INTRAVENOUS LIPID EMULSION TREATMENT REDUCES SYMPTOMS OF BREVETOXICOSIS IN TURTLES (TRACHEMYS SCRIPTA).

Harmful algal blooms (HABs) occur when excess nutrients allow dinoflagellates to reproduce in large numbers. Marine animals are affected by blooms when algal toxins are ingested or inhaled. In the Gulf of Mexico, near annual blooms of Karenia brevis release a suite of compounds (brevetoxins) that cause sea turtle morbidity and mortality. The primary treatment at rehabilitation facilities for brevetoxin-exposed sea turtles is supportive care, and it has been difficult to design alternative treatment strategies without an understanding of the effects of brevetoxins in turtles in vivo. Previous studies using the freshwater turtle as a model species showed that brevetoxin-3 impacts the nervous and muscular systems, and is detoxified and eliminated primarily through the liver, bile, and feces. In this study, freshwater turtles (Trachemys scripta) were exposed to brevetoxin (PbTx-3) intratracheally at doses causing clear systemic effects, and treatment strategies aimed at reducing the postexposure neurological and muscular deficits were tested. Brevetoxin-exposed T. scripta displayed the same behaviors as animals admitted to rehabilitation centers for toxin exposure, ranging from muscle twitching and incoordination to paralysis and unresponsiveness. Two treatment regimes were tested: cholestyramine, a bile acid sequestrant; and an intravenous lipid emulsion treatment (Intralipidt) that provides an expanded circulating lipid volume. Cholestyramine was administered orally 1 hr and 6 hr post PbTx-3 exposure, but this regime failed to increase toxin clearance. Animals treated with Intralipid (100 mg/kg) 30 min after PbTx-3 exposure had greatly reduced symptoms of brevetoxicosis within the first 2 hr compared with animals that did not receive the treatment, and appeared fully recovered within 24 hr compared with toxin-exposed control animals that did not receive Intralipid. The results strongly suggest that Intralipid treatment for lipophilic toxins such as PbTx-3 has the potential to reduce morbidity and mortality in HAB-exposed sea turtles.

Development and Optimization of Gastro-Retentive Controlled-Release Tablet of Calcium-Disodium Edentate and its In Vivo Gamma Scintigraphic Evaluation.

Medical management of heavy metal toxicity, including radioactive ones, is a cause for concern because of their increased use in energy production, healthcare, and mining. Though chelating agents like EDTA and DTPA in parenteral form are available, no suitable oral formulation is there that can trap ingested heavy metal toxicants in the stomach itself, preventing their systemic absorption. The objective of the present study was to develop and optimize gastro-retentive controlled-release tablets of calcium-disodium edentate (Ca-Na2EDTA). Gastro-retentive tablet of Ca-Na2EDTA was prepared by direct compression method. Thirteen tablet formulations were designed using HPMC-K4M, sodium chloride, and carbopol-934 along with effervescing agents sodium bicarbonate and citric acid. Tablet swelling ability, in vitro buoyancy, and drug dissolution studies were conducted in 0.1 N HCl at 37 ± 0.5°C. Ca-Na2EDTA was radiolabeled with technetium-99m for scintigraphy-based in vivo evaluation. Formula F8 (Ca-Na2EDTA 200 mg, carbopol 100 mg, avicel 55 mg, citric acid 30 mg, NaHCO3 70 mg, NaCl 100 mg, and HPMC 95 mg) was found to be optimum in terms of excellent floating properties and sustained drug release. F8 fitted best for Korsmeyer-Peppas equation with an R (2) value of 0.993. Gamma scintigraphy in humans showed mean gastric retention period of 6 h. Stability studies carried out in accordance with ICH guidelines and analyzed at time intervals of 0, 1, 2, 4, and 6 months have indicated insignificant difference in tablet hardness, drug content, total floating duration, or matrix integrity of the optimized formulation. Gastro-retentive, controlled-release tablet of Ca-Na2EDTA was successfully developed using effervescent technique as a potential oral antidote for neutralizing ingested heavy metal toxicity.

Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil.

