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Objective: To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP)., Animals: 6 adult university-owned horses., Methods: For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-β1, IL-1β, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays., Results: There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP., Clinical Relevance: These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

Background: Right dorsal colitis (RDC) is a nonsteroidal anti-inflammatory drug (NSAID) induced, protein losing enteropathy in horses associated with a high case fatality rate., Objectives: To describe signalment, NSAID usage, clinical presentations, clinical pathology, ultrasonographic findings, treatments, outcomes, and factors associated with survival in horses diagnosed with RDC., Animals: Thirty-five horses from 7 Australian equine hospitals diagnosed with RDC., Methods: Retrospective case series. Clinical records of cases were accepted if definitively or presumptively diagnosed by an internist with RDC and had ≥3 of: hypoproteinemia or hypoalbuminemia; diarrhea with negative test results for infectious diseases; colic for which other diseases were excluded or right dorsal colon thickening on ultrasound. Descriptive data analysis was performed for categorical and continuous variables. Univariate binominal logistic regressions were used to assess factors associated with survival., Results: An overdose of NSAIDs occurred in 84% (21/25) cases where dose was known. Common clinical presentations included diarrhea (69%; 22/32), colic (61%; 20/33), and tachycardia (53%, 17/32). Common clinicopathological findings included hypoalbuminemia (83%; 26/31), hypocalcaemia (79%, 23/29), and hyperlactatemia (77%, 14/18). The right dorsal colon wall appeared subjectively thickened in 77% (24/31) cases using ultrasonography. Case fatality rate was 43% (15/35). Odds of survival significantly decreased with increasing heart rate (odds 0.84, 95% CI = 0.71-0.92, P = .01), packed cell volume (odds 0.91, 95% CI 0.82-0.98, P = .05) and abnormal appearance of mucous membranes (odds 0.05, 95% CI 0.005-0.28, P = .001) on hospital presentation., Conclusions and Clinical Importance: An overdose of NSAIDs is common in horses diagnosed with RDC. Serum albumin concentrations should be monitored in horses receiving a prolonged course of NSAIDs. Overall prognosis for RDC remains fair., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known., Objective: Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone-induced GI injury could be ameliorated by the use of a nutritional therapeutic., Animals: Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic., Methods: This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability., Results: Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02-fold (95% confidence interval [CI], 0.1.89-4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment., Conclusions and Clinical Importance: Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Objective: To examine the association between prerace administration of phenylbutazone and the risk of musculoskeletal injury (MSI) and fatal injury in Thoroughbred racehorses that raced between 2006 and 2015 at 2 of the 4 official racetracks in Argentina., Sample: Data from racetrack databases and veterinary reports on 283,193 race starts., Procedures: Data were collected relating to race performance and injury outcomes for starts at these tracks. The incidence of MSI and fatal injury was calculated for each year, stratified by the declared prerace administration of phenylbutazone. Univariable logistic regression, followed by multivariable logistic regression, was used to identify significant risk factors for both MSI and fatal injury., Results: Analyses identified associations between the declared prerace administration of phenylbutazone and the risk of MSI and fatal injury during racing. Horses with declared prerace phenylbutazone administration had greater odds of MSI (OR, 1.45 [95% CI, 1.03 to 2.04]) and fatal injury (OR, 1.59 [95% CI, 1.1 to 2.27]) than did horses racing without prerace phenylbutazone administration. These associations remained significant when other risk factors were accounted for in both multivariable models., Conclusions and Clinical Relevance: Results suggested an association between the prerace administration of phenylbutazone and the risk of MSI and fatal injury in Thoroughbred racehorses during racing. Although these results did not imply a direct causal relationship between prerace phenylbutazone administration and injury, they may be considered in the development of more conservative medication policies to optimize racehorse welfare in North and Latin America.

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para -positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1 , 7 , 8 and 13 ⁻ 15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13 ⁻ 15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.

Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in both veterinary and human medicine. Gastrointestinal injury is a frequent adverse event associated with NSAID use and evidence suggests that NSAIDs induce gastrointestinal microbial imbalance (i.e., dysbiosis) in both animals and people. It is unknown, however, whether cyclooxygenase (COX)-2-selective NSAIDs induce dysbiosis, or if this phenomenon occurs in horses administered any class of NSAIDs. Therefore, our objectives were to determine whether the composition and diversity of the fecal microbiota of adult horses were altered by NSAID use, and whether these effects differed between non-selective and COX-2-selective NSAIDs. Twenty-five adult horses were randomly assigned to 1 of 3 groups: control (n = 5); phenylbutazone (n = 10); or, firocoxib (n = 10). Treatments were administered for 10 days. Fecal samples were collected every 5 days for 25 days. DNA was extracted from feces and the 16S rRNA gene amplified and sequenced to determine the composition of the microbiota and the inferred metagenome. While the fecal microbiota profile of the control group remained stable over time, the phenylbutazone and firocoxib groups had decreased diversity, and alteration of their microbiota profiles was most pronounced at day 10. Similarly, there were clear alterations of the inferred metagenome at day 10 compared to all other days, indicating that use of both non-selective and selective COX inhibitors resulted in temporary alterations of the fecal microbiota and inferred metagenome. Dysbiosis associated with NSAID administration is clinically relevant because dysbiosis has been associated with several important diseases of horses including abdominal pain (colic), colitis, enteric infections, and laminitis., Competing Interests: The authors have declared that no competing interests exist.

The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.

Previously we have developed a transgenic zebrafish line (LiPan) with liver-specific red fluorescent protein (DsRed) expression under the fabp10a promoter. Since red fluorescence in the liver greatly facilitates the observation of liver in live LiPan fry, we envision that the LiPan zebrafish may provide a useful tool in analyses of hepatotoxicity based on changes of liver red fluorescence intensity and size. In this study, we first tested four well-established hepatotoxins (acetaminophen, aspirin, isoniazid and phenylbutazone) in LiPan fry and demonstrated that these hepatotoxins could significantly reduce both liver red fluorescence and liver size in a dosage-dependent manner, thus the two measurable parameters could be used as indicators of hepatotoxicity. We then tested the LiPan fry with nine other chemicals including environmental toxicants and human drugs. Three (mefenamic acid, lindane, and arsenate) behave like hepatotoxins in reduction of liver red fluorescence, while three others (17β-estradiol, TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin] and NDMA [N-nitrosodimethylamine]) caused increase of liver red fluorescence and the liver size. Ethanol and two other chemicals, amoxicillin (antibiotics) and chlorphenamine (pain killer) did not resulted in significant changes of liver red fluorescence and liver size. By quantitative RT-PCR analysis, we found that the changes of red fluorescence intensity caused by different chemicals correlated to the changes of endogenous fabp10a RNA expression, indicating that the measured hepatotoxicity was related to fatty acid transportation and metabolism. Finally we tested a mixture of four hepatotoxins and observed a significant reduction of red fluorescence in the liver at concentrations below the lowest effective concentrations of individual hepatotoxins, suggesting that the transgenic zebrafish assay is capable of reporting compound hepatotoxicity effect from chemical mixtures. Thus, the LiPan transgenic fry provide a rapid and convenient in vivo hepatotoxicity assay that should be applicable to high-throughput hepatotoxicity test in drug screening as well as in biomonitoring environmental toxicants.

Case Description: A 15-year-old Quarter Horse gelding and a 26-year-old Thoroughbred gelding were evaluated because of hematuria of 4 to 6 days' duration following prolonged oral administration of phenylbutazone., Clinical Findings: The horses had received either treatment with phenylbutazone for 3 months or intermittent long-term phenylbutazone treatment prior to development of hematuria. Each horse was systemically stable but had orthopedic or neurologic problems. Clinicopathologic findings included normochromic normocytic anemia in both horses and hypoalbuminemia and high BUN concentration in 1 horse. In both horses, urinalysis revealed proteinuria and RBCs, but no evidence of WBCs or bacteria. Ulceration and hemorrhage of the urinary bladder with no evidence of uroliths were observed via cystoscopy. Gastric ulceration along the margo plicatus was observed via gastroscopy., Treatment and Outcome: For each horse, phenylbutazone treatment was discontinued and a synthetic prostaglandin (misoprostol) was administered. The hematuria resolved, and results of a follow-up CBC, serum biochemical analysis, urinalysis, and cystoscopy 25 or 30 days after cessation of phenylbutazone treatment were unremarkable in both cases., Clinical Relevance: Given the known adverse effects of NSAID treatment in several species, phenylbutazone and its metabolites were suspected to have caused ulceration of the urinary bladder, resulting in hematuria, in the 2 horses. A definitive cause of urinary bladder ulceration was not confirmed in these cases; however, resolution of ulceration after discontinuation of phenylbutazone treatment and administration of synthetic prostaglandins and exclusion of other causes suggested an association between phenylbutazone administration and ulcerative cystitis in these horses.

