Adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation and a single subcutaneous infusion of carboplatin.

OBJECTIVE: To evaluate adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation followed by a single SC infusion of carboplatin. ANIMALS: 45 client-owned dogs with appendicular osteosarcoma treated with limb amputation and SC infusion of carboplatin between January 1, 2006, and January 15, 2017. PROCEDURES: Medical records were reviewed, and data collected included signalment, tumor location, treatment, results of clinicopathologic analyses and diagnostic imaging, adverse effects of chemotherapy, metastasis-free interval, survival time, and communications with owners and referring veterinarians. Findings were evaluated with the Kaplan-Meier survival analysis and Mantel-Haenszel log-rank test. RESULTS: 45 dogs were identified that met the inclusion criteria (12 of the 45 dogs had been reported in a previous case series). No dogs had pulmonary metastases detectable by CT or radiography before treatment. All dogs completed the protocol as planned. Median survival time (MST) was 196 days; metastasis-free interval was 197 days. Three of the 45 (7%) dogs required hospitalization for gastrointestinal signs related to chemotherapy. There were no chemotherapy-related deaths. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that although treatment with SC infusion of carboplatin was well tolerated, the MST for dogs in the present study was similar to reported MSTs in dogs with appendicular osteosarcoma treated with limb amputation alone and was in the lower range of historically reported survival times for dogs receiving IV adjunctive chemotherapy. Therefore, we could not recommend this protocol of SC infusion of carboplatin but recommended that protocols with IV administration of carboplatin be used instead.

Intramammary antimicrobial treatment of subclinical mastitis and cow performance later in lactation.

The aim of this study was to evaluate long-term therapeutic effects of antimicrobial treatment of recently acquired subclinical mastitis (RASCM) during lactation. Quarter-level clinical mastitis (CM) follow-up, composite somatic cell counts (SCC), and cow-level milk yield later in lactation were evaluated using follow-up data from 2 previously published linked randomized field trials. The first trial randomly assigned antimicrobial treatment with any intramammary product or negative control to culture-positive quarters of cows having a first elevated composite SCC after 2 consecutive low composite SCC measurements. Untreated cows that had a second elevated composite SCC at the next measurement and were staphylococci-positive (i.e., Staphylococcus aureus or non-aureus staphylococci) were randomly assigned to treatment or control. Quarter-level CM cases were reported by the participating herd personnel, and milk yield and composite SCC data were obtained from the regular test-day recording. Frailty survival models were used to evaluate the long-term therapeutic effects of antimicrobial treatment of RASCM on quarter-level CM follow-up. Mixed linear regression models were applied to quantify the effect on milk yield and composite SCC. Data of 638 quarters from 486 cows in 38 herds were available for statistical analyses, of which 229 quarters of 175 cows received antimicrobial treatment for RASCM. Antimicrobial treatment culminated in reduced composite SCC levels later in lactation but did not result in different milk yield levels or CM follow-up compared with control cows. Antimicrobial treatment of cows with RASCM should therefore only be considered in exceptional situations given the current focus on antimicrobial usage reduction in animal husbandry.

Randomized, controlled, superiority study of extended duration of therapy with an intramammary antibiotic for treatment of clinical mastitis.

