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Effect of naproxen on bleeding time in the horse
11
EFFECT OF NAPROXEN ON BLEEDING TIME IN THE HORSE
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Mary McDowell and Steven L Wickler M.S.,Ph.D.,DVM
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t=5_ INTRODUCTION
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3
Steroids, while extremely effective at reducing inflammation, also have the potential to cause deleterious side effects. These concerns have placed an even more intensive use of the nonsteroidal anti-inflammatory drugs (NSAIDS). Phenylbutazone, known in its vernacularform as "bute" is a household name as well as being an inexpensive treatment. 12Over 20 years of use has demonstrated its efficacy and dependability in a variety of conditions.2 Because of their costs and availability, NSA1Ds are used, at times, without knowledge of their side effects. Fortunately, toxieities with NSA1Ds are rare. Side effects that may be seen after prolonged administration inetude ulceration of the gastrointestinal tract, and of the mouth and tongue. 15In general, NSA1Ds have been shown to cause central nervous system depression at high doses, and to cause irritation and ulceration of the gastrointestinal tract at low doses. 13 NSA1Ds may also affect platelet function which impacts bleeding time. Acetylsalieylic acid has been shown to have a significant effect on bleeding time when compared with fltmixin meglumine and phenylbutazone.~The latter two drugs had relativelyno effect on bleeding time. Since naproxen is another effective NS.MD, the current study was initiated to assess the effect of naproxen on bleeding time.
MATERIALS AND METHODS Fourteen Arabian horses were used ranging in age from 4 to 20 years (average= 12). There were eight geldings and six mares. The horses were kept in 12 x 24 foot paddocks and fed a pelleted radon of alfalfa hay. Prior to the beginningof the study, bleeding times were measured on each horse. Bleeding times were determined using a Surgicutt (Baxter Scientific,product #]3-4237-10) Authors address:EquineResearchClinic, CaliforniaPolytechnicInstitute, 3801 W. TempleAvenue,Pomona,CA 91768 Acknowledgements:We wish to thank MelissaHowerand the faculty and staff of the W.K~KelloggArabianHorseCenter.EquiproxenTM(naproxen) was donatedby SyntexAnimalHealth,Inc.
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Figure 1. Effect of naprexen on bleeding times. Bleeding time, in minutes, is plotted for each day of the study for control (open bar) and treatment animals (closed bar). Treatment animals received naproxen following Day 0 measurements. Thin bars represent + 1 SEM. instrument, Whatman No. 40 absorbent filter paper and a stopwatch. The Surgicutt immanent produces a standardized I mm incision for measuring bleeding times. To prevent interfering blood flow from cutaneous vessels, a sphygmomanometer cuff was placed on the forelegjust proximal to theincisionand inflated to 40 mm for one minute. While the cuff was maintainedat 40 mm Hg an incisionwas m adejust distal to the carpus on the caudolateral aspect of each leg. At 30 second intervals, blood flow was blotted, using #40 Whatman filter paper, from the incision. To avoid creating aniatrogenicprolongationof the bleeding time, care was taken not to touch the edges of the incision with the filter paper. Horses were then paired based on their bleeding times and one individualof the pair was randomly assigned to receive naproxen (EquiproxenTM),5 mg/kg, IV, once daily for three days. Bleeding times were measured on three consecutive mornings in both the treatment and control groups.
RESULTS Naproxen had no effect on bleeding time. Values obtained from treated animals were not significantlydifferent from those taken from control animals. (Fig. 1) Mean bleeding times on the day prior to treatment (Day O) were: 6.14 min (se= I..27) for control animals ( range of 3.5 min - 14.0 min) and 6.92 min (se= .968) for animals assigned to the treatment group ( range of 2.5 rain- 10.5 rain). Mean bleeding times for controls on days 1, 2, &
EQUINE VETERINARY SCIENCE
3 were: 11.07 min (se= 1.13), 8.43 min (se= .905), 7.57 min (se= 1.02), respectively, and mean bleeding times for treatment animals were: 9.0 min (se= 1.62), 9.28 min (se= .702), 7.64 min (se= 1.01 ), respectively.
