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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 α 1 -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., (© 2024. The Author(s).)

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 α 1 -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 α 2 -adrenergic receptors, while at high concentrations, the effect of the antagonism of α 1 -adrenergic receptor prevails. In addition, levamisole induces endothelial dysfunction by reducing NO bioavailability, and this effect could be in part mediated by oxidative stress., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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.

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., (© The Author(s) 2014.)

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.

The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue-like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCA-associated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves., (Copyright © 2014 by the American Society of Nephrology.)

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., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Cocaine-induced leukoencephalopathy is a rare neurological complication. It is most likely related to the substances used to adulterate the cocaine. Levamisole is one of the most common adulterants of cocaine and causes reversible leukoencephalopathy. Patients display severe neurological symptoms that resolve at termination of the exposure. MRI shows diffuse white matter involvement with sparing of the U fibers, without brain stem or cerebellar involvement. We describe the case of a woman with three neurologic episodes and remitting and recurrent brain white matter lesions.

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.

This paper describes the fabrication and use of a microfluidic device for performing whole-animal chemical screens using non-invasive electrophysiological readouts of neuromuscular function in the nematode worm, C. elegans. The device consists of an array of microchannels to which electrodes are attached to form recording modules capable of detecting the electrical activity of the pharynx, a heart-like neuromuscular organ involved in feeding. The array is coupled to a tree-like arrangement of distribution channels that automatically delivers one nematode to each recording module. The same channels are then used to perfuse the recording modules with test solutions while recording the electropharyngeogram (EPG) from each worm with sufficient sensitivity to detect each pharyngeal contraction. The device accurately reported the acute effects of known anthelmintics (anti-nematode drugs) and also correctly distinguished a specific drug-resistant mutant strain of C. elegans from wild type. The approach described here is readily adaptable to parasitic species for the identification of novel anthelmintics. It is also applicable in toxicology and drug discovery programs for human metabolic and degenerative diseases for which C. elegans is used as a model.

In order to describe the clinical and serologic features of a cutaneous vasculitis due to cocaine contaminated with the adulterant levamisole, we report four new cases of this syndrome along with 12 previously reported cases identified through a PubMed Literature search (1964 to March 2011). Of the 16 patients described, the average age was 43, with a female predominance (81% of patients). Over half of patients had involvement of the earlobes, and the rash frequently affected the extremities in a "retiform" pattern. Leukopenia or neutropenia was reported in 56% of patients. Ninety-three percent were anti-neutrophil cytoplasmic antibody positive, and 63% tested positive for anti-phospholipid antibodies. The predominant pattern seen on histopathological examination of the skin was small vessel vasculitis and/or a thrombotic vasculopathy. Treatment in these patients varied widely, with several patients showing improvement or resolution of the rash without specific therapy following cessation of illicit drug use. This new cutaneous vasculitis syndrome can be recognized by its characteristic rash and skin pathology, together with leukopenia and autoantibody production. Certain clinical features can be attributed to the adulterant levamisole, though cocaine as well may play a role in its pathogenesis.

Based on the best available data, approximately 2.1 million Americans use illicit cocaine each month; for the last several months, 30% of that cocaine has been "cut" with a veterinary pharmaceutical, levamisole. Levamisole can cause agranulocytosis, leaving patients susceptible to fulminate and opportunistic infections and also can cause a debilitating cutaneous necrotizing vasculitis. In this manuscript, we describe a case and provide an image of levamisole-induced necrotizing vasculitis of the ears., (© American College of Medical Toxicology 2010)

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., (Copyright © 2011 S. Karger AG, Basel.)

