Effects of large doses of phenylbutazone administration to horses

Robert J. MacKay, BVSc; T. W. French, DVM; Hai T. Nguyen, VMD, MS; I. G. Mayhew, BVSc, PhD

SUMMARY The effects oflarge doses of phenylbutazone were eval­

uated in clinically normal horses. The drug was given to 4 groups of 2 horses each at the rate of 30 mg/kg of body weight, orally, or 30, 15, or 8 mg/kg rv daily for up to 2 weeks. All horses became anorectic and depressed after 2 to 4 phenylbutazone treatments, and the horses given 15 or 30 mg/kg died on or between days 4 and 7 of treat­ment. A decrease in total blood neutrophil count occurred in all horses, and was associated with toxic left shift in horses given the 2 larger dosage schedules. The horses also had progressive increases in serum urea nitrogen, creatinine, and phosphorus concentrations, accompanied by decreasing serum calcium concentrations. There was a progressive decrease in total serum protein in all8 horses. Gastrointestinal ulcerations, renal papillary necrosis, and vascular thromboses were the predominant postmortem findings.

Phenylbutazone (PBZ) was first synthesized in 1946, and was introduced into human and veterinary medicine shortly thereafter. 1 I t remains the most widely used and arguably the most effective anti-inflammatory agent available for the equine species.2

Phenylbutazone is classified, with other compounds of diverse chemical structure but similar biologic actions, as a nonsteroidal anti-inflammatory drug (NSAID). Al­though its exact mode of action is unknown, PBZ, in com­mon with other NSAID , is thought to diminish the inflammatory response by interfering with the synthesis of prostaglandins in damaged tissues.3 •4 The well-known analgesic and antipyretic properties of PBZ in horses and other animals reflect these effects on inflammation of bone, joints, and other soft tissues.2.3

Although PBZ has been used extensively and success­fully for the management of painful rheumatic diseases of human beings, the occurrence of undesirable side ef­fects has limited its use in recent years. It has been es­timated that between 10% and 45% of human beings

~ived for publication July 7, 1981. From the Departments of Medical Sciences (Mackay, Mayhew) and Metabo­

lism (French), and the Division of Comparative Pathology {Nguyen), College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.

Published as journal series No. 4443, Flonda Agricultural Experimental Sta· tion.

The authors thank Virginia L. Sayer and Linda Siedlik for technical assist­ance.

774

treated with PBZ develop clinical signs of toxicosis.5 Al­though these complications are usually mild and revers­ible, many fatalities directly attributable to the drug have been reported.6 Some of the reported side effects were fluid retention and edema, skin rashes, nausea and vom­iting, systemic hypersensitivity reactions, oral and gas­trointestinal ulceration and bleeding, various renal disorders, hepatitis, and bone marrow depress ion. In vet­erinary literature, there are scattered reports of PBZ tox­icosis in dogs 7 ·9 and cats. 10

Recommendations for PBZ dosages in horses vary slightly among different manufacturers. The maximum daily dose and duration of therapy suggested for one brand• is 8.8 mg/kg of body weight for 2 days. Another manu­facturer recommends a maximum of 2 g (4.4 mg/kg) of their productb daily for 5 days, continued (if necessary) by oral therapy. The maximum oral dose for 450-kg horses is generally 4 g, with reevaluation of treatment after 5 days. Such doses are apparently well tolerated.2 •3 Several horses were given daily oral treatments of 2 g of PBZ for periods of 32 days, 11 6 months,2 and up to 3 years12 with­out developing clinical or hematologic abnormalities. In another study, 2 ponies were given the drug IV at a dosage rate of6.6 mg/kg for 1 day, followed by 4 mg/kg for 6 days without any adverse effects.13 However, in 4 of 6 horses given PBZ IV at a dosage of 8 mg/kg daily, there were marked decreases in plasma protein values by the 13th day of treatment. 14 The occurrence of fever, anorexia, diarrhea, and death in horses was attributed to the use of PBZ at recommended dosage levels (not specified) at an equine hospital in Switzerland.15 At the same clinic, 3 horses became anorectic and developed leukopenia after each was given 2 g of the drug orally twice daily for an unspecified period. Three other horses were given daily doses of 7.5 mg of PBz/kg IV and 2 became depressed, anorectic, and febrile . One of these horses died after 8 treatments. Each of the 3 horses became profoundly neu­tropenic ( < 2,000 cells/mm3 ) and had abnormal liver function tests during treatment. Neutrophil counts in­creased rapidly to > 10,000 cells/mm3 aft.er medication was stopped.

