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16 african patients with diagnosed W. bancroft's filariasis admitted to Pedro Kourí Tropical Medicine Institute were subjected to a therapeutic management with levamisole: 300 mg as starting dosage, and 150 mg/day for seven days. 11 patients had been previously treated with several courses of diethylcarbamazine (DEC), but a low microfilaremia persisted in them. In the other 5 patients the only medication used was levamisole. A rapid fall in microfilaria concentrations was found from the first day of treatment on in all patients. Eventually, 14 patients (87,5%) were negative and two patients (12,5%) persisted having low microfilaremia and their concentrations lowered by 89 ad 93% respectively.
Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.
At the neuromuscular junction (NMJ), the binding of the excitatory neurotransmitter acetylcholine (ACh) to postsynaptic receptors leads to muscle contraction. As in vertebrate skeletal muscle, cholinergic signaling in the body wall muscles of the model organism Caenorhabditis elegans is required for locomotion. Exposure to levamisole, a pharmacological agonist of one class of ACh receptors on the body wall muscles, causes time-dependent paralysis of wild-type animals. Altered sensitivity to levamisole suggests defects in signaling at the NMJ or muscle function. Here, a protocol for a liquid levamisole assay performed on C. elegans grown in 24-well plates is presented. Vigorous swimming of the animals in liquid allows for the assessment and quantitation of levamisole-induced paralysis in hundreds of worms over a one-hour time period without requiring physical manipulation. This procedure can be used with both wild-type and mutants that have altered sensitivity to levamisole to demonstrate the functional consequences of altered signaling at the NMJ.
Cholinergic anthelmintics (like levamisole) are important drugs but resistance with reduced responses by the parasite to these compounds is a concern. There is a need to study and understand mechanisms that affect the amplitude of the responses of parasites to these drugs. In this paper, we study interactions of levamisole and ryanodine receptors on contractions of Ascaris suum body muscle flaps. In our second paper, we extend these observations to examine electrophysiological interactions of levamisole, ryanodine receptors (RyRs) and AF2. We report that the maximum force of contraction, g(max), was dependent on the extracellular concentration of calcium but the levamisole EC(50) (0.8 microM) was not. The relationship between maximum force of contraction and extracellular calcium was described by the Michaelis-Menten equation with a K(m) of 1.8mM. Ryanodine inhibited g(max) without effect on EC(50); ryanodine inhibited only 44% of the maximum contraction (K(i) of 40 nM), revealing a ryanodine-insensitive component in the levamisole excitation-contraction pathway. Dantrolene had the same effect as ryanodine but was less potent. The neuropeptide AF2 (1 microM) decreased the levamisole EC(50) to 0.2 microM without effect on g(max); 0.1 microM ryanodine and 100 microM dantrolene, inhibited the g(max) of the AF2-potentiated levamisole response. High concentrations of caffeine, 30 mM, produced weak contraction of the body-flap preparation. Caffeine behaved like ryanodine in that it inhibited the maximum force of contraction, g(max), without effects on the levamisole EC(50). Thus, RyRs play a modulatory role in the levamisole excitation-contraction pathway by affecting the maximum force of contraction without an effect on levamisole EC(50). The levamisole excitation-contraction coupling is graded and has at least two pathways: one sensitive to ryanodine and one not.
Present evidence regarding the efficacy and safety of levamisole in childhood nephrotic syndrome (NS), particularly the steroid-sensitive NS (SSNS), is limited. We searched relevant databases such as PubMed/MEDLINE, Embase, Google Scholar, and Cochrane CENTRAL till June 30, 2020. We included 12 studies for evidence synthesis (5 were clinical trials that included 326 children). The proportion of children without relapses at 6-12 months was higher in the levamisole group as compared to steroids (relative risk [RR]: 5.9 [95% Confidence interval (CI): 0.13-264.8], I2 = 85%). Levamisole as compared to the control increased the proportion of children without relapses at 6-12 months (RR: 3.55 [95% CI: 2.19-5.75], I2 = 0%). The GRADE evidence was of "very-low certainty" except for the comparison of levamisole with control, the latter being of "moderate certainty." To conclude, levamisole given to children with SSNS is beneficial in preventing relapses and achieving remission as compared to placebo or low-dose steroids. Good-quality trials are needed to provide a robust evidence in this regard. PROSPERO Registration number: CRD42018086247.
