Many researchers have attempted to resolve the problems associated with the claims that generic drugs are therapeutically inactive. The objective of this study was to investigate one drug - phenylbutazone - and to determine the overall quality of 23 brands of this drug on the Canadian market. Potency, content uniformity and availability of the drug from the dosage form were investigated. A spectrophotometric method suitable for the analysis of individual phenylbutazone .tablets was developed. This method involved the extraction of the drug from the tablets with alcohol, appreciate dilution with distilled water and spectrophotometric analysis of the aqueous solution. The dissolution and disintegration characteristics of twelve products were studied by two different methods. The official disintegration test described in the Food and Drugs Regulations and a stirrer method similar to that outlined by Levy and Hayes (31) were used. The results of individual tablet assay showed that four products would be rejected on the basis of potency or content uniformity. Two other products, although complying with official requirements, would appear to show questionable characteristics. Two products would be rejected on the basis of disintegration times while six others demonstrated excessive variability in their disintegration characteristics. The official disintegration apparatus was rejected for dissolution studies. A modified version of the apparatus described by Levy and Hayes (31) was considered adequate for this investigation. The dissolution profiles indicated that one product would be classified as "excellent"; seven as "good" and four as "poor" with respect to drug release in vitro. Preliminary studies indicate that there may be a definite correlation between in vitro dissolution and in vivo availability (as measured by drug content in the blood). This abstract represents the true content of the thesis submitted. / Pharmaceutical Sciences, Faculty of / Graduate

Thesis (Ph. D.)--Oregon State University, 2004. / Printout. Includes bibliographical references. Also available on the World Wide Web.

In this study the metabolism of the anti-arthritic drug, phenylbutazone, was investigated in female Wistar rats, and the results compared with those of other workers in this field. Two interrelated projects were undertaken. The first covered the pattern of excretion, isolation and characterisation of the metabolites and decomposition products of phenylbutazone in rats dosed post-orally with the drug. It was found that the major route of excretion was via the urine and over 50% of the administered dose was excreted in the first 24 hours by this route. A small percentage of the dose was excreted in the faeces. The following compounds were identified using chromatographic and autoradiographic techniques: p-Hydroxy derivative of phenylbutazone γ-Hydroxy derivative of phenylbutazone in both its molecular forms (ring lactone and straight chain hydroxyl) 4-Hydroxy derivative of phenylbutazone p-γ-Dihydroxy derivative of phenylbutazone p-4-Dihydroxy derivative of phenylbutazone Hydrolysable conjugates (possibly glucuronides) Water soluble non-hydrolysable conjugates. The second project dealt with the quantitation of the water insoluble compounds isolated in the initial work. Using a unique technique, combining inverse isotope dilution assay and spectrophotometric analysis, it was found that the major metabolite was the γ-hydroxy derivative of phenylbutazone, present in both its molecular forms. Oxyphenbutazone was a minor metabolite and the p-γ-dihydroxy derivative of phenylbutazone was present only in very low concentration. These results did not conform with those of previous workers in this field who reported the γ-hydroxy derivative of phenylbutazone, in one molecular form only, as the major metabolite and the dihydroxy derivative as the second metabolite with a higher concentration in the urine than oxyphenbutazone. This disparity could be due to the fact that these workers took no account of the presence of the two molecular forms of the γ-hydroxy derivative of phenylbutazone with their different polarities and different Rf values. The present study showed that the straight chain hydroxyl isomer was probably mistakenly identified as the p-γ-dihydroxy derivative of phenylbutazone. This theory is supported by the fact that the percentage dose recovered by the previous workers of the γ-hydroxy and p-γ-dihydroxy derivatives together equalled the percentage dose recovered in this study of the two molecular forms of the γ-hydroxy derivative. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

A completely automatic continuous flow dissolution procedure was developed and tested. Pertinent dissolution conditions were investigated and chosen to study the dissolution characteristics of seven brands of phenylbutazone tablets. A pumping system enabled the simulated digestive fluid to flow from the dissolution vessel into the flow cell of a recording spectrophotometer for a continuous recording of the drug concentration in the dissolution medium, which was gradually changed from an acidic medium to a basic one. From the "in vitrott” data obtained by this test procedure, a T₅₀% value of 120 minutes was chosen as a limit of acceptance for the test products. The "in vivo" characteristics of six of the brands were compared with those observed for a pharmaceutically acceptable product. Of the seven test products, only four were acceptable on the basis of both the "in vitro" and the "in vivo" data. Correlation of the "in vitro" and the "in vivo" data resulted in "least squares" lines with negative slopes. / Pharmaceutical Sciences, Faculty of / Graduate

Phenylbutazone was first synthesized in 1946 by H. Stenzyl during his investigation on pyrazole and pyrazoline derivatives. Although these compounds had been studied during the previous fifty years, the pharmacological properties were only recently recognized. It has been used clinically since 1952. Two other pharmaceutical agents of the pyrazole group are phenazone and amidopyrine; these were used as early as the nineteenth century. While phenazone and aminopyrine have basic properties, phenylbutazone exhibits distinctly acidic ones and is capable of forming salts with organic and inorganic bases. In order to achieve a more basic understanding of how phenylbutazone produces effects, the following brief survey of the work that has been done with this compound is presented.