The objectives of this study were to evaluate the efficacy of therapy of clinical mastitis following intramammary infusion of 2 durations of intramammary antibiotic therapy and to analyze clinical and microbiology data at enrollment or within 4 d of commencement of treatment as potential predictors of subsequent clinical and bacteriological cure. A total of 304 glands were randomly assigned to intramammary treatment with a combination of amoxicillin, clavulanic acid, and prednisolone either 3 times at 12-h intervals (3×12, n = 156) or 5 times at 12-h intervals (5×12 hourly, n = 148). At enrollment (d 0), assessments were made of the cow's demeanor, rectal temperature, teat-end hyperkeratosis, presence of heat or swelling of the gland, presence of clots in the milk, and California Mastitis Test (CMT) score. Cows were revisited on d 4, 14, and 21 and assessed for rectal temperature, the presence of clots in milk, heat or swelling of the gland, and CMT score. Milk samples were collected from enrolled glands for bacteriology (d 0, 4, 14, and 21) and for somatic cell count (d 14 and 21). Data were analyzed using generalized linear models. Treatment group was the key independent variable, but herd was included in the models. Other potentially confounding variables were included where associated at the bivariate level. A second series of analyses were undertaken to predict likelihood of clinical and bacteriological cure using the clinical signs cow age and days in milk, as well as bacteriological results at d 0 and 4. Although we found a higher clinical failure rate in the 3×12 than 5×12 hourly treatment group (28.2 ± 5.0 vs. 13.4 ± 3.6%, respectively), we noted no difference in bacteriological cure percentage (73.3 ± 7.8 vs. 72.0 ± 7.4%, respectively). The presence of heat or swelling at d 4, days in milk at initiation of treatment, age of the cow, and change in CMT score between d 0 and 4 were predictive of clinical and bacteriological cure. We concluded that increasing the duration of treatment resulted in significantly fewer clinical failures, but had no effect on cure proportion, somatic cell count, or new infection rate. Knowledge of cow age and days in milk and clinical signs were predictive of clinical and bacteriological cure proportion and may provide guidance for producers, under veterinary direction, as to when to extend or recommence therapy.

Survey of owner subcutaneous fluid practices in cats with chronic kidney disease.

Objectives The purpose of this study was to survey owners regarding their practices and experiences with the administration of subcutaneous (SC) fluids at home to cats with chronic kidney disease (CKD) to gain insight that might help more owners be successful with the procedure. Methods A web-based survey was advertised online. Owners of 468 cats with CKD participated, 399 of whom administered SC fluids. Results Fifty-nine percent of the cats were domestic shorthairs, with >85% of the cats being 10 years of age or older. IRIS stage 3 was most commonly represented (37%). Ninety-five percent of owners said they discussed giving fluids with their veterinarian, with only 42% of those discussions involving additional educational resources. A large majority of owners (85%) said it was either an easy, somewhat easy/no stress or okay experience for them, and a large majority (89%) reported that the experience was easy/no stress, somewhat easy or okay experience for their cats. To increase tolerance, 57% said they gave a treat to their cat afterwards, and 60% said they warmed the fluids. Sixty-one percent reported using a 20 G or larger needle, with 49% saying size of needle affected tolerance. Seventy-four percent also felt that the length of time it took to administer fluids affected tolerance. One-hundred milliliters was the most commonly given fluid amount. Hydration status was monitored by 40% of owners by various methods, with 40% of those saying they skipped or added fluids based on hydration assessment. Conclusions and relevance A majority of owners gave positive feedback about their ability to learn and administer SC fluids to their cat wth CKD. Owners reported several strategies that they felt improved tolerance of fluid administration. Overall, the protocol should be tailored to the preference of the cat for best possible long-term success.

Neosaxitoxin, a Paralytic Shellfish Poison toxin, effectively manages bucked shins pain, as a local long-acting pain blocker in an equine model.

Local anesthesia is an effective method to control pain. Neosaxitoxin is a phycotoxin whose molecular mechanism includes a reversible inhibition of voltage-gated sodium channels at the axonal level, impeding nerve impulse propagation. The present study was designed to evaluate the clinical efficacy of Neosaxitoxin as a local long-acting pain blocker in horse bucked shins, and it was found to effectively control pain. While Neosaxitoxin and Gonyautoxin, another Paralytic Shellfish Poison (PSP) toxin, have been successfully used in humans as long-lasting pain blockers, this finding marks the first time a PSP has been shown to have an established effect in veterinary medicine.

Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity.

