A fatal case after an intravenous injection of levamisole.

Levamisole is a drug originally prescribed as an antihelmintic. Because of the occurrence of severe cases of agranulocytosis and leukoencephalitis it was removed from the French market in 1998 for human use, while it remains available for veterinary use. Nowadays in France its only use in humans is regulated by authorization for temporary use for its immunomodulatory properties in the treatment of nephritic syndrome.A 52-year-old man was found dead at his farm. Injection points were observed on his arm and a syringe containing a dark orange-brown liquid was found near the body. At his home, the discovery of a letter highlighted suicidal intent. Analysis of the aforementioned liquid, peripheral blood and urine confirmed the unique presence of levamisole. The femoral blood concentration of levamisole was of 25 mg/L whereas the femoral blood concentrations reported in cases of fatalities after cocaine use do not exceed 0.0056 mg/L. In humans, levamisole can be detected in biological samples after cocaine use as this drug is also an adulterant and one of its metabolites (aminorex) seems to have amphetamine-like properties. In this case, the man consumed levamisole from time to time for its stimulant and strengthening effects.Cases of fatal poisoning using levamisole are very rare and poorly documented, which makes the interpretation of postmortem blood levamisole concentration difficult.

Suspected levamisole intoxication in calves.

CASE HISTORY: A group of 32 Friesian and four Hereford calves, 3-4 months old with body weights between 100-120 kg, were purchased from a weaner sale. On arrival at the property the Hereford calves were treated with a combination anthelmintic containing 2 g/L abamectin and 80 g/L levamisole hydrochloride. Shortly afterwards they developed tremors and frothing from the mouth, and two died overnight. The Friesian calves were treated with the same anthelmintic on the following day, when some showed hypersalivation and frothing from the mouth. CLINICAL FINDINGS: Examination of the three most severely affected Friesian calves revealed severe nicotinic-type symptoms including hypersalivation, frothing from the mouth, muscle tremors, recumbency, rapid respiration, hyperaesthesia, and central nervous system depression. Other calves showed mild to moderate signs of intoxication including restlessness, tail switching, salivation, tremors, frequent defaecation, mild colic and jaw chomping. Two calves died shortly afterwards. An adverse drug event investigation revealed that the formulation and quality of the anthelmintic was within the correct specification, and that the drench gun was functioning correctly. DIAGNOSIS: Suspected levamisole intoxication due to a combination of possible overdosing, dehydration, and stress caused by transportation and prolonged yarding. CLINICAL RELEVANCE: Susceptibility to levamisole toxicity in New Zealand calves can be increased if factors like dehydration or stress are present. Levamisole has a narrow margin of safety, and overdosing in calves can easily occur if the dose rate is not based on their actual weight or health status.

Immune-mediated agranulocytosis caused by the cocaine adulterant levamisole: a case for reactive metabolite(s) involvement.

The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.

Hyponatremia associated with levamisole-adulterated cocaine use in emergency department patients.

An increasing percentage of US cocaine has been adulterated with levamisole, an immunomodulator associated with agranulocytosis. We describe 3 emergency department patients with hyponatremia and cocaine use. Despite extensive evaluation, the cause of the hyponatremia was not elucidated but resolved during hospitalization. Because hyponatremia has not previously been associated with cocaine, we sought to uncover a plausible explanation that might be contributing to this new finding. Levamisole was detected in all 3 patients. Although we are unable to confirm causality, we propose that levamisole-adulterated cocaine may have contributed to the hyponatremia described in these patients.

Pulmonary-renal syndrome secondary to cocaine-levamisole-induced vasculitis: A case report. / Síndrome pulmón-riñón secundario a vasculitis por cocaína/levamisol: reporte de caso.

Pulmonary-renal syndrome has rarely been reported as the clinical presentation of vasculitis caused by the consumption of cocaine adulterated with levamisole. We report the case of a patient in whom we detected the clinical manifestations and indicate the difficulties that arose in relation to the diagnostic and therapeutic approach.

