Cough elixir overdose causing toxic leuco-encephalopathy and serotonin syndrome.

Acute toxic leukoencephalopathy and serotonin syndrome are rare neurological complications associated with various drugs and toxins, some of which overlap. However, the co-occurrence of these conditions is poorly documented. We present the case of a 14-year-old boy who suddenly developed altered consciousness and autonomic dysfunction after consuming excessive quantities of cough remedies containing dextromethorphan, chlorphenamine, dichlorobenzyl alcohol, and amylmetacreson. Magnetic resonance imaging of the brain revealed distinct white matter lesions. With supportive care, the patient rapidly improved, and the magnetic resonance imaging abnormalities disappeared. The swift resolution, typical magnetic resonance imaging findings, and a history of exposure to drugs affecting the central nervous system's serotonergic system suggested concurrent acute toxic leukoencephalopathy and serotonin syndrome. The components of cough medications can be hazardous in overdose due to their potential to enhance serotonin toxicity and cause direct or indirect central nervous system white matter damage. Early recognition and appropriate treatment are essential for recovery.

A large-scale retrospective study of opioid poisoning in New York State with implications for targeted interventions.

Opioid overdose related deaths have increased dramatically in recent years. Combating the opioid epidemic requires better understanding of the epidemiology of opioid poisoning (OP). To discover trends and patterns of opioid poisoning and the demographic and regional disparities, we analyzed large scale patient visits data in New York State (NYS). Demographic, spatial, temporal and correlation analyses were performed for all OP patients extracted from the claims data in the New York Statewide Planning and Research Cooperative System (SPARCS) from 2010 to 2016, along with Decennial US Census and American Community Survey zip code level data. 58,481 patients with at least one OP diagnosis and a valid NYS zip code address were included. Main outcome and measures include OP patient counts and rates per 100,000 population, patient level factors (gender, age, race and ethnicity, residential zip code), and zip code level social demographic factors. The results showed that the OP rate increased by 364.6%, and by 741.5% for the age group > 65 years. There were wide disparities among groups by race and ethnicity on rates and age distributions of OP. Heroin and non-heroin based OP rates demonstrated distinct temporal trends as well as major geospatial variation. The findings highlighted strong demographic disparity of OP patients, evolving patterns and substantial geospatial variation.

Time-Dependent Changes in the Serum Levels of Neurobiochemical Factors After Acute Methadone Overdose in Adolescent Male Rat.

Acute methadone toxicity is a major public health concern which has adverse effects on brain tissue and results in recurrent or delayed respiratory arrest. Our study aimed to investigate the time-dependent changes in several serum biochemical markers of brain damage, spatial working memory, and the brain tissue following acute methadone overdose. Adolescent male rats underwent an intraperitoneal (i.p.) injection of 15 mg/kg methadone. In case of apnea occurrence, resuscitation was performed by a ventilatory pump and administrating naloxone (2 mg/kg; i.p.). The animals were classified into groups of treated rats; methadone and naloxone-Apnea (M/N-Apnea), M/N-Sedate, Methadone, Naloxone, and control (saline) groups. The serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein factors, and (Lactate/Pyruvate) L/P ratio were evaluated at the time-points of 6, 24, and 48 h (h). We found that the alterations of S100B and L/P ratio were considerable in the M/N-Apnea and Methadone groups from the early hours post-methadone overdose, while NSE serum levels elevation was observed only in M/N-Apnea group with a delay at 48 h. Further, we assessed the spatial working memory (Y-maze test), morphological changes, and neuronal loss. The impaired spontaneous alternation behavior was detected in the M/N-Apnea groups on days 5 and 10 post-methadone overdose. The morphological changes of neurons and the neuronal loss were detectable in the CA1, striatum, and cerebellum regions, which were pronounced in both M/N-Apnea and Methadone groups. Together, our findings suggest that alterations in the serum levels of S100B and NSE factors as well as L/P ratio could be induced by methadone overdose with the presence or absence of apnea before the memory impairment and tissue injury in adolescent male rats.

Does a hypoxic injury from a non-fatal overdose lead to an Alzheimer Disease?

