Evidence for the efficacy of the emetic PP796 in paraquat SL20 formulations - a narrative review of published and unpublished evidence.

BACKGROUND: The bipyridyl herbicide paraquat was first introduced into agriculture in the 1960s by Imperial Chemical Industries. Due to issues with unintentional poisoning, the centrally acting emetic PP796 was added in 1976 to the company's 20% paraquat ion soluble liquid (SL20) formulations (Gramoxone®) at a concentration of 0.5 g/L or 0.05% (equivalent to 0.071 mg/kg in a 70 kg adult ingesting a minimum lethal dose of 10 mL) to induce early vomiting (within 30 min), reduce paraquat absorption from the gut, and prevent deaths. Its presence in paraquat products was subsequently mandated by the Food and Agriculture Organization Committee of Experts on Pesticides in Agriculture (predecessor to the current FAO/WHO Joint Meeting on Pesticide Specifications). However, no primary pre-clinical or clinical data have been published regarding the effectiveness of PP796. We reviewed the published literature and unpublished company reports for data on the effectiveness of PP796. METHODS: PubMed and Google were searched for published studies on the emetic using the search terms "paraquat" and ["emetic" or "PP796"]. Company documents reporting pre-clinical and clinical studies were accessed at the website of U.S. Right to Know (https://usrtk.org/pesticides/paraquat-papers/). Primary study reports were sought as well as overviews written by company toxicologists. RESULTS: Pre-clinical dog and monkey studies indicated that the PP796 EC50 dose for vomiting was around 0.5-2 mg/kg. Further increasing the PP796 concentration speeded up the time to first vomit and reduced the amount of paraquat absorbed (as assessed by the 0-24 h plasma area-under-the-curve) 100-fold compared to a control group receiving no PP796. However, the dose selected for paraquat SL20 formulations by the company (0.5 g/L or 0.05%) was based exclusively on a phase II study in the early 1970s involving five volunteers receiving 3 different doses, with only two individuals actually vomiting, supplemented by data from 37 patients taking 2 mg in clinical trials. A UK-mandated toxicovigilance study in the 1980s identified only 21 patients ingesting paraquat SL20 with PP796 for whom data on time to vomit was available; of these patients, 11 vomited within 30 min (52.4%, 95%CI 31-73.7%). No effect on mortality could be identified from any study of paraquat SL containing 0.05% PP796. A clinical study in Sri Lanka 30 years after the emetic was first introduced, of a revised formulation (Gramoxone® Inteon) containing a three-fold higher amount of PP796, as well as MgSO4 and an alginate, showed increased rates of early vomiting and modestly reduced mortality for patients ingesting up to 100 mL. CONCLUSION: Pre-clinical studies showed a clear dose response for PP796 to cause early vomiting, with effective doses in the 0.5-20 mg/kg range. A too low concentration of PP796 was selected for paraquat formulations based on an inadequate phase II study. Currently, evidence that PP796 at 0.05% in paraquat SL20 causes more rapid vomiting after ingestion is weak or unpublished; no evidence of clinical benefit or fewer deaths has been identified. There is no evidence to support the FAO/WHO Joint Meeting on Pesticide Specifications mandate to include PP796 or any other emetic in paraquat products. Products with higher emetic concentrations have been developed but are not widely used; it is possible they may prevent deaths.

Radiation-induced nausea and vomiting: a comparison between MASCC/ESMO, ASCO, and NCCN antiemetic guidelines.

PURPOSE: Radiation-induced nausea and vomiting (RINV) can affect 50-80% of patients undergoing radiotherapy and negatively impacts quality of life. This review aimed to compare the most recent RINV antiemetic guidelines produced by the Multinational Association for Supportive Care in Cancer (MASCC), the European Society of Clinical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN). Future improvements to the guidelines and the need for further research in RINV were also discussed. METHODS: Antiemetic guidelines produced by MASCC/ESMO, ASCO, and NCCN were examined to identify similarities, differences, and inadequacies within the guidelines. RESULTS: Areas of dissension within the guidelines include the addition of dexamethasone to moderate-risk antiemetic regimens, the prophylactic treatment of RINV in the low-risk categories, and the appropriate treatment for breakthrough emesis. The guidelines are in accordance that high-risk radiotherapy regimens should be treated prophylactically with a serotonin receptor antagonist and for those undergoing concurrent chemotherapy and radiotherapy, antiemetic treatment should be prescribed according to the emetic risk associated with their respective chemotherapy regimen. Low- and minimal-risk recommendations are based on low-level evidence and informal consensus. CONCLUSION: RINV is a frequent and distressing side effect of radiotherapy and requires further research to establish effective antiemetic guidelines and ensure optimal treatment outcomes.