No description available.

Thesis (MAppSc in Pharm) -- University of South Australia, 1993

A utilização do tramadol por via sistêmica é uma ótima opção no tratamento analgésico pós-operatório em outras espécies, promovendo analgesia satisfatória e de duração moderada com mínimos efeitos colaterais. Entretanto, os efeitos do emprego deste fármaco na espécie eqüina ainda são pouco conhecidos, bem como sua real aplicação, pois faltam estudos clínicos nesta espécie. Portanto, este estudo teve o intuito de comparar a ação analgésica da administração de tramadol, fenilbutazona, ou ambas combinações em cavalos submetidos à cirurgias de artroscopia. Avaliou-se o efeito analgésico através da escala numérica de dor, escala descritiva composta, escala facial e escala proposta por Lascelles. Foram também avaliadas as alterações na freqüência cardíaca, freqüência respiratória, alterações de motilidade gastrointestinal, recuperação anestésica, bem como os níveis sérico de cortisol, TNF-α, IL-1Ra, e IL-10. Foram utilizados 18 animais provenientes do Serviço de Cirurgia do Hospital Veterinário da Universidade de São Paulo. Estes animais foram distribuídos em 3 grupos de forma aleatória, com 6 animais em cada grupo. Os animais receberam os analgésicos antes do estímulo cirúrgico, o grupo T recebeu tramadol, na dose de 2 mg/kg pela via intravenosa, o grupo F recebeu fenilbutazona, na dose de 4,4 mg/kg pela via intravenosa e o grupo TF recebeu a associação de ambos os fármacos. Os parâmetros FC, FR, temperatura, motilidade intestinal e analgesia foram avaliados por 6 horas. Os resultados foram analisados estatisticamente pelos testes de Kruskal-Wallis, Friedman, ANOVA, e ao pós teste de Tukey, com nível de significância de 5%. Não houve diferença entre os tratamentos em relação ao peso, idade, tempo cirúrgico, escore de recuperação anestésica, FC, FR, temperatura, motilidade gastrointestinal, dosagem sérica de cortisol e citocinas, e nas escalas de avaliação de dor. Com base nos resultados obtidos, pôde-se concluir que o tramadol, a fenilbutazona e a associação tramadol-fenilbutazona promoveram analgesia de boa qualidade no pós-operatório de artroscopia em cavalos; o tramadol na dosagem de 2 mg/kg mostrou eficácia analgésica semelhante à fenilbutazona; e não foram observado efeitos adversos relacionados aos parâmetros fisiológicos durante o período do estudo. / The use of tramadol systemically is a great option for treating postoperative pain in other species, providing satisfactory analgesia with moderate duration and minimal side effects. However, the effects of this drug in horses are still poorly understood, and also its application, because clinical trials are lacking in this species. Therefore, the present study aimed to compare the analgesic effect of tramadol, phenylbutazone, or both combinations in horses undergoing arthroscopic surgery. The analgesic effect was evaluated using numeric pain scale, descriptive composite pain scale, facial scale and the scale proposed by Lascelles. Changes in heart rate, respiratory rate, gastrointestinal motility, anesthesia recovery, and the serum levels of cortisol, TNF-α, IL-1Ra, and IL-10 were also evaluated. Eighteen animals from the Department of Surgery of the Veterinary Hospital at the University of São Paulo were used. These animals were divided into 3 groups randomly, with 6 animals in each group. The animals received analgesics before surgical stimulus, group T received tramadol, 2 mg/kg intravenously, group F received phenylbutazone, 4,4 mg/kg intravenously, and group TF received the combination of both drugs. The parameters HR, temperature, motility and analgesia were assessed for 6 hours. The results were statistically analyzed by the tests Kruskal-Wallis, Friedman, ANOVA and Tukey post test, with significance level of 5%. There was no difference between treatments in relation to weight, age, duration of surgery, anesthetic recovery score, HR, temperature, gastrointestinal motility, serum cortisol and cytokines, and the rating scales of pain. Based on these results, we conclude that tramadol, phenylbutazone and tramadol-phenylbutazone promoted good analgesia in arthroscopy postoperative period in horses; tramadol dosage of 2 mg/kg presented similar analgesic efficacy to phenylbutazone, and there was no adverse effect related to physiological parameters during the study period.

