Kinetic analysis of demethylation of 13C-aminopyrine in healthy dogs

OBJECTIVE: To describe the kinetics of demethylation of 13C-aminopyrine in healthy dogs for use in determining the most appropriate time for collection of blood samples for a 13C-aminopyrine demethylation blood test for evaluation of hepatic function. ANIMALS: 9 healthy dogs. PROCEDURES: A 2-mL baseline blood sample was collected into an evacuated heparinized tube, and 13C-aminopyrine was administered to each dog (2 mg/kg, IV). Additional 2-mL blood samples were collected 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 240, 300, and 360 minutes after 13C-aminopyrine administration. The CO2 was extracted from blood samples by addition of a strong acid, and the percentage dose of 13CO2 (PCD) in the extracted gas was determined by fractional mass spectrometry. RESULTS: No dogs had gross evidence of adverse effects, and all had an increase in PCD after IV administration of 13C-aminopyrine. The PCD had the least variability among 5 variables used to evaluate hepatic demethylating capacity. Peak PCD was detected at 30 minutes in 1 dog, 45 minutes in 5 dogs, 60 minutes in 2 dogs, and 75 minutes in 1 dog. The mean PCD for the 9 dogs peaked at 45 minutes after 13C-aminopyrine administration. CONCLUSIONS AND CLINICAL RELEVANCE: PCD appears to be the preferable variable for evaluation of hepatic demethylating capacity. Intravenous administration of 13C-aminopyrine leads to a consistent increase in PCD. Mean PCD peaked 45 minutes after administration, suggesting that blood sample collection 45 minutes after 13C-aminopyrine administration may be appropriate for use in estimating hepatic demethylating capacity.     

Preliminary studies of a canine 13C-aminopyrine demethylation blood test.

The objectives of this study were to determine whether a 13C-aminopyrine demethylation blood test is technically feasible in clinically healthy dogs, whether oral administration of 13C-aminopyrine causes a detectable increase in percent dose/min (PCD) of 13C administered as 13C-aminopyrine and recovered in gas extracted from blood, and whether gas extraction efficiency has an impact on PCD. A dose of 2 mg/kg body weight of 13C-aminopyrine dissolved in deionized water was administered orally to 6 clinically healthy dogs. Blood samples were taken from each dog 0, 30, 60, and 120 min after administration of the 13C-aminopyrine. Carbon dioxide was extracted from blood samples by addition of acid and analyzed by fractional mass spectrometry. None of the 6 dogs showed any side effects after 13C-aminopyrine administration. All 6 dogs showed a measurable increase of the PCD in gas samples extracted from blood samples at 30 min, 60 min, and 120 min after 13C-aminopyrine administration. Coefficients of variation between the triplicate samples were statistically significantly higher for the %CO2, a measure of extraction efficiency, than for PCD values (P < 0.0001). The 13C-aminopyrine demethylation blood test described here is technically feasible. Oral administration of 13C-aminopyrine did not lead to gross side effects in the 6 dogs. Clinically healthy dogs show a measurable increase of PCD in gas extracted from blood samples after oral administration of 13C-aminopyrine. Efficiency of CO2 extraction from blood samples does not have an impact on PCD determined from these blood samples. This test may prove useful to evaluate hepatic function in dogs.     

Development of a 13C-glycocholic acid blood test to assess bacterial metabolic activity of the small intestine in canines

The objectives of this study were to establish optimal doses of 13C-glycocolic acid (GCA) for use in a GCA blood test as a marker for canine small intestinal bacterial metabolic activity. Four doses of GCA were administered orally to 8 healthy dogs. Blood samples were collected at various time points up to 480 min. The percent dose/min of 13C administered as GCA (PCD) and cumulative PCD (CUMPCD) were determined by fractional mass spectrometry. No dog showed any clinically obvious side effects. Doses of 1 and 2 mg/kg of bodyweight (BW) led to a significant increase in PCD and CUMPCD (P < 0.001). The mean CUMPCD was significantly higher for the 1 mg/kg BW dose compared with the 2 and 4 mg/kg BW doses (P < 0.05). Administration of 1 mg/kg BW of 13C-glycocholic acid led to an increase in CUMPCD over baseline in gas extracted from blood samples and appears to be the best parameter to evaluate for future clinical studies.     

