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The relative efficacy of antidotes.

For many physicians an antidote is an antidote. According to the International Programme on Chemical Safety definition, an antidote is a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. Given this wide definition, the efficacy of an antidote may vary considerably depending on which toxic action(s) being counteracted and the level of counteracting power. An almost 100% efficacy is seen using specific antagonists, such as naloxone in opiate poisoning or flumazenil in benzodiazepine poisoning, e.g. resulting in complete reversal of opiate toxicity unless complications, such as anoxic brain damage, have developed. At the other end of the efficacy scale, we may place chelating agents for heavy metal poisoning and diazepam for organophosphorus insecticide poisoning which are considered only to be an adjuncts to supportive care. When teaching clinical toxicology or recommending the use of antidotes in poisoned patients, the expected efficacy level of the antidote in question should be stressed. This may be particularly important in severe poisoning when the antidote may only be considered as an important adjunct to supportive care, e.g. deferoxamine in acute iron poisoning. Unless this is stressed, the unexperienced physician may rely too much on the antidote and pay insufficient attention to the supportive care. The varying efficacy levels will be discussed based on the presently ongoing International Programme on Chemical Safety/Commission of the European Communities evaluation program on antidotes.

Antidotes↗

An update of antidote availability in veterinary medicine.

Lack of commercially available antidotes for animals is an issue of significant concern to the American Board of Veterinary Toxicology. A few antidotes are available for food animals through extra-label use, regulatory discretion and compounding. However, regulatory restrictions arising from human food, safety concerns have limited the availability of food animal antidotes. Use of some antidotes in food animals requires establishment of an investigational new animal drug application. Antidotes are generally more available for non-food animals from several sources: approved animal drugs, extra-label use of approved animal and human drugs, regulatory discretion and compounding. Present alternatives are discussed as well as the need for legislation to increase antidote availability. Human food safety will always be an issue for food animal antidotes. Future availability of non-food animal and food animal antidotes will depend on several mechanisms and may include the establishment of veterinary antidote depots. Stakeholders are encouraged to participate in identifying and implementing these mechanisms.

Animal Husbandry↗

Availability of antidotes in hospital pharmacies in Greece.

We determined the availability of poisoning antidotes in the pharmacies of state hospitals in Greece and in Health Centers of the island of Crete. A questionnaire survey was sent to all pharmacy directors of hospitals with emergency departments, asking them to report anonymously the amount currently in stock of each of 12 common antidotes. Questionnaires were sent to 100 pharmacy directors and 68 (68%) of them replied. Only 2 (3%) of the 68 hospitals stocked all 12 antidotes. The percentage of sufficient stocking for individual antidotes ranged from 6% (for digoxin immune fab) to 91% (for methylene blue). Recent circulation of government guidelines for antidote stocking and hospital type had no significant effect on antidote stocking. In a multiple regression analysis, hospital type (prefectural, regional, university hospital) and smaller hospital size were not predictors of the number of antidotes sufficiently stocked. Storing of key poisoning antidotes is inadequate in regional as well as in prefectural hospitals in Greece. Antidotes, including those which should be used without delay to be effective, are often not available, even for the commoner poisons in Greece such as pesticides.

Antidotes↗

[Effect of diazepam on the effectiveness of antidote therapy in eliminating the acute lethal effects of soman in mice].

BACKGROUND: The currently used antidotal treatment of intoxication with nerve agents, consisting of an anticholinergic drug and an acetylcholinesterase reactivator, is often completed with the anticonvulsive drug diazepam to prevent poisoned organisms from centrally mediated seizures and subsequent tonic-clonic convulsions. The aim of this study was to find out whether the complementation of the antidotal treatment with diazepam can influence antidotal treatment-induced elimination of acute lethal effects of the chosen nerve agent--soman. METHODS AND RESULTS: In experiments on mice, the values of medium lethal dose of soman in the case of 24 h surviving of soman-exposed mice, treated with the basic antidotes involving various types of anticholinergic drugs and acetylcholinesterase reactivators, were evaluated and compared to the values of medium lethal dose of soman in mice treated with antidotes completed with diazepam. Our findings confirm that diazepam is able to enhance the efficacy of basic antidotal treatment to eliminate acute lethal effects of soman if atropin is used as anticholinergic drug. On the other hand, no ability of diazepam to enhance soman-induced lethal effects was demonstrated if an anticholinergic drug with central effects such as benactyzine, biperiden or scopolamin was used. The ability of diazepam to influence the efficacy of antidotes to eliminate soman-induced acute lethal effects was only observed in the case of using the oxime HI-6 as acetycholinesterase reactivator. CONCLUSIONS: The most perspective antidotal mixture against soman, consisting of the oxime HI-6 and atropine, should be complemented by diazepam no only because of the prevention of poisoned organisms from centrally mediated seizures and subsequent tonic-clonic convulsions but also because of the increase in the ability of antidotal treatment to eliminate soman-induced acute lethal effects.

