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Summary

Dynamics of plasma ferulenol concentration and its effect on the vitamin K-dependent coagulation factors, prothrombin time (pt), and activated partial thromboplastin time (aptt) were determined in 4 sheep intoxicated individually with 600 g of powdered Ferula communis variety brevifolia (fcb) given in 8 doses at intervals of 6 hours. Ferulenol was detected in the plasma of all sheep at initial blood sample collection, 6 hours after the first dose of approximately 75 g of fcb was placed in the rumen. The last observed peak of approximately 20 μg/ml was detected at about 12 hours after the last of 8 doses, and the mean concentration then decreased to < 1 μg/ml during the next 70 hours. Maximal concentration of ferulenol and time for plasma clearance varied with individual sheep. The pt increased steadily to a maximum of 6 times normal about 70 hours after the last peak plasma ferulenol concentration and about 80 hours after fcb administration was stopped. The pt then returned to almost normal (ratio of 1.12) from the maximum (ratio of 6.12) within approximately 5 days. The aptt results generally paralleled the pt results, but the change was not as marked. Maximal pt and aptt ratios were animal - dependent and not always related to plasma ferulenol concentration. The activity of all the vitamin K-dependent coagulation factors was depressed, but the variations were unique to each factor. Factor V, a vitamin K-independent coagulation factor actually had a brief period of increased plasma activity. We concluded that the effects on P, T aptt, and vitamin K-dependent coagulation factors induced in sheep intoxicated with fcb were consistent with the coumarinic structure of ferulenol, the intoxicating compound in fcb, which seems to have a short-term anticoagulation effect.

Free access
in American Journal of Veterinary Research

Abstract

Objective

To evaluate the effects of dilution on Stability of xanthine in canine urine stored at −20 C, and to evaluate the effects of storage at −20 C on Stability of xanthine in canine plasma.

Animals

6 reproductively intact female Beagles, 3.9 to 4.2 years old and weighing 8.5 to 10.1 kg.

Procedure

Dogs were fed a 31.4% protein (dry weight), meat-based diet for 21 days, and administered allopurinol (15 mg/kg of body weight, q 12 h) during days 14 to 21; urine and plasma samples were obtained on day 22, Urine samples were preserved undiluted or diluted, and divided into 1-ml aliquots for storage at −20 C for 1 to 12 weeks. Plasma samples were divided into 1-ml aliquots for storage at −20 C for 1 to 12 weeks. Urine and plasma xanthine concentrations were measured on day of collection (baseline) and after 1, 2, 4, 6, 9, and 12 weeks.

Results

Dilution of urine samples did not have a significant effect on consistency of xanthine concentration measured for up to 12 weeks of storage. Although xanthine concentration did not differ significantly between undiluted and diluted urine samples, average xanthine concentration measured in diluted samples was consistently higher, compared with that in undiluted samples. Compared with baseline values, plasma xanthine concentration was significantly lower at 6, 9, and 12 weeks of storage.

Conclusions

Measurement of xanthine concentration is reproducible in undiluted or diluted urine samples for up to 12 weeks, although dilution may provide better results. Measurement of plasma xanthine concentration is reproducible in samples stored for up to 4 weeks.

Clinical Relevance

To ensure reproducibility of measurements of xanthine concentration in urine samples collected from dogs that are affected with urate uroliths and receiving allopurinol, urine should be diluted 1:20 with deionized water. These measurements may be useful for monitoring dogs that are receiving allopurinol for dissolution or prevention of urate uroliths. (Am J Vet Res 1997;58:118–120)

Free access
in American Journal of Veterinary Research

Abstract

Objective

To evaluate the effects of dilution and alkalinization, separately and together, on the stability of uric acid in canine urine stored at −20 C.

Design

Prospective-controlled study.

Animals

5 dogs with confirmed ammonium urate uroliths, 6 Beagles, and 6 mixed-breed dogs.

Procedure

Dogs were fed a 31.4% protein (dry weight), meat-based diet for 21 days, and urine samples were collected on day 22. Urine samples were preserved, using combinations of dilution and alkalinization, and divided into 1-ml aliquots for storage at −20 C for 1 to 12 weeks. Urine uric acid concentrations were measured, using high-performance liquid chromatography, on day of collection (baseline), and after 1, 2, 4, 8, and 12 weeks.

Results

Alkalinization did not have a significant effect on reproducibility of measurements of uric acid concentrations in urine; however, dilution did have a significant effect. Compared with baseline, uric acid concentrations in urine samples collected from dogs with ammonium urate uroliths and Beagles and diluted 1:10 or 1:20 with deionized water were not different after storage for 1 to 12 weeks. Uric acid concentrations in urine samples collected from mixed-breed dogs did not differ from baseline values during the 12-week storage period whether samples were undiluted or were diluted 1:10 or 1:20 with deionized water.

