Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ANTIDOTES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed2006

Multiple centrally acting antidotes protect against severe organophosphate toxicity.

BACKGROUND: Accumulation of acetylcholine in the central nervous system is believed to account for the rapid lethality of organophosphate pesticides and chemical nerve agents. Diazepam is known to supplement atropine therapy, but its specific mechanism of action is uncertain. OBJECTIVES: To test four centrally acting agents for early antidotal efficacy in severe dichlorvos poisoning in the murine model. METHODS: The up-and-down method was used to dose four candidate antidotes: diazepam, xylazine, morphine, and ketamine. Antidotes were administered subcutaneously to unsedated adult Sprague-Dawley rats who were pretreated with 3 mg/kg intraperitoneal glycopyrrolate. All animals received 20 mg/kg of dichlorvos subcutaneously 5 minutes later. A blinded observer adjudicated the outcomes of 10-minute mortality and survival time. RESULTS: All animals pretreated with either no antidote (8/8 deaths) or glycopyrrolate alone (8/8) died within 10 minutes of dichlorvos injection. Pretreatment with diazepam (3/9 deaths), or xylazine (3/9), decreased lethality substantially (Fisher p = 0.007; median effective doses, 0.12 mg/kg and 3.0 mg/kg, respectively). Intermediate doses of morphine (3.1 to 5.5 mg/kg) resulted in survival, but higher doses did not, presumably because of excessive respiratory depression (7/11 deaths; p = 0.09). Ketamine (7/8 deaths) was ineffective as an antidote. Survival times also were prolonged in the diazepam and xylazine groups (log-rank p < 0.001) and, to a lesser degree, the morphine group (p = 0.07). CONCLUSIONS: Doses of diazepam, xylazine, and morphine below those used for deep sedation protect against severe dichlorvos poisoning, implying that several distinct central mechanisms are each sufficient to avert lethality. These findings suggest new possibilities for prophylaxis or therapy.

Animals↗
PubMed2003

Antidotal treatment of cyanide poisoning.

Cyanide poisoning may result from different exposures: residential fires, industrial accidents, drug and plant intoxication. Clinical features include coma, respiratory arrest and cardiovascular collapse. The biological hallmark is lactic acidosis. A plasma lactate concentration > or = 10 mmol/L in fire victims without severe burns and > or = 8 mmol/L in pure cyanide poisoned patients is a sensitive and specific indicator of cyanide intoxication. Many antidotes are available and efficient. However, therapeutic strategies are still debated. Our objective was to compare conventional treatments to hydroxocobalamin. This article reviews the literature on cyanide poisoning treatment. Conventional treatment of cyanide poisoning includes decontamination, supportive and specific treatment. Decontamination should be adapted to the route of poisoning and never postpone supportive treatment. Basic life support includes immediate administration of high flow of oxygen, airway protection and cardiopulmonary resuscitation. Advanced life support includes mechanical ventilation, catecholamine and sodium bicarbonate infusion. Supportive treatment is efficient but does not modify the time course or the body burden of cyanide. Numerous antidotes are available. Oxygen counteracts efficiently cyanide action at the mitochondrial level. Sodium thiosulfate, methemoglobin forming agents and cobalt compounds act efficiently by complexing or transforming cyanide into non-toxic stable derivatives. However, regarding the main clinical condition of cyanide poisoning, i.e. smoke inhalation, we should take into account not only the efficiency of antidotes but also their safety. Sodium thiosulfate is both efficient and safe, but acts with delay. Methemoglobin-forming agents are potent, but due to the transformation of hemoglobin into methemoglobin, they impair tissue delivery of oxygen. Experimental data showed increased mortality in carbon monoxide- and cyanide-poisoned rats treated with these agents. Cobalt EDTA and hydroxocobalamin are efficient and act immediately. Cobalt EDTA is more potent on a molar basis; however, numerous side effects limit its use to evidenced cyanide poisoning. In a prospective study, hydroxocobalamin appeared safe in fire victims with or without cyanide poisoning. The only reported side effect was a red coloration of skin and urine. In conclusion, antidotes are beneficial in cyanide poisoning. In suspected cyanide-poisoned patients, we recommend the use of hydroxocobalamin as first-line antidote, owing to its safety. In massive cyanide poisoning, due to the limited potency of hydroxocobalamin, continuous infusion of sodium thiosulfate should be associated.

