Acute toxicity following analytically confirmed use of the novel psychoactive substance (NPS) methiopropamine. A report from the Identification of Novel psychoActive substances (IONA) study.

Objective: Use of the New Psychoactive Substance (NPS) methiopropamine was first reported in 2011, but there are limited data on its acute toxicity. We report 11 patients presenting with analytically confirmed methiopropamine use. Methods: Adults presenting to 26 hospitals in the UK with severe acute toxicity after suspected NPS use were recruited from March 2015 to April 2018. Clinical features were recorded and biological samples analysed using tandem mass spectrometry. Results: Methiopropamine was detected in 11 of 414 patients, with the last detection in August 2016. It was the only substance detected in one patient; other substances detected included other NPS in nine and conventional drugs of misuse in five. Common features included tachycardia (10/11), agitation (7/11), confusion (7/11), reduced level of consciousness (5/11), hallucinations (5/11) and a raised creatine kinase (7/11). The median length of hospital stay was 17 hours; ten were discharged without sequelae and one was transferred for in-patient psychiatric treatment. Conclusions: Methiopropamine was only detected during 2015 and 2016; most patients had other drugs detected, particularly other NPS. Raised CK was common but it is not possible to determine the degree to which this and other features could be contributed to by co-use of other substances.

New drug controls and reduced hospital presentations due to novel psychoactive substances in Edinburgh.

AIMS: Recreational use of novel psychoactive substance (NPS) has become increasingly common. We aimed to assess the association of national legislation and local trading standards activity with hospital presentations. METHODS: We established observational cohorts of patients with recreational drug toxicity presenting to Edinburgh Royal Infirmary and dying with detectable recreational drugs in Edinburgh. We assessed associations with two temporary class drug-orders (April 2015: methylphenidates, Nov 2015: methiopropamine), the Psychoactive Substances Act (June 2016), and trading standards forfeiture orders (October 2015). RESULTS: The methylphenidate temporary class drug-order was associated with rapid 46.7% (P = 0.002) and 21.0% (P = 0.003) reductions in presentations and admissions, respectively, for NPS drug toxicity, comparing 12 months before with 6 months after. The change was greatest for ethylphenidate toxicity (96.7% reduction in admissions, P < 0.001) that was partly offset by a tripling in synthetic cannabinoid receptor agonist cases (P < 0.001) over the next 6 months. This increase reversed following trading standards activity removing all NPS drugs from local shops in October 2015, associated with 64.3% (P < 0.001) and 83.7% (P < 0.001) reductions in presentations and admissions, respectively, for all NPS drugs over the next 12 months. The effect was sustained and associated with a reduced postmortem detection of stimulant NPS drugs. The two interventions prevented an estimated 557 (95% confidence interval 327-934) NPS admissions during 2016, saving an estimated £303 030 (£177 901-508 133) in hospital costs. CONCLUSIONS: We show here that drug legislation and trading standards activity may be associated with effective and sustained prevention. Widespread adoption of trading standards enforcement, together with focused legislation, may turn the tide against these highly-damaging drugs.

An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system.

OBJECTIVE: Characterize clinical presentations and outcomes of dabigatran and rivaroxaban exposures reported to a poison control system. METHODS: Data for cases of dabigatran and rivaroxaban exposures called into the California Poison Control System from January 2011 to July 2013 were collected. Data collected included patient demographics, type of exposure, medication, dosage, vital signs, laboratory values, interventions, outcomes, and disposition. Exclusion criteria included confirmed nonexposures or miscoded cases. RESULTS: A total of 56 cases were identified, with 7 excluded, leaving 37 dabigatran and 12 rivaroxaban cases. Children age 12 years or less accounted for 5 dabigatran and 2 rivaroxaban cases. Bleeding was reported in 15 dabigatran cases. There were 4 cases of acute self-harm overdose with dabigatran ranging from 1800 to 3900 mg. Mild bleeding was reported in only one of these overdose cases. There were 2 fatal hemorrhages in dabigatran cases, both in chronic therapeutic dosing. Bleeding was reported in 5 rivaroxaban cases, all in patients with chronic exposure; no deaths were reported. There were no adverse outcomes in pediatric patients. Coagulation parameters did not correlate well with bleeding. CONCLUSIONS: In our series, the greatest risk of adverse events was in patients chronically taking these agents, irrespective of excess dosing. Acute self-harm ingestions and accidental pediatric ingestions had few adverse effects, although massive overdose can lead to abnormal coagulation studies. It does not appear that single low-dose ingestions of either medication will lead to clinically significant bleeding. It may be possible to manage some pediatric exposures and most accidental ingestions with observation.