Conclusions

Measurements of uric acid concentration are most reproducible in canine urine samples stored at −20 C for 1 to 12 weeks when samples are diluted 1:20 with deionized water.

Clinical Relevance

To ensure reproducibility of measurements of uric acid concentration in urine samples collected from dogs affected with urate uroliths, urine should be diluted 1:20 with deionized water. Alkalinization is not necessary, and is not recommended because of the additional step in processing and its potential to interfere with measurement of other urinary analytes. (Am J Vet Res 1996;57:787–790)

Free access
in American Journal of Veterinary Research

Abstract

Objectives

To determine whether diet influences the metabolism of IV administered allopurinol in healthy dogs.

Animals

6 healthy female Beagles, 4.9 to 5.2 years old and weighing 9.6 to 11.5 kg.

Procedures

Allopurinol was administered IV (10 mg/kg) while dogs consumed a 10.4% protein (dry weight), casein-based diet or a 31.4% (dry weight), meat-based diet. After each dose, plasma samples were obtained at timed intervals, and concentrations of allopurinol and its active metabolite, oxypurinol, were determined by high-performance liquid chromatography. An iterative, nonlinear regression analytical program was used to determine the weighted leastsquares, best-fit curves for plasma allopurinol and oxypurinol concentration-time data. From these data, pharmacokinetic parameters were calculated.

Results

Pharmacokinetic parameters for allopurinol and oxypurinol were not different when comparing the effect of diet.

Conclusion

There is no influence of diet on pharmacokinetic parameters of allopurinol or oxypurinol.

Clinical Relevance

In contrast to observations in human beings, allopurinol metabolism is not influenced by diet. Therefore, formation of xanthine-containing calculi in dogs consuming a high-protein diet and receiving allopurinol is probably not attributable to alteration of allopurinol metabolism. (Am J Vet Res 1997;58:511–515)

Free access
in American Journal of Veterinary Research

Objective

To compare the analgesic effects of epidural administration of morphine (MOR), bupivacaine hydrochloride (BUP), their combination (COM), and 0.9% sterile NaCl solution (SAL) in dogs undergoing hind limb orthopedic surgeries.

Design

Blinded, randomized clinical trial.

Animals

41 healthy dogs admitted for elective orthopedic surgeries involving the pelvis or hind limbs.

Procedure

Analgesic and control agents were administered postoperatively prior to recovery from isoflurane anesthesia. Ten dogs received MOR, 0.1 mg/ kg of body weight; 10 received BUP, 0.5%, 1 ml/10- cm distance from the occipital protuberance to the lumbosacral space; 11 received COM; and 10 received SAL epidurally. Dogs were monitored for 24 hours after epidural injection for pain score, heart and respiratory rates, blood pressure, time to required administration of supplemental analgesic agent, total number of supplemental doses of analgesic agent required, and plasma concentrations of cortisol, MOR, and BUP.

Results

Pain scores were significantly lower in dogs in the COM and BUP groups than in dogs in the SAL group. Pain scores also were significantly lower in dogs in the COM group than in dogs in the MOR group. Time to required administration of supplemental analgesic agent was longer for dogs in the COM group than for dogs in the MOR and SAL groups. Total number of supplemental doses of analgesic agent required was lower for dogs in the BUP and COM groups than for dogs in the SAL group.

Clinical Implications

Postoperative epidural administration of COM or BUP alone provides longerlasting analgesia, compared with MOR or SAL. (J Am Vet Med Assoc 1996;209:698-607)

Free access
in Journal of the American Veterinary Medical Association

SUMMARY

Hyperxanthinuria and xanthine uroliths have been recognized with increased frequency in dogs with ammonium urate uroliths that had been given allopurinol. We hypothesized that dietary modification might reduce the magnitude of uric acid and xanthine excretion in urine of dogs given allopurinol. To test this hypothesis, excretion of metabolites, volume, and pH were determined in 24-hour urine samples produced by 6 healthy Beagles during periods of allopurinol administration (15 mg/kg of body weight, PO, q 12 h) and consumption of 2 special purpose diets: a 10.4% protein (dry matter), casein-based diet and a 31.4% protein (dry matter), meat-based diet.