Antidotes↗
PubMed1992

[Logistics of antidotes in Switzerland].

Antidotal compounds are principally classified into three groups. The most important compounds are available in all hospitals and pharmacies. They guarantee the basic supply of antidotes in all part of Switzerland. More specific antidotes are constantly available in 24 regional centres, some of which being further specialized in certain areas (e.g. Cantonal Pharmacy of Zurich: anti-venoms and radionucleotide-antidotes). Ongoing routine collaboration between the Swiss Toxicological Information Centre (STIC) and the Swiss Association of Hospital Pharmacists (GSASA) is important for continuous and competent information about the availability of newly developed antidotal drugs in Switzerland.

Antidotes↗
PubMed1985

Effects of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats.

Oral N-acetylcysteine (NAC), IV NAC, and IV sodium sulfate were evaluated as treatments for cats dosed orally with toxic sublethal doses of acetaminophen (APAP). Six cats were given single oral doses of 120 mg of APAP/kg of body weight and the respective antidote at 4.5, 8.5, and 12.5 hours after APAP dosing in 3 separate trials. The cats were given each antidotal treatment in random order with at least 3 weeks separating the individual APAP-treated trials. Clinical signs, plasma APAP half-lives, clinical chemical values, and APAP urinary excretion and metabolites were studied. Results were compared (P less than 0.05) with each other and with those of a control group of 6 cats given identical APAP doses, but given no antidotal treatment. At the dosage levels used, oral NAC, IV NAC, and IV sodium sulfate were equally effective antidotes, as measured by decreased methemoglobinemia, increased whole blood reduced glutathione, decreased APAP half-lives, and increased urinary excretion of the APAP-sulfate conjugate. All the antidotal treatments produced results significantly different from those in the control cats.

Acetaminophen↗
PubMed1984

The anecdotal antidotes.

The author reviews obscure or unusual antidote recommendations, emphasizing antidotes or antidote uses that are not generally acknowledged or that have little experimental or clinical confirmation of their efficacy. Also included are unusual uses of well known antidotes. Among the antidotes considered are naloxone, physostigmine, folate, Prussian blue, n-acetylcysteine, cimetidine, subcutaneous magnesium salts, nicotinamide, and thioctic acid.

Acetylcysteine↗
PubMed1988

Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse.

The highly vesicant nature of the alkylating anticancer agent mechlorethamine (HN2, or nitrogen mustard) requires careful i.v. technique during its administration. Skin toxicity due to HN2 extravasation is severe and typically prolonged over several months. Mouse skin toxicity studies were carried out to find a local antidote to decrease the severity of tissue damage by this agent. Intradermal (i.d.) HN2 (0.005-0.5 mg) caused dose-dependent skin ulcers in the mouse. Isotonic sodium thiosulfate Na2S2O3 (0.167 M) or hypertonic (0.34 M) Na2S2O3 (0.05 ml) given immediately after HN2 significantly reduced the mean HN2 ulceration area and the total time of ulceration. Ineffective local HN2 antidotes included hyaluronidase, hydrocortisone, and sodium chloride, all given i.d. Topical applications of DMSO, cold, and heat were also ineffective. Sodium thiosulfate is believed to chemically neutralize reactive mechlorethamine-alkylating species and thus decrease skin toxicity. Thiosulfate dosing studies showed that a molar excess of at least 200:1 (Na2S2O3:HN2) was required for significant antidotal activity. If thiosulfate treatment was delayed 4-24 h after HN2, no antidotal effects were obtained. We conclude that sodium thiosulfate can decrease the severity of local tissue damage caused by HN2. It should be considered the antidote of choice in the setting of clinical HN2 extravasations.