DISCUSSION In the horse, naproxen had no effects on bleeding times. However, in the human, naproxen does effect bleeding time. The mechanism is by inhibiting collagen-induced platelet aggregation [in citrated platelet-rich plasma] u at the second wave of aggregation. This second wave of aggregation occurs when platelet interaction with collagen leads to the release of adeno sine diphosphate (ADP) and activation of the prostaglandin arachidonate pathway to release thromboxane A2.4 The uniqueness of second wave of aggregation in humans explains, in part, the lack of effect of naproxen on bleeding times in the horse. ~ In the equine industry, naproxen has been reported to be effective against cases of myositis (tying-up)6 as well as being recommended for relief of inflammation, pain and lameness associated with inflammatory conditions of the musculoskeletal system, and arthritis. Specific antibiotic therapy is required when naproxen is used to alleviate inflammation associated with irffectionJ 4 Naproxen is recommended for joint pain, stiffness, inflammation and swelling of arthritis in human medicine. TMIt can also be used as a general pain reliever and treatment for painful or difficult menstruation.9 Adverse reactions of naproxen include dizziness, headache, and nausea. These side effects are considered to result from the inhibition of the formation of prostaglandins.~3 Naproxen is contraindicated for use in individuals with allergic reactions to aspirin or other non-steroidal anti-inflammatories and with a history of gastrointestinal tract disease? Taking aspirin and naproxen concurrently can increase the risk o f stomach ulcers. 3 When large doses are given, some central nervous system depressionmay be caused, otherwise, the adverse effects are gastrointestinal irritation and ulceration.3.s The broad use of naproxen in human medicine is unfortunately not paralleled in equine medicine. The manufacturer's removal of naproxen from the equine industry due to financial reasons has left an unfortunate gap in NSAID therapy for the horse.
REFERENCES t. Cronberg S, et al: Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scandinavian Journal of Haemato/ogy 33:155-59,1984. 2. Robert A: Effects of prostaglandins on the stomach and the intestine. Prostaglandins 6:523-532,1974. 3. Griffith, H Winter: Complete guide to Prescription & Nonprescription Drugs. H P Books, Tucson, Arizona p 510-511,1983. 4. Harker I_A,Fuster V: Pharmacology of Platelet Inhibitors. JACC8(6):21 B-32B,1986. 5. Hart FD: Naproxen and gastrointestinal haemorrhage. British Medical Journal 2:51,1979. 6. Kilian JG, Jones EW, Hamm D, et al: The efficacy of Volume 10, Number 3, 1989
equiproxen(naproxen) in a unique equine myosifis model. ProcAm Equine Pract 20:201,1974. 7. Kopp KJ, et al: Template bleeding time and thromboxane generation in the horse: Effect of three non-steroidal anti-inflammatory drugs. Equine VetJ 17(4):322-324. 8. Lanza FL, et al: The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers. Digestive Diseases and Sciences 22(11): 823,1979. 9. Merohini M, et al: Pirprofen, naproxen and placebo in the treatment of primary dysmenorrhea. Drugs under Experimental& Clinical Research 13(11) :699-705,1987. 10. Modell's Drugs in current use and New Drugs ed. DA Hussar, Ph. D: p 93,1989, Springer Publishing Company, Inc., New York 11. Nadell J, et al: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. JournalofC/inica/Pharmacology 14:176-182,1974. 12. Pharmacological Basis of Large Animal Medicine eds JA Bogan, P Lees & AT Yoxall. p 414 Table 19.3,1983. Blackwell Scientific Publications, West Sussex. 13. Robert A: Effects of prostaglandins on the stomach and the intestine. Prostaglandins 6:523-532,1974. 14. Syntex Animal Health, Inc. Subsidiary of Syntex Agribusiness, inc. West Des Moines, Iowa 50265 15. Wilhelmi G: Species differences in susceptibility to the gastreulcerogenic action of anti-inflammatory agents. Pharmacology 11:220,1974.
ULTRASONOGRAPHIC EXAMINATIONOF EQUINE TENDONS AND LIGAMENTS Norman W. Rantanen DVM, MS Optimal ultrasonographic examination of the tendons and hgaments of the horse requires high frequency transducers and a precise knowledge of the anatomy. It is important to image the tendon or ligament in more than one plane to confmn or deny a lesion. Because echoes which comprise the image are reflections from tissue acoustic interfaces, it follows that the tissue planes should be struck as close to 90 ° as possible. The analogy of throwing a ball at a fiat wall can be used as a comparison. If a ball is thrown at 90 ° to the wall, it will return to the thrower. If it is thrown at an angle, however, it will likely bounce away and not return to the thro wet. The same can be s aid of the ultresound beam if it strikes a tissue interface at 90 °, a larger portion of the sound beam will remm to the transducer. Why is this important and what relationship does it have to the sagittal plane? If the tendon fibers are not struck at 90° in cross section, reflection of the sound beam occurs decreasing the number of returning echoes. 1 This causes the tendon to appear more echolucent than normal. In the diagnosis of acute tendon and ligament injury, it has been shown that echolucency equates with hemorrhage and fiber separation. 2 If images are made only in cross section and the fibers are not struck at 90 ° , error in interpretation may occur. Opposing sagittal (or long axis) images at each level of the tendon will preclude this from happening. If a lesion, seen on 163
EFFECT OF NAPROXEN ON BLEEDING TIME IN THE HORSE
lO
"
--
9
I
I
i
"
i
~a
i
c .~:
Mary McDowell and Steven L Wickler M.S.,Ph.D.,DVM
=; E
7
--
-g
T
t=5_ INTRODUCTION
4
3
Steroids, while extremely effective at reducing inflammation, also have the potential to cause deleterious side effects. These concerns have placed an even more intensive use of the nonsteroidal anti-inflammatory drugs (NSAIDS). Phenylbutazone, known in its vernacularform as "bute" is a household name as well as being an inexpensive treatment. 12Over 20 years of use has demonstrated its efficacy and dependability in a variety of conditions.2 Because of their costs and availability, NSA1Ds are used, at times, without knowledge of their side effects. Fortunately, toxieities with NSA1Ds are rare. Side effects that may be seen after prolonged administration inetude ulceration of the gastrointestinal tract, and of the mouth and tongue. 15In general, NSA1Ds have been shown to cause central nervous system depression at high doses, and to cause irritation and ulceration of the gastrointestinal tract at low doses. 13 NSA1Ds may also affect platelet function which impacts bleeding time. Acetylsalieylic acid has been shown to have a significant effect on bleeding time when compared with fltmixin meglumine and phenylbutazone.~The latter two drugs had relativelyno effect on bleeding time. Since naproxen is another effective NS.MD, the current study was initiated to assess the effect of naproxen on bleeding time.