In case reports lacking substantive documentation, PBZ usage in the horse has also been linked to low PCV and hemoglobin concentration,16 hypoplastic anemia,17 intes­tinal ulceration resulting in fatal hemorrhage in a foal and colic in adult horses,18 acute depression and shock in

• Phenylbutawne iruecuon, 200 mg/ml, Med-Tech Inc, Elwood, Kan. b Butawlidin, Jensen-Salsbery, Division of Richardson-Merrel lnc, Kansas

City Mo. .

Am J Vet Res, Vol 44, No. 5

ponies, 19 epistaxis, 18 and depressant or tranquillizing ef­fects.2

There have been limited investigations into the effects of higher (> 8.8 mg/kg daily) doses of PBZ in the equine species. One horse died after administration of 16 g orally (per day) for 4 days. Postmortem examination revealed intestinal ulcers, but other tissues were too autolyzed for examination.•• During the same investigation, intestinal, gastric, and oral ulcers were found in a horse that was euthanatized after administration of 8 g of PBZ daily for 9 days. There was also necrotizing phlebitis of portal ven­ules in this horse, and in another that had been given 2-g doses daily for 32 days_. 1 In another study,I3 8 ponies were given PBZ orally at a rate of8.1 to 14.6 mg/kg daily. All, but one, developed clinical signs of toxicosis, and 3 ponies died after 10 to 14 days of treatment. The most consistent serum biochemical abnormality was an ap­proximately 25% decrease in serum protein values. Lin­gual ulcerations, diarrhea, and ventral edema were seen in all ponies. At necropsy, there were ulcerations of the large colon in each pony, and gastric ulceration was found in 1 pony.

Materials and Methods Experiment 1- Two clinically normal horses, a mature Thor­

oughbred mare and her 10-month-old colt, were used. Each of the horses was given 30 mg of PBzlkg of body weight, orally, once daily until death. Phenylbutazone (1 g) tablets• (6 for the foal and 12 for the mare) were crushed and mixed with 60 ml of molasses for dosing by syringe.

Clinicopathologic examination- The horses were observed for clinical signs twice daily during the study. Samples of blood were withdrawn from the jugular veins daily and were allowed to clot. Serum was harvested and stored at - 20 C for a maxi­mum of 2 weeks before determination of sorbitol dehydrogenase (SOH) and -y-glutamyl transferase (GGT) activities, and up to 3 months for the remaining biochemical determinations.

Postmortem examination-Within 2 hours of death, a com­plete necropsy examination was performed. Representative tis­sues were removed and fixed in 10% buffered formalin. After fixation, the tissues were embedded in paraffin, sectioned at 6 J.l.m, and stained with hematoxylin and eosin for light micro­scopic examination.

Experiment2-Seven mature mares (ages 7 to 22) of various breeds were used. The horses were kept in stalls and monitored for 4 to 7 days before the experiment. Six of the horses were assigned to 3 treatment groups of 2 horses each, and the other horse served as a control. The treatment groups were given single daily IV PBZ injections• (20%) of 30, 15, or 8 mg/kg and the control horse was given a volume of PBZ solvent mixture equal to that contained in 30 mg of aqueous PBZ solution/kg. Treatments were given over 3 minutes via a 100-cm polyethy­lene catheter sutured into a jugular vein. Those horses in ex­tremis or surviving 14 days were euthanatized with an overdose of sodium pentobarbital.

Clinicopathologic examination-Horses were observed as in experiment 1, and serum samples were collected daily. In ad­dition, 3-ml samples of blood were withdrawn into vacuum tubes containing disodium EDTA for daily wac and platelet counts and PCV and plasma protein determinations. Blood was smeared on glass slides, air-dried, fixed in anhydrous methanol, and stained with Wright-Giemsa stain for later examination. Urine samples were obtained periodically by clean urethral cathe-

• W. A. Butler, Columbus, Ohio.

May 1983

terization for routine urinalysis. Rectal fecal samples were col­lected daily and tested for the presence of occult blood, using a standard reagent tablet (Hematestd). Samples of bone marrow were aspirated from the sternum before and during treatment, via a 13-gauge needle and stylet. The aspirates were smeared on glass slides, air-dried, fixed in methanol, and stained with Wright-Giemsa stain for later examination. Postmortem ex­amination was performed as in experiment 1.

Results Clinical signs (experiments 1 and 2)-Horse 9 (8 mg/

kg, IV) died from complications of a ruptured cecum after 4 treatments following signs of colic for 2 days. Hema­tologic and serum biochemical data from this horse are not presented; however, summaries of clinical and post­mortem examinations are included.

