Broad-spectrum Anthelmintic Activity Research Articles

CONTRIBUCIONES CIENTIFICAS DE LA FMVZ-UADY SOBRE Petiveria alliacea: ALTERNATIVA DE CONTROL DE GARRAPATAS Y NEMATODOS EN ANIMALES DOMÉSTIC

<p><strong>Background.</strong> In tropical and subtropical regions of the world, ticks and nematodes negatively affect the health and welfare of animals, the search for natural alternatives for parasite control is necessary to reduce resistance and dependence to antiparasitics. <strong>Objective</strong>. To present the main findings on the acaricidal and anthelmintic activity of <em>Petiveria alliacea</em> against ticks and nematodes of domestic animals. <strong>Methodology.</strong> Scientific articles were compiled from studies carried out by the animal health academic research group of the Faculty of Veterinary Medicine and Zootechnics of the Autonomous University of Yucatán. The review focused on the use of methanolic extracts and compounds from <em>P. alliacea</em> against larvae and adults of <em>Rhipicephalus microplus</em>, as well as against nematodes of the order strongylida such as <em>Ancylostoma</em> spp., <em>Haemonchus</em> spp. and cyathostomids. <strong>Main findings. </strong>Research on the biological activity of <em>P. alliacea</em> extracts have shown their acaricidal and anthelmintic potential. Extracts of <em>P. alliacea</em> showed high mortality rates on larvae and adult females of <em>R. microplus</em> resistant to ixodicides, as well as a decrease in reproductive parameters (inhibition of oviposition and hatching inhibition). The acaricidal activity of <em>P. alliacea</em> is attributed to the presence of the sulfur compounds dibenzyl trisulfide and dibenzyl disulfide, which cause histological damage to the reproductive system of adult females, affecting the oogenesis process. Additionally, <em>P. alliacea</em> demonstrated broad spectrum anthelmintic activity, exhibiting high percentages of hatching inhibition on <em>A. caninum</em>, <em>H. placei</em> and cyathostomid eggs. A difference was also observed in the acaricidal and anthelmintic activity depending on the part of the plant and the time of collection. <strong>Implications.</strong> Further studies are needed to identify anthelmintic active compounds of <em>P. alliacea</em>, elucidate the mechanisms of action of these compounds, and test both acaricidal and anthelmintic compounds in <em>in vivo</em> studies. <strong>Conclusions</strong>. The extracts of <em>P. alliacea</em> and its compounds showed high acaricidal and anthelmintic activity against <em>R. microplus</em> ticks and nematodes of the order strongylida of domestic animals, due to this, they are a potential control alternative for broad spectrum.</p>

Preparation of Pharmaceutical Formula of Rafoxanide and Levamisole 6% Suspension as Pilot Production

A 100 litter of pharmaceutical formula of veterinary drug Rafoxanide and Levamisole with 6% suspension as pilot production was prepared. The formula contains two active ingredients with a broad spectrum anthelmintic activity. Rafoxanide belong belongs to salicylanilide group used for treatment and control of mature and immature liver flukes in cattle, sheep and goats. Levamisole belongs to Bezimidazole compounds and is active against gastrointestinal worms and against lung worms in cattle, sheep and goats. The drug formula is a white color suspension prepared according to scientific literature. Information was collected for all substances in the formulation for active ingredient ingredients and additives. The chemical assay was carried out on the active ingredients and the final formula and the results showed that they conform to the constitutional specifications. The results of the chemical assay of Rafoxanide (102.7%) and levamisole (101%) were found to be within the approved constitutional limits (90-110%) with the adoption of the results of stability study at temperatures (40, 50, 60 °C). The stability of the pharmaceutical formula was observed within the permissible constitutional limits.

Chemical composition and broad-spectrum anthelmintic activity of a cultivar of toothache plant, Acmella oleracea, from Mizoram, India

