The efficacy of subcutaneous slow-release melatonin implants in the prevention of canine flank alopecia recurrence is uncertain: A double-blind, randomized, placebo-controlled study

BACKGROUND: Canine flank alopecia (CFA) is characterized by seasonally recurring noninflammatory, occasionally hyperpigmented alopecia predominantly in the thoracolumbar area. Previous studies suggest that reduced production of endogenous melatonin may play a role in the pathogenesis of this condition, and placebo-controlled studies on the efficacy of preventative melatonin treatment are lacking. OBJECTIVE: To evaluate the efficacy of subcutaneous slow-release melatonin implants in the prevention of CFA recurrence. ANIMALS: Twenty-one client-owned dogs with a history of CFA were included in the study. MATERIALS AND METHODS: At time (T)0, a general physical and dermatological examination was performed on each dog, blood was collected for serum biochemistry analysis and two skin biopsies were taken from alopecic areas on the nonsedated affected dogs after subcutaneous injection with 2% lidocaine. Dogs with normal blood work and histological results compatible with CFA were included in the study. Participating dogs were randomly assigned to receive either placebo or 18 mg melatonin subcutaneously in the interscapular area, approximately 2 months before expected CFA onset (T1). CFA recurrence was scored qualitatively as complete, ≤50% recurrence, or no recurrence at 5 and 7 months after the intervention (T2 and T3, respectively). RESULTS: At T3, in dogs treated with placebo (nine of 17), the percentages for complete recurrence, ≤50% recurrence and no recurrence were 44%, 0% and 56%, respectively. In dogs treated with melatonin (eight of 17), these percentages were 25%, 50% and 25%, respectively. There were no statistically significant differences in the scores between melatonin-treated dogs and placebo-treated dogs (p = 0.40). In three of eight melatonin-treated dogs, mild transient swelling was observed at the injection site. CONCLUSIONS: This study did not provide evidence that an 18 mg melatonin implant treatment, although well-tolerated, is efficacious in preventing recurrence of CFA in affected dogs

Sensitivity to Experiencing Alcohol Hangovers: Reconsideration of the 0.11% Blood Alcohol Concentration (BAC) Threshold for Having a Hangover

The 2010 Alcohol Hangover Research Group consensus paper defined a cutoff blood alcohol concentration (BAC) of 0.11% as a toxicological threshold indicating that sufficient alcohol had been consumed to develop a hangover. The cutoff was based on previous research and applied mostly in studies comprising student samples. Previously, we showed that sensitivity to hangovers depends on (estimated) BAC during acute intoxication, with a greater percentage of drinkers reporting hangovers at higher BAC levels. However, a substantial number of participants also reported hangovers at comparatively lower BAC levels. This calls the suitability of the 0.11% threshold into question. Recent research has shown that subjective intoxication, i.e., the level of severity of reported drunkenness, and not BAC, is the most important determinant of hangover severity. Non-student samples often have a much lower alcohol intake compared to student samples, and overall BACs often remain below 0.11%. Despite these lower BACs, many non-student participants report having a hangover, especially when their subjective intoxication levels are high. This may be the case when alcohol consumption on the drinking occasion that results in a hangover significantly exceeds their “normal” drinking level, irrespective of whether they meet the 0.11% threshold in any of these conditions. Whereas consumers may have relative tolerance to the adverse effects at their “regular” drinking level, considerably higher alcohol intake—irrespective of the absolute amount—may consequentially result in a next-day hangover. Taken together, these findings suggest that the 0.11% threshold value as a criterion for having a hangover should be abandoned

Potential of ESBL-producing Escherichia coli selection in bovine feces after intramammary administration of first generation cephalosporins using in vitro experiments

Abstract: Selection and spread of Extended Spectrum Beta-Lactamase (ESBL) -producing Enterobacteriaceae within animal production systems and potential spillover to humans is a major concern. Intramammary treatment of dairy cows with first-generation cephalosporins is a common practice and potentially selects for ESBL-producing Enterobacteriaceae, although it is unknown whether this really occurs in the bovine fecal environment. We aimed to study the potential effects of intramammary application of cephapirin (CP) and cefalonium (CL) to select for ESBL-producing Escherichia coli in the intestinal content of treated dairy cows and in manure slurry, using in vitro competition experiments with ESBL and non-ESBL E. coli isolates. No selection of ESBL-producing E. coli was observed at or below concentrations of 0.8 µg/ml and 4.0 µg/ml in bovine feces for CP and CL, respectively, and at or below 8.0 µg/ml and 4.0 µg/ml, respectively, in manure slurry. We calculated that the maximum concentration of CP and CL after intramammary treatment with commercial products will not exceed 0.29 µg/ml in feces and 0.03 µg/ml in manure slurry. Therefore, the results of this study did not find evidence supporting the selection of ESBL-producing E. coli in bovine feces or in manure slurry after intramammary use of commercial CP or CL-containing products