Long term consequence of non-fatal overdose in people who use opioids are not well understood. The intermittent exposure to non-fatal overdose leads to a tauopathy that is often accompanied by abrogated neuroprotective response, abnormal amyloid processing and other pathologies. The scope and limitations of available literature are discussed including neuropathologies associated with opioid and overdose exposures, contributing comorbidities and proteinopathies. Contrasting postmortem data of overdose victims with animal models of opioid neuropathologies and hypoxic injury paints a picture distinct from other proteinopathies as well as effects of moderate opioid exposure. Furthermore the reported biochemical changes and potential targets for therapeutic intervention were mapped pointing to underlying imbalance between tau kinases and phosphatases that is characteristic of Alzheimer Disease.

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury.

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

1,4-Butanediol overdose mimicking toxic alcohol exposure.

Context: 1,4-butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) analogue with a similarly narrow therapeutic window that is becoming a more common cause of recreational overdose. Reports of confirmed exposures are limited.Case details: A 44 year-old man who had consumed alcohol subsequently became unconscious after ingesting what was thought to be GHB. The presentation was not entirely consistent with GHB poisoning, including a longer duration of unconsciousness and features that mimicked toxic alcohol exposure including a high anion gap metabolic acidosis (HAGMA) and osmol gap. The patient was treated supportively with intubation, haemodiafiltration and intravenous ethanol until the diagnosis was refined using specific laboratory testing. The concentration of 1,4-BD was the highest reported in the literature and the outcome favourable.Discussion: This case highlights pharmacokinetic issues peculiar to 1,4-BD, including the interaction with ethanol which delays the onset of psychoactive effects from 1,4-BD's metabolite GHB, and dose-dependent pharmacokinetics. In overdose, 1,4-BD can induce a HAGMA and other features of toxic alcohol poisoning. Managing an unconscious patient with these features can prompt certain treatments until the diagnosis is refined, which can require specific laboratory testing to identify the culprit. The actual risk of toxic alcohol and other causes is adjusted on a case-by-case basis from the history of exposure and local epidemiology of substance use and poisoning.

An HIV-infected Patient with No Serious Adverse Events after Overdosing on Raltegravir.

Patients with HIV infection represent a high-risk group for medication overdose because of the high frequency of complicating psychiatric disorders. Raltegravir is well-known for its low frequency of adverse effects. We herein report a 42-year-old Japanese man with HIV infection who was hospitalized 6 hours after overdosing with 24,000 mg of raltegravir in a suicide attempt. No serious adverse events occurred, although the plasma concentration of raltegravir at 18 hours after the overdose was 79,871.1 ng/mL. Raltegravir may be well-indicated for HIV patients at risk of overdosing.

Case Report: Analytically Confirmed Severe Albenzadole Overdose Presenting with Alopecia and Pancytopenia.

Internet-facilitated self-diagnosis and treatment is becoming more prevalent, putting individuals at risk of toxicity when drugs are acquired without medical oversight. We report a patient with delusional parasitosis who consumed veterinary albendazole purchased on the Internet, leading to pancytopenia, transaminase elevation, and alopecia. A 53-year-old man was sent to the emergency department (ED) by his gastroenterologist because of abnormal laboratory results. The patient had chronic abdominal pain and believed he was infected with parasites. He purchased two bottles of veterinary-grade albendazole on the Internet, and over the 3 weeks before his ED visit, he consumed 113.6 g of albendazole (a normal maximal daily dose is 800 mg). Five days before admission, he noticed hair loss and a rash on his face. His examination was notable for significant scalp hair loss and hyperpigmentation along the jaw line. Laboratory studies were remarkable for pancytopenia (most notably a white blood cell count (WBC) of 0.4 × 103 cells/mm3, with an absolute neutrophil count (ANC) of 0 × 103 cells/mm3) and transaminase elevation (aspartate aminotransferase [AST] 268 IU/L, alanine aminotransferase [ALT] 89 IU/L). He developed a fever and was treated with antibiotics and colony-stimulating factors for presumed neutropenic bacteremia. Over the course of 1 week, his hepatic function normalized and his ANC increased to 3,000 × 103 cells/mm3. Serial albendazole and albendazole sulfoxide concentrations were measured in serum and urine by liquid chromatography-quadruple time-of-flight mass spectrometry. On day 2, his serum concentrations were 20.7 ng/mL and 4,257.7 ng/mL for albendazole and albendazole sulfoxide, respectively. A typical peak therapeutic concentration for albendazole sulfoxide occuring at 2-5 hours post-ingestion is 220-1,580 ng/mL. Known adverse effects of albendazole include alopecia, transaminase elevation, and neutropenia. Pancytopenia leading to death from septic shock is reported. In our patient, prolonged use of high-dose albendazole resulted in a significant body burden of albendazole and albendazole sulfoxide, leading to pancytopenia, transaminase elevation, and alopecia. He recovered with supportive therapy.