Use of a 13C-aminopyrine blood test: first clinical impressions

The purpose of this study was to collect initial data to determine the potential clinical usefulness of a ¹³C-aminopyrine demethylation blood test, and whether additional clinical investigation is warranted. Six dogs, initially suspected of having hepatic disease based on their history, physical examination, imaging studies, general laboratory parameters, or any combination of the above, were enrolled in the study. A baseline blood sample was collected, 2 mg/kg ¹³C-aminopyrine was administered intravenously, and another blood sample was collected 45 min afterwards. Carbon dioxide was extracted from the blood samples and analyzed using fractional mass spectrometry. Results from the ¹³C-aminopyrine demethylation blood test were compared to clinical data and histologic findings. Intravenous administration of ¹³C-aminopyrine leads to a decrease in the percent dose of ¹³C recovered from dogs with histologically confirmed liver disease. Based on our results, a full-scale investigation of the potential clinical usefulness of a ¹³C-aminopyrine demethylation blood test for assessment of hepatic function in dogs is warranted.     

Comparison of the carbon 13-labeled octanoic acid breath test and ultrasonography for assessment of gastric emptying of a semisolid meal in dogs

OBJECTIVE: To compare the rate of gastric emptying of a semisolid meal by use of the carbon 13-labeled octanoic acid breath test (13C-OBT) and gastric emptying ultrasonography (GEU) in dogs. ANIMALS: 10 healthy dogs. PROCEDURE: Food was withheld from dogs for 12 hours before ingestion of a test meal (bread, egg, and skimmed milk) containing 13C-octanoic acid. The gastric antrum was visualized by use of a 6.5-MHz microconvex transducer, and the area of the ellipse defined by the craniocaudal and ventrodorsal diameters of the stomach was measured. Samples of expired air and antral images were obtained 30 minutes before ingestion of the test meal and then every 15 minutes for 4 hours and every 30 minutes for a further 2 hours. The half-dose recovery time with the 13C-OBT (t1/2[BT]) and the gastric half emtying time with GEU (t50%[GEU]) was calculated. RESULTS: Mean +/- SD values for the t1/2(BT) and t50%(GEU) were 3.44 +/- 0.48 hours and 1.89 +/- 0.78 hours, respectively. A significant correlation was detected between the t1/2(BT) and t50%(GEU), although there was a large (1.55 hours) mean difference between these indices. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that there was a correlation between the rate of solid-phase gastric emptying assessed by use of GEU and the 13C-OBT in dogs. Gastric emptying ultrasonography may be a useful, noninvasive method for assessment of the rate of solid-phase gastric emptying in dogs.     

Effect of oral administration of unfractionated heparin (UFH) on coagulation parameters in plasma and levels of urine and fecal heparin in dogs

The effects of heparin administration, by the oral route, were evaluated in dogs. In single and multiple dose studies (single 7.5 mg/kg, multiple 3 × 7.5 mg/kg per 48 h), plasma, urine, and fecal samples were collected at various times up to 120 h after oral administration of unfractionated heparin. Changes in plasma and urine anti-Xa activity, plasma and urine anti-IIa activity, plasma activated partial thromboplastin time (APTT) and antithrombin (ATIII), and chemical heparin in urine and feces were examined with time. There was support for heparin absorption, with significant differences in APTT, heparin in plasma as determined by anti-Xa activity (Heptest) in the single dose study and plasma anti-Xa activity, anti-IIa activity and ATIII; and chemical heparin in urine in the multiple dose study. No clinical evidence of bleeding was detected in any dog during the studies. Oral heparin therapy may be applicable for thromboembolic disease in animals. Further studies are warranted to determine the effects of oral heparin at the endothelial level in the dog.     

Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221 cases (1993-1998)

OBJECTIVE: To evaluate glycemic response to insulin treatment in dogs with diabetes mellitus. DESIGN: Retrospective study. ANIMALS: 221 dogs with diabetes mellitus. PROCEDURE: Type and dosage of insulin used, minimum and maximum blood glucose concentrations, time of blood glucose concentration nadir, and optimal duration of action of insulin were determined on the basis of data obtained prior to initial examination at the teaching hospital (127 dogs), at the time of initial examination (212 dogs), at the time a second follow-up blood glucose curve was performed (59 dogs), and at the time of clinical control of diabetes mellitus (83 dogs). RESULTS: Prior to examination, 69 of 127 dogs (54%) received 1 s.c. insulin injection daily. Thirty-one dogs (24%) received a high dose of insulin (i.e., > 1.5 U/kg [0.7 U/lb] of body weight); 27 of these dogs (87%) received 1 injection/d. Eleven of 16 dogs (69%) that were hypoglycemic (blood glucose concentration < 80 mg/dl) also received 1 injection/d. However, optimal duration of action of insulin was > 12 hours in only 5 of 83 dogs (6%) evaluated at the time diabetes mellitus was clinically controlled. At that time, only 1 dog (1%) received a high dose of insulin, and the dog received 2 injections/d. Moreover, 8 of 10 dogs (80%) with hypoglycemia received 1 injection/d. CONCLUSIONS AND CLINICAL RELEVANCE: Most dogs with diabetes mellitus are clinically regulated with 2 daily insulin injections. Administration of a high dose of insulin or development of hypoglycemia may be more common in diabetic dogs that receive insulin once daily, compared with dogs that receive insulin twice daily.     

Detection of Bartonella henselae DNA in two dogs with pyogranulomatous lymphadenitis

CASE DESCRIPTION: 1 dog evaluated because of inappetence and lameness of the left hind limb of 1 day's duration and 1 dog evaluated because of inappetence, fever, and lymphadenopathy of 2 weeks' duration. CLINICAL FINDINGS: Histologic examination of excisional biopsy specimens from lymph nodes revealed pyogranulomatous lymphadenitis in both dogs. Quantitative real-time PCR assays detected Bartonella henselae DNA in blood samples and affected lymph node specimens from both dogs. Antibodies against B. henselae were not detected via immunofluorescent antibody testing during active disease in either dog. TREATMENT AND OUTCOME: 1 dog recovered after 6 weeks of treatment with doxycycline (5 mg/kg [2.3 mg/lb], p.o., q 12 h), whereas the other dog recovered after receiving a combination of azithromycin (14.5 mg/kg [6.6 mg/lb], p.o., q 24 h for 21 days), doxycycline (17.3 mg/kg [7.9 mg/lb], p.o., q 24 h for 4 weeks), and immunosuppressive corticosteroid (prednisone [3 mg/kg {1.4 mg/lb}, p.o., q 24 h], tapered by decreasing the daily dose by 25% every 2 weeks) treatment. CLINICAL RELEVANCE: B. henselae is implicated as a possible cause or a cofactor in the development of pyogranulomatous lymphadenitis in dogs. In dogs with pyogranulomatous lymphadenitis, immunofluorescent assays may not detect antibodies against B. henselae. Molecular testing, including PCR assay of affected tissues, may provide an alternative diagnostic method for detection of B. henselae DNA in pyogranulomatous lymph nodes.     