A two year carcinogenicity study of anthelmintic drug levamisole (LV) was performed using 50 male and 50 female F344 rats at dietary drug concentrations of 0, 60, or 300 ppm. The daily intakes of LV were calculated to be 2.6, 12.9 mg/kg b.w./day for males and 2.9, 14.1mg/kg b.w./day for females, respectively. No significant differences in general condition and survival rate (82%, 74%, 80% in males and 84%, 84%, 84% in females, respectively) were observed. In the 300 ppm group, suppression of body weight gain was observed from the onset of treatment and reduction in final body weights was 6% in males and 11% in females. Significant increases in the absolute and/or relative weights of the lungs, heart, spleen, liver, kidneys, and adrenals were observed in males and/or females treated with 300 ppm. Some of high incidences neoplasms were observed, and there were also tendencies to increase for mammary gland fibroma and thoracic/abdominal cavity mesothelioma in males. However, there were no significant inter-group differences in incidences, histopathological types or differences compared with historical control data. Thus, it was concluded that LV was not carcinogenic to male and female F344 rats under the experimental conditions., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Levamisole produces seizures in man and is also known to activate the neuronal nicotinic acetylcholine receptors, which are further known to elicit seizure activity. Therefore, the present study has been designed to investigate the role of nicotinic acetylcholine receptor activation in the seizure-inducing effect of levamisole. Levamisole, at the doses of 5, 10 and 20 mg kg(-1), i.p. were used to elicit seizures in mice. Seizures were assessed in terms of the onset time of Straub's tail phenomenon, jerky movements of whole body and convulsions. Additionally, an isobolographic design was used to examine the interaction of systemically administered levamisole and nicotine. Prior administration of 2, 2, 6, 6-tetramethylpiperidin-4-yl heptanoate (TMPH), a selective inhibitor of neuronal nicotinic acetylcholine receptors, markedly attenuated the seizure-inducing effect of levamisole. Moreover, administration of TMPH per se did not produce any behavioural changes in mice. Furthermore, nicotine was observed exert a synergistic interaction with levamisole. Therefore, it may be suggested that levamisole-induced reduction in seizure threshold might be ascribed to the activation of a neuronal nicotinic acetylcholine receptor activation-linked mechanism.

Pesticide resistance is a major concern in natural populations and a model trait to study adaptation. Despite the importance of this trait, the dynamics of its evolution and of its ecological consequences remain largely unstudied. To fill this gap, we performed experimental evolution with replicated populations of Caenorhabditis elegans exposed to the pesticide Levamisole during 20 generations. Exposure to Levamisole resulted in decreased survival, fecundity and male frequency, which declined from 30% to zero. This was not due to differential susceptibility of males. Rather, the drug affected mobility, resulting in fewer encounters, probably leading to reduced outcrossing rates. Adaptation, i.e., increased survival and fecundity, occurred within 10 and 20 generations, respectively. Male frequency also increased by generation 20. Adaptation costs were undetected in the ancestral environment and in presence of Ivermectin, another widely-used pesticide with an opposite physiological effect. Our results demonstrate that pesticide resistance can evolve at an extremely rapid pace. Furthermore, we unravel the effects of behaviour on life-history traits and test the environmental dependence of adaptation costs. This study establishes experimental evolution as a powerful tool to tackle pesticide resistance, and paves the way to further investigations manipulating environmental and/or genetic factors underlying adaptation to pesticides.

The causes of population cycles fascinate and perplex ecologist. Most work have focused on single processes, whether extrinsic or intrinsic, more rarely on how different processes might interact to cause or mould the unstable population dynamics. In red grouse (Lagopus lagopus scoticus), two causal mechanisms have been supported: territorial behaviour (changes in autumn aggressiveness) and parasites (parasite induced reduction in fecundity). Here, we report on how these two regulatory processes might interact, by testing whether the parasite suspected to cause the grouse cycles, the nematode Trichostrongylus tenuis, reduces male autumn territorial behaviour. We either treated males with an anthelmintic, to remove parasites (dosed or D-males), or challenged them with infective T. tenuis larvae, to increase parasite intensity (challenged or C-males). We first show that dosing was effective in removing T. tenuis parasites, while parasite intensities increased in challenged birds during the autumn. Because old males initially had more parasites than young males, the treatments generated greater differences in parasite intensity in old than in young males. We also show that various aspects of territorial behaviour (increase in testosterone-dependent comb size in autumn, territorial call rate, likelihood of winning territorial interactions and over-winter survival) were significantly higher in dosed than in challenged males, but in old birds only. Our data thus supported the hypothesis that parasites reduce male aggressiveness during the autumn territorial contests, and could thereby influence recruitment. Our results also highlight that the territorial behaviour of young males, which have fewer parasites, is not as limited by parasites as that of old, previously territorial males. We discuss the implications of these findings for our understanding of the processes regulating red grouse populations and causing their complex, unstable population dynamics.

