Evaluation of treatment with doxorubicin and piroxicam or doxorubicin alone for multicentric lymphoma in dogs

OBJECTIVE: To evaluate the antitumor and toxic effects of treatment with doxorubicin combined with piroxicam or doxorubicin alone for multicentric lymphoma in dogs. DESIGN: Nonrandomized clinical trial. ANIMALS: 75 dogs with multicentric lymphoma. PROCEDURE: 33 dogs were treated with doxorubicin (30 mg/m2, IV, q 21 d, for 3 doses) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h); results were compared with a historical control group of 42 dogs treated with doxorubicin (30 mg/M2, IV, q 21 d, for 3 doses) alone. Results-The percentages of dogs that had remission with doxorubicin-piroxicam treatment (79%) or doxorubicin treatment alone (74%) were not significantly different. Median duration of first remission was 130 days with doxorubicin-piroxicam and 147 days with doxorubicin alone; these values were not significantly different. Severe toxicosis was observed in 22% of dogs treated with doxorubicin-piroxicam and 17% of dogs treated with doxorubicin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Both treatment protocols were efficacious and well tolerated. The doxorubicin-piroxicam treatment was no more effective regarding response rate, remission duration, or survival duration, compared with the control group treated with doxorubicin alone.     

Pharmacokinetics of clindamycin HCl administered intravenously, intramuscularly and subcutaneously to dogs

A buffered aqueous solution of clindamycin Hcl (200 mg/mL) was injected intravenously (i.v.) intramuscularly (i.m.) and subcutaneously (s.c.) in a non-randomized, partial cross-over trial involving six male and six female dogs. Blood samples were collected at conventional, predetermined time periods and serum drug concentrations were determined by microbiological assay. Dogs were observed clinically for signs of pain, and activity of serum creatine phosphokinase (CPK) was monitored after i.m. dosing. The i.v. data from five of the dogs best fitted a two-compartment open-system pharmacokinetic model whereas a non-compartment model was most suitable for analysis of the data from the remaining seven dogs. The mean i.v. elimination half-life (t1/2 beta) and the mean residence time (MRT) were 124 and 143 min, respectively. The mean volume of distribution at steady state (Vss) was 0.86 L/kg. Little pain was recorded upon i.m. injection; mean peak serum drug concentration (Cmax) was 4.4 micrograms/mL, the elimination half-life (t1/2el) was 247 min and the calculated bioavailability (F) was 115% of the i.v. dose. Serum CPK activity was elevated to 25-fold the pretreatment level in samples collected 4, 8 and 12 h after i.m. injection. Pain was not recorded after s.c. drug administration; the mean Cmax of 20.8 micrograms/mL was significantly greater than the corresponding value for the i.m. route, and F was 310%. The s.c. route appears to be superior to the i.m. route in terms of local tolerance and serum drug level; a 10 mg/kg SID treatment regimen is suggested for treatment of canine infections due to clindamycin sensitive bacteria.     

Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma

BACKGROUND: Various chemotherapy protocols for treating lymphoma in dogs have been published; however, comparison of protocols from different studies is difficult, especially when evaluating survival time and toxicoses. HYPOTHESIS: The choice of COAP (C, cyclophosphamide; O, vincristine; A, cytosine arabinoside; P, prednisone) and a modified University of Wisconsin 19-week (UW-19) induction protocol has no influence on overall survival times in dogs with lymphoma. ANIMALS: One hundred and one dogs with multicentric lymphoma. METHODS: Retrospective study (2001-2006). Dogs induced with either an 8-week COP-based protocol (C, cyclophosphamide; O, vincristine; and P, prednisone) with maintenance therapy (COAP group) or a 19-week CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisone) based protocol (UW-19 group) were compared in terms of the duration of first remission, survival time, toxicoses, and cost. RESULTS: There were 71 dogs in the COAP group and 30 dogs in the UW-19 group. Various protocols were used after the first relapse. The median duration of the first remission for the COAP and UW-19 groups were 94 days (range, 6-356 days) and 174 days (28-438 days), respectively (P < .01). The median survival times for dogs in the COAP and UW-19 groups were 309 days (6-620 days) and 275 days (70-1102+ days), respectively (P = .09). Dogs in the COAP group had a hazard ratio of 1.9 (95% CI 1.1-3.4) for death relative to the UW-19 group (P = .03), after controlling for the confounders (World Health Organization clinical stage, age, sex, use of doxorubicin during reinduction). The severity of neutropenia and gastrointestinal toxicoses were significantly higher in the UW-19 group than in the COAP group (P = .01 and P < .01, respectively). CONCLUSION AND CLINICAL IMPORTANCE: Use of a long-term doxorubicin-containing sequential combination chemotherapy protocol is associated with a decreased risk of relapse and death relative to a non-doxorubicin-containing protocol.     