A retrospective review of isolated duloxetine-exposure cases.

BACKGROUND: Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) approved in the US for the treatment of major depression, generalized anxiety, fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain. Given the limited published information regarding human overdoses to this medication, our goal was to characterize such exposures. METHODS: We retrospectively reviewed a state poison system's database for all single agent exposures to duloxetine from 2004-2011. Data collected included age, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co-ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. RESULTS: 159 cases were identified. 106 were included for review. Of 61 pediatric and adolescent cases (0-19 years old) identified, 53 involved unintentional overdose. Three patients experienced symptoms and none were admitted. All intentional ingestions(8) were seen in the emergency department, two patients experienced symptoms. No intentional ingestion was admitted for medical care. Fifty-one adult cases were included for review. Four adult patients were admitted following intentional duloxetine overdose with resolution of symptoms within 24 hours. Three adults were evaluated in a HCF following non-self-harm exposures to duloxetine. None of these patients were admitted. The remaining 15 adult patients with non-self-harm exposures were safely managed at home. CONCLUSION: The majority of non-self-harm duloxetine-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require further hospitalization. Intentional pediatric/adolescent and adult duloxetine exposures were managed in a healthcare facility but rarely resulted in further hospitalization, serious morbidity, or mortality.

Single-agent duloxetine ingestions.

Duloxetine is a serotonin and norepinephrine reuptake inhibitor, which is mainly used to treat depression. This retrospective study describes the demographic and clinical effects of duloxetine ingestions reported to the National Poison Data System (NPDS). NPDS data were searched for duloxetine exposures between 2004 and 2010. A total of 11,373 patients were included and exposures were divided into three groups of ages ≤6 years old, 7-12 years and >12 years. Neurological clinical effects occurred in 6.1% of the patients aged ≤6 years, 13.0% of the patients aged 7-12 years and 24.6% of the patients aged >12 years. Cardiovascular effects occurred in 1.4% of the patients aged ≤6 years old, 2.5% of the patients aged 7-12 years and 11.6% of the patients aged >12 years. Gastrointestinal effects occurred in 4.1% of the patients aged ≤6 years old, 16.6% of the patients aged 7-12 years and 13.8% of the patients aged >12 years. Tachycardia, nausea, vomiting, agitation/irritability, dizziness/vertigo and drowsiness were among the most common clinical effects in all three groups. Overall, 61.4% of the patients aged ≤6 years and 77.5% of the patients aged 7-12 years were managed in a non-health care facility, while 55.8% of the patients aged >12 years were referred to or already in a health care facility. We conclude that the majority of ingestions are benign in both pediatrics and adults. Most symptomatic patients have neurologic, gastrointestinal and cardiovascular effects. Most pediatric patients will be able to be managed in a non-health care facility.

Acute massive pulmonary thromboembolism due to acute intoxication by duloxetine: a case report.

Duloxetine (Cymbalta) is a potent serotonin norepinephrine reuptake inhibitor used for the management of major depression and pain associated with diabetic peripheral neuropathy. Cymbalta delayed-release capsules contain Duloxetine HCl equivalent to 20, 30, 60 mg of Duloxetine. The ingestion of high quantities of Duloxetine may have serious outcomes such as venous thrombosis, causing cardiac respiratory arrest. The Authors outline a case report of an elderly woman, suffering from depression, found dead in her apartment. The cause of death was attributed to acute massive pulmonary thromboembolism due to acute intoxication of Duloxetine bought the day before. The thesis supported by the authors and confirmed by the data from other studies is that a massive intake of Duloxetine drug increases considerably the medication's side effects such as somnolence, dry mouth, fatigue, insomnia, dizziness, constipation, considerable increases in recumbent systolic and diastolic blood pressure, and a small decrease in heart rate.

Cevimeline (Evoxac ®) overdose.

Cevimeline (Evoxac ®) is an oral muscarinic agent that has been recently approved for the treatment of xerostomia in the setting of Sjogren's syndrome. Its toxicity in overdose has not been reported in the medical literature to date. We report a previously healthy patient who intentionally ingested approximately 10 mg/kg of cevimeline and presented with symptoms of muscarinic excess and mental status depression. The patient recovered uneventfully after receiving activated charcoal and supportive care. This report describes the first documented cevimeline overdose.

Coma after overdose with duloxetine.

