and WD.
INTERVENTIONS
Sodium dimercaptopropanesulfonate (DMPS) was given during hospitalization. D-penicillamine and zinc sulfate treatment was initiated after discharge for long-term control.
OUTCOMES
Postural and intention tremor disappeared, and other symptoms and signs markedly improved after treatment.
LESSONS
In this study, we reported on the first case of a child who simultaneously presented WD and OCA, bringing up the possibility of a presumable link between these 2 rare diseases.
Topics: Albinism, Oculocutaneous; Asian People; Astringents; Chelating Agents; Female; Hepatolenticular Degeneration; Humans; Magnetic Resonance Imaging; Mutation; Penicillamine; Treatment Outcome; Unithiol; Young Adult; Zinc Sulfate
PubMed: 30558096
DOI: 10.1097/MD.0000000000013744 -
International Journal of Nanomedicine 2018The objective of this study was to evaluate the antitumor activity of lipophilic bismuth nanoparticles (BisBAL NPs) on breast cancer cells.
AIM
The objective of this study was to evaluate the antitumor activity of lipophilic bismuth nanoparticles (BisBAL NPs) on breast cancer cells.
MATERIALS AND METHODS
The effect of varying concentrations of BisBAL NPs was evaluated on human MCF-7 breast cancer cells and on MCF-10A fibrocystic mammary epitheliocytes as noncancer control cells. Cell viability was evaluated with the MTT assay, plasma membrane integrity was analyzed with the calcein AM assay, genotoxicity with the comet assay, and apoptosis with the Annexin V/7-AAD assay.
RESULTS
BisBAL NPs were spherical in shape (average diameter, 28 nm) and agglomerated into dense electronic clusters. BisBAL NP induced a dose-dependent growth inhibition. Most importantly, growth inhibition was higher for MCF-7 cells than for MCF-10A cells. At 1 µM BisBAL NP, MCF-7 growth inhibition was 51%, while it was 11% for MCF-10A; at 25 µM BisBAL NP, the growth inhibition was 81% for MCF-7 and 24% for MCF-10A. With respect to mechanisms of action, a 24-hour exposure of 10 and 100 µM BisBAL NP caused loss of cell membrane integrity and fragmentation of tumor cell DNA. BisBAL NPs at 10 µM were genotoxic to and caused apoptosis of breast cancer cells.
CONCLUSION
BisBAL NP-induced growth inhibition is dose dependent, and breast cancer cells are more vulnerable than noncancer breast cells. The mechanism of action of BisBAL NPs may include loss of plasma membrane integrity and a genotoxic effect on the genomic DNA of breast cancer cells.
Topics: Antineoplastic Agents; Apoptosis; Bismuth; Breast Neoplasms; Cell Membrane Permeability; Cell Survival; Comet Assay; DNA Damage; Dimercaprol; Female; Humans; MCF-7 Cells; Nanoparticles; Organometallic Compounds
PubMed: 30323596
DOI: 10.2147/IJN.S179095 -
Journal of Traditional Chinese Medicine... Oct 2018To evaluate the efficacy and safety of gandouling plus sodium dimercaptosulphonate (DMPS) on neurological Wilson's disease (WD) in patients.
OBJECTIVE
To evaluate the efficacy and safety of gandouling plus sodium dimercaptosulphonate (DMPS) on neurological Wilson's disease (WD) in patients.
METHODS
We retrospectively evaluated the clinical records of 125 WD patients with neurological syndromes who were treated with gandouling plus sodium DMPS or DMPS used alone. All patients had a history of neurological deterioration during their diseases courses. The clinical efficacies, adverse reactions, and results of the various hematological and biochemical investigations were recorded for statistical analysis.
RESULTS
92.30% (60 patients) of the WD patients treated with the combined therapy experienced an improved or stable neurological condition paralleled by a significantly improved GAS score. Meanwhile, the WBC and PLT counts stabilized, liver function and renal function were improved or remained stable. The combined therapy also obviously promoted the 24-h urinary copper excretion. In particular, only 30.76% of the WD patients experienced mild adverse reactions, including neurological deterioration in 5 patients (7.69%), hepatic worsening in 1 subject (1.89%), which was less frequently than those in the control group treated with DMPS only.
CONCLUSION
Our findings indicate that the safety and efficacy of gandou-ling plus DMPS is superior to those of DMPS used alone in the WD patients with neurological symptoms.
Topics: Adolescent; Adult; China; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Hepatolenticular Degeneration; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Unithiol; Young Adult
PubMed: 32185997
DOI: No ID Found -
Neurology India 2018
Topics: Adult; Cerebellar Ataxia; Chelating Agents; Dimercaprol; Humans; Male; Medicine, Ayurvedic; Mercury; Mercury Poisoning; Treatment Outcome
PubMed: 30233025
DOI: 10.4103/0028-3886.241403 -
Tremor and Other Hyperkinetic Movements... 2018Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults.... (Review)
Review
BACKGROUND
Wilson disease (WD) is an inherited neurometabolic disorder that results in excessive copper deposition in the liver and the brain, affecting children and young adults. Without treatment the disease is invariably fatal. Though treatments for WD have been available since the 1950s, the disease continues to be associated with considerable morbidity and mortality because of missed diagnosis, and delayed or inadequate treatment. In this paper we survey WD-related literature in order to review recent advances in WD treatment.
METHODS
We performed a literature search using the PubMed database for articles relating to WD and its medical treatment. We reviewed the articles, and cross-references of relevant articles, to summarize the current practices for treatment of WD.
RESULTS
The survey shows that if WD is properly treated, in most patients the liver can be stabilized, even severe neurological disability reversed, and patients can resume normal lives.
DISCUSSION
Medical treatment for WD includes use of copper chelators (penicillamine, trientine, dimercaprol, dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and drugs that decrease gastrointestinal copper absorption. Our knowledge of the treatment approaches has benefited from the large systematic clinical studies that have been conducted over the last decade. For each drug used to treat WD, we surveyed its development, indication for use, dosing, efficacy, and adverse effects.
Topics: Hepatolenticular Degeneration; Humans
PubMed: 29520330
DOI: 10.7916/D841881D -
The Cochrane Database of Systematic... Feb 2018Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites.
OBJECTIVES
To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews.
SELECTION CRITERIA
Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software.
MAIN RESULTS
We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults.
AUTHORS' CONCLUSIONS
These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.
Topics: Acetaminophen; Acetylcysteine; Analgesics, Non-Narcotic; Antidotes; Charcoal; Cysteamine; Dimercaprol; Drug Overdose; Gastric Lavage; Humans; Intestinal Absorption; Liver Failure, Acute; Liver Transplantation; Methionine; Randomized Controlled Trials as Topic
PubMed: 29473717
DOI: 10.1002/14651858.CD003328.pub3