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Official websites use. Share sensitive information only on official, secure websites. Levamisole is an imidazothiazole chemical most frequently used as an antihelminthic agent in cattle. Over the last decade, levamisole has been increasingly encountered as an additive in both powder and crack cocaine. In vivo , levamisole is metabolized to aminorex, a compound with amphetamine-like psychostimulatory properties and a long half-life; a priori , this property allows levamisole to potentiate and prolong the stimulatory effects of cocaine while bulking up the drug to increase profit for the dealer. As use of cocaine cut with levamisole becomes more prevalent, complications directly attributable to the chemical are increasingly being recognized. Amphetamine and cocaine are abused for stimulatory effects achieved through the alteration of monoamine concentration and duration at the synapse. Amphetamine increases monoamine release, whereas cocaine targets monoamine reuptake, including the serotonin reuptake transporter SERT , norepinephrine transporter NET , and dopamine transporter DAT. Ultimately, both cocaine and amphetamines prolong the actions of serotonin, norepinephrine, and dopamine at the synaptic cleft until they are eventually broken down by monoamine oxidase MAO and catechol-o-methyl transferase COMT 1. When introduced into the body, cocaine is quickly metabolized by hepatic and plasma cholinesterases; it has a half-life of only 30 to 60 minutes 2. Its metabolites are water-soluble and excreted by the kidneys 2. Since monoamine metabolism plays an important role in the dopamine reward system, it's not surprising that polymorphisms in the COMT gene have been associated not only with cocaine dependence, but also with a number of substance abuse disorders 3. In using cocaine and other drugs affecting dopamine release and reuptake, individuals with a low-activity COMT allele may have even further reduction in the rate of dopamine metabolism at the synapse and are subsequently suspected to experience a prolonged effect of dopamine in the brain, increasing the duration and intensity of the high and ultimately driving future reward-seeking behavior and cocaine dependence 3. Cutting can occur at any stage of the chain of distribution, but a study analyzing cocaine seized by the Brazilian Federal Police found that drugs intended for international trafficking had already been significantly adulterated prior to leaving Brazil 5. Many diluting agents e. However, a variety of pharmacologically active chemicals are used as cutting agents because of their physical or chemical resemblance to cocaine, their low cost, or their added physiological effects; these substances are correctly referred to as adulterants, as opposed to diluents, which have no physiologic effect 4 , 6. For example, caffeine is a common additive to cocaine and heroin because it is cheap and widely available 4. Further, adding caffeine to heroin allows the heroin to vaporize at a lower temperature when smoked, thus mildly increasing its efficacy. On the other hand, as a stimulant, caffeine makes a mild contribution to the intrinsic effects of cocaine 4. Heroin has a bitter taste, so it is sometimes cut with the bitter-tasting antifungal griseofulvin to give the impression that the heroin is a purer sample. An ideal cutting agent physically resembles the drug it is used to adulterate; accordingly, chemicals used to cut powder cocaine hydrocholoride are typically white powders. The most commonly encountered white powder additives include, in addition to sugars and starches, lidocaine, levamisole, and diltiazem. A purchaser sampling cocaine before a possible buy notes the numbing effect of the drug on the gums, since cocaine has an anesthetic effect on mucous membranes; a benefit of cutting cocaine with lidocaine is that the latter is a more powerful anesthetic than cocaine, potentiating the impression that the cocaine is of higher quality 4. The literature yields no clear explanation for the fairly common use of diltiazem as a cutting agent; while it arguably confers some cardioprotective effect through its vasodilatory properties, it is a relatively expensive chemical; drug runners are hardly known for their largess. Other common additives to cocaine include hydroxyzine a first-generation antihistamine , levamisole, and phenacetin an analgesic 4 , 7 , 8. First produced in 12 , the imidazothiazole derivative levamisole 8 is an anthelminthic agent that acts as a ganglion stimulant in mammals and as a depolarizing muscular blocker in nematodes. By stimulating acetylcholine receptors AChR , levamisole results in calcium influx and causes sustained muscle contraction Aminorex, a levamisole metabolite and amphetamine-like substance, was marketed as an anorectic appetite suppressant in the mids in Austria, Switzerland, and Germany. It was subsequently found to cause pulmonary vasoconstriction and after a number of fatalities due to pulmonary hypertension, the drug was subsequently withdrawn in 1 , 8 , In humans, levamisole was used clinically as an anthelminthic and as an immunomodulatory agent for inflammatory conditions such as pediatric nephritic syndrome and rheumatoid arthritis 15 and colorectal cancer brand name: Ergamisol In , it was withdrawn from the US market due to side effects and is currently marketed only for veterinary purposes 1 , 8 , although detection of its metabolites—including aminorex, rexamino, and 4-phenylimidazolidinone II —in some recent official blood and urine samples from racehorses has highlighted the potential use of levamisole to dope