Zolpidem is a widely prescribed anti-insomnia agent. Although most pediatric zolpidem ingestions are benign, large ingestions can cause significant central nervous system (CNS) depression. Flumazenil has been reported to reverse the CNS effects of zolpidem. We describe a case of a large pediatric zolpidem ingestion resulting in profound CNS depression that responded to flumazenil administration. Serial zolpidem serum levels confirmed the ingestion. A 10-year-old boy with trisomy 21 presented to the emergency department 1 hour after he was found sedate with several zolpidem 5-mg tablets in his mouth. Seventeen tables (85 mg) were unaccounted for from a prescription bottle. He became unarousable approximately 2 hours after his ingestion. Flumazenil 0.2 mg intravenously was given with rapid return to his baseline mental status. He became resedate 1 hour later but was arousable. Sixteen hours after his presentation, he was asymptomatic. Serial zolpidem serum levels were obtained, showed an initial level of 310 ng/mL, and demonstrated zero-order kinetics. Zolpidem is an imidazopyridine, which binds to the benzodiazepine receptor. It is rapidly absorbed and has a short-half life. Unintentional pediatric ingestions of zolpidem are typically well tolerated. However, this case demonstrates that large ingestions may cause significant and prolonged CNS depression. Flumazenil, a benzodiazepine receptor antagonist, has been described to reverse the effects of zolpidem in adult ingestions. There are few published reports describing flumazenil use in pediatric ingestion patients. This case suggests that flumazenil may be an effective treatment for zolpidem-induced CNS depression in the pediatric patient.

Intracellular plutonium: removal by liposome-encapsulated chelating agent.

Chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were successfully encapsulated within lipid spherules (that is, liposomes). Encapsutlated [(14)C]EDTA, given intravenously to mice, was retained longer in tissues that nonencapsulated [(14)C]EDTA. Encapsulated DTPA, given to mice 3 days after pluttonium injection, removed an additional fraction of plutonium in the liver, presumably intracellular, not available to nonencapslulated DTPA. It also further increased urinary excretion of plutonium. Introduction of chelating agents into cells by liposomal encapsulation is a promising new approach to the treatment of metal poisoning

Compliance for single and multiple dose regimens of superactivated charcoal: a prospective study of patients in a clinical trial.

BACKGROUND: Although activated charcoal is widely used for the treatment of self-poisoning, its effectiveness is unknown. An important consideration is patient compliance since poor compliance will limit effectiveness. We aimed to describe compliance in a randomized controlled trial (RCT) performed in Sri Lanka, presuming that this would set the upper limits for compliance in routine clinical use. METHOD: 1,103 patients randomized to single or multiple (six doses q4h) 50 g doses of superactivated charcoal were prospectively observed. Charcoal was given by study doctors who recorded the amount ingested and the amount of persuasion required for the patients to drink the charcoal. RESULTS: 559 patients were randomized to receive one dose and 544 to receive six doses. Data was available for 1,071 (97%) patients. Eighty-eight were unable to complete their course; 98 required a NG tube, leaving 885 patients that received the first dose by mouth. The mean estimated amount of the prescribed dose of charcoal taken orally as a single or first dose was 83% (95% C.I. 82-84%). For patients receiving multiple doses, this amount fell over the next five doses to 66% (63-69%). While only 3.2% of patients refused the first dose, 12.3% refused the sixth. Relatively less persuasion was required for patients ingesting the first or single dose; 38% of patients required intense persuasion by the sixth dose. CONCLUSION: Compliance for a single dose of superactivated charcoal among trial patients was good. However, even in the ideal circumstances of a RCT, compliance decreased thereafter for patients taking more than one dose.

Modification of allergenicity and immunogenicity of formate dehydrogenase by conjugation with linear mono methoxy poly ethylene glycol: improvement in detoxification of formate in methanol poisoning.

