Intravenous Lipid Emulsion in the Management of Amlodipine Overdose

Objective:

To report a case of amlodipine overdose successfully treated with intravenous lipid emulsion (ILE).

Case Summary:

A 47-year-old, 110 kg female ingested at least 350 mg of amlodipine with an unknown amount of ethanol. Initial blood pressure was 103/57 mm Hg, mean arterial pressure (MAP) 72 mm Hg, and heart rate 113 beats per minute. In the early clinical course, activated charcoal, intravenous fluid, and calcium boluses were administered. Worsening hypotension prompted a 100 mL bolus of 20% ILE. Stable hemodynamics were maintained for 2 hours. Subsequently, profound hypotension and shock developed (MAP 38 mm Hg), which failed to fully respond to 3 vasopressor agents, calcium, and glucagon. With continuing shock despite optimized vasopressors, an infusion of 2,300 mL 20% ILE was administered over 4.5 hours (20.9 mL/kg infusion total). By completion of the infusion, 2 vasopressors were tapered off and MAP remained above 70 mm Hg; within 12 hours, no further interventions were required. Possible adverse events of ILE, lipemia and hypoxia, were experienced but quickly resolved. The patient survived to hospital discharge within 8 days.

Discussion:

Toxicity of amlodipine presents similar to distributive shock as both are due to marked peripheral vasodilation. There are numerous interventions in the management of amlodipine overdose, despite which many patients continue to suffer life-threatening shock as observed with this patient. ILE has been used with promising preliminary results as salvage therapy in case reports of other lipophilic molecules. This is the first report of lone amlodipine overdose treated with ILE.

Conclusion:

ILE is a novel antidote for overdoses of lipophilic substances and demonstrated efficacy in this case of amlodipine overdose without the use of hyperinsulinemic euglycemia.Cardiovascular medications were the second leading cause of death from medication overdose in 2010, with amlodipine contributing to 24 of those fatalities.¹ Calcium channel blocker (CCB) toxicity presents a particular clinical challenge due to the negative cardiac conduction and contractility properties, along with potent peripheral vasodilatory effects. All CCBs act through blockade of voltage gated L-type calcium channels.^2-4 At therapeutic doses, dihydropyridine CCBs (amlodipine, nifedipine, felodipine, nimodipine, and nicardipine) act by relaxation of smooth muscle surrounding blood vessels in the periphery and heart.³ Non-dihydropyridine CCBs (diltiazem and verapamil) work in the cardiac nodal tissue to slow conduction and demonstrate negative chronotropic, dromotropic, and inotropic effects.³ However, at toxic levels this difference in site of effect between classes is less pronounced,^2,5 thus all dihydropyridine and non-dihydropyridine CCBs may cause hypotension, bradycardia, heart block, and shock.There are a number of therapeutic modalities used in the management of CCB overdose, including fluid resuscitation, intravenous calcium, glucagon, atropine, hyperinsulinemic euglycemia, and vasopressor agents. Despite these interventions, CCB toxicity continues to cause significant mortality. We report the successful use of an emerging treatment strategy, intravenous lipid emulsion (ILE), in the management of amlodipine toxicity, despite hyperinsulinemic euglycemia not being provided.     

Use of a Physostigmine Continuous Infusion for the Treatment of Severe and Recurrent Antimuscarinic Toxicity in a Mixed Drug Overdose

Introduction

Physostigmine was once a widely used antidote for the treatment of antimuscarinic toxicity. However, reports describing the association of physostigmine with asystole and seizures in severe tricyclic antidepressant poisoning resulted in a decrease in use. Recent literature has demonstrated that physostigmine is a safe and effective antidote for the treatment of antimuscarinic toxicity. There are only two previously published articles regarding the use of physostigmine administered as a continuous intravenous infusion for persistent antimuscarinic toxicity. We present a case of physostigmine continuous infusion for the treatment of antimuscarinic symptoms in a polydrug overdose due to the ingestion of diphenhydramine along with bupropion, citalopram, acetaminophen, and naproxen.

Case Presentation

A 13-year-old female presented with hyperthermia, myoclonus and rigidity, hallucinations, severe agitation, and antimuscarinic toxicity including inability to sweat after a polydrug overdose. Several doses of lorazepam were administered followed by physostigmine which produced resolution of hallucinations and attenuation of the antimuscarinic symptoms including perspiration, temperature improvement, and decreased agitation. After periods of improvement and recurrence of antimuscarinic effects, a continuous infusion of physostigmine was administered at 2 mg/h and continued for almost 8 h to maintain attenuation of symptoms. GABAergic agents including lorazepam and phenobarbital were used later in the hospital course for presumed symptoms of serotonergic and adrenergic toxicity after resolution of antimuscarinic effects. The patient did not experience any adverse effects of physostigmine administration.