All horses given PBZ orally or IV became acutely an­orectic and depressed on day 2, 3, or 4 (ie, after 2, 3, or 4 treatments). With the exception of horse 8 (8 mg/kg, IV), clinical deterioration continued until death or until eu­thanasia was performed in extremis on or between days 4 and 7. Horse 8 was intermittently anorectic and slightly depressed between days 3 and 10, but appeared clinically normal thereafter. A striking 'brick-red' discoloration of oral mucous membranes was noticed in the horses given 30 mg/kg orally or IV. In addition, numerous large oral and lingual ulcerations developed in the mare and foal treated orally. Diarrhea occurred in horses 2, 4 (30 mg/ kg), 6, and 7 (15 mg/kg). Other clinical signs varied widely among individual horses (Table 1).

Hematologic results (experiment 2)- Hematologic ex-· aminations were performed on the first days of the ex­periment and on the day of spontaneous death or euthanasia (Table 2). In each horse, trends indicated by these results were supported by additional examinations (data not shown) made on intervening days.

Profound, progressive neutropenia and toxic left shift occurred in horses given daily doses of 30 mg/kg and 15 mg/kg (Table 2). These changes could be detected within 12 hours of the first treatment in the horses at the highest dosage level (horses 4 and 5). Horse 8 (8 mg/kg) did not develop a consistent neutropenia, although mature neu­trophil counts of < 3,000 cells/mm3 were recorded on 7 of 14 treatment days compared with that on 0 of6 pretreat­ment days.

The WBC changes were accompanied by an increasing PCV in horses 4 through 7 (those given 30 and 15 mg/kg). The PCV of horse 8 did not change significantly during the experiment.

Platelet counts decreased during PBZ treatment in all horses, except horse 8 (8 mg/kg), but remained within the limits of normal ranges.20

Bone marrow aspirates (experiment 2)- The results of the examination of bone marrow aspirates are shown in Table 3. Three of the 4 horses in the 2 higher dosage groups had a lower myeloid/erythroid (MIE) ratio after t reatment compared with that before treatment. This was largely due to a relative decrease in the number of ma­ture neutrophils in posttreatment samples. A posttreat-

d Ames Co, Division of Miles Laboratories Inc, Elkhart, Ind.

775

TABLE 1-Experimental design and summary of major clinical signs and tests for fecal occult blood

Anorexia Red Fecal No. treatment Horse Dose and Tongue mucous Dementia, occult days before

No. (mg/kglday) depression ulcers membranes Dyspnea Diarrhea thrashing Colic blood death

30 PO + + + + + 5 (3) (4) (4) (5) (4)

2 30 PO + + + + · + 6 (3) (4) (4) (4) (5)

3 Control

4 301V + + + + 6 (2) (4) (6) (6)

5 30 IV + + + 4 (3) (3) (4)

6 15 IV + + + + 5 (2) (2) (2) (3)

7 15 IV + + + 7 (2) (4) (4)

8 81V 14(Euthanasia) 9 81V + 4

No. io parentheses are the day the clinical sign was first recorded. PO = per os. + = Clinical signs present; - = no clinical signs present.

TABLE 2 Hematologic results on pretreatment day (day 0) and on day of spontaneous death

Meta- Band Horse PCV Myelo- myelo- neutro-

No Day (mgldl) WBC cytes cytes phils

a• 0 36 12,100 0 0 0 14 36 11,750 0 0 0

4 0 33 9,550 0 0 0 6 52 3,400 646 612 748

5 0 43 8,850 0 0 0 4 69 2,200 0 88 352

6 0 31 8,250 0 0 0 4 51 7,550 255 900 3,075

7 0 34 11,150 0 0 0 7 61 2,300 138 276 644

8 0 39 10,150 0 0 0 14 44 6,150 0 0 0

• Control.

TABLE 3-Analyses of bone marrow aspirates Pretreatment Posttreatment

Mature Mature neutrophils neutrophils

Horse WE (%) Day WE (%) Comment

3* 0.62 16.8 14 0.60 15.8 Normal morphologic features 4 0.41 11.8 3 0.21 2.0 Slight cytoplasmic basophilia

of neutrophil precursors 5 0.69 19.2 3 0.27 0.6 Slight cytoplasmic basophilia

of neutrophil precursors

6 0.85 18.5 4 1.50 1.7 Increased neutrophil precur-sors; cytoplasmic basophilia

7 0.87 21.4 4 0.36 0.9 Decrease in band neutrophils from 9.2% to 3%

8 0.69 19.4 14 1.35 28.0 General increase in cells of neutrophil series

• Control.

ment aspirate from horse 6 also had a relative decrease in mature neutrophils, but the M!E ratio actually in­creased due to a higher proportion of neutrophil precur­sors. Slight cytoplasmic basophilia of neutrophil precursors was the only evidence of toxicosis in posttreatment sam­ples from these horses . In horse 8, the MIE ratio doubled due to a uniform increase in cells of the neutrophil series. The morphologic features and abundance of cells of the erythroid and megakaryocytic series did not appear to change significantly in any horse.