The batch experiments were conducted to understand sorption process of bithionol (BIT) in yellow soil (YS) and red soil (RS), while column leaching experiments were performed to evaluate the leaching behavior of BIT and levamisole (LEV) in the tested soils. The adsorption and desorption data fitted well with the Freundlich isotherms (R2 ≥ 0.94). The distribution coefficient of BIT in the YS and RS were 104 and 98.3 L/kg, respectively. Hysteresis was observed for bithionol desorption in the YS and RS, with hysteresis coefficient of 0.917 and 0.928, respectively. Dissolved organic matter (DOM) addition and acid condition enhanced the adsorption of BIT in the soil. Both BIT and LEV showed poor leaching potential in the tested soils. More than 80% of BIT and LEV remained in the surface soil layer and the amount of the two target compounds in the leachates accounted for less than 1% of overall recovery. DOM showed little influence on the concentration of BIT and LEV in the leachates collected at different time. The results could fill the gap on the behavior of BIT and LEV in soil under laboratory conditions.
Currently, levamisole is the most common cocaine adulterant worldwide and it is known to induce a variety of adverse side effects. Animal studies and human case reports suggest potential neurotoxicity of the compound but neither neuroanatomical nor cognitive effects of levamisole have been systematically investigated in cocaine users so far. We examined cognitive performance and cortical structural differences between chronic cocaine users with low and high recent exposure to levamisole objectively determined by quantitative toxicological hair analyses. In Study 1, we compared 26 chronic cocaine users with low levamisole exposure (lowLevCU), 49 matched cocaine users with high levamisole exposure (highLevCU), and 78 matched stimulant-naive controls regarding cognitive functioning employing a comprehensive neuropsychological test battery. In Study 2, we investigated cortical thickness by use of T1-weighted MRI in a subgroup of 12 lowLevCU, 17 highLevCU, and 38 stimulant-naive controls. In Study 1, both cocaine user groups showed significant impairments in the cognitive domains of attention and working memory as well as in the global cognitive index. However, highLevCU showed significantly worse executive functions compared to lowLevCU although both groups did not differ in severity of cocaine consumption and other clinical dimensions. Study 2 revealed that highLevCU, displayed reduced cortical thickness specifically in the middle frontal gyrus compared to both controls and lowLevCU. Our results suggest that levamisole exposure during the last months in cocaine users is associated with increased executive function impairments and pronounced thinning of the lateral prefrontal cortex. Consequently, prevention and drug policy-making should aim to reduce levamisole contamination of street cocaine.
Cocaine use has been associated with vascular pathologies, including cerebral white matter hyperintensities. Street cocaine is most often adulterated with levamisole, an anthelminthic drug that may also be associated with vascular toxicity. However, whether levamisole exposure from cocaine consumption further accelerates the development of white matter lesions remains unknown.
The experiment was conducted to determine of levamisole (0.2 ml/kg-BW), Vitamin E (80 mg)+selenium (1.6 mg), and aflatoxin (B1) (positive control) compared with group without aflatoxin (negative control) on some liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), as well as to study the histopathological changes.
With the increasing number of free-range domestic chickens, helminth parasites have potentially become more of a threat to commercial flocks in recent years, and routine poultry deworming is needed to improve the efficiency of chicken production. The present study deals with a field trial to study the efficacy of two generally used anthelmintics, fenbendazole and levamisole, against gastrointestinal nematodes of domestic chickens in northern Iran.
The ongoing and widespread emergence of resistance to the existing anti-nematodal pharmacopeia has made it imperative to develop new anthelminthic agents. Historically, plants have been important sources of therapeutic compounds and offer an alternative to synthetic drugs. Monoterpenoids are phytochemicals that have been shown to produce acute toxic effects in insects and nematodes. Previous studies have shown nicotinic acetylcholine receptors (nAChRs) to be possible targets for naturally occurring plant metabolites such as carvacrol and carveol. In this study we examined the effects of monoterpenoid compounds on a levamisole sensitive nAChR from Oesophagostomum dentatum and a nicotine sensitive nAChR from Ascaris suum. We expressed the receptors in Xenopus laevis oocytes and used two-electrode voltage-clamp to characterize the effect of various compounds on these cys-loop receptors. At 100 μM the majority of these compounds acted as antagonists. Interestingly, further experiments revealed that both 0.1 μM and 10 μM menthol potentiated acetylcholine and levamisole responses in the levamisole sensitive receptor but not the nicotine sensitive receptor. We also investigated the effects of 0.1 μM menthol on the contractility of A. suum somatic muscle strips. Menthol produced significant potentiation of peak contractions at each concentration of acetylcholine. The positive allosteric modulatory effects of menthol in both in vivo and in vitro experiments suggests menthol as a promising candidate for combination therapy with cholinergic anthelmintics.
