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Levamisole

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Last Updated: 02 December 2020

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Levamisole

Chemical and physical data
3D model ( JSmol )Interactive image
Density1.31 g/cm 3
FormulaC 11 H 12 N 2 S
Melting point60 C (140 F)
Molar mass204.29 gmol 1
Clinical data
AHFS / Drugs.comMicromedex Detailed Consumer Information
ATC codeP02CE01 ( WHO ) QP52AE01 ( WHO )
License dataUS DailyMed : Levamisole
MedlinePlusa697011
Routes of administrationBy mouth
Trade namesErgamisol
Identifiers
CAS Number14769-73-4 Y
ChEBICHEBI:6432 N
ChEMBLChEMBL1454 Y
ChemSpider25037 Y
CompTox Dashboard ( EPA )DTXSID4023206
DrugBankDB00848 Y
ECHA InfoCard100.035.290
IUPHAR/BPS7210
KEGGD08114 Y
PubChem CID26879
UNII2880D3468G
Legal status
Legal statusCA : Withdrawn drug, US : Withdrawn, Rx-only ( RU )
Pharmacokinetic data
Elimination half-life3-4 hours
ExcretionUrine (70%)
MetabolismLiver

Cocaine use and its related complications are well-know public health issues. More than 5 million Americans use Cocaine regularly via insufflation, inhalation, and injection. 1 Cocaine's effects on the health care system across multiple medical disciplines, but clinicians may be less cognizant of problems caused by some of the adulterants added to Cocaine. Recent recognition of Levamisole-induced agranulocytosis, vasculitis, and other complications, from contaminated Cocaine, dictates that physicians should be aware of these potential problems. Since 2006, several cases of severe agranulocytosis associated with Cocaine use have been report. 2 3 Epidemiological studies of initial cases reported by the New Mexico Department of Health find evidence of Levamisole, antihelminthic agent, in drug paraphernalia of Cocaine users. 2 Levamisole was also detected using gas chromatography / mass spectrometry in postmortem blood specimen from a Cocaine user who died of Serratia marcescens sepsis secondary to agranulocytosis. During the New Mexico investigation, public health officials in British Columbia and Alberta, Canada, also reported similar findings in Cocaine users presented with leukopenia. 3 These findings were reported to the Centers for Disease Control and Prevention Epi-X and poison Control Centers. Subsequently, similar cases of severe agranulocytosis were reported in Colorado and Washington. All patients admit to recent Cocaine use or test positive for Cocaine on standard urine Drug screen. 2, concurrent with clinical reports of Cocaine-related agranulocytosis, technical reports of Levamisole-adulterate Cocaine have appeared in literature since 2002. 4 Outside of North America, published reports of Levamisole detected by GC / MS in Cocaine users appeared in Luxembourg and the United Kingdom in 2005. 5 6 Similar findings in Drug Enforcement-seize Cocaine shipments were reported around that time in the United States, Canada, Italy, and Australia. The 6 concentration of Levamisole in Cocaine has steadily increased since it was first detect. Concentration was less than 1% in 2001 8 and in 2009, Levamisole comprised approximately 10% of each Cocaine sample. 8 by July 2009, DEA reported that 69% of Cocaine entering the United States contained Levamisole, 9 while in the United Kingdom, Levamisole was found in over 50% of Cocaine samples test. 7 in an analysis of Cocaine users in Seattle, Washington, approximately 80% of users who test positive for Cocaine also test positive for Levamisole. 4 Levamisole is also used to adulterate other illicit substances; seized heroin supplies in 2008 and 2009 were found to contain trace amounts of Levamisole.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Adulterant in illegal drugs

