Levamisole, a cocaine cutting agent, induces acute and subchronic systemic alterations in Wistar rats.

The use of the anthelmintic levamisole as a cocaine adulterant has been increasing worldwide. Complications caused by this association include systemic vasculitis, agranulocytosis, neutropenia, tissue necrosis, pulmonary hemorrhage, and renal injury. Data about toxicity of levamisole are scarce, therefore the aim of this study was to evaluate the acute and subchronic toxic effects of levamisole in rats. Male Wistar rats received saline or levamisole by intraperitoneal route at the doses of 12, 24 and 36 mg/kg in the acute toxicity test; and at 3, 6 and 12 mg/kg in the subchronic toxicity test. Toxicity was evaluated using behavioral, cognitive, renal, hematological, biochemical and histopathological parameters. Acute administration of levamisole caused behavioral and histopathological alterations. Subchronic administration caused behavioral, cognitive and hematological alterations (p < 0.0001 and p < 0.05, respectively), impairment of liver and kidney functions (p < 0.05), and changes of antioxidant defenses (p ≤ 0.0001). Both administrations produced toxic effects of clinical relevance, which make levamisole a dangerous cutting agent. Furthermore, the knowledge of these effects can contribute to the correct diagnosis and treatment of cocaine dependents with unusual systemic alterations.

Levamisole-a Toxic Adulterant in Illicit Drug Preparations: a Review.

ABSTRACT: Discovered in the 1960s, the common anthelminthic levamisole has seen widespread use in veterinary applications. Its use rapidly expanded thereafter to include human medical treatments for a variety of acute and chronic disorders. Because of reports of severe adverse effects, the US Food and Drug Administration withdrew levamisole's approval for human use in 2000; however, medical options outside the United States and illicit options worldwide allow continued accessibility to levamisole. The compound is rapidly metabolized in the body, with at least 2 known active metabolites. Levamisole has a broad range of immunomodulatory effects, including both stimulatory and inhibitory effects on immune responses. It is generally well tolerated at therapeutic concentrations, although a variety of autoimmune-related adverse effects have been reported, including agranulocytosis, leukopenia, purpura, and visible necrotized skin tissue. Individuals with levamisole-compromised immune systems are more susceptible to infections, including COVID-19. Since the early 2000's, levamisole has been frequently used as an adulterating agent in illicit street drugs, especially cocaine, fentanyl, and heroin. Although its prevalence has varied over time and geographically, levamisole has been detected in up to 79% of the street supply of cocaine at levels up to 74% by weight. Its presence in illicit drug markets also raises concern over the potential for exposure of children and neonates, although this is supported by only limited anecdotal evidence. Levamisole is not currently included in routine drug testing panels, although a variety of confirmatory testing techniques exist across a range of antemortem and postmortem specimen options. Because of its varying presence in illicit drug markets, both the medical and forensic communities need to be aware of levamisole and its potential impact on toxicological investigations.

Facial cutaneous necrosis associated with suspected levamisole toxicity from tainted cocaine abuse.

OBJECTIVE: This study aimed to illustrate the otorhinolaryngologic manifestations of levamisole toxicity and illuminate the features of this diagnosis. METHODS: We describe a case of a known cocaine abuser with suspected levamisole toxicity who developed cutaneous necrosis of the cheeks, earlobes, nose, upper and lower lip, and the midline hard palate. We also review the existing clinical literature about this emerging phenomenon. RESULTS: Levamisole is a common adulterant in cocaine distributed in the United States and has been reported to cause microvascular thrombosis and vasculitis with resultant skin necrosis in cocaine abusers. The distribution of skin findings characteristically involves the cheeks, earlobes, nose, lips, and hard palate and responds variably to cessation of cocaine use. In its most severe cases, immune suppression and/or surgical debridement may be required. CONCLUSION: Levamisole toxicity can frequently involve the ears, nose, and throat tissues. Otorhinolaryngologists should recognize these manifestations to expeditiously diagnose and manage this condition. Failure to do so promptly can lead to complications that may necessitate reconstructive or amputation surgery.