Surgical Management of Levamisole-Adulterated Cocaine Induced Soft Tissue Necrosis: Case Study and Treatment Algorithm.

Levamisole is an increasingly common cocaine adulterant that can cause severe and rapid onset cutaneous vasculitis in humans. While most cases may be managed conservatively, we describe a series of patients in whom the extent of skin and soft tissue necrosis mandated surgical intervention. A retrospective review of all patients admitted to one of two regional burn centers between 2006 and 2016 for soft tissue necrosis after exposure to levamisole-adulterated cocaine was included in our study. Ten patients, majority female (9/10) with an average age of 43.4 years (range 31-57), were included. Cocaine usage before presentation averaged 6 days (range 1-14). Presenting complaints consisted of arthralgia (5/10), fever (7/10), and purpuric lesions (10/10). Average TBSA involvement was 23.5% (range 4-70). Immunological testing revealed perinuclear antineutrophil cytoplasmic antibody (pANCA+) in 8 of 10 and cytoplasmic antineutrophil cytoplasmic antibody (cANCA+) in 4 of 8 patients. Operative intervention occurred by postadmission day 11.6 (range 3-30). The mean number of operations required was 3 (range 2-6); length of stay averaged 46.8 days (range 14-120); and survival to discharge was 100% (10/10). To our knowledge, this is the largest case study detailing the surgical management of levamisole-associated skin necrosis. Additionally, we describe the most extensive case of this disease process at 70% TBSA involvement. Based on our experience, we recommend waiting for purpuric rash resolution and soft tissue necrosis to be fully demarcated before fascial debridement and then staged skin grafting with allograft followed by autograft.

A Case Report on Suspected Levamisole-Induced Pseudovasculitis.

INTRODUCTION: Levamisole-induced pseudovasculitis should be considered in patients with inconsistent anti-neutrophil cytoplasmic antibodies (ANCA) pattern and history of cocaine use. CASE PRESENTATION: A 50-year-old man presented to the emergency department with symptoms of bilateral pulmonary emboli. His hospital course was complicated by multiple end organ failure, which improved dramatically with prednisone. Although he was diagnosed previously with granulomatosis with polyangiitis due to positive proteinase 3 (PR3), myeloperoxidase (MPO), perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) and cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA) markers, his longstanding cocaine use and history of skin ulcers, thrombotic events, and febrile illnesses suggested a diagnosis of levamisole-induced pseudovasculitis instead. DISCUSSION: Differentiating between vasculitides can be challenging due to similar clinical and laboratory findings. To differentiate the two, biopsies should be obtained. The absence of granulomas or leukocytoclasia, and the presence of vasculopathic purpura, should guide clinicians toward pseudovasculitis. CONCLUSION: It is important to maintain a high index of suspicion for pseudovasculitis because long-term corticosteroid use to treat granulomatosis with polyangiitis can lead to detrimental effects.

Levamisole adulterated cocaine and pulmonary vasculitis: Presentation of two lethal cases and brief literature review.