Influence of asparaginase on a combination chemotherapy protocol for canine multicentric lymphoma

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.     

Weekly administration of low-dose doxorubicin for treatment of malignant lymphoma in dogs

Nine dogs with intermediate- or high-grade lymphoma were prospectively entered into a protocol to be given a total of 15 weekly doses of doxorubicin (10 mg/m2 of body surface, IV) in an attempt to eliminate all clinical evidence of neoplasia, with minimal risk of drug toxicity. Eight of these dogs did not complete the protocol because of progression of the disease. The median number of doses administered to dogs that developed progressive disease before the regimen was completed was 5 (range, 2 to 9). Seven dogs achieved partial (n = 5) or complete (n = 2) remission, with median duration of 14 days (range, 7 to 231 days). The dog that was given all 15 weekly treatments remained in complete remission for 231 days. Complete remission that lasted for 14 days was observed in another dog. Toxicosis developed in 3 dogs; signs of toxicosis were generally mild and included colitis (n = 1), vomiting (n = 1), neutropenia (n = 1), and lethargy (n = 1). The lowest neutrophil count (1,876 cells/microliter) was seen in one dog after 7 doses of doxorubicin were given. Doxorubicin at dosage of 10 mg/m2/wk appears to be safe, but is generally ineffective for treatment of lymphoma.     

The pharmacokinetics and analgesic effects of extended‐release buprenorphine administered subcutaneously in healthy dogs

Buprenorphine is a partial μ agonist opioid used for analgesia in dogs. An extended‐release formulation (ER‐buprenorphine) has been shown to provide effective analgesia for 72 hr in rats and mice. Six healthy mongrel dogs were enrolled in a randomized, blinded crossover design to describe and compare the pharmacokinetics and pharmacodynamics of ER‐buprenorphine administered subcutaneous at 0.2 mg/kg (ER‐B) and commercially available buprenorphine for injection intravenously at 0.02 mg/kg (IV‐B). After drug administration, serial blood samples were collected to measure plasma buprenorphine concentrations using liquid chromatography/mass spectrometry detection. Heart rate, respiratory rate, body temperature, sedation score, and thermal threshold latency were recorded throughout the study. Median (range) terminal half‐life, time to maximum concentration, and maximum plasma concentration of ER‐buprenorphine were 12.74 hr (10.43–18.84 hr), 8 hr (4–36 hr), and 5.00 ng/ml (4.29–10.98 ng/ml), respectively. Mild bradycardia, hypothermia, and inappetence were noted in both groups. Thermal threshold latency was significantly prolonged compared to baseline up to 12 hr and up to 72 hr in IV‐B and ER‐B, respectively. These results showed that ER‐buprenorphine administered at a dose of 0.2 mg/kg resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration.     

Pharmacokinetics of intramuscularly administered pethidine in dogs and the influence of anaesthesia and surgery

The plasma concentration of pethidine was measured after it had been administered intramuscularly to fully conscious dogs, and to dogs in the postoperative period and during general anaesthesia. The absorption of the drug was erratic except in the anaesthetised animals and the plasma concentrations of the drug were also higher in this group. Correlation of plasma concentrations of the drug with its analgesic activity revealed a 'critical' concentration of pethidine of 0.4 micrograms/ml for complete analgesia; useful though not complete analgesia was achieved with concentrations above 0.2 micrograms/ml. These concentrations were maintained for 90 minutes after the administration of the drug at a dose of 2.0 mg/kg and for 120 minutes after a dose of 3.5 mg/kg.     

CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma

Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at presentation experienced a significantly longer OST (323 versus 212 days, P=0.01).     

The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.     

