A fatal case of venlafaxine overdose

Introduction

Based on its primary action of serotonin reuptake inhibition, venlafaxine overdose would be expected to result in serotonergic effects.

Case Report

A 40 year old male ingested venlafaxine without co-ingestants in a suicide attempt. The patient developed refractory ventricular fibrillation and expired approximately 9 hours post-ingestion. ECG monitoring revealed significant QRS and QT_C interval prolongation prior to his demise.

Discussion

A literature review of venlafaxine overdose cases and investigation into its mechanism of action was conducted. The potential for sodium channel blockade and implications for therapy are discussed.     

The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose

AIMS

To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination.

METHODS

Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t₉₀) of seizure, respectively.

RESULTS

A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03–0.08), 0.19 (0.09–0.35) and 0.75 (0.30–0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25–0.89), 0.71 (0.35–1.22) and 0.25 (0.08–0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t₉₀ values for first seizure was 26 h and was not affected by dose or decontamination procedure.

CONCLUSION

SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring.     

A report of two deaths from massive ibuprofen ingestion

Introduction

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion.

Case 1

A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 μg/mL: the therapeutic range is 10–50 μg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired.

Case 2

A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 μg/mL and serum valproate concentration was 560 μg/mL: the therapeutic range is 50–100 μg/mL. In spite of supportive care and hemodialysis, he expired.

Discussion

We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.     

The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells

Rationale

Antidepressants could exert neuroprotective effects against various insults and the antidepressant-like effect may result from its neuroprotective effects. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is a key signaling pathway in mediating cell survival. However, no information is available regarding the interaction of FoxO3a and antidepressants.

Objectives

PC12 cells treated with corticosterone were used as a model to study the protective effect of venlafaxine and underlying mechanisms.

Methods

Methyl thiazolyl tetrazolium (MTT) assay, Hoechst staining, and the observation of FoxO3a subcellular location were used to study the protective effect of venlafaxine against cell damage caused by corticosterone. Pretreatments with various pathway inhibitors were used to investigate the possible pathways involved in the protection of venlafaxine. The phosphorylation of Akt and FoxO3a was analyzed by Western blot.

Results

Corticosterone decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a and the apoptosis of PC12 cells. Venlafaxine concentration-dependently protected PC12 cells against corticosterone. The protective effect of venlafaxine was reversed by LY294002 and wortmannin, two PI3K inhibitors, and Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MAPK kinase) inhibitor PD98059 and the p38 MAPK inhibitor PD160316 had no effect. Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a, and the nuclear translocation of Foxo3a induced by corticosterone.

Conclusions

Venlafaxine protects PC12 cells against corticosterone-induced cell death by modulating the activity of the PI3K/Akt/FoxO3a pathway.     

Tretinoin overdose: A first case report

Introduction

Tretinoin (Vesanoid) is an all-trans-retinoic acid, and is related to retinol (Vitamin A). To date, there have been several case reports on overdose with its isomer isotretinoin, but none involving overdose of tretinoin. We report the first known case of a patient who ingested a massive overdose of tretinoin.

Case Report

A 31-year-old man ingested 1000 mg of tretinoin (100 pills of Vesanoid 10 mg) in a suicide attempt. He developed nonbloody diarrhea, but otherwise had no complaints. Clinical examination was normal. The patient was treated with activated charcoal and was hydrated. The patient’s blood results did not show any deterioration on the third consecutive day. He was discharged well on the third day, but was subsequently lost to follow-up.

Discussion

Although there has been no reported experience with acute tretinoin overdose in humans, our patient took a dose approximately 3 times the recommended maximum tolerated daily dose in patients with myelodysplastic syndrome or solid tumors (195 mg/m² per day). Overdose with other retinoids such as isotretinoin have been associated with only minor symptoms that resolved quickly. Our patient had diarrhea, which also resolved quickly with symptomatic treatment and hydration.

Conclusion

We believe this to be the first case report of an acute oral overdose of tretinoin. The patient developed diarrhea, but was otherwise asymptomatic.     

Evolving epidemiology of drug-induced seizures reported to a poison control center system

Introduction

We sought to determine whether or not the causes and consequences of drug-induced seizures have changed in the last decade.