In the present study, we want to evaluate if adulterant levamisole alters, maybe even enhances the cardiac effects of cocaine. We work with animal model, isolate perfuse Langendorff heart, and expose post mortem harvest hearts of rats to different quantities of cocaine, levamisole and mixture of these two substances while monitoring functional parameters heart rate, cardiac flow and leave ventricular pressure. This observing approach was chosen with a view to unclear cases of death in Forensic routine work that are related to consumption of only low amounts of cocaine. Results of hearts of the control group show that administration of ACN or extra amount of buffer solution alone over 5 min has some effects on functional parameters monitored throughout experiments. However, range of these alterations was smaller than ones observed when hearts were exposed to cocaine and / or levamisole. Therefore, results of study hearts can be attributed to the effects of two substances on heart function and are not merely derived from experimental setup. Results of hearts that were exposed to cocaine comply with the cardiac effects of cocaine that have been published before. For example, our experiments come up with a decrease in heart rate and coronary flow as was also described by Simkhovich et al. And Vitullo et al. Decrease of coronary flow and initial increase of LVP max with subsequent decrease until end of experiment also go along with the findings of Simkhovich et al. As underlying mechanisms, blocking of potassium and sodium channels, resulting in systolic and diastolic dysfunction, arrhythmias and decrease of myocardial contractility and ejection fraction has been describe. Cocaine stimulates release of endothelin-1 which causes vasoconstriction in endothelial cells and inhibits production of vasodilating nitric oxide, resulting in coronary artery spasms that can explain the CF-decrease in our experiments. Furthermore, decrease of heart rate in cocaine hearts during exposure period, with the exception of hearts exposed to 1 g and 2 g cocaine, might be connected to the fact that cocaine blocks fast sodium channels and stabilizes the axonal membrane. With view to heart rate, severe bradycardia is not uncommon in cocaine users according to Mahoney et al. Levamisole inhibits monoamine oxidase and has agonistic effects on nicotinic receptors in nematodes and mammalian muscles. In our experiment, levamisole triggered an increase of LVP max during the exposure period in some cases, which might be caused by blocking of open acetylcholine receptors resulting in calcium influx. This mechanism might also be responsible for increase in blood pressure and cases of pulmonary hypertension that have been observed under treatment of patients with levamisole. In our experiments, there was a slight increase in coronary flow and deceleration of heart rate while hearts were exposed to levamisole. In recovery period, heart rate accelerate, seemingly dose dependent, for at least 5 minutes up to 120 min.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Characteristics of Levamisole Toxicity

Patients with Levamisole Toxicity typically present with cutaneous manifestations consisting of large, painful hemorrhagic bullae and / or necrosis. Face is commonly affect, especially bilateral helixes and cheeks. Similar bullae can be present elsewhere in the body, with case reports documenting involvement of the abdomen, chest, lower back, buttocks, and legs. Retiform Purpura with or without bullae may also be prominent. 3 23 24 pathologic mechanism of these symptoms is unclear, as some patients present with true Vasculitis while others present with pseudovasculitis. Among cases presenting as true Vasculitis, direct immunofluorescence findings suggest immune complex-mediate Vasculitis with vascular deposits of IgM, IgA, IgG, and C3, and vascular staining for fibrin. 23 24 29 30 in addition to characteristic cutaneous manifestations, majority of patients complain of arthralgias, most commonly involving large joints. Ear, nose, and throat complaints are also common, as are feelings of generalized malaise and fatigue. 31 laboratory findings include leukopenia, neutropenia, agranulocytosis, positive antinuclear antibody titers, positive Anti-proteinase 3 titers, and positive perinuclear or cytoplasmic staining patterns for antineutrophil cytoplasmic antibodies. Absolute neutrophil counts ranging from 0 to 3000 have been report, and these patients are at high risk of infection. 32 Bone marrow biopsies from such patients have shown markedly decreased production of all cell lines. When positive, antinuclear antibody is often mildly or moderately elevate, most commonly in speckled pattern. Anti-double-strand DNA and lupus anticoagulant findings are also inconsistently positive in various case reports and series. 23 24 32-36 Complement studies typically yield normal results, although mildly decreased levels of C4 and / or C3 have been report. Urine toxicology studies are usually positive for Cocaine and occasionally for Levamisole. 24 37 38 Levamisole may also be found in drug paraphernalia such as pipes, paper currency, or other tools used for smoking or snorting Cocaine. The Antihuman elastase antibody is both sensitive and specific for Levamisole-induced Vasculitis. 33 Hyponatremia have also been report, 39 and pulmonary hemorrhage and renal failure can also occur. 31 Biopsy of cutaneous lesions reveals leukocytoclastic Vasculitis, thrombotic microangiopathy, panniculitis, and / or gross necrosis. On renal Biopsy of patients with Acute kidney failure, pauci-immune focal necrotizing crescentic glomerulonephritis is find. 31 natural progression of this condition is generally benign, as most symptoms will resolve without intervention. Complete cessation of Cocaine use is absolutely necessary because symptoms can recur on rechallenge. Systemic infection in those with agranulocytosis may require hospitalization.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Challenges

