Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension.

BACKGROUND: Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis. METHODS: In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring. RESULTS: Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively. CONCLUSIONS: Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).

Hyperhomocysteinemia in acute hepatic porphyria (AHP) and implications for treatment with givosiran.

INTRODUCTION: 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, hyperhomocysteinemia (HHcy), has been reported in patients with acute hepatic porphyria (AHP), a family of rare genetic disorders caused by defects in hepatic heme biosynthesis. AREAS COVERED: 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. EXPERT OPINION: 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 ß-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 levels >100 µmol/L; and involving patients with homocysteine levels >30 µmol/L in decisions to supplement.

Evaluating the Patient with Reported Gadolinium-Associated Illness.

INTRODUCTION: Gadolinium-based contrast agents (GBCAs) have been increasingly used in clinical practice since their introduction in the 1980s. Recently, increased public attention has been given to patients who report new symptoms following GBCA exposure. This review details the current knowledge surrounding GBCAs, with a focus on the known and proposed disease states that may be associated with GBCAs. Recommendations for the appropriate clinical workup of a patient suspected of having symptoms attributable to gadolinium exposure are included. DISCUSSION: GBCAs are known to precipitate the disease state nephrogenic systemic fibrosis (NSF), a syndrome characterized by skin thickening in patients with preexisting renal disease. An additional syndrome, termed gadolinium deposition disease, has been proposed to describe patients with normal renal function who develop an array of symptoms following GBCA exposure. While there is a potential physiologic basis for the development of this condition, there is no conclusive evidence to support a causal relationship between GBCA administration and the reported symptoms yet. Clinical evaluation revolves around focused history-taking and physical examination, given the absence of a reliable link between patient symptoms and measured gadolinium levels. There are no recommended treatments for suspected gadolinium deposition disease. Chelation therapy, which is not approved for this indication, carries undue risk without documented efficacy. CONCLUSIONS: The extent to which GBCAs contribute to clinically relevant adverse effects remains an important and evolving field of study. NSF remains the only proven disease state associated with GBCA exposure. Additional data are required to evaluate whether other symptoms should be attributed to GBCAs.

Correction to: The Toxicology Investigators Consortium Case Registry-The 2017 Annual Report.

Please note the Collaborators for this article listed in the Acknowledgements.

The Toxicology Investigators Consortium Case Registry-the 2017 Annual Report.

The Toxicology Investigators Consortium (ToxIC) Case Registry was established by the American College of Medical Toxicology in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultations will be entered. The objective of this eighth annual report is to summarize the Registry's 2017 data and activity with its additional 7577 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2017. Detailed data was collected from these cases and aggregated to provide information which includes demographics (e.g., age, gender, race, ethnicity), reason for medical toxicology evaluation (e.g., intentional pharmaceutical exposure, envenomation, withdrawal from a substance), agent and agent class, clinical signs and symptoms (e.g., vital sign abnormalities, organ system dysfunction), treatments and antidotes administered, fatality, and life support withdrawal data. Females were involved in 50.4% of cases. Transgender demographic information collection was initiated in 2017 to better represent the population and there were 36 cases involving transgender patients. Adults aged 19-65 were the most commonly reported age group. Non-opioid analgesics were the most commonly reported agent class, with acetaminophen again the most common agent reported. There were 93 fatalities reported in 2017. Treatment interventions were frequently reported with 30.6% receiving specific antidotal therapy. Major trends in demographics and exposure characteristics remained similar to past years' reports. While treatment interventions were commonly required, fatalities were rare.

The Toxicology Investigators Consortium Case Registry-the 2016 Experience.