Administration of acepromazine maleate to 31 dogs with a history of seizures

Objective: To retrospectively evaluate the incidence of seizures in dogs presenting with a history of seizures that were treated with acepromazine (ACE) during hospitalization. Design: Retrospective study. Setting: Privately owned emergency and referral hospital. Animals: Thirty‐one client‐owned dogs. Interventions: Administration of ACE. Measurements and main results: The medical records from dogs with an acute or chronic seizure history that received ACE were reviewed. Factors evaluated included presenting complaint, seizure history, ACE dosage, duration of observation, seizure activity, and other medications used. Thirty‐one dogs qualified for the study: 20 males and 11 females. Age range was 3 months to 14.9 years. Presenting complaint was seizure in 28/31 dogs. There was a prior history of seizures in 22/31 dogs, and 15/22 were currently on antiseizure medication. ACE was given 1–5 times per dog. Mean ACE dose was 0.029 mg/kg IV (range: 0.008–0.057 mg/kg; n=46), 0.036 mg/kg IM (range: 0.017–0.059 mg/kg; n=14), 0.53 mg/kg PO (n=2). Twenty‐seven dogs did not seizure after administration of ACE within the observation period (mean: 16.4 hours, range: 0.25–66 hours). Twenty‐five dogs received antiseizure medication before ACE. Eight seizure episodes occurred in 4 dogs (all of whom presented for seizures) within 0.3–10 hours after ACE administration. Conclusions: There was no observed correlation between ACE administration in dogs with a seizure history and the recurrence of seizure activity during hospitalization. The time from ACE administration to seizure activity was greater than expected for measurable effects to be seen in 1 dog (10 hour). Further studies with a larger group and alternative ACE doses are needed to more thoroughly evaluate the safety of short‐term ACE use in dogs with a seizure history.     

Dose effect and benefits of glycopyrrolate in the treatment of bradycardia in anesthetized dogs.

This study evaluated the effectiveness of glycopyrrolate (0.005 or 0.01 mg/kg body weight (BW)) in anesthetized dogs (n = 40) for reversal of bradycardia (< 65 beats/min). Following random intravenous (i.v.) treatment, heart rate was determined at 5 min and, if it was < or = 70 beats/min, the lower dose was repeated. A 2-way analysis of variance considered dose and animal size (< or = 10 kg, > 10 kg) effects (P < 0.05). Glycopyrrolate produced a significant increase in heart rate and infrequent tachycardia (< or = 150 beats/min), which was not dose-related. The size of the dog produced a significant effect on baseline heart rate (higher in small), rate following the first dose (lower in small), and requirement for retreatment (47% in small, 13% in large). In a separate group of anesthetized dogs (n = 20), the blood pressure effect of glycopyrrolate (0.01 mg/kg BW, i.v.) treatment of bradycardia (65-85 beats/min, weight-adjusted) was studied. A significant increase in systolic, diastolic, and mean blood pressure was produced. In conclusion, the effective dose of glycopyrrolate treatment is size-related and produces a beneficial effect on blood pressure.     

Pharmacokinetics and pharmacodynamics of a therapeutic dose of unfractionated heparin (200 U/kg) administered subcutaneously or intravenously to healthy dogs

BACKGROUND: Heparin treatment has been recommended for dogs in hypercoagulable states such as disseminated intravascular coagulation, however, potential benefits have to be balanced against the bleeding risk if overdosage occurs. A better understanding of the pharmacology of heparin and tests to monitor heparin therapy in dogs may help prevent therapeutic hazards. OBJECTIVES: The purpose of this study was to evaluate the effects of 200 U/kg of sodium unfractionated heparin (UFH) on coagulation times in dogs after intravenous (IV) and subcutaneous (SC) administration and to compare these effects with plasma heparin concentrations assessed by its antifactor Xa (aXa) activity. METHODS: 200 U/kg of UFH were administered IV and SC to 5 healthy adult Beagle dogs with a washout period of at least 3 days. Activated partial thromboplastin time (APTT), prothrombin time (PT), and plasma aXa activity were determined in serial blood samples. RESULTS: After IV injection, PT remained unchanged except for a slight increase in 1 dog; APTT was not measurable (>60 seconds) for 45-90 minutes, and then decreased gradually to baseline values between 150 and 240 minutes. High plasma heparin concentrations were observed (maximal concentration = 4.64 +/-1.4 aXa U/mL) and decreased according to a slightly concave-convex pattern on a semilogarithmic curve, but returned to baseline slightly more slowly (t240-t300 minutes) than did APTT. After SC administration, APTT was moderately prolonged (by a ratio of 1.55 +/-0.28 APTT t0, range 1.35-2.01) between 1 and 4 hours after administration. Plasma aXa activity reached a maximum of 0.56 +/-0.20 aXa U/mL (range 0.42-0.9 U/mL) after 132 +/-26.8 minutes; this lasted for 102 +/-26.8 minutes. Prolongation of APTTs of 120-160% corresponded to plasma heparin concentrations of 0.3-0.7 aXa U/mL. CONCLUSIONS: As in humans, the pharmacokinetics of UFH in dogs was nonlinear. Administration of 200 U/kg of UFH SC in healthy dogs resulted in sustained plasma heparin concentrations in accordance with human recommendations for thrombosis treatment or prevention, without excessively increased bleeding risks. In these conditions, APTT can be used as a surrogate to assess plasma heparin concentrations. These findings need to be confirmed in diseased animals.     