Drug Abuse-Related Neuroinflammation in Human Postmortem Brains: An Immunohistochemical Approach.

The aim of the study was to investigate blood-brain barrier alterations, neuroinflammation, and glial responses in drug abusers. Five immunohistochemical markers (CD3, zonula occludens-1 [ZO-1], intracellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule [VCAM-1], and glial fibrillary acidic protein [GFAP]) were assessed on postmortem brain samples collected from drug abusers who died from acute intoxication of cocaine, heroin, or a combination of both, compared with controls. CD3 and ICAM-1 immunopositivity were significantly stronger in drug abusers than in controls. VCAM-1 immunopositivity was similar across drug abuser and control groups. In heroin abusers, significantly lower ZO-1 immunopositivity was observed relative to controls. GFAP positivity did not show significant differences between groups, but its distribution within the brain did differ. Both cocaine and heroin abuse promoted neuroinflammation, increasing expression of ICAM-1 and recruiting CD3+ lymphocytes. Heroin affected the molecular integrity of tight junctions, as reflected by reduced ZO-1 expression. The outcomes of the present study are, overall, consistent with prior available evidence, which is almost exclusively from studies conducted in vitro or in animal models. These findings provide important information about the downstream consequences of neuroinflammation in drug abusers and may help to inform the development of potential therapeutic targets.

Acetaminophen hepatotoxicity: A mitochondrial perspective.

Acetaminophen (APAP) is a highly effective analgesic, which is safe at therapeutic doses. However, an overdose can cause hepatotoxicity and even liver failure. APAP toxicity is currently the most common cause of acute liver failure in the United States. Decades of research on mechanisms of liver injury have established the role of mitochondria as central players in APAP-induced hepatocyte necrosis and this chapter examines the various facets of the organelle's involvement in the process of injury as well as in resolution of damage. The injury process is initiated by formation of a reactive metabolite, which binds to sulfhydryl groups of cellular proteins including mitochondrial proteins. This inhibits the electron transport chain and leads to formation of reactive oxygen species, which induce the activation of redox-sensitive members of the MAP kinase family ultimately causing activation of c-Jun N terminal kinase, JNK. Translocation of JNK to the mitochondria then amplifies mitochondrial dysfunction, ultimately resulting in mitochondrial permeability transition and release of mitochondrial intermembrane proteins, which trigger nuclear DNA fragmentation. Together, these events result in hepatocyte necrosis, while adaptive mechanisms such as mitophagy remove damaged mitochondria and minimize the extent of the injury. This oscillation between recovery and necrosis is predominant in cells at the edge of the necrotic area in the liver, where induction of mitochondrial biogenesis is important for liver regeneration. All these aspects of mitochondria in APAP hepatotoxicity, as well as their relevance to humans with APAP overdose and development of therapeutic approaches will be examined in detail in this chapter.

Schizophrenia in high risk opioid users: A short communication on an autopsy study.

The prevalence of schizophrenia among high risk opioid users was investigated as part of a wider investigation into opioid-related deaths. We found that over 6% of our sample of 312 decedents of opioid overdose had received a schizophrenia related diagnosis over a 36 month period prior to their death. This represents a near 8× increase on previously estimated period prevalence of schizophrenia in the general population. Though not conclusive, our findings raise questions about the extent to which opioid drugs are used by people with schizophrenia, and about how to best address high risk opioid use in people with schizophrenia.

