Medical honey for canine nasal intertrigo: A randomized, blinded, placebo-controlled, adaptive clinical trial to support antimicrobial stewardship in veterinary dermatology.

Intertrigo is a skin fold dermatitis often requiring recurrent treatment with topical antiseptics or antibiotics, which can select antimicrobial resistance. To minimize this risk, we tested the effectiveness of medical-grade Manuka honey at treating intertrigo as compared to a placebo hydrogel. We additionally characterized the culturable microbial flora of intertrigo and recorded any adverse effect with either treatment. During this randomized, placebo-controlled, double-blinded, adaptive group-sequential trial, the owners washed the affected sites on their dog with water, dried and applied a thin film of either the honey or the placebo product once daily for 21 days. Cytological and lesional composite scores, owner-assessed pruritus, and microbial cultures were assessed prior to treatment and on Day-22. The fixed effects of time, treatment, and animal-related variables on the pruritus and on each composite score, accounting for random dog effect, were estimated separately with generalized linear mixed models for repeated count outcomes (α = 0.05). The null hypothesis of equal treatment effects was rejected at the first interim analysis. The placebo (n = 16 dogs) outperformed the medical honey (n = 13 dogs) at improving both the cytological score (Treatment×Time = -0.35±0.17; P = 0.04) and clinical score (Treatment×Time = -0.28±0.13; P = 0.04). A microbial burden score higher than 4 increased the severity of the cytological score (dichotomous score: 0.29±0.11; P = 0.01), which in turn increased the severity of the clinical score and pruritus score. For every unit increase in cytological score, the linear predictor of clinical score increased by 0.042±0.019 (P = 0.03), and the one of pruritus score increased by 0.12±0.05 (P = 0.01). However, medical honey outperformed the placebo at alleviating the dog's owner-assessed pruritus after statistically controlling for masking effects (Time = -0.94±0.24; P = 0.002; and Treatment×Time = 0.80±0.36; P = 0.04). Unilateral tests of the least-square mean estimates revealed that honey only significantly improved the pruritus (Hommel-adjusted P = 0.003), while the placebo only improved the cytological and clinical scores (Hommel-adjusted P = 0.01 and 0.002, respectively). Taken together, these results question the value of Manuka honey at treating nasal intertrigo in dogs

Pharmacokinetics of Lidocaine Hydrochloride Administered with or without Adrenaline for the Paravertebral Brachial Plexus Block in Dogs

<div><p>Adrenaline is known to prolong the duration of local anesthesia but its effects on the pharmacokinetic processes of local anesthetic drugs are not fully understood. Our objective was to develop a compartmental model for quantification of adrenaline’s impact on the pharmacokinetics of perineurally-injected lidocaine in the dog. Dogs were subjected to paravertebral brachial plexus block using lidocaine alone or adrenalinated lidocaine. Data was collected through a prospective, randomised, blinded crossover protocol performed over three periods. Blood samples were collected during 180 minutes following block execution. Compartmental pharmacokinetic models were developed and their goodness-of-fit were compared. The lowering effects of adrenaline on the absorption of lidocaine were statistically determined with one-sided tests. A one-compartment disposition model with two successive zero-order absorption processes best fitted our experimental data. Adrenaline decreased the peak plasma lidocaine concentration by approximately 60% (<i>P <</i> 0.001), decreased this local anesthetic’s fast and slow zero-order absorption rates respectively by 50% and 90% (<i>P</i> = 0.046, and <i>P</i> < 0.001), which respective durations were prolonged by 90% and 1300% (<i>P</i> < 0.020 and <i>P</i> < 0.001). Lidocaine demonstrated a previously unreported atypical absorption profile following its paravertebral injection in dogs. Adrenaline decreased the absorption rate of lidocaine and prolonged the duration of its absorption.</p></div

Best and worst fits to the individual time-courses of plasma lidocaine concentration in dogs.

<p>Predicted plasma lidocaine concentrations were generated by the refined alternative model (i.e. Model C, with two time-constrained, asynchronous zero-order drug absorption rates per system). (A) Best fit: Dog B, plain lidocaine data. (B) Worst fit: Dog E, plain lidocaine data. (C) Best fit: Dog B, adrenalinated lidocaine data. (D) Worst fit: Dog E, adrenalinated lidocaine data. Cp, plasma drug concentration.</p

Lidocaine standardized residuals of the standard and alternative compartmental models <i>vs</i>. time following lidocaine administration.