Sixty-seven million pounds of horsemeat derived from American horses were sent abroad for human consumption last year. Horses are not raised as food animals in the United States, and mechanisms to ensure the removal of horses treated with banned substances from the food chain are inadequate at best. Phenylbutazone (PBZ) is the most commonly used non-steroidal anti-inflammatory drug (NSAID) in equine practice. Thoroughbred (TB) race horses like other horse breeds are slaughtered for human consumption. Phenylbutazone is banned for use in any animal intended for human consumption because it causes serious and lethal idiosyncratic adverse effects in humans. The number of horses that have received phenylbutazone prior to being sent to slaughter for human consumption is unknown but its presence in some is highly likely. We identified eighteen TB race horses that were given PBZ on race day and sent for intended slaughter by matching their registered name to their race track drug record over a five year period. Sixteen rescued TB race horses were given PBZ on race day. Thus, PBZ residues may be present in some horsemeat derived from American horses. The permissive allowance of such horsemeat used for human consumption poses a serious public health risk., (Published by Elsevier Ltd.)

Necrotising fasciitis can be life threatening, requiring prompt diagnosis and surgical debridement. We report a case of necrotising fasciitis caused by an adulterate traditional Asian medication--Jamu Pegal Linu, containing toxic levels of phenylbutazone and dipyrone. The patient presented with severe neutropenia and sepsis. An urgent extensive debridement was carried out (within 6 hours of presentation). Repeated debridements were performed on days 2 and 5, augmented with antibiotics and granulocyte colony-stimulating factor.

A 15 year old Oldenburger gelding was treated during 3 weeks for laminitis with the anticoagulant phenprocoumone (27 mg orally, once daily) and concurrent administration of phenylbutazone (2-4 g orally, twice daily). After this treatment the animal was presented to the Equine Clinic University of Zurich with a history of acute colic and advanced symptoms of shock. On the basis of the clinical signs and laboratory values, a diagnosis of combined drug induced coagulopathy was made. The horse was treated with the antidote Vitamine-K1 (0.5 mg/kg, subcutaneously). Eventually, the general condition of the animal worsened and it was therefore euthanized. Necropsy revealed profound, multifocal hemorrhagic diathesis of the serosal surface of the viscera, as well as bleeding into the visceral cavities. This case shows that concurrent administration of phenprocoumone and phenylbutazone may lead to drug interactions that increase the anticoagulation effect of the coumarine-derivative. Simultaneous use of coumarine-derivatives and phenylbutazone is therefore contraindicated due to the higher risk of bleeding. A reasonable treatment of horses with anticoagulants requires regular monitoring with constant evaluation of coagulation status and special attention to potential drug interactions.

Objective: To compare efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis., Design: Randomized controlled clinical trial., Animals: 253 client-owned horses with naturally occurring osteoarthritis., Procedures: Horses were treated with firocoxib (0.1 mg/kg [0.045 mg/lb], PO, q 24 h) or phenylbutazone (4.4 mg/kg [2 mg/lb], PO, q 24 h) for 14 days. Physical examinations and lameness evaluations were performed prior to treatment and after 7 and 14 days. Clinical improvement was defined as a reduction of at least 1 lameness grade or a combined reduction of at least 3 points in scores for pain during manipulation or palpation, joint swelling, joint circumference, and range of motion., Results: Proportion of horses clinically improved on day 14 for the firocoxib group (104/123 [84.6%]) was not significantly different from the proportion for the phenylbutazone group (103/119 [86.6%]). Proportion of horses that were improved on day 14 was significantly greater for horses treated with firocoxib than for horses treated with phenylbutazone with regard to score for pain on manipulation or palpation (P = 0.028), joint circumference score (P = 0.026), and range of motion score (P = 0.012), but not for overall lameness score or joint swelling score. No direct treatment-related adverse effects were detected during the study., Conclusions and Clinical Relevance: Results suggested that overall clinical efficacy of a paste formulation of firocoxib in horses with naturally occurring osteoarthritis was comparable to efficacy of a paste formulation of phenylbutazone.