Serum amyloid A is not a marker for relapse of multicentric lymphoma in dogs

BACKGROUND: Serum amyloid A (SAA) is an acute phase protein whose concentration increases in inflammatory, infectious, and neoplastic conditions in animals and human beings. Multicentric lymphoma is a common cancer in dogs, and chemotherapy is indicated to attain long-term survival. However, frequent relapses lead to changes in chemotherapeutic protocols. OBJECTIVES: The aims of this study were to evaluate SAA as a marker for relapse of multicentric lymphoma in dogs and to determine whether chemotherapy induces changes in the concentration of SAA during treatment. METHODS: SAA was measured by an ELISA test in healthy control dogs (n=20), in healthy dogs receiving chemotherapy (n=8), and in dogs with lymphoma (n=20). All dogs receiving chemotherapy were randomly assigned to 2 treatment groups, one receiving cyclophosphamide, vincristine, and prednisone (CVP) and the other receiving vincristine, cyclophosphamide, methotrexate, and L-asparaginase (VCMA) protocols. SAA concentration was determined before chemotherapy at weeks 1-4 in healthy dogs receiving chemotherapy and in dogs with lymphoma, then every 3 weeks for 4 months in healthy dogs, and at relapse and in the sample prior to relapse in dogs with lymphoma. SAA was measured only once in the healthy control dogs. Results were analyzed using repeated measures ANOVA followed by Tukey multiple comparison tests to compare groups and weeks of treatment. RESULTS: Mean SAA concentration was significantly higher in dogs with lymphoma before chemotherapy compared with healthy and chemotherapy control dogs. No increase in SAA concentration was found at relapse. No differences were observed in SAA concentration based on type of chemotherapy protocol. CONCLUSIONS: SAA is not a marker of relapse in dogs with multicentric lymphoma, nor does chemotherapy regimen affect SAA concentration.     

Prevalence of leukemic blood and bone marrow in dogs with multicentric lymphoma

Multicentric lymphoma was diagnosed in 53 dogs. A study was performed to evaluate the prevalence of leukemic involvement in blood samples, bone marrow aspirates, and bone marrow core biopsy specimens at the time of initial diagnosis. Data indicated that 57% (30/53) of the dogs were leukemic when all materials were considered relative to the presence of cellular atypia or immaturity and abnormal tissue distribution. In the 30 leukemic dogs, detection was made in the specimens with the following frequency: 15 in blood (50%), 18 in bone marrow aspirates (60%), and 29 in bone marrow core biopsy specimens (97%). Five cases (17%) were only detected by core biopsy examination, even when dogs with bone marrow lymphocytosis of greater than 15% of nucleated cells were considered leukemic. Nondiffuse histologic colonization patterns accounted for the lack of correlation between the type of bone marrow specimens. Clinical staging for treatment response and prognosis was best determined by evaluation of concurrently obtained blood samples, bone marrow aspirates, and bone marrow core biopsy specimens.     

Comparison of mitotane treatment for adrenal tumor versus pituitary-dependent hyperadrenocorticism in dogs.

The purpose of this study was to determine the sensitivity of dogs with hyperadrenocorticism to treatment with the adrenocorticolytic agent mitotane. Specifically, we looked for differences in response to treatment using this drug in dogs with adrenocortical tumors (adrenal tumor hyperadrenocorticism, ATH) vs those with pituitary-dependent hyperadrenocorticism (PDH). For inclusion in this study, each dog must have had clinical signs, data base laboratory abnormalities, and endocrine screening test results consistent with the diagnosis of hyperadrenocorticism. Further, each dog had to have been treated for at least 6 months with mitotane and have histologic evidence for adrenocortical or pituitary neoplasia (all dogs were necropsied). Thirteen dogs with ATH (8 carcinomas, 5 adenomas) were identified. The ages and body weights of these 13 dogs were computer-matched to 13 dogs with PDH. All dogs were initially treated with approximately 50 mg of mitotane/kg/d of body weight. Reexaminations were performed after 7, 30, 90, and 180 days of treatment. Individual dosages varied widely after the initial 5 to 12 days of treatment. The mean (+/- SD) dose of mitotane (mg/kg/d) for the first 7 days of treatment was 47.5 +/- 9.4 for dogs with ATH vs 45.7 +/- 11.9 for dogs with PDH. The mean plasma cortisol concentrations 1 hour after ACTH administration at the 7-day recheck were significantly higher in dogs with ATH (502 +/- 386 nmol/L) than in dogs with PDH (88 +/- 94 nmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of 3 protocols for treatment after induction of remission in dogs with lymphoma