Endoscopic removal of a gastric pharmacobezoar induced by clomipramine, lorazepam, and domperidone overdose: a case report.

INTRODUCTION: Gastric pharmacobezoars are a rare entity that can induce mechanical gastric outlet obstructions and sometimes prolong toxic pharmacological effects. Certain medications, such as sustained-release forms, contain cellulose derivatives that may contribute to the adhesion between pills and lead to the creation of an aggregate resulting in a pharmacobezoar. Case reports are rare, and official guidelines are needed to help medical teams choose proper treatment options. CASE PRESENTATION: Our patient was a 40-year-old Caucasian woman with borderline personality disorder and active suicidal thoughts who was found unconscious after a massive drug consumption of slow-release clomipramine, lorazepam, and domperidone. On her arrival in the emergency room, endotracheal intubation was preformed to protect her airway, and a chest x-ray revealed multiple coffee grain-sized opaque masses in the stomach. She was treated with activated charcoal followed by two endoscopic gastric decontaminations 12 h apart in order to extract a massive gastric pharmacobezoar by manual removal of the tablets. CONCLUSION: This case demonstrates that in the case of a massive drug consumption, a pharmacobezoar should be suspected, particularly when cellulose-coated pills are ingested. Severe poisoning due to delayed drug release from the gastric aggregate is a potential complication. Detection by x-ray is crucial, and treatment is centered on removal of the aggregate. The technique of decontamination varies among experts, and no formal recommendations exist to date. It seems reasonable that endoscopic evaluation should be performed in order to determine the appropriate technique of decontamination. Care should be patient-oriented and take into account the clinical presentation and any organ failure, and it should not be determined solely by the suspected medication ingested. Thus, serum levels are not sufficient to guide management of tricyclic antidepressant intoxication.

Unexpected deadly outcome of a body packer - a case of drowning and illegal drug trafficking with review

The human body is often used for illegal drug trafficking around the world. This may be done by concealing the drugs inside the body, so-called "body packing". This can lead to life-threatening conditions, mainly by leakage of the illegal substances in lethal amounts into the circulation system, which may cause fatal consequences due to acute drug overdose. Most of these cases present as sudden unexpected deaths. However, we present herein a case in which the death of an unidentified victim, which was notified as a case of seawater drowning in a non-suspicious manner, but later proved to be the death of a body packer as a result of drowning due to a morphine overdose. This case highlights the importance of investigating deaths even in unidentified bodies and the different presentations of fatal consequences of a body packer, which previously have not been described in literature.

Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose.

The serine protease plasmin degrades extracellular matrix (ECM) components both directly and indirectly through activation of matrix metalloproteinases. Excessive plasmin activity and subsequent ECM degradation cause hepatic sinusoidal fragility and hemorrhage in developing embryos. We report here that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises hepatic sinusoidal vascular integrity in adult animals. We found that hepatic plasmin activity is up-regulated significantly at 6 hours after APAP overdose. This plasmin up-regulation precedes both degradation of the ECM component fibronectin around liver vasculature and bleeding from centrilobular sinusoids. Importantly, administration of the pharmacological plasmin inhibitor tranexamic acid or genetic reduction of plasminogen, the circulating zymogen of plasmin, ameliorates APAP-induced hepatic fibronectin degradation and sinusoidal bleeding. Conclusion: These studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose. (Hepatology 2018; 00:1-13).

Concomitant Acute Toxic Leukoencephalopathy and Posterior Reversible Encephalopathy Syndrome.