Objective: To assess effects of treatment with phenylbutazone (PBZ) or a combination of PBZ and flunixin meglumine in horses., Animals: 24 adult horses., Procedure: 13 horses received nonsteroidal antiinflammatory drugs (NSAIDs) in a crossover design. Eleven control horses were exposed to similar environmental conditions. Treated horses received PBZ (2.2 mg/kg, PO, q 12 h, for 5 days) and a combination of PBZ and flunixin meglumine (PBZ, 2.2 mg/kg, PO, q 12 h, for 5 days; flunixin meglumine, 1.1 mg/kg, IV, q 12 h, for 5 days). Serum samples were obtained on day 0 (first day of treatment) and day 5, and total protein, albumin, and globulin were measured., Results: 1 horse was euthanatized with severe hypoproteinemia, hypoalbuminemia, and colitis during the combination treatment. Comparisons revealed no significant difference between control horses and horses treated with PBZ alone. There was a significant difference between control and treated horses when administered a combination of PBZ and flunixin meglumine. Correction for horses with values >2 SDs from the mean revealed a significant difference between control horses and horses administered the combination treatment, between control horses and horses administered PBZ alone, and between horses receiving the combination treatment and PBZ alone. Gastroscopy of 4 horses revealed substantial gastric ulcers when receiving the combination NSAID treatment., Conclusions and Clinical Relevance: Analysis of results of the study indicates the need for caution when administering a combination NSAID treatment to horses because the detrimental effects may outweigh any potential benefits.

Objective: To determine whether ultrasonography would be useful in the diagnosis of right dorsal colitis in horses., Design: Retrospective study., Animals: 5 horses with right dorsal colitis and 15 healthy adult horses., Procedure: Mural thickness and appearance of the right dorsal colon were determined from ultrasonographic images obtained at right intercostal spaces 10, 11, 12, 13, and 14., Results: The right dorsal colon could be imaged most consistently at the right 11th, 12th, and 13th intercostal spaces, below the margin of the lung and axial to the liver. Mural thickness measured from ultrasonographic images was significantly greater in horses with right dorsal colitis than in healthy horses. The right dorsal colon in affected horses had a prominent hypoechoic layer associated with submucosal edema and inflammatory infiltrates. Successful treatment of 1 horse with right dorsal colitis was associated with a decrease in mural thickness coincident with an increase in serum albumin and total protein concentrations and weight gain. A decrease in mural thickness was also observed in a second horse treated for right dorsal colitis that was not associated with healing of the right dorsal colon or an increase in serum albumin concentration but rather thinning of a segment of the right dorsal colon that eventually ruptured., Conclusions and Clinical Relevance: Results suggest that ultrasonographic measurement of mural thickness and evaluation of the appearance of the right dorsal colon may be useful in the diagnosis of right dorsal colitis in horses.

Photosensitivity reactions due to non-steroidal anti-inflammatory drugs (NSAID) are well-known side-effects of these agents and are usually attributed to ultraviolet (UV) radiation. Eight NSAID (carprofen, diclofenac, ibuprofen, ketoprofen, naproxen, piroxicam, phenylbutazone, tiaprofenic acid) were assessed in a photohemolysis test for phototoxic effects in the visible light range. For the studies an experimental visible light lamp was used, emitting 5% UVA at most. To control for UVA-induced effects, additional samples were exposed to appropriate UVA doses from an UVA source and as well to the visible light lamp while being covered by a GG 400 or GG 420 filter. Photo-induced hemolysis was found after exposure to the visible light lamp with carprofen, ketoprofen, naproxen, piroxicam, phenylbutazone or tiaprofenic acid; diclofenac or ibuprofen did not cause photohemolysis. Control irradiation with UVA induced minor hemolysis only with carprofen, ketoprofen and tiaprofenic acid. When the samples were exposed to the filtered visible light lamp, using the GG 400 filter, photohemolysis was found with carprofen, naproxen and phenylbutazone and, using the GG 420 filter, with carprofen and phenylbutazone. Phototoxic effects induced by visible light may be of importance with regard to clinical photosensitization.

