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PubMed2002

Newer antidotal therapies.

Although the availability of an antidote for a toxic agent does not take away the primary responsibility of the clinician to manage the patient's clinical signs, the use of antidotes in appropriate situations can result in a more rapid recovery with potentially fewer long-term complications. Recent advances in pharmacology and molecular biology have resulted in the development of new and safer antidotal therapies for the management of toxicosis. The progress in immunotoxicotherapy over the last two decades continues and may ultimately lead to an era when the clinical toxicologist has a vast array of antibody fragments available for use with specific toxic agents. Development of specific pharmacologic antagonists for other agents should also enable the clinician to more reliably manage toxicoses. In spite of all these potential advances, the management of most toxicoses still relies on the application of sound veterinary medical principles.

Animals↗

PubMedDate not supplied

Quantitative structure-activity relationships and possible mechanisms of action of bispyridinium oximes as antidotes against pinacolyl methylphosphonofluoridate.

The antidotal efficacy of bispyridinium oximes against the poisoning by pinacolyl methylphosphonofluoridate can be correlated well with their physicochemical parameters. Good correlation was observed between the efficacy of antagonism against pinacolyl methylphosphonofluoridate and antinicotinic action of these oximes. X-ray structural analysis showed that these oximes possessed structural similarity to nicotine and acetylcholine of nicotinic conformation. A new model of antidotal action, other than reactivation, against the poisoning by pinacolyl methylphosphonofluoridate was proposed for these bispyridinium oximes through nicotinic receptor binding. The antagonistic efficacy of these antidotes against pinacolyl methylphosphonofluoridate may be attributed to their direct antagonism at nicotinic receptor as well as reactivation of inhibited acetylcholinesterase.

Animals↗

PubMedDate not supplied

2,3-Dithioerythritol, a possible new arsenic antidote.

British antilewisite (2,3-dimercaptopropanol; BAL) has long been used as an arsenic antidote, but its therapeutic efficacy is limited by its inherent toxicity. We synthesized two less toxic derivatives of BAL and investigated their potential as antidotes to organic arsenic. The new compounds, 2,3-dithioerythritol (DTE) and 2,2-dimethyl-4-(hydroxymethyl)-1,3-dithiolane (isopropylidene derivative of BAL), react readily with phenyldichloroarsine (PDA) to yield the expected corresponding cyclic 1,3-dithioarsolanes. The BAL derivatives were compared to BAL in terms of their cytotoxicity and their ability to rescue PDA-poisoned mouse lymphoma cells in culture. The dithiolane was not a good antidote in the cultured cell system. In contrast, DTE was less toxic than BAL or DMSA and was superior at improving cell survival in PDA-exposed cells.

Animals↗

PubMed2002

The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage.

BACKGROUND: A plasma acetaminophen (INN, paracetamol) half-life of more than 4 hours has been correlated with hepatotoxicity in acetaminophen overdosing not treated with an antidote. Acetaminophen half-life has not been studied in patients receiving the antidote N -acetylcysteine. METHODS: Prospectively, 112 patients with acetaminophen overdosage all treated with intravenous N -acetylcysteine were studied. A minimum of 2 plasma acetaminophen values >20 micromol/L were available for calculation of acetaminophen half-life, assuming first-order kinetics. RESULTS: Overall, the median acetaminophen half-life was 5.4 hours (range, 0.8-119.7 hours). Forty-eight patients with no or little hepatotoxicity (ALT <1000 U/L), 43 patients with hepatotoxicity without encephalopathy, and 21 patients with hepatotoxicity and encephalopathy had acetaminophen half-lives of 3.0 hours (range, 0.8-10.0 hours), 6.4 hours (range, 1.3-19.0 hours), and 18.4 hours (range, 4.6-119.7 hours), respectively (P <.001). An acetaminophen half-life >4 hours was observed in 71 patients, and 56 of those (79%) had hepatotoxicity (ALT >1000 U/L or coma). Thirty-three of 41 patients (81%) with an acetaminophen half-life <4 hours had no hepatotoxicity. A receiver operating characteristic curve analysis showed that an acetaminophen half-life of 5.5 hours provided better discrimination; hepatotoxicity was therefore present in 49 of 54 patients with an acetaminophen half-life >5.5 hours (positive predictive value, 91%) and in 15 of 58 patients with a half-life below this limit (negative predictive value, 74%) despite treatment with N -acetylcysteine. CONCLUSIONS: Acetaminophen half-life correlates well with the degree of liver damage in patients treated with the antidote N-acetylcysteine. Longer half-lives reflect a greater toxic effect on the liver.

Acetaminophen↗

PubMed1983

Homer's moly identified as Galanthus nivalis L.: physiologic antidote to stramonium poisoning.

