Antileishmanial efficacy and tolerability of combined treatment with non-ionic surfactant vesicle formulations of sodium stibogluconate and paromomycin in dogs.

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

Pharmacokinetics of Immediate and Sustained Release Cephalexin Administered by Different Routes to Llamas (Lama glama).

We investigate the pharmacokinetics of two different cephalexin formulations administered to llamas by the intravenous (IV), intramuscular (IM), and subcutaneous (SC) routes, the minimum inhibitory concentration (MIC) of cephalexin against some Escherichia coli and staphylococci isolated from llamas, and we apply the PK/PD modelling approach, so that effective dosage recommendations for this species could be made. Six llamas received immediate (10 mg/kg, IV, IM, and SC) and sustained (8 mg/kg IM, SC) release cephalexin. Pharmacokinetic parameters were calculated by noncompartmental approach. Immediate release SC administration produced a significantly longer elimination half-life as compared with the IV and IM administration (1.3 ± 0.2 versus 0.6 ± 0.1 and 0.6 ± 0.1 h, resp.) and higher mean absorption time as compared with the IM administration (1.7 ± 0.5 versus 0.6 ± 0.4 h). Absolute bioavailability was in the range of 72-89% for both formulations and routes of administration. Cephalexin MIC90 values against staphylococci and E. coli were 1.0 and 8.0 µg/mL, respectively. Our results show that the immediate release formulation (10 mg/kg) would be effective for treating staphylococcal infections administered every 8 h (IM) or 12 h (SC), whereas the sustained release formulation (8 mg/kg) would require the IM or SC administration every 12 or 24 h, respectively.

Chronokinetics of ceftazidime after intramuscular administration to dogs.

Ceftazidime, a third-generation cephalosporin, is widely used for the treatment of Pseudomonas aeruginosa infections. The aims of the present study were to characterize the pharmacokinetics of ceftazidime and to estimate the T > MIC against P. aeruginosa, after its intramuscular (i.m.) administration at two different dosing times (08:30 h and 20:30 h) to dogs, in order to determine whether time-of-day administration modifies ceftazidime pharmacokinetics and/or predicted clinical antipseudomonal efficacy. Six female healthy beagle dogs were administered ceftazidime pentahydrate by the intramuscular route in a single dose of 25 mg/kg at both 08:30 and 20:30 h, two weeks apart. Plasma ceftazidime concentrations were determined by microbiological assay. Pharmacokinetic parameters and time above the minimum inhibitory concentration (T > MIC) and 4xMIC for Pseudomonas aeruginosa were calculated from the disposition curve of each dog. No differences between the daytime and nighttime administrations were found for the main pharmacokinetic parameters, including C(max), t(max), t((1/2) lambda), AUC, and MRT; however, the high interindividual variability shown by these values and the small number of individuals may account for this lack of difference. Rate of absorption (k(a)) was significantly higher after the 20:30 h than 08:30 h administration. No significant differences between T > MIC were found when comparing the 08:30 h and 20:30 h administrations. Mean T > MIC values predicted a favorable bacteriostatic effect for all susceptible strains of P. aeruginosa for the 12 h dosing interval at both dosing times. Our results suggest that similar antipseudomonal activity may be expected when ceftazidime is administered at 8:30 and 20:30 h; however, as only two timepoints of drug administration were explored, we are unable to draw any conclusions for other treatment times during the 24 h.

Chronopharmacological study of cephalexin in dogs.

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first-generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration-time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83+/-3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10:00 and 22:00 h, with a two-week interval of time between the two clock-time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52+/-2.7 vs. 18.77+/-2.8 microg/mL) administration. The elimination half-life was prolonged 1.5-fold after the 22:00 h compared to the 10:00 h administration (2.69+/-0.9 vs. 1.79+/-0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration-time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 microg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10:00 and 22:00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single-dose study require confirmation by future steady-state, multiple-dose studies. If such studies are confirmatory, no administration-time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.

Ciprofloxacin and norfloxacin pharmacokinetics and prostatic fluid penetration in dogs after multiple oral dosing.

The aims of this study were to assess the pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) indices predictive of clinical outcome of ciprofloxacin (CIP) and norfloxacin (NOR) after multiple oral dosing, and to investigate their penetration into prostatic fluid in dogs. Eight dogs received seven oral doses b.i.d. of NOR (20 mg/kg) and CIP (15 mg/kg). Drug concentrations were determined in blood and in two prostatic fluid samples. Prostatic fluid concentrations were lower than plasma concentrations for both drugs. No statistically significant differences were determined between the pharmacokinetic parameters calculated after the first and seventh doses for either CIP or NOR. The PK/PD indices were found to be useful for predicting bacteriological outcome for fluoroquinolones (area under the disposition curve/minimum inhibitory concentration [MIC] and peak plasma concentration/MIC) and indicate that with this dose regimen CIP presents a more favourable disposition than NOR for successful clinical outcome.