Serum biochemical results (experiments 1 and 2)-A summary of serum biochemical analyses from the first

776

No. of cellslmml

Segmented neutro- Lympho- Mono- Eosin- Baso-

phils cytes cytes ophils phils Platelets

8,107 1,936 847 1,.210 0 222 6,463 3,995 0 1,292 0 250 6,876 1,814 860 0 0 477.5

952 476 0 0 0 135 5,930 2,390 443 0 88 300

220 1,320 476 0 0 160

4,785 1,898 412 1,073 82 215 1,575 1,425 300 0 0 117.5 7,805 2,788 223 334 0 245

92 1,150 0 0 0 160 6,598 2,233 609 710 0 222.5 1,907 3,382 492 369 0 207.5

and last days of each experiment are shown in Table 4. The most consistent alterations occurred in horses on the 2 higher dosage schedules (IV or orally). There were pro­gressive increases in serum urea nitrogen (SUN), creati-

- nine, and phosphorus concentrations, accompanied by decreasing serum calcium concentrations. The changes in electrolyte concentrations could be detected by the 2nd treatment day. Similar changes were not seen in horse 8, which was given 8 mg/kg daily.

There was a progressive decrease in total serum pro­tein (TP) concentration in all the PBZ-treated horses. In the horses in the 2 higher IV dosage groups, the decrease in TP occurred in the face of an increasing PCV. The change in TP was most marked in horse 8 (8 mg/kg) in which the TP decreased from 7.1 g/dl to 4.0 g/dl after 14 days. Al­bumin and globulin were affected almost equally.

Moderate elevations in serum alkaline phosphatase (ALP) activity occurred in horses given 15 mg/kg and 30 mg/kg daily. However, other enzyme activities and serum bilirubin concentrations did not change significantly dur-. ing treatment.

Urinalyses-The results of 6 urinalyses performed be­fore and during treatment of horse 8 were unremarkable. In the horses given the higher doses, trace-to-slight pro­teinuria (0 to 30 mg/dl) was the only abnormality detect­able by the use of multireagent dipsticks (N-Multistixd). Examination of urinary sediments was unremarkable, with

Am J Vet Res, Vol 44, No. 5

TABLE 4-Biochemical results recorded on day 0 and on day of spontaneous death or euthanasia

HC0 3 Creal.- Bili- Albu- Glob-Horse Na K Cl Ca p (m Eq/ SUN inine rubin SOH ALP GCT min ulin TP

No. Day (mEq!L) (mEqiL) (mEqiL) (mgtd l) (mgld)) LJ (mg/dl) (mg/dl) (mgt d)) <IUILJ (lUlL) (l UlL) (g/dl ) (gld)) (gldl)

1 0 138 4.3 100 11.1 3.6 NO 22 5 133 3.2 94 6.2 5.7 NO 31

2 0 141 3.7 100 10.9 4.8 NO 11 7 113 4.8 73 9.4 13.4 NO 85

a• 0 138 3.8 105 11.5 2.9 24 14 14 139 4.2 105 10.9 3.5 25 17

4 0 135 4.6 95 11.2 2.9 26 14 6 126 3.3 83 7.0 9.1 24 45

5 0 137 3.5 95 11.5 4.4 23 14 4 147 3.2 92 11.4 6.2 23 58

6 0 136 3.7 104 11.1 4.2 24 11 4 140 3.5 99 9.4 6.2 14 32

7 0 134 3.8 99 11.8 4.7 22 11 7 130 3.9 8 1 5.4 10.8 24 43

8 0 137 3.7 102 11.7 3.2 25 11 14 132 4 .5 99 10.1 4.7 15 18

•con t rol . NO = not determined.

the exception of moderate hematuria and pyuria in horse 2 on days 5 and 7. Tubular casts were not seen. The spe­cific gravities of urine samples were not determined.