The antidotal properties of certain naturally occurring medicinal plants against central nervous system intoxication appear to have been empirically established in ancient times. Homer, in his epic poem, the Odyssey, described a plant, "moly," used by Odysseus as an antidote against Circe's poisonous drugs. Centrally acting anticholinergic agents are thought to have been used by Circe to induce amnesia and a delusional state in Odysseus' crew. We present evidence to support the hypothesis that "moly" might have been the snowdrop, Galanthus nivalis, which contains galanthamine, a centrally acting anticholinesterase. Thus the description of "moly" as an antidote in Homer's Odyssey may represent the oldest recorded use of an anticholinesterase to reverse central anticholinergic intoxication.

Antidotes↗

PubMed2006

Update on antidotes for pediatric poisoning.

Antidotes are playing an increasing role in therapy for pediatric poisonings. Although initial response to all pediatric poisonings begins with basic stabilization, knowledge of specific antidotes, their mechanisms of action, safety profile in pediatrics, and dosing regimens can be life-saving for pediatric victims of nerve gas exposure, acetaminophen toxicity, methanol and ethylene glycol ingestion, and snakebites. This article presents an overview of the pathophysiology, symptoms, antidotes, and emergency management of these toxicological emergencies.

Acetaminophen↗

PubMed1984

Antidotal treatment of the acute cardiovascular toxicity of verapamil.

Rats anaesthetized with pentobarbital and ventilated artificially were infused with 0.15 mg/kg/min. verapamil; without antidotal treatment, they died after 51.1+/-7.1 min. The survival time more than trebled upon an additional infusion with calcium chloride, epinephrine, isoprenaline, orciprenaline or prenalterol and nearly doubled upon administration of a plasma expander. It was not increased, however, by treatment with angiotensin or atropine. The infusion of verapamil declined the arterial blood pressure by 75%, and heart rate, cardiac output and peripheral resistance by about 50%; in the ECG, sinus bradycardia followed by AV-dissociation with nodal rhythm occurred. All antidotes that raised the lethal dose of verapamil increased the cardiac output. Calcium and the sympathomimetics with alpha-adrenergic activity also counteracted the verapamil-induced hypotension. Calcium did not influence the ECG alterations produced by verapamil, while the sympathomimetics restored the sinus rhythm or accelerated the nodal pacemaker. Calcium, epinephrine and isoprenaline also antagonized the strong decrease of left-ventricular dp/dt max. induced by verapamil. In conclusion, calcium as well as sympathomimetic amines are potent antidotes against the cardiovascular toxicity of verapamil, the latter being superior to calcium in their ability to improve pacemaker activity and AV-conduction.

Animals↗

PubMed1993

Efficacy of antidotes against soman poisoning in female physostigmine-protected rats.

Female rats have been found much more sensitive to lethal effects of soman than male rats. Therefore it was of interest to examine the efficacy of different antidotes against soman poisoning in females which are usually not being used in soman poisoning studies. The effects of acetylcholinesterase (AChE) non-reactivating antidotes atropine and diazepam were analyzed in combination with physostigmine prophylaxis against supralethal doses of soman. Physostigmine prophylaxis was much more effective when supplemented by atropine and diazepam therapy, applied at the onset of the first signs of poisoning. The interval between the injection of a supralethal dose of soman and the appearance of signs of poisoning was shorter in physostigmine pretreated animals than in non-pretreated controls poisoned with the same supralethal dose of soman. The prophylactic effect of physostigmine (used at maximal dose) disappeared in about 120 min. The addition of HI-6, an AChE-reactivating oxime, to atropine + diazepam therapy further increased the survival in soman-poisoned and physostigmine-pretreated rats, yielding the highest protective ratio of 6.4. Pretreatment with physostigmine offered marked protection against inhibition of AChE by soman, as shown by enzyme activity determination in different brain regions and in diaphragm muscle. Application of HI-6 in addition to the combination of the above mentioned antidotes even preserved more AChE activity in the skeletal muscle but did not influence inhibition of the enzyme in brain.

Acetylcholinesterase↗

PubMed1968

Tetraethylammonium chloride as an antidote for certain insecticides in mice.

In tests on mice, tetraethylammonium chloride (TEAC) was superior to atropine sulfate as an antidote for some carbamate insecticides and nicotine; it did not produce the traumatic and sometimes fatal reactions caused by atropine sulfate, although injections of the two antidotes provided equal protection against lethal oral doses of the carbamates Zectran, NIA-10242, and Lannate. The effects of TEAC were not evaluated against the carbamates Sevin and Baygon because acute oral toxicity values could not be determined. Results with Matacil were inconclusive. Tetraethylammonium chloride was not an effective antidote against the organophosphate Parathion, but its use fully eliminates the effects of nicotine intoxication.

Animals↗

PubMed1984

Structure-activity relationships among dithiocarbamate antidotes for acute cadmium chloride intoxication.