Animals↗
PubMedDate not supplied

Effectiveness of intramuscularly administered cyanide antidotes on methemoglobin formation and survival.

Successful first aid therapy for cyanide intoxication is dependent upon immediate administration of antidotes which directly or indirectly interact with the cyanide ion to remove it from circulation. Owing to the severe respiratory, cardiovascular and convulsive episodes following acute cyanide intoxication, the most practical approach is to administer antidotes by intramuscular injection. Exceptionally rapid methemoglobin formers-hydroxylamine hydrochloride (HH) and dimethylaminophenol (DMAP)-are usually able to prevent the lethal effect of cyanide following intramuscular injections in doses sufficient to induce 20% methemoglobin (HH = 20 mg kg-1 and DMAP = 2 mg kg-1). Sodium nitrite, the methemoglobin inducer approved for military use, must be administered by intravenous infusion because it is not an effective cyanide antidote by the intramuscular route. In the normal unintoxicated animal an intramuscular injection of 20 mg kg-1 sodium nitrite will form 20% methemoglobin; however, in acute cyanide intoxication the associated severe bradycardia appears to limit the rate of absorption and thus the rapid formation of methemoglobin. If the bradycardia is prevented or reversed by atropine, the rate of absorption of sodium nitrite and the formation of methemoglobin is able to reverse the otherwise lethal effects of cyanide. Thus, an intramuscularly administered combination of 20 mg kg-1 sodium nitrite and 1 mg kg-1 atropine sulfate, rapidly absorbed from the intramuscular site, appears to achieve the same degree of effectiveness against acute cyanide intoxication as intramuscularly administered HH or DMAP. It would appear from these studies that HH, DMAP and sodium nitrite with atropine are all potentially effective intramuscular antidotes for acute cyanide poisoning.

Aminophenols↗
PubMedDate not supplied

Relationship between physicochemical properties of prussian blue and its efficacy as antidote against thallium poisoning.

In the present work we established a relationship between some physicochemical properties of two different batches of Prussian blue (PB) and their in vivo efficacy as an antidote against thallium poisoning. The physicochemical properties studied were crystallite size and thallium-adsorbing capacity. One of the batches was synthesized and the other was obtained from commercial sources. The synthesized PB batch with the smallest crystallite size had both the highest adsorption capacity and antidotal efficacy. Synthesized PB protected 100% of the animals against one LD50 thallium dose, whereas the commercial PB batch protected only 80%. Thallium content in blood and tissues (liver, kidney, brain) was also analysed after antidotal PB treatment in rats previously intoxicated with a sublethal dose of T1+. Animals treated with synthesized PB showed significantly less thallium in blood and tissue contents than those values of commercial PB-treated rats, indicating better antidotal properties of the synthesized PB. According to the present study we suggest an in vivo evaluation of the compound before distribution of the product to toxicological units, if X-ray diffractometric analysis is not available, in order to identify and determine the crystallite size of the compound as it plays an important role in the efficacy of PB.

Adsorption↗
PubMed1984

[N-Acetylcysteine as an antidote in accidental acrylonitrile poisoning].

Acute acrylonitrile intoxications are followed by loss of consciousness, convulsions, respiratory arrest, and may end fatally. Common cyanide antidotes have not proved to be effective. In previous animal experiments we could demonstrate that the cyanide antidotes show some protective effect only after oral acrylonitrile application. Only a minimal amount of inhaled acrylonitrile will be transformed into cyanide, in contrast to pharmacokinetics after oral intake. After acrylonitrile inhalation the toxic effect of the whole molecule ( cyanethylation ) is important, and sulfhydryl compounds show antidotal effects. Further animal experiments demonstrate the superior antidotal effects of N-acetyl-cysteine after acrylonitrile inhalation. Intravenous injection of N-acetyl-cysteine in high doses is recommended according to the treatment of paracetamol poisoning.