The Toxicology Investigators Consortium (ToxIC) Case Registry was established by the American College of Medical Toxicology in 2010. The Registry contains data from participating sites with the agreement that all bedside medical toxicology consultations will be entered. Currently, 83% of accredited medical toxicology fellowship programs in the USA participate. The Registry continues to grow each year, and as of 31 December 2016, a new milestone was reached, with more than 50,000 cases reported since its inception. The objective of this seventh annual report is to summarize the Registry's 2016 data and activity with its additional 8529 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2016. Detailed data was collected from these cases and aggregated to provide information which includes the following: demographics (age, gender, race, ethnicity, HIV status), reason for medical toxicology evaluation (intentional pharmaceutical exposure, envenomation, withdrawal from a substance), agent and agent class, clinical signs and symptoms (vital sign abnormalities, organ system dysfunction), treatments and antidotes administered, fatality and life support withdrawal data. Fifty percent of cases involved females, and adults aged 19-65 were the most commonly reported. There were 86 patients (1.0%) with HIV-positive status known. Non-opioid analgesics were the most commonly reported agent class, with acetaminophen the most common agent reported. There were 126 fatalities reported in 2016 (1.5% of cases). Major trends in demographics and exposure characteristics remained similar overall with past years' reports. While treatment interventions were commonly required, fatalities were rare.

The Toxicology Investigators Consortium Case Registry-the 2015 Experience.

The American College of Medical Toxicology established the Toxicology Investigators Consortium (ToxIC) Case Registry in 2010. The Registry contains all medical toxicology consultations performed at participating sites. The Registry has continued to grow since its inception, and as of December 31, 2015, contains 43,099 cases. This is the sixth annual report of the ToxIC Registry, summarizing the additional 8115 cases entered in 2015. Cases were identified by a query of the Registry for all cases entered between January 1 and December 31, 2015. Specific data reviewed for analysis included demographics (age, race, gender), source of consultation, reason for consultation, agents and agent classes involved in exposures, signs, symptoms, clinical findings, fatalities, and treatment. By the end of 2015, there were 50 active sites, consisting of 101 separate health-care facilities; 51.2 % of cases involved females. Adults between the ages of 19 and 65 made up the majority (64.2 %) of Registry cases. Caucasian race was the most commonly reported (55.6 %); 9.6 % of cases were identified as Hispanic ethnicity. Inpatient and emergency department referrals were by far the most common referral sources (92.9 %). Intentional pharmaceutical exposures remained the most frequent reason for consultation, making up 52.3 % of cases. Of these intentional pharmaceutical exposures, 69 % represented an attempt at self-harm, and 85.6 % of these were a suicide attempt. Nonopioid analgesics, sedative-hypnotics, and antidepressant agents were the most commonly reported agent classes in 2015. Almost one-third of Registry cases involved a diagnosed toxidrome (32.8 %), with a sedative-hypnotic toxidrome being the most frequently described. Significant vital sign abnormalities were recorded in 25.3 % of cases. There were 98 fatalities reported in the Registry (1.2 %). Adverse drug reactions were reported in 4.3 % of cases. Toxicological treatment was given in 65.3 % of cases, with 33.0 % receiving specific antidotal therapy. Exposure characteristics and trends overall were similar to prior years. While treatment interventions were required in the majority of cases, fatalities were rare.

The Toxicology Investigators Consortium Case Registry--the 2014 Experience.

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. The Registry was queried for all cases entered between January 1 and December 31, 2014. Specific data reviewed for analysis included demographics (age, gender, ethnicity), source of consultation, reasons for consultation, agents involved in toxicological exposures, signs, symptoms, clinical findings, fatalities, and treatment. In 2014, 9172 cases were entered in the Registry across 47 active member sites. Females accounted for 51.1 % of cases. The majority (65.1 %) of cases were adults between the ages of 19 and 65. Caucasians made up the largest identified ethnic group (48.9 %). Most Registry cases originated from the inpatient setting (93.5 %), with a large majority of these consultations coming from the emergency department or inpatient admission services. Intentional and unintentional pharmaceutical exposures continued to be the most frequent reasons for consultation, accounting for 61.7 % of cases. Among cases of intentional pharmaceutical exposure, 62.4 % were associated with a self-harm attempt. Non-pharmaceutical exposures accounted for 14.1 % of Registry cases. Similar to the past years, non-opioid analgesics, sedative-hypnotics, and opioids were the most commonly encountered agents. Clinical signs or symptoms were noted in 81.9 % of cases. There were 89 recorded fatalities (0.97 %). Medical treatment (e.g., antidotes, antivenom, chelators, supportive care) was rendered in 62.3 % of cases. Patient demographics and exposure characteristics in 2014 Registry cases remain similar to prior years. The majority of consultations arose in the acute care setting (emergency department or inpatient) and involved exposures to pharmaceutical products. Among exposures, non-opioid analgesics, sedative/hypnotics, and opioids were the most frequently encountered. A majority of cases required some form of treatment, but fatalities were rare.

