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At least 19 recordsLinked to original sources
PubMed1988

Thermodynamic evaluation of activated charcoal as a poison antidote by high-performance liquid chromatography. II: In vitro method for the evaluation of activated charcoal as a poison antidote.

A previous report detailed the derivation and validation of an equation for calculating the Gibbs free energy of liquid-solid adsorption via high-performance liquid chromatography (HPLC). This study utilizes an improved form of that equation in conjunction with an in vitro model of solute adsorption to give an ordered listing of the antidotal activity of activated charcoal towards different drugs and other chemicals. The in vitro model consists of an activated charcoal column with a nominal particle diameter of 15 micron and a surface area of 447 x 10(4) cm2/g, together with a series of acetonitrile:water mobile phases at pH 3. A simple and efficient procedure was developed for ranking the solutes. First, each compound was run in an acetonitrile(ACN):water mobile phase chosen to give a convenient retention time and ideal chromatographic response. The capacity factor for this mobile phase was extrapolated to give a predicted capacity factor for a 35:65 (v/v) ACN:water mobile phase using an empirical equation developed from the exhaustive chromatography of four standard compounds (phenobarbital, strychnine, cyclohexanone, methyl ethyl ketone) in a variety of ACN:water mobile phases. In addition to the standards, 12 other compounds (glutethimide, chlordiazepoxide, quinine, brucine, d-propoxyphene, pentobarbital, methyprylon, methadone, meperidine, codeine, antipyrine, morphine) were evaluated. Based on these data, the Gibbs free energies of liquid-solid adsorption for these compounds were calculated and used to evaluate activated charcoal as a poison antidote for them. The results indicate that a rapid and accurate estimation of the utility of activated charcoal as an antidote for drugs and toxic substances can be obtained from a single chromatographic run of the test compound.

Adsorption↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1975

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↗
PubMed1992

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↗
PubMed1989

Attenuation of soman-induced lesions of skeletal muscle by acetylcholinesterase reactivating and non-reactivating antidotes.

It has been reported recently that some oximes reactivating acetylcholinesterase (AChE) exhibit concomitant ganglion-blocking effects which presumably could contribute independently to their powerful antidotal action in organophosphate inhibitor (OPI) poisoning, thus mimicking some unrelated substances which are effective antidotes without reactivating AChE. This raises the question whether OPI-induced muscle lesions, like some other symptoms could also be attenuated by oximes and other antidotes in the absence of AChE reactivation. To test this possibility, the oxime HI-6 was applied at increasing time intervals after the injection of soman until and beyond the point when soman-AChE complex becomes completely "aged" and not capable of reactivation. As the examples of OPI antidotes which do not reactivate AChE, the muscarinic antagonist atropine and the ganglion-blocking agent hexamethonium were also tested on possible attenuation of muscle lesions. The proportions of fibers with lesions, AChE inhibition and muscle fasciculations in experimental groups relative to the controls treated with soman only were evaluated. The results show that HI-6 can attenuate lesions only if AChE is partially reactivated and muscle fasciculations are permanently eliminated. However, atropine does not affect either AChE inhibition or muscle fasciculations and is also ineffective in counteracting the lesions in spite of its potency as an effective general antidote. Hexamethonium also does not affect AChE inhibition, but abolishes fasciculations and effectively attenuates muscle lesions. The latter findings reveal the existence of lesion-protecting mechanisms unrelated to AChE reactivation, which if further elucidated might become potentially relevant for additional treatment in OPI poisoning.

Acetylcholinesterase↗
PubMed1985

The antidotal action of thiosulfate following acute nitroprusside infusion in dogs.

The authors previously demonstrated in dogs that a bolus dose of sodium thiosulfate maintained enhanced cyanide metabolism throughout a 1-h infusion of sodium nitroprusside (SNP). To further test this antidotal action, a bolus dose of thiosulfate (150 mg . kg-1) was given to eight dogs at the end of a 60-min near-lethal infusion of nitroprusside (3 mg . kg-1). Within 2 min of the antidote, mean plasma thiocyanate levels (70.3 mumol . l-1) were significantly higher than those of seven control dogs given nitroprusside only (45.9 mumol . l-1, P = 0.002) and plateaued at 153.8 mumol . l-1 within 60 min, while the control values only reached 79.1 mumol . l-1 (P less than 0.001). Although differences between plasma cyanide levels in the two groups only attained significance 1 h after administering the antidote (0.8 vs. 2.74 mumol . l-1, P = 0.03), red blood cell cyanide concentrations were significantly lower in the antidote group within 5 min (166 vs. 225 mumol . l-1, P = 0.004) and remained so throughout the 2-h observation period. Compared with the controls, there was an impressive reduction in mean half-lives of plasma cyanide (25.1 vs. 74.1 min) and red blood cell cyanide (22.4 vs. 203.6 min). Similarly, peak cyanide levels occurred much sooner following the antidote (mean times: plasma cyanide 2.9 vs. 5.9 min; red blood cell cyanide 0.25 vs. 11 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Imbalance↗
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↗
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↗
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↗
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↗
PubMed1992

The poison center as a reservoir for antidotes for veterinary poisoning emergencies.