Levamisole Impairs Vascular Function by Blocking α-Adrenergic Receptors and Reducing NO Bioavailability in Rabbit Renal Artery.

Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.

Rheumatic manifestations of cocaine use.

PURPOSE OF REVIEW: Cocaine use is associated with several rheumatic syndromes. This review summarizes these clinical manifestations and highlights recent developments linked to levamisole-adulterated cocaine. RECENT FINDINGS: Cocaine use has been linked to several distinctive syndromes that can be difficult to distinguish from idiopathic rheumatic diseases. These disorders can range in severity from purely cosmetic damage to organ and/or life-threatening disease that includes sinonasal destruction and vasculitis. Many of these illnesses are associated with antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear and atypical perinuclear patterns). With the recent introduction of levamisole as a cocaine adulterant, a newly reported syndrome has emerged that is associated with neutropenia, retiform purpura with cutaneous necrosis and autoantibodies consisting of high-titre perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) with specificities for 'atypical' antigens. SUMMARY: Cocaine use is associated with clinical syndromes that closely mimic other primary rheumatic diseases. Given the high prevalence of cocaine use and its adulteration with levamisole, clinicians should be familiar with these rheumatic manifestations in order to avoid misdiagnosis and unnecessary treatment with potentially toxic therapies.

Levamisole toxicity mimicking autoimmune disease.

BACKGROUND: Levamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole-tainted cocaine have been widely described. A vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment. OBJECTIVE: We hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management. METHODS: This was a case series. RESULTS: Six patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy. LIMITATIONS: This observational study is limited by sample size. CONCLUSIONS: Patients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity but also other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides.

Deleterious effects of levamisole, a cocaine adulterant, in rabbit aorta.

Levamisole, a veterinary anthelmintic drug, is one of the most widely used and dangerous cocaine adulterants. Like cocaine, levamisole acutely blocks noradrenaline reuptake but with much less potency, although its vascular effects are not well known. In this study, we evaluated the vascular effects of levamisole and cocaine in rabbit aortic rings used for isometric recording of tension in organ baths and protein expression by western blot. Our results indicated that levamisole (10-5-10-3 M) induced a concentration-dependent relaxation in rings precontracted with noradrenaline (10-7-3 × 10-7 M). Furthermore, it reduced the contractile response to phenylephrine (10-9-3 × 10-5 M) that was not modified by cocaine (10-5-10-4 M), and reduced α1-adrenergic receptor expression. Levamisole (10-6-10-4 M) produced a potentiation of the electrical field stimulation that was not further enhanced by the combination of both drugs. However, high concentrations of levamisole (10-3 M) abolished adrenergic neurotransmission whether administered alone or with cocaine (10-4 M). In addition, levamisole (10-5-10-3 M) also decreased endothelium-dependent relaxation to acetylcholine that was not further impaired by cocaine (10-4 M), and that was partially reversed by superoxide dismutase (SOD, 200 U/ml). These results demonstrate that levamisole has a dual effect on the adrenergic system, and its effects are independent of the presence of cocaine. At lower concentrations, it enhances the contractile sympathetic response by blocking presynaptic α2-adrenergic receptors, while at high concentrations, the effect of the antagonism of α1-adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress.

Necrosis of ears after use of cocaine probably adulterated with levamisole.

BACKGROUND/AIMS: Levamisole is an anthelminthic drug with immunomodulatory properties that has been found to be an adulterant of cocaine in the last 2 years. It was present at least in 70% of tainted cocaine in the U.S.A. in 2009. METHODS: We present the case of a 40-year-old patient with a history of weekend cocaine use who consulted for bilateral necrotic lesions in the ears that had appeared 3 days after the last use. RESULTS: Levamisole causes a typical clinical picture characterized by bilateral necrosis of the ears, positive perinuclear antineutrophil cytoplasmic antibodies and laboratory findings of antiphospholipid syndrome, such as anticardiolipin antibodies and/or lupus anticoagulant. CONCLUSION: Dermatologists should be aware of this new entity, which is likely to be more and more frequent due to the increasing use of cocaine. Here we describe a clinical case that is likely to be secondary to levamisole-tainted cocaine and review the literature.