Methods

We conducted a retrospective review of all calls to the California Poison Control System in 2003 in which seizures occurred in association with poisoning or drug intoxication. We reviewed the poison center chart of each case to determine the drug(s) involved, the type of seizures, and the medical outcome. We compared the cause of reported seizures to that found in previous investigations.

Results

386 cases were evaluated and related to poisoning or drug intoxication. The leading causes of seizures were bupropion (89 cases, 23%), diphenhydramine (32 cases, 8.3%), tricyclic antidepressants (30 cases,7.7%), tramadol (29 cases, 7.5%), amphetamines (27 cases, 6.9%), isoniazid (23 cases, 5.9%), and venlafaxine (23 cases, 5.9%). Since 1993, there was a statistically significant increase in antidepressant related seizures but a decrease in TCA and cocaine related seizures. In 265 patients (68.6%) only a single seizure was reported, while 3.6% (14 cases) reported status epilepticus. Two-thirds (65.5%) of the cases involved suicide attempts and 14.8% the direct result of drug abuse. There were 7 deaths. Of the 7 deaths, 4 people had significant hyperthermia. There was a statistically significant increased risk of death associated with stimulant exposure.

Conclusion

While tricyclic antidepressants, antihistamines, stimulants, and isoniazid remain common causes of drug induced seizures, bupropion, tramadol, and venlafaxine have emerged as common causes of drug-induced seizures for which poison center consultation is requested.     

Acute Oral Potassium Overdose: The Role of Hemodialysis

Introduction

Hyperkalemia is a common condition, particularly in the setting of renal dysfunction. Hyperkalemia due to intentional oral potassium overdose is not commonly reported.

Case Report

We present a case of acute intentional potassium overdose in a patient with normal renal function resulting in significant hyperkalemia, with a maximum serum potassium concentration of 11 mEq/L. Despite an initial course complicated by various unstable cardiac rhythms, including ventricular tachycardia, ventricular fibrillation, and pulseless electrical activity, the patient was discharged from the hospital neurologically intact. Treatment for hyperkalemia included hemodialysis.

Discussion

The role of dialysis in potassium overdose is poorly defined.

Conclusion

Based on this case and a review of the medical literature, we recommend hemodialysis for cases of potassium overdose with hemodynamic instability and significantly elevated serum potassium concentrations that do not respond promptly to medical therapy. Hemodialysis should also be considered in cases with underlying renal dysfunction.     

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine

Introduction

Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations.

Methods

An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations.

Results

In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG.

Conclusion

The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

     

Methadone Toxicity and Possible Induction and Enhanced Elimination in a Premature Neonate

Introduction

Reports describing methadone overdose in adult and pediatric patient populations are not uncommon. Reports in the preterm neonate patient population, however, are infrequent even though the utilization of methadone in that population continues to increase. Significant age-related pharmacokinetic differences complicate the management of methadone overdose in neonates, and literature involving methadone toxicokinetics and toxicodynamics in pediatric and neonate populations is largely limited.

Case Report

The clinical course and pharmacologic data of a massive methadone overdose in a 20-day-old male neonate is described, and a contemporary review of developmental pharmacology is presented.

Discussion

As clinicians continue to use methadone in neonates, they should be aware of the many significant peculiarities regarding its toxicology and pharmacology in that patient population.     

Deliberate Fingolimod Overdose Presenting with Delayed Hypotension and Bradycardia Responsive to Atropine

Introduction

Fingolimod is an immunomodulating agent used in multiple sclerosis (MS). It is a sphingosine-1-phosphate (S1P) receptor agonist prescribed for relapsing forms of MS to delay onset of physical disability. As fingolimod is known to cause first-dose bradycardia, telemetry is recommended for the first 6 h post-dose. We present the first reported case of deliberate fingolimod overdose requiring atropine administration for bradycardia and hemodynamic instability.

Case report

A 33-year-old woman ingested 14 mg of fingolimod and 2 g of phenoxymethylpenicillin. After presenting to the emergency department 19 h later, she was initially hemodynamically stable (heart rate (HR) 60, blood pressure (BP) 113/89 mmHg). Two hours later, she then developed bradycardia (HR 48) and hypotension (87/57 mmHg). Despite intravenous fluids, stabilisation was only achieved after administration of atropine (300 μg). She was then admitted to the intensive care unit (ICU) for further monitoring where another episode of bradycardia and hypotension required atropine. She was monitored in the ICU for 48 h and then discharged on day 5 with no further episodes.

