Efficacy of dinotefuran, permethrin and pyriproxyfen combination spot-on on dogs against Phlebotomus perniciosus and Ctenocephalides canis.

This study was conducted to evaluate the efficacy of a new topical ectoparasiticidal spot-on containing 4.95% dinotefuran (w/w), 36.08% permethrin (w/w) and 0.44% pyriproxyfen (w/w) (Vectra 3D, Ceva, Libourne, France) against Portuguese strain of Phlebotomus perniciosus and a French strain of Ctenocephalides canis in dogs. Twelve beagle dogs were exposed for 1 h to 100 P. perniciosus on day 6 for allocation in two groups. One group was treated on day 0, and the other group was the control group. The dogs were exposed for 1 h to 100 P. perniciosus on days 1, 7, 14, 21 and 28. After each sandfly challenge, the same dogs were infested with 100 C. canis. Counts of living fleas were determined 48 h after infestation on days 4, 3, 9, 16, 23 and 30. For sandflies, the anti-feeding effect was 96.9, 99.7, 98.7, 83.5 and 87.0 % on days 1, 7, 14, 21 and 28, respectively. The mortality effect was 97.8, 99.8, 73.7, 27.5 and 39.6% on days 1, 7, 14, 21 and 28, respectively. At each challenge point, the mortality and anti-feeding effects on sandflies were significantly different between the control and treatment groups (p < 0.05). The adulticidal effect on C. canis remained above 99% throughout the study period. The results indicate that a combination with dinotefuran, permethrin and pyriproxyfen may be used as an effective part of an overall flea and sandfly control strategy in dogs for monthly use.

Safety of spironolactone in dogs with chronic heart failure because of degenerative valvular disease: a population-based, longitudinal study.

BACKGROUND: Spironolactone treatment in humans is associated with an increased risk of hyperkalemia and renal dysfunction. HYPOTHESIS: Dogs with cardiac disease treated with spironolactone, in addition to conventional therapy, are not at higher risk for adverse events (AEs) than those receiving solely conventional therapy. ANIMALS: One hundred and ninety-six client-owned dogs with naturally occurring myxomatous mitral valve disease. METHODS: Prospective, double-blinded field study with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin-converting enzyme inhibitor, plus furosemide and digoxin if needed). Safety was compared between treatment groups, using the frequency of AEs, death caused by cardiac disease, renal disease, or both, and variations in serum sodium, potassium, urea, and creatinine concentrations. For the latter, population-specific reference intervals were established and out of range values (ORV) analyzed. RESULTS: The number of AEs was similar in the spironolactone and reference groups (188 and 208, respectively), when followed for median duration of 217 days (range [2-1,333]). At each study time point, the percentage of dogs showing ORV was similar between groups. There were a higher number of deaths because of cardiac disease, renal disease or both in the reference group (30.7% versus 13.7%) (P = .0043). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with heart failure receiving spironolactone in addition to conventional treatment are not at a higher risk for AEs, death caused by cardiac disease, renal disease, or both, hyperkalemia, or azotemia.

Efficacy of permethrin, dinotefuran and pyriproxyfen on adult fleas, flea eggs collection, and flea egg development following transplantation of mature female fleas (Ctenocephalides felis felis) from cats to dogs.

A novel spot-on formulation combining permethrin, pyriproxifen and dinotefuran (Vectra 3D™ spot-on solution for dogs) was evaluated in adult Beagle dogs in a study to determine adulticidal efficacy, egg laying inhibition and viability of Ctenocephalides felis felis eggs (development and emergence of fleas from the collected eggs). Prior to treatment sixteen dogs were checked for their ability to keep fleas 24 hours after infestation and were allocated to treatment groups: 8 dogs served as untreated controls, and 8 dogs were treated once with the tested formulation. The spot on was administered respecting the laboratory recommendations at a dosage of 65-126 mg/kg of permethrin; 8.9-17.4 mg/kg of dinotefuran and 0.8-1.5mg/kg of pyriproxyfen. Each dog was infested with 100 adult cat fleas ready to lay eggs after 72 hours spent feeding on cats. Dogs were infested 24 hours after treatment and then weekly during 63 days. Eggs were collected and counted 24 hours after each infestation and dogs were combed 48 hours after each infestation. Fleas were counted and removed. Collected eggs were placed in incubator to study their development in larvae and into newly emerged adults. A single treatment provided 99.7% adulticidal efficacy on fleas within 48 hours after treatment and controlled re-infestations for up to 30 days (efficacy >96.20%, p<0.05). The egg laying inhibition was over 92.3% for up to 29 days (p<0.05). The adult emergence inhibition remained 100% during 8 weeks after treatment and was 99.8% nine weeks after treatment (p<0.001).

