Faculty Bibliography

Background: Amygdalin, marketed misleadingly by the misnomer "Vitamin B17", is a cyanogenic glycoside found in certain seeds (apricot, bitter almond, etc.). When swallowed, it is hydrolyzed in the small intestine into cyanide, and absorbed systemically. Despite a ban from the U.S. FDA and a Cochrane Review concluding no benefit to treat cancer, amygdalin is still available for purchase over the internet in 500mg capsules, each containing up to 30mg of cyanide. Thus, an estimated adult LD50 is as few as four capsules. We present a massive intentional overdose of amygdalin, with delayed recurrent hyperlactatemia, and successful combination antidotal therapy. Case report: A 33-year-old woman presented to the ED approximately 5 h after intentionally ingesting 40 capsules of 500mg amygdalin (20 g). On arrival, her vital signs were: HR 127/min, BP 112/65mmHg, RR 25/min, SpO2 98%. She was in agitated delirium, diaphoretic and mydriatic with an ECG notable for QTc 538ms. Lorazepam 2mg and magnesium sulfate 2 g were administered for agitation and prolonged QTc, respectively. Within 30 min of sedation, she became comatose, more tachypneic/diaphoretic, and hypotensive; therefore, 5 g hydroxocobalamin was empirically administered. Her pre-treatment venous blood gas showed: pH 7.27, pCO2 17.1mmHg, HCO3 7.7mmol/l, and lactate 14.1mmol/l. After initial treatment, she was noted to have oral foaming and hypoxia, so was intubated with sodium bicarbonate pre-treatment and another 5 g of hydroxocobalamin was given along with 25 g of sodium thiosulfate. Her BP normalized, QTc shortened, and lactate fell to 0.9mmol/l. Approximately 12 h later, her BP decreased to 60 s/40 s, her lactate increased to 8.1mmol/l and her QTc prolonged to 547 ms. Norepinephrine and vasopressin were started, activated charcoal was given and magnesium sulfate, sodium bicarbonate, hydroxocobalamin and sodium thiosulfate were redosed as previously with an improvement in vital signs, decrease in QTc and clearance of lactate. Her course was complicated by pneumonia, requiring continued sedation and ventilation, but she was extubated with no neurologic deficits on hospital day 9. Initial serum cyanide concentration was found to be 400mcg/l. Case discussion: Given that each 500mg capsule of amygdalin contains up to 30mg of cyanide, this patient ingested as much as 1.2 g of cyanide. The first-line antidote, hydroxocobalamin, has a binding ratio of 50:1 by molecular weight. So, for every 5 g of hydroxocobalamin, only approximately 100mg (4-5 capsules) of hydrogen cyanide will be sequestered. As might be expected, toxicity recurred due to ongoing absorption and/or decreased motility to the distal gut, where the majority of cyanide absorption may occur. Finally, we demonstrate the need to redose hydroxocobalamin and sodium thiosulfate in the case of recurrent cyanide toxicity from massive amygdalin overdose. Conclusions: Amygdalin remains a significant threat to human life with no role as a clinical therapeutic. Internet marketers should be held accountable by government authorities. We present a case of severe, recurrent cyanide toxicity secondary to massive amygdalin overdose, requiring multiple staggered doses of hydroxocobalamin and sodium thiosulfate