Closantel (CLS) is highly effective against adult liver flukes after its oral or subcutaneous (sc) administration in ruminants. Trans-tegumental diffusion and oral ingestion are the two potential routes available for the entry of drugs into Fasciola hepatica. The work reported here contributes to improve the understanding of CLS pharmacology. The main goals of were: I) to determine the pattern of in vivo CLS accumulation into adult F. hepatica and relevant tissues in CLS-treated sheep; II) to investigate the influence of the physicochemical composition of the incubation medium on the CLS diffusion process into adult F. hepatica; III) to assess the ovicidal activity of CLS against F. hepatica eggs; and IV) to investigate the in vivo effect of CLS treatment on glutathione S-transferases activity in adult liver flukes exposed to CLS. Fourteen healthy sheep were each orally infected with 75 F. hepatica metacercariae. Sixteen (16) weeks after infection, animals were treated with CLS by oral (n = 6, 10 mg/kg) or sub-cutaneous (sc) (n = 6, 5 mg/kg) route. At 12, 24 and 36 h post-treatment, animals were sacrificed (n = 2) and samples of blood, bile and adult F. hepatica were collected. In addition, flukes recovered from non-treated sheep (n = 2) were ex vivo incubated (60 min) in the presence of CLS in either RPMI or bile as incubation medium. CLS concentration was measured by HPLC. The ovicidal activity of CLS was investigated using eggs obtained from the bile of untreated sheep. Finally, glutathione S-transferase activity in F. hepatica recovered from untreated and CLS-treated sheep was assessed. In the in vivo studies, the highest CLS concentrations were measured in plasma and adult liver flukes. A positive correlation was observed between CLS concentration in plasma and in F. hepatica. Results obtained in the current work indicate that the in vivo accumulation of CLS into adult liver flukes occurs mainly by the oral route. After ex vivo incubation, the uptake of CLS by the parasite was markedly diminished in the presence of bile compared with that observed in the presence of RPMI as incubation medium. CLS lacks ovicidal activity at therapeutically relevant concentrations. Lastly, CLS significantly increased glutathione S-transferase activity in flukes recovered at 12 h (oral treatment) and 24 h (sc treatment), compared to the control liver flukes.

Pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD integration of ceftiofur after a single intravenous, subcutaneous and subcutaneous-LA administration in lactating goats.

BACKGROUND: Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration-time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy. RESULTS: The pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested. CONCLUSIONS: The systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica. Subcutaneous administration of the long-acting formulation showed safety and tolerance for all the animals used. Ceftiofur concentrations exceeded the MIC and MBC for up to 72 h and MPC for up 32 h in serum. Thus, this drug could be effective in treating infectious diseases of goats caused by M. haemolytica at a dose of 6 mg/kg with the SC-LA formulation.

Effect of a constant rate infusion of cytosine arabinoside on mortality in dogs with meningoencephalitis of unknown origin.

Administration of cytosine arabinoside (CA) by continuous rate infusion (CRI) has pharmacokinetic and pharmacodynamic advantages over traditional intermittent dosing. Whether these advantages translate into clinical efficacy remains unknown. The aim of this study was to assess the efficacy and safety of CRI of CA in dogs with meningoencephalitis of unknown origin (MUO) and to compare outcomes with a group of historical control dogs treated with conventional intermittent subcutaneous (SC) administration of CA; both groups received adjunctive prednisolone. It was hypothesised that a CRI of CA for 24 h at 100 mg/m(2) would improve survival and lesion resolution compared with conventional SC delivery of 50 mg/m(2) every 12 h for 48 h. Eighty dogs with suspected MUO were recruited from consecutive dogs presenting with suspected MUO from 2006 to 2015. All dogs underwent routine clinical evaluation, magnetic resonance imaging of the brain and cerebrospinal fluid analysis. There were 39 dogs in the SC group and 41 dogs in the CRI group; baseline characteristics were similar in both groups. Survival at 3 months was 22/39 (44%) with SC delivery versus 37/41 (90%) with CRI. No dose-limiting toxicities were noted for either group. The resolution rate of magnetic resonance imaging and cerebrospinal fluid abnormalities at the 3 month re-examination were substantially improved in the CRI group versus the SC group. The CRI regimen produced a survival advantage over the SC route of administration without clinically significant toxicity. These data supports the routine use of CRI at first presentation for the treatment of MUO in dogs.

