Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing–Preliminary Investigation

Doxycycline (DXC) is a broad-spectrum antibacterial antimicrobial administered to horses for the treatment of bacterial infections which may also affect donkeys. Donkeys have a different metabolism than horses, leading to differences in the pharmacokinetics of drugs compared to horses. This study aimed to describe the population pharmacokinetics of DXC in donkeys. Five doses of DXC hyclate (10 mg/kg) were administered via a nasogastric tube, q12 h, to eight non-fasted, healthy, adult jennies. Serum, urine, synovial fluid and endometrium were collected for 72 h following the first administration. Doxycycline concentration was measured by competitive enzyme immunoassay. Serum concentrations versus time data were fitted simultaneously using the stochastic approximation expectation-maximization algorithm for nonlinear mixed effects. A one-compartment model with linear elimination and first-order absorption after intragastric administration, best described the available pharmacokinetic data. Final parameter estimates indicate that DXC has a high volume of distribution (108 L/kg) as well as high absorption (10.3 h-1) in donkeys. However, results suggest that oral DXC at 10 mg/kg q12 h in donkeys would not result in a therapeutic concentration in serum, urine, synovial fluid or endometrium by comparison to the minimum inhibitory concentration of common equine pathogens. Further studies are recommended to identify appropriate dosage and dosing intervals of oral DXC in donkeys

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

Current data strongly suggest herpes simplex virus type 1 (HSV-1) infection in the brain as a contributing factor to Alzheimer’s disease (AD). The consequences of HSV-1 brain infection are multilateral, not only are neurons and glial cells damaged, but modifications also occur in their environment, preventing the transmission of signals and fulfillment of homeostatic and immune functions, which can greatly contribute to the development of disease. In this review, we discuss the pathological alterations in the central nervous system (CNS) cells that occur, following HSV-1 infection. We describe the changes in neurons, astrocytes, microglia, and oligodendrocytes related to the production of inflammatory factors, transition of glial cells into a reactive state, oxidative damage, Aβ secretion, tau hyperphosphorylation, apoptosis, and autophagy. Further, HSV-1 infection can affect processes observed during brain aging, and advanced age favors HSV-1 reactivation as well as the entry of the virus into the brain. The host activates pattern recognition receptors (PRRs) for an effective antiviral response during HSV-1 brain infection, which primarily engages type I interferons (IFNs). Future studies regarding the influence of innate immune deficits on AD development, as well as supporting the neuroprotective properties of glial cells, would reveal valuable information on how to harness cytotoxic inflammatory milieu to counter AD initiation and progression

Comprehensive molecular dissection of dermatophilus congolensis genome and first observation of tet(Z) tetracycline resistance

Dermatophilus congolensis is a bacterial pathogen mostly of ruminant livestock in the tropics/subtropics and certain temperate climate areas. It causes dermatophilosis, a skin disease that threatens food security by lowering animal productivity and compromising animal health and welfare. Since it is a prevalent infection in ruminants, dermatophilosis warrants more research. There is limited understanding of its pathogenicity, and as such, there is no registered vaccine against D. congolensis. To better understanding the genomics of D. congolensis, the primary aim of this work was to investigate this bacterium using whole-genome sequencing and bioinformatic analysis. D. congolensis is a high GC member of the Actinobacteria and encodes approximately 2527 genes. It has an open pan-genome, contains many potential virulence factors, secondary metabolites and encodes at least 23 housekeeping genes associated with antimicrobial susceptibility mechanisms and some isolates have an acquired antimicrobial resistance gene. Our isolates contain a single CRISPR array Cas type IE with classical 8 Cas genes. Although the isolates originate from the same geographical location there is some genomic diversity among them. In conclusion, we present the first detailed genomic study on D. congolensis, including the first observation of tet(Z), a tetracycline resistance-conferring gene