Suxibuzone Research Articles

Multicentre, controlled, randomised and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses

In horses, it has been demonstrated that suxibuzone (SBZ) has a lower gastric ulcerogenic effect than phenylbutazone (PBZ). However, no field trials have been reported comparing the efficacy of the drugs in alleviating lameness. To compare the therapeutic effect of SBZ to that of PBZ when administered orally in lame horses. Acceptability of both products was also compared. Lame horses (n = 155) were used in a multicentre, controlled, randomised and double-blinded clinical trial. Horses were treated orally with either SBZ or PBZ at equivalent therapeutic dosages. PBZ was given to 79 horses at a dose of 4.4 mg/kg bwt/12 h for 2 days, followed by 2.2 mg/kg bwt/12 h for 6 days. SBZ was given to 76 horses at 6.6 mg/kg bwt/12 h for 2 days, followed by 3.3 mg/kg bwt/ 12 h for 6 days. Efficacy of treatments was evaluated by clinicians in equine practices according to lameness progression throughout the study. Product ingestion was checked daily to evaluate product acceptability. Although SBZ showed a statistically significant tendency to have a better efficacy than PBZ (Odds ratio = 2.7; P = 0.016), significance dissipated once the analysis was adjusted for some imbalanced baseline covariates, confirming that they were actually related to the apparent advantage of SBZ over PBZ. Product acceptability was significantly higher in the SBZ group than in the PBZ group (96.1% vs. 77.2%; P = 0.001). SBZ and PBZ did not show significant differences in alleviating lameness in horses. However, SBZ had better product acceptability when administered orally with some food. SBZ is a good therapeutic alternative to PBZ in horses since there is no significant difference in alleviating lameness between the 2 therapies.

Rapid confirmatory analysis of non-steroidal anti-inflammatory drugs in bovine milk by rapid resolution liquid chromatography tandem mass spectrometry

A rapid method has been developed to analyse carprofen (CPF), diclofenac (DCF), mefenamic acid (MFN), niflumic acid (NIFLU), naproxen (NAP), oxyphenylbutazone (OXYPHEN), phenylbutazone (PBZ) and suxibuzone (SUXI) residues in bovine milk. Milk samples are extracted with acetonitrile and sample extracts were purified on Evolute™ ABN solid phase extraction cartridges. Aliquots were analysed by rapid resolution liquid chromatography tandem mass spectrometry (RRLC-MS/MS) with a runtime of 6.5 min. The method was validated in bovine milk, according to the criteria defined in Commission Decision 2002/657/EC. CCα values of 0.46, 1.08, 0.92, 1.26, 1.29, 2.12, 0.55 and 2.86 ng mL −1 were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. CCβ values of 0.79, 1.85, 1.56, 2.15, 2.19, 3.62, 0.94 and 4.87 ng mL −1 were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. The measurement uncertainty of the method was estimated at 9, 28, 28, 45, 46, 45, 10 and 39% for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI. Fortifying bovine milk samples ( n = 18) in three separate assays, show the accuracy of the method to be between 82 and 108%. The precision of the method, expressed as RSD values for the within-lab reproducibility at the three levels of fortification (5, 7.5 and 10 ng mL −1) was less than 16%, respectively. The advantage of the method is that low ng mL −1 levels can be detected and quantitatively confirmed rapidly in milk and that 3 batches of samples can be analysed within a single day using RRLC-MS/MS with a runtime of 6.5 min.

Lower gastric ulcerogenic effect of suxibuzone compared to phenylbutazone when administered orally to horses

The objective was to compare the gastrointestinal and general toxicity of suxibuzone (SBZ) to that of phenylbutazone (PBZ) when administered orally in horses. Fifteen healthy horses were allocated to three treatment groups. One group received a high dose of PBZ for two weeks; the second group was given an equimolecular dosage of SBZ; and a third group received placebo. Horses were daily monitored, and blood samples were collected before and during the study. On day 18, complete post-mortem examinations were performed. One horse treated with PBZ showed clinical signs of NSAID toxicosis. Small oral ulcers were also detected in other two horses from the PBZ group and in two horses from the SBZ group. There were no statistical differences in the blood parameters among groups. Ulcers in the stomach’s glandular mucosa were observed in all horses of the PBZ group, while only two horses of the SBZ group showed ulcerations. PBZ horses had a significant higher ulcerated area, and gastric ulcers were significantly deeper than those in the SBZ and placebo groups. No other lesions were found in any other tissue. In conclusion, SBZ causes significantly lower gastric ulcerogenic effect than PBZ when administered orally at equimolecular doses in horses.

Disposition and tolerance of suxibuzone in horses.

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.

Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses.

A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (< 0.04 microgram/mL). Plasma PBZ and OPBZ concentrations were detected between 30 min and 72 h after granulate and paste administration. Mean plasma concentration of PBZ peaked at 5 h (34.5 +/- 6.7 micrograms/mL) and at 7 h (38.8 +/- 8.4 micrograms/mL), and mean area under the concentration-time curve (AUC0-->LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.