Potential of ESBL-producing Escherichia coli selection in bovine feces after intramammary administration of first generation cephalosporins using in vitro experiments

Selection and spread of Extended Spectrum Beta-Lactamase (ESBL) -producing Enterobacteriaceae within animal production systems and potential spillover to humans is a major concern. Intramammary treatment of dairy cows with first-generation cephalosporins is a common practice and potentially selects for ESBL-producing Enterobacteriaceae, although it is unknown whether this really occurs in the bovine fecal environment. We aimed to study the potential effects of intramammary application of cephapirin (CP) and cefalonium (CL) to select for ESBL-producing Escherichia coli in the intestinal content of treated dairy cows and in manure slurry, using in vitro competition experiments with ESBL and non-ESBL E. coli isolates. No selection of ESBL-producing E. coli was observed at or below concentrations of 0.8 µg/ml and 4.0 µg/ml in bovine feces for CP and CL, respectively, and at or below 8.0 µg/ml and 4.0 µg/ml, respectively, in manure slurry. We calculated that the maximum concentration of CP and CL after intramammary treatment with commercial products will not exceed 0.29 µg/ml in feces and 0.03 µg/ml in manure slurry. Therefore, the results of this study did not find evidence supporting the selection of ESBL-producing E. coli in bovine feces or in manure slurry after intramammary use of commercial CP or CL-containing products

Epithelial integrity, junctional complexes, and biomarkers associated with intestinal functions

An intact intestinal barrier is crucial for immune homeostasis and its impairment activates the immune system and may result in chronic inflammation. The epithelial cells of the intestinal barrier are connected by tight junctions, which form an anastomosing network sealing adjacent epithelial cells. Tight junctions are composed of transmembrane and cytoplasmic scaffolding proteins. Transmembrane tight junction proteins at the apical-lateral membrane of the cell consist of occludin, claudins, junctional adhesion molecules, and tricellulin. Cytoplasmic scaffolding proteins, including zonula occludens, cingulin and afadin, provide a direct link between transmembrane tight junction proteins and the intracellular cytoskeleton. Each individual component of the tight junction network closely interacts with each other to form an efficient intestinal barrier. This review aims to describe the molecular structure of intestinal epithelial tight junction proteins and to characterize their organization and interaction. Moreover, clinically important biomarkers associated with impairment of gastrointestinal integrity are discussed

Use of a new antimicrobial consumption monitoring system (Vet-AMNet): Application to Dutch dairy sector over a 9-year period

INTRODUCTION: The urgency of preventing the increase of antimicrobial resistance has been emphasized by international authorities such as the World Health Organization, European Medicines Agency, and World Organization for Animal Health. Monitoring systems capable of reporting antimicrobial consumption data are regarded as a crucial pillar of this fight. The Vet-AMNet system was developed to collect and analyze national antimicrobial consumption data in Portuguese dairy farms to support the veterinary authority in stewardship actions and to assist both veterinarians and farmers in daily decisions related to antimicrobials. METHODS: To evaluate the robustness of the system and other identified critical success factors, it was used to analyze antimicrobial consumption data available from the Dutch dairy cow sector over the period from 2012 to 2020. The data previously used for publications by the Netherlands Veterinary Medicines Institute (SDa) were imported and pre-processed by the Vet-AMNet system according to the SDa's standard operating procedure and the Dutch metrics to measure antimicrobial consumption were calculated. RESULTS: By comparing the outputs with the figures generated by the system established in the Netherlands, the Portuguese system was validated. Antimicrobial consumption data from the Dutch dairy sector during the 9-year period will be presented in unpublished graphs and tables, where each molecule's pharmaceutical formulation, pharmacotherapeutic group and line of choice will be related and discussed, illustrating the evolution of sectorial antimicrobial consumption against a background of a strong national antimicrobial policy initiated by public-private cooperation and supported by legislation

