Estudio Comparativo de la Efectividad Antiinflamatoria Postoperatoria al usar Dexametasona Endovenoso Versus Ketoprofeno Endovenoso previo a la exodoncia de terceros Molares Mandibulares Incluidos

RESUMEN: La exodoncia de terceros molares incluidos conlleva la mayoría de las veces un cuadro inflamatorio agudo, dolor postoperatorio y trismus. En la actualidad, se han propuesto diversos protocolos farmacológicos con el fin de prevenir estas complicaciones, donde los más utilizados son los analgésicos y corticoides. Comparar Dexametasona y Ketoprofeno endovenoso previo a la cirugía de terceros molares mandibulares incluidos, en el control del edema, dolor y trismus. Se realizó un estudio experimental, analítico de corte transversal, autorizado por el comité de ética de la Universidad Andrés Bello. Se escogieron 30 sujetos que requerían exodoncia de terceros molares mandibulares incluidos, de forma aleatoria 15 sujetos recibieron Dexametasona 4 mg endovenoso y 15 Ketoprofeno 200 mg endovenoso 30 minutos antes de la intervención. El procedimiento quirúrgico fue estandarizado, se evaluó el edema facial, trismus y dolor postquirúrgico a los 2 y 7 días terminada la cirugía. Se presentó una diferencia estadísticamente significativa solo en 2 mediadas faciales, de las 5 tomadas, al comparar el porcentaje de edema a los 7 días postoperatorias entre ambos grupos experimentales. La mayoría del grupo Dexametasona presentó un edema de mayor volumen en comparación al grupo Ketoprofeno. En relación al dolor y trismus, sólo se observan diferencias significativas en la intensidad del dolor evaluada a los 7 días, siendo mayor en el grupo Ketoprofeno. En las otras variables medidas, la presencia de odontosección en la cirugía generó una diferencia estadísticamente significativa, siendo mayor el edema en los que se les realizó odontosección. Esta diferencia se vio principalmente en el grupo Ketoprofeno evaluado a los 2 días postoperatorios. El uso de cualquiera de los 2 fármacos está bien indicado para aliviar el dolor e inflamación en este tipo de cirugía. Pese a que el grupo tratado con Dexametasona presentó menor dolor, no fue una diferencia significativa en comparación al grupo con Ketoprofeno.

ABSTRACT: The extraction of included third molars most of the time involves an acute inflammatory picture, postoperative pain and trismus. At present, various pharmacological protocols have been proposed in order to prevent these complications, where the most widely used are analgesics and corticosteroids. Compare Dexamethasone and Ketoprofen used intravenously prior to surgery of mandibular third molars included, in the control of edema, pain and trismus. An experimental, analytical, cross- sectional study was carried out, authorized by the ethics committee of the Andrés Bello University. Thirty subjects who required extraction of included mandibular third molars were chosen, 15randomly received intravenous Dexamethasone 4 mg and 15 intravenous Ketoprofen 200 mg 30 minutes before the intervention. The surgical procedure was standardized, facial edema, trismus and postoperative pain were evaluated at 2 and 7 days after the surgery. There was a statistically significant difference only in 2 facial measures, of the 5 taken, when comparing the percentage of edema at 7 postoperative days between both experimental groups. Most of the Dexamethasone group had a larger volume ede- ma compared to the Ketoprofen group. In relation to pain and trismus, significant differences were only observed in the intensity of pain evaluated at 7 days, being greater in the Ketoprofen group. In the other variables measured, the presence of a dental section in the surgery generated a statistically significant difference, with the edema being greater in those who underwent a dental section. This difference was mainly seen in the Ketoprofen group evaluated at 2 postoperative days. The use of any of the 2 drugs is well indicated to alleviate the pain and inflammation of the patient generated by the trauma caused by this type of surgery. Although the group treated with Dexamethasone presented less pain, it was not a significant difference compared to the group with Ketoprofen.

Profilaxia da pancreatite pós-colangiopancreatografia retrógrada endoscópica: avaliação de dois regimes com AINEs diferentes / Post endoscopic retrograde cholangiopancreatography pancreatitis prophylaxis: evaluation of two different nsaid regimens

ABSTRACT BACKGROUND: Endoscopic retrograde cholangiopancreatography is a widely used therapeutic modality for the pancreaticobiliary tree. However, it is responsible for the highest rates of complications among the endoscopic procedures, especially post-endoscopic retrograde cholangiopancreatography pancreatitis. The preventive methods include mechanical and pharmacological approaches, such as the use of non-steroidal anti-inflammatory drugs. OBJECTIVE: To compare the efficacy of two different strategies using non-steroidal anti-inflammatory drugs for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis, and to clarify the uncertainty about the route of administration of non-steroidal anti-inflammatory drugs in the prevention of this complication. METHODS: This was a prospective trial. Two therapeutic groups were compared with a control group that was composed of patients who underwent endoscopic retrograde cholangiopancreatography, performed in the same service and by the same team in the period preceding the study (historical series), without the administration of any type of prophylaxis. The first group received 100 mg rectal diclofenac. The second group received 100 mg intravenous ketoprofen. Both groups were compared, separately and jointly, with the control group. RESULTS: Post-endoscopic retrograde cholangiopancreatography pancreatitis occurred in 4.39% (12/273) of the participants. In the group without prophylaxis, the incidence was 6.89% (10/145). Among those who received intravenous ketoprofen, the incidence was 2.56% (2/78). No cases of acute post-procedural pancreatitis were observed in the group that received rectal diclofenac (0/52). Although there was no statistical difference between the therapeutic groups when they were separately analyzed, a statistical difference in the prevention of post-procedural pancreatitis was observed when they were analyzed together (P=0.037). CONCLUSION: This study provides evidence for the efficacy of non-steroidal anti-inflammatory drugs in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis.