Mushroom Poisoning Cases in Dogs and Cats: Diagnosis and Treatment of Hepatotoxic, Neurotoxic, Gastroenterotoxic, Nephrotoxic, and Muscarinic Mushrooms.

Ingestion of poisonous mushrooms by small animals can lead to liver failure, neurotoxicity, or gastrointestinal irritation. Although amanita poisoning can be lethal, ingestion of other toxic mushrooms is generally self-limiting and not life threatening. Most cases are undiagnosed, as routine diagnostic tests only exist for amanitins and psilocin. Early detection of amanitin exposure can greatly aid in the therapeutic intervention by allowing veterinarians to make timely decisions regarding patient management. Treatment is generally supportive, but specific therapeutic measures exist for amanitin and psilocin exposures.

Assessment of dexmedetomidine and other agents for emesis induction in cats: 43 cases (2009-2014).

OBJECTIVE: To compare the use of dexmedetomidine hydrochloride, xylazine hydrochloride, and hydrogen peroxide for emesis induction in cats. DESIGN: Retrospective case series. ANIMALS: 43 client-owned cats for which emesis induction was attempted because of known or suspected toxicant ingestion or recent ingestion of a string foreign body. PROCEDURES: Data collected from the cats' medical records included type, dose, and route of administration of emetic agent; outcome of attempted emesis induction; time until emesis or postemesis administration of a reversal agent (to counter sedative effects of the emetic agent); and adverse events. RESULTS: Emesis induction was attempted by oral administration of hydrogen peroxide (n = 3) or IM or IV administration of xylazine (25 [including 1 cat that had already received hydrogen peroxide]) or dexmedetomidine (16). No cat that received hydrogen peroxide vomited. Emesis was induced in 11 of 25 xylazine-treated cats and in 13 of 16 dexmedetomidine-treated cats. Dexmedetomidine was more likely to cause vomiting than xylazine (OR, 5.5; 95% confidence interval, 1.1 to 36). The median dose of dexmedetomidine that caused emesis was 7.0 µg/kg (3.2 µg/lb; range, 0.96 to 10.0 µg/kg [0.44 to 4.55 µg/lb]). The elapsed time until emesis or postemesis reversal agent administration was recorded for 5 xylazine-treated cats (median interval, 10 minutes [range, 5 to 175 minutes]) and 10 dexmedetomidine-treated cats (median interval, 5 minutes [range, 1 to 12 minutes]). Sedation was the only adverse effect, occurring in 2 xylazine-treated cats and 1 dexmedetomidine-treated cat. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dexmedetomidine can be used successfully to induce emesis in cats.

Position paper update: ipecac syrup for gastrointestinal decontamination.

CONTEXT: An update of the first position paper on ipecac syrup from 1997 was published by the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists in 2004. The aims of this paper are to briefly summarize the content of the 2004 Position Paper and to present any new data. METHODS: A systematic review of the literature from the year 2003 forward. RESULTS: The literature search yielded a limited number of meaningful articles, and there remains no convincing evidence from clinical studies that ipecac improves the outcome of poisoned patients. Furthermore, the availability of ipecac is rapidly diminishing. CONCLUSIONS: The routine administration of ipecac at the site of ingestion or in the emergency department should definitely be avoided. Ipecac may delay the administration or reduce the effectiveness of activated charcoal, oral antidotes, and whole bowel irrigation. There is not sufficient evidence to warrant any change in the previous ipecac position papers. There are, however, insufficient data to support or exclude ipecac administration soon after ingestion of some specific poisons in rare situations.

Effects on a Poison Center's (PC) triage and follow-up after implementing the no Ipecac use policy.

For years, The American Academy of Pediatrics (AAP) had supported home use of syrup of Ipecac. However, due to mounting evidence that Ipecac use did not improve outcome nor reduce Emergency Department (ED) referrals, the AAP in November of 2003 issued a statement that Ipecac not be used for the home management of poison ingestion. To determine if the cessation of the use of Ipecac for home ingestions is associated with an increased number of follow-up calls, an increased time of observation at home and an increase in the number of ED referrals for care by poison center staff were administered. Fifty randomly selected pediatric (<6 years) cases that received Ipecac ("Ipecac" group) from January 1, 2003 to October 31, 2003 were selected for study. Up to two controls ("no Ipecac" group) were matched by age, amount ingested, and by toxin. Controls were selected from the 2004-2006 time period (Ipecac no longer in use). Fifty "Ipecac" cases and 84 "no Ipecac" controls were analyzed. The groups had no significant differences with respect to percent symptomatic, median time post-ingestion, mean age, and distribution of toxin categories (e.g., antidepressants, beta blockers, etc.). The "no Ipecac" group had nearly ten times the odds of ED referral compared to the "Ipecac" group, (OR = 9.9, 95%CI 3.3-32.2). The mean total hours of follow-up was not significantly different between the groups (diff = -1.1, t = -1.8, p = 0.07). The mean number of follow-up calls was significantly less in the "no Ipecac" group (diff = -1.4 calls, t = -6.8, p < 0.001). Toxicology consults were greater in the "no Ipecac" group (chi (2 )= 4.05, p = 0.04); however, consults were not associated with ED referral. For the time period from 2004 to 2006, the "no Ipecac" policy resulted in an increase in ED referrals at our center. While prior studies have shown that not using Ipecac did not affect clinical outcome, our research suggested that it may have initially influenced triaging outcome. Since the use of Ipecac by centers was once a commonly used home remedy for some ingestions (albeit without rigorously established efficacy), poison center personnel had to transition to the "no Ipecac" policy. Although our referrals increased during a transitional period of time, referral rates have since stabilized and returned to baseline.

The outcome of North American pediatric unintentional mushroom ingestions with various decontamination treatments: an analysis of 14 years of TESS data.

The optimum empiric decontamination therapy for unintentional pediatric mushroom ingestion is not known. We sought to determine case outcomes for unintentional mushroom ingestions in children by decontamination therapies utilized. The 1992-2005 American Association of Poison Control Centers Toxic Exposure Surveillance System was queried for cases of unintentional acute mushroom ingestions in children age <6 years. Cases were excluded if outcome was unknown, if exposure was coded as unrelated to the symptoms, or if there was co-ingestion of a non-mycoid substance. The treatment subgroups analyzed were ipecac, single-dose activated charcoal, and no gastric decontamination. 82,330 cases met the inclusion criteria with 22,454 cases excluded. There were 16 cases with major effects and no deaths. There were 57,531 cases in the three treatment subgroups. There was a significantly smaller percentage of cases with moderate or major outcomes in the ipecac subgroup compared to the no decontamination subgroup. There was a significantly greater percentage of cases with moderate or major outcomes in the activated charcoal compared to the no decontamination subgroup. If decontamination therapy is being performed, and this data suggests it may not be necessary, syrup of ipecac could still be considered an effective option.

Management of yellow oleander poisoning.

