Clinical Evaluation of Tavocept to Decrease Diuresis Time and Volume in Dogs with Bladder Cancer Receiving Cisplatin

Background

Transitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of nephrotoxicity. Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased the required infusion/diuresis volume in clinical trials in humans.

Hypothesis/Objectives

We hypothesized that Tavocept would decrease diuresis volume and time and facilitate safe administration of a cisplatin/piroxicam protocol to dogs with bladder cancer. Secondary objectives were to compare response rate and survival times to an historical comparator group treated without Tavocept.

Animals

Fourteen client‐owned dogs were prospectively enrolled.

Methods

Tumor volume was measured by computed tomography at days 0, 42, and 84. Dogs received combination Tavocept/cisplatin with a shortened diuresis protocol. A total of 4 doses was planned, with concurrent administration of piroxicam. Serial biochemical analyses were evaluated for azotemia.

Results

A 90‐minute infusion/diuresis time was used for all dogs. Three dogs (21%) had concurrent increases in serum creatinine (>2.0 mg/dL) and BUN (>42 mg/dL) concentrations; 2 of these dogs were isosthenuric. This frequency of nephrotoxicity is significantly less (P = 0.0406) than that of an historical control group treated without Tavocept. Overall response rate was 27%. Median survival time was comparable to historical controls (253 vs. 246 days).

Conclusions and Clinical Importance

Tavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia. Survival time was comparable, but the response rate was inferior to an historical comparator group. Further evaluation in other tumors susceptible to platinum agents is warranted.     

Noninferiority trial investigating the efficacy of a nonantibiotic intramammary therapy in the treatment of mild‐to‐moderate clinical mastitis in dairy cows with longer lasting udder diseases

A nonblinded, positively controlled, noninferiority trial was conducted to evaluate the efficacy of an alternative, nonantibiotic therapy with Masti Veyxym^® to reduce ineffective antibiotic usage in the treatment of nonsevere clinical mastitis (CM) in cows with longer lasting udder diseases. The solely intramammary treatment with Masti Veyxym^® (three applications, 12 hr apart) and the combined treatment with Masti Veyxym^® and antibiotics as usual on the farm according to label of the respective product were compared with the reference treatment of solely antibiotic therapy. The matched field study was conducted on eight free‐stall dairy farms located in Eastern Germany. Cases of mild‐to‐moderate CM in cows with longer lasting high somatic cell counts in preceding dairy herd improvement test days and with previous CM cases in current lactation were randomly allocated to one of the three treatment groups. A foremilk sample of the affected quarter was taken before treatment and again approximately 14 days and 21 days after the end of therapy for cyto‐bacteriological examination. Primary outcomes were clinical cure (CC) and no CM recurrence within 60 days after the end of treatment (no R60). Bacteriological cure (BC) and quarter somatic cell count (QSCC) cure were chosen as secondary outcomes although low probabilities of BC and QSCC cure for selected cows were expected. The study resulted in the following findings: the pathogens mostly cultured from pretreatment samples were Streptococcus uberis, followed by Staphylococcus aureus and coagulase‐negative staphylococci. There were no significant differences between the two test treatments in comparison with the reference treatment regarding all outcome variables. The sole therapy with Masti Veyxym^® resulted in a numerically lower likelihood of BC without significant differences to the reference treatment. The combined therapy group showed a numerically higher nonrecurrence rate than the two other treatment groups and noninferiority compared to the reference treatment was proven. Having regard to the selection criteria of cows in this study, the findings indicated that sole treatment with Masti Veyxym^® in nonsevere CM cases may constitute an alternative therapy to reduce antibiotics. However, noninferiority evaluations were mostly inconclusive. Further investigations with a larger sample size are required to confirm the results and to make a clear statement on noninferiority.     

Anticancer effects of resveratrol in canine hemangiosarcoma cell lines

Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti‐proliferative and/or pro‐apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD‐1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen‐activated protein kinase (MAPK), AMP‐activated protein kinase (AMPK) and extracellular signal‐regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth‐inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro‐apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.     

Influence of inflammation on serum concentration, molecular heterogeneity and drug binding properties of canine alpha–1–acid glycoprotein

The concentration and the heterogeneity of alpha-1-acid glycoprotein (alpha-1-AGP) and oxprenolol binding were determined in serum of healthy dogs and dogs with inflammatory disease. In inflammation, an increase in the mean alpha-1-AGP concentration from 0.47 to 2.85 g/l was accompanied by a reduction in the mean free oxprenolol fraction from 25% to 6%. alpha-1-AGP concentration and oxprenolol binding were inversely correlated. The heterogeneity of canine alpha-1-AGP remained essentially unchanged in dogs with inflammation and, in both these dogs and the controls, between five and seven forms with different isoelectric points and one single concanavalin A-reactive form were detected. It is concluded that in dogs, as in humans, oxprenolol binds to serum alpha-1-AGP. Changes in serum binding of oxprenolol during inflammation result from a change in the serum concentration of alpha-1-AGP rather than a change of molecular heterogeneity.     

