Levamisole derivatives as immune modulators for the treatment of amyotrophic lateral sclerosis (ALS).

Aim: To discover derivatives of the anthelmintic drug levamisole, which has been reported to possess immune-modulatory properties, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of the racemic version of levamisole, tetramisole, as well as eleven analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant cytokines. Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.

Aim: To discover derivatives of the antiparasitic worm drug levamisole, which has been reported to be able to modulate the immune response, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of a variation of levamisole, tetramisole, as well as 11 analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant immune-modulatory substances (cytokines). Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.

Influence of sustained deworming pressure on the anthelmintic resistance status in strongyles of sheep under field conditions.

Anthelmintic resistance (AR) status in Madras Red sheep from selected field flocks of a government funded scheme, covered by regular, sustained anthelmintic treatment for more than 10 years was determined. Parameters such as fecal egg count reduction test (FECRT), larval paralysis assay (LPA), and allele-specific-PCR (AS-PCR) were used to test the efficacy of fenbendazole, tetramisole, and ivermectin at recommended doses, in two seasons. Sheep belonging to non-beneficiary farmers were used as controls. Mean FECRT values of beneficiary group during winter and summer seasons were 77.77 and 76.04, 93.65 and 92.12, and 95.37 and 98.06 %, respectively, for fenbendazole, tetramisole, and ivermectin. In the non-beneficiary groups, the corresponding values were 74.82 and 81.09 %, 96.05 and 97.40 %, and 97.26 and 98.23 %, respectively. The results revealed resistance to fenbendazole, suspect resistance to tetramisole and susceptibility to ivermectin in beneficiary flock. In non-beneficiary flock, while resistance was noticed against fenbendazole, both tetramisole and ivermectin were effective. FECR values were found to be significantly different between beneficiary and non-beneficiary groups against tetramisole. The results of LPA confirmed this finding, as 50 % of the Haemonchus contortus larvae were paralyzed at the concentration of 0.0156 µg/ml in the beneficiary group, while those of non-beneficiary groups required lower concentrations of 0.0078 µg/ml. AS-PCR revealed the predominance of heterozygous susceptible population of H. contortus in the beneficiary group. In this study, resistance to fenbendazole was confirmed in both the beneficiary and non-beneficiary groups and this could be attributed to frequent use of benzimidazoles as seen from the deworming records. Emergence of tetramisole resistance was detected in the beneficiary group, where the drug was used continuously for 4 years. Ivermectin was found to be effective in all the flocks. It is recommended that the practice of routine deworming of three to four times a year should be avoided, as it can lead to emergence of anthelmintic resistance.

Anthelmintic resistance of nematode parasites of small ruminants in eastern Ethiopia: exploitation of refugia to restore anthelmintic efficacy.

Faecal egg count reduction tests (FECRT) were conducted in May 2003 to determine the efficacy of anthelmintics used for treatment against nematode parasites in separately managed sheep and goat flocks at Alemaya University in eastern Ethiopia. These tests revealed high levels of anthelmintic resistance to albendazole, tetramisole, the combination of these two drugs, and to ivermectin in the goat flock (predominantly infected by Haemonchus contortus and Trichostrongylus spp.), whereas all drugs were highly efficacious in the sheep flock. A second FECRT confirmed these observations. Following this, a new management system was implemented on the goat flock for a period of 9 months (January-September 2004) in an attempt to restore the anthelmintic efficacy. This involved a combination of measures: eliminating the existing parasite infections in the goats, exclusion from the traditional goat pastures, and introducing communal grazing of the goats with the university sheep flock and livestock owned by neighbouring small-holder farmers. A second series of FECRTs (Tests 3 and 4) conducted 7 months after this change in management, showed high levels of efficacy to all three drugs (albendazole, tetramisole and ivermectin) in the goat flock. This is the first field study to demonstrate that anthelmintic efficacy in the control of nematode parasites of small ruminants can be restored by exploiting refugia.

Anthelmintic resistance on an organized sheep farm in India.