racehorses Initially regarded as a curious contaminant, levamisole in cocaine gradually began to develop a higher profile. In April , New Mexico experienced a mysterious cluster of cases of agranulocytosis 9. Further investigation revealed cocaine as the common exposure in 11 cases between April and November 9. Around the same time, in November , public health officials in British Columbia and Alberta, Canada, reported detection of an additional drug, levamisole, from cocaine samples and paraphernalia of cocaine users with agranulocytosis 9. An additional ten cases of agranulocytosis were identified in cocaine abusers between April and November , in Seattle, Washington, and of the 21 New Mexico agranulocytosis cases, levamisole was detected in four of five specimens taken from patients 9. Shortly thereafter, a series of six cases was identified in which levamisole-contaminated cocaine exposure was associated with the development of purpura, vasculitis, and neutropenia; all six patients presented with purpura and necrotic skin lesions on various parts of the body, with bilateral ear necrosis occurring in five of the six patients, skin biopsy results revealed intravascular thrombi in four patients, small vessel vasculitis in two patients, leukocytoclastic vasculitis in two patients, and neutropenia in three patients On its own, cocaine can precipitate life-threatening cardiac events, even at fairly low doses and in the absence of apparent underlying cardiovascular system CVS disease 2 , 19 ; however, patients with cocaine-associated myocardial infarction MI have been observed to be of older age and have a medical history significant for coronary artery disease CAD and chest pain although less frequently As a sympathomimetic, cocaine induces vasoconstriction, raises blood pressure, and has positive chronotropic and inotropic effects on the heart 15 , 19 , With chronic use, it accelerates atherosclerosis, increases platelet aggregation, and prompts plaque rupture and thrombus formation It is believed that increased myocardial oxygen demand in response to cocaine intoxication produces ischemia, particularly via generalized vasoconstriction of the coronary arteries, thereby raising the risk of MI, and, subsequently, arrhythmias such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes 19 , 20 , Development of arrhythmias is also associated with cocaine's effects on ion channels. Sodium channel blockade by cocaine is associated with wide QRS complex tachycardia, which is similar to the tachycardia associated with the sodium channel blocking effects of tricyclic antidepressants TCAs Potassium channel blockade, on the other hand, may result in a widened QT with absent or insignificant prolongation of QRS, and atypical T waves may also be seen. In severe cases, potassium channel blockade can lead to monomorphic or polymorphic ventricular tachycardia i. Arrhythmia may also result from catecholamine excess, presenting in milder cases with psychomotor agitation and benign sinus tachycardia manageable with supportive care, or in more severe cases with reentrant supraventricular tachycardia or atrial fibrillation Other associated CVS complications include myocarditis, endocarditis, hypertensive crisis, cardiomyopathy, and aortic dissection or rupture 2. Seizures are another common complication 19 , as well as toxic leukoencephalopathy Toxic effects of cocaine emerge at concentrations of 0. The final common mechanistic pathway in sudden death associated with cocaine use is typically an arrhythmia Most frequently, autopsy in cocaine-related sudden death reveals no gross structural cardiac abnormality. Levamisole is to times less potent than cocaine in blocking norepinephrine NE and dopamine DA reuptake, and it has low affinity for the serotonin transporter 1. The drug is available in tablet, solution, or powder form It has a half-life of three to eight hours and is subject to first-pass metabolism, and some of its metabolites p-hydroxylevamisole undergo conjugation with glucuronic acid as well 25 , As such, its clearance depends on normal hepatic and renal function Despite its short serum half-life, levamisole has a high volume of distribution In vivo , levamisole is metabolized to aminorex, which is bioactive 1. A study of levamisole metabolism demonstrated the presence of unchanged levamisole and several metabolites including aminorex in the urine: mg of levamisole were administered orally to a human subject, and of that only 0. Aminorex reached its peak concentration in the urine within seven hours of levamisole administration and could be detected for up to 54 hours after levamisole was ingested The potency of aminorex has been found to be comparable to cocaine, and aminorex may be responsible for levamisole's psychostimulant effects due to its amphetamine-like properties 1. Levamisole, which is highly lipophilic, readily crosses the blood brain barrier BBB and has a longer half-life than cocaine 1. As such, at high doses it may reach higher concentrations in the brain than cocaine and potentiate the action of cocaine by providing additional neurotransmitter releasing action on NET, DAT, and SERT 1. Levamisole also prolongs the actions of cocaine by decreasing its metabolism by cholinesterase, which processes cocaine to its inactive metabolites and it has been suggested that levamisole may change ganglionic nicotinic receptors and increase the number of D1 dopamine receptors in the brain as well 8 , Furthermore, due to its longer half-life as previously noted, aminorex is detectable in human urine up to 54 hours after levamisole administration , levamisole may continue to affect