It is estimated that over 70% of cocaine consumed in the United States today is contaminated with Levamisole. This case demonstrates the need to maintain high clinical suspicion of Levamisole-induced ANCA-associate Vasculitis in patients with characteristic signs and symptoms but also with pre-existing systemic lupus erythematosus. A 54-year-old Caucasian-American female with a history of SLE on plaquenil 200 mg daily presented to the office with complaint of pruritic rash on her face, back, abdomen and all extremities for 1 year. Rash first appears on her upper extremities and then progresses to her legs. She denies history of fever, weight loss, alopecia, dry mouth, oral ulcers, painful red eyes, photosensitivity, dysphagia, recurrent miscarriages, or blood clots but does report myalgia and arthralgia in systems review. Further, patients admit to crack Cocaine use but report abstinence for the past 18 months. On examination, vital signs were within normal limits. Skin examination revealed features of retiform purpura on her upper and lower extremities-brightly contour and irregularly border areas of necrosis. Stage II ulcer on the medial surface of her right ankle with some serosanguineous discharge was also discover. The remainder of her physical examination results were unremarkable. Investigations reveal leukopenia with white blood cell count of 2 000 cells / L, absolute neutrophil count of 520 cells / L, and an elevated erythrocyte sedimentation rate of 47 MM / h. Lupus anticoagulant ratio was > 1: 2, perinuclear ANCA 1: 640, anti-PR3 antibody 18. 7, ANA titer 1: 320, and anti-SSA were positive > 8. 0, cryoglobulins, anti-cardiolipin antibody, anti-dsDNA, anti-Smith, anti-SSB, anti-RNP, and complement profile were negative or normal. Give her history as well as clinical findings on examination, urine drug screening was ordered and was positive for Cocaine; subsequent Gas chromatography-mass spectrometry was also positive for Levamisole. Punch biopsy of skin from involved areas show Leukocytoclastic Vasculitis with fibrin thrombi, angiocentric infiltrates of mixed inflammatory cells, and small vessel thrombosis with multiple fibrin thrombi in the lumen of vessels. Give patients ' history, supportive skin findings, lab profile, and biopsy results, we question prior diagnosis of SLE and instead favor Levamisole-induced Vasculitis. As such, she was treated with 10 days of oral steroids, 20 mg daily, and her skin findings subsequent improve. Investigational studies have been performed to determine the basis for adulterating Cocaine with Levamisole. Levamisole may potentially inhibit degradation of monoamine neurotransmitters dopamine, norepinephrine, and serotonin in central and peripheral nervous systems leading to reuptake inhibition, prolonged duration of action, and enhanced activity which subsequent may result in enhanced psychotropic effects. Patients with Levamisole-induced Vasculitis usually present with tender, purpuric rash in retiform or stellate pattern with or without central necrosis involving extremities; however, 39% of patients may present without cutaneous findings. Syndrome has a very interesting spectrum of autoantibody findings. High-titer P-ANCA are almost always find, and about 50% of cases also have C-ANCA positivity. Specific antigens responsible for generating these patterns are not yet clearly define.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

1. Introduction

Have report synthesis of 5 6-diaryl-2 3-dihydroimidazothiazoles AS anti-inflammatory agents. The most potent compound having a 4-flurophenyl group at 6 position and 4-pyridyl group at 5 position of imidazothiazole ring showed 27% and 38% inhibition after 3 and 16 days, respectively, in adjuvant arthritis rat assay for anti-inflammatory activity. The Compound showed 69% stimulation when evaluated by low-grade contact sensitivity to oxazolone in C52B1 / 6 mice for immunoregulatory activity. Bender et al. Have also reported synthesis of 5 6-diaryl-2 3-dihydroimidazothiazoles AS immunoregulatory and anti-inflammatory agents. Desoxybenzoin was converted to-bromodesoxybenzoin, which was condensed with 2-aminothiazoline to get intermediate which was deprotonated and cyclized in excess of the base to obtain the compound. Upon dehydration of 46 or acidic workup results in aromatization of heterocyclic ring AS show in Fig. 12. 11. Above say compounds were designed by combining salient pharmacophoric features of two bioactive compounds, that is, anti-inflammatory agent flumizole and the immunoregulatory agent Levamisole. Compound can be considered AS lead compound AS it shows better activity in inflammation, arthritis, and immunoregulation compared to Levamisole and flumizole. The Compound shows 24%, 34%, and 21% inhibition in the respective L-3, L-16, and R-16 rat adjuvant-induced arthritis models. Replacement of the 4-methoxy group of the compound with the 4-fluoro group resulted in the compound having 39%, 36%, and 49% inhibition in L-3, L-16, and R-16 rat adjuvant-induced arthritis models, respectively. Therien et al. Have report 5 6-diarylimidazothiazole derivatives AS selective COX-2 inhibitors. Condensation of-bromodiarylethanones with suitable 2-aminothiazoles in presence of ethanol or iso-pentanol yield 5 6-diarylimidazothiazole derivatives AS show in Fig. 12. 12. Compound offer IC 50 values of 0. 016 M and more than 50 M for inhibition of PGE 2 production in arachidonic acid stimulate Chinese hamster ovary cells transfected by Human COX-2 and COX-1, respectively, indicating its selectivity for COX-2. Introduction of fluoro group at para position of phenyl ring attached to 6 position of compound yield compound having an IC 50 value of 0. 014 M, while attachment of one more fluoro group at 3 positions of phenyl ring attached to 6 positions of compound yield compound having an IC 50 value of 0. 012 M. Introduction of methyl group at 2 positions of compound result in the compound having an IC 50 value of 0. 012 M. Roy et al. Have report 5 6-diarylthiazolotriazoles AS selective COX-2 inhibitors. These compounds were synthesize by condensation of compound with diaryl ketone to get compound which was cyclized in biphasic mixture of polyphosphoric acid and xylene at 140C to get thiazolotriazole AS show in Fig. 12. 13. The Compound shows IC 50 values of 0. 010 M and 43 M for COX-2 and COX-1, respectively, with high COX-2 selectivity. The introduction of the CF 3 group in the compound resulted in the compound having an IC 50 value of 0. 003 M against COX-2, however, its selectivity decrease.