Significantly lower values of uric acid (P = 0.004), xanthine (P = 0.003), ammonia (P = 0.0002), net acid (P = 0.0001), titratable acid (P = 0.0002), and creatinine (P = 0.01) excreted during a 24-hour period were detected when dogs consumed the casein-based diet and were given allopurinol, compared with the 24-hour period when the same dogs consumed the meat-based diet and were given allopurinol. For the same 24-hour period, urine pH values, urine volumes, and urine bicarbonate values were significantly (P = 0.0004, P = 0.04, and P = 0.002, respectively) higher during the period when the dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol. Endogenous creatinine clearance was significantly (P = 0.006) lower when dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol. Significantly lower concentrations of plasma uric acid (P = 0.0001), plasma xanthine (P = 0.01), and serum urea nitrogen (P = 0.0001) were detected when dogs consumed the casein-based diet and were given allopurinol than when they consumed the meat-based diet and were given allopurinol. On the basis of these results, use of the casein-based diet and allopurinol in protocols designed for dissolution of urate uroliths may be beneficial in preventing hyperxanthinuria and xanthine urolith formation.

Free access
in American Journal of Veterinary Research

Abstract

Objective

To evaluate the influence of 3 diets used to dissolve or prevent ammonium urate uroliths in dogs, and a diet formulated for growth, on 24-hour excretions of uric acid, ammonia, net acid, titratable acid, bicarbonate, and creatinine: 24-hour urine volumes: pH values of 24-hour urine samples; plasma uric acid concentration; serum creatinine concentration; and endogenous creatinine clearance values.

Design

Randomized block.

Animals

Six reproductively intact female Beagles, 3.9 to 4.2 years old, weighing 8.5 to 11.1 kg.

Procedures

Four diets were evaluated for their ability to dissolve magnesium ammonium phosphate hexahydrate (struvite) uroliths (diet S); to minimize uric acid excretion (diet U); to minimize clinical signs associated with renal failure (diet K); and to promote growth in pups (diet P). Each diet was fed for 14 days; then 24-hour urine samples were collected. An adult maintenance diet was fed during a 7-day washout period.

Results

Consumption of diet U was associated with lowest plasma uric acid concentration, lowest 24-hour urinary uric acid, ammonia, titratable acid, and net acid excretions, lowest endogenous creatinine clearance values, highest 24-hour urinary bicarbonate excretion and urine pH values, and highest 24-hour urine volumes. Consumption of diet P was associated with opposite results; results of consumption of diets S and K were intermediate between those for diets U and P.

Conclusion

Consumption of diet U by healthy Beagles is associated with reduced magnitude of urinary excretion of uric acid and ammonia, with alkaluria, and with polyuria, which may be beneficial in the management of ammonium urate uroliths in dogs.

Clinical Relevance

Results support use of diet U for management of ammonium urate urolithiasis in dogs.(Am J Vet Res 1996;57:324-328)

Free access
in American Journal of Veterinary Research

Summary

Urine uric acid-to-urine creatinine ratios (uua:uc), urine uric acid concentrations, urine uric acid concentrations corrected for glomerular filtration rate, and urinary uric acid fractional excretions were compared with 24-hour urinary uric acid excretions measured in 6 healthy adult female Beagles. Comparisons, using correlation analysis, were made when dogs consumed a 10.4% protein (dry weight), casein-based diet and a 31.4% protein (dry weight), meat-based diet. The uua:uc, urine uric acid concentrations corrected for glomerular filtration rate, and urinary uric acid fractional excretions were not reliable estimates of 24-hour urinary uric acid excretions during consumption of either diet. Urine uric acid concentrations in samples collected 2, 4, 6, and 24 hours after initiation of collection correlated with 24-hour urinary uric acid excretions when dogs consumed the casein-based diet; correlation was not found at any time interval when dogs consumed the meatbased diet. Therefore, determination of 24-hour urinary uric acid excretion is recommended because uua:uc are unreliable.

Free access
in American Journal of Veterinary Research

Abstract

Objectives

To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol.

Animals

6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg.

Procedure

In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined.

Results

Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg.

Conclusions

Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food.

Clinical Relevance

A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of > 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding. (Am J Vet Res 1997;58:504–510)

Free access
in American Journal of Veterinary Research

SUMMARY

Urine activity product ratios of uric acid, sodium urate, and ammonium urate and urinary excretion of metabolites were determined in 24-hour samples produced by 6 healthy Beagles during periods of consumption of a low-protein, casein-based diet (diet A) and a high-protein, meat-based diet (diet B). Comparison of effects of diet A with those of diet B revealed: significantly lower activity product ratios of uric acid (P = 0.025), sodium urate (P = 0.045), and ammonium urate (P = 0.0045); significantly lower 24-hour urinary excretion of uric acid (P = 0.002), ammonia (P = 0.0002), sodium (P = 0.01), calcium (P = 0.005), phosphorus (P = 0.0003), magnesium (P = 0.01), and oxalic acid (P = 0.004); significantly (P = 0.0001) higher 24-hour urine pH; and significantly (P = 0.01) lower endogenous creatinine clearance. These results suggest that consumption of diet A minimizes changes in urine that predispose dogs to uric acid, sodium urate, and ammonium urate urolithiasis.

Free access
in American Journal of Veterinary Research