Acute Disease↗

Acute acrylonitrile toxicity: studies on the mechanism of the antidotal effect of D- and L-cysteine and their N-acetyl derivatives in the rat.

Thiol-containing antidotes for acute acrylonitrile (AN) toxicity may exert their action by chemically reacting with AN, by replacing critical sulfhydryl groups cyanoethylated by AN, and by detoxifying cyanide produced from AN metabolism. We have evaluated the ability of the optical isomers of cysteine and N-acetylcysteine to act as antidotes against AN toxicity in order to assess the relative importance of each of these three antidotal mechanisms. The toxicity of AN was determined in male Sprague-Dawley rats and compared to the toxicity determined after treatment with 2 mmol/kg of thiol antidote by computing a protective index (median lethal dose with antidote/median lethal dose without antidote). The protective indices of L-cysteine, D-cysteine, N-acetyl-L-cysteine, and N-acetyl-D-cysteine were 2.03, 1.97, 1.76, and 1.25, respectively. Measurements of urinary mercapturates, derived from the non-oxidative pathway of AN metabolism, indicated that none of the antidotes was able to significantly increase the excretion of these metabolites. Blood cyanide generated from the oxidative metabolism of AN and butyronitrile was also determined. All of the antidotes, except N-acetyl-D-cysteine, lowered blood cyanide levels. A comparison of these results with the predicted relative abilities of the enantiomers to participate in each of the three antidotal mechanisms leads to the conclusion that, under these experimental conditions, the best correlation exists with the cyanide detoxification mechanism.

Acetylcysteine↗

Antidotes--inappropriate timely availability.

The aim of this study was to determine the availability of antidotes to poisons in Wales and the South West of England. A stocklist of antidotes that are available to accident and emergency departments was requested and was compared with recommendations from the International Programme on Chemical Safety (IPCS). Chief pharmacists were invited to complete a short questionnaire regarding knowledge of existing guidelines. Thirty-four of 43 centres replied (response rate 77%). No department held all 36 antidotes (mean 13, range 7-33). All departments held antidotes that were frequently used. Ninety-one percent of departments held one cyanide antidote. Eighty-eight percent held one heavy metal chelating agent. The remaining antidotes were variably stocked. New agents such as 4-methylpyrazole, hydroxocobalamin and the heavy metal chelating agents DMSA and DMPS were infrequently held. Twenty of 34 chief pharmacists were unfamiliar with existing UK guidelines. A trend exists whereby larger departments stocked more antidotes. Some antidotes to poisons are not available in a timely fashion in Wales and the South West of England. There is a lack of awareness of existing guidelines. New recommendations relevant to clinical need and local practice should ideally be developed.

Antidotes↗

[Antidote availability in Norway].

BACKGROUND: Antidotes are therapeutic substances that are used primarily to counteract the toxic action of poisonous agents and thus have an important role in the treatment of poisoning. Antidote availability is crucial for the poisoned patient; it is important that hospitals keep antidotes in stock to treat these patients. Most antidotes are expensive, infrequently used, and have short shelf-lives. This makes hospital stocking economically difficult. In Norway, there is no national antidote programme. MATERIAL AND METHODS: The National Poisons Information Centre recently made an inquiry about antidote stocking in Norwegian hospitals. RESULTS AND INTERPRETATION: This survey showed that the antidote availability is not satisfactory. The availability of antidotes in Norwegian hospitals is discussed and recommendations are given.

Antidotes↗

Antidotes to vesicant chemotherapy extravasations.