Discussion

Physostigmine administered as a continuous infusion may be a reasonable treatment option for severe and recurrent symptoms related to antimuscarinic toxicity.     

Four-year experience with methotrexate exposures

Introduction

Unintentional methotrexate (MTX) acute oral overdose is rarely reported.

Methods

We conducted a retrospective chart review of all human exposure calls (> 150,000 charts) for MTX ingestions reported to our Poison Center during 2000–2003.

Results

Thirteen patients met the criteria. The average amount of MTX ingested was 13.03 mg (data from 7 cases), and the average patient age was 43 years (20 months to 80 years). No significant toxicities occurred.

Discussion

Although intravenous MTX toxicity can be severe, this does not appear to be a phenomenon associated with either acute unintentional or suicidal oral ingestion.     

Dermal Exposure to a Compounded Pain Cream Resulting in Severely Elevated Clonidine Concentration

Introduction

Clonidine is an imidazoline derivative antihypertensive medication that is also used as adjunctive therapy for neuropathic pain disorders via topical administration. Clonidine overdose can manifest both central and peripheral alpha-adrenergic agonist effects.

Case Report

A 23-year-old man presented to an emergency department with altered mental status, bradycardia, and hypertension after suspected overdose. He had rubbed a specially compounded medicinal cream over his entire body containing clonidine 0.2 % (w/w), gabapentin 6 %, imipramine 3 %, ketamine 10 %, lidocaine 2 %, and mefenamic acid 1 %. The patient presented with severe hypertension, bradycardia, and altered mental status. He was found to have a subarachnoid hemorrhage and was treated for hypertensive emergency. Toxicological analysis of initial blood samples revealed a serum clonidine concentration of 5,200 ng/ml. At 6-month follow-up, the patient had made a full recovery.

Discussion

There are limited reports of topical clonidine toxicity, and to our knowledge, this case involves the highest concentration yet reported following clonidine overdose by any route of exposure. The severely elevated serum clonidine concentration found in our patient demonstrates the possibility of toxicity resulting from inappropriate use of such a product. At high serum concentrations, the pharmacodynamic effects of clonidine appear to cause significant peripheral alpha-1 adrenergic stimulation. Toxicologists should be aware of the increasing use of topical clonidine preparations for the treatment of neuropathic pain and the potential for toxicity.     

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.     

Almost a tragedy: severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy

Background

Methotrexate (MTX), an antimetabolite of folic acid, is the drug of choice for the nonsurgical management of ectopic pregnancy. MTX-related toxicity may include leukopenia, thrombocytopenia, pancytopenia, nausea, vomiting, stomatitis, mucositis, and liver and lung toxicity, depending primarily on the dosage of the drug and patients' renal function. Currently, the use of MTX in hemodialysis patients, even at a low dosage, is controversial, and no clear-cut guidelines are available.

Case report

We report here a rare case of a life-threatening complication characterized by severe pancytopenia and skin and mucosal injury, which developed in a young patient on hemodialysis after oral treatment with MTX for ectopic pregnancy.

Conclusion

We conclude that even low-dose MTX administration is not to be used in patients with renal insufficiency, and when no other therapeutic options are available we suggest taking several clinical measures to prevent or treat myelosuppression.     

The role of fat emulsion therapy in a rodent model of propranolol toxicity: A preliminary study

Introduction

In animal models, lipid emulsion therapy has been shown to ameliorate toxicity from a number of lipid soluble agents. This preliminary study addresses the hypothesis that pretreatment with lipid emulsion protects against propranolol toxicity in rodents.

Methods

Ten spontaneously ventilating Rattus norvegicus rats were pretreated with either lipid emulsion or 0.9% normal saline before undergoing a constant infusion of propranolol until death. An electrocardiogram (ECG) sampling of heart rate and a QRS duration was performed at two-minute intervals until demise.

Results

There was no significant difference in lethal doses of propranolol between groups. Comparison of percent change in QRS prolongation and heart rate reduction was performed at 60% of the mean lethal dose in control animals. The percent change in QRS duration was reduced (from ?0.9 to 17.3, p = 0.016) in the intralipid pretreatment group. Attenuation of propranolol-induced bradycardia observed in the lipid emulsion group approached statistical significance (0% vs. 10.3%, p = 0.06).

Interpretation

The results suggest that lipid emulsion may be effective in ameliorating propranolol toxicity in rats. Previous work gives reason to postulate a pharmacokinetic mechanism for this effect. The results represent encouraging exploratory work, and further work is planned to evaluate the role of lipid emulsion therapy in propranolol toxicity.     

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.     

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.     

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 Toxicity after Amitriptyline Overdose in a Patient Deficient in CYP2D6 Activity

Introduction

Amitriptyline and its metabolite, nortriptyline, are metabolized, in part, by CYP2D6, a polymorphic enzyme. About 8% of Caucasians are deficient in CYP2D6 activity.