Acetylcysteine↗
PubMed2000

Evaluation of antidotes for extravasation injury produced by 6-hydroxymethylacylfulvene (MGI 114), a novel cytotoxic antitumor agent, in an intradermal toxicity model in rats.

MGI 114 (HMAF, 6-hydroxymethylacylfulvene) is a cytotoxic drug currently in phase II human clinical trials. As with other anticancer agents, inadvertent drug extravasation may result in perivascular irritation and/or necrosis. In this study the degree of soft tissue injury produced by MGI 114 after intradermal administration to rats was quantified and four potential antidotes for extravasation injuries caused by MGI 114 were evaluated. Intradermal injections of MGI 114 (0.2 ml, concentrations 0.1, 0.5 or 1.0 mg/ml) and a positive control, doxorubicin (0.2 ml, concentration 2 mg/ml) were administered to male Fischer 344 rats in an experiment designed to establish a model for antidote evaluation. Dermal lesions at the injection sites were measured and quantitated as the total area under the lesion area-time curve (AUC). Physiological saline, sodium thiosulfate, dimethylsulfoxide (DMSO) and local cooling, were then compared as potential antidotes in this model. In the initial study, dermal lesions (erythema, ulcerations and eschar formation) occurred at the MGI 114- and doxorubicin-treated sites. The lesion area resulting from MGI 114 was dose-related and was greatest at approximately 5 days, with resolution by day 7-22. Doxorubicin-induced lesions were comparable in area to those induced by the highest dose of MGI 114, but persisted approximately twice as long. In the antidote study, sodium thiosulfate administration resulted in approximately 20% diminution of lesion area and AUC value when compared to untreated controls. Normal saline caused slight reductions in maximum lesion area, but had little effect on AUC values. Local cooling also caused a modest reduction in the maximum lesion area, but actually resulted in higher AUC values by prolonging eschar duration. DMSO provided near complete tissue protection from intradermal exposure to MGI 114. In this model MGI 114 and doxorubicin were found to produce similar soft tissue injuries, but MGI 114-induced lesions tended to show a more rapid resolution. Topical DMSO treatment was found to produce the most effective protection against MGI 114-induced local tissue irritation and necrosis.

Administration, Cutaneous↗
PubMed1987

Application of a hepatocyte-erythrocyte coincubation system to studies of cyanide antidotal mechanisms.

A coincubation system composed of hepatocytes in primary monolayer culture and erythrocytes suspended in the culture medium was developed and used as a model for investigations of mechanisms of cyanide antidote action at the cellular level. Hepatocyte ATP was used as the cytotoxicity indicator. Treatment of rat hepatocytes in the coincubation system with KCN (1.0 mM) for 10 min at 37 degrees C selectively reduced hepatocyte ATP levels to 33 +/- 15% of control (no KCN added) levels. 4-dimethylaminophenol (DMAP), cobalt(II) chloride, sodium nitrite, sodium thiosulfate, or a combination of the last two antidotes added to the KCN-containing medium significantly reversed ATP depression and the response was concentration dependent. The relative effectiveness, on a molar basis, was estimated to be DMAP greater than CoCl2 much greater than NaNO2 congruent to Na2S2O3. NaNO2 and DMAP induced methemoglobin formation in the absence of cyanide and cyanmethemoglobin formation in its presence; erythrocytes were required in the medium for effectiveness. CoCl2 produced neither cyanmethemoglobin nor thiocyanate in appreciable quantities nor required erythrocytes for antagonism. Na2S2O3 converted cyanide to thiocyanate and reversed ATP depression without erythrocytes in the medium. The addition of erythrocytes increased these rates significantly and to a greater extent than albumin. The overall results are consistent with previously proposed modes of action for these antidotes. However, the enhancement in cyanide metabolism and ATP recovery with Na2S2O3 and erythrocytes in the system was unexpected and raises the possibility that erythrocytes may contribute to cyanide disposition and antagonism in vivo when this antidote is administered.