The first case reports of levamisole-related disease in cocaine users were published in 2010, although levamisole adulteration of cocaine was first recognized several years earlier. Currently, more than 70% of street cocaine seizures, in the US and the EU, contain levamisole, which could potentially be converted to aminorex, though the reasons for this practice still remain obscure. Here we report two fatal cases of isolated pulmonary vasculitis in abusers of levamisole-adulterated cocaine, where a complete autopsy, full toxicological analysis by gas chromatography-mass spectrometry (GC-MS) using a previously published method of Karch et al. and histological examination were performed. A control group composed of 11 cases of cocaine related deaths, where the presence of levamisole was excluded in blood, urine and hair, was used. Recent literature on the human pharmacokinetics of levamisole and aminorex is also reviewed. The toxicological analysis revealed positive qualitative and quantitative results for cocaine, benzoylecgonine and levamisole in both cases. In case 1 levamisole was found at the concentration of 13.5 and 61.3mg/L in blood and urine respectively, whereas in case 2 at 17.9 and 70.2mg/L. The histological examination highlighted in case 1 in heart samples microscopic evidence of the typical remodeling changes associated with chronic stimulant abuse, whereas lungs showed numerous lymphocytes surrounding and infiltrating the wall of small pulmonary vessels and a perivascular fibrosis with transforming fibroblasts. In case 2, the myocardial samples showed wide fields of myocardial necrosis characterized by hypercontraction of the myocytes with thickened Z-lines and short sarcomeres, whereas lung samples showed a significant intimal thickening of arteriole walls and lymphocytic infiltration of the wall and edema. Moreover, there were also numerous perivascular lymphocytic infiltrates. Although the pathological cardiac findings have allowed us to establish the cause of death in both cases, the presence of pulmonary vasculitis in the lungs represent a further complication. If the disease had progressed to hemorrhage, it certainly would have been a contributory cause of death. The two cases here reported allow us to advance a hypothesis about the possible correlation between the consumption of levamisole adulterated cocaine and pulmonary vasculitis and the comparison of these findings with the control group support this hypothesis. However, this hypothesis is still weak, taking into consideration the fact that pulmonary vasculitis was detected in 2 cases only, making it impossible to exclude a different etiology of this finding. Only through careful histological lung examinations of further cases of fatalities, related to levamisole adulterated cocaine, can this hypothesis be confirmed or refuted.

Levamisole-adulterated cocaine: Two fatal case reports and evaluation of possible cocaine toxicity potentiation.

Levamisole has been identified as a cocaine adulterant in the United States since 2002. Although there is a variation in the percentage of levamisole in cocaine samples between European countries, measurement of levamisole in human samples of cocaine users has become increasingly important. To our best knowledge, only five deaths are reported (one twice) as a result of complications secondary to levamisole-tainted cocaine and none of these cases reports the post-mortem levamisole concentration. In this article, we present the post-mortem levamisole concentrations in fluids and tissues in two young cocaine users, dead after levamisole-adulterated cocaine intake. With the dearth of levamisole reported concentrations in literature, this particular report is of interest to the forensic toxicological and pathological communities. This article aims to be a supplementary alert to aware the risk that may occur using levamisole-adulterated cocaine and an incentive to publication of toxicity reports and new researches involving the combination of levamisole and cocaine.

Levamisole-Adulterated Cocaine Toxicity: Would You Recognize It?

Adulteration of cocaine with levamisole is common and can induce serious medical complications. Levamisole is an antihelminthic agent originally approved as an immunomodulator in the treatment of autoimmune disorders and as a chemotherapy adjunct. It was withdrawn from the US market in 2000 but is available in veterinary medicine. Cocaine-using patients may present with nonspecific constitutional symptoms, cutaneous eruptions, leukopenia, vasculitis, and organ damage. Skin manifestations may include severe necrosis, especially of the ear lobes. Here, a case of levamisole toxicity is presented and treatment options are discussed.

Purpura and leukopenia in a cocaine user.

A previously healthy 42-year-old woman presented to the emergency department (ED) for arthralgias and painful lesions on her ears, feet, and knee (Figures 1 and 2) that had developed over the last month. She had no significant past medical history and was not taking any prescribed medications. The rash was purpuric with violaceous borders and hemorrhagic bullae. While she had mild pain with movement, her joint examination was otherwise normal and without signs of infection. ED laboratory testing revealed leukopenia (2500/mm(3)) and cocaine metabolites in her urine.

Levamisole-Contaminated Cocaine Use in HIV-Infected and Uninfected Unstably Housed Women.