OBJECTIVE: To describe a case of a patient who became comatose after taking an overdose of duloxetine, a serotonin-norepinephrine reuptake inhibitor. CASE SUMMARY: A 49-year-old male ingested an overdose of duloxetine approximately 2 hours before presentation to the emergency department. On arrival he was drowsy, but easily awakened and oriented, with Glasgow Coma Score 14 (eyes 3, motor 6, verbal 5). Immediately after admission, charcoal and magnesium sulfate were given to prevent further systemic absorption of medication through the gastrointestinal tract. No gastric lavage was performed. Six hours after drug intake the patient became unconscious (Glasgow Coma Score 7, eyes 2, motor 4, verbal 1). Full toxicologic screening showed a toxic duloxetine plasma concentration of 0.86 mg/L. The patient was admitted to the intensive care unit (ICU) and, on arrival, urinary retention was noted. During ICU admission the patient remained hemodynamically stable; approximately 12 hours after ingestion of duloxetine, he regained consciousness. Over the next 3 days the urinary output decreased to 60 mL/day. After 4 days patient was discharged without any remaining symptoms. Based on repeated plasma duloxetine serum concentration determinations, a plasma half-life of duloxetine was calculated to be 18 hours (reference range 9-19). DISCUSSION: The Naranjo probability scale suggested that duloxetine was the probable cause for the symptoms described. CONCLUSION: Overdose with duloxetine can induce coma several hours after intake, with a fast reversal in our case.

Adverse events, toxicity and post-mortem data on duloxetine: case reports and literature survey.

Duloxetine, a dual acting norepinephrine serotonin reuptake inhibitor, is a relatively new pharmacologic agent utilized in the treatment of depression, as well as diabetic neuropathic pain, fibromyalgia, and female stress urinary incontinence. This expanding scope of usage will inevitably lead to its eventual appearance during routine post-mortem toxicologic assays. Currently there is a paucity of post-mortem toxicologic data concerning duloxetine. The current report provides six additional case reports of post-mortem duloxetine levels, along with a review of duloxetine's pharmacokinetics, and the toxicologic manifestations which have been reported in the literature. The post-mortem levels reported, including the highest level recorded to date, are integrated with previously published reports to generate a foundation for a nascent guide to the interpretation of post-mortem duloxetine levels that could be encountered during routine post-mortem toxicologic analyses, and establish a basis upon which the establishment of toxic and lethal thresholds for this compound can be further elucidated with greater clarity.

1,3-Propane sultone, an extremely potent experimental carcinogen: what should be expected in humans?

1,3-Propane sultone is directly alkylating, genotoxic and carcinogenic. In rats, it induces local and systemic tumours at multiple target sites. Preponderant systemic tumours occur at the central nervous system, especially gliomas. Other localisations include the mammary gland, the intestine, the haematopoietic system and the kidneys. In the German chemical industry, 1,3-propane sultone had been manufactured and used in limited amounts in the 1950s and 1960s, and for a very few purposes until the 1970s. The number of persons in contact with the compound is unknown but was limited. The medical history of some cases could be traced. As cerebral gliomas are the main systemic tumours induced by 1,3-propane sultone experimentally, the occurrence of a glioblastoma among previously exposed persons appears conspicuous. Three intestinal malignancies were recorded among the cases observed. Also noteworthy is one case of a duodenal carcinoma, normally a rare human malignancy. Two haematopoietic/lymphatic malignancies of different nature have been observed, and there was one case of a renal cell carcinoma. These malignancies observed within a group of persons exposed to 1,3-propane sultone appear surprisingly consistent with the expectations from the available animal studies. The present case studies point to long latency times (up to 30-40 years or more) after limited periods of past exposure.

A report of acute overdosage of the anti-serotonergic drug pizotifen.

An acute overdosage of 30 mg of pizotifen causing a pyrexial illness is reported. The clinical features suggest that the effects of overdosage are principally due to the anticholinergic activity of this drug. Resolution of symptoms occurred after 10 hours, without specific therapy.

Effects of thiophene on the Purkinje cell dendritic tree: a quantitative Golgi study.

A quantitative analysis was made of alterations in the dentritic organisation of Purkinje cells in the cerebellum of the adult rat following the administration of the degranulating agent, thiophene. This substance completely eliminated the granule cell population in a number of regions of cerebellar cortex. Purkinje cell dentdritic trees in these regions were markedly reduced in size when compared with control cells and provided evidence for a non-random loss of dentritic segments. Other dendritic abnormalities were noted. These results were discussed in relation to current theories of neuronal maintenance, and the feasibility of using toxic degranulating agents, such as thiophene, was considered.