Necropsy results-The results of gross and histologic postmortem examinations are summarized in Table 5. Al­though some of the more spectacular necropsy findings were unique to individual horses (eg, diaphragmatic her­nia in horse 5, colonic infarction in horse 6), a number of qualitatively similar changes occurred in most or all of the treated horses. Gastric mucosal damage was found in 6 of 8 horses. The lesions were present only in the glan­dular mucosa , and ranged from microscopic erosions to 2-to 4-cm ulcerations extending into the submucosa. Intes­tinal mucosal erosions or ulcerations were detected his­tologically in 6 horses in the small and/or large intestine. Intestinal ulcers were apparent grossly in horses 4, 7, and 8. Other more variable findings were submucosal edema, inflammatory infiltrates in the lamina propria and sub­mucosa, and thrombosis and proliferation of vessels ad­jacent to large ulcerations.

Morphologic abnormalities were detected in the kid­neys of all PBZ-treated horses. The severity of renal le­sions appeared to be dose related. Focal segments of renal papillary necrosis were evident grossly as discrete 0.2 to 1 em brownish -green, wedge-shaped discolorations under the renal crest in one or more papillae in 4 of 6 horses in the higher dosage groups. Histologically, these areas ap­peared as coagulation necrosis with loss of cellular defi­nition. Evidence of inflammation in adjacent viable tissues was not seen. In addition, there was swelling, necrosis, and sloughing of tubular epithelial cells, most prominent in medullary collecting tubules, and medullary interst i­tial edema. These les ions were present but mild in horses 8 and 9 (8 mg/kg). Degenerative changes in proximal tu­bular cells, tubular casts, and lymphocytic cortical infil­trates were inconsistently present.

All livers were gross ly normal and hepatocellular changes were mild or absent. However, clumps of bacilli were seen in portal veins and adjacent sinusoids in horse 7. In addition there was partial thrombosis and necrosis of portal venules noticed in some liver sections in ho~Pe

May 1983

1.3 1.0 1.1 320 27 .2 2.8 4.5 7.3 1.4 1.2 3.3 345 26 1.9 2.5 4.4 1.5 0 .6 NO 400 15 .3 2.1 4.2 6.3 4.2 0 .7 NO 675 9.8 1.7 3.4 5.1

1.1 1.1 2.7 300 21.7 2.2 3.8 6.1 1.3 0.9 2.0 32 1 17.9 2.2 3.9 6.2 1.6 0.8 2.7 155 15.8 2.5 2.9 5.4 2.7 1.4 1.6 460 11.0 2.1 2.4 4.5

1.4 2.5 1.2 200 9.6 3.2 2.8 6.0 2.5 2.9 2.6 330 9.1 2.9 2.5 5.4 1.8 1.8 4.5 330 9.9 2.8 3.4 6.2 2.1 2.8 3.0 455 11.6 2.4 3.0 5.4

1.4 1.8 3.0 325 16.3 2.6 3.5 6.1 3.3 2.9 2.7 1,050 13 .4 2.0 2.8 4.8 1.3 2 .2 3.3 240 16.6 3.3 3.8 7.1 1.2 1.3 1.7 130 8.9 2.0 2.0 4.0

1. There was also pulmonary arterial thrombosis and in­farction of a sect ion of lung in this horse. Lesser thrombi were seen in the pulmonary vasculature of 3 other horses (No. 4, 6, and 9). These thrombi were not occlusive and did not appear to be associated with major lung lesions.

Control horse-The results of clinical and laboratory examinations of the control horse were within normal limits during the experiment. Abnormalities were not found during pos tmortem examination.

Discussion Phenylbutazone has a narrow therapeutic index in

horses. All 6 horses given daily doses of 15 mg/kg or 30 mg/kg died or were euthanat ized in extremis within 8 days of beginning treatment. Marked lesions and hema­tologic changes were also demonstrated in a horse given 8 mg/kg daily. The doses of PBZ used in this experiment were all well in excess of manufacturers recommenda­tions for both amount of drug and duration of therapy. However, because of a general belief among veterinarians in the safety and the dose-dependent analgesic effect of the drug, recommended dose schedules are frequently ex­ceeded. Daily doses of 6 to 8 g of PBZ (approx 13.2 to 17.6 mg/kg) for several days or more are not uncommon.

