Field evaluation of the efficacy of tolfenamic acid administered in one single preoperative injection for the prevention of postoperative pain in the dog.

In this randomized, placebo-controlled, blinded field trial, 62 dogs (of which four were excluded) taken to a veterinary practice for orthopaedic surgery with a postoperative painful component were enrolled to assess the efficacy of a preoperative intramuscular injection of tolfenamic acid (TA) at a dose of 4 mg/kg in preventing postoperative pain. The animals were clinically examined at T1 + 1H, T1 + 4H, T1 + 24H (T1 = extubation). The efficacy results showed a statistical effect of TA in preventing postoperative pain with the evolution in the pain statistically in favour of TA treatment (Visual Analogue Scale). This was confirmed by the sum of the scores calculated at T1 + 24H that was statistically higher in the placebo group, and by the evolution in the respiratory rate, which was statistically lower in the TA-treated animals after surgery. TA treatment was very well tolerated as no clinical sign (except one isolated case of vomiting and diarrhoea, i.e. 3.5%) or change in biochemical and haematological values was observed and as no interaction with the anaesthetic drugs and with marbofloxacin was reported.

Pharmacokinetics of marbofloxacin in lactating cows after repeated intramuscular administrations and pharmacodynamics against mastitis isolated strains.

The plasma and milk pharmacokinetics of marbofloxacin, a fluoroquinolone antibacterial compound, were evaluated in dairy cows, as well as its pharmacodynamic characteristics against mastitis-isolated pathogens. Marbofloxacin was given intramuscularly as a 10% aqueous solution to dairy cows either at a single dose or at repeated doses of 2 mg/kg once daily for 3 d. Blood and milk samples were collected for the determination of the concentration of marbofloxacin and of its putative metabolites: N-desmethyl-marbofloxacin and N-oxide-marbofloxacin. Bacterial field isolates were from milk samples collected from dairy cows suspected of having an intramammary infection. After identification, the minimal inhibitory concentration (MIC) was determined against the isolated strains. The maximal marbofloxacin concentration (Cmax) observed in milk after the first administration was 1.024 microg/mL, and the area under the curve during the first dosing interval was 6.513 microg/h per milliliter. After the third administration, these parameters were slightly increased (about 20% at most). Both metabolites were detected in the milk, but their concentrations were below the limit of quantification. The MIC against 90% of the population (MIC90) of Escherichia coli was 0.016 microg/mL, and it was 0.229 microg/mL against Staphylococcus aureus. The following surrogate clinical outcome markers were obtained against E. coli strains: a Cmax/MIC ratio of 67 and an area under the curve/MIC ratio of 407 h. Hence, a possible efficacy of marbofloxacin in the treatment of E. coli-induced mastitis could be expected as the endpoints of 10 and 250 h, respectively, are reached.

Clinical evaluation of bioadhesive ophthalmic drug inserts (BODI) for the treatment of external ocular infections in dogs.

In the case of external ocular diseases such as conjunctivitis, keratoconjunctivitis sicca (KCS) and superficial corneal ulcers, topical administration of eyedrops containing an antibacterial agent is often prescribed. Numerous daily instillations of eyedrops over several days are required for successful treatment, often leading to bad compliance. In addition, the reflex lachrymation following instillation promotes rapid elimination of the drug from the corneal surface. To overcome the disadvantage of repeated instillations, a soluble bioadhesive ophthalmic drug insert (BODI) to be placed in the lower cul de sac of the eye was developed. The clinical efficacy, after deposition of one insert and a classical eyedrop treatment (Tiacil), Virbac Laboratories), was investigated in dogs presenting conjunctivitis, superficial corneal ulcer or keratoconjunctivitis sicca (KCS). Similar total clinical recovery results were obtained after 3 and 7 days for both treatments. BODI can therefore advantageously be prescribed for the treatment of external ophthalmic diseases, by reducing the treatment to a single application and therefore improving compliance compared to classical eyedrop treatment.

Comparison of two oral electrolyte solutions for the treatment of dehydrated calves with experimentally-induced diarrhoea.