Oral doxycycline pharmacokinetics: Lambs in comparison with sheep

The pharmacokinetics of doxycycline was investigated in lactating sheep and lambs after oral administration at a dose of 10 mg/kg. Concentrations in plasma and milk were assayed with HPLC-PDA analysis. Doxycycline penetrates into the milk, and levels (0.38 ± 0.21 μg/ml) were found 0.5 hr after the treatment. The results suggest that the lambs can be exposed to doxycycline by suckling milk from their treated mothers. Population pharmacokinetic analysis showed a positive relationship between age, which reflects the stage of development of rumen function, and clearance. Possible explanations for the observed differences include the undeveloped rumen in lambs, the differences in the feed and liver function as evidenced by the blood biochemical parameters aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which were significantly lower in lambs (62.67 ± 27.83 U/L and 8.50 ± 6.80 U/L) than in sheep (114.33 ± 20.77 U/L and 18.00 ± 3.16 U/L)

Tramadol Steady-State Pharmacokinetics of Immediate-Release Capsules and Sustained-Release Tablets in Dogs

Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs

Sub-Antimicrobial Dosage Scheme of Doxycycline for the Chronic Treatment of Bronchiectasis in a Dog

A 9-month-old German shepherd dog was examined because of a chronic cough, exercise intolerance and labored breathing, as well as recurrent episodes of lethargy with anorexia. Multifocal severe bronchiectasis and neutrophilic bronchitis was found with thoracic computed tomography and cytology of bronchoalveolar lavage fluid, respectively. While oral azithromycin was administered, clinical signs were absent. However, stopping azithromycin lead repeatedly to presumed bacterial pneumonia within 1-2 months. With sub-antimicrobial dosed oral doxycycline (initially 1.5 mg/kg once daily for 3 months, then 0.7-0.5 mg/kg once daily for 6 months), the dog remained free from clinical signs. Bronchiectasis is characterized by marked irreversible bronchial dilation. Accumulation of intraluminal mucopurulent material and neutrophilic inflammation cause chronic cough and recurrent bacterial pneumonia. For therapy, life-long oral antibiotics are recommended. Chronic antibiotic administration, however, can select resistant bacterial strains. Though both azithromycin and doxycycline possess anti-inflammatory effects, doxycycline has these off-target properties at a sub-antimicrobial dose. In this report, a chronic sub-antimicrobial dose of doxycycline resulted in the resolution of chronic cough, exercise intolerance and labored breathing, and prevented recurrence of suspected bacterial pneumonia in the long-term in a dog with severe bronchiectasis. Beneficial effect of doxycycline is probably related to its anti-inflammatory effects rather than its antimicrobial properties

Quantifying topical antimicrobial use before and during participation in an antimicrobial stewardship programme in Dutch companion animal clinics

The emergence of bacterial strains resistant to topical antimicrobials in both human and veterinary medicine has raised concerns over retaining the efficacy of these preparations. Yet, little information is available regarding the use of topical antimicrobials in either sector for planning targeted interventions. This study aims to quantify the use of topical antimicrobials in 44 Dutch companion animal clinics before and during their participation in an antimicrobial stewardship programme (ASP), to explore the effect of the intervention on topical antimicrobial use (AMU). Hence, prescription and clinic animal population data, collected from July 2012 until June 2018 were used. Specifically, the period from July 2012 until June 2015 was defined as pre-intervention period, whereas clinics started to participate in the ASP from March 2016 onwards. As quantification metric, the Defined Daily Dose for Animals (DDDA) was used and a mixed effect times series model with auto-regression was applied to monthly topical AMU data. The intervention effect was modelled using a step function with a change in (linear) time trend and clinic characteristics, as potential determinants of topical AMU, were assessed using a multivariable regression model. A seasonal pattern was identified, in the pre-intervention period, where topical AMU was highest in July-August and lowest in February-March. In addition, total topical AMU appeared to significantly decrease over time in the pre-intervention period and the proportion of dogs in the clinic was positively associated with topical AMU. The intervention effect was significant only for second line and for skin product AMU. This study demonstrates that during participation in an ASP, second line and skin product AMU decreased in Dutch companion animal clinics. Additionally, this study demonstrates the existence of a seasonal effect and a decrease in topical AMU over time already before introduction of a targeted intervention