Effects of intramammary infusions of casein hydrolysate, ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and lactose at drying-off on mammary gland involution.

The transition from the lactation to the dry period in dairy cows is a period of high risk for acquiring new intramammary infections. This risk is reduced when involution of mammary glands is completed. Consequently, strategies that accelerate the involution process after drying-off could reduce the incidence of mastitis. The objective of this study was to assess the effect of 3 different treatments on mammary gland involution. Each quarter of 8 Holstein cows in late lactation was randomly assigned at drying-off to an intramammary infusion of casein hydrolysate (CNH; 70 mg), ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 5.7 g), lactose (5.1g), or saline 0.9% (control) solutions. Milk samples were collected on the last 2 d before and 1, 3, 5, 7, 10, and 14 d after the last milking for determining concentrations of mammary gland involution markers. Lactoferrin, somatic cell counts (SCC), BSA, and Na(+) concentrations, as well as matrix metalloproteinase-2 and matrix metalloproteinase-9 activities gradually increased in mammary secretions during the first 2 wk following the last milking, whereas milk citrate and K(+) concentrations decreased. As involution advanced, the Na(+):K(+) ratio increased, whereas the citrate:lactoferrin ratio decreased. Compared with mammary secretions from control quarters, mammary secretions of quarters infused with CNH had higher SCC on d 1, 3, 5, and 7, and greater BSA concentrations on d 1, 3, and 5. Similarly, the CNH treatment induced a faster increase in lactoferrin concentrations, which were greater than in milk from control quarters on d 3, 5, and 7 after drying-off. Milk citrate concentrations were unaffected by CNH but the citrate:lactoferrin ratio was lower in CNH-treated quarters on d 3 and 5 than in control quarters. Moreover, CNH treatment hastened the increase in Na(+) concentration and in the Na(+):K(+) ratio on d 1. Infusion of CNH also led to an increase in proteolytic activities, with greater matrix metalloproteinase 9 activities on d 1 and 3. The EGTA infusion increased SCC above that of control quarters on d 1 and 3 but it had no effect on the other parameters. Lactose infusion had no effect on any of the involution markers. In this study, intramammary infusions of CNH were the most efficient treatment to accelerate mammary gland involution, suggesting a potential role of CNH as a local milk secretion inhibitor during milk stasis.

Evaluation of a single subcutaneous infusion of carboplatin as adjuvant chemotherapy for dogs with osteosarcoma: 17 cases (2006-2010).

OBJECTIVE: To evaluate adverse effects and survival times in dogs with osteosarcoma that received a single SC infusion of carboplatin as adjunctive chemotherapeutic treatment following limb amputation or limb-sparing surgery. DESIGN: Retrospective case series. ANIMALS: 17 client-owned dogs with spontaneously occurring osteosarcoma. PROCEDURES: Medical records of dogs that underwent limb amputation or limb-sparing surgery followed by a single continuous SC infusion of carboplatin (total dose, 300 mg/m(2) infused over 3, 5, or 7 days) were evaluated. Signalment, tumor location, type of surgery (amputation or limb-sparing), duration of carboplatin infusion, results of hematologic and serum biochemical analyses, and adverse effects were recorded. Kaplan-Meier survival analysis was performed. RESULTS: Median survival time for all dogs was 365 days. Nine dogs had adverse bone marrow-related (hematologic) effects, 1 had adverse gastrointestinal effects, and 7 had infections at the surgical site. No significant differences were detected in survival times of dogs grouped according to tumor location, type of surgery, duration of carboplatin infusion, or development of postoperative infection. CONCLUSIONS AND CLINICAL RELEVANCE: Median survival time and adverse effects in dogs with osteosarcoma that received a single SC infusion of carboplatin over a 3-, 5-, or 7-day period as adjunctive treatment following limb amputation or limb-sparing surgery were comparable to those of previously reported chemotherapy protocols requiring IV drug administration over several weeks. Further investigation is needed to evaluate the efficacy of this protocol as adjunctive treatment for osteosarcoma and other tumors in dogs.