Introduction: Overdoses of bupropion XL can result in severe morbidity and mortality. Prolonged toxicity may be related to slow drug release through a complex drug delivery system (DDS). Treatment of bupropion toxicity is largely supportive and includes activated charcoal (AC) and/or whole-bowel irrigation (WBI) with PEG-ELS. However, data are lacking on bupropion adsorption to AC, and the effects of PEG-ELS on drug release from the DDS and on AC adsorption. Aims: The primary aim of this study is to measure the in vitro effects of AC and PEG-ELS in a simulated human gastrointestinal model at therapeutic dosing and mimicking an overdose scenario. Methods: There were two main series; simulated gastric and simulated intestinal contents. Each series had five arms done in triplicate at a final volume of 500 ml at 37 degreeC, and repeated at two bupropion XL doses; 300mg and 3000 mg. Study arms were: (1) bupropion only; (2) bupropion plus 50 g AC added at 1 h (AC Only); (3) bupropion plus 250 ml PEG-ELS added at 1 h (PEG Only); (4) bupropion plus 50 g AC added at 1 h and 250 ml PEGELS added at 1.5 h; (5) bupropion plus 250 ml PEG-ELS added at 1 h and 50 g AC added at 1.5 h. Samples were collected at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h to determine the bupropion concentration using HPLC. Areas under the isotherm curve at 8 h (AUC 8 h) were calculated and overall differences in mean AUC 8 h were tested using analysis of variance; post-hoc pairwise comparisons were performed using Tukey student t-tests. All analysis was stratified by initial bupropion concentration. Results: At the 300mg dose (Figure 1), compared to control, the study arms (AC, PEG or both) were all associated with differences in the AUC 8 h (p<.01) and not altered by fluid pH (p=.513). Also at this dose, all experimental arms had a lower AUC 8 h compared to control, though the effect size for the PEG Only arm was smaller (p=.02). At the 3000mg dose (Figure 2), the mean AUC 8 h was lowest in the AC Only group and highest in the PEG Only group. Compared to control, the AC Only group had the lowest AUC 8 h in both types of fluids (p<.01). The experimental arm with PEG added to AC lowered AUC 8 h in intestinal fluid (p<.01) but not in gastric fluid (p=.052). Both experimental arms that started with PEG were not significantly different compared to control (p>.05). Overall, AUC's were higher in gastric fluid compared to intestinal fluid (p<.01). Conclusions: In this in vitro model, AC adsorbs bupropion, though that adsorption appears to be affected by the specific media (gastric versus intestinal fluid). These results also suggest that PEG-ELS interferes with AC adsorption of bupropion. The clinical significance of this is unknown. This study was partially funded by a research grant from the American Academy of Clinical Toxicology

CONTEXT: Ciguatera fish poisoning arises primarily from consumption of carnivorous reef fish caught in tropical and sub-tropical waters. Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels. Characteristics of ciguatera fish poisoning include early nausea, vomiting, and diarrhea in the first one to two days post ingestion, followed by the appearance of sensory disturbances. The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold. OBJECTIVE: To discuss and appraise the evidence regarding the use of mannitol or other drugs in treating ciguatera framed in the historical context of the last four decades. METHODS: We searched PubMed and Embase for all years from 1966 to March 31, 2017 with search terms "ciguatera", "mannitol", and "treatment". These searches identified 85 articles, of which 36 were relevant to the review question. We searched Google Scholar to supplement the primary search and reviewed the references of articles for sources overlooked in the original searches. These secondary searches identified another 23 references. We excluded six clinical reports (two case series and four case reports) which did not clearly describe ciguatera or which lacked information on treatment or outcome. Fifty-three clinical articles remained for review. We searched PubMed using "ciguatera" AND "treatment" NOT "mannitol" to better identify reports describing other treatments. The search identified 128 articles, of which nine described specific pharmacological treatments and their outcomes. We combined our findings into a consensus review of the evidence both for and against the use of mannitol or other medications for ciguatera fish poisoning. Early human evidence of effectiveness of mannitol: A 1988 report described an unexpected discovery that intravenous mannitol could rapidly and effectively treat ciguatera fish poisoning. Several other uncontrolled case series and case reports appeared to support the use of mannitol. In 2002, a small randomized, controlled trial reported no significant difference between mannitol and normal saline. Subsequent case reports have cited this study as the reason for or to withhold mannitol. Thus, some controversy exists regarding whether mannitol is useful or not for treating ciguatera fish poisoning. Basic science and animal research on ciguatera and mannitol: In vitro experiments of isolated neurons demonstrate that ciguatoxins produce neuronal edema, open certain sodium channels, block potassium channels, cause uncontrolled and repetitive action potentials after a stimulus. Addition of mannitol decreases the edema and reduces the uncommanded action potentials. However, intraperitoneal injection of ciguatoxin in rats increases neuronal refractory period and slows nerve conduction velocity. Treatment with mannitol fails to correct these effects. Comparative trials of mannitol: Evidence supporting mannitol for ciguatera fish poisoning includes four uncontrolled case series, one prospective, unblinded comparative trial and several case reports. Evidence against mannitol consists of one RCT, which has a small sample size and several potential limitations. Empirical human experience with other treatments: Evidence regarding other treatments consists only of ten case reports and three overlapping case series that describe using amitriptyline, fluoxetine, duloxetine, gabapentin, pregabalin, or tocainide. For each of these, a long duration of treatment appears to be necessary to maintain symptomatic improvement. None of these treatments has been shown to be superior to mannitol. CONCLUSIONS: It is reasonable to consider using intravenous mannitol in cases of acute ciguatera fish poisoning. Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases. However, the human evidence is of low quality for all treatments.