Proteins specified by bovine herpesvirus-2

Polypeptides synthesized in bovine testes cells infected with bovine herpesvirus type 2 were labeled with [35S]methionine and were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Thirty-eight virus-induced proteins, ranging in molecular weight from 32,000 to 149,000, were detectable by analysis of whole cell lysates between postinfection hours 2 and 36. A similar number was immunoprecipitated by rabbit antiserum to bovine herpesvirus type 2. Twelve proteins incorporated [3H]glucosamine. On the basis of their temporal characteristics and their pattern of synthesis in the presence of cycloheximide and dactinomycin, 3 proteins, including at least one that was nondetectable in the absence of drugs, were classified as alpha proteins, 4 as beta proteins, 1 as a beta/gamma protein, and 27 as gamma proteins. Host cell protein synthesis was not reduced substantially until postinfection hours 22 to 28.     

Long-term study (2005–2010) on the vaccination with BoHV-1 glycoprotein E-deleted marker vaccine in selected two dairy herds in Turkey

A follow-up study from 2005 to 2010 was carried out in two herds where eradication programme for the bovine herpes virus-1 (BoHV-1) infection depends on the vaccination with inactivated glycoprotein E-deleted vaccine that was started in 2001 following the vaccination with inactivated conventional vaccine between 1999 and 2001. For serological screening, a total of 12,976 sera sampled over several sampling times approximately 6 months of interval during 5 years (2005–2010) were tested for glycoprotein E (gE)- and glycoprotein B-specific antibodies using ELISA. According to the serological evidence, the long-term persistence of BoHV-1 antibodies, success of marker vaccine, first vaccination time of the calves in herds regularly vaccinated, etc. were discussed in this paper. In conclusion, the vaccination programme using gE (?) marker vaccines, with making efforts to prevent the other factors about transmission of infection, was suggested for the eradication of BoHV-1 infection in Turkey as many EU countries. This is the first report on the BoHV-1 eradication programme in some dairy cattle in Turkey.     

Effects of protein-energetic supplementation frequency on growth performance and nutritional characteristics of grazing beef cattle

Two experiments were conducted to evaluate reduced supplementation frequencies for grazing beef cattle in rainy season. In experiment 1, evaluating the nutritional parameters, four rumen-cannulated Nellore bulls (BW = 410 kg) were used. In experiment 2, evaluating animal performance, 48 Nellore bulls (BW = 358 kg) were used. The treatments were as follows: mineral supplement (MS) alone and MS plus protein-energy supplement provided 3×, 5× and 7×/week. Supplementation frequency did not affect (P > 0.05) intake and digestibility. Average daily gain was greater (P < 0.001) to supplementation compared with MS. The supplementation 5×/week resulted in greater weight gain per hectare (9.24) and higher economic returns during the study period (1.64%) compared to other supplementations. Supplementation 5×/week increased animal performance and positively influenced economic returns.     

Effect of adding Lactobacillus plantarum or a formic acid containing-product to fermented liquid feed on gastrointestinal ecology and growth performance of piglets

A study was carried out to investigate whether adding a starter culture or a formic acid containing-product to fermented liquid feed of suboptimal microbial quality could improve the characteristics of the mixture and the gastrointestinal ecology and growth performance of piglets. Four experimental diets were prepared: Feed and water were mixed in the ratio 1:2.5 (w/w) in four closed tanks. Diet 1) Three times daily, 50% of the mixture stored in the tank was removed and then replaced with an equal amount of fresh feed and water, (FLF), positive control; Diet 2) Three times daily, 95% of the mixture stored in the tank was removed and then replaced with an equal amount of fresh feed and water. Escherichia coli K12 (1 × 10⁶/g) was added every morning (COLI); Diet 3) as the COLI treatment and added Lactobacillus plantarum VTT E-78076 (1 × 10⁶/g) every morning (+PLANTARUM); and Diet 4) as the COLI treatment and added 0.26 g AIV/KemiSile 2 plus/100 g mixture three times daily (+ACID). One hundred and sixty weaners were used. On day 14, one littermate from each pen was killed and the gastrointestinal tract removed. The remaining piglets were used to measure the effect of the experimental diets on growth performance during the first six weeks post-weaning. The +ACID diet had lower numbers of lactic acid bacteria and Enterobacteriaceae, higher numbers of yeasts, and lower concentration of lactic acid and acetic acid than the COLI and +PLANTARUM diets. Feeding the +PLANTARUM and the +ACID diets increased daily weight gain during the six weeks post-weaning (P ≤ 0.02) compared to feeding the COLI diet. The +ACID group showed the highest numerical daily feed intake in all periods. The gain/feed during the six weeks post-weaning tended to be lowest in the COLI group (P < 0.10). The counts of lactic acid bacteria able to grow at 20 °C were lowest in the stomach (P ≤ 0.003) and distal small intestine (P ≤ 0.06) of the +ACID group. The counts of yeasts able to grow at 37 °C in the stomach were highest in the +ACID (P ≤ 0.01) and FLF groups (P ≤ 0.09). The number of yeasts able to grow at 20 °C in the stomach and distal small intestine was highest in the FLF fed piglets, followed by the +ACID group. This study showed that addition of L. plantarum VTT E-78076 or AIV/KemiSile 2 plus to fermented liquid feed of suboptimal microbial quality improved growth performance without affecting the gastrointestinal ecology of piglets substantially.