Discussion

Fingolimod is known to cause bradycardia in the first 6 h post first therapeutic dose. Following intentional overdose, onset of bradycardia occurred at 21 h post-ingestion and was associated with hypotension. Atropine was successful in treating bradycardia and associated hypotension.     

Late-onset seizures associated with quetiapine poisoning

Introduction

Quetiapine, a second-generation antipsychotic, acts at multiple brain neurotransmitter receptors and has the potential for serious complications. Although seizures have been described in the literature, delayed seizure onset has not been reported. We report the first case of delayed seizures after a significant quetiapine overdose.

Case Report

A 27-year-old female presented to the emergency department following an overdose of approximately 30 g of quetiapine. Twenty-four hours after arrival, the patient had 2 seizures. The patient was then intubated and remained in the ICU for four days. EEG was negative for epileptiform activity. The serum quetiapine levels (MedTox, St. Paul, MN) were 8.67 mg/L on hospital day one and 3.28 mg/L on hospital day three.

Discussion

Quetiapine poisoning, with serum levels, associated with seizures has been reported in one prior case. Our case report represents late-onset seizures with serum levels above therapeutic range (> 1 mg/L). The serum concentrations of quetiapine in this case were consistent with those in postmortem case reports.     

The modulation of venlafaxine on cortical activation of language area in healthy subjects with fMRI study

Rationale

Previous studies have shown that selective serotonin reuptake inhibitors, activators of the cortex, apparently improved language functional recovery after brain damage rather than simply affective disorders.

Objective

Our aim was to determine whether venlafaxine (an agonist of both norepinephrine and 5-hydroxytryptamine) could modulate language cortex function.

Methods

A double-blind, crossover, randomized design was used to compare two 7-day treatment sessions with either venlafaxine (75?mg per day) or placebo. A functional magnetic resonance imaging experiment and two language function tests were performed on eight healthy males (mean age, 28.25?±?3.15?years) at the end of each session, i.e., study entry, after venlafaxine, and after placebo (days 0, 7, and 18). Hyperactivation (venlafaxine minus placebo >0) or hypoactivation (placebo minus venlafaxine >0) by venlaxafine was assessed on the basis of the activation–baseline contrast.

Results

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l-Carnitine for the Treatment of a Calcium Channel Blocker and Metformin Poisoning

Introduction

The object of the current communication is to discuss the theory and the evidence for the use of l-carnitine in calcium channel blocker and metformin poisonings.

Case Report

A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of l-carnitine was administered as a last resort. One hour after l-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days.

Discussion

l-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.     

Prolonged Use of Intravenous Lipid Emulsion in a Severe Tricyclic Antidepressant Overdose

Introduction

Intravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear.

Case Report

A patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae.

Discussion

A low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose.     

Pramipexole Overdose Associated with Visual Hallucinations,Agitation and Myoclonus

Introduction

Pramipexole is a dopamine D₂ receptor agonist used to treat idiopathic Parkinson’s disease and primary restless legs syndrome. There is limited information on pramipexole overdose.

Case Report

A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h.

Discussion

Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.

     

SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study

Introduction

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressants which have high affinity to both serotonin transporter (SERT) and norepinephrine transporter (NET). In studies in vitro, SNRIs have been reported to show a large variability in the affinity ratio between SERT and NET. For instance, the reported affinity ratio is about 30 for venlafaxine and 1.6 for milnacipran. In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran.

Methods

PET measurements with [¹¹C]MADAM and [¹⁸F]FMeNER-D₂ were performed in two female cynomolgus monkeys at baseline and after pretreatment with venlafaxine and milnacipran, respectively. Relationships between dose, plasma concentration, and transporter occupancy were evaluated by saturation analysis using a hyperbolic function. Binding affinity (Kd^plasma) was expressed by the dose or plasma concentration at which 50 % of the transporter was occupied.

Results

SERT and NET occupancy by venlafaxine and milnacipran increased in a dose and plasma concentration-dependent manner. The Kd^plasma ratio of SERT to NET was 1.9 for venlafaxine and 0.6 for milnacipran.