This study was carried out to establish the effects of therapeutic and toxic doses of levamisole on thyroid hormone levels and some biochemical parameters in sheep. Twelve Akkaraman ewes were used. Levamisole was given orally at doses of 7.5 mg kg(-1) (group 1) and 40 mg kg(-1) (group 2) to the animals. Blood samples were taken from the jugular vein at 2, 4, 8, 24, 48, 96 and 144 h after the administrations. Serum thyroid hormones and some biochemical parameters were determined on these samples. When compared with the control levels, no significant changes were observed in triiodothyronine (T3) and thyroxin (T4) levels in group 1. Although levamisole was found to increase the levels of total T3, it decreased the levels of total T4 in group 2. On the other hand, free T3 and free T4 levels were not changed in either group. While serum alkaline phosphatase (ALP) activities were decreased, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatinine kinase (CK) activities were increased significantly by levamisole. However, it increased the serum albumin and cholesterol levels, but decreased the inorganic phosphate levels in groups 1 and 2. On the other hand, when compared with the control levels, no significant changes were detected in serum sodium, potassium and calcium levels. In conclusion, therapeutic and toxic doses of levamisole were determined to affect thyroid metabolism and some biochemical parameters in sheep.

Behavior, even in simple metazoans, depends upon integrated processes at the subcellular, cellular, and organismal level, and thus is susceptible to disruption by a broad spectrum of chemicals. Locomotor behavior (movement) of the small free-living nematode Caenorhabditis elegans has proven to be useful in assessing toxicity. Recently reported observations suggest that behavioral change (reduced movement) occurs after 4 h of exposure to heavy metals, and that with abbreviated exposure, the concentration-response relationship for Pb (a known neurotoxic metal) differs from that for Cu. In this study, movement was evaluated after 4-h exposures for nine compounds from three chemical classes: organic pesticides, organic solvents, and heavy metals. Concentration-dependent reduction of movement was observed for all test compounds with the exception of mebendazole, for which test concentrations were limited by solubility. Within each chemical class, movement was more sensitive to the neurotoxic compounds than to substances not believed to be neurotoxic, as evidenced by behavioral effective concentration to reduce average worm movement to 50% of the control movement values (e.g., levamisole and chlorpyrifos < mebendazole, ethanol and acetone < dimethylsulfoxide, and Pb and Al < Cu). These observations are discussed as they relate to the use of acute behavioral tests in assessing general chemical toxicity, and the enhanced value of 4-h testing for the detection of neural toxicants.

Using the murine sperm-head abnormality test, the mutagenicity of pyrantel pamoate, levamisole, albendazole, mebendazole and niridazole was evaluated. Pyrantel pamoate and niridazole induced increases in sperm-head abnormalities statistically significant over the negative controls at all the dose levels that were considered; the induction was dose-dependent indicating that both drugs might be mutagenic. Levamisole, albendazole, mebendazole and thiabendazole, all were unable to induce statistically significant increases in sperm-head abnormalities over the negative controls at all the dose levels tested; there was no correlation between dose level of administered drugs and incidence of abnormal sperms, indicating that the drugs might not be mutagenic.

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.

A survey was conducted on the occurrence of anthelmintic resistance of trichostrongylids on commercial sheep farms in the highveld of Zimbabwe. On ten farms the efficacy of fenbendazole, levamisole and rafoxanide was tested by a faecal egg count reduction test. Benzimidazole resistance was additionally examined using an egg hatch assay with thiabendazole. Results of the faecal egg count reduction tests and larval differentiations showed fenbendazole resistance of Haemonchus sp. on all investigated farms. Resistance of Haemonchus sp. against rafoxanide was demonstrated on all farms with reliable egg counts. Levamisole resistance of Haemonchus sp. was found on most farms but 2 farms showed an efficacy of 100%.