Right dorsal colitis in horses has been associated with administration of phenylbutazone. Although reports of right dorsal colitis in this species have described surgical treatment associated with a poor prognosis, we have had success treating this condition medically. This report describes 5 horses with right dorsal colitis confirmed during celiotomy that were initially managed medically. All horses had a history of intermittent abdominal pain; weight loss was noted in only 1 horse. The doses (2.0 to 4.6 mg/kg PO bid) and duration (5 to 30 days) of administration of phenylbutazone were not unusually high relative to those recommended (4.4 mg/kg PO bid). Hypoproteinemia and hypoalbuminemia were observed in all horses at the time of admission; packed cell volume was low in 4 horses, and hypocalcemia was also observed in 4 horses. Three of 5 horses (60%) appeared to respond to dietary management and discontinuation of administration of nonsteroidal anti-inflammatory drugs. Dietary management consisted of feeding pelleted feed, and restricting or eliminating roughage for a period of at least 3 months. Two horses developed strictures of the right dorsal colon. One horse that developed a colonic stricture, possibly because its owners did not comply with recommendations for management, was subsequently treated surgically. The remaining horse that developed a stricture of the right dorsal colon was euthanized. These data indicate that some horses with right dorsal colitis can be successfully managed with medical treatment.

Moderate to severe ulcerative colitis of the right dorsal colon was diagnosed by necropsy or by exploratory celiotomy and biopsy in 13 horses with a primary clinical complaint of either colic, diarrhea, or weight loss. Clinical signs varied from acute fulminating diarrhea (possibly with fever), colic, dehydration, endotoxic shock and death, to a chronic condition manifested by mild intermittent colic up to several months in duration, and weight loss with or without mild diarrhea. In a large percentage of the horses, those affected had been hypovolemic and received nonsteroidal anti-inflammatory drugs (NSAID) or had received inappropriately high doses of phenylbutazone before the onset of illness. Experimental treatment of two horses with high doses of a phenylbutazone oral paste preparation (6 gm once daily for 5 days) and limitation of their water intake to approximately one half of maintenance requirement (for 5 days) resulted in reproduction of ulcerative colitis involving only the right dorsal colon, which was apparent at necropsy examination 11 and 15 days after initiation of drug use. It was concluded that localized ulcerative lesions in the right dorsal colon may be a previously unreported manifestation of toxicity due to the administration of NSAID.

The human population may be exposed to potentially leukemogenic agents, either in the form of drugs and food additives or as environmental contaminants and pollutants. However, in spite of the large number and diversity of these chemicals, only a few have been implicated as human leukemogens. One such agent is benzene, a known bone marrow depressant. A number of case reports have associated chronic exposure to this agent with the development of acute leukemia, as have several epidemiologic surveys. Treatment with various antitumor agents, including procarbazine, melphalan, thio-TEPA, chlorambucil, and cyclophosphamide, has also been associated with the development of acute leukemia. In addition, chloramphenicol and phenylbutazone have been implicated as human leukemogens, but the association between exposure to these two agents and acute leukemia appears at present to be weaker than it is for benzene and antitumor agent exposure. Despite such associations between exposure to chemicals and acute leukemia, several important problems exist with regard to implicating specific agents in the development of this neoplasm in man, including the paucity of animal models for chemically induced leukemia, and the frequent necessity to rely on single case reports or clusters of cases in which chemical exposures are associated with acute leukemia. Future efforts should be directed at performing properly designed and well executed epidemiologic studies, and at developing new in vitro and in vivo models for the study of this neoplasm.

