Haemonchus contortus, a gastrointestinal nematode parasite of sheep, is mainly controlled by anthelmintics; the occurrence of anthelmintic resistance leads to treatment failures and increases economic burden. Because molecular mechanisms involved in drug resistance can be elucidated by genomic studies, an extreme quantitative trait locus (X-QTL) mapping approach was used to identify co-segregation of the resistance phenotype with genetic markers to detect the genome-wide variants associated with monepantel resistance in H. contortus. A cross between H. contortus isolates using parental susceptible (Par-S) males and monepantel resistant (Par-R) females resulted in SR progeny, while reciprocal cross resulted in RS progeny. Pools (n = 30,000) of infective larvae (L3) recovered from Par-R, and from SR and RS populations in the F3 generation, collected both before (unselected group) and 7 days after (selected group) selection with monepantel treatment in sheep hosts, were subjected to genome sequencing (Pool-Seq). Pairwise comparisons of allele frequencies between unselected and selected groups were performed for each population by Fisher’s exact test (FET) and for both populations combined by a Cochran-Mantel-Haenszel (CMH) test. Mapping rates varied from 80.29 to 81.77% at a 90.4X mean coverage of aligned reads. After correction for multiple testing, significant (P < 0.05) changes in allele frequencies were detected by FET for 6 and 57 single nucleotide polymorphisms (SNPs) in the SR and RS populations, respectively, and by the CMH test for 124 SNPs in both populations. The significant variants located on chromosome 2 generated a selection signal in a genomic region harboring the mptl-1, deg-3 and des-2 genes, previously reported as candidates for monepantel resistance. In addition, three new variants were identified in the mptl-1 gene. This study expands knowledge on genome-wide molecular events underlying H. contortus resistance to monepantel. The identification of a genome region harboring major genes previously associated with monepantel resistance supports the results of the employed X-QTL approach. In addition, a deletion in exon 11 of the mptl-1 gene should be further investigated as the putative causal mutation leading to monepantel resistance.

Gastrointestinal nematodes significantly affect the ovine industry, andHaemonchus contortusis considered the most pathogenic parasite in tropical regions. This situation is aggravated when the main strategy to control worms fails because of the genetic resistance that parasites acquire against anthelmintics. Aiming to anticipate the events involved in anthelmintic resistance, we induced monepantel resistance inH. contortusbyin vivosubdosing of sheep hosts. Four successive passages of a monepantel-susceptibleH. contortusisolate in Santa Ines or Ile de France sheep hosts resulted in three monepantel-resistant (efficacy varying from 0 to 58.5%)H. contortusisolates. Sheep hosts were treated from 0.075 mg/kg to the therapeutic dose of 2.5 mg/kg of monepantel in 19–26 rounds of selection for 112–133 weeks. Success in inducingH. contortusresistance to monepantel may have been affected by worm burden and by host–parasite interactions, including a possible effect of the breed of sheep hosts. We conclude that subdosing of sheep, although time-consuming, is an efficientin vivostrategy for the induction of monepantel resistance inH. contortus. The resistant parasites can be used in further studies to elucidate the genetic and biochemical events involved in the acquisition of anthelmintic resistance.

Metronomic chemotherapy (MC) represents an emerging strategy in veterinary oncology which involves the continuous or regularly scheduled administration of low-dose chemotherapeutic agents. Unlike conventional protocols known as maximum tolerated dose chemotherapy (MTDC), MC aims to inhibit tumor angiogenesis, stimulate antitumor immune responses, and delay or prevent the emergence of drug resistance. This review is structured into three key sections: the mechanisms of action of MC; its clinical indications in dogs and cats, particularly for advanced or treatment-resistant cancers; and reported outcomes regarding efficacy, safety, and tolerability. Additionally, we explore the growing interest in combining MC with other therapies, as well as the challenges and future directions for optimizing its use. Current evidence suggests that MC is a promising and well-tolerated option for managing various malignancies—such as carcinomas, sarcomas, and hemangiosarcomas—especially in patients who are not candidates for MTDC.