Case Report

We present the case of a comatose woman who intentionally overdosed on amitriptyline and displayed rising serum total tricyclic antidepressant concentrations for at least 6 days after admission. Serial immunoassay total tricyclic antidepressant concentrations in our patient showed gradual decline beginning day 7, although the patient did not regain normal mental status until day 12. Genotyping revealed the patient to be homozygous for the CYP2D6*4 allele, the most common explanation of CYP2D6 enzymatic deficiency among Caucasians. Patients taking tricyclic antidepressants who are homozygous for CYP2D6*4 demonstrate >3 times concentration–time curve (AUCs) and prolonged elimination half-lives, especially of secondary amines such as nortriptyline.

Discussion

We believe this is the first report describing toxicokinetics after tricyclic antidepressant overdose in a CYP2D6-deficient patient.     

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.     

A Retrospective Study of Clinical Effects of Powdered Caffeine Exposures Reported to Three US Poison Control Centers

Introduction

Anhydrous caffeine, often sold on the Internet as a powdered caffeine product, is sold as “pure caffeine” to be used as an additive to beverages and has also been used as an ingredient in energy supplement products.

Methods

This is a retrospective multiple-poison center chart review of calls regarding powdered caffeine to poison centers covering Oregon, Alaska, Guam, Washington, and Utah between January 1, 2013 and June 30, 2015.

Results

There were 40 calls to three poison centers over 30 months for powdered caffeine exposure. The majority of patients were over age 19 (52.5 %; 21/40) and male (70 %; 28/40). Sixty percent (24/40) of the patients were symptomatic but only 10 % (4/40) required admission; 52.5 % (21/40) of the patient calls were for inadvertent overdose of powdered caffeine; one patient overdosed in a self-harm attempt.

Discussion

Powdered caffeine calls to three poison centers during a 30-month study period were rare, and severe caffeine toxicity due to exposure was found in few patients. The majority of symptoms were reported after an inadvertent powdered caffeine overdose.

Conclusions

An analysis of calls to three poison centers for powdered caffeine found that exposures were uncommon, but did result in toxicity, and highlighted that the lack of clear dosing instructions on product packaging may place patients at risk of inadvertent overdose.

     

Intralipid infusion ameliorates propranolol-induced hypotension in rabbits

Objective

Recent case reports of successful amelioration of lipid-soluble drug toxidromes with Intralipid infusion have prompted interest in the scope of lipid emulsions as antidotal therapy. Propranolol is a highly lipid-soluble, nonselective beta-blocker with additional local-anaesthetic properties. We explored the hypothesis that propranolol toxicity may be similarly attenuated by Intralipid infusion in a rabbit model.

Methods

Twenty sedated, invasively monitored, and mechanically ventilated New Zealand White rabbits underwent propranolol infusion at 4.2 mg/min to a target mean arterial pressure (MAP) of 60% baseline MAP. Animals subsequently received 6 ml/kg 20% Intralipid, or 6 ml/kg 0.9% saline solution over a 4-minute period. Pulse rate and MAP were recorded at 2.5-minute intervals to 15 minutes.

Results

MAP was greatest in the Intralipid group (median 69 mmHg, interquartile range [IQR] 17.5 mmHg Intralipid vs. median 53 mmHg, IQR 12.75 mmHg saline;p = 0.029) at 15 minutes. No difference was observed in first derivative of MAP, or pulse rate between groups.

Conclusions

Propranolol-induced hypotension is ameliorated by Intralipid infusion in this intact rabbit model. The mechanism of action remains to be elucidated.     

Use of neostigmine for the management of drug induced ileus in severe poisonings

Introduction

Effective whole bowel irrigation may be difficult in the presence of drug-induced ileus. Neostigmine, which inhibits the enzymatic degradation of acetylcholine, has been suggested to improve drug-induced ileus. We present two poisoning cases in which neostigmine was used to facilitate gut decontamination complicated by ileus.

Case Reports

A 47-year-old woman, after overdose with sodium valproate, venlafaxine, and ibuprofen, developed ileus that prevented whole bowel irrigation. Neostigmine, 2.5 mg intravenously followed by 1.25 mg three hours later, led to improved bowel transit and successful whole bowel irrigation. A 25-year-old man developed ileus after overdose with venlafaxine, dothiepin, and ethanol. Neostigmine administration led to improved intestinal motility and successful whole bowel irrigation.

Discussion

We demonstrate facilitated gut decontamination temporally associated with administration of neostigmine in two patients judged to have drug-induced ileus following overdose. No significant adverse events related to neostigmine were observed.     