The histories of 269 patients whose death certificates did not mention a drug as the cause of aplastic anaemia or agranulocytosis were investigated. Eighty-three deaths were probably caused by drugs, the most common cause of aplastic anaemia being treatment with phenylbutazone (28 deaths) and oxyphenbutazone (11 deaths). Thirteen out of 17 deaths from agranulocytosis were attributed to co-trimoxazole treatment. A separate survey of general practitioners' prescriptions enabled the mortality to be estimated. With the addition of one death due to oxyphenbutazone and four deaths due to phenylbutazone that were reported independently to the committee, the mortality from oxyphenbutazone was 3-8 per 100 000 and from phenylbutazone 2-2 per 100 000. With phenylbutazone the rates varied from under 1 death per 100 000 for men aged under 65 years to 6 per 100 000 for women aged 65 and over. Small numbers precluded estimates for oxyphenbutazone in these subgroups, although a similar trend was suggested. No particular indication for treatment seems to carry a higher risk, the main concern being the use of these two drugs in elderly patients.

Two studies on 41 patients with osteoarthrosis of the hip or knee have shown fenoprofen-a compound with analgesic and anti-inflammatory properties-to be an effective addition to the drug treatment of these conditions. It was found to be superior to paracetamol but no statistically significant difference was shown in a comparison with phenylbutazone.

A double-blind cross-over study is described in which ketoprofen (Orudis) is compared with phenylbutazone in 14 patients with ankylosing spondylitis. Results indicated a significant patient preference for phenylbutazone with greater improvement in the ESR. However, the absence of objective and laboratory deterioration with ketoprofen, when compared with the initial, or control, assessments, suggests that it may prove a useful alternative to phenylbutazone in spondylitic disease.

Thirty-five cases of renal medullary crest necrosis morphologically similar to the renal papillary necrosis of analgesic nephropathy as described in man and rats are reported in horses receiving maintenance dosages of phenylbutazone. The primary lesion is a well-demarcated focal medullary necrosis resulting in sequestration of fragments of the renal crest. Renal cortical lesions are considered secondary to the medullary necrosis and consist of segmental pallor as a result of tubular dilatation, filtrate retention, and interstitial edema. Ischemia in concert with phenylbutazone is suggested as the etiology. Renal medullary crest necrosis is presented as more appropriate morphological terminology for this lesion in the equine species than renal papillary necrosis as is used in man and rats.

Effects of a newly synthesized compound, N-acetyl-L-carnosine aluminum (CL-1700), on the formation of various types of acute gastric lesions were studied in rats. CL-1700 at 300 or 1,000 mg/kg (p.o.) significantly inhibited Shay ulcers and water-immersion stress- and aspirin-induced erosions in pylorus-ligated rats, and indomethacin- or phenylbutazone-induced erosions. CL-1700 had a weak effect on water-immersion stress-induced erosions in rats with an intact pylorus. CL-1700 at 100 or 300 mg/kg (i.p.) significantly inhibited Shay ulcers and water-immersion stress-induced erosions in rats with an intact pylorus. However, this compound (i.p.) had no effect on aspirin- and indomethacin-induced gastric erosions. CL-1700 at 1,000 mg/kg (i.d.) significantly reduced the gastric acid output in pylorus-ligated rats but at 300 or 1,000 mg/kg (p.o.) increased the volume, pepsin output and raised the pH value. The effects of CL-1700 on experimental gastric lesions were slightly weaker than those of aluminum sucrose sulfate but almost equal to or better than those of cimetidine. However, the effects of CL-1700 were much more potent than those of gefarnate. As CL-1700 appears to be a promising new anti-gastric lesion agent, the mechanisms of action are now under investigation.

The fifteenth quarterly clinicopathological conference was held at the Royal College of Physicians of London on 29 July 1976. The conference was chaired by Professor Sheila Sherlock (1). She began by introducing Professor Jean-Pierre Benhamou (2), professor of gastroenterology at the Beaujon-Clichy Hospital, University of Paris, who was to open the discussion of the case. Professor Sherlock emphasised that this case had no great dénouement but was more a talking point for various aspects of hepatology, a review of the state of the art. Dr James Scott (3) presented the case, and Dr R Dick (4) described the radiological findings.