Context A variety of Acmella oleracea (L.) R.K. Jansen (Asteraceae) is used by the Mizo people of India and Myanmar for intestinal helminthiasis. Objective To perform a chemical analysis of the plant extract using gas chromatography-mass spectrometry (GC-MS) and test the anthelmintic activity on intestinal parasites. Materials and methods An extract of the aerial parts was prepared in hexane and analysed using GC-MS. Survival test was performed in vitro on the cestode, Taenia tetragona, and the nematode, Ascaridia perspicillum. Concentrations of 1.25, 2.5, 5, 10 and 20 mg/mL, prepared in phosphate-buffered saline (PBS) with 1% dimethylsulphoxide (DMSO), were tested. Negative control was maintained in PBS with DMSO, and albendazole was used as a reference drug. Each treatment consisted of six worms and was done until death was confirmed. Scanning electron microscopy was used to describe the structural changes. Results Nineteen compounds were detected. The major compounds were fatty alcohols such as 3,7,11,15-tetramethylhexadec-2-en-1-ol and (9Z)-9-hexadecen-1-ol. Important bioactive compounds including an alkylamide, N-isobutyl-(2E,4Z,8Z,10E)-dodecatetraenamide, and a triterpenoid, lupeol, were also confirmed. The lethal concentration (LC50) of the plant extract was 5128.61 ppm on T. tetragona and 8921.50 ppm on A. perspicillum. Tegumental shrinkage, erosion of microtriches, and distortion of the suckers were observed on the cestode. The nematode showed collapse of the lips and shrunk cuticle. Conclusions Acmella oleracea contains important bioactive compounds, which are responsible for the broad-spectrum anthelmintic activity. Further study on the pharmacology of the compounds is warranted.

Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics

Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm parasites. Here, we performed omics-driven knowledge-based identification of chokepoint enzymes as anthelmintic targets. We prioritized 10 of 186 phylogenetically conserved chokepoint enzymes and undertook a target class repurposing approach to test and identify new small molecules with broad spectrum anthelmintic activity. First, we identified and tested 94 commercially available compounds using an in vitro phenotypic assay, and discovered 11 hits that inhibited nematode motility. Based on these findings, we performed chemogenomic screening and tested 32 additional compounds, identifying 6 more active hits. Overall, 6 intestinal (single-species), 5 potential pan-intestinal (whipworm and hookworm) and 6 pan-Phylum Nematoda (intestinal and filarial species) small molecule inhibitors were identified, including multiple azoles, Tadalafil and Torin-1. The active hit compounds targeted three different target classes in humans, which are involved in various pathways, including carbohydrate, amino acid and nucleotide metabolism. Last, using representative inhibitors from each target class, we demonstrated in vivo efficacy characterized by negative effects on parasite fecundity in hamsters infected with hookworms.

Anthelmintic Activity of Fruit Extract and Fractions of Piper longum L. In vitro

The present study was aimed to assess the in vitro ovicidal, larvicidal and adulticidal activity of methanolic extract and its fractions from fruits of Piper longum against strongyle ova, larvae and adult amphistomes respectively. The fruits of P. longum was identified and the accession number 006 was obtained. The phytochemical analysis revealed the presence of tannins, flavonoids, glycosides, phenolics, diterpenes and triterpenes in extract and fractions of P. longum. The extract and fractions were diluted serially in 6.25 per cent tween 80 to obtain concentrations of 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.91 and 1.95 mg/mL. Ivermectin and thiabendazole at 10 μg/mL acted as positive controls and 6.25 per cent tween 80 as negative control. The methanolic extract was highly active against ova with IC50 of 0.026 mg/mL. The n-hexane fraction was potent in inducing larval mortality with IC50 of 1.383 mg/mL while chloroform fraction inhibited larval migration with IC50 of 1.796 mg/mL. Amphistomes were highly sensitive for methanolic extract of P. longum which possessed IC50 of 5.493 mg/mL Based on IC50 values, the methanolic extract was found to be most potent while chloroform fraction was effective against ova, larvae and also adults. GCMS analysis of potent methanolic extract revealed the presence of piperidinone, hydrocinnamic acid, ethylhexahydro azepine, methyleugenol, hexadecanoic acid and caryophyllene oxide which may have contributed for the anthelmintic activity. The acute oral toxicity study revealed mild vascular changes in liver. From the present study, it can be concluded that chloroform fraction of P. longum possessed maximum broad spectrum anthelmintic activity comparable to controls.

Evaluation of broad-spectrum anthelmintic activity in a novel assay against Haemonchus contortus, Trichostrongylus colubriformis and T. sigmodontis in the gerbil Meriones unguiculatus

The gerbil Meriones unguiculatus, infected with three species of nematodes, each located in a separate part of the gastrointestinal tract, provided a reliable laboratory assay for the evaluation of broad-spectrum anthelmintic activity. Gerbils harbouring 6-day-old infections of Haemonchus contortus, Trichostrongylus colubriformis and T. sigmodontis were given selected broad-spectrum anthelmintics by gavage. Three benzimidazoles, thiabendazole, oxfendazole and albendazole, a tetrahydropyrimidine, morantel, an imidazothiazole, levamisole hydrochloride, a macrocyclic lactone, ivermectin and an experimental natural product, paraherquamide, were active against all three nematodes at various dosages. Trichostrongylus colubriformis was most sensitive to levamisole hydrochloride, morantel, thiabendazole and paraherquamide whereas ivermectin, oxfendazole and albendazole were more effective against H. contortus. All compounds were active against the caecal nematode T. sigmodontis although it was less sensitive than T. colubriformis. Haemonchus contortus was more sensitive than T. sigmodontis to all anthelmintics tested except thiabendazole.

