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Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria.

ABSTRACT: BACKGROUND:The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (?-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis. METHODS:In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells. FINDINGS:HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 ?M, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 ?M. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies. CONCLUSION:These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.

SUBMITTER: El-Saber Batiha G

PROVIDER: S-EPMC7018007 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria.

El-Saber Batiha Gaber G Magdy Beshbishy Amany A Stephen Adeyemi Oluyomi O Nadwa Eman E Rashwan Eman E Yokoyama Naoaki N Igarashi Ikuo I

PloS one 20200213 2

<h4>Background</h4>The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis.<h4>Methods</h4>In this study, the inhibitory ...[more]

PMID: 32053698

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Project description:BackgroundThe Babesia microti-like parasite is an emerging tick-borne piroplasm that has been detected in a range of hosts worldwide. Babesia vulpes, which is found in dogs and foxes, has been reclassified from B. microti-like parasites. The relationships among these B. microti-like parasites and B. vulpes with respect to host range and geographical origin have not been elucidated.MethodsBlood samples were collected from 27 raccoon dogs in South Korea and used to screen for B. microti-like parasites based on a PCR assay targeting the 18S rRNA gene of Babesia. For comparative purposes, in addition to 18S rRNA sequences from nine raccoon dogs, we also analyzed 18S rRNA sequences from B. microti-like parasites infecting hosts in different geographical regions worldwide obtained from the GenBank database, giving 123 sequences in total. The genetic variation and evolutionary relationships among these sequences were examined based on analyses using DnaSP, MEGA, Arlequine, and BEAST software.ResultsBabesia microti-like parasites were identified in nine raccoon dogs and found to be related to B. vulpes obtained from Spanish dogs. Among the 123 sequences from 14 countries and various hosts, we identified 43 haplotypes with high genetic variance. Based on the genetic variance and phylogenetic analyses, we established that the B. microti-like parasites isolated in different geographical regions and from hosts belonging to five orders showed higher among-population variation than within-population variation. Babesia vulpes parasites infecting carnivore hosts, including raccoon dogs, foxes, skunks and dogs, appear to be genetically distinct from B. microti-like parasites infecting hosts belonging to the other orders.ConclusionsOur study demonstrated the genetic variation and evolutionary relationships among 18S rRNA sequences obtained from blood samples collected from various hosts and different geographical regions. Babesia vulpes was identified from raccoon dogs in South Korea. In addition, higher genetic variations were observed among populations of different hosts and geographical origins and, in particular, low connectivity was observed among host populations in the order Carnivora and those in other orders. These results suggest the B. vulpes, a piroplasmid species pathogenic in domestic dogs and wild canines, is genetically and evolutionarily different from B. microti-like parasites.

Project description:BackgroundTheileria annae is a tick-transmitted small piroplasmid that infects dogs and foxes in North America and Europe. Due to disagreement on its placement in the Theileria or Babesia genera, several synonyms have been used for this parasite, including Babesia Spanish dog isolate, Babesia microti-like, Babesia (Theileria) annae, and Babesia cf. microti. Infections by this parasite cause anemia, thrombocytopenia, and azotemia in dogs but are mostly subclinical in red foxes (Vulpes vulpes). Furthermore, high infection rates have been detected among red fox populations in distant regions strongly suggesting that these canines act as the parasite's natural host. This study aims to reassess and harmonize the phylogenetic placement and binomen of T. annae within the order Piroplasmida.MethodsFour molecular phylogenetic trees were constructed using a maximum likelihood algorithm based on DNA alignments of: (i) near-complete 18S rRNA gene sequences (n = 76 and n = 93), (ii) near-complete and incomplete 18S rRNA gene sequences (n = 92), and (iii) tubulin-beta gene sequences (n = 32) from B. microti and B. microti-related parasites including those detected in dogs and foxes.ResultsAll phylogenetic trees demonstrate that T. annae and its synonyms are not Theileria parasites but are most closely related with B. microti. The phylogenetic tree based on the 18S rRNA gene forms two separate branches with high bootstrap value, of which one branch corresponds to Babesia species infecting rodents, humans, and macaques, while the other corresponds to species exclusively infecting carnivores. Within the carnivore group, T. annae and its synonyms from distant regions segregate into a single clade with a highly significant bootstrap value corroborating their separate species identity.ConclusionPhylogenetic analysis clearly shows that T. annae and its synonyms do not pertain to Theileria and can be clearly defined as a separate species. Based on the facts that T. annae and its synonyms have not been shown to have a leukocyte stage, as expected in Theileria, do not infect humans and rodents as B. microti, and cluster phylogenetically as a separate species, this study proposes to name this parasite Babesia vulpes sp. nov., after its natural host, the red fox V. vulpes.

Dataset Information

Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria.

Publications

Safety and efficacy of hydroxyurea and eflornithine against most blood parasites Babesia and Theileria.

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