Evaluation of a modified acetaminophen absorption test to estimate the abomasal emptying rate in Holstein-Friesian heifers.

OBJECTIVE: To assess the suitability of the modified acetaminophen absorption test for evaluation of abomasal emptying rate in ruminating cattle. ANIMALS: 7 Holstein-Friesian heifers. PROCEDURES: In a crossover study design, heifers consecutively underwent an IV infusion of 1 L of saline (0.9% NaCl) solution (control treatment), 1 L of saline solution containing metoclopramide (0.1 mg/kg), and 1 L of saline solution containing atropine (0.1 mg/kg), with an interval of 15 days between treatments. Immediately after each treatment, acetaminophen diluted in ethanol (50 mg/kg) was infused transcutaneously into the abomasum. Blood samples were obtained repeatedly for measurement of plasma acetaminophen concentration, and pharmacokinetic data were obtained. RESULTS: Maximum plasma acetaminophen concentration was significantly lower after atropine treatment than after control or metoclopramide treatment, whereas no difference was identified between control and metoclopramide treatments. The interval to maximum plasma acetaminophen concentration was significantly longer in atropine-treated versus metoclopramide-treated heifers. The interval to maximum acetaminophen concentration obtained from a pharmacokinetic model was significantly longer for atropine than for control and metoclopramide treatment. Similarly, areas under the plasma acetaminophen concentration-time curves for the first 60, 90, 120, and 240 minutes after administration were significantly lower for atropine versus metoclopramide or control treatment, whereas differences between metoclopramide and control treatments were not identified. CONCLUSIONS AND CLINICAL RELEVANCE: The modified acetaminophen absorption test was a practical, minimally invasive, and reliable method to assess abomasal emptying in cattle. Metoclopramide administered at a dose of 0.1 mg/kg did not increase the abomasal emptying rate.

Hydrogenated castor oil nanoparticles as carriers for the subcutaneous administration of tilmicosin: in vitro and in vivo studies.

Tilmicosin-loaded solid lipid nanoparticles (SLN) were prepared with hydrogenated castor oil (HCO) by o/w emulsion-solvent evaporation technique. The nanoparticle diameters, surface charges, drug loadings and encapsulation efficiencies of different formulations were 90 approximately 230 nm, -6.5 approximately -12.5 mV, 40.3 approximately 59.2% and 5.7 approximately 11.7% (w/w), respectively. In vitro release studies of the tilmicosin-loaded nanoparticles showed a sustained release and the released tilmicosin had the same antibacterial activity as that of the free drug. Pharmacokinetics study after subcutaneous administration to Balb/c mice demonstrated that a single dose of tilmicosin-loaded nanoparticles resulted in sustained serum drug levels (>0.1 microg/mL) for 8 days, as compared with only 5 h for the same amount of tilmicosin phosphate solution. The time to maximum concentration (Tmax), half-life of absorption (T(1/2) ab) and half-life of elimination (T(1/2) el) of tilmicosin-loaded nanoparticles were much longer than those of tilmicosin phosphate solution. Tissue section showed that drug-loaded nanoparticles caused no inflammation at the injection site. Cytotoxicity study in cell culture and acute toxicity test in mice demonstrated that the nanoparticles had little or no toxicity. The results of this exploratory study suggest that the HCO-SLN could be a useful system for the delivery of tilmicosin by subcutaneous administration.