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Homocysteine is a sulfur-containing amino acid formed in the intermediary metabolism of methionine. Amino acid metabolism and heme biosynthesis pathways are complexly intertwined. Plasma homocysteine elevation,This article summarizes published case series in which givosiran, a subcutaneously administered small interfering RNA approved for AHP treatment, appeared to exacerbate dysregulated homocysteine metabolism in patients with AHP. A comprehensive exploratory analysis of ENVISION trial data demonstrated that on a population level, givosiran increased homocysteine but with wide interpatient variations, and there is no proof of correlations between HHcy and changes in efficacy or safety of givosiran.The strong correlation and co-increase of homocysteine and methionine suggest that HHcy associated with givosiran is likely attributable to the impaired trans-sulfuration pathway catalyzed by cystathionine β-synthase, which uses vitamin B6 as a cofactor. Data-based consensus supports monitoring total plasma homocysteine and vitamin B6, B12, and folate levels before and during givosiran treatment; supplementing with pyridoxine/vitamin B6 in patients with homocysteine levels100 μmol/L; and involving patients with homocysteine levels30 μmol/L in decisions to supplement.

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions >90% and 24-h SBP reductions >10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions >90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT >90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, leads to accumulation of heme intermediates, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) that may result in neurovisceral attacks. ENVISION (NCT03338816) is an ongoing study, evaluating efficacy and safety of givosiran in symptomatic AHP patients in a 6-month double blind (DB) period and a 30-month open label extension (OLE) period. While the efficacy and safety profile of givosiran has previously been reported in the DB period, here its effect through Month 18 of the OLE period is reported. Methods: ENVISION is an ongoing Phase 3 global, randomized, placebo-controlled study. Exploratory efficacy outcome measures in the OLE included composite porphyria attacks (i.e. those requiring hospitalization, urgent care, or IV-hemin at home), ALA/PBG levels and hemin use. In addition, quality of life assessments (Physical Component Summary Short Form-12 [PCS SF-12], EuroQoL Visual analog scale [EQ-VAS]), the Porphyria Patient Experience Questionnaire (PPEQ), and missed days of work were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results: As of January 10, 2020, 94 patients completed the DB period and 93 patients entered the OLE (placebo/givosiran=46; givosiran/givosiran=47). Mean exposure to givosiran at data cutoff was 12.97 [SD=3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0-16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0-11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0-51.6) whilst receiving placebo during the 6-month DB period. The average number of attacks per patient over time following givosiran treatment continued to decline during the OLE period for both groups (Figure 1). Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. Improvements in PCS SF-12 scores at Month 6 (mean change from baseline=+5.1 [SD=9.0]) were maintained at Month 18 (mean change from baseline=+7.0 [7.0]) for givosiran/givosiran patients, with similar improvements observed in placebo/givosiran patients at Month 18 (mean change from baseline=+9.9 [8.2]). Continued givosiran treatment in givosiran/givosiran patients led to further improvements in EQ VAS compared with DB period (mean change from baseline 5.2 at completion of the DB period [SD=22.2] and 13.7 [22.5] at Month 18 during the OLE period), with placebo/givosiran patients also showing improvements at Month 18 (mean change from baseline 8.3 [SD=18.5]). Placebo/givosiran patients reported improvements in PPEQ scores (traveling, social activities, planning future events, household chores, exercise, and treatment satisfaction) since initiating givosiran, comparable to the improvement observed in the givosiran group during the DB period. Additionally there was a decrease in the number of work days missed due to porphyria in the past 4 weeks at Month 6 (mean=6.7 days [SD=7.8], n=20/46) compared with Month 18 (2.5 [5.1], n=23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) occurring during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal events were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE compared with DB period. Conclusion: In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed. Disclosures Kuter: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Dova: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Shire: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Rees:AstraZeneca: Other: Data monitoring committee membership; Novartis: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring; Alnylam Pharmaceuticals: Consultancy, Honoraria; Emmanus Medical: Consultancy, Honoraria. Ventura:Alnylam Pharmaceuticals: Consultancy, Honoraria; Recordati Rare Diseases: Consultancy, Honoraria. Balwani:Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording; Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding. Gouya:Alnylam Pharmaceuticals: Consultancy, Honoraria, Other: Scientific meeting. Simon:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Liu:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ko:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Rhyee:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silver:Alnylam Pharmaceuticals: Other: Travel reimbursement, Research Funding; Blue Care Network: Consultancy; Oncology Business Review: Speakers Bureau.

