Search

Pritelivir is a novel viral helicase‐primase inhibitor active against herpes simplex virus. In vitro drug‐drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug‐drug interaction potential. [ABSTRACT FROM AUTHOR]

Synodontis catfishes in Lake Tanganyika have undergone a modest radiation, with differences among species in reproductive strategies, including one species that has evolved to be an obligate brood parasite. Here, we provide insights into the reproductive traits and histology of male and female reproductive organs of five Lake Tanganyika Synodontis species (S. irsacae, S. melanostictus, S. multipunctatus, S. petricola and S. polli). We describe the structures employed in oogenesis, spermiogenesis and spermiation. We show that the shape and size of the urogenital papilla is a valuable trait for sex determination in all species except S. polli, where the imprecision reached > 20 %. From a histological perspective, the inter-specific structural differences associated with the type of reproductive strategy were not found in the ovaries. However, testicular histology indicated variations in spermiation structures among species, namely in S. multipunctatus and S. irsacae. The differences identified may be related to variation in reproductive strategies among species. In particular, weaker eosinophily of testicular secretions was found in S. multipunctatus than in other species, suggesting the possibility of a different composition. Experimental manipulation of environmental and hormonal stimuli represents a promising direction for further research into the structural and functional diversity of male gonads in Synodontis species from Lake Tanganyika. [ABSTRACT FROM AUTHOR]

Host–parasite dynamics involve coevolutionary arms races, which may lead to host specialization and ensuing diversification. Our general understanding of the evolution of host specialization in brood parasites is compromised by a restricted focus on bird and insect lineages. The cuckoo catfish (Synodontis multipunctatus) is an obligate parasite of parental care of mouthbrooding cichlids in Lake Tanganyika. Given the ecological and taxonomic diversity of mouthbrooding cichlids in the lake, we hypothesized the existence of sympatric host‐specific lineages in the cuckoo catfish. In a sample of 779 broods from 20 cichlid species, we found four species parasitized by cuckoo catfish (with prevalence of parasitism of 2%–18%). All parasitized cichlids were from the tribe Tropheini, maternal mouthbrooders that spawn over a substrate (rather than in open water). Phylogenetic analysis based on genomic (ddRAD sequencing) and mitochondrial (Dloop) data from cuckoo catfish embryos showed an absence of host‐specific lineages. This was corroborated by analyses of genetic structure and co‐ancestry matrix. Within host species, parasitism was not associated with any individual characteristic we recorded (parent size, water depth), but was costly as parasitized parents carried smaller clutches of their own offspring. We conclude that the cuckoo catfish is an intermediate generalist and discuss costs, benefits and constraints of host specialization in this species and brood parasites in general. [ABSTRACT FROM AUTHOR]

When one of two parents disappears in the midst of caring for offspring, the remaining parent is left with several options. They can either (1) desert the brood, (2) continue caring on their own and reject propositions from new potential partners, or (3) continue caring but remain receptive to re-mating opportunities. The presence of a brood may increase re-mating success of single parents, either because brood care is perceived as a signal of partner quality, or because prospective mates perceive the brood as potential energy source. In this field experiment, we used the socially monogamous, biparental cichlid fish Variabilichromis moorii to examine the re-mating strategy of males with or without dependent offspring after the loss of their female partner. Partner vacancies were filled quickly by new females, and these females engaged in high levels of affiliative behavior with the males. The new females engaged in territorial defense, but focused primarily against intruding conspecifics, likely as a means to repel rivals. The males, in turn, took over the majority of territorial defense against intruding heterospecifics. Interestingly, males that still had offspring from their previous partnerships did not show aggression toward their new female partners, even when those females were infanticidal and cannibalizing the males' current offspring. Overall, our experiment shows that single fathers of a biparental species will re-mate quickly even at the detriment to their current offspring. [ABSTRACT FROM AUTHOR]

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV‐seropositive, allogeneic, hematopoietic stem‐cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P‐glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P‐glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011‐004516‐39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5‐mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28‐day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady‐state letermovir reduced digoxin area under the plasma concentration–time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half‐life and elimination rate remained similar in both conditions. The between‐subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration–time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin. [ABSTRACT FROM AUTHOR]

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem‐cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme‐specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single‐dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days –4 and –2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration–time curve from time 0 to the last measurable concentration ratio of midazolam to 1‐hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8‐13.1; 49% increase) and oral (3.3‐5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition. [ABSTRACT FROM AUTHOR]