Evaluation of the efficacy of emodepside+praziquantel topical solution against cestode (Dipylidium caninum, Taenia taeniaeformis, and Echinococcus multilocularis) infections in cats

Emodepside+praziquantel topical solution was developed to provide broad-spectrum anthelmintic activity against gastrointestinal parasites in cats. Eight controlled studies were conducted to evaluate the efficacy of a topical solution of emodepside (3 mg/kg) and praziquantel (12 mg/kg) (Profender, BayerAG, Leverkusen, Germany) against feline infections with three species of cestodes. Studies featured naturally acquired infections of Dipylidium caninum or Taenia taeniaeformis, or experimental infections with Echinococcus multilocularis that were placebo-controlled, randomized and blinded. Cats were euthanatized and necropsied between 2 and 11 days after treatment, depending on the target parasite. The efficacy of emodepside+praziquantel topical solution was 100% against D. caninum and T. taeniaeformis, and 98.5- 100% against E. multilocularis. No significant systemic or local adverse reactions to treatment were noted in cats that received the combination. Topical treatment of cats with emodepside+praziquantel topical solution was safe and highly effective against cestode infections.

Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals.

Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.

Synthesis of avermectin B 1-4″,4″a-oxide: a precursor of potent anthelmintic agents

Treatment of 4″-oxo-5-OTBDMS-Avermectin B 1 ( 2) with trimethylsilyldiazomethane or diazomethane resulted in the stereoselective formation of the 4″,4″a-oxide ( 3) in addition to the ring-expanded oxepinyl epoxide ( 4). The resultant epoxides were opened regiospecifically with sulfur, amine and halogen nucleophiles. The new 4″-substituted avermectins thus formed exhibited potent, broad-spectrum anthelmintic activity.

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.

Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance.

Avermectin B1a, a macrocyclic lactone with broad spectrum anthelmintic activity, affects neuromuscular transmission in the lobster stretcher muscle. Perfusion of the muscle with 1-10 microgram of the drug per ml eliminates inhibitory postsynaptic potentials within a few minutes. Intracellularly recorded excitatory postsynaptic potentials are gradually reduced in amplitude over 20-30 min, and their falling phases become faster; there is no effect, however, on extracellularly recorded excitatory potentials. Avermectin B1a reduced the input resistance of the muscle fibers with a time course similar to that of the reduction of excitatory potentials. Washing for up to 2 hr with drug-free solution fails to reverse the drug's effects. However, perfusion with 20 microgram of picrotoxin per ml results in recovery of the excitatory potentials and input resistance. Avermectin B1a also blocks the firing of the crayfish stretch receptor neuron, and this block is also reversed by picrotoxin. We hypothesize that the reduction in excitatory postsynaptic potentials after avermectin B1a treatment is caused solely by reduction in membrane resistance; additional experiments suggest that the reduction in membrane resistance is due to the opening of membrane Cl- channels, perhaps including those regulated by gamma-aminobutyric acid at the inhibitory synapse.

Thiabendazole in human filariasis

Thiabendazole was used in the treatment of patients with Loa loa, A. perstans and O. volvulus infections, in a dose of 25 mg. per kg. twice a day for 5–10 days, and was found ineffective. This study was prompted by its reported efficacy in the treatment of tropical eosinophilia and trichinosis. Doses larger than the one prescribed were found to increase the frequency of toxic effects in patients and were therefore abandoned. The broad spectrum anthelmintic activity of thiabendazole against A. lumbricoides, hookworm, Strongyloides stercoralis and to a less extent Trichuris trichiura was, however, confirmed in this study.

Broad-spectrum intestinal anthelmintic activity of dithiazanine

The principle of effective broad-spectrum anthelmintic activity against human intestinal nematode infections has been demonstrated by the therapeutic results obtained with dithiazanine. In proper dosage, this polyvermicide is therapeutic for trichuriasis, strongyloidiasis, ascariasis and enterobiasis. The drug has only moderate anthelmintic activity against the hookworm,Necator americanus. It fills a need for a therapeutic for trichuriasis and strongyloidiasis. Dithiazanine is useful for the treatment of patients with either single or multiple intestinal helminthic infections.