Acetaminophen is the most common toxic ingestion in the United States, causing 400 deaths per year. Poisoning occurs both intentionally and unintentionally, with suicidal intent, overuse for treatment of pain, and ingestion of multiple medications containing acetaminophen all contributing. Aspirin poisoning remains a concern even though its popularity as an analgesic and antipyretic has decreased over time. Among nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), ibuprofen and naproxen are the most commonly encountered in overdose, likely due to their easy availability as over-the-counter medications. This review covers the principles of toxicity, immediate stabilization, diagnosis and definitive therapy, and disposition and outcomes related to acetaminophen, aspirin, and ibuprofen and other NSAIDs. Tables describe N-acetylcysteine dosing, King’s College criteria for acetaminophen-induced liver failure, and indications for hemodialysis in aspirin poisoning. Figures include a pie chart showing acetaminophen metabolization, the Rumack-Matthew nomogram, and a graph showing frequency of hepatotoxicity in patients receiving N-acetylcysteine. This review contains 3 highly rendered figures, 3 tables, and 97 references.

Background: Hydrogen Sulfide (H2S) has become a method of suicide that has gained popularity across the world in the recent years. The traditional means included a well-sealed car in a remote location. The completion rate of suicide was very high and living patient contact is rarely made. Case Discussion: A 35 year old female was discovered in her apartment after a suicide attempt in an apartment room, utilizing H2S. A multiple tiered response included Emergency Physicians from the onset of the case both on scene and at the receiving facility advising on scene safety, toxicological issues and management. The patient required intubation in the field and supportive care, but ultimately was discharged from the hospital neurologically intact. No first responders or bystanders were seriously affected. Discussion: With rapid on scene care and early and aggressive critical care this patient survived without deficit. First responders and emergency physicians need to be aware of this novel method of self-harm and the implications for patients, emergency personnel and bystanders.

The Toxicology Investigators Consortium (ToxIC) Case Registry was established in 2010 by the American College of Medical Toxicology. The Registry includes all medical toxicology consultations performed at participating sites. This report summarizes the Registry data for 2013. A query of the ToxIC Registry was carried out for the dates of January 1 through December 31, 2013. Specific data reviewed for analysis included demographics (age, gender), source of consultation, reasons for consultation, agents involved in toxicological exposures, signs, symptoms and clinical findings, and treatment. A total of 8,598 cases were entered into the Registry in 2013. Females accounted for 49.2 % of cases, males for 47.7 %, and gender was not reported in 3.1 %. The majority of patients (63.4 %) were adults between the ages of 19 and 65 years. There were 93 fatalities (1.1 %). Most referrals for medical toxicology consultation originated from the emergency department (59.7 %) or inpatient services (16.7 %). Exposures to pharmaceutical products (intentional and unintentional) made up 50.0 % of cases. Illicit drug abuse (8.0 %) and adverse drug reactions (ADRs) (4.8 %) were the next most frequent reasons for consultation. Similar to past years, nonopioid analgesics, sedative-hypnotics, and opioids were the most commonly encountered agents. Symptoms or clinical findings were documented in 71.1 % of patients. Of all cases, 54.6 % required some form of medical treatment (antidotes, antivenom, chelation, specific types of supportive care). This report serves as a comprehensive survey of medical toxicology practice within participating institutions. Prior trends continued to apply this year and indicate analgesic (opioid and nonopioid), sedative-hypnotic/muscle relaxant agents, illicit drug use, and ADRs continue to be major toxicological problems. Cases requiring medical toxicology consultation in 2013 predominantly involved pharmaceuticals and illicit drugs. Reasons for these drug exposures were diverse and included intentional overdose, unintentional exposure, withdrawal syndromes, and ADRs. Nonopioid analgesics, sedative-hypnotic agents, and opioids remained the most frequently encountered agent classes. While over half of cases required some form of medical treatment, fatalities were uncommon.

We developed recommendations for antidote stocking at hospitals that provide emergency care.An expert panel representing diverse perspectives (clinical pharmacology, clinical toxicology, critical care medicine, clinical pharmacy, emergency medicine, internal medicine, pediatrics, poison centers, pulmonary medicine, and hospital accreditation) was formed to create recommendations for antidote stocking. Using a standardized summary of the medical literature, the primary reviewer for each antidote proposed guidelines for antidote stocking to the full panel. The panel used a formal iterative process to reach their recommendation for the quantity of an antidote that should be stocked and the acceptable period for delivery of each antidote.The panel recommended consideration of 24 antidotes for stocking. The panel recommended that 12 of the antidotes be available for immediate administration on patient arrival. In most hospitals, this period requires that the antidote be stocked in the emergency department. Another 9 antidotes were recommended for availability within 1 hour of the decision to administer, allowing the antidote to be stocked in the hospital pharmacy if the hospital has a mechanism for prompt delivery of antidotes. The panel identified additional antidotes that should be stocked by the hospital but are not usually needed within the first hour of treatment. The panel recommended that each hospital perform a formal antidote hazard vulnerability assessment to determine the need for antidote stocking in that hospital.The antidote expert recommendations provide a tool to be used in creating practices for appropriate and adequate antidote stocking in hospitals that provide emergency care.