neurotransmitter reuptake, providing amphetamine-like stimulant effects even after cocaine is no longer present and its direct effects have worn off 1. In addition to these psychoactive characteristics, addition of levamisole to cocaine increases profits as a diluent 7 , 8 , These features make levamisole and aminorex an attractive choice as a cocaine additive 1. As much higher doses of levamisole are required to affect monoamine reuptake in a way similar to cocaine, users of drugs containing a high levamisole-to-cocaine ratio are likely to consume significant amounts in order to achieve the desired effects, putting them at higher risks of severe side effects of the adulterants 1. Levamisole use can present with a number of adverse effects, include nausea and vomiting, headache, fatigue, fever, diarrhea, myalgia, dizziness, confusion, and rash Serious complications include agranulocytosis, leukopenia, thrombocytopenia, vasculopathy and vasculitis, dermal necrosis, leukoencephalopathy, psychosis, pulmonary hypertension and hemorrhage, glomerulonephritis, emboli, arthritis, CAD, and collapse 1 , 8 , 25 , Some of these complications—including agranulocytosis, skin rash, dermal necrosis, vasculopathy and vasculitis, and glomerulonephritis—appear to be associated with levamisole's propensity to provoke hypersensitivity reactions in people with certain genetic predispositions 12 , For instance, Le Garff et al. Such reactions have been reported previously, with reoccurrence of symptoms after reexposure More than half of those who develop agranulocytosis have ANCA, and a recent case-control study demonstrated a significant association between cocaine associated agranulocytosis and HLA-B27 frequently associated with the seronegative spondyloarthropathies, including ankylosing spondylitis and reactive arthritis 16 , Anti-HNE has been observed in many cases, although whether it is diagnostic for levamisole-induced agranulocytosis and cutaneous vasculitis has not yet been determined Levamisole-associated vasculitis appears to be related to circulation and deposition of immune complexes The side effect of pulmonary hypertension sometimes observed in association with exposure to levamisole is consistent with aminorex's effect on SERT and is theorized to be due to dysregulation of peripheral serotonin transporters and serotonin efflux 1. Toxicological detection of cocaine with levamisole has been reported in association with a number of case fatalities, typically attributed to pathology of the heart, brain, or lungs. Indorato et al. The first, a year-old male, had engaged in an intravenous cocaine binge with a friend. Shortly thereafter, he was transported to the emergency department ED via ambulance with complaints of chest pain and nausea, and died on arrival. Autopsy revealed a heart weighing g and histological analyses revealed minor atherosclerotic CAD, pulmonary edema with low protein content, and focal segmental glomerulosclerosis FSGS. In the second case, a year-old male who had snorted cocaine was found deceased in a car. Autopsy findings were unrevealing: histological examination of sections of the g heart revealed localized fibrosis and minor atherosclerotic CAD. Cocaine and levamisole were detected in heart blood in both patients. In both patients, levamisole concentrations were highest in the blood, lungs, and liver Brajkovic et al. A year-old man was delivered to the hospital with no vital signs, and efforts at resuscitation were unsuccessful. Autopsy revealed 66 packets of cocaine in his digestive tract, one of which had ruptured, leading to severe intoxication. Investigation revealed hyperemia of the majority of the patient's internal organs and edema of the lungs and brain. High concentrations of cocaine, its metabolites, and levamisole were detected in postmortem blood and tissues In these cases, the relative contributory roles of cocaine and levamisole cannot be discerned; the circumstances and the blood concentrations of cocaine encountered in many of these cases would be considered sufficient in and of themselves to cause death. Indeed, it is likely that most forensic pathologists practicing in the United States today have assigned such deaths simply to acute cocaine intoxication, without considering levamisole toxicity as a contributory factor. While sequelae of long-term levamisole exposure have been documented, little is known regarding the acute effects of exposure to high concentrations of the drug and the potential mechanism of death in associated fatalities, but it is possible that levamisole enhances the toxic effects of cocaine on the CVS just as it potentiates cocaine's psychostimulant effects, ultimately leading to sudden death in these patients Michaud et al. Electrocardiogram ECG revealed ventricular fibrillation. Examination of the heart, weighing g, revealed two fibrous scars consistent with healed infarctions in the left ventricular myocardium. Pleural effusions and pulmonary edema were also present. Histological analysis revealed eosinophil infiltration of the adventitia and intima of the left anterior descending LAD artery. Levamisole was detected in the urine and pericardial fluid Although vasculitis and eosinophilic myocarditis have been reported as a complication of cocaine use, eosinophilic inflammation of the coronary arteries has not. Eosinophil infiltration of the coronary arteries has, however, been associated with coronary dissection and Kounis syndrome hypersensitivity coronary syndrome , which includes vasospastic allergic angina, and allergic MI and stent thrombosis with eosinophil and mast cell infiltration of the occluding thrombus. As