The foregoing sections have reviewed the experimental studies and clinical anecdotes describing potential pharmacologic antidotes to extravasations of vesicant anticancer agents. Numerous prior reviews have also suggested specific antidotes or very conservative, non-pharmacologic approaches. Many antidotal approaches to extravasation have not been experimentally validated and thus, few 'antidotes' share a rationale which is founded on positive experimental and clinical studies. However, using this criteria, a few active antidotes can be distilled from the literature. These are outlined in Table 6. These antidotes include isotonic (1/6 M) sodium thiosulfate for mechlorethamine (and optionally for cisplatin), hyaluronidase for the vinca alkaloids (and optionally for epipodophyllotoxins such as etoposide), and cooling with very topical DMSO and low dose hydrocortisone for the anthracyclines. For the alkylating agent mitomycin C, topical DMSO has been effective experimentally but has not yet received clinical validation, at least in published studies. Nonetheless, the severity of mitomycin C ulcerations and the documented safety of topical DMSO in the small series of doxorubicin extravasation patients argues for its use when mitomycin extravasates in the clinic. Furthermore, except for DMSO, all of these extravasation antidotes are listed in the official FDA-approved package inserts for each vesicant agent. Thus, the inserts for vincristine and vinblastine specify hyaluronidase, for doxorubicin, glucocorticosteroids, and for mechlorethamine, sodium thiosulfate. New studies are clearly needed to clarify the role of topical DMSO with anthracyclines and mitomycin C. In addition, efforts should be made to begin clinical development of radical dimers such as DHM3 which can directly inactivate quinone-containing vesicants like doxorubicin and mitomycin C. Although the incidence of chemotherapy extravasation may be lessened with vascular access devices, it nonetheless, continues to comprise a serious and highly litigious area of oncology practice. This commands continued extravasation intervention studies and diligent prevention when ever possible.

Animals↗

Neuroprotective efficacy of pharmacological pretreatment and antidotal treatment in tabun-poisoned rats.

To study the influence of pharmacological pretreatment (PANPAL) and antidotal treatment (obidoxime plus atropine) on tabun-induced neurotoxicity, male albino rats were poisoned with a lethal dose of tabun (280 microg/kg i.m.; 100% of LD(50) value) and observed at 24 h and 7 days following tabun challenge. The neurotoxicity of tabun was evaluated using a functional observational battery (FOB) and an automatic measurement of motor activity. Pharmacological pretreatment as well as antidotal treatment were able to eliminate most of tabun-induced neurotoxic effects observed at 24 h following tabun poisoning. However, there was not significant difference between the efficacy of PANPAL and antidotal treatment to eliminate tabun-induced neurotoxicity in rats. The combination of PANPAL pretreatment and antidotal treatment seems to be slightly more effective in the elimination of tabun-induced neurotoxicity in rats at 24 h following tabun challenge in comparison with the administration of PANPAL pretreatment or antidotal treatment alone. At 7 days following tabun poisoning, very few neurotoxic signs in tabun-poisoned rats were observed regardless of administration of pharmacological pretreatment or antidotal treatment. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is not only able to protect the experimental animals from the lethal effects of tabun but also to eliminate most of tabun-induced signs of neurotoxicity in tabun-poisoned rats.

Animals↗

On-site availability of selected antidotes: results of a survey of Massachusetts hospitals.

Hospital pharmacies in Massachusetts were surveyed to determine their patterns of stocking antidotes. Mailed questionnaires were completed by hospital pharmacy directors at 82 of 93 acute care institutions (87% response rate). Results confirmed great variability in on-site accessibility of antidotes. Only 8 of the 82 hospitals (9.8%) stocked all of 14 common antidotes inventoried by the survey. Even fewer hospital pharmacies stocked specific antidotes (eg, Crotalid anti-venin, digoxin-specific Fab antibodies, pyridoxine) in an adequate quantity to treat one poisoned adult. Larger hospitals and those with a 24-hour pharmacy were more likely to have certain antidotes than smaller institutions. We conclude that Massachusetts hospitals do not carry complete inventories of 14 common antidotes. It is important that poisoned patients be referred to medical centers with adequate toxicological care. Improved guidelines for the accessibility of antidotes need to be developed and made available to hospital pharmacies and emergency departments.

Antidotes↗

Current status of food animal antidotes.

The availability of antidotes in veterinary medicine has been an issue for more than a decade. Antidotes are available for food animals through extralabel use, regulatory discretion, and compounding. There is little economic incentive for pharmaceutical companies to pursue approval of antidotes and other drug products that have a small market. In addition, human food safety concerns must be addressed when approving antidotes for use in food animals. This article provides a brief history of antidote availability, current mechanisms for procuring food animal antidotes, and availability of specific antidotes for use in food animals.