The finding of oral, gastric, and intestinal mucosal erosions and ulcerations is consistent with previous re­ports of PBZ toxicosis in horses. u ·13

•14 It is not known pre­

cisely how P B Z damages mucosal cells. Propos P.d mechanisms have included alteration of the mucous layer in the stomach, interference with a protective effect of prostaglandins, and decreased replacement of desqua­mated mucosal cells.21•22 Gas trointestinal lesions were produced by oral and IV administration in horses in this study, but too few animals were used to determine whether the drug was more ulcerogenic when given orally, as has been suggested for aspirin in human beings.23 Severe lin­gual ulceration occurred only in horses treated orally in our study, suggesting a mainly local irritant effect of the drug. The development of oral lesions could probably have been avoided if the PBZ had been delivered directly into the pharynx (eg, by balling gun) or stomach.

i78

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Serum leakage into the intestinal lumen through damaged gastrointestinal mucosae probably accounted for most of the decrease in serum protein in our horses. Ran­dom urinalyses failed to indicate heavy protein loss in the urine. Using 51Cr-labeled plasma albumin, previous workers have demonstrated increased fecal losses of pro­tein in ponies given large doses ofPBZ (10.0 mg/kg/day). 14 Hemodilution and decreased serum protein as a result of increased sodium and H 20 retention occur commonly in human beings taking PBZ.24 Such an effect was unlikely in our study, however, because all but 1 horse had an increasing PCV and clinical evidence of dehydration. It is of interest that hematologic evidence of protein loss did not correlate well with the presence of detectable amounts of fecal occult blood.

There was a striking uniformity in the occurrence and distribution of renal lesions in horses given 15 or 30 mg of PBzlkg daily. In addition to grossly obvious renal pap­illary necrosis (seen in 4 of 6 horses), there was a con­sistent pattern of medullary interstitial edema and tubular epithelial cell necrosis predominantly affecting collecting tubules. Some degree of clinical renal failure was asso­ciated with the lesions in these horses as indicated by progressive increases in SUN, serum creatinine, and phos­phorus concentrations and decreases in serum calcium. Similar biochemical changes were seen in ponies treated orally with high dosage levels of PBZ, but the results of postmortem examination of the kidneys were not re­ported. 13 The renal tubular changes in the horses given 8 mg/kg daily were mild, and in horse 8, were not asso­ciated with obvious serum biochemical abnormalities.

In rats, PBZ has been shown to cause renal papillary necrosis acutely25 and after long-term administration.26 Renal tubular degeneration and necrosis were noticed in a dog9 and several cats10 that died after administration of large dosages of PBZ. A comparable clinical and path­ologic syndrome known as analgesic nephropathy often follows abuse of a variety of NSAID drugs in human beings. 27 Phenacetin and phenacetin-aspirin combinations are most frequently incriminated, but PBZ has been associated with renal papillary necrosis in several case reports.28·29 The focal accumulations of lymphocytes in the renal cortices of horses 5 and 6 may represent an early phase in the development of cortical interstitial inflammation and scarring which, in addition to renal papillary necrosis, are the characteristic changes in chronic analgesic ne­phropathies of human beings and laboratory animals.30

It is interesting that renal lesions were produced so read­ily in our experimental horses when the use of massive doses of a variety of NSAID has failed to produce a con­sistent model for analgesic nephropathy in various ani­mals.31

Renal papillary necrosis has been described in horses treated with PBZ or other NSAID.32 The lesions were some­times associated with severe renal disease, and in other cases were considered an incidental finding. It is not clear why the renal papilla is susceptible to NSAID, but both direct toxic effects33 and ischemia secondary to vascular effects31 have been proposed to explain the distribution of lesions in analgesic nephropathies. Loss of maximal concentrating ability and sterile pyuria occur as a con­sequence of the tubular-interstitial inflammation and ne­crosis characteristic of analgesic nephropathies of human beings and experimental animals.27 As in the present study, proteinuria is usually mild to moderate.

Am J Vet Res, Vol 44, No. 5

The occurrence of neutropenia and toxic left shift in horses given PBZ is in general agreement with observa­tions of previous investigators 16 who reported the devel­opment of reversible neutropenia ( < 2,000 cells/mm3 ) in horses given daily doses of 4 g orally or 7.5 mglkg rv. Only those horses given 15 or 30 mg/kg became consist­ently neutropenic. The mechanism of this profound neu­tropenia is difficult to determine. It is apparent from examination of peripheral blood and bone marrow aspi­rates that there was severe depletion of circulating and bone marrow pools of mature neutrophils. Possible expla­nations are suppression of granulopoiesis, as has been suggested previously in similarly affected dogs,7 and/or increased loss (destruction, consumption, or sequestra­bon) of circulating neutrophils. The rapid ( < 12 hours) onset of neutropenia in horses 4 and 5 (30 mg/kg) and the lack of serious toxic changes in bone marrow aspirates indicate that bone marrow suppression was probably not the only cause of neutropenia. In addition to direct toxic effects of the drug, increased bacterial endotoxin absorp­tion through damaged intestinal mucosa may have con­tributed to the ~BC picture. The effects of neutrophils in the horses in this study appeared to be dose-related and are probably not comparable with the idiosyncratic oc­currence of aplastic anemia or agranulocytosis in human beings given PBZ occasionally.34 •36