A novel case of ocular cicatricial pemphigoid induced by levamisole-adulterated cocaine.

AIM: To report a case of ocular cicatricial pemphigoid caused by levamisole-adulterated cocaine. METHODS: Case report. RESULTS: A 54-year-old woman with multi-systemic levamisole-induced vasculitis which triggered bilateral cicatrizing conjunctivitis refractory to conventional immunosuppressants due to continued cocaine misuse. CONCLUSION: Levamisole-induced vasculitis is a significant public health issue due to its popularity as an adulterant to cocaine. Our report suggests that levamisole caused vasculitis and ocular cicatricial pemphigoid in this case. Ocular manifestation of this syndrome is rare.

Specific collagens maintain the cuticle permeability barrier in Caenorhabditis elegans.

Collagen-enriched cuticle forms the outermost layer of skin in nematode Caenorhabditis elegans. The nematode's genome encodes 177 collagens, but little is known about their role in maintaining the structure or barrier function of the cuticle. In this study, we found six permeability determining (PD) collagens. Loss of any of these PD collagens-DPY-2, DPY-3, DPY-7, DPY-8, DPY-9, and DPY-10-led to enhanced susceptibility of nematodes to paraquat (PQ) and antihelminthic drugs- levamisole and ivermectin. Upon exposure to PQ, PD collagen mutants accumulated more PQ and incurred more damage and death despite the robust activation of antioxidant machinery. We find that BLMP-1, a zinc finger transcription factor, maintains the barrier function of the cuticle by regulating the expression of PD collagens. We show that the permeability barrier maintained by PD collagens acts in parallel to FOXO transcription factor DAF-16 to enhance survival of insulin-like receptor mutant, daf-2. In all, this study shows that PD collagens regulate cuticle permeability by maintaining the structure of C. elegans cuticle and thus provide protection against exogenous toxins.

Cocaine-induced multifocal leukoencephalopathy mimicking Balo's concentric sclerosis: A 2-year follow-up with serial imaging of a single patient.

Cocaine abuse may cause stroke, metabolic or multifocal inflammatory leukoencephalopathy. We described a patient with cocaine abuse who presented with Balo's type acute multifocal leukoencephalopathy. Magnetic Resonance Imaging (MRI) of the brain showed onion like patchy concentric ring enhancement on T1-weighted MRI with gadolinium. Balo's Concentric Sclerosis like radiological findings related to cocaine has not been reported. Levamisole is now frequently used as an ingredient in cocaine and may cause leukoencephalopathy. It is recommended to check urine levamisole levels in patients with cocaine-induced leukoencephalopathy with or without mimicking Balo's Concentric Sclerosis. On the other hand, it is also possible that the cocaine use was coincidental and this was a demyelinating case arising de novo in patient who uses cocaine.

Unexpected Complication of Cocaine-Associated Anti-Neutrophil Cytoplasmic Antibody Vasculitis Related to Persistent In-Hospital Cocaine Use.