Animal Husbandry↗

Survey of the stocking of poison antidotes in Alabama hospitals.

BACKGROUND: We wanted to estimate the current antidote supply in Alabama hospitals, establish if certain antidotes were stocked more than others, and identify certain parameters (eg, treatment level of care, licensed bed size, or county population) as predictors for the current antidote supply. METHODS: We faxed surveys to treatment level I/II hospitals and a random sample of treatment level III hospitals. Antidote supply was reported for digoxin immune Fab, pyridoxine, ethanol, pralidoxime, antivenin (Crotalidae), deferoxamine, cyanide, naloxone, and fomepizole. RESULTS: Of treatment level I/II and level III hospitals surveyed, 28 (100%) and 20 (71.4%) responded, respectively. None (0%) of the hospitals surveyed had adequate stocking for all nine antidotes. The results illustrate the common practice of understocking poison antidotes. CONCLUSIONS: Hospitals must reevaluate their current antidote inventories for meeting the needs of acutely poisoned patients. Policy containing specific guidelines must be developed and uniformly adopted as standard of practice.

Alabama↗

Antidotes for acute cardenolide (cardiac glycoside) poisoning.

BACKGROUND: Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited. OBJECTIVES: To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin. SEARCH STRATEGY: We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified. DATA COLLECTION AND ANALYSIS: We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate. MAIN RESULTS: Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. AUTHORS' CONCLUSIONS: There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.

Acute Disease↗

Reduced glutathione esters--antidotes to toxicity. Cytotoxicity induced by hydrogen peroxide, 1-chloro-2,4-dinitrobenzene, and menadione in murine P388D1 macrophages in vitro.

Repletion of depleted cellular reduced glutathione (GSH) levels in oxidative stress and exposure to arylating agents is a strategy for the development of antidotes to chemical toxicity. The effect of GSH, reduced glutathione ethyl monoester (GSHEt), and reduced glutathione ethyl diester (GSHEt2) on the cytotoxicity of hydrogen peroxide, 1-chloro-2,4-dinitrobenzene (CDNB), and menadione to P388D1 macrophages in vitro was investigated. The median toxic concentration TC50 values of the toxicants were hydrogen peroxide 24 +/- 2 mM (N = 19), CDNB 63 +/- 6 microM (N = 18), and menadione 30 +/- 4 microM (N = 22). Reduced glutathione, GSHEt, and GSHEt2 were poor antidotes to hydrogen peroxide toxicity. Indeed, the observed antidote effects were attributed to the nonenzymatic reaction of the GSH derivatives with hydrogen peroxide in the extracellular medium. Reduced glutathione ethyl diester was a more potent antidote of CDNB- and menadione-mediated toxicity than GSHEt and GSH. For cell incubations with the approximate median toxic concentration TC50 values of hydrogen peroxide, CDNB, and menadione, the respective median effective antidote concentration EC50 values were GSHEt 23.8 +/- 4.1 mM (N = 9), 3.6 +/- 0.6 mM (N = 11), and 226 +/- 93 microM (N = 12); and GSHEt2 20.4 +/- 1.9 mM (N = 6), 603 +/- 2 microM (N = 9), and 7.6 +/- 2.3 microM (N = 12). Reduced glutathione ethyl diester was a potent antidote to CDNB- and menadione-induced toxicities but not to hydrogen peroxide-induced toxicity under acute intoxication conditions.

Animals↗

The efficiency of aquocobalamine as an antidote in cyanide poisoning when given alone or combined with sodium thiosulfate.

The antidotal activities of aquocobalamineacetates and sodium thiosulfate were tested in guinea pigs and cats. The animals were attached to artificial respirators throughout the experiment and were poisoned with a continuous infusion of sodium cyanide solution (4.1 muMol/kg.min NaCN). The rate of action of each antidote was determined from the time taken for the HCN exhalation to drop below the level of 100 nMol/kg.min in quinea pigs, and to values below 25 nMol/kg.min in cats; the detoxifying capacity of each antidote was determined from the time taken for the HCN exhalation to rise above the said values and the time interval for normal function of heart activity to be restored. Aquobalamine was characterized by its rapid rate of reaction in both the animal species; its detoxifying capacity showed, however, according to our expectations, variations corresponding to the applied doses. The combination of the antidotes aquocobalamine (100 mg/kg) and thiosulfate (500 mg/kg) proved to possess high rate of reaction and a large detoxifying capacity in guinea pigs. Similar results were obtained in cats with antidote doses of 200 mg/kg aquocobalamine combined with 500 mg/kg thiosulfate. The slow rate of reaction and large detoxifying capacity of thiosulfate were confirmed in our experiments. It combination with aquocobalamine showed no undesirable change in its antidotal action providing a time interval of 1 min was maintained between the 2 injections.