Changes in blood pressure following escalating doses of phenylpropanolamine and a suggested protocol for monitoring

This prospective, cross-over, blinded study evaluated the effect of various doses of phenylpropanolamine (PPA) on blood pressure in dogs. Dogs were randomized to receive a placebo or 1 of 3 dosages of immediate release PPA, q12h for 7 days [1 mg/kg body weight (BW), 2 mg/kg BW, or 4 mg/kg BW] in a cross-over design. Blood pressure was recorded every 2 h, for 12 h, on days 1 and 7. There were significant increases in systolic, diastolic, and mean blood pressure following administration of PPA at 2 mg/kg BW and 4 mg/kg BW. A significant decrease in heart rate was also noted at all PPA dosages, but not in the placebo. Administration of PPA was associated with a dose response increase in blood pressure. Dosages of up to 2 mg/kg BW should be considered safe in healthy dogs.     

Severe gastrointestinal bleeding secondary to lornoxicam in the dog

Six dogs with lornoxicam induced severe gastrointestinal bleeding are described. The ingested dose ranged between 0.5 - 5.1?mg/kg BW (median 0.63?mg/kg BW). The severity of the bloodloss anemia was moderate to severe with PCV values ranging between 12 - 27 % (median 16 %) and serum albumin concentrations between 12 - 22 g/l (median 16 g/l). One dog had evidence of chronic thrombocytopathia over 13 days and clinicopathologic findings of gastrointestinal bleeding over 55 days. None of the dogs developed kidney injuries. The clinical condition required transfusion of blood products in 5 of 6 cases. One dog with a perforated duodenal ulcer and septic peritonitis survived until discharge but had to be euthanized later on due to recrudescent clinical signs (hematemesis, melena). The median length of hospitalisation was 12 days (5 - 14). No correlation was seen between the ingested dose and severity of clinical signs. Lornoxicam ingestion leads to severe and longlasting gastrointestinal bleeding in the dog and requires immediate intensive therapy.     

Long-term anaesthesia with propofol and alfentanil in the dog and its partial reversal with nalbuphine

Prolonged surgical anaesthesia in the dog was induced with propofol (6.5 ± 1.3 mg/kg) followed by alfentanil (25.5 ± 5 μg/kg) (mean ± 1 sd) and maintained with a continuous infusion of propofol (0.14 to 0.18 mg/kg/min) and alfentanil (2 to 3 μg/kg/min). Neuromuscular blockade was produced with vecuronium (0.1 mg/kg). After induction of anaesthesia with propofol, administration of alfentanil to dogs which had received no pre-anaesthetic medication produced cardiac arrest and apnoea. Administration of atropine intravenously immediately prior to alfentanil prevented these cardiac depressant effects. The cardiac depressant effect of alfentanil was not as severe in a second group of dogs in which anaesthesia was induced with thiopentone. After commencing the continuous infusion anaesthetic regime and establishment of IPPV, blood pressure and heart rate remained stable during the remaining 4 to 6 h period of anaesthesia. Recovery from anaesthesia was smooth and uneventful. The depressant effects of alfentanil on respiration and on consciousness were reversed rapidly by administration of nalbuphine (10 mg total dose). The smooth recovery and the integration of anaesthesia and post operative analgesia attained by the reversal of alfentanil with nalbuphine make this an attractive anaesthetic regime for major surgery in dogs, provided that facilities for IPPV are available.     