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog.

Fifteen Beagle dogs were used to describe the anti-aldosterone effect of spironolactone (0, 0.8, 2 and 8 mg/kg) in a hyperaldosteronism model. The magnitude of the aldosterone response observed in this model was very similar to the one described in a dog with congestive heart failure (CHF). Each dog was allocated to a treatment group according to a 5 x 5 Latin square crossover design for five periods with a washout period of 7 days between each period. A maximal possible effect (E(max)) model was employed to determine the basic pharmacodynamic parameters of spironolactone, measured by high-performance liquid chromatography, in antagonizing the renal effects of aldosterone. The change in urinary sodium/potassium ratio in response to a single dose of aldosterone was calculated. The inhibition of this response by oral spironolactone administration was assessed. Aldosterone alone decreased sodium excretion by approximately 35% and urinary potassium concentrations increased by 25%, whereas the urine volume decreased, as expected. The effect of aldosterone on the Na(+)/K(+) ratio was completely reversed (88% inhibition) at a dose of 2 mg spironolactone/kg, while at the dose of 0.8 mg/kg, partial reversal was seen (27.5% inhibition). Urine flow rate was not significantly modified by either aldosterone treatment or aldosterone with spironolactone. The dose of spironolactone required to inhibit the action of aldosterone by 50% (ED(50)) was estimated to be 1.08 +/- 0.28 mg/kg. The E(max) was a ratio of 1.089 +/- 0.085, close to the observed value in negative control group (1.00 +/- 0.18). The proposed spironolactone dose using this E(max) model was 2 mg/kg b.w. once daily for the management.

Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease.

BACKGROUND: Spironolactone, an aldosterone antagonist, has been demonstrated to decrease mortality in human patients when added to other cardiac therapies. HYPOTHESIS: Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). ANIMALS: Between February 2003 and March 2005, 221 dogs were recruited in Europe. Nine dogs were excluded from analysis, leaving 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). METHODS: Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. RESULTS: Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22-0.90; log rank test, P = .017). Risk of cardiac-related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13-0.76; P = .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). CONCLUSION AND CLINICAL IMPORTANCE: Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD.

Determination of a dosage regimen of colistin by pharmacokinetic/pharmacodynamic integration and modeling for treatment of G.I.T. disease in pigs.

Colistin is an antimicrobial drug of the polymyxin group and COLIVET SOLUTION is an aqueous solution containing colistin sulphate (2 x 10(6) IU/mL), formulated for oral administration. The target species is the pig, particularly the suckling and post weaning animal. This investigation was undertaken to provide pharmacokinetic and pharmacodynamic data on which to base the selection of dosage rate and interval of the solution for the treatment of porcine colibacillosis. Colistin absorption from the gastrointestinal tract of young pigs, when administered at dosage rates of 25,000, 50,000 and 100,000 IU/kg, was slight or absent. The drug was therefore restricted almost entirely to the required site of action. The colistin concentration-time profile within the jejunum and ileum was established, and this enabled determination of the pharmacokinetic variables, maximum concentration (C(max)) and area under curve (AUC) and derivation of the surrogate indices of antibacterial activity, C(max)/minimum inhibitory concentration (MIC) and AUC/MIC through integration of in vivo data with the results of in vitro potency studies for four strains of Escherichia coli. In the in vitro bacterial growth inhibition studies colistin acted by a concentration-dependent killing mechanism. Numerical values for the surrogate parameter AUC/MIC producing bactericidal and eradication effects of colistin against four strains of E. coli were established by PK-PD modeling based on the sigmoidal E(max) equation. These data were used to predict a daily dosage regimen for colistin.

The efficacy of an oral treatment with paromomycin against an experimental infection with Giardia in calves.

A controlled and blinded study was conducted to evaluate the efficacy and safety of a treatment with paromomycin sulphate against an experimental Giardia infection in calves. Animals were infected with 10(5)Giardia cysts of cattle origin and were either treated 11 days later with 25, 50 or 75 mg paromomycin/(kg body weight per day) during 5 consecutive days or not treated (control group). Efficacy was evaluated based on reduction in cyst excretion. Furthermore weight gain and diarrhea scores were monitored. In the group treated with 75 mg/kg per day there was a 100% reduction in cyst excretion until 9 days after the start of the treatment (D9) and a very high reduction (> or =98%) until D13. There was a high reduction (> or =93%) until D9 and D13 in the groups treated with 25 and 50 mg/kg, respectively. The cumulative cyst excretion on D13 was significantly (P<0.05) lower in the groups treated with 75 and 50 mg/kg compared to the control group. Although there was a trend towards higher weight gain and less diarrhea in the treated groups, differences between groups were not significant. No adverse reactions to the paromomycin treatment were recorded. Furthermore, the need for reliable parameters for evaluation of treatments against protozoal infections is emphasised.