BACKGROUND: Single bolus intravenous infusion of native formate dehydrogenase (FD), isolated from Candida boidinii was found to eliminate formate, a highly toxic metabolite in methanol poisoning. In order to prevent immunological reactions which might be produced by multiple dosing of formate dehydrogenase and to prolong the serum half life of the enzyme, the N-hydroxysuccinimidyl ester of methoxy polyethylene glycol propionic acid (mPEG-SPA 5000) was conjugated to native formate dehydrogenase. METHOD: PEGylation reactions were run at 20 degrees C for 30 min in a reaction buffer (0.2 mol/l sodium phosphate buffer, pH 8.3). The PEGylated molecules were purified from unreacted PEG with Amicon Ultra-4 (10 K) and by Sephacryl S-300 HR gel-filtration chromatography. Unreacted formate dehydrogenase molecules were removed by DEAE Sepharose FF anion-exchange chromatography. PEG-FD enzyme molecules obtained from reacting ratio of FD/PEG of 1/40 had an enzyme activity of 68% of unmodified enzyme. Immunogenicity of PEGylated and native enzyme was evaluated by ELISA. Allergenicity was evaluated by active systemic anaphylaxis and passive cutaneous anaphylaxis tests. In vivo efficacy of PEG-FD or native FD was comparatively evaluated by single intravenous administration of PEG-FD or native FD in folate deficient methanol intoxicated albino rats along with Carbicarb buffer infusion. Methanol and formate were estimated at specific time points respectively with HPLC and fluorescence spectrophotometer. RESULT: PEG-FD had comparatively longer half life and lower immunogenicity than native FD. PEG-FD had better in vivo efficacy than native FD in eliminating the formate. CONCLUSION: Conjugation of mPEG-SPA 5000 with native FD reduces its immunogenicity and increases its efficacy in detoxification of formate in methanol poisoning.

Polymer antidotes for toxin sequestration.

Toxins delivered by envenomation, secreted by microorganisms, or unintentionally ingested can pose an immediate threat to life. Rapid intervention coupled with the appropriate antidote is required to mitigate the threat. Many antidotes are biological products and their cost, methods of production, potential for eliciting immunogenic responses, the time needed to generate them, and stability issues contribute to their limited availability and effectiveness. These factors exacerbate a world-wide challenge for providing treatment. In this review we evaluate a number of polymer constructs that may serve as alternative antidotes. The range of toxins investigated includes those from sources such as plants, animals and bacteria. The development of polymeric heavy metal sequestrants for use as antidotes to heavy metal poisoning faces similar challenges, thus recent findings in this area have also been included. Two general strategies have emerged for the development of polymeric antidotes. In one, the polymer acts as a scaffold for the presentation of ligands with a known affinity for the toxin. A second strategy is to generate polymers with an intrinsic affinity, and in some cases selectivity, to a range of toxins. Importantly, in vivo efficacy has been demonstrated for each of these strategies, which suggests that these approaches hold promise as an alternative to biological or small molecule based treatments.

Use of N-acetylcysteine in clinical toxicology.

The major use of N-acetylcysteine in clinical toxicology is in the treatment of acetaminophen (paracetamol) overdosage. The hepatorenal toxicity of acetaminophen is mediated by a reactive metabolite normally detoxified by reduced glutathione. If glutathione is depleted, covalent binding to macromolecules and/or oxidation of thiol enzymes can lead to cell death. Oral or intravenous N-acetylcysteine or oral D,L-methionine mitigates acetaminophen-induced hepatorenal damage if given within 10 hours, but becomes less effective thereafter. In vivo, N-acetylcysteine forms L-cysteine, cystine, L-methionine, glutathione, and mixed disulfides; L-methionine also forms cysteine, thus giving rise to glutathione and other products. Oral therapy with N-acetylcysteine or methionine for acetaminophen poisoning is contraindicated in the presence of coma or vomiting, or if activated charcoal has been given by mouth. Nausea, vomiting, and diarrhea may also occur as a result of oral N-acetylcysteine administration. Anaphylactoid reactions including angioedema, bronchospasm, flushing, hypotension, nausea/vomiting, rash, tachycardia, and respiratory distress may occur 15-60 minutes into N-acetylcysteine infusion (20 hours intravenous regimen) in up to 10% of patients. Following accidental intravenous overdosage, the adverse reactions of N-acetylcysteine are similar but more severe; fatalities have occurred. A reduction in the loading dose of N-acetylcysteine may reduce the risk of adverse reactions while maintaining efficacy. Administration of N-acetylcysteine for a longer period might provide enhanced protection for patients in whom acetaminophen absorption or elimination is delayed. N-acetylcysteine may also have a role in the treatment of toxicity from carbon tetrachloride, chloroform, 1,2-dichloropropane, and other compounds. The possible use of N-acetylcysteine and other agents in the prevention of the neuropsychiatric sequelae of acute carbon monoxide poisoning is an important area for future research.