INTRODUCTION: Levamisole-adulterated cocaine has been implicated in anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. We present a case of spontaneous intraperitoneal hemorrhage, an unexpectedly severe complication of cocaine-related ANCA vasculitis, developing late during hospitalization. CASE REPORT: An adult male with a history of hepatitis C, distant cocaine use, and limited health care presented to a local emergency department (ED) with volume overload, renal failure, hyperkalemia and non-anion gap metabolic acidosis. An extensive workup ensued, followed by pulse-dose methylprednisolone and plasma exchange for ANCA vasculitis with crescentic glomerulonephritis. Tachycardia and hypertension persisted throughout hospitalization despite treatment. On hospital day (HD) 13, his abdomen became distended and tender. Mental status and blood pressure declined, and he was emergently intubated. Paracentesis revealed frank blood; hemoglobin declined from 10.6 to 4.6 g/dL during 10 hours. Laparotomy revealed 3.5 L of intraperitoneal blood and a bleeding omental vessel. Histopathology revealed necrotic aneurysmal dilatation diagnostic of systemic vasculitis. Urine cocaine metabolite was positive on HD #13, consistent with the patient's report of in-hospital cocaine use. He was discharged on HD #28 without further complications with plans for outpatient hemodialysis. DISCUSSION: ANCA vasculitis is widely reported following levamisole-adulterated cocaine use. Catastrophic in-hospital hemorrhage due to ANCA vasculitis and vascular necrosis, though previously unreported, may occur with ongoing cocaine use.

Teratogenic study of phenobarbital and levamisole on mouse fetus liver tissue using biospectroscopy.

Biospectroscopic investigations have attracted attention of both the clinicians and basic sciences researchers in recent years. Scientists are discovering new areas for FTIR biospectroscopy applications in medicine. The aim of this study was to measure the possibility of FTIR-MSP application for the recognition and detection of fetus abnormalities after exposure of pregnant mouse to phenobarbital (PB) and levamisole (LEV) alone or in combination. PB is one of the most widely used antiepileptic drugs (AEDs), with sedative and hypnotic effects. When used by pregnant women, it is known to be a teratogenic agent. LEV is an antihelminthic drug with some applications in immune-deficiency as well as colon cancer therapy. Four groups of ten pregnant mice were selected for the experiments as follows: one control group received only standard diet, one group was injected with 120mg/kg of BP, one group was injected with 10mg/kg of LEV, and the last group was treated simultaneously with both BP and LEV at the above mentioned doses. Drugs administration was performed on gestation day 9 and fetuses were dissected on pregnancy day 15. Each dissected fetus was fixed, dehydrated and embedded in paraffin. Sections of liver (10µm) were prepared from control and treated groups by microtome and deparaffinized with xylene. The spectra were taken by FTIR-MSP in the region of 4000-400cm(-1). All the spectra were normalized based on amide II band (1545cm(-1)) after baseline correction of the entire spectrum, followed by classification using PCA, ANN and SVM. Both morphological and spectral changes were shown in the treated fetuses as compared to the fetuses in the control group. While cleft palate and C-R elongation were seen in PB injected fetuses, developmental retardation was mostly seen in the LEV injected group. Biospectroscopy revealed that both drugs mainly affected the cellular lipids and proteins, with LEV causing more changes in amide I and lipid regions than PB. Application of PCA, ANN and SVM methods were able to successfully classify these FTIR spectroscopic data and discriminate between control and treated groups of fetuses, making it a new potential tool for drugs teratogenic investigations.

[Thrombotic vasculopathy probably associated with cocaine contaminated with levamisole: report of 2 cases]. / Vasculopatía trombótica por cocaína probablemente adulterada con levamisol: reporte de 2 casos.

The vasculities are complex diseases. Their cutaneous manifestations are very important and often mirror several pathologies. Cocaine use has been related to both, vasculitis and thrombotic vasculopathy and pseudovasculitis. A new syndrome has been described in association with its adulteration with levamisole. It can be very serious, leading patients to death. This is relevant as levamisole-adultered cocaine seems to be increasingly offered to consumers. Our goal is to report the first two cases in Mexico, which faces an important raise in cocaine use, emphasizing that a high suspicion based on certain characteristics allows for early recognition and adequate treatment.

Las vasculitis son enfermedades complejas con manifestaciones cutáneas importantes que pueden traducir diversas patologías. El uso de cocaína está relacionado con casos tanto de vasculitis y vasculopatía trombótica, como de pseudovasculitis. Recientemente se ha descrito una condición peculiar asociada a su forma adulterada con levamisol, la cual puede ser incluso mortal, y cuya frecuencia va en aumento. Nuestro objetivo es reportar los primeros dos casos de alta sospecha en México, que enfrenta un incremento en el consumo de cocaína, enfatizando en que ciertas características y la realización de determinados estudios permiten la identificación temprana y el tratamiento adecuado de esta condición.