Bovine mastitis and intramammary drug delivery: review and perspectives.

Intramammary infections (IMIs) represent a major feature in bovine pathology. The treatment of IMIs concern antimicrobial substances. Therapeutic strategies involve administration of immediate release formulations during lactation with or without long-acting formulations during the dry period. Current treatments are not very successful and cure rates are poor, especially towards Staphylococcus aureus which is responsible for chronic infections and huge economic losses. New strategies have recently been investigated. These include particular immunomodulators like lysostaphin or cytokines, and novel formulations (e.g. liposomes, microparticles or nanoparticles) that allow uptake of the active component by phagocytes and thus prolong an enhanced antibacterial activity.

Labile conjugation of a hydrophilic drug to PLA oligomers to modify a drug delivery system: cephradin in a PLAGA matrix.

The physical entrapment of a hydrophilic drug within degradable microspheres is generally difficult because of poor entrapment yield and/or fast release, depending on the microsphere fabrication method. In order to counter the effects of drug hydrophilicity, it is proposed to covalently attach the drug to lactic acid oligomers, with the aim of achieving temporary hydrophobization and slower release controlled by the separation of the drug from the degradable link within the polymer matrix. This strategy was tested on microspheres of the antibiotic cephradin. As the prodrug form, the entrapment of the drug was almost quantitative. The prodrug did degrade in an aqueous medium, modelling body fluids, but cleavage did not occur at the drug-oligomer junction and drug molecules bearing two lactyl residual units were released. When the prodrug is entrapped within a PLAGA matrix, no release was observed within the experimental time period. However, data suggest that conjugation via a bond more sensitive to hydrolysis than the main chain PLA ester bonds should make the system work as desired.

Salivary fluoride concentrations following applications of bioadhesive tablets and mouthrinses.

Presence of elevated fluoride concentration in saliva is important for the prevention of caries. In the present study, we developed an intra-oral bioadhesive tablet aimed at delivering F(-) in the mouth over a prolonged period of time. Various tablet formulations were tested in vivo for their tolerance and adhesiveness. Two formulations were selected for further studies on salivary fluoride clearance. For comparison, mouthrinses with increasing F(-) concentrations were also examined. Results indicate that a bioadhesive tablet located on the upper gingiva is able to sustain salivary F(-) concentrations for about 10h without major side effects. Mouthrinses with high F(-) concentration were able to prolong salivary fluoride retention for more than 6h.

Cephradin-plaga microspheres for sustained delivery to cattle.

In the field of controlled drug delivery, most of the reported work is aimed at introducing new systems, or at providing basic information on the critical parameters which affect release profiles in vitro and occasionally in vivo. The situation is totally different when one wants to fulfil the specific requirements imposed by the marketing of a sustained release device to be used in humans or in animals eaten by human beings. The control of the release characteristics is then a difficult challenge. In this work, attempts were made to combine cephradin, a hydrophilic beta-lactam antibiotic, and bioresorbable polymeric matrices of a poly(alpha-hydroxy acid) in the form of microspheres with the aim of delivering the antibiotic to cattle at a dose rate of 4-5 mg/kg/day over a 3-4 days period after i.m. injection. PLAGA aliphatic polyesters were selected because they are already FDA approved as matrices. The solvent evaporation technique using PVA as the emulsion stabilizer was selected because it is efficient and can be extended to an industrial scale. Various experimental conditions were used in order to obtain the highest encapsulation yields compatible with the desired specifications. Decreasing the volume of the aqueous phase and adding a water-miscible organic solvent/non-solvent of cephradin failed. In contrast, microspheres containing up to 30% cephradin were prepared after addition of sodium chloride to the aqueous dispersing phase. The amount of entrapped drug was raised to 40% by decreasing the temperature and the pressure. Preliminary investigations using dogs showed that 20% cephradin microspheres prepared under these conditions extended the presence of cephradin in the blood circulation up to 48 h. Increasing the load led to higher blood concentrations but shorter sustained release. The fact that the microspheres were for cattle limited the volume of the injection and thus the amount of microspheres to be administered. The other limiting factors were related to microsphere morphology.

Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections.