Ultrastructural changes induced in vitro by thiabendazole, levamisole, pyrantel and ivermectin in the free living larval stages of two trichostrongyles (Heligmosomoides polygyrus and Haemonchus contortus) were analysed. The observed damage for each anthelmintic is related to the known mode of action and compared to the damage commonly described in adults. The advantage of using larvae to study the effects of anthelmintics on the fine structure of nematodes rather than adults is described. Thiabendazole induced alteration of the cellular organization especially epithelial cells of the digestive tract. Changes in mitochondria were also seen. Levamisole caused contraction of muscle fibres whereas no specific lesions were observed with pyrantel. Ivermectin caused an hypertrophy of muscular groups. The interest of such a technique in research on the modes of action of anthelmintics is emphasized.

Co(II), Ni(II), Cu(II) and Zn(II) complexes of levamisole (LMS) were prepared and characterized by elemental analyses, IR spectroscopy, 1H and 13C NMR and mass spectrometry. The following general formula was derived: M(LMS)2Cl2, where M = Co, Ni, Cu, Zn. It was established that LMS behaved as a monodentate ligand and the coordination was accomplished through the N-7 atom. The toxicity and the immunomodulating activity of the complexes on mice and rats in comparison with uncomplexed LMS was assayed. The metals in the complexes exerted different changes in the toxicity of LMS. The complex containing Zn(II) was less toxic and manifested higher immunomodulating activity than LMS.

The effects of levamisole (LMS) (2.5 mg/kg), mechlorethamine (MCHT) (5 or 600 micrograms/kg) and sodium diethyldithiocarbamate (DTC) (20 mg/kg) on primary humoral response of SRBC immunized rats were investigated. Each drug mentioned potentiates the primary humoral response to SRBC by increasing the number of plaque forming cells (PFC) and the level of anti-SRBC antibodies. Comparatively the strongest effect reflected in the increased quantity of PFC occurs after a single administration of the drugs, 48 h after antigen stimulation. The effect of DTC is twice lower than that of LMS or MCHT (5 micrograms/kg). Moreover, accelerated production of IgG (7S anti-SRBC antibodies) is a result of a single administration of LMS and MCHT (5 micrograms/kg) 72 h or 96 h after immunization or five days' DTC treatment at 24 hours intervals. MCHT administered at a dose of 600 micrograms/kg suppresses humoral response of the immunized rats both after a single dosage and five days' treatment at 24 hours intervals.

During produced by sheep for up to 1 week post-treatment (drenching) with ivermectin caused significant mortality to newly emerged larvae of the bushfly Musca vetustissima. Dung from sheep drenched with a mixture of levamisole and oxfendazole also resulted in larval mortality, but here the effect was limited to the first 48 h after treatment. Flies reared through to the adult stage on dung collected up to 32 days post-drenching were tested for evidence of fluctuating asymmetry, which is an indicator of developmental stress. None was found for either drench treatment, although there was evidence that ivermectin residues directly affected wing size. The introduced dung beetle, Euoniticellus fulvus was also found to be sensitive to ivermectin residues in sheep dung. Dung produced during the first day after drenching caused mortality among newly emerged beetles and delayed the reproductive development of survivors. However, beetles in which ovarian development was impaired regained their reproductive capacity following transfer to nontoxic dung. Day 1 dung caused no mortality among sexually mature beetles, although there was a significant reduction in their fecundity. Dung collected from 2 to 10 days post-drenching had no detectable effects on either the survival or reproductive development of adult beetles, regardless of age. Residues in dung collected 1-2 days post-drenching caused 100% mortality in beetle larvae, but by Day 5 there was no evidence of acute toxicity. These findings indicate that insects feeding on the dung of ivermectin-treated sheep display adverse effects similar in range to those reported for cattle dung. However, their duration is much more transient, owing probably to differences in drug formulation and route of administration.