MATERIALS AND METHODS Fourteen Arabian horses were used ranging in age from 4 to 20 years (average= 12). There were eight geldings and six mares. The horses were kept in 12 x 24 foot paddocks and fed a pelleted radon of alfalfa hay. Prior to the beginningof the study, bleeding times were measured on each horse. Bleeding times were determined using a Surgicutt (Baxter Scientific,product #]3-4237-10) Authors address:EquineResearchClinic, CaliforniaPolytechnicInstitute, 3801 W. TempleAvenue,Pomona,CA 91768 Acknowledgements:We wish to thank MelissaHowerand the faculty and staff of the W.K~KelloggArabianHorseCenter.EquiproxenTM(naproxen) was donatedby SyntexAnimalHealth,Inc.
162
--
--
2
--
1
--
0
I
DAY
0
DAY I
DAY 2
DAY 3
Figure 1. Effect of naprexen on bleeding times. Bleeding time, in minutes, is plotted for each day of the study for control (open bar) and treatment animals (closed bar). Treatment animals received naproxen following Day 0 measurements. Thin bars represent + 1 SEM. instrument, Whatman No. 40 absorbent filter paper and a stopwatch. The Surgicutt immanent produces a standardized I mm incision for measuring bleeding times. To prevent interfering blood flow from cutaneous vessels, a sphygmomanometer cuff was placed on the forelegjust proximal to theincisionand inflated to 40 mm for one minute. While the cuff was maintainedat 40 mm Hg an incisionwas m adejust distal to the carpus on the caudolateral aspect of each leg. At 30 second intervals, blood flow was blotted, using #40 Whatman filter paper, from the incision. To avoid creating aniatrogenicprolongationof the bleeding time, care was taken not to touch the edges of the incision with the filter paper. Horses were then paired based on their bleeding times and one individualof the pair was randomly assigned to receive naproxen (EquiproxenTM),5 mg/kg, IV, once daily for three days. Bleeding times were measured on three consecutive mornings in both the treatment and control groups.
RESULTS Naproxen had no effect on bleeding time. Values obtained from treated animals were not significantlydifferent from those taken from control animals. (Fig. 1) Mean bleeding times on the day prior to treatment (Day O) were: 6.14 min (se= I..27) for control animals ( range of 3.5 min - 14.0 min) and 6.92 min (se= .968) for animals assigned to the treatment group ( range of 2.5 rain- 10.5 rain). Mean bleeding times for controls on days 1, 2, &
EQUINE VETERINARY SCIENCE
3 were: 11.07 min (se= 1.13), 8.43 min (se= .905), 7.57 min (se= 1.02), respectively, and mean bleeding times for treatment animals were: 9.0 min (se= 1.62), 9.28 min (se= .702), 7.64 min (se= 1.01 ), respectively.