In the case of external ophthalmic infections, repeated instillations of antibiotics are required to reach therapeutic level, above the minimal inhibitory concentration (MIC). An additional administration of a corticosteroid is often needed, in order to limit the precorneal damages caused by the infection. However, repeated administration of a corticosteroid can increase intraocular pressure and thus lead to glaucoma. To overcome the disadvantages of separated and repeated instillations of two products and to avoid the side effects of dexamethasone, a soluble insert containing gentamicin sulfate and dexamethasone phosphate was developed. The new system ensures the concomitant release of the two drugs during the first 10 h of treatment, followed by an adequate concentration of gentamicin sulfate, above the MIC of 4.0 microgram ml-1, during 50 h, due to a combination of gentamicin sulfate with cellulose acetate phthalate, which reduces the solubility of gentamicin.

Evaluation of soluble Bioadhesive Ophthalmic Drug Inserts (BODI) for prolonged release of gentamicin: lachrymal pharmacokinetics and ocular tolerance.

The purpose of this investigation was the evaluation of Bioadhesive Ophthalmic Drug Inserts (BODI) for prolonged release of gentamicin sulfate (GS) in tears. The BODIs (length 5.0 mm, diameter 2.0 mm, weight 20.5 mg, average GS content 5.0 mg) were prepared by extrusion of a mixture based on hydroxypropylcellulose (HPC), ethylcellulose (EC) and carbomer. Two methods were tested to prolong the release of GS in tears: (1) preliminary treatment of GS and (2) use of a less hydrophilic polymer than HPC, hydroxypropylmethylcellulose (HPMC), as a vehicle constituent. The preliminary treatment consisted of the formation of a GS/cellulose acetate phthalate (CAP) solid dispersion (ratio GS/CAP: 10/6) made in acetonic medium, and in the coating of GS/EC granules (GS/EC ratio: 10/0.5) with an aqueous dispersion of CAP, to form a GS/EC/CAP coprecipitate (GS/EC/CAP ratio: 10/0.5/6). Inserts containing GS/CAP solid dispersion, GS/EC/CAP coprecipitate and HPMC resulted in improved time of efficacy (t(eff)) (43.8, 23.3, and 33.1 h, respectively), when compared to inserts containing GS without preliminary treatment (t(eff) = 11.9 h). A high irritation level was observed for inserts containing the GS/EC/CAP and HPMC. A relation between t(eff) and irritation score was established, emphasizing the importance of irritability as a factor during the evaluation of the potential of these systems.

Ocular drug delivery in veterinary medicine.

This paper provides a comprehensive overview of the various approaches currently used in the development of ocular drug delivery systems for the treatment of ocular diseases in animals. It is obvious from the literature that most of the products that are currently available are derived from human medicine without consideration given to the differences which exist between the anatomy and physiology of the eye of various animal species which ultimately affect product design and performance. As a result, many of the products for animal use seem in many circumstances inappropriate for animal care. The article deals with some aspects of eye anatomy and physiology of different animals, and then provides an overview of the most commonly encountered pathologies. The paper then discusses the currently available drug products and finally reviews new delivery concepts. Several hundred references are included in the paper and provide access to further information on the subject.

Ocular availability of gentamicin in small animals after topical administration of a conventional eye drop solution and a novel long acting bioadhesive ophthalmic drug insert.

PURPOSE: Gentamicin eye drop solutions have a short precorneal residence time. The present study investigates the effect of gentamicin using a new long acting delivery Bioadhesive Ophthalmic Insert (BODI) in healthy dogs and rabbits and compares the results with a conventional regimen using an eye drop solution. METHODS: In vivo assays were performed on animals after deposition of one BODI and instillations of an eye drop solution. Tear samples were collected over 72 hours and 60 minutes, in the case of inserts and eye drop solution respectively. The gentamicin concentration profiles in tear fluid (determined by a fluorescent polarization immunoassay technique) was individually analyzed, in each animal, in relation with the minimum inhibitory concentration observed in vitro against some bacteria. A non classical pharmacokinetic approach was used for the analysis of the topically applied drug substance, involving two parameters: the efficacy area under the curve (AUCeff) and the efficacy time (teff). RESULTS: In the case of the eye drop solution, the AUCeff were higher in dogs (2.80 10(3) - 3.64 10(3) [micrograms ml-1 h]) than in rabbits (0.64 x 10(3) - 0.95 x 10(3) [micrograms ml-1 h]); the teff had a similar behavior: 6-15 [h] in dogs and 2-6 [h] in rabbits. In the case of BODIs, the AUCeff and the teff were quite similar between dogs and rabbits: 190 10(3) - 205 10(3) [micrograms ml-1 h] and 70-76 [h], respectively. The AUCeff and the teff were always much higher in the case of BODIs than for the eye drop solution both in dogs and rabbits. CONCLUSIONS: This study shows that topical administration of gentamicin using BODIs can improve treatment due to the decreasing number of applications while ensuring an effective level of antibiotic in tears controlled by the device.