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H.P.M.C.) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The δ-form, the commercially available stable form and the α and β metastable forms (nomenclature after Muller, 1978) were isolated. The α form was found to be unstable on storage. A 2 fold increase in intrinsic dissolution rate was observed for the metastable β-polymorph compared with the stable δ-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H.P.M.C. and poloxamer 188, were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H.P.M.C. was found to form a "high energy" complex with phenylbutazone which melted 10°C lower than the parent drug. When prepared by spray drying H.P.M.C. inhibited the formation of the metastable β-polymorph of phenylbutazone. A 2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex with phenylbutazone and unlike H.P.M.C. did not inhibit the formation of the β-polymorph. For both crystallised and spray dried samples a 3 fold increase in dissolution rate was obtained at polymer levels of 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of selected phenylbutazone:polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compaction of phenylbutazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (δ-form), samples of spray dried phenylbutazone (β-form) and samples containing different concentrations of H.P.M.C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H.P.M.C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H.P.M.C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H.P.M.C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples.

Made available in DSpace on 2014-06-11T19:31:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-08-02Bitstream added on 2014-06-13T20:21:55Z : No. of bitstreams: 1 bopp_s_dr_jabo.pdf: 2368102 bytes, checksum: ca8aa928b7d82169029b655fe0d9d7df (MD5) / Os equinos apresentam predisposição elevada às lesões do sistema locomotor desenvolvendo, em consequência disso, respostas inflamatória e álgica. O anti-inflamatório não esteroidal fenilbutazona é um dos fármacos mais utilizados no tratamento da inflamação e da dor músculo-esquelética nos equinos. Objetivou-se com este estudo avaliar os efeitos clínicos da administração em dose única de fenilbutazona nas doses de 2,2, 4,4 ou 16,6 mg/kg por via intravenosa em equinos submetidos à claudicação experimental reversível induzida por dois parafusos fixados à ferradura, ajustados para exercerem pressão solear e, consequentemente, causar desconforto e claudicação controlada. Por meio deste modelo, estudou-se a concentração plasmática da fenilbutazona e da oxifembutazona e a resposta clínica de seis equinos adultos, saudáveis submetidos a três doses de fenilbutazona, em um intervalo de sete dias. Os parafusos foram apertados e ajustados para produzirem compressão solear capaz de induzir claudicação de grau 3 ou 4, segundo escala da AAEP, e foram mantidos por um período de 24h. Avaliou-se grau de claudicação, frequência cardíaca, frequência respiratória, pressão arterial sistólica, sons intestinais, concentração plasmática da fenilbutazona e oxifembutazona, parâmetros hematológicos e bioquímicos. As três doses demonstraram eficácia clínica, sem produção de efeitos adversos. A concentração plasmática da fenilbutazona e da oxifembutazona foi diretamente proporcional à dose aplicada, entretanto o aumento da dose não aumentou a eficácia, haja vista que não houve diferença entre os tratamentos com fenilbutazona na redução do grau de claudicação / Horses present high predisposition to lesions in the locomotor system and consequent development of inflammatory and pain responses. Nonsteroidal anti-inflammatory phenylbutazone is one of the most used drugs in the treatment of inflammation and musculoskeletal pain in horses. The aim of this study was to evaluate the clinical effects of single intravenous administration of phenylbutazone in doses of 2.2, 4.4 or 16.6 mg/kg in horses submitted to experimental reversible lameness induced by two screws attached to horseshoe and adjusted to exert solar pressure and cause discomfort and controlled lameness. By this model, we studied plasma concentration of phenylbutazone and oxyphenbutazone and clinical response of six adult healthy horses submitted to three doses of phenylbutazone in an interval of seven days. Screws were tightened and adjusted to produce compression of the sole and induce lameness of third or fourth degree, according to the AAEP scale, staying in place for 24 hours. We have assessed lameness degree, heart rate, respiratory rate, systolic blood pressure, bowel sounds, plasma concentration of phenylbutazone and oxyphenbutazone, and hematological and biochemical parameters. All three doses of phenylbutazone demonstrated clinical efficacy without producing adverse effects. Plasma concentration of phenylbutazone and oxyphenbutazone was directly proportional to the applied dose, however the increase of dose did not increase its efficiency, since there was no difference between treatments with phenylbutazone in the reduction of the degree of lameness.