Eight sodium dithiocarbamates (NaS2CNR1R2) have been examined as antidotes for acute cadmium intoxication. While all of them possess an ability to increase survival when given to mice 2 hr after a lethal (greater than 99%) intraperitoneal injection of 10 mg/kg of CdCl2 X 2.5H2O, their effects on the organ distribution of cadmium vary considerably. It has been possible to show that the accumulation of cadmium in the brain and kidney as well as the survival rates can be correlated with a numerical measure of the polarity of the groups R1 and R2. Each factor has a different dependence on the polarity, but it is possible to construct a composite factor for antidotal efficacy which incorporates survival rate, brain cadmium levels and kidney cadmium levels. The factor constructed here exhibits an optimal value approximately in the middle of the polarity range studied. Compounds which have R1 = -CH2CH1OH and R2 = -CH2CH2OH, or -CH3 or -C2H5 appear to be the most effective antidotes of the compounds examined.

Acute Disease↗

PubMed1995

Antidotal action of atropine sulfate against insecticide benfuracarb poisoning in rats.

The antidotal action of atropine sulfate and 2-pyridine aldoxime methiodide (2-PAM) against poisoning attributable to the new procarbamate insecticide benfuracarb [(ethyl N-[2,3-dihydro-2,2-dimethylbenzofuran-7-yloxycarbonyl (methyl) aminothio]-N-isopropyl-beta-alaninate] was compared utilizing rats as our experimental model. Both the intraperitoneal and oral administrations of these antidotes were examined after five, ten, fifteen and thirty minutes exposure periods, following treatment with benfuracarb at dose levels approximating LD50 and LD100. The results obtained demonstrate that both the intraperitoneal and oral administrations of atropine sulfate blocked or significantly reduced the toxic effects of benfuracarb and protected the animals from death. The intraperitoneal administration route appears to be more effective than was the oral route. In addition, the administration of atropine sulfate after the shorter period (up to 15 minutes), following exposure to benfuracarb, improved antidotal action, particularly with the LD100 dose of benfuracarb. It is suggested that atropine sulfate antagonizes benfuracarb poisoning by blocking acetylcholine (ACh) receptors, as many other carbamate insecticides, since benfuracarb was an in vivo cholinesterase (ChE) inhibitor and the toxic effect of benfuracarb was reduced by atropine sulfate. 2-PAM, however, did not significantly block or reduce the toxic effects of benfuracarb.

Administration, Oral↗

PubMedDate not supplied

Comparison of nitrite treatment and stroma-free methemoglobin solution as antidotes for cyanide poisoning in a rat model.

The standard nitrite/thiosulfate regimen for cyanide poisoning was tested in our rat model. By modifying the treatment regimen and the nitrite solution an effective antidote against an LD90 of cyanide could be produced. However, this treatment was effective against two times the LD90 only when administered ten minutes prior to cyanide injection. These results are in marked contrast to our results with stroma-free methemoglobin solutions (SFMS) which showed SFMS to be a highly effective antidote against four times the LD90 when administered 30 seconds after an intravenous injection of cyanide. SFMS proved to be an effective antidote for two times the LD90 when administered up to sixty seconds after the cessation of respiration.

Animals↗

PubMed1986

Experimental investigations on the antidotal treatment of nifedipine overdosage.

Rats anesthetized with pentobarbital and ventilated artificially were infused with 0.5 mg/kg X min nifedipine. They exhibited a sharp decline of blood pressure, heart rate, cardiac output and peripheral resistance and died after 62.3 +/- 5.3 min of infusion. In the ECG, sinus bradycardia followed by AV-dissociation and an escape rhythm originating from the AV-node or the bundle of His occurred. The survival time of nifedipine-infused rats increased by 100% and more upon additional infusion with calcium chloride, calcium gluconate, isoproterenol or dopamine and by 50% after prenalterol. Epinephrine, norepinephrine, angiotensin amide and the plasma expander polygeline were ineffective in this respect. All drugs prolonging the survival time elevated the cardiac output. Ca++ and dopamine also increased the blood pressure whereas isoproterenol accelerated the escape rhythm. Similar cardiovascular changes as in rats occurred in rabbits infused with 0.2 mg/kg X min nifedipine, the survival time without antidotal treatment amounting to 46.3 +/- 7.9 min. Calcium chloride more than doubled the survival time in rabbits, too, but isoproterenol and dopamine proved to be ineffective. Excess calcium did not overcome the inhibitory effects of nifedipine on pacemaker activity, atrioventricular conduction and peripheral resistance. The antidotal efficacy of calcium appears to be attributable to a reversal of the negative inotropic activity of nifedipine. In conclusion, Ca++ seems to be the drug of choice for the antidotal treatment of nifedipine intoxication.

Animals↗

PubMed2002

The influence of anticholinergic drug and oxime selection on the effectiveness of antidotal treatment against tabun-induced poisoning in mice.

1. The influence of oximes (pralidoxime, obidoxime, HI-6) and anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the effectiveness of antidotal treatment to eliminate tabun-induced lethal effects was studied in mice. 2. Obidoxime seems to be the most efficacious oxime for the elimination of tabun-induced lethal effects in mice, although the difference in the efficacy of obidoxime and HI-6 is not significant when they are combined with atropine. 3. Obidoxime and HI-6 when combined with centrally acting anticholinergic drugs (benactyzine, biperiden and scopolamine) seem to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. 4. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of antidotal mixture in the case of antidotal treatment of tabun-induced acute poisoning.

Animals↗

PubMed1992

[Do antidotes have a future? The example of 4-methylpyrazole and hydroxocobalamin].

In all probability the future progress in the "molecular" approach of therapy in acute poisoning within the next 20 years or so will be more rapid than the "mechanistic" approach, which undoubtedly has brought considerable improvements in the overall survival of these patients in the past. Principally molecular antidotes can act on three different levels, a) prior to the cellular targets (e.g. through modifications of toxokinetics), b) at specific cellular receptors through competition for binding (e.g. naloxone and flumazenil), and c) after the receptor sites through unspecific counteraction of toxic effects (e.g. betablockers for intoxications with theophylline). Immune-antidotes act prior to cellular receptors. Examples are the digoxin antibodies and the anti-venoms as well as the very recently developed and not yet clinically tested antibodies against antidepressive drugs and against colchicine. Two newer antidotes, the 4-methylpyrazole and the hydroxocobalamin, act also prior the cellular targets of the corresponding toxic compounds. Thus, 4-Methylpyrazole decreases the degradation of ethylene-glycol by inhibiting alcohol dehydrogenase, which results in a higher excretion of unchanged ethylene-glycol in urine. Hydroxycobalamin complexes with cyanides to form the physiologic vitamin B12. In order to allow an equimolar neutralization of ingested cyanides a concentrated preparation containing 5 g of hydroxycobalamin was developed, the pharmacokinetic properties of which are discussed.

Antidotes↗

PubMed2005

The influence of the time of antidotal treatment administration on the potency of newly developed oximes to counteract acute toxic effects of tabun in mice.

(1) The influence of the time of administration of antidotal treatment consisting of anticholinergic drug (atropine) and newly developed oxime (K027 or K048) on its effectiveness to eliminate tabun-induced lethal toxic effects was studied in mice. (2) The therapeutic efficacy of antidotal treatment of tabun-induced acute poisoning depends on the time of its administration regardless of the choice of the oxime. (3) Our results show that both oximes studied (K027, K048) are able to sufficiently eliminate lethal effects of tabun. Nevertheless, their efficacy significantly decreases when they were administered 5 min after tabun poisoning. (4) The findings support the hypothesis that both newly developed oximes appear to be suitable oximes to counteract acute toxicity of tabun although their ability to eliminate lethal toxic effects of tabun significantly decreases with prolonged time interval between tabun challenge and antidotal treatment administration.

Animals↗

PubMed2006

Pyridinium, imidazolium and quinuclidinium compounds: toxicity and antidotal effects against the nerve agents Tabun and Soman.

This paper discusses the toxicity and antidotal effects of 32 compounds. Screening studies have shown that these compounds combined with atropine are effective antidotes against the organophosphate nerve agents Tabun and/or Soman, having a therapeutic factor equal or greater than 2.0 when tested in mice or rats. We analysed the results of these studies, and recommend that these compounds should be studied in more detail simultaneously with conventional antidotes (PAM-2, HI-6, Toxogonin, TMB-4) in order to assess whether they could broaden the choice of compounds now available for the treatment of organophosphate poisoning.

Animals↗

PubMed2006

Comparison of effects of different antidotes on tabun-induced cognitive impairment in rats using water maze.

In the past, scientists focused on the development of antidotes (mainly anticholinergics in combination with reactivators of inhibited acetylcholinesterase-oximes) to increase the number of surviving nerve agent-intoxicated individuals. Recently, they are interested in antidotes able not only to protect nerve agent-poisoned men from lethal toxic effects but also to improve their life quality by improvement of their central cognitive functions. In our study, the water maze was used to measure spatial working learning and memory in the case of tabun-induced cognitive impairment in albino Wistar rats. Antidotal treatment consisted of atropine alone or a combination of atropine with an oxime (obidoxime, trimedoxime or oxime HI-6). Our results suggest that atropine alone is not sufficient as a treatment for saving cognitive functions impaired by tabun. On the other hand, the addition of oxime to atropine contributes to improvement of cognitive performance in tabun-poisoned rats regardless of type of oxime.

Animals↗