The disposition of suxibuzone in the horse

A high performance liquid chromatographic method is described to determine the anti-inflammatory drug suxibuzone (SXB) and its major metabolites phenylbutazone (PBZ) and oxyphenbutazone (OPBZ) in equine plasma and urine. When suxibuzone (6 mg/kg) was administered intravenously (i.v.) or orally (p.o.) no parent drug was detected in plasma or in urine. The disposition of the metabolite PBZ (i.v.) could be described by a 2 compartment model with a beta half-life varying from 7.40 to 8.35 h. Due to severe side effects the use of i.v. suxibuzone should not be encouraged in the horse. PBZ and OPBZ were detected in plasma and urine after p.o. SXB administration. Peak plasma PBZ concentrations (8.8 +/- 3.0 micrograms/ml) occurred 6 h after oral dosing and the terminal exponential constant was 0.11 +/- 0.01 h-1. Phenylbutazone and oxyphenbutazone were detectable in urine (> 1 microgram/ml) for at least 36 h, after p.o. administration. SXB was not hydrolyzed in vitro by horse plasma. Equine liver homogenates however appeared to have a very high capacity for hydrolysing SXB, indicating that first-pass effect could be responsible for the rapid disappearance of this NSAID in the horse.

Promotion of hepatocarcinogenesis by suxibuzone in rats initiated with 3′-methyl-4-dimethylaminoazobenzene

Among phenylbutazone (PZ) and its related compounds, suxibuzone (SUX) caused the most extensive decrease in pyruvate kinase (PK) activity with lower toxicity. Therefore, we studied the effect of SUX on rat hepatocarcinogenesis to confirm our assumption that an agent which causes a prolonged decrease in PK activity in rat liver promotes hepatocarcinogenesis. For initiation rats were fed a diet containing 0.06% 3′-methyl-4-dimethylaminoazobenzene (3′-Me-DAB) for 4 weeks. At the end of 53 weeks of the experiment the incidences of liver tumors were 14.3 and 70.0% in the rats fed basal diet and in the rats fed 0.5% SUX diet, respectively, after the initiation. No tumors were observed in rats fed the SUX diet without the initiation. The result shows that SUX promotes hepatocarcinogenesis and supports the above assumption.

The biological fate of 4-butyl-4-(beta-carboxypropionyloxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione (suxibuzone), antiinflammatory drug. II. The biological fate of suxibuzone (SB) after daily oral administration (author's transl)

The biological fate of 4-butyl-4-(β-carboxypropionyloxymethyl)-1, 2-diphenyl-3, 5-pyrazolidinedione : suxibuzone (SB) was studied in rats and beagle dogs. Furthermore, the effects of SB on liver microsomal drug metabolizing enzyme systems in rats were compared with those of phenylbutazone (PB), after daily oral administration of SB or PB for 1 week. 1) The biological fate of SB was different in rats and dogs and in the former a sex difference was noted. 2) Liver microsomal drug metabolizing enzyme systems were induced especially in male. 3) No difference between the two drugs was noted. However, when a single oral dose of SB was administered, keeping the PB schedule the same as above, the plasma half-life of PB was markedly shortened and maximum plasma levels of metabolites were rapidly reached. These results suggest that the biological fate of SB was stimulated by the enhancement or induction of liver microsomal drug metabolizing enzyme systems due to PB and its metabolites after daily oral administration.

The Biological Fate of Suxibuzone V

The biological fate of suxibuzone (SB), a new non-steroidal anti-inflammatory agent, was studied in healthy male volunteers with single oral doses and compared with that of phenylbutazone (PB) by a cross-over test, with the following results:1) PB, oxyphenbutazone (Oxy-PB), and γ-hydroxy-phenylbutazone (γ-Hydroxy-PB) were identified in plasma after oral administration of SB. Moreover these metabolites, their glucuronides, SB-glucuronide, 4-hydroxymethyl-phenylbutazone (4-HM-PB)-glucuronide, and p, γ-dihydroxy-phenylbutazone (p, γ-DH-PB) were found in urine.2) Peak plasma concentration of the metabolites was obtained 4 hrs after a single oral dose of 426 mg of SB when the concentration of PB, the main metaboliteof SB, was 36μg/ml, much the same as the corresponding level in the volunteers receiving PB. On the other hand, there was no difference between volunteers receiving SB and PB interms of the concentration of Oxy-PB. But the concentration of γ-Hydroxy-PB was higher after oral SB than after oral PB.3) Urinary excretion of the metabolites was about 8% of the administered dose up to 16 8hrs after oral doses of SB or PB, but in the period shortly after oral doses of SB, Oxy-PB-glucuronide and γ-Hydroxy-PB were excreted to ag reater extent than after oral doses of PB.4) From these results in the plasma and urine after oral doses of SB, it was found that SB may be characterized as a prodrug of PB.5) During the experiment, no side effects or abnormalities were observed in the medical examination and laboratory test except for a slight decrease in the uric acid level in plasma.