Effect of delayed treatment with sodium polystyrene sulfonate on serum lithium concentrations in mice.

OBJECTIVES: To determine the efficacy of sodium polystyrene sulfonate (SPS) in lowering serum lithium (Li) concentrations. Specifically, to determine the effects of both different doses of SPS and different times to treatment with SPS on serum Li levels. METHODS: The study was a controlled, single-dose murine trial of SPS on serum Li levels. Male CD-1 mice (n = 525) were given orogastric LiCl and then divided into three main treatment groups: group SPS received a single orogastric administration of SPS in a dose of 5 gm/kg body weight at either 0, 15, 30, 45, or 90 minutes after LiCl; group half-SPS received a single orogastric administration of SPS in a dose of 2.5 gm/kg body weight at times equivalent to those of group SPS; and the control group received orogastric deionized water in a volume equivalent to that of group SPS at 0, 15, 30, 45, or 90 minutes after LiCl. Subgroups of seven to ten mice in each of the four treatment groups were sacrificed at one, two, four, and eight hours after administration of LiCl, and their blood was analyzed for Li concentration. RESULTS: 1) Single doses of SPS significantly lowered serum Li concentrations; 2) this effect was dose-related; 3) the delays in administration of SPS used in this study did not significantly reduce its ability to lower serum Li concentrations; and 4) even when administered after peak serum Li concentrations had been achieved, a single dose of SPS was effective in lowering serum Li levels. CONCLUSIONS: SPS may be efficacious in the treatment for Li toxicity under certain circumstances, even when there is delay to treatment. Additional study is warranted to further characterize the ability of SPS to alter Li kinetics.

Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity.

Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.

[Self-poisoning with Datura stramonium. 3 case reports]. / Intoxication volontaire par Datura stramonium. 3 observations.

BACKGROUND: Datura stramonium is a hallucinogenic plant that causes serious poisoning. Due to its easy availability and strong anticholinergic properties, substance users and teens may use Datura stramonium as a drug. Consumption of any part of the plant can result in severe toxicity. CASE REPORTS: 3 cases of acute self-poisoning by ingestion of Datura stramonium are reported. The patients presented with a typical anticholinergic syndrome: agitation, confusion, hallucinations and combative behaviour; all of them had mydriasis, but dry mouth and tachycardia were less common. All these 3 subjects had a good prognosis but have required hospitalisation because of severe psychiatric derangement with agitated behaviour. The patients were favourably managed with only symptomatic treatment. DISCUSSION: This article reviews the clinical syndrome associated with the toxicity. The severity of hallucinations and confusion, associated with pupillary dilation, flushing, dry mouth, and tachycardia, are related with Datura intoxication. Symptomatic treatment is efficient. CONCLUSION: Primary care physicians might be informed about the abuse of Datura stramonium, often associated with substance misuse, and the need to educate risk-patients.

[Experimental study on the action of EDTA-liposome to remove mercury from the mice given methylmercury chloride].

It was reported that experimental study on the action of EDTA-Liposome to remove mercury from the mice given methylmercury chloride showed that elimination of methylmercury chloride from brain, testicle, liver, kidney and blood of mice treated by EDTA-Liposome was more significant than that of mice treated by EDTA alone. Mercury level in feces of EDTA-Liposome treated group increased significantly (P < 0.001). The advantages of treatment with EDTA-Liposome were discussed. Applying EDTA-Liposome is an efficient method in therapy of metal poisoning.

[Acute arsenic poisoning]. / Akut arsenforgiftning.

We report three cases of arsenic poisoning in a chemical factory. Three workers were exposed to vinyzene 10,10'-oxydephenarsine and developed mild symptoms of acute poisoning. All patients were treated with dimercaprol, and recovered after a few days. Urine analysis did not show increased arsenic excretion, but this could be due to the large urine samples taken. It is recommended that a urine sample is taken right after admission to hospital and new samples after eight and 16 hours.

[Cholestyramine for digoxin intoxication].