BACKGROUND AND PURPOSE: Posterior reversible encephalopathy syndrome (PRES) and acute toxic leukoencephalopathy (ATL) are both potentially reversible clinicoradiologic entities. Although their magnetic resonance imaging (MRI) findings differ, rarely both may occur simultaneously in acutely encephalopathic patients. Our aim was to determine the incidence and causes of concomitant "ATL-PRES." METHODS: Retrospective search of suspected acutely encephalopathic adults since 1998 throughout our picture archiving and communication system revealed 167 patients with PRES and 106 patients with ATL. Images of these patients were retrospectively evaluated by two neuroradiologists and a fellow to identify the cases which carry both features of PRES and ATL. Imaging findings were scored based on previously reported scoring system as mild, moderate, and severe. The clinical outcome of the patients was determined according to the modified Rankin scale. RESULTS: Our search revealed a series of 6 patients (%2.2) in 273 patients who presented acutely with either encephalopathy or seizures, caused by various etiologies, including immunosuppression following transplantation (n = 2), hypertensive crisis (n = 2), chemotherapy (n = 1), and sepsis (n = 1). MRI demonstrated findings consistent with both PRES and ATL simultaneously on FLAIR and diffusion weighted imaging. Severity of imaging findings of concomitant "ATL-PRES" was concordant with each other (rho ≈ 1.0, P < .00001), and each patient eventually returned to clinical baseline. This finding, along with their similar etiologies, raises the possibility of an underlying common pathophysiologic thread, perhaps being endothelial toxicity. CONCLUSIONS: Concomitant "ATL-PRES" was found in 2.2% of the patients in a large cohort of ATL and PRES. Etiologies varied. Clinical symptoms and MRI findings were potentially reversible.

Analytical Approaches in Fatal Intoxication Cases Involving New Synthetic Opioids.

BACKGROUND: Synthetic opioids are compounds that were created to act on the opioid receptors. Novel synthetic opioids include various analogs of fentanyl (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, furanylfentanyl, 4-fluorobutyrylfentanyl or ocfentanil) and newly emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. In the last years, these drugs have rapidly emerged on the recreational drug market, and their abuse has been increasing worldwide. Due to the high potency and the low dose required to produce desired effects, the risk of overdose for these compounds including severe health implications, is quite high. Several fatal intoxication cases related to the abuse of synthetic opioids have recently been reported in the literature. CONCLUSION: As a consequence, the detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and distribution in body fluids. We overviewed the analytical approaches for the investigation of synthetic opioids in postmortem samples reported in the literature, with special emphasis given to cases of lethal intoxication.

Blocking interleukin-4 enhances efficacy of vaccines for treatment of opioid abuse and prevention of opioid overdose.

Vaccines offer an option to treat heroin and prescription opioid abuse and prevent fatal overdoses. Opioid vaccines elicit antibodies that block opioid distribution to the brain and reduce opioid-induced behavioral effects and toxicity. The major limitation to the translation of addiction vaccines is that efficacy is observed only in subjects achieving optimal drug-specific serum antibody levels. This study tested whether efficacy of a vaccine against oxycodone is increased by immunomodulators targeting key cytokine signaling pathways involved in B and T cell lymphocyte activation. Blockage of IL-4 signaling increased vaccine efficacy in blocking oxycodone distribution to the brain and protection against opioid-induced behavior and toxicity in mice. This strategy generalized to a peptide-protein conjugate immunogen, and a tetanus-diphtheria-pertussis vaccine. These data demonstrate that cytokine-based immunomodulators increase efficacy of vaccines against small molecules, peptides and proteins, and identify IL-4 as a pharmacological target for improving efficacy of next-generation vaccines.

Prophylactic administration of carnosine and melatonin abates the incidence of renal toxicity induced by an over dose of titanium dioxide nanoparticles.

The alleviative effects of two antioxidants, carnosine (Car) and melatonin (Mel), against titanium dioxide nanoparticles (TiO2 -NPs) toxicity-induced oxidative and inflammatory renal damage were examined in rats. Administration of these antioxidants along with TiO2 -NPs effectively reduced serum urea, uric acid, creatinine, glucose, tumor necrosis factor-α, interleukin-6, C-reactive protein, immunoglobulin G, vascular endothelial growth factor, and nitric oxide, as well as a significant amelioration of the decrease in glutathione levels in renal tissue was observed, compared to those in rats treated with TiO2 -NPs alone. The renoprotective properties of the antioxidants were confirmed by reduced intensity of renal damage as demonstrated by histological findings. In conclusion, Car and Mel play protective roles against TiO2 -NPs-induced renal inflammation and oxidative injury, likely due to their antioxidant and anti-inflammatory properties.