How does Levamisole HCL work?

Levamisole HCL is absorbed through the gut, can also be absorbed through skin and is distributed throughout the body. Levamisole affects neurotransmitters and paralyze worm. Fish then pass inactive worms. Good gravel vacuuming is advised after treatment to remove paralyzed worms. It is not ovicidal, which means it will not affect eggs already present, but it will affect the larval stage of the worm. To ensure complete eradication of parasite, treat again after remaining eggs have hatch. The mechanism of action for its immunostimulating effects are not well understood. It is believed that it restores cell-mediate immune function in peripheral T-lymphocytes and stimulates phagocytosis by monocytes. Drugs appear to restore depressed immune function rather than to stimulate response to above-normal levels. There are multitudes of medical studies being done with its use in humans and animals, goal being to attain understanding of its immunomodulating mechanism. Mechanism will be define, with time. However, at the time of writing of this article, there is no complete answer to this question. For us, it is enough to know that it does stimulate immune function in fish that are suffering due to parasites or disease. LD-50 of levamisole is 250 mg / l per 24 hours. This level of dosage is much higher than that which is prescribed for use in freshwater bath. Only extreme overdosing with this medication will result in death to your fish. Few accounts of adverse side effects in aquaria have been noted even with much higher than currently accepted appropriate dosing. How long will it stay in my fish and how do I get it out of my tank? Levamisole HCL is rapidly absorbed into the digestive system. Less than 6% of medication is excrete unchanged in urine and feces. Half-live for several species have been record: absorption is systemic within 3-4 hours. Within three days, 70% of medication will be go from fish via its excretory system. The vast majority of compound will have been metabolized by your fish. The remainder can be removed by water changes and / or adding activated charcoal to your filtration system.


What is Levamisole Hydrochloride?

Levamisole possesses better activity than its racemic form tetramisole. At single oral dose of 2. 5-5 mg / kg, drug has been found to give 100% cures against ascariasis in humans. Recommend dose of Levamisole for treating. Lumbricoides is 40-80 mg for children and 150 mg for adults. It also exhibits high activity against hookworms,. Duodenale and N. Americanus. Typical treatment using 2. 5 mg / kg of Levamisole may bring out about 90% cures against ascariasis and 80% cures against hookworm infections. However, its activity against enterobiasis, trichuriasis and strongyloidiasis is not very encouraging. Levamisole is a well tolerated drug producing virtually no side effects at therapeutic doses. However, few cases may show intestinal symptoms, headache and dizziness, which are mild and of transient duration.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

