Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

Analytical Separation of Closantel Enantiomers by HPLC

Closantel is an antiparasitic drug marketed in a racemic form with one chiral center. It is meaningful to develop a method for separating and analyzing the closantel enantiomers. In this work, two enantiomeric separation methods of closantel were explored by normal-phase high-performance liquid chromatography. The influences of the chiral stationary phase (CSP) structure, the mobile phase composition, the nature and proportion of different mobile phase modifiers (alcohols and acids), and the column temperature on the enantiomeric separation of closantel were investigated in detail. The two enantiomers were successfully separated on the novel CSP of isopropyl derivatives of cyclofructan 6 and n-hexane-isopropanol-trifluoroacetic acid (97:3:0.1, v/v/v) as a mobile phase with a resolution (Rs) of about 2.48. The enantiomers were also well separated on the CSP of tris-carbamates of amylose with a higher Rs (about 3.79) when a mixture of n-hexane-isopropanol-trifluoroacetic acid (55:45:0.1, v/v/v) was used as mobile phase. Thus, the proposed separation methods can facilitate molecular pharmacological and biological research on closantel and its enantiomers.

The Pattern of Blood–Milk Exchange for Antiparasitic Drugs in Dairy Ruminants

The prolonged persistence of milk residual concentration of different antiparasitic drugs in lactating dairy animals should be considered before recommending their use (label or extra-label) for parasite control in dairy animals. The partition blood-to-milk ratio for different antiparasitic compounds depends on their ability to diffuse across the mammary gland epithelium. The high lipophilicity of some of the most widely used antiparasitic drugs explains their high partition into milk and the extended persistence of high residual concentrations in milk after treatment. Most of the antiparasitic drug compounds studied were shown to be stable in various milk-related industrial processes. Thus, the levels of residues detected in raw milk can be directly applicable to estimating consumer exposure and dietary intake calculations when consuming heat-processed fluid milk. However, after milk is processed to obtain milk products such as cheese, yogurt, ricotta, and butter, the residues of lipophilic antiparasitic drugs are higher than those measured in the milk used for their elaboration. This review article contributes pharmacokinetics-based information, which is useful to understand the relevance of rational drug-based parasite control in lactating dairy ruminants to avoid undesirable consequences of residual drug concentrations in milk and derived products intended for human consumption.

Study of the pharmacokinetics of moxidectin in the body of carnivores using an antiparasitic drug in the form of tablets

The purpose of the research is studying the pharmacokinetics of moxidectin in the blood serum of cats and dogs after a single administration of antiparasitic drug «Neoterika Protecto tablets».Materials and methods. The studies were performed at the premises of the Kurilovo experimental farm of the VNIIP – FSC VIEV on clinically healthy animals of both sexes aged 1-4 years, namely, 6 cats weighing 1.5–2.0 kg and 6 dogs weighing 10.3–13.8 kg. The drug was administered once orally at the rate of 1.5 mg of moxidectin per 1 kg of body weight. Blood samples were taken in the amount of 2 ml from cats and 4–5 ml from dogs before the drug and after 3, 6, 12, 24 hours, and 3, 6, 10, 20, 45, 60, 75, and 90 days. The study used the high-performance liquid chromatography. We determined the moxidectin content in the blood serum. Based on the results, we calculated the pharmacokinetic parameters of the active substance in the body of cats and dogs.Results and discussion. It was found that the active substance concentration within 3 hours after a single use of the moxidectin-based drug in the form of tablets reached a level of 134.8–498.0 ng/ml in cats and 479.08–1459.4 ng/ml in dogs; moxidectin was present in the bloodstream of cats and dogs for 90 days. Thus, a single administration of the drug at the recommended therapeutic dose of 1.5 mg/kg allows for the therapeutic moxidectin concentration to be maintained for 90 days.

Antibiotic treatment increases yellowness of carotenoid feather coloration in male greenfinches (Chloris chloris)

Carotenoid plumage coloration is an important sexually selected trait in many bird species. However, the mechanisms ensuring the honesty of signals based on carotenoid pigments remain unclear. It has recently been suggested that intestinal integrity, which is affected by gut parasites and microbiota and influences nutrient absorption and acquisition, mediates the relationship between carotenoid ornamentation and individual quality. Here, we test whether carotenoid plumage coloration in greenfinches (Chloris chloris) is affected by the treatment of an antibiotic or an antiparasitic drug. We captured wild greenfinches (N = 71) and administered anticoccidial medication toltrazuril (TOLTRA) to one group, antibiotic metronidazole (METRO) to the second group to target trichomonosis, and the third group received no medication. In the METRO group, feathers grown during the experiment had significantly higher chroma of yellow parts, but there was no effect of TOLTRA on feather chroma. The results suggest that METRO increased the efficiency of carotenoid modification or deposition to the feathers rather than nutrient acquisition and/or freed energy resources that could be invested in coloration. Alternatively, though not measured, METRO might have affected microbial community and host physiology as microbial metabolites can modulate mitochondrial and immune function.