Animal poisonings account for a significant number of the cases responded to by poison centers. The majority of consultations involve small animals and do not necessitate the use of large amounts of pharmacologic antagonists, such as atropine to treat anticholinesterase pesticide poisonings. However, large animals such as cattle present unique management problems, since phenomenal amounts of antidotes may be needed to treat a herd of cattle, creating a significant economic impact. The most challenging dilemma is providing 24-h availability and a means of acquisition of sufficient quantities of antidotes to reduce the economic impact of large-animal poisonings. In conjunction with a state veterinary medical association, a RPIC serves as a depot for the storage and distribution of emergency veterinary antidotes. Sufficient quantities of atropine, methylene blue, calcium EDTA, sodium nitrite and thiosulfate, and activated charcoal are available via the RPIC to treat a herd of 200 cattle. The antidotes are available only for emergency treatment and with a veterinary prescription. The 24-h nature of the poison center makes it an ideal location to serve the needs of veterinarians.

Animals↗
PubMedDate not supplied

Antidotes to lethal cocaine toxicity in the rat.

Cocaine, like catecholamines or angiotensin II, may induce lethal cardiac or cerebral damage. Restrained rats were fitted with a caudal arterial catheter for on-line cardiovascular monitoring and antidote administration. They were given 60 mg/kg of cocaine i.p., a dose which produces behavioral and cardiovascular effects, convulsions and death in an average time of 10 min. Selected antidotes were administered 5 min after the lethal dose of cocaine. Incidence of lethality was not changed by propranolol, prazosin, labetalol, diazepam or enalaprilat, a converting enzyme inhibitor. Animals treated with any one of the following agents, alpha- or beta-blockers, diazepam or competitive inhibitors of angiotensin II [Sar-1-ile-8] and [Sar-1-thr-8] angiotensin II, presented myocardial infarction. All animals treated with calcium channel antagonists or enalaprilat, whether they survived or not, did not present myocardial infarction. Treatment with nitrendipine, flunarizine or diltiazem, resulted in survival of the animals with no observable aftereffects. Similar results were observed when enalaprilat was administered, with diazepam as an antidote, to a lethal dose of cocaine. Antagonists to the sympatho-adrenal system and to the renin angiotensin system appear to be effective antidotes to cocaine toxicity in the present experimental model.

Adrenergic alpha-Antagonists↗
PubMed1990

Evaluation of potential antidotes for sodium fluoroacetate in mice.

Pathogenesis in fluoroacetate poisoning is multifactorial. Biochemically it is characterized by lethal synthesis of fluorocitrate, causing hypocalcemia, and energy deficiency through blockade of the TCA cycle. Calcium gluconate (CaG) was chosen to antagonize hypocalcemia, while sodium alpha kelogluterate (NaKG) and sodium succinate (NaSuc) were selected as potential antidotes to revive the TCA cycle. Effectiveness of each of these antidotes individually and in certain combinations was tested in mice exposed to lethal doses (15 mg/kg ip) of sodium fluoroacetate (NaFAC). Antidotal treatments were administered at 15 min, 4 h, 10 h, 24 h, and 36 h after NaFAC. All 3 of the antidotes alone, as well as a combination of CaG with NaKG, were ineffective in reducing mortality in mice after NaFAC. On the other hand, a combination of CaG (130 mg/kg) with NaSuc (240 mg/kg) was effective if the 2 solutions were either injected at separate sites or mixed in the same syringe just prior to injection. Similar solutions, if mixed for 24 h or longer before administrations, were ineffective. Increasing the dose of NaSuc to 360 or 480 mg/kg with CaG (130 mg/kg) was unrewarding. These results indicate that CaG in combination with 240 mg NaSuc/kg offer a promising therapy modality in NaFAC intoxication. Additional studies involving biochemical parameters and other species are needed to confirm the efficacy and mechanism(s) of action of this combination.

Animals↗