Monitoring anthelmintic resistance in strongyle nematodes by the faecal egg count reduction test and a commercial larval development assay on an organized sheep farm in the semi-arid area of Rajasthan revealed the emergence of resistance to benzimidazoles and rafoxanide and a potential risk of the development of levamisole/tetramisole resistance. A benzimidazole/levamisole combination, avermectins and closantel were each found to be efficacious.

Comparative anthelmintic activity of strategic sustained low-level administration of albendazole in feed pellets compared to single doses of closantel and tetramisole against natural ovine parasitic gastroenteritis.

The strategic use of single therapeutic doses of closantel, tetramisole or sustained low-level administration of albendazole in feed pellets in controlling naturally acquired parasitic gastroenteritis in sheep was investigated on a farm in semi-arid Rajasthan, India. A total of 303 5- to 6-month-old sheep were divided into three groups. Two groups were dosed with single therapeutic doses of closantel and tetramisole and the third group was given a low-level medication with albendazole through feed pellets for 30 days. Faecal egg counts revealed significantly lower counts (p<0.001) in the group treated with closantel compared to the other two groups. The faecal egg counts in the group receiving sustained low-level albendazole rose after withdrawal of the medication but remained significantly lower than those in the group treated with tetramisole up to 7 weeks after treatment (p<0.05). On the other hand, in the group treated with tetramisole, the mean faecal egg count rose from 3 weeks after treatment and remained continuously higher than those in any other group up to 12 weeks after treatment. The closantel-treated group gained more body weight but the first six-monthly greasy fleece yield was greater in the group treated with medicated pellets. During the first 3 months of the experiment, three animals in the group treated with tetramisole died of parasitic gastroenteritis. Following sustained low-level administration of albendazole in feed pellets, the plasma disposition curve of both the sulphoxide and sulphone metabolites reached its plateau level by day 5 and remained almost constant thereafter. The comparative cost-effectiveness of the three treatment regimes during the first 3 months of treatment was best for the group treated with closantel followed by the group treated with medicated feed pellets.

[Levamisole- and tetramisole-resistant gastrointestinal nematodes in sheep]. / Nález gastrointestinálnych nematódov u oviec rezistentných k levamizolu a tetramizolu.

Two experiments were carried out with sheep naturally infected with gastrointestinal nematodes to evaluate efficacy of anthelmintics using in vivo faecal egg count reduction (FECR) test. In experiment 1 with 28 ewes, the following efficacy of anthelmintics given at recommended dose rates was observed: albendazole 99.4%, ivermectin 99.3% and levamisole 81.8%. In experiment 2 with 18 ewes, tetramisole exhibited 71.3% efficacy. Suspected resistance to imidothiazole anthelmintics was confirmed by in vitro larval development test (LDT)--minimal inhibition concentration (MIC) values were estimated at 2.0 micrograms/ml. Infective larvae L3 cultivated from eggs produced by the population of resistant helminths were identified as Ostertagia and Trichostrongylus spp.

[Udder compatibility of tetramisole and levamisole hydrochloride and suggestion for the prescription of their intramammary use in cattle against Prototheca zopfii]. / Euterverträglichkeit von Tetramisol- und Levamisolhydrochlorid und Rezepturvorschlag zum intramammären Einsatz beim Rind gegen Prototheca zopfii.

Preparations with 4 percent Tetramisole or Levamisole hydrochloride were compatible in the mammary gland after application up to 40 ml/quarter (4 mg/kg body mass) for up to 6 milking times. 100 ml of the preparations were also clinically compatible in a single quarter (10 mg/kg body mass) on several days. After intramammary application of 30 ml/quarter (3 mg/kg body mass) Prototheca suppressing values in milk serum were evident for at least 6 hours. One application of 200 ml in one quarter has caused Prototheca suppressing values for 36 hours in milk serum up to dilution 1:4. Nilverm given to cattle in high dosage orally did not lead to Prototheca suppressing values in milk sera.

[Experimental Prototheca mastitis in cattle and therapy with tetramisole hydrochloride]. / Experimentelle Prototheken-Mastitis beim Rind und Therapie mit Tetramisolhydrochlorid.