Traditional Latvian herbal medicinal plants used to treat parasite infections of small ruminants: A review

Numerous treatment agents offering prophylaxis against livestock parasites are commercially available. However, because of increasing antiparasitic drug resistance, the increased popularity of environmentally friendly lifestyle choices, and organic farming, there is more demand for new alternatives to livestock anthelmintic control strategies and medications. It is important to develop antiparasitics that are safe, effective, inexpensive, and environmentally safe. Local, traditional herbal plants such as tansy, mugwort, wormwood, and heather may serve as treatments for intestinal parasites of sheep. This overview provides knowledge of traditional Latvian plants with antiparasitic activities to establish a database for further research to develop new herbal antiparasitic drugs.

Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities

As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries. However, the slow roll-out of vaccines and insufficient global supply remains a challenge to turn the tide of the pandemic. Moreover, vaccines are important tools for preventing the disease but therapeutic tools to treat patients are also needed. As such, since the beginning of the pandemic, repurposed FDA-approved drugs have been sought as potential therapeutic options for COVID-19 due to their known safety profiles and potential anti-viral effects. One of these drugs is ivermectin (IVM), an antiparasitic drug created in the 1970s. IVM later exerted antiviral activity against various viruses including SARS-CoV-2. In this review, we delineate the story of how this antiparasitic drug was eventually identified as a potential treatment option for COVID-19. We review SARS-CoV-2 lifecycle, the role of the nucleocapsid protein, the turning points in past research that provided initial ‘hints’ for IVM’s antiviral activity and its molecular mechanism of action- and finally, we culminate with the current clinical findings.

Antiparasitic Drugs for the Ttreatment and Prevention of Horse Diseases

В последние годы в Республике Беларусь активно создаются фермерские хозяйства, увеличивается поголовье лошадей на частных подворьях. Перспективным направлением является спортивное коневодство и конный туризм. Эффективное ведение отрасли современного коневодства сдерживают различные причины, среди которых немаловажную роль играют инвазионные болезни. Приводятся статистические данные по распространению паразитозов желудочно-кишечного тракта лошадей на территории Республики Беларусь в период 2004–2020 гг. Проведён ряд исследований по изучению терапевтической эффективности противопаразитарных препаратов различных фармакологических групп при моно- и полиинвазиях желудочно-кишечного тракта лошадей. Установлена высокая экстенсэффективность препаратов авермектинового ряда (авермектиновая паста 1%, паста эквисект 1%, паста алезан, ривертин 1%, универм) при нематодозах желудочно-кишечного тракта лошадей и гастерофилёзе. Получена высокая эффективность от применения нового комплексного противопаразитарного препарата для лошадей «Празимакс» при моно- и полиинвазиях, вызванных паразитами желудочно-кишечного тракта, среди которых нематоды тонкого и толстого кишечника, личинки гастерофилюсов и аноплоцефалид. In recent years, farms have been actively established in the Republic of Belarus, and the number of horses in private farms has been increasing. A promising direction is sports horse breeding and equestrian tourism. The effective management of the modern horse breeding industry is restrained by various causes, among which invasion diseases play non unimportant role. Statistical data on the spread of parasites of the gastrointestinal tract of horses in the territory of the Republic of Belarus in the period 2004–2020 are given. A number of researches have been conducted to study the therapeutic effectiveness of antiparasitic drugs of various pharmacological groups in mono- and polyinvasions of the gastrointestinal tract of horses. The high extensefficiency of avermectin series preparations (avermectin paste 1%, ekvisekt paste 1%, alezan paste, rivertin 1%, uniderm) was established with nematodosis of the gastrointestinal tract of horses and gasterophylosis. High efficiency was obtained from the use of a new complex antiparasitic drug for horses "Prazimax" in mono- and polyinvasions caused by parasites of the gastrointestinal tract, including nematodes of the small and large intestines, larvae of gastrophilus and anoplocephalids.