Local thrombophlebitis in horses injected with PBZ oc­curs commonly.2•3 The drug may also have thrombotic effects at s ites distant to administration, as was shown by the presence of necrotizing thrombophlebitis of portal venules and pulmonary arterial thrombosis in horse 1 (treated orally), colonic vein thrombosis in horse 6 (treated IV), and partial pulmonary vascular thrombosis in 3 horses treated IV. Necrotizing phlebitis of the portal veins has been reported previously in 2 horses given PBZ orally,11

probably reflecting the higher portal venous concentra­tion when the drug is given orally, rather than IV.

Generally, there was little or no morphologic evidence for hepatotoxicity, and the liver-specific enzyme (SOH, GGT) activities did not increase appreciably during the study. The observed increases in ALP may have originated, at least in part, from c! .maged intestinal mucosa, lysed neu­trophils, or other extrahepatic tissues.

Despite the evidence presented in the present report, there is little doubt that PBZ at recommended doses is well tolerated by the equine species. However, such var­iables as errors in body weight estimation, the possibility of drug interactions, or individual or breed variations in drug meta bolism, and the presence of preexisting disease states, may render a given animal susceptible to PBZ tox­icosis even at prescribed doses.36 It has been well shown in animal models of aspirin nephropathy that a state of hydropenia (dehydration) must exist for expression of the nephrotoxic potential of the drug.37 Also, many NSAID cause gastrointestinal side effects that are more severe in ar­thritic human beings and animals than in healthy indi­viduals.38·39 Rats with adjuvant-induced arthritis were more susceptible to the gastrointestinal effects of PBZ than were healthy controls.40 Such considerations may be rel­evant to the analgesic management of severely painful, immobilizing conditions of horses such as laminitis, pleu­ritis, and septic arthritis in which large doses of PBZ are commonly used, and hydration may be poor. Careful clin­ical and laboratory monitoring of PBZ-treated horses is

May 1983

advisable if serious toxic effects are to be avoided, espe­cially when large doses are used in stressed or dehydrated patients.

Further work in this area is necessary before defini­tive recommendations about additional label warnings can be made.

References 1. JefTcott LB, Colles CM: Phenylbutazone and the horse-a review.

Equine Vet J 9:105- 110, 1977. 2. Gabel AA, Tobin T, Ray RS, et al: Phenylbutazone in horses: A

review. J Equine Med Surg 1:221-225, 1977. 3. Tobin T: Pharmacology review: The nonsteroidal anti-inflam­

matory drugs. I. Phenylbutazone. J Equine Med Surg 3:150-156, 1979. 4. Simon LS, Mills JA: Nonsteroidal anti-inflammatory drugs. N

Engl J Med 302:1179-1185, 1980. 5. Flower RJ, Moncada S, VaneJR: Analgesic-antipyretics and anti­

inflammatory agents: Drugs employed in the treatment of gout, in Gil­man AG, Goodman LS, Gilman A (ed): Goodman and Gilman's The Pharrrw.cologic Basis of Therapeutics, ed 6. New York, MacMillan Pub· lishing Co, 1980.

6. Mauer EF: The toxic effect of phenylbutazone (butazolidin): Re­view of the literature and report of the twenty-third death following its use. N Engl J Med 253:404-411, 1955.

7. Schalm OW: Phenylbutazone toxicity in two dogs. Canine Pra.ct 6:47-50, 1979.

8. Watson ADJ, Wilson JT, Turner OM, et al: Phenylbutazone-in­duced blood dyscrasias suspected in three dogs. Vet Rec 107:239--241 , 1980.

9. Tandy J, Thorpe E: A fatal syndrome in a dog following admin­istration of phenylbutazone. Vet Rec 81:39S-399, 1967.

10. Carlisle CH, Penny RHC, Prescott CW, et al: Tox.ic effects of phenylbutazone on the cat. Br Vet J 124:560-567, 1968.

11. Gabriel KL, Martin JE: Phenylbutazone: Short-term versus long­term administ ration to Thoroughbred and Standardbred horses. JAm Vet Med A ssoc 140:337-341, 1962.