Adenosine Triphosphate↗
PubMed1988

Guidelines for nonclinical toxicology studies for chemical warfare agent (CWA) antidotes and pretreatments.

The following is a review of FDA's guidelines for nonclinical toxicology studies as applied to chemical warfare agent (CWA) antidotes and pretreatments. These specific guidelines are of major interest to the U.S. Army Medical Research and Development Command which is a full-scale developer of pharmaceuticals and active in the research and development of antidotes and pretreatments against CWAs. Antidotes and pretreatments against CWAs are unique classes of drugs whose nonclinical requirements are unlike most other pharmaceuticals. However, these guidelines have general applicability to pharmaceutical developers in the private sector and apply to any antidote or pretreatment regardless of the indication.

Antidotes↗
PubMed1994

Combined D-penicillamine and prussian blue as antidotal treatment against thallotoxicosis in rats: evaluation of cerebellar lesions.

Rats were treated with a single dose of thallium acetate (32 mg/kg i.p.) and the antidotal effect of D-penicillamine and prussian blue given alone or in combination was assessed by means of evaluation of the thallium-induced cerebellar histological lesions. After thallium poisoning (24 h), antidotes were administered for 4 days as follows: D-penicillamine (DP) 25 mg/kg, i.p. twice daily; prussian blue (PB), 50 mg/kg p.o., twice daily. Mortality among the treatment groups was as follows: control, 87.5%; DP, 100%; PB, 56.25%; DP+PB, 25%. Three days after these treatments, rats treated with the combination DP+PB presented a significantly lower number of altered Purkinje cells in cerebellum as compared with those of the thallium alone treated animals, indicating adequate protection by this antidote treatment against thallium neurotoxicity. Prussian blue protected against thallium-induced neurotoxicity to a lesser extent as compared with the effects obtained by the DP+PB protection. DP did not protect against thallium-induced alterations of Purkinje cells. These results confirm the efficacy of the combined antidotal treatment of DP and PB against thallium toxicity in rats, and support the possible application in human cases of thallotoxicosis.

Animals↗
PubMed1987

Hydroxycobalamin/sodium thiosulfate as a cyanide antidote.

Severe, acute cyanide poisoning is uncommon and can be very difficult to diagnose if a history of exposure is unavailable. Victims of smoke inhalation may have significant cyanide poisoning as well as carbon monoxide toxicity. The Lilly Cyanide Antidote Kit currently available in America unfortunately has its own inherent toxicity. An efficacious antidote lacking toxicity is desirable, especially in cases where the diagnosis of cyanide poisoning cannot be made with certainty. Hydroxycobalamin/sodium thiosulfate has been used in France since 1970. Both components have been shown to be safe and efficacious in animal studies. Case reports of human cyanide poisoning treated with hydroxycobalamin/sodium thiosulfate have been published only in French. Animal and human data on the use of this antidotal combination are reviewed. Hydroxycobalamin/sodium thiosulfate is an efficacious cyanide antidote with little inherent toxicity.

Acute Disease↗
PubMed2006

Development of antidotes: problems and strategies.

Antidotes against chemical warfare agents are "orphan drugs" given that these poisonings are rare. Therefore, they are of limited interest to the pharmaceutical industry. For this reason, and recognizing the increasing threat of terrorist or asymmetrical use of chemical warfare agents, the responsibility for research into medical countermeasures against these weapons is of primary interest to armies. Accordingly, the research activities of the Bundeswehr Institute of Pharmacology and Toxicology are dedicated to improving diagnosis, prophylaxis and therapy of individuals who are exposed to a chemical agent. Here, antidote development and testing are a high priority in the research program, particularly with respect to organophosphorus (OP) nerve agents and sulphur mustard. The Institute has been coordinating research activities undertaken in house and in collaboration with external researchers. The research program aims to develop primarily in vitro models to minimize the sacrifice of animals, using strategies, which involve human material early in antidote testing. An animal model using isolated mouse diaphragm demonstrated the correlation between AChE activity and neuromuscular function. A similar relationship was found between erythrocyte AChE and neuromuscular function in patients with acute OP pesticide poisoning. In vitro rate constants of the various reactions that are involved in enzyme inhibition and reactivation using human material were used for prediction of what would happen in vivo. This prediction could be confirmed in a patient with acute OP pesticide poisoning. Finally, computer models are being established to estimate the therapeutic effect of an antidote in various human poisoning scenarios. This approach is necessary to compensate for the lack of human clinical pharmacodynamic studies that are usually required for drug regulatory approval, given the obvious ethical issues preventing human volunteer studies with these agents.