3. Results

As intended by matching procedure, three groups do not differ regarding age, verbal IQ, sex distribution, and smoking status. Additionally, there were no differences regarding average price pay for 1 g of cocaine and socioeconomic status between both groups. However, both CU groups had significantly fewer years of education and higher BDI scores than controls but do not differ from each other. Moreover, highLevCU display significantly higher ADHD-SR scores than lowLevCU. As a consequence of group classification, two CU groups differ strongly in their absolute levamisole concentrations and levamisole-related LCR but display similar values in any other cocaine-related hair toxicology or self-report cocaine use parameter. Additionally, hair samples and cumulative doses reveal clear dominance of cocaine compared with other illegal drugs, as intended by inclusion and exclusion criteria. As shown before in this sample 15, controls and CU differ significantly in GCI and all four domains = 10. 64-28. 34, p 0. 001 Table S5. Three-group ANCOVAs control vs. LowLevCU vs. HighLevCU for GCI f2147 = 15. 26, p < 0. 001 and across all four cognitive domains f2147 = 6. 70-10. 45, p = 0. 002-0. 0001 show significant group effects Fig. 2A, Table S6. Linear trends across groups were shown for all comparisons p < 0. 01-0. 001, suggesting not only cocaine but also levamisole effect on cognitive functioning. Post hoc pairwise comparisons show that lowLevCU differs from controls in GCI, attention, and working memory domain, while highLevCU differs from controls in all cognitive domains Fig. 2A. In general, effect sizes were considerably higher for highLevCU d = 0. 57-0. 80 compared to lowLevCU d = 0. 32-0. 59. Subsequently, to adjust for even subtle differences in cocaine use intensity, both CU groups were compared using ANCOVAs in which abstinence duration and cumulative lifetime dose of cocaine were additionally include. Here, highLevCU shows stronger impairment of executive functions with medium effect size compared to lowLevCU F 1 68 = 5. 02, p < 0. 05, d = 0. 55. Additionally, GCI F 1 68 = 3. 21, p = 0. 08 0. 42 and declarative memory F 1 68 = 3. 21, p = 0. 08, d = 0. 44 show statistical trends towards significance with approximately medium effect size Fig. 2B. Impact on executive function was mainly driven by worse performance in IDE task and recall consistency Table S7, indicating more pronounced impairments specifically in rule acquisition and reversal learning as well as in memory organization in highLevCU. Exploratory analysis of IDE stages revealed that highLevCU makes more errors specifically in intradimensional set-shifting pre-ED errors: F 1 68 = 0. 01, p < 0. 05, d = 0. 64 but not in extradimensional set-shifting ED errors: F 1 68 = 6. 02, p = 0. 94, d = 0. 02; Figure S3. Notably, in the combined CU group, executive function performance correlated negatively with log-transformed levamisole values in hair samples r = 0. 23, p < 0. 05, one-tail; Figure S4.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

4. Discussion

The Patient is a 46 year old woman with a history of polysubstance abuse, suspect rheumatoid arthritis, asthma, and untreated hepatitis C who presented to ED with a painful hemorrhagic rash. Rash begins 4 days prior to admission as tender erythematous patches on both thighs, then turn deep purple and become blood-fill bullae. She also reported diffuse arthralgias and epigastric pain, but no fevers, chills, or additional constitutional symptoms. Notably, two years prior, she had had a similar but milder presentation after Cocaine exposure outside hospital, where she improved with pulse steroids. She denies drug use, but urine toxicology was positive for Cocaine and cannabinoids. Physical exam was notable for 25 15 cm palpable purpura on anterior surfaces of bilateral thighs, with focal areas of blistering and skin tearing. There were also smaller lesions on the right lateral shin and dorsal surfaces of bilateral hands. She was hypotensive on presentation and was admitted to MICU for concern about Stevens Johnson Syndrome. Admission labs were notable for normocytic anemia of 8. 9 with a white blood cell count of 3. 69 with an absolute lymphocyte count of 920 and normal platelet count. Serum creatinine was 1. 9 mg / dL. ANA titer was 1: 80. P-ANCA was positive; C-ANCA was negative. MPO ELISA was positive. C3 and C4 were both decreased at 42 and 7 mg / dL respectively. Cardiolipin IgM was positive at 42 mpl units and IgG and IgA were negative. RF and Ro, La, SCL-70, RNP, smith antibodies were all negative. The Cryofibrinogen screen was negative, as was extended infectious work up. She was diagnosed with Levamisole induced cutaneous vasculitis. Due to the extent of her wounds, she was transferred to the Burn Wound Unit and later received debridement, excision and grafting of her lower extremity wounds. Medically, she receives prednisone, wound care, and pain management with good recovery; her AKI resolved with fluids. She declined biopsy on this visit. One year later, she present again with purpura and bullae of hands and feet, as well as reticulo-papular rash affecting bilateral arms and posterior thighs and ulceration of lip and tongue. During this hospitalization, she received punch biopsy of lesion on her right wrist, which showed small vessel necrotizing leukocytoclastic vasculitis. Although testing for Levamisole was not perform, based on clinical presentation, serology and skin pathology, diagnosis of Levamisole adulterate Cocaine vasculitis was make. She was treated with stress dose methylprednisolone and transition to oral prednisone dose of 20mg per day, in addition to wound care. She recovered and was discharged with plan to taper her prednisone.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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