Animals↗

[Availability of antidotes in the event of accidents or attacks with chemical weapons].

BACKGROUND: In this report, we aimed to determine the availability of six antidotes for victims of accidents or attacks with chemical weapons. MATERIAL AND METHOD: Telephone interviews with 6 Catalan hospitals and 8 hospitals from the community of Castilla y León. We evaluated the availability of antidotes in the hypothetical event of a massive intoxication with 600 affected people. RESULTS: Only 3 out of the 14 hospitals had all 6 antidotes. Only atropine and, in Catalan hospitals, sodium thiosulfate were available in enough quantities to treat all victims. With regard to the remaining antidotes, the percentage of treated patients would have been fewer than 50%. The less available antidote was hydroxocobalamine. CONCLUSIONS: We have found both qualitative and quantitative deficiencies of antidotes for the treatment of people intoxicated by chemical weapons.

Accidents↗

Neuroprotective effects of currently used antidotes in tabun-poisoned rats.

The neuroprotective effects of antidotes (atropine, pralidoxime/atropine, obidoxime/atropine and HI-6/atropine mixtures) on rats poisoned with tabun at a lethal dose (220 microg/kg intramuscularly; 100% of LD50 value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hr and 7 days after tabun challenge. The results indicate that atropine alone is not able to protect the rats from the lethal effects of tabun. Three non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine alone died within 24 hr. On the other hand, atropine combined with all tested oximes allows all tabun-poisoned rats to survive at least 7 days following tabun challenge. Obidoxime combined with atropine seems to be the most effective antidotal treatment for the elimination of tabun-induced neurotoxicity in the case of lethal poisoning among tested antidotal mixtures. The antidotal mixture consisting of atropine and HI-6 is significantly less effective than the combination of atropine with obidoxime in the elimination of tabun-induced neurotoxicity in rats at 24 hr following tabun challenge. Pralidoxime in combination with atropine appears to be practically ineffective to decrease tabun-induced neurotoxicity at 24 hours as well as 7 days following tabun poisoning. Due to its neuroprotective effects, obidoxime seems to be the most effective and most suitable oxime for the antidotal treatment of acute tabun exposure among currently used oximes. Thus, the replacement of obidoxime by a more effective acetylcholinesterase reactivator for soman poisoning, the oxime HI-6, can to a small extent diminish the neuroprotective efficacy of antidotal treatment in the case of acute tabun poisonings.

Animals↗

Intoxications with anticholinesterases: effect of different combinations of antidotes on the dynamics of acetylcholine in mouse brain.

Intoxications with organophosphorus compounds are normally treated with a mixture of atropine and an enzyme regenerating oxime. The addition of diazepam to the conventional drug therapy is reported to greatly improve the antidotal effect. The implication of the cholinergic system in such intoxications prompted us to study the effect of different combinations of antidotes on the acetylcholine (ACh) synthesizing system in mouse brain in vivo. The antidotes studied in this paper are diazepam, HI-6 and 1-hyoscyamine, the active enantiomer of atropine. Diazepam decreases the synthesis rate of ACh both when administered separately and in combination with 1-hyoscyamine and HI-6. This is in contrast to 1-hyoscyamine which, in addition to blocking muscarinic receptors, also increases the release and rate of synthesis of ACh, which probably is an unfavourable effect of the antidote. This might at least partly explain the advantage of combining 1-hyoscyamine and an oxime with diazepam in intoxications with anticholinesterases. Mice administered soman (0.75 x LD50), after pretreatment with the three-drug combination of antidotes, show no cholinergic symptoms despite a 50% increase in endogenous ACh. The rate of synthesis of ACh in these mice is in the same range as in animals administered diazepam alone. Mice administered the same dose of soman with no antidotal pretreatment suffer from severe tremor and salivation, and have a strongly reduced synthesis rate of ACh.

Acetylcholine↗