Susac-like syndrome in a chronic cocaine abuser: could levamisole play a role?

INTRODUCTION: Toxic leukoencephalopathy is a possible but rare complication of chronic cocaine abuse. The role of adulterants, mainly levamisole, is still debated. CASE REPORT: We describe an atypical case of fatal leukoencephalopathy mimicking Susac syndrome in a 22-year-old man who was chronically abusing cannabis and cocaine. Exposure to levamisole as adulterant to cocaine was proven by hair analysis. Despite cessation of exposure to cocaine and aggressive immunosuppressive therapy, the patient remained in a minimally conscious state until death. DISCUSSION: Susac syndrome is a rare entity, and its etiology is not yet fully elucidated. The toxic etiologies have been poorly investigated to date. Further observations are required to determine if cocaine and/or adulterants might play a significant role.

Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer.

PURPOSE: To determine the maximum tolerable dose (MTD) and activity of levamisole administered concurrently with 5-fluorouracil (5-FU) in a standard 5-day course. To determine the pharmacokinetics of levamisole during the course of treatment. PATIENTS AND METHODS: Levamisole was administered to 38 patients orally three times a day for 5 days concurrently with a course of 5-FU administered daily by rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who received escalating doses of levamisole. The activity of the combination was evaluated in 18 patients who received levamisole at the MTD with 5-FU. The pharmacokinetics of levamisole were characterized in ten patients at the MTD level. RESULTS: Intractable vomiting, confusion and vertigo were the major dose-limiting toxicities. The MTD of oral levamisole was 100 mg/m2 administered three times a day concurrently with 450 mg/m2 per day intravenous 5-FU for 5 consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18 patients with measurable disease at the MTD. Peak plasma concentrations of 1 microg/ml (range 0.6-1.3 microg/ml) were achieved 90 min (range 60-360 min) after an oral dose of 100 mg/m2 levamisole with a 3.5-fold accumulation noted following 4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were about 5% of parent drug. Little parent drug (2-5%) was detected in urine. CONCLUSIONS: Levamisole may be administered safely with 5-FU at doses which are up to four to five times greater than those presently given in conventional regimens. The recommended dose of levamisole combined with 5-FU for future research protocols is 75 mg/m2 t.i.d for 5 days.

Induction and exacerbation of hyaline droplet formation in the proximal tubular cells of the kidneys from male rats receiving a variety of pharmacological agents.

Kidneys from male and female Wistar rats dosed with 1 of 3 chemically unrelated pharmacological agents, a pyrazoline BW540C, a naphthoquinone BW58C and the levoisomer of tetramisole, levamisole or the light hydrocarbon Decalin, were examined by light and electron microscopy. Paraffin histology showed that all 4 agents induced and exacerbated hyaline droplet accumulation in the renal proximal tubular cells of the male rats. Resin histology at both the light and electron microscope level, along with cytochemical procedures for acid phosphatase and the protein 'alpha 2U globulin', helped further in the characterisation of these cytoplasmic inclusions. These techniques confirmed that the accumulation of hyaline droplets seen by paraffin histology represented an increase in the size and number of secondary lysosomes which have been shown to be involved in protein uptake and metabolism. Time course studies showed that increased numbers of small dense lysosomes appear first, which then increase in size, presumably by fusion. Crystalloid bodies form in these large lysosomes eventually giving rise to rectilinear bodies. The accumulation of these protein laden secondary lysosomes took place primarily in the cells of the S1 and S2 segments of the proximal tubules. In extreme cases of lysosomal accumulation however, loading of the S3 segments was noted. In tubules where cellular inclusion loading was heavy, there was evidence of increased cell turnover. The kidneys of female rats dosed with any one of the 4 agents appeared normal.