BACKGROUND: The optimal treatment after inducing complete remission (CR) in dogs with lymphoma has not been established. HYPOTHESIS: After inducing CR with L-asparaginase, vincristine, cyclophosphamide, doxorubicin, prednisone (L-CHOP); consolidation with either half-body radiation therapy (HBRT); or lomustine (CCNU) and mechlorethamine, vincristine, procarbazine, prednisone (MOPP) would improve first remission duration compared with continuing a CHOP-based protocol for an additional 4 months. ANIMALS: Dogs with stage III-V lymphoma. METHODS: Prospective clinical trial in which dogs initially were treated with an 8-week induction protocol that consisted of L-CHOP. Dogs in CR after induction were then allocated to 1 of 2 consolidation arms. A chemotherapy consolidation arm consisted of 2 treatments with CCNU and 1 cycle of MOPP. A HBRT arm consisted of 2 sequential 8.0-Gy fractions to the cranial and caudal half-body separated by 30 days. Vincristine was given between fractions. Results of the consolidation arms also were compared with a historical group treated with the same 8-week induction protocol followed by CHOP therapy until week 24. RESULTS: Overall, 67% of the dogs were in CR after 8 weeks of induction chemotherapy and were compared. Fifty-two dogs were in the historical arm, 23 in the CCNU/MOPP arm, and 27 in the HBRT arm. No difference in first remission duration was found among groups. Median first remission duration for the historical, CCNU/MOPP, and HBRT arms were 307, 274, and 209 days, respectively (P = .28). Overall second CR rate was 82% and was not different among groups (all P > or = .58). Overall remission duration (P = .28) and survival time (P = .48) were not different among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Consolidation with either CCNU/MOPP or HBRT showed no advantage over a standard CHOP-based protocol.     

Cardiorespiratory and anesthetic effects produced by the combination of butorphanol,medetomidine and alfaxalone administered intramuscularly in Beagle dogs

This study evaluated anesthesia quality, degree of analgesia and cardiorespiratory parameters after intramuscular (IM) injection of a combination of butorphanol (0.1 mg/kg), medetomidine (10 µg/kg) and alfaxalone (1.5 mg/kg) in ten healthy adult Beagle dogs. Rectal temperature (T), heart rate (HR), respiratory rate (f_R), arterial pressure, arterial blood gases and M-mode echocardiographic left ventricular (LV) indices were measured before drug administration and every 10 min thereafter until extubation. Mean duration of anesthesia, recovery and analgesia were 89 ± 17, 6 ± 1 and 80 ± 12 min. HR, f_R, partial pressure of arterial CO₂ and O₂, arterial pressure, and LV contractility were significantly altered during anesthesia. IM administration of the drug combination provided acceptable anesthesia, but produced substantial cardiorespiratory suppression.     

Comparison of quality of induction of anaesthesia between intramuscularly administered ketamine, intravenously administered ketamine and intravenously administered propofol in xylazine premedicated cats

The quality of induction of general anesthesia produced by ketamine and propofol, 2 of the most commonly used anaesthetic agents in cats, was assessed. Eighteen cats admitted for elective procedures were randomly assigned to 3 groups and then premedicated with xylazine 0.75 mg/kg intramuscularly before anaesthesia was induced with ketamine 15 mg/kg intramuscularly (KetIM group), ketamine 10 mg/kg intravenously (KetIV group) or propofol 4 mg/kg intravenously (PropIV group). Quality of induction of general anaesthesia was determined by scoring ease of intubation, degree of struggling, and vocalisation during the induction period. The quality of induction of anaesthesia of intramuscularly administered ketamine was inferior to that of intravenously administered ketamine, while intravenously administered propofol showed little difference in quality of induction from ketamine administered by both the intramuscular and intravenous routes. There were no significant differences between groups in the ease of intubation scores, while vocalisation and struggling were more common in cats that received ketamine intramuscularly than in those that received intravenously administered ketamine or propofol for induction of anaesthesia. Laryngospasms occurred in 2 cats that received propofol. The heart rates and respiratory rates decreased after xylazine premedication and either remained the same or decreased further after induction for all 3 groups, but remained within normal acceptable limits. This study indicates that the 3 regimens are associated with acceptable induction characteristics, but administration of ketamine intravenously is superior to its administration intramuscularly and laryngeal desensitisation is recommended to avoid laryngospasms.