BACKGROUND: Poisoning due to deliberate self-harm with the seeds of yellow oleander (Thevetia peruviana) results in significant morbidity and mortality each year in South Asia. Yellow oleander seeds contain highly toxic cardiac glycosides including thevetins A and B and neriifolin. A wide variety of bradyarrhythmias and tachyarrhythmias occur following ingestion. Important epidemiological and clinical differences exist between poisoning due to yellow oleander and digoxin; yellow oleander poisoning is commonly seen in younger patients without preexisting illness or comorbidity. Assessment and initial management. Initial assessment and management is similar to other poisonings. No definite criteria are available for risk stratification. Continuous ECG monitoring for at least 24 h is necessary to detect arrhythmias; longer monitoring is appropriate in patients with severe poisoning. Supportive care. Correction of dehydration with normal saline is necessary, and antiemetics are used to control severe vomiting. Electrolytes. Hypokalemia worsens toxicity due to digitalis glycosides, and hyperkalemia is life-threatening. Both must be corrected. Hyperkalemia is due to extracellular shift of potassium rather than an increase in total body potassium and is best treated with insulin-dextrose infusion. Intravenous calcium increases the risk of cardiac arrhythmias and is not recommended in treating hyperkalemia. Oral or rectal administration of sodium polystyrene sulfonate resin may result in hypokalemia when used together with digoxin-specific antibody fragments. Unlike digoxin toxicity, serum magnesium concentrations are less likely to be affected in yellow oleander poisoning. The effect of magnesium concentrations on toxicity and outcome is not known. Hypomagnesaemia should be corrected as it can worsen cardiac glycoside toxicity. Gastric decontamination. The place of emesis induction and gastric lavage has not been investigated, although they are used in practice. Gastric decontamination by the use of single dose and multiple doses of activated charcoal has been evaluated in two randomized controlled trials, with contradictory results. Methodological differences (severity of poisoning in recruited patients, duration of treatment, compliance) between the two trials, together with differences in mortality rates in control groups, have led to much controversy. No firm recommendation for or against the use of multiple doses of activated charcoal can be made at present, and further studies are needed. Single-dose activated charcoal is probably beneficial. Activated charcoal is clearly safe. Arrhythmia management. Bradyarrhythmias are commonly managed with atropine, isoprenaline, and temporary cardiac pacing in severe cases, although without trial evidence of survival benefit, or adequate evaluation of possible risks. Accelerating the heart rate with atropine or beta-adrenergic agents theoretically increases the risk of tachyarrhythmias, and it has been claimed that atropine increases tachyarrhythmic deaths. Further studies are required. Tachyarrhythmias have a poor prognosis and are more difficult to treat. Lidocaine is the preferred antiarrhythmic; the role of intravenous magnesium is uncertain. Digoxin-specific antibody fragments. Digoxin-specific antibody fragments are effective in reverting life-threatening cardiac arrhythmias; prospective observational studies show a beneficial effect on mortality. High cost and lack of availability limit the widespread use of digoxin-specific antibody fragments in developing countries. CONCLUSIONS: Digoxin-specific antibody fragments remain the only proven therapy for yellow oleander poisoning. Further studies are needed to determine the place of activated charcoal, the benefits or risks of atropine and isoprenaline, the place and choice of antiarrhythmics, and the effect of intravenous magnesium in yellow oleander poisoning.

Responding to pediatric poisoning.

Make sure you know how to act quickly if a child ingests a toxic substance and what to teach parents to prevent accidental poisonings.

Ipecacuanha: the South American vomiting root.

The story of ipecacuanha, derived from the plant Cephaelis, is a fascinating one. It was discovered in Brazil in the 1600s and then transported to Paris in the latter part of the same century. It was used there by the physician Helvetius on various members of the French royal court to treat the flux (dysentery) with some success. Later, in the eighteenth century, it was taken up by the physician and privateer Thomas Dover and became, with opium, a fundamental constituent of his celebrated powder, which was used widely to treat fevers and agues for the next 200 years. Progress was then delayed until the early 1800s when the School of Chemistry at Paris established that the dried root of ipecac contained two powerful alkaloids, emetine and cephaeline, that consistently caused vomiting and diarrhoea. The discovery of the pathogenic amoeba, Entamoeba histolytica, in the latter part of the nineteenth century, allowed a distinction to be made between the two main forms of dysentery (amoebic and bacillary). Emetine was shown to be active against the amoebic form of dysentery but ineffective against that caused by bacteria. Ipecacuanha, its root and the pure alkaloid emetine have now been abandoned on the grounds of toxicity. They have been replaced by safer, more effective compounds. Nevertheless, they deserve an honoured place in the history of medicine, especially in the search for an effective treatment for amoebic dysentery.

Pediatric poisonings: recognition, assessment, and management.

Poisoning represents one of the most common medical emergencies encountered in young children in the United States, and accounts for a significant proportion of emergency room visits for the adolescent population. Poisoning is a significant and persistent cause of morbidity and mortality in children and adolescents. The scope of toxic substances involved in poisoning is broad, and requires health care providers to have an extensive knowledge of signs and symptoms of poisoning and specific therapeutic interventions and antidotes. Most children who ingest poisons suffer no harm; however, health care providers must recognize, assess, and manage those exposures that are most likely to cause serious injury, illness, or death and initiate appropriate management to minimize the physical injury that may occur.