In one cow all 4 quarters were infected with 2 x 10(8) germs of Prototheca zopfii each. 2 quarters of it were treated over 6 subsequent milking times with 20 ml Tetramisole hydrochloride (4 mg/kg body mass) in each case. Clinical symptoms diminished within 3-24 hours after the first application in comparison with the control quarters distinctly. Macroscopic alterations in the treated quarters could be found for a short time only, whereas they were evident in the control quarters for up to 2 days. The milk cell counts were raised til the 5. day p.i. The number of Prototheca excreted by treated quarters in each ml initial milk was reduced to 38% and in each ml end milk to 67% in comparison with the 2 control quarters. A more potent reduction of Prototheca can be expected after the application of Levamisole hydrochloride. At the future therapy applications after every milking time for at least 3 days with 25-40 ml of the preparations in each quarter are recommended. A total dose per animal and application time of 150 ml preparations (6 g Levamisole hydrochloride = 15 mg/kg body mass) must not be exceeded. Before Levamisole hydrochloride may be used for patients, susceptibility tests are necessary of the strains of Prototheca zopfii present and additional investigations for the reliability of the results hitherto obtained in one experimental Prototheca mastitis only.

Controlled tests of activity of several antiparasitic compounds against natural infections of Haemonchus contortus and other helminths in lambs from a flock established in 1962.

Antiparasitic activity of several compounds was evaluated over a long period (about 25 years) in the same flock of sheep. Haemonchus contortus was of special interest, including its relation to drug resistance, especially to thiabendazole and other benzimidazoles, in addition to phenothiazine. Eleven compounds were evaluated in 15 controlled tests, done between 1966 and 1989 in naturally infected lambs (n = 145) born and raised on the same pasture. Sheep were first placed on the pasture in 1962, and a few more were added thereafter. Internal parasites in these sheep were classified in 3 general categories: indeterminate exposure to parasiticides; H contortus, resistant to thiabendazole; and H contortus, resistant to phenothiazine. The parasitic infections probably became more homogeneous after several years because of few introductions of outside sheep after initial establishment of the flock. Activity against naturally acquired internal helminths was evaluated for cambendazole (CBZ: dosage, 20 mg/kg of body weight), fenbendazole (FBZ: 5 or 7.5 mg/kg), mebendazole (MBZ: 10 mg/kg); oxfendazole (OFZ: 3.5 or 10 mg/kg), oxibendazole (OBZ: 10 mg/kg); parbendazole (PBZ: 15 mg/kg), phenothiazine (PTZ: 550 mg/kg); pyrantel pamoate (PRT: 25 mg base/kg), tetramizole (TET: 15 mg/kg); thiabendazole (TBZ: 30 or 44 mg/kg), and trichlorfon (TCF: 100 mg/kg). Thiabendazole was used more often (9 tests) than the other compounds. Thiabendazole was more active against mature H contortus in later years than when first used in 1966, although it was never 100% effective. Efficacy against immature H contortus for TBZ did not exceed 86%. Activity against immature and mature stages of this parasite was good overall for the other benzimidazoles.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Nippostrongylus brasiliensis in normal and SPF rats using tetramisole loaded into zeolite.

Administration to rats of tetramisole loaded into zeolite was more successful in killing adults of Nippostrongylus brasiliensis than the administration of tetramisole alone. The most successful treatment occurred in SPF (Specific Pathogen Free) rats dosed with tetramisole loaded into zeolite and no worms were present in this group at autopsy eight days post-infection. It is concluded that the slow release of drug from the zeolite matrix improved its efficacy, especially in removing worms from low-grade infections.

Isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole with broad-spectrum anthelmintic activity.

A series of isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (tetramisole) is described. The compounds are prepared by the S-alkylation of the thioureas that were obtained either by the reaction of an amine with 6-(3-isothiocyanatophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b] thiazole or by the reaction of an isothiocyanate with 6-(3-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. These derivatives have an improved spectrum of activity over tetramisole and are active against nematodes, cestodes, and trematodes. The structure-activity relationships are discussed.