A growing number of case reports cite serious health complications linked to the cocaine adulterant, levamisole and women are disproportionately affected; however, the clinical effects are not well established. Between April and October of 2010, we conducted a cross-sectional study among 222 homeless and unstably housed women (116 human immunodeficiency virus [HIV]-infected and 106 HIV-uninfected). Immune markers and behavioral factors were compared in separate models by cocaine and levamisole exposure. Overall, 63% of participants were toxicology positive for cocaine/benzoylecgonine, 85% of whom also tested positive for levamisole. Differences in immune markers did not reach levels of significance among HIV-uninfected persons. Compared to HIV-infected persons who were negative for both cocaine and levamisole, the adjusted odds of low white blood cell count were significantly higher among HIV-infected persons positive for both (p = 0.03), but not for those positive for cocaine only. Neutrophil count and HIV viral load did not differ by cocaine and levamisole status among HIV-infected persons. In a separate model, the adjusted odds of testing positive for levamisole were higher among African American women compared to Caucasian and Asian women (p = 0.02). In the context of high levamisole prevalence, results suggest that decreased immune function as a result of levamisole exposure occurs mainly in individuals who are already immune compromised (e.g., HIV-positive), and race/ethnicity appears to be an important factor in understanding levamisole exposure among cocaine-using women. While larger and geographically diverse studies are needed to elucidate these initial findings, results suggest that levamisole may be one mechanism of immune dysfunction in HIV-infected cocaine-using women.

Drug interactions of levamisole with pyrantel tartrate and dichlorvos in pigs.

The LD50 from subcutaneous administration of levamisole in castrated male pigs (15 to 25 kg) was established as 39.8 mg/kg. Oral administration of dichlorvos (60 mg/kg, 3 times the anthelmintic dosage level) 1 hour before levamisole injection lowered blood cholinesterase activity to approximately 60% that of the controls, but did not change the LD50 of levamisole. In contrast, oral administration of pyrantel tartrate (25 mg/kg, an anthelmintic dosage level) did not lower blood cholinesterase activity, but rather, increased the toxicity by lowering the LD50 of levamisole from 39.8 mg/kg to 27.5 mg/kg. The data supported the hypothesis that levamisole toxicity was enhanced by nicotine-like compounds (ie, pyrantel), but was not affected by organophosphates (ie, dichlorvos).

Levamisole toxicosis in a dog.

A single oral dose of levamisole hydrochloride given at the rate of 12 mg/kg was believed responsible for bradycardia, tachypnea, hypothermia, cerebrocortical depression, and diarrhea in a dog. Supportive treatment and symptomatic treatment for the bradycardia were required for 4 days. In addition to these previously reported abnormalities associated with levamisole toxicosis, cerebrocortical depression and multiple foci of irritation were characterized by electroencephalography.

The effects of levamisole poisoning on the haematological and biochemical parameters in dogs.

This study was designed to evaluate possible organ and system disorders associated with experimentally induced levamisole poisoning in dogs. For this purpose, twelve clinically healthy dogs of different ages, sexes and breeds were used. They were divided into two equal groups (Group A and Group B) and given levamisole orally at a dose of 25 mg/kg of body weight daily for three days. The dogs in Group B were also injected with atropin sulphate (0.04 mg/kg of body weight) subcutaneously (sc) 1 hour after each administration of levamisole. Routine clinical examinations were made and some haematological, biochemical and blood gas parameters were established at various times after administration of levamisole. The dogs in Group A developed severe neurological signs, gastric haemorrhage, bloody vomiting, colic, anaemia and four dogs died. In Group B these signs were mild and only one dog died. Levamisole poisoning was characterised by a significant reduction in the total number of red blood cells (RBCs), concentration of haemoglobin (Hb) and packed cell volume (PCV), and by anaemia. Peripheral blood pH, actual bicarbonate of plasma (HCO3), actual base excess (BE), partial pressure of oxygen (pO2) and saturated oxygen (O2SAT) increased in both groups of animals and these dogs developed metabolic alkalosis 48 hours after the first administration of levamisole. The results of the study also show that levamisole poisoning in dogs causes a significant increase in the activity of serum alanine aminotransferase (ALT) and of alkaline phosphatase (AP) and in the concentration of urea in both Group A and Group B. In the study, atropin sulphate reduced the severity of the clinical signs and the number of deaths, but it was not alone sufficient to remedy levamisole poisoning in dogs.