DISCUSSION In the horse, naproxen had no effects on bleeding times. However, in the human, naproxen does effect bleeding time. The mechanism is by inhibiting collagen-induced platelet aggregation [in citrated platelet-rich plasma] u at the second wave of aggregation. This second wave of aggregation occurs when platelet interaction with collagen leads to the release of adeno sine diphosphate (ADP) and activation of the prostaglandin arachidonate pathway to release thromboxane A2.4 The uniqueness of second wave of aggregation in humans explains, in part, the lack of effect of naproxen on bleeding times in the horse. ~ In the equine industry, naproxen has been reported to be effective against cases of myositis (tying-up)6 as well as being recommended for relief of inflammation, pain and lameness associated with inflammatory conditions of the musculoskeletal system, and arthritis. Specific antibiotic therapy is required when naproxen is used to alleviate inflammation associated with irffectionJ 4 Naproxen is recommended for joint pain, stiffness, inflammation and swelling of arthritis in human medicine. TMIt can also be used as a general pain reliever and treatment for painful or difficult menstruation.9 Adverse reactions of naproxen include dizziness, headache, and nausea. These side effects are considered to result from the inhibition of the formation of prostaglandins.~3 Naproxen is contraindicated for use in individuals with allergic reactions to aspirin or other non-steroidal anti-inflammatories and with a history of gastrointestinal tract disease? Taking aspirin and naproxen concurrently can increase the risk o f stomach ulcers. 3 When large doses are given, some central nervous system depressionmay be caused, otherwise, the adverse effects are gastrointestinal irritation and ulceration.3.s The broad use of naproxen in human medicine is unfortunately not paralleled in equine medicine. The manufacturer's removal of naproxen from the equine industry due to financial reasons has left an unfortunate gap in NSAID therapy for the horse.
REFERENCES t. Cronberg S, et al: Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scandinavian Journal of Haemato/ogy 33:155-59,1984. 2. Robert A: Effects of prostaglandins on the stomach and the intestine. Prostaglandins 6:523-532,1974. 3. Griffith, H Winter: Complete guide to Prescription & Nonprescription Drugs. H P Books, Tucson, Arizona p 510-511,1983. 4. Harker I_A,Fuster V: Pharmacology of Platelet Inhibitors. JACC8(6):21 B-32B,1986. 5. Hart FD: Naproxen and gastrointestinal haemorrhage. British Medical Journal 2:51,1979. 6. Kilian JG, Jones EW, Hamm D, et al: The efficacy of Volume 10, Number 3, 1989
equiproxen(naproxen) in a unique equine myosifis model. ProcAm Equine Pract 20:201,1974. 7. Kopp KJ, et al: Template bleeding time and thromboxane generation in the horse: Effect of three non-steroidal anti-inflammatory drugs. Equine VetJ 17(4):322-324. 8. Lanza FL, et al: The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers. Digestive Diseases and Sciences 22(11): 823,1979. 9. Merohini M, et al: Pirprofen, naproxen and placebo in the treatment of primary dysmenorrhea. Drugs under Experimental& Clinical Research 13(11) :699-705,1987. 10. Modell's Drugs in current use and New Drugs ed. DA Hussar, Ph. D: p 93,1989, Springer Publishing Company, Inc., New York 11. Nadell J, et al: Effect of naproxen and of aspirin on bleeding time and platelet aggregation. JournalofC/inica/Pharmacology 14:176-182,1974. 12. Pharmacological Basis of Large Animal Medicine eds JA Bogan, P Lees & AT Yoxall. p 414 Table 19.3,1983. Blackwell Scientific Publications, West Sussex. 13. Robert A: Effects of prostaglandins on the stomach and the intestine. Prostaglandins 6:523-532,1974. 14. Syntex Animal Health, Inc. Subsidiary of Syntex Agribusiness, inc. West Des Moines, Iowa 50265 15. Wilhelmi G: Species differences in susceptibility to the gastreulcerogenic action of anti-inflammatory agents. Pharmacology 11:220,1974.
ULTRASONOGRAPHIC EXAMINATIONOF EQUINE TENDONS AND LIGAMENTS Norman W. Rantanen DVM, MS Optimal ultrasonographic examination of the tendons and hgaments of the horse requires high frequency transducers and a precise knowledge of the anatomy. It is important to image the tendon or ligament in more than one plane to confmn or deny a lesion. Because echoes which comprise the image are reflections from tissue acoustic interfaces, it follows that the tissue planes should be struck as close to 90 ° as possible. The analogy of throwing a ball at a fiat wall can be used as a comparison. If a ball is thrown at 90 ° to the wall, it will return to the thrower. If it is thrown at an angle, however, it will likely bounce away and not return to the thro wet. The same can be s aid of the ultresound beam if it strikes a tissue interface at 90 °, a larger portion of the sound beam will remm to the transducer. Why is this important and what relationship does it have to the sagittal plane? If the tendon fibers are not struck at 90° in cross section, reflection of the sound beam occurs decreasing the number of returning echoes. 1 This causes the tendon to appear more echolucent than normal. In the diagnosis of acute tendon and ligament injury, it has been shown that echolucency equates with hemorrhage and fiber separation. 2 If images are made only in cross section and the fibers are not struck at 90 ° , error in interpretation may occur. Opposing sagittal (or long axis) images at each level of the tendon will preclude this from happening. If a lesion, seen on 163