Animals↗
PubMed2006

A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery.

Heparin and protamine are the standard anticoagulant-antidote regimen used in almost every cardiopulmonary bypass (CPB) procedure even though both are associated with an array of complications and toxicities. Here we demonstrate that an anticoagulant aptamer-antidote pair targeting factor IXa can replace heparin and protamine in a porcine CPB model and also limit the adverse effects on thrombin generation, inflammation, and cardiac physiology associated with heparin and protamine use. These results demonstrate that targeting clotting factors upstream of thrombin in the coagulation cascade can potentially reduce the perioperative pathologies associated with CPB and suggest that the aptamer-antidote pair to FIXa may improve the outcome of patients undergoing CPB. In particular, this novel anticoagulant-antidote pair may prove to be useful in patients diagnosed with heparin-induced thrombocytopenia or those who have been sensitized to protamine, particularly patients who have insulin-dependent diabetes.

Animals↗
PubMed1998

The positive influence of a cholinergic-anticholinergic pretreatment and antidotal treatment on rats poisoned with supralethal doses of soman.

The influence of pretreatment with the drug mixture (pyridostigmine, benactyzine and trihexyphenidyle), and antidotal treatment (the oxime HI-6 in combination with benactyzine) on respiration, circulation and survival of experimental animals poisoned with supralethal doses of soman (2 x LD50) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. Untreated soman poisoning caused rapid respiratory depression, progressive bradycardia and a short-term increase in the mean arterial pressure, followed immediately by hypotension. The poisoned rats died on average within 10 min from respiratory and circulatory insufficiency. A cholinergic-anticholinergic pretreatment alone partially prevented changes in monitored physiological variables, caused by soman, but only for a few minutes; post-poisoning treatment with antidotes, also alone, had similar effects. The rats died on average within 30 min from respiratory and circulatory failure. When rats were pretreated by the drug mixture and treated by antidotes, respiration as well as circulation were completely restored and the rats survived at least 120 min following soman challenge. The results of the investigation suggest that cholinergic-anticholinergic pretreatment seems able to enhance the efficacy of antidotal treatment in restoring respiratory and circulatory changes induced by soman.

Animals↗
PubMed2000

Stability study of a new antidote drug combination (Atropine-HI-6-Prodiazepam) for treatment of organophosphate poisoning.

The main purpose of this study was to investigate the chemical stability of a new antidote combination for the treatment of organophosphate poisoning. The antidote combination was packed (enclosed) in two plastic compartments separated by a barrier film. One of them contained a powder oxime cholinesterase reactivator (HI-6-monohydrate 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro xyimino)meth yl]-pyridinium dichloride). The other contained an anticholinergic (Atropine) and an anticonvulsant (Prodiazepam or Avizafone (L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide dihydrochloride) drug in a liquid mixture. The plastic compartments were mounted in an autoinjector device to study the dissolution of HI-6 by ejection of the solution. Drug analysis was performed by high-performance liquid chromatography. The results obtained after 6 months show that this new antidote combination is stable. The amount of each antidote is unchanged during the study. Some known degradation products can be detected in small amounts. The autoinjector mechanism used, gives a complete dissolution of HI-6 powder in the liquid mixture throughout the study.

Antidotes↗