We compared the ability of two oral electrolyte solutions to resuscitate calves with experimentally induced diarrhoea and dehydration. Sucrose solution, furosemide, spironolactone, and hydrochlorothiazide were administered to 18 male Holstein-Friesian calves to induce diarrhoea and dehydration. Clinical changes after 24 h included severe diarrhoea, moderate dehydration (8-10% body weight), azotemia, and clinical depression. Calves were then randomly assigned to one of three treatment groups (milk replacer, 2 L every 12 h; hyperosmotic oral electrolyte solution, 2 L every 12 h; iso-osmotic oral electrolyte solution, 1.5 L every 6 to 12 h) and followed for an additional 48 h. Compared to feeding milk replacer, the hyperosmotic solution significantly (P< 0.05) improved hydration status, increased body weight, maintained urine production, decreased the degree of clinical depression and prevented development of metabolic acidosis, although serum glucose concentration was decreased at 24 h and 48 h. The hyperosmotic solution produced a similar resuscitative response to the iso-osmotic solution, but maintained higher serum glucose concentrations and lower serum beta-OH butyrate and non-esterified fatty-acid concentrations, indicating that the hyperosmotic solution provided greater nutritional support. The hyperosmotic solution rehydrated calves faster and more effectively than feeding equivalent volumes of milk replacer and can, therefore, be recommended as part of the initial treatment of dehydrated calves with diarrhoea.

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.

Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration.

Six dogs were treated with a single intravenous (i.v.) dose (2 mg/kg) of marbofloxacin, followed by single oral (p.o.) doses of marbofloxacin at 1, 2 and 4 mg/kg, according to a three-way crossover design. The same experimental design was used for the subcutaneous (s.c.) route. In addition, a long-term trial involving eight dogs given oral doses of marbofloxacin at 2, 4 and 6 mg/kg/day for thirteen weeks was carried out. Plasma and urine samples were collected during the first two trials, plasma and skin samples were collected after the second of these trials. Plasma, urine and skin concentrations of marbofloxacin were determined by a reverse phase liquid chromatographic method. Mean pharmacokinetic parameters after i.v. administration were the following: t1/2 beta = 12.4 h; ClB = 0.10 L/h.kg; Varea = 1.9 L/kg. The oral bioavailability of marbofloxacin was close to 100% for the three doses. At 2 mg/kg, Cmax of 1.4 micrograms/mliter was reached at tmax of 2.5 h. Mean AUC and Cmax values had a statistically significant linear relationship with the doses administered. About 40% of the administered dose was excreted in urine as unchanged parent drug. After s.c. administration, the calculated parameters were close to those obtained after oral administration, except tmax (about 1 h) which was shorter. The mean skin to plasma concentration ratio after the long-term trial was 1.6, suggesting good tissue penetration of marbofloxacin.

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.

Use of an oral antiseptic bioadhesive tablet in dogs.

V3703 (Stomadhex) is a tablet with bioadhesive properties enabling it to remain in place for several hours after it has been placed on the oral mucosa. It continuously releases chlorhexidine and niacinamide. In a study conducted in 15 dogs, the tablets were well tolerated by the animals. The product significantly reduced (p < 0.05): dental plaque; quantitative periodontopathogen and total anaerobic bacterial counts; spirochetes; and halitosis when used daily over a 14 day period. Gingivitis was also reduced, though not significantly (p = 0.07). Stomadhex treatment can provide a carry-over effect following dental scaling by reducing oral microflora and retarding the reappearance of dental plaque.

Antibacterial activity of marbofloxacin. A new fluoroquinolone for veterinary use against canine and feline isolates.

Marbofloxacin is a new fluoroquinolone developed exclusively for veterinary use. Minimum inhibitory concentrations of marbofloxacin were assessed for 816 recent isolates associated with canine or feline diseases. Marbofloxacin showed a broad spectrum of activity against gram-negative and gram-positive bacteria. In vitro rates of killing of marbofloxacin and enrofloxacin were compared against strains of Staphylococcus intermedius and Pasteurella multocida, and the results showed no marked difference between the two antibiotics. The duration of bactericidal activity was evaluated ex vivo in the urine of dogs and cats treated with marbofloxacin and lasted from 2 to 5 days after a single administration according to the dosages. Post-antibiotic effect durations were determined with Escherichia coli, Pasteurella multocida, Staphylococcus aureus and Staphylococcus intermedius and were found almost equal to those of enrofloxacin or ciprofloxacin. These results predict a great potential for marbofloxacin in the treatment of a wide range of diseases in dogs and cats.

A field evaluation of the efficacy of tolfenamic acid and oxytetracycline in the treatment of bovine respiratory disease.

In a blinded multicentre trial 313 cattle showing clinical signs of respiratory disease were allocated randomly into three groups, treated intramuscularly with a long-acting oxytetracycline formulation at a dose rate of 20 mg/kg bodyweight in combination with vehicle alone (placebo) or with tolfenamic acid at 2 mg/kg bodyweight once or on two occasions with a 48-h interdosing interval. The clinical status of the animals was monitored for 5 days using a specific scoring system and weight gain was calculated between day 0 and day 21. Relapses were monitored from day 5 until day 21. When oxytetracycline was combined with two injections of tolfenamic acid, there was a significant (P < 0.04) improvement in the clinical resolution. This regimen also produced non-significant improvements in cure rate, reduced frequency of relapses and improved weight gain.