Helminth parasites rely on fast-synaptic transmission in their neuromusculature to experience the outside world and respond to it. Acetylcholine plays a pivotal role in this and its receptors are targeted by a wide variety of both natural and synthetic compounds used in human health and for the control of parasitic disease. The model, Caenorhabditis elegans is characterized by a large number of acetylcholine receptor subunit genes, a feature shared across the nematodes. This dynamic family is characterized by both gene duplication and loss between species. The pentameric levamisole-sensitive acetylcholine receptor has been characterized from C. elegans, comprised of five different subunits. More recently, cognate receptors have been reconstituted from multiple parasitic nematodes that are found to vary in subunit composition. In order to understand the implications of receptor composition change and the origins of potentially novel drug targets, we investigated a specific example of subunit duplication based on analysis of genome data for 25 species from the 50 helminth genome initiative. We found multiple independent duplications of the unc-29, acetylcholine receptor subunit, where codon substitution rate analysis identified positive, directional selection acting on amino acid positions associated with subunit assembly. Characterization of four gene copies from a model parasitic nematode, Haemonchus contortus, demonstrated that each copy has acquired unique functional characteristics based on phenotype rescue of transgenic C. elegans and electrophysiology of receptors reconstituted in Xenopus oocytes. We found evidence that a specific incompatibility has evolved for two subunits co-expressed in muscle. We demonstrated that functional divergence of acetylcholine receptors, driven by directional selection, can occur more rapidly than previously thought and may be mediated by alteration of receptor assembly. This phenomenon is common among the clade V parasitic nematodes and this work provides a foundation for understanding the broader context of changing anthelmintic drug targets across the parasitic nematodes.
Cocaine-related deaths occur regularly in forensic routine work. In cases in which the detected concentration of cocaine is rather low and other causes of death apart from intoxication can be ruled out, the question arises if adulterants of cocaine might have played a crucial role. In the present study, cardiac effects of cocaine, of the adulterant levamisole and of mixtures of both were evaluated using the isolated perfused Langendorff heart. While exposed to the substances, functional parameters heart rate, left ventricular pressure and coronary flow were documented. Relevant alterations of these parameters were found for cocaine as well as for levamisole. Exposing the hearts to a mixture of both resulted in a combination of these effects; the emergence of new alterations or an obvious aggravation were not detected. Nevertheless, the results imply that the consumption of cocaine adulterated with levamisole bares an increased risk for cardiac complications, especially in the presence of preexisting cardiac pathologies.
Cholinergic agonists, like levamisole, are a major class of anthelmintic drugs that are known to act selectively on nicotinic acetylcholine receptors (nAChRs) on the somatic muscle and nerves of nematode parasites to produce their contraction and spastic paralysis. Previous studies have suggested that in addition to the nAChRs found on muscle and nerves, there are nAChRs on non-excitable tissues of nematode parasites. We looked for evidence of nAChRs expression in the cells of the intestine of the large pig nematode, Ascaris suum, using RT-PCR and RNAscope in situ hybridization and detected mRNA of nAChR subunits in the cells. These subunits include components of the putative levamisole receptor in A. suum muscle: Asu-unc-38, Asu-unc-29, Asu-unc-63 and Asu-acr-8. Relative expression of these mRNAs in A. suum intestine was quantified by qPCR. We also looked for and found expression of G protein-linked acetylcholine receptors (Asu-gar-1). We used Fluo-3 AM to detect intracellular calcium changes in response to receptor activation by acetylcholine (as a non-selective agonist) and levamisole (as an L-type nAChR agonist) to look for evidence of functioning nAChRs in the intestine. We found that both acetylcholine and levamisole elicited increases in intracellular calcium but their signal profiles in isolated intestinal tissues were different, suggesting activation of different receptor sets. The levamisole responses were blocked by mecamylamine, a nicotinic receptor antagonist in A. suum, indicating the activation of intestinal nAChRs rather than G protein-linked acetylcholine receptors (GARs) by levamisole. The detection of nAChRs in cells of the intestine, in addition to those on muscles and nerves, reveals another site of action of the cholinergic anthelmintics and a site that may contribute to the synergistic interactions of cholinergic anthelmintics with other anthelmintics that affect the intestine (Cry5B).
Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use.