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte l-type Ca²⁺ currents, intracellular Ca²⁺, and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/MS verapamil assays showed that addition of ILE (0.03–5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode’s solution containing 5 μM verapamil recovered l-type Ca²⁺ currents (I_Ca). Recovery was concentration dependent, with significant I_Ca recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on I_Ca in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca²⁺. Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.     

Efficacy and Safety of Fenofibric Acid Co-Administered with Low- or Moderate-Dose Statin in Patients with Mixed Dyslipidemia and Type 2 Diabetes Mellitus

Background

Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus.

Objective

To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population.

Study Design

A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials.

Setting

Multiple clinical research facilities in the US and Canada.

Patients

Patients with mixed dyslipidemia and type 2 diabetes (n= 586).

Intervention

Fenofibric acid (Trilipix®) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor®] 10, 20, or 40 mg; simvastatin [Zocor®] 20, 40, or 80 mg; or atorvastatin [Lipitor®] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin.

Main Outcome Measure

Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events.

Results

Fenofibric acid + low-dose statin resulted in significantly (p<0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (?43.9%) than low-dose statin monotherapy (4.7% and ?18.1%, respectively) and significantly (p<0.001) greater reductions in lowdensity lipoprotein cholesterol (LDL-C) [?34.0%] than fenofibric acid monotherapy (?5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p≤0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (?43.4%) than moderate-dose statin monotherapy (8.7% and ?24.2%, respectively) and significantly (p<0.001) greater reductions in LDL-C (?32.6%) than fenofibric acid monotherapy (?5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments.

Conclusion

Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy.     

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.     

Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion

Rationale

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics.

Objectives

The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior.

Methods

Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1–5 mg/kg), fluoxetine, amitriptyline, or bupropion (10–30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior.

Results

The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST.

Conclusion

These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.     

The Impact of Upper Gastrointestinal Symptoms on Nonadherence to, and Discontinuation of, Low-Dose Acetylsalicylic Acid in Patients with Cardiovascular Risk

Background

While low-dose acetylsalicylic acid (ASA [aspirin]; 75–325 mg) is a mainstay of cardiovascular (CV) protection in patients at high risk of CV events, such protection may be compromised due to poor adherence (or discontinuation) resulting from gastrointestinal (GI) adverse events. To date, however, the link between GI adverse events and nonadherence to, and discontinuation of, low-dose ASA is not well established in the literature.

Objective

The aim of this study was to characterize the real-world impact of upper GI symptoms on low-dose ASA nonadherence and discontinuation in patients with CV risk taking low-dose ASA for CV protection.

Study Design

Multicenter, observational, noninterventional study.

Setting

Primary-care, cardiology, and practice group centers in the US, Canada, and France.

Patients

Subjects aged ≥18 years at risk of, or with confirmed, CV disease, and who had been prescribed or recommended low-dose ASA (75–325 mg daily) by a physician.

Main Outcome Measure

Adherence to low-dose ASA was assessed using 3 months of data prospectively collected using an electronic diary (completed at least three times/day). Adherence was defined as low-dose ASA intake of ≥75% over the 3-month eDiary phase. Discontinuation was defined as no reported low-dose ASA intake for ≥7 continuous days. The odds of daily adherence were calculated using a mixed-model analysis for repeated measures, and a Cox-proportional hazard model was used to assess the association between upper GI symptoms and time to discontinuation of low-dose ASA.

Results

Overall, 340 patients (mean age 50 years; 59% women) participated in the analysis. Most patients (75%) were low-dose ASA naíve at inclusion, and had not experienced upper GI symptoms within the previous 14 days. Among these patients, the onset of upper GI symptoms was rapid; symptoms were reported by 19% of patients on the first day of the study, rising to 46% of patients at the end of the first week. Over the 3-month study period, 18% of patients were nonadherent to low-dose ASA treatment. The occurrence of upper GI symptoms negatively affected low-dose ASA adherence, in both the overall patient population (odds ratio [OR] = 0.84; 95% CI 0.70, 1.0) and among patients who were low-dose ASA naíve at baseline (OR = 0.76; 95% CI 0.57, 1.0). A total of 13% of patients discontinued low-dose ASA therapy. For the overall cohort and for the low-dose ASA-naíve patients at baseline, more than three episodes of upper GI symptoms during the previous week was associated with an increased risk of low-dose ASA discontinuation compared with no episodes of upper GI symptoms during the previous week (hazard ratio [HR] = 2.60; 95% CI 1.00, 6.80, and HR = 7.52; 95% CI 2.57, 22.04, respectively).

Conclusions

Upper GI symptoms can lead to nonadherence to, and discontinuation of, low-dose ASA CV-protective therapy. Patients who initiate low-dose ASA may experience an early onset of upper GI symptoms. (Trial registration number: NCT00681759 [ClinicalTrials.gov Identifier]; AstraZeneca study code: D961FC00004)