The effect of L-tetramisole (Levamisole, Decaris) on the physiological interferon beta (INF beta) production by freshly isolated peritoneal cells of BALB/c, NZB and C3H mouse strains was studied. We have shown that these strains differ in their ability to produce physiological IFN. Peritoneal cells of individual BALB/c and NZB mice differed significantly in ability to produce the physiological IFN, but most of these animals are good producers, while the cells isolated from C3H mice are not. High concentrations of L-tetramisole (250 and 500 micrograms/ml) suppressed IFN synthesis in the cells from BALB/c and NZB mice. Lower concentration of L-tetramisole (125 micrograms/ml) inhibited the IFN production only partially and this effect was observed when the IFN production was high. When the IFN production was very low, L-tetramisole slightly increased the synthesis. L-tetramisole affected the production of the physiological IFN, but not the production of IFN induced by Newcastle disease virus (NDV) in the peritoneal cells of mice or in L929 cells.

Toxicity and tissue residue depletion studies were conducted in young goats, using an oral drench formulation of levamisole hydrochloride. In the target animal toxicity study, 3 groups of 5 goats each were given levamisole orally to provide approximately 11.88, 23.76, or 35.64 mg of levamisole HCl/kg/d for 3 consecutive days; a fourth group of 5 goats served as untreated controls. Blood samples were taken for analysis of levamisole 1 day prior to dosing and 1, 2, 3, 4, and 7 days following the third dose. At the 35.64-mg/kg dose, 2 of 5 goats responded with typical cholinergic signs of toxicosis on each of the 3 days of dosing. The times for the onset of clinical signs of toxicosis ranged from 18 to 63 minutes, with an average duration of 32 minutes. Administration of 23.76 mg of levamisole HCl/kg resulted in hyperactive behavior in 1 of 5 goats only on the first day of dosing; no abnormal behavior was observed in any of the 5 goats following the second or third dose of levamisole HCl at 23.76 mg/kg. Untoward effects were not seen in the 5 goats dosed at 11.88 mg of levamisole HCl/kg or in the controls during the 3-day dosing period or in the following 7-day observation period. Overall, the observed signs of toxicosis did not become more severe, affect more goats, or persist for a longer period on subsequent dosing days.(ABSTRACT TRUNCATED AT 250 WORDS)

It was shown that levamisol administered orally to mice induced production of interferon with its maximum level in 4-6 hours and prolonged subsequent circulation in the host (the observation period of 5 days). Antiviral activity of levamisol in experimental forest-spring encephalitis was shown (protection of 35-40 per cent). When levamisol were used in combination with polyguacyl, an additive effect was recorded.

A phase I study of levamisole in patients with cancer was undertaken to determine its therapeutic dose range, side effects, limiting toxicity, and influence on immune function. Simultaneously, a group of patients receiving adjuvant combination chemotherapy for carcinoma of the breast were entered in a randomized study to observe whether levamisole was capable of overcoming the immunodepressive effects of cytotoxic drugs. In the phase I trial the doses used ranged from 65 to 410 mg/m2. The maximum tolerated dose was 358 mg/m2. Side effects were generally low in intensity and related to the gastrointestinal and central nervous systems; the limiting toxic effect was intractable nausea. Significant changes in immune test values were noted in both acute and chronic trials. Alterations in immunoglobulin levels, complemented values, and numbers and types of lymphocytes and mitogenic responses to concanavalin A as well as specific mitogens were observed. In the randomized trial there was no difference between the chemoimmunotherapy and chemotherapy-alone groups.

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).

Defined was the acute toxicity LD50 of a 7.5 per cent solution of the Levamizol-Pharmachim preparation following its subcutaneous application to albino mice and rats. Sheep and pigs were also injected subcutaneously with the same solution and their tolerance of the preparation was defined at rates of 7.5, 22.5, and 37.5 mg per kg body mass. Comparative clinical testing was carried out of the 7.5 per cent solution of Levamizol-Pharmachim and Nilverm (ICI, England) with regard to their action against sexually mature strongylates in sheep and against swine ascaridiasis and Esophagostomum infection. It was found that the subcutaneous injection of albino mice with a 7.5 per cent solution of the preparation at the rate of 90 mg/kg was in fact the LD50 dose with this route of application. In the case of albino rats LD50 turned out to be 120 mg/kg. Levamizol had good tolerance with adult swine and pigs at subcutaneous introduction in a dose of 7.5 mg/kg. Death cases were recorded with these animals with the use of 37.5 mg/kg, which was 5 times the ED50 dose. The preparation was shown to be suitable for both therapeutic and prophylactic worming of sheep and swine.