Uso del tetramisol en el tratamiento de la gripe / Use of tetramisol for grippe therapy

Se estudiaron 100 niños menores de 15 años que presentaron síndrome gripal, que asistieron al Cuerpo de Guardia de nuestro centro en la fase aguda de la afección y a los que se les dio como parte del tratamiento tetramisol en dosis de 2,5 mg/kg/d, por vía oral, durante 14 días. La evolución de éstos fue comparada con la de otros 100 niños con igual afección que acudieron durante el mismo período y con la distribución de edad similar, los que se utilizaron como grupo control y los cuales sólo recibieron tratamiento convencional. (AU)

[Trials of immunostimulation of an antitoxic response with levamisole in the immunization of sheep with a combined clostridial vaccine]. / Opiti za imunostimulatsiia na antitoksichniia otgovor posredstvom levamizol pri imunizirane na ovtse s kombinirana klostridialna vaksina.

Comparative investigations were carried out on the antibody level in test animals--sheep, vaccinated with a polyvaccine against C and D enterotoxemia and necrotic hepatitis as well as in combined application with Levamisol. It was found that with the use of the preparation the stimulation of immunogenesis with type D and necrotic hepatitis--type B antigens (included in the composition of the polyvaccine) was enhanced. No stimulation of immunogenesis with the type C specific antigen was found within the period of investigation. Immunity was better built up when the animals were treated with the combined product as compared with the controls, given the polyvaccine without Levamisol.

Response of preadult Necator americanus to some known anthelmintics in hamsters.

Hamsters infected with laboratory-adapted preadult Necator americanus were dosed with 6 reference anthelmintics. Their efficacy was measured in terms of percentage cure of infected animals as well as percentage worm reduction following treatment. Mebendazole and pyrantel were equally effective in this system. Other anthelmintics, including anti-hookworm compound, bephenium hydroxynaphthoate, were less effective. The comparative results revealed that the N. americanus model is sensitive and reliable for identifying and characterizing new anti-parasite preparations.

[Helminths in an Askaniia-Nova herd of eland and experiences in eradicating Strongylata infestation]. / Izuchenie gel'mintov u Askaniiskogo stada antilop kanna i opyt ikh ozdorovleniia ot strongiliatozov.

Parasitological complex studies of the available eland stock (60 individuals) were first carried out. As a result 100 % infection rate of the herd and the age dynamics of strongylatoses were revealed. The autopsy of animals have shown that five species of six species of nematodes and one species of cestodes are common parasites of ruminants of the Ukraine steppe zone and two species are specific parasites of eland. For sanitation of the herd an anthelminthic preparation produced in Hungary was used. The preparation decreased the initial infection rate to 7.3%.

[Research on the cat stomach worm, Ollulanus tricuspis (Leuckart, 1865)--state of the art]. / Der Magenwurm der Katze, Ollulanus tricuspis (Leuckart, 1865)--zum gegenwärtigen Stand der Kenntnis.

The stomach worm of the cat with an unusual cycle has a special place among the nematodes. O. tricuspis can develop and breed endogen as well as exogen, the infection of other hosts with freedom of movement, takes place through the ingestion of vomitus material containing parasites. As the conventional coproscopic methods of routine diagnosis have failed, the examination of gastric mucus or gastric mucosal scrapings post mortem offers itself. Intra vitam a provocated vomitus or a gastric irrigation are the diagnostic methods of choice. Increased vomiting of unknown genesis should, however, evoke suspicion relating to an O. tricuspis-infection and suggest an examination of the material. Besides the cat, dog, pig, wild cat, fox, cheetah, lion and tiger act as natural or inadequate hosts. Pathological alterations or clinical symptoms are more obvious in unusual carriers of parasites. Therapeutically only Citarin 2,5% was convincing.

[Toxicological and clinical research on Pharmachim's levamisole]. / Toksikologichni i klinichni prouchvaniia na levamizol "Farmakhim".

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.