Correlation of serum phenytoin (diphenylhydantoin) with the administration of oral and intravenous phenytoin in dogs

The concentration of serum phenytoin was determined in normal dogs following the administration of phenytoin by either the intravenous or oral route. An intravenous dose of 11 and 33 mg/kg of body weight was given to six dogs and a further dose of 44 mg/kg was given to two dogs. Serial blood samples were taken following the three doses for determination of pharmacokinetic parameters. The mean half-life was 3.35, 3.84 and 4.57 h as the dose was increased. Signs of toxicity occurred immediately following the infusion of phenytoin (emesis, ataxia and seizures). In the first oral studies, serial blood samples were taken for 2 consecutive days following a dose of 11 and 88 mg/kg, t.i.d. The time—concentration profiles of phenytoin varied significantly from one day to the next in the same dog. In the second oral study, blood samples were taken at 3 and 7 h following a dose of 11, 22, 44, 66 and 88 mg/kg, t.i.d. There was a poor correlation between the size of the oral dose and the concentration of serum phenytoin. Due to the short half-life and poor absorption of phenytoin in dogs, it was concluded that the oral administration of phenytoin in dogs produces sub-therapeutic and erratic serum concentrations of phenytoin which makes its efficacy as an anti-convulsant questionable.     

Effects of intramuscular administration of low doses of medetomidine and medetomidine-butorphanol in middle-aged and old dogs.

OBJECTIVE: To determine effects of low doses of medetomidine administered with and without butorphanol and glycopyrrolate to middle-aged and old dogs. DESIGN: Prospective randomized clinical trial. ANIMALS: 88 healthy dogs > or = 5 years old. PROCEDURE: Dogs were assigned randomly to receive medetomidine (2, 5, or 10 micrograms/kg [0.9, 2.3, or 4.6 micrograms/lb] of body weight, i.m.) alone or with glycopyrrolate (0.01 mg/kg [0.005 mg/lb], s.c.), medetomidine (10 micrograms/kg) and butorphanol (0.2 mg/kg [0.1 mg/lb], i.m.), or medetomidine (10 micrograms/kg), butorphanol (0.2 mg/kg), and glycopyrrolate (0.01 mg/kg). Anesthesia was induced with thiopental sodium and maintained with isoflurane. Degree of sedation and analgesia were determined before and after medetomidine administration. Respiratory rate, heart rate, and mean arterial blood pressure were determined 10 and 30 minutes after medetomidine administration. Adverse effects and amounts of thiopental and isoflurane used were recorded. RESULTS: Sedation increased after medetomidine administration in 79 of 88 dogs, but decreased in 7 dogs that received 2 or 5 micrograms of medetomidine/kg. Mean postsedation analgesia score and amounts of thiopental and isoflurane used were less in dogs that received medetomidine and butorphanol, compared with other groups. Respiratory rate, heart rate, and blood pressure were not different among groups. Significantly more adverse effects developed in dogs that did not receive glycopyrrolate. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of medetomidine (10 micrograms/kg, i.m.) and butorphanol (0.2 mg/kg, i.m.) induced sedation and analgesia and reduced amounts of thiopental and isoflurane required for anesthesia in middle-aged and old dogs. Glycopyrrolate decreased frequency of medetomidine-associated adverse effects.     

Evaluation of histamine release during constant rate infusion of morphine in dogs