12. Dunn PS: A clinician's views of the use and misuse of phenyl­butazone. Equine Vet J 4:6~5. 1972.

13. Snow DH, Bogan JA, Douglas TA, eta!: Phenylbutazone toxicity in ponies. Vet Rec 105:26-30, 1979.

14. Snow DH, Douglas TA, Thompson H, et al: Phenylbutazone tox­icity in ponies (letter). Vet Rec 106:68, 1980.

15. Wanner F , RollinghofT W, Gerber H, et al: Demethylation, hy­droxylation and acetylation in the horse: Side effects of repeated phen­ylbutazone medication, in Tobin T, Blake JW, Wood WE (ed): Proc 3rd lnt Symp Equine Medication, 1980, pp 455--464.

16. Roberts DV: Panel report. Mod Vet Pract 53:67--69, 1972. 17. Dunavant ML, Murray ES: Clinical evidence of phenylbutazone­

induced aplastic anemia. Proc 1st lnt Symp Equine Herrw.tol, 1975, pp 353-355.

18. Hopes R: Uses and misuses of anti-inflammatory drugs in race· horses. Equine Vet J 4:66--68, 1972.

19. Chandler N: Phenylbutazone toxicity in ponies (letter). Vet Rec 105:108, 1979.

20. Schalm OW, J ain NC, Carroll EJ: Veterinary Hematology, ed 3. Philadelphia, Lea & Febiger, 1975, p 184.

21. Max M, Menguy R: Influence of aspirin and phenylbutazone on the rate of turn over of gastric mucosal cells. Digestion 2:67- 72, 1969.

22. Cooke AR: Drug damage to the gastroduodenum, in Sleisenger MH, Fortran JA (ed): Gastrointestinal Disease. Philadelphia, WB Saun­ders Co, 1978, pp 807-825.

23. Meilants H, Veys EM, Verbruggen G, et al: Salicylate-induced gastrointestinal bleeding. J Rheumatol 6:210-218, 1978.

24. Meiers HG, Wetzels E: Phenylbutazone und nierenfunktionen. Arzneimittel(orsch 14:252-254, 1964.

25. Arnold L, Collins C, Starmer GA: Renal and gastric lesions after phenylbutazone a nd indomethacin in the rat. Pathology 6:303-306, 1974.

26. Nanra RS, Chirawong P, Kincaid-Smith P: Renal papillary ne­crosis in rats produced by aspirin, APC and other analgesics, in Kincaid­Smith P, Fiariley KF (ed): Renal Infection and Renal Scarring. Mel· bourne, Mercedes Publishing Co, 1971, pp 347-358.

27. Goldberg M, Murray TG: Analgesic-associated nephropathy: An important cause of renal disease in the United States? N Engl J Med 299:716-718, 1978.

779

28. Morales A, Steyn J: Papillary necrosis following phenylbutazone ingestion. Arch Surg 103:42()....421, 1971.

29. Jackson B, Lawrence JR: Renal papillary necrosis associated with indomethacin and phenylbutazone treated rheumatoid arthritis. Aust NZ J Med 8:165-167, 1978.

30. Abrahams C, Levin NW: Experimentally induced analgesic ne­phropathy. Med Pract 13:50&-514, 1967.

31. Molland AE: Experimental renal papillary necrosis. Kidney lnt 13:5-14, 1978.

32. King JM: Pathologic topics-diagnostic case of the month. Ithaca, NY, Cornell University Press, Veterinary News, vol 44, No 11, 1980.

33. Clausen E: Histological changes in rabbit kidneys induced by phenacetin and acetylsalicylic acid. Lancet 2:123-124, 1964.

34. McCarthy DD, Chalmers TM: Hematological complications of phenylbutazone therapy: Review of the literature and report of two cases. Can Med Assoc J 90:1061-1067, 1964.

780

35. deGruchy GC: Drug Induced Blood Disorders. Oxford, England, Blackwell Scientific Publications, 1975.

36. Lees P , Michell AR: Phenylbutazone toxicity in ponies (letter). Vet Rec 105:150-151, 1979.

37. Nanra RS, Kincaid-Smith P: Papillary necrosis in rats caused by aspirin a nd aspirin-containing mixtures. Br Med J 3:559-561, 1970.

38. DiPasquale G, Welaj P: Neurogenic potential of indomethacin in arthritic and nonarthritic rats. J Pharm Pharnu:u:o/25:831-832, 1973.

39. Holla nder JE: Arthritis and allied conditions: A Textbook of Rheumatology. Philadelphia, Lea & Febiger, 1966.

40. Shriver DA, Dove PA, White CB, eta!: A profile of the gastroin­testinal toxicity of aspirin, indomethacin, oxaprozin, phenylbutazone, and fentiazac in arthritic a nd Lewis normal rats. Toxicol Appl Phar­nu:u:ol42:15-83, 1977.

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