Serotonin toxicity association with concomitant antidepressants and rasagiline treatment: retrospective study (STACCATO).

BACKGROUND: The serotonin toxicity syndrome (STS) is a potential risk with concurrent use of the monoamine oxidase type-B inhibitor rasagiline and antidepressants. OBJECTIVE: To assess systematically the occurrence of STS in patients with Parkinson disease (PD) treated with rasagiline plus antidepressants (R+ATD), rasagiline without antidepressants (R), or antidepressants plus anti-PD dopaminergic medications (ATD) other than either rasagiline or selegiline. METHODS: A phase IV multicenter retrospective cohort study was conducted of patients with PD who began receiving R+ATD, R, or ATD between September 1, 2006, and December 31, 2008. Medical records were reviewed for patient demographics, treatment details, and hospitalizations/emergency department (ED) visits. An adjudication committee independently reviewed records to verify case ascertainment and used the Hunter Serotonin Toxicity Criteria for case definition. Outcome variables were analyzed by descriptive statistics. RESULTS: A total of 1504 patients with PD (471 with R+ATD; 511 with R; and 525 with ATD) were enrolled from 37 sites. In the R+ATD and ATD groups, selective serotonin reuptake inhibitors (SSRIs) were most frequently used (74.5% and 77%, respectively). In the R+ATD and ATD groups, mean duration of antidepressant use (tricyclic, SSRI, and other) were 50.5-53.5 weeks and 51.7-80.9 weeks, respectively. Overall, 195 patients (13%) from all three groups had one or more hospitalization/ED visits. No cases of STS were identified in any group. CONCLUSIONS: In this large multicenter retrospective cohort study, concurrent administration of R+ATD was not associated with STS. The findings of this phase IV study expand the drug interaction and pharmacovigilance safety awareness for the use of antidepressants in patients with PD.

The toxicology investigators consortium case registry-the 2013 experience.

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.

Status epilepticus in a child secondary to ingestion of skin-lightening cream.

The popularity of the Internet and online media has led to the increased availability of prescription-strength, skin-lightening products contributing to a rise in their use among people with various skin pigment disorders. These products may contain a wide variety of active ingredients such as heavy metals, hydroquinone, and corticosteroids that can be highly toxic, especially after prolonged application. For decades, there have been case reports of both corticosteroid and heavy metal toxicity related to skin-lightening cream use. We report a case of a child who developed status epilepticus after ingesting a skin-lightening solution containing 2% hydroquinone. The toxicodynamics of hydroquinone and its effects on the central nervous system are discussed.

Acute kidney injury due to intravenous bleach injection.

INTRODUCTION: Sodium hypochlorite is the active ingredient in bleach, a ubiquitous household disinfectant, and has known toxicities depending on route of exposure and amount. Acute kidney injury due to sodium hypochlorite exposure has never been reported. Patients that did develop nephrotoxicity following bleach exposure did so due to development of other risk factors for kidney injury such as volume depletion or sepsis. DISCUSSION: We report a patient who presented with black urine after parenteral self-administration of a large quantity of bleach. We review the clinical presentation, laboratory and biopsy findings, and outcome as well as discuss possible mechanisms of sodium hypochlorite toxicity and management strategies.

Sulfur mustard exposure presenting to a community emergency department.

We report dermal exposure to a chemical warfare agent, sulfur mustard, in a 28-year-old commercial fisherman. Chemical warfare agents such as sulfur mustard are considered potential terrorist weapons, and suspected exposure requires notification of federal authorities. We address potential pitfalls when alerting authorities and methods to avoid such obstacles, and we describe the clinical management of sulfur mustard toxicity.