The use of the anthelmintic levamisole as a cocaine adulterant has been increasing worldwide. Complications caused by this association include systemic vasculitis, agranulocytosis, neutropenia, tissue necrosis, pulmonary hemorrhage, and renal injury. Data about toxicity of levamisole are scarce, therefore the aim of this study was to evaluate the acute and subchronic toxic effects of levamisole in rats. Male Wistar rats received saline or levamisole by intraperitoneal route at the doses of 12, 24 and 36 mg/kg in the acute toxicity test; and at 3, 6 and 12 mg/kg in the subchronic toxicity test. Toxicity was evaluated using behavioral, cognitive, renal, hematological, biochemical and histopathological parameters. Acute administration of levamisole caused behavioral and histopathological alterations. Subchronic administration caused behavioral, cognitive and hematological alterations (p < 0.0001 and p < 0.05, respectively), impairment of liver and kidney functions (p < 0.05), and changes of antioxidant defenses (p ≤ 0.0001). Both administrations produced toxic effects of clinical relevance, which make levamisole a dangerous cutting agent. Furthermore, the knowledge of these effects can contribute to the correct diagnosis and treatment of cocaine dependents with unusual systemic alterations.
Levamisole (LEVA) is used to treat worm infections, but it can also inhibit cancer cell growth by inhibiting the aldehyde dehydrogenase pathway. Therefore, here, we developed a drug carrier targeting CD133, a biomarker overexpressed in ovarian cancer cells. The particle structure and cytotoxicity of the prepared LEVA-containing particles-called LEVA/PVP/PMMA microparticles (MPs) (because it used matrix material polyvinylpyrrolidone (PVP) and poly(methylmethacrylate) (PMMA))-were investigated in the ovarian cancer cell lines SKOV-3 and CP70. The particle size of the MPs was determined to be 1.0-1.5 µm and to be monodispersed. The hydrophilic property of PVP created a porous MP surface after the MPs were soaked in water for 20 min, which aided the leaching of the hydrophilic LEVA out of the MPs. The encapsulation efficiency of LEVA/PVP/PMMA MPs could reach up to 20%. Free-form LEVA released 50% of drugs in <1 h and 90% of drugs in 1 day, whereas the drug release rate of LEVA/PVP/PMMA MPs was much slower; 50% released in 4 h and only 70% of drugs released in 1 day. In the in vitro cell model test, 5 mM free-form LEVA and 0.1 g/mL CD133 targeted LEVA/PVP/PMMA MPs reduced SKOV-3 cell viability by 60%; 0.1 g/mL LEVA/PVP/PMMA MPs was equivalent to a similar dosage of the free drug. In addition, the cytotoxicity of CD133-conjugated LEVA/PVP/PMMA MPs shows a different cytotoxicity response toward cell lines. For SKOV-3 cells, treatment with free-form LEVA or CD133-conjugated LEVA/PVP/PMMA MPs exerted dose-dependent cytotoxic effects on SKOV-3 cell viability. However, CD133-conjugated LEVA/PVP/PMMA MPs demonstrated no significant dose-dependent cytotoxic efficacy toward CP70 cells.
Haemonchus contortus is a haematophagous parasitic nematode that infects small ruminants and causes significant animal health concerns and economic losses within the livestock industry on a global scale. Treatment primarily depends on broad-spectrum anthelmintics, however, resistance is established or rapidly emerging against all major drug classes. Levamisole (LEV) remains an important treatment option for parasite control, as resistance to LEV is less prevalent than to members of other major classes of anthelmintics. LEV is an acetylcholine receptor (AChR) agonist that, when bound, results in paralysis of the worm. Numerous studies implicated the AChR sub-unit, ACR-8, in LEV sensitivity and in particular, the presence of a truncated acr-8 transcript or a deletion in the acr-8 locus in some resistant isolates. Recently, a single non-synonymous SNP in acr-8 conferring a serine-to-threonine substitution (S168T) was identified that was strongly associated with LEV resistance. Here, we investigate the role of genetic variation at the acr-8 locus in a controlled genetic cross between the LEV susceptible MHco3(ISE) and LEV resistant MHco18(UGA2004) isolates of H. contortus. Using single worm PCR assays, we found that the presence of S168T was strongly associated with LEV resistance in the parental isolates and F3 progeny of the genetic cross surviving LEV treatment. We developed and optimised an allele-specific PCR assay for the detection of S168T and validated the assay using laboratory isolates and field samples that were phenotyped for LEV resistance. In the LEV-resistant field population, a high proportion (>75%) of L3 encoded the S168T variant, whereas the variant was absent in the susceptible isolates studied. These data further support the potential role of acr-8 S168T in LEV resistance, with the allele-specific PCR providing an important step towards establishing a sensitive molecular diagnostic test for LEV resistance.
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