<p>(A) Plain lidocaine data predicted by Model A (i.e. one first-order absorption rate per system). (B) Plain lidocaine data predicted by Model B (i.e. two asynchronous first-order absorption rates per system). (C) Adrenalinated lidocaine data predicted by Model A. (D) Adrenalinated lidocaine data predicted by Model B. A third degree polynomial curve (continuous line) has been added to highlight the trend in the residuals.</p

Compartmental pharmacokinetic models used for the analysis of paravertebrally injected lidocaine in dogs.

<p>Each model comprises one system for each of the two tested lidocaine formulations. (A) Standard model, with a single first-order absorption rate per system. (B) Alternative model, with two asynchronous first-order absorption rates per system. (C) Refined alternative model, with two time-constrained, asynchronous zero-order absorption rates per system. CL/F, apparent total clearance; Dose_j, total amount of lidocaine administered (hereafter, subscript j = “LI” codes for the plain lidocaine formulation, and j = “LA” the adrenalinated lidocaine formulation); Dur_1,j, duration of zero-order absorption from the first (early) absorption compartment; Dur_2,j, duration of zero-order absorption from the second (late) absorption compartment; f_j, dose fraction entering the first (early) absorption compartment; k_a,j, first-order absorption rate constant; k_a1,j, first-order absorption rate constant of the first (early) absorption compartment; k_a2,j, first-order absorption rate constant of the second (late) absorption compartment; k_01,j, zero-order absorption rate of the first (early) absorption compartment; k_02,j, zero-order absorption rate of the second (late) absorption compartment; V/F, apparent distribution volume; <b>τ</b>_i, lag-time of the second (late) absorption process; X_j, amount of drug present in the disposition compartment; X_a,j, amount of drug present in the absorption compartment; X_a1,j, amount of drug in the first (early) absorption compartment; X_a2,j, amount of drug in the second (late) absorption compartment.</p

Lidocaine standardized residuals of the alternative and refined alternative compartmental models <i>vs</i>. time following lidocaine administration.

<p>(A) Plain lidocaine data predicted by Model B (i.e. with two asynchronous first-order absorption rates per system). (B) Plain lidocaine data predicted by Model C (i.e. with two time-constrained, asynchronous zero-order absorption rates per system). (C) Adrenalinated lidocaine data predicted by Model B. (D) Adrenalinated lidocaine data predicted by Model C. A third-degree polynomial curve (continuous line) has been added to help visualizing the trend in the residuals.</p

Lidocaine standardized residuals of the standard and alternative compartmental models <i>vs</i>. model-predicted plasma lidocaine concentration.

<p>(A) Plain lidocaine data predicted by Model A (i.e. one single first-order absorption rate per system). (B) Plain lidocaine data predicted by Model B (i.e. two asynchronous first-order absorption rates per system). (C) Adrenalinated lidocaine data predicted by Model A. (D) Adrenalinated lidocaine data predicted by Model B. A third degree polynomial curve (continuous line) has been added to highlight the trend in the residuals.</p

Estimated pharmacokinetic parameters of paravertebrally injected lidocaine in dogs, and statistical comparison of plain and adrenalinated formulations.

<p>Estimated pharmacokinetic parameters of paravertebrally injected lidocaine in dogs, and statistical comparison of plain and adrenalinated formulations.</p

Individual time-courses of plasma lidocaine concentrations in dogs.

<p>(A) Paravertebral dosing of 6 mg/kg plain lidocaine formulation. (B) Paravertebral dosing of 6 mg/kg adrenalinated lidocaine formulation. The time-concentration data is delineated in linear coordinates (main graphs) and semilogarithmic coordinates (insert graphs).</p

Observed <i>vs</i>. individual-conditional model-predicted plasma lidocaine concentrations following administration of plain or adrenalinated lidocaine in dogs.

<p>(A) Standard model (i.e. with one first-order absorption rate per system). (B) Alternative model (i.e. with two asynchronous first-order absorption rates per system). (C) Refined alternative model (i.e. with two time-constrained, asynchronous zero-order absorption rates per system). An identity line (<i>i</i>.<i>e</i>. Y = X) has been added to each plot as the expected relationship. Squares, plain lidocaine data. Cross marks, adrenalinated lidocaine data.</p