Three patients developed a haemorrhagic eruption on the hands after taking phenylbutazone. The reaction appeared within two weeks of taking the drug and is probably an allergic capillaritis. All patients showed generalised capillary fragility with a positive Hess test which became negative within a week of stopping the drug. A mechanism is suggested for the development and distribution of the blisters.

A survey of 763 patients with rheumatoid arthritis and 145 with osteoarthritis in six clinics in New Zealand showed no association between aspirin intake and a score designed to detect analgesic nephropathy. Analgesic nephropathy was diagnosed clinically in three patients taking APC (aspirin, phenacetin, and caffeine or codeine or both) and in one who took aspirin and phenylbutazone and was suspected in one who took aspirin and paracetamol. Isolated aspirin was not implicated. The study showed that most people can take large quantities of salicylates without renal injury.The findings are, however, consistent with the view that there is a risk from APC compounds taken in large quantity, but the numbers at risk in this study were small. Aspirin may have an additive effect with other analgesics in causing renal damage. An increased frequency of urinary tract symptoms in those taking analgesics requires further investigation.

A total of 125 patients with rheumatoid arthritis were investigated about their drug therapy before referral to a specialist centre. Most referrals were from general practitioners. Only 47 of the patients had received salicylates as the first drug and 18 had never had them at all. Soluble aspirin was the preparation of salicylates most frequently prescribed (for 63 patients). Only 60 patients had been given an adequate dose and only 62 an adequate course of treatment with salicylates. In 28 patients salicylates had been stopped on account of side effects. About one-third of the patients had been prescribed oral corticosteroids.The referral letters were poor in giving details of past and present drug therapy, and there were serious omissions in reporting of previous side effects.Seventy-five general practitioners were asked to rate several currently marketed antirheumatic drugs in terms of effectiveness. Though prednisolone 15 mg daily ranked higher than aspirin 4 g daily the difference was not significant. The study shows the inadequacies of drug prescribing for rheumatoid arthritis in the Glasgow area.

A previously healthy woman developed severe, periodic neutropenia after ingestion of phenylbutazone. Oscillations in the monocyte count and hemoglobin concentrations also occurred. The neutropenic episodes were associated with severe bacterial infections requiring hospitalization. Lithium induced a transient interruption in the neutropenia, but continued use was ineffective. Prednisone in a dosage of 100 mg daily successfully interrupted the neutrophil cycling and prevented infection. The patient has remained in remission on 10 mg of prednisone on alternate days.

A register of reported adverse reactions, recently made available to major hospitals and medical schools gives an indication of prescribing habits under the N.H.S. in England and Wales. An analysis is made here of the chief medicaments allegedly leading to death. Such data are incomplete because of lack of knowledge of the total use of each drug in the United Kingdom and because reporting of adverse reactions is very incomplete. Nevertheless, data about various groups of drugs do draw attention to some hazards and should encourage more widespread reporting of reactions to drugs and other medicaments.

Acetanilide like phenylbutazone is paraoxidized by the liver endoplasmic reticulum as a primary biotransformation step. Both compounds were given at different times to each of 10 healthy volunteer subjects and the plasma disappearances measured. Correlation was shown between plasma clearance values of the two compounds (r = + 0.7067; P < 0.05).Eight patients with hypoplastic anaemia after phenylbutazone therapy were investigated. Plasma clearance values and half lives of acetanilide were measured in this group of patients and compared with those of a group of 30 healthy volunteer controls. There was a significant decrease in clearance (P < 0.01) and lengthening of half lives (P < 0.001 in the patients with phenylbutazone-associated hypoplasia. Five patients with idiopathic aplastic anaemia-that is, without history of antecedent phenylbutazone ingestion-were similarly investigated with acetanilide and there was no significant difference between the results in these patients and those in the control group.It is suggested that relatively poor paraoxidation of phenylbutazone producing high blood concentrations on a given dose may be a factor responsible for the drug-associated hypoplasia even though it does not explain the similar pattern of adverse reactions reported in association with oral administration of the metabolite oxyphenbutazone.