OBJECTIVE: To evaluate histamine release and selected physiologic variables during constant rate infusion (CRI) of morphine in dogs. ANIMALS: Five healthy, conscious, intact female dogs. MATERIAL AND METHODS: Using a Latin square, repeated-measures design, dogs were randomly assigned to three treatment groups to receive a 4-hour CRI of saline (SAL), or a loading dose of morphine at 0.3 mg kg(-1) (LM), or 0.6 mg kg(-1) (HM), followed by an infusion of 0.17 mg kg(-1) hour(-1) (LM) and 0.34 mg kg(-1) hour(-1) (HM) respectively. Dogs received each of the three treatments at intervals of at least 7 days. Plasma histamine concentration, skin flushing, edema and wheals, heart rate and rhythm and non-invasive arterial blood pressure were measured before the loading dose and at 1, 2, 5, 15, 30, 60, 120, 180 and 240 minutes during the CRI, or at the time of occurrence. RESULTS: The loading dose induced the highest histamine release in the HM group being statistically higher than the SAL group. The histamine release obtained in the LM group after the loading dose did not differ from SAL. During the infusion, plasma histamine levels were numerically higher in the LM group. Besides one dog that developed hypotension for 2 minutes after the loading dose in the HM group and one dog that showed occasional ventricular premature contractions during both morphine infusions, cardiovascular variables were similar among the three treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Both doses of morphine induced variable histamine release with minimal adverse cardiovascular effects in these conscious, healthy dogs. The plasma histamine levels obtained may be associated with significant hemodynamic changes in patients with limited cardiovascular reserve and sympathetic nervous tone.     

A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma

Twenty-eight dogs with lymphoma were treated with a 12-week, 5-drug chemotherapy protocol concluding with high-dose cyclophosphamide supported by autologous bone marrow transplants. A dose escalation design was used to determine the maximum tolerated cyclophosphamide dose (MTD) in this setting. Three cyclophosphamide dose levels were given: 300 mg/ m2 IV (groupl, 3 dogs), 400 mg/m2 IV (group 2, 12 dogs), and 500 mg/m2 IV (group 3, 13 dogs); and the MTD was 500 mg/m2 IV. Toxicity was common but mild, and the dose-limiting toxicity was myelosuppression, specifically neutropenia. No dog died as a result of treatment-related toxicity. One dog in group 3 developed fever, neutropenia, and presumed sepsis and responded promptly to routine management. No other dog required hospitalization. Lower stage and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3]) compared with the lower doses combined (groups 1 and 2) were significantly associated with longer remission duration (all P < .0001). Median remission duration for dogs in group 3 was 54 weeks, compared with 21 weeks for dogs in groups 1 and 2 combined. Factors associated with longer survival time were lower stage (P = .042) and higher cyclophosphamide dose (both increasing dose [study groups 1-3], and the highest dose [group 3] compared with the lower doses combined [groups 1 and 2]) (P = .027). Median survival time for dogs in group 3 was 139 weeks, compared with 43 weeks and 68 weeks for dogs in groups 1 and 2, respectively.     

Effects of urine alkalization and activated charcoal on the pharmacokinetics of orally administered carprofen in dogs

OBJECTIVE: To investigate the effects of oral administration of activated charcoal (AC) and urine alkalinization via oral administration of sodium bicarbonate on the pharmacokinetics of orally administered carprofen in dogs. ANIMALS: 6 neutered male Beagles. PROCEDURES: Each dog underwent 3 experiments (6-week interval between experiments). The dogs received a single dose of carprofen (16 mg/kg) orally at the beginning of each experiment; after 30 minutes, sodium bicarbonate (40 mg/kg, PO), AC solution (2.5 g/kg, PO), or no other treatments were administered. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography at intervals until 48 hours after carprofen administration. Data were analyzed by use of a Student paired t test or Wilcoxon matched-pairs rank test. RESULTS: Compared with the control treatment, administration of AC decreased plasma carprofen concentrations (mean +/- SD maximum concentration was 85.9 +/- 11.9 mg/L and 58.1 +/- 17.6 mg/L, and area under the time-concentration curve was 960 +/- 233 mg/L x h and 373 +/- 133 mg/L x h after control and AC treatment, respectively). The elimination half-life remained constant. Administration of sodium bicarbonate had no effect on plasma drug concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: After oral administration of carprofen in dogs, administration of AC effectively decreased maximum plasma carprofen concentration, compared with the control treatment, probably by decreasing carprofen absorption. Results suggest that AC can be used to reduce systemic carprofen absorption in dogs receiving an overdose of carprofen. Oral administration of 1 dose of sodium bicarbonate had no apparent impact on carprofen kinetics in dogs.