Cholestyramine, a bile acid sequestering resin, has been reported to bind digitalis in vitro. We gave 4 g every 6 hours to 3 patients with non-life threatening digoxin intoxication. In all 3 serum digoxin concentrations and digoxin half-life decreased: from 50 to 32 hours, from 50 to 10 hours and from 46 to 16 hours in the 3 cases, respectively. Cholestyramine is potentially useful and safe adjunct medication for non-life threatening digoxin intoxication.

[Therapeutic trial for promotion of fecal excretion of PCDFs and PCBs by the administration of cholestyramine in Yusho patients].

Any effective therapy for elimination of causal agents remaining in Yusho patients was not found until now. To know the profile of fecal excretion of polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs), the amounts of PCDFs and PCBs in the stool of six Yusho patients with the typical symptoms were determined. The stool samples of Yusho patients were collected in 1989. PCDFs, i.e., 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PnCDF), 1,2,3,4,7,8- and 1,2,3,6,7,8-hexachlorodibenzofurans (HxCDFs), 1,2,3,4,6,7,8-heptachlorodibenzofuran (HpCDF) and octachlorodibenzofuran (OCDF) were detected in all of the samples. PCDFs found in the stool samples were mostly PnCDF and HxCDFs. Of PCDFs detected, PnCDF and HxCDFs contributed to 42 +/- 4.7% and 43 +/- 5.5% as mean +/- SE, respectively. The fecal excretion of PnCDF and HxCDFs in Yusho patients was 720 +/- 490 pg/day and 790 +/- 620 pg/day as mean +/- SE, respectively. On the other hand, the fecal excretion of PnCDF and HxCDFs in normal controls was 32 +/- 13 pg/day and 47 +/- 5.2 pg/day as mean +/- SE, respectively. The fecal excretion of PnCDF and HxCDFs in Yusho patients was about 23 times and 17 times each higher than that in normal controls. The fecal excretion of PCBs in Yusho patients and normal controls was 400 +/- 430 ng/day and 150 +/- 39 ng/day, respectively, as mean +/- SE. In order to promote the excretion of these toxic chemicals in the stool of Yusho patients, the patients were continuously administered with cholestyramine, an anion exchange resin, at a dose of 4 g, 3 times a day, for 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

[Treatment of Yusho patients with cholestyramine].

Six typical Yusho patients (3 men, 48-58 years old, and 3 women, 45-55 years old) were treated with cholestyramine, 8-12 g/day, for 24 weeks. Improvement of some symptoms, such as arthralgia and malaise, was observed in 2 men, although this effect was non-specific. None of the patients showed increment of excretion of polychlorinated biphenyl or polychlorodibenzofuran into feces.

[Therapeutic trials for promotion of faecal excretion of PCDFs by the administration of rice bran fiber and cholestyramine in Yusho patients].

It is well-known that Yusho disease was caused by polychlorinated dibenzofurans (PCDFs), and that 2, 3, 4, 7, 8-Pentachlorodibenzofuran (PnCDF), 1, 2, 3, 4, 7, 8- and 1, 2, 3, 6, 7, 8-Hexachlorodibenzofurans (HxCDFs) still retain in the patient bodies. As patients usually suffer from various chronic syndrome, an effective treatment is extremely needed. In order to assess the rice bran fiber (RBF) and cholestyramine on stimulating faecal excretion of PCDFs, two clinical trials were carried out in 1990 and 1991. In the first trial in 1990, 10 g of RBF (dietary fiber content was 50%) and 4 g of cholestyramine were administered to four Yusho patients three times a day for a week. The stool from patients were collected a week before and during the administration. These were pooled respectively, and then two samples for measurement. In the second trial in 1991, 10 g of dietary fiber rich RBF (refined-RBF, dietary fiber content was 85%) and 4 g of cholestyramine were administered to four Yusho patients three times a day for two weeks. In this trial, three stool samples were obtained from each patient, ie., a week before administration, and first and second week during administration. Level of PCDFs was determined by high resorption GC/MS and the following results were obtained. 1) In the first trial (1990) the faecal excretion of PnCDF and HxCDFs increased at the rates of 42-88% and 7-47%, respectively, in three out of four patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning.

Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 10(9) /l, haematocrit of 28% and platelet count of 280 × 10(9) /l. The prothrombin time (PT) was > 200 s (normal range 10.5-15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20-45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8-1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversed-phase liquid chromatography.