a toxic substance known to induce hypersensitivity reactions, the presence of eosinophils may be related to levamisole exposure via allergic or immune-mediated mechanisms Hantson et al. Magnetic resonance imaging MRI revealed multiple sclerosis MS -like leukoencephalopathy throughout the supra- and infratentorial white matter and within the corpus callosum, mimicking Susac syndrome Susac syndrome, an autoimmune microangiopathy of the brain, retina, and cochlea characterized by encephalopathy, occlusions of branches of the retinal artery, and hearing loss, presents with midline lesions of the corpus callosum. Although a specific offending antigen has yet to be identified in Susac syndrome, anti-endothelial cell antibodies have been detected in a subset of patients, and examination of the cerebrospinal fluid CSF typically reveals elevated protein and mild lymphocytic pleiocytosis, which may reflect dysfunction of the blood brain barrier BBB. In this particular patient, the lesions in the corpus callosum advanced to become necrotic and cystic. Despite interventions, the patient remained minimally conscious and died after three months from septic complications Although the exact etiology in this patient is unclear, multifocal inflammatory leukoencephalopathy has been reported in association with levamisole monotherapy, and levamisole was detected in this patient via hair testing 23 , In patients with levamisole-induced leukoencephalopathy, T2 MRI reveals hyperintense foci, which may be enhanced with gadolinium or accompanied by edema. Brain biopsy reveals active demyelination with loss of myelin and lymphocytic infiltration of the perivascular space Karch et al. He had a history of cocaine and heroin abuse, as well as a history of asthma, and had undergone nine months of methadone replacement therapy. Consistent with this history, inhalers salbutamol, salmeterol, fluticasone were found in his possession, as well as 8 mg of white powder. Morphine, 6-monoacetylmorphine, cocaine, benzoylecgonine, methadone, and EDPP were detected in multiple biological samples, and levamisole and aminorex were detected in the urine and hair. Analysis of the white powder revealed it to be Microscopic examination of lung tissue revealed findings consistent with idiopathic pulmonary hypertension IPH , including fibromuscular dysplasia and intimal hypertrophy obliterating the lumen of almost half of the small pulmonary arteries. Focal regions of over-inflation were also present, along with anthracosis consistent with smoking crack cocaine In a more recent publication, Karch et al. The first, a year-old man with an extensive history of cocaine abuse, was taken to the hospital due to bizarre behavior, but died suddenly. Autopsy revealed the presence of severe pulmonary edema and a significantly enlarged heart. While microscopic examination of the heart revealed changes consistent with long-term abuse of stimulants, histological examination of the lungs revealed pulmonary edema and lymphocytic infiltration of small pulmonary vessels, along with perivascular fibrosis and transforming fibroblasts. The second case described a year-old male—again with a long history of cocaine abuse—who reportedly collapsed at a party approximately 30 minutes after snorting cocaine and died shortly thereafter. Autopsy revealed a heart of normal size and shape, although hypertrophy of the left ventricular wall was noted. The only other findings were severe edema of the lungs and brain. Histologic examination of the heart revealed regions of myocardial necrosis with hyper-contracted myocytes, while examination of the lungs revealed edema, intimal thickening and lymphocytic infiltration of arteriolar walls, and perivascular infiltrates. The vascular lymphocytic infiltrate was mixed in both cases, containing B cells and T cells; when compared to a control group of 11 cocaine-associated deaths where levamisole was not present, the authors noted that no pulmonary vasculitis was detected in any of these cases. This suggests that the pulmonary lymphocytic vasculitis demonstrated in the two presented cases may be a complication of levamisole use or its metabolite In many ways, levamisole may be the ideal cutting agent for manufacturers and distributers. Easy to obtain, inexpensive, physically similar in its presentation, and with the inherent ability to potentiate and prolong the effects of the primary agent, it seems the perfect choice for maximizing profit while leaving consumers none the wiser… except in those cases with deadly consequences. The cause of death in patients with cocaine and levamisole intoxication may be due to any number of mechanisms, ultimately severely impacting the heart, lungs, and brain. Given its prominence as a cocaine additive, its presence in a majority of cocaine specimens evaluated in numerous centers around the world, its known side effect profile and role in autoimmune reactions, and potential role in facilitating or exacerbating pathological processes leading to sudden death, toxicological screening for levamisole is an appropriate element in the analysis of suspected cocaine-related fatalities. The authors, reviewers, editors, and publication staff do not report any relevant conflicts of interest. As a library, NLM provides access to scientific literature. Acad Forensic Pathol. Find articles by Nadia Solomon. Find articles by Jonathan Hayes. This article has been corrected. See Acad Forensic Pathol. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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Bled buying coke

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Bled buying coke