Conclusions

In this nonhuman primate PET study, the affinity in vivo for SERT and NET, respectively, was shown to be at a similar level for venlafaxine and milnacipran. Both drugs were found to produce balanced inhibition of SERT and NET binding. This observation is not consistent with previous in vitro binding data and illustrates the need to characterize antidepressants at in vivo condition.     

N-acetylcysteine for the prevention of non-contrast media agent-induced kidney injury: from preclinical data to clinical evidence

Purpose

To review available evidence on the effectiveness of N-acetylcysteine (NAC) as a prophylactic agent in the prevention of non-contrast media agent-induced kidney injury.

Method

Data were collected by searching Scopus, PubMed, Medline, Science direct and Cochrane database systematic reviews. A total of 26 relevant experimental studies up to the date of publication were included in the review.

Results

Available evidence shows that NAC has the potential to exert significant protective or ameliorative effects against drug-induced kidney injury in experimental models. The possible suggested renoprotective mechanisms of NAC in different experimental settings were acting as an antioxidant by restoring the pool of intracellular reduced glutathione, scavenging of free radicals, and/or interacting with reactive oxygen species.

Conclusion

Whether the administration of NAC could be an effective protective clinical strategy to prevent drug-induced kidney injury or not is a question that remains to be answered in future clinical trials.     

Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment

Rationale

Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT_1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial.

Objectives

The aim of this study was to evaluate the effect of venlafaxine (10 mg kg^?1 day^?1, p.o.) after 21 days of treatment on the density of 5-HT_1B receptors and their functionality in rat brain.

Methods

Effects of chronic venlafaxine were evaluated at different levels of 5-HT_1B receptor by using receptor autoradiography, [³⁵S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT_1B agonist.

Results

Our results show that venlafaxine induced an increase in sensitivity of 5-HT_1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density.

Conclusions

These results demonstrate that adaptive changes on 5-HT_1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.     

Positive Outcome After Intentional Overdose of Dabigatran

Introduction

Dabigatran (Pradaxa?), an orally active direct thrombin inhibitor, was approved by the United States Food and Drug Administration for the prevention of stroke in patients with atrial fibrillation in October 2010. Life-threatening consequences from dabigatran therapy include hemorrhage and bleeding complications, but they typically occur after renal impairment. We describe the first case report of intentional, acute overdose with dabigatran.

Case Report

A 57-year-old woman with a medical history of depression and atrial fibrillation presented to the emergency department after ingesting 11.25 g of dabigatran in a suicide attempt. Despite an ecchymosis indicative of prior trauma, there was no evidence of acute bleeding. After receiving gastric lavage and activated charcoal therapy in the emergency department, she was admitted to the ICU. On presentation, dabigatran blood levels measured 970 ng/mL and thrombin clot times measured above the testable limits (>120 s) until 52 h post-arrival. The remainder of her clinical course was uncomplicated, and the patient was transferred to an inpatient psychiatric unit for depression follow-up.

Discussion

This case shows the clinical course of a patient with an acute, massive dabigatran overdose with no significant clinical consequences. Currently, there is no ideal method to monitor anticoagulation levels; there is no pharmacologic reversal method, and hemodialysis is an undesirable treatment option.     

Engineered Andrographolide Nanoparticles Mitigate Paracetamol Hepatotoxicity in Mice

Purpose

Paracetamol (acetaminophen, APAP) overdose is often fatal due to progressive and irreversible hepatic necrosis. The aim of this work was to design Andrographolide (AG) loaded nanoparticles to prevent similar hepatic necrosis.

Methods

Functionalized AG-loaded PLGA nanoparticles carrying different densities of heparin were prepared following a facile emulsion solvent evaporation technique. Nanoparticle morphology, loading and release kinetics were studied. Hepatic localization of the nanoparticles was investigated in both normal and APAP damaged conditions using FITC fluorescent probe. Different serum parameters and liver histopathology were further examined as indicators of hepatic condition before and after treatment.

Result

A collection of heparin functionalized AG-loaded PLGA nanoparticles were designed. Low amount of heparin on the particle surface could rapidly localize the nanoparticles up to the liver. The new functionalized AG nanoparticles affect efficient hepatoprotection in experimental mouse APAP overdose conditions. AG nanoparticle hepatoprotection was due to the rapid regeneration of antioxidant capacity and hepatic GSH store.

Conclusions

Engineered nanoparticles loaded with AG provided a fast protection in APAP induced acute liver failure.