Acute respiratory distress associated with inhaled hydrocarbon.

BACKGROUND: Pneumonitis is a well-known complication following aspiration of ingested liquid hydrocarbons. There are few data about acute pulmonary toxicity from unintentional hydrocarbon inhalation; most human cases involve products containing a fluoropolymer in combination with hydrocarbons. METHODS: Case report of a 45-year-old male who presented with respiratory distress after a 15-min inhalational exposure to a canvas waterproofing spray containing liquefied petroleum gas, ethylene glycol monobutyl ether, and isopropanol. RESULTS: Patients had symptoms, exam findings, and chest X-ray that were consistent with an acute pneumonitis. CONCLUSION: Acute pulmonary injury can occur after a short exposure to an inhaled hydrocarbon and associated symptoms appear to respond to supportive measures, including oxygen, corticosteroids, and bronchodilators.

Clinical course of repeated supratherapeutic ingestion of acetaminophen.

BACKGROUND: Repeated supratherapeutic ingestion (RSTI) of acetaminophen (APAP) is recognized as an important cause of APAP-related morbidity and mortality. This study describes the characteristics and clinical course of patients with RSTI, and identifies the risk factors for developing hepatotoxicity and death. METHODS: This secondary analysis of a multicenter retrospective chart review studied patients treated with IV and/or oral N-acetylcysteine for acetaminophen poisoning. For this analysis, we included all subjects coded as RSTIs, defined as ingestions of greater than 4 g of APAP per 24 h over a period longer than 8 h. Data collected include demographics, coingestants, comorbidities, presenting laboratory data, and outcomes. The analysis includes descriptive statistics and associations of demographic and clinical factors with patient outcome. RESULTS: Of the 503 patients enrolled, 119 (23.7%) were RSTI. The mean age was 39.6 years (SD ± 15); 63.9% of the patients were females, 60.5% Caucasians, 27.7% alcoholics, 5% malnourished, 10.9% had viral hepatitis, and 3.4% had other liver diseases. Coingestants included ethanol, opioids, and antihistamines (17.6, 48.7, and 19.3%, respectively). Among this group, 44 patients developed hepatotoxicity, two received liver transplants, and four died (37.0, 1.7, and 3.4%, respectively). The risk for hepatotoxicity increased with a history of alcoholism, viral hepatitis, and other liver diseases. A history of alcoholism and an elevated presenting serum creatinine were associated with increased risk for death/transplant. The lowest presenting ALT levels in a subject who developed hepatotoxicity and who died were 252 and 426 IU/l, respectively. CONCLUSION: RSTI-induced hepatotoxicity and poor outcomes can be predicted at the patient's presentation. All patients with RSTI who developed hepatotoxicity presented with an abnormal ALT. A history of alcoholism and an elevated creatinine at presentation are markers of increased risk for hepatotoxicity and death.

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose.

BACKGROUND: Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. METHODS: Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. RESULTS: Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin. CONCLUSIONS: Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.

Prolonged delirium after quetiapine overdose.

Quetiapine is an atypical antipsychotic agent increasingly used to treat schizophrenia and bipolar disorder in pediatric patients. Few published data exist concerning quetiapine's effects in therapeutic settings or short-term overdose in pediatric and adolescent populations. In this report, we describe a 15-year-old adolescent girl who experienced continued delirium 5 days after an overdose of quetiapine, trazodone, and clonidine. The patient initially presented with sedation and stable vital signs. After 3 days of gradual improvement, she experienced episodes of delirium coinciding with an increase in resting heart rate. On the basis of suspicion for quetiapine-associated antimuscarinic effects, the patient was administered intravenously with physostigmine on the fifth day after ingestion. Treatment resulted in a brief resolution of symptoms. Serum quetiapine levels measured 1 day and 5 days after ingestion were 3400 and 4800 ng/mL, respectively. The use of physostigmine and interpretation of serum levels are discussed further.