RESUMO CONTEXTO: A colangiopancreatografia retrógrada endoscópica (CPRE) é uma modalidade terapêutica amplamente utilizada para vias biliopancreáticas, responsável pelas taxas mais elevadas de complicações entre os procedimentos endoscópicos, especialmente a pancreatite pós-CPRE (PPC). Os métodos preventivos incluem abordagens mecânicas e farmacológicas, entre elas, a utilização de antinflamatórios não esteroidais (AINEs). OBJETIVO: Comparar a eficácia de duas estratégias diferentes utilizando AINEs para a prevenção de PPC. Elucidar o cenário incerto sobre a via de administração do AINEs na prevenção da PPC. MÉTODOS - Ensaio clínico prospectivo. Duas estratégias terapêuticas foram comparadas a um grupo controle, composto por pacientes submetidos a CPRE no mesmo serviço e com a mesma equipe no período anterior ao estudo (série histórica), que não recebeu qualquer tipo de profilaxia. O primeiro grupo experimental recebeu 100 mg de diclofenaco via retal, o segundo grupo recebeu 100 mg de cetoprofeno endovenoso. Ambos os grupos foram comparados separadamente e em associação com o grupo de controle. RESULTADOS: A PPC ocorreu em 4,39% (12/273) dos participantes. No grupo sem profilaxia, esta incidência foi de 6,89% (10/145); entre os que receberam cetoprofeno endovenoso foi de 2,56% (2/78). Não houve casos de pancreatite aguda após o procedimento no grupo que recebeu diclofenaco via retal (0/52). Apesar de não haver diferença estatística entre estes grupos analisados separadamente, quando os dois grupos terapêuticos são analisados em conjunto estes apresentam diferenças estatísticas na prevenção da PPC (P=0,037). CONCLUSÃO: Este estudo foi capaz de corroborar a eficácia da utilização de AINEs para a profilaxia de pancreatite pós-CPRE.

Effect of flunixin or ketoprofen in caudectomy by elastration in lambs: pain and neutrophil function

ABSTRACT: Painful procedures can affect the function of innate immune cells, such as neutrophils and macrophages, increasing the risk of infectious diseases. The present work aimed to verify if the analgesics flunixin meglumine or ketoprofen can attenuate the pain/discomfort of newborn lambs submitted by elastration tail docking and thereby avoid the impairment of blood granulocytes function. Twenty-one neonate lambs were divided into three treatments: the control group (n=7), not subjected to caudectomy; the flunixin group (n=7), subjected to caudectomy under local anesthesia and analgesia with two doses of flunixin meglumine; and the ketoprofen group (n=7), subjected to caudectomy under local anesthesia and two doses of ketoprofen. Pain indicators were observed by pain posture score (PS), the number of vocalizations (V), frequency of the movement of the ears (EF), and respiratory rates (RR), observed by a 10 minutes videos for each time points: -15min, 6h, 48h, and 144h. At the same time points, the reactive oxygen species (ROS) production and phagocytosis of blood granulocytes were measured by flow cytometry. At 6h after caudectomy, there was a pain indicator increase (RR, V, and PS), a blood granulocyte percentage increase, and a granulocytes phagocytosis reduction for both groups. At 48h, the ketoprofen group spend more time in pain posture and, at 144h, they exhibited a ROS production granulocyte reduction without signs of pain. We conclude the flunixin meglumine and ketoprofen did not prevent the acute pain/discomfort caused by caudectomy, because the groups showed a pain behavior and impaired of the innate immune response however, the flunixin meglumine was effective in controlling the chronic pain and their effects on blood granulocytes function in compare ketoprofen.

RESUMO: Procedimentos dolorosos podem afetar a função das células imunes inatas como neutrófilos e macrófagos, aumentando o risco de ocorrer doenças infeciosas. Desta maneira, o presente trabalho pretendeu verificar se os analgésicos flunixin meglumine ou cetoprofeno conseguem atenuar a dor/desconforto de cordeiros neonatos submetidos a caudectomia por elastração, evitando assim o comprometimento da função dos granulócitos sanguíneos. Para tanto 21 cordeiras foram aleatoriamente divididas em três tratamentos: grupo controle (n=7) não submetido a caudectomia, grupo flunixin (n=7) submetido a caudectomia precedida por anestesia local e duas doses de flunixin meglumine, e cetoprofeno (n=7) submetido a caudectomia precedida por anestesia local e duas doses de cetoprofeno. Mensurou-se os indicadores de dor/desconforto após caudectomia por observações de escore de postura de dor (EP), número de vocalizações (V), frequência de movimentar as orelhas (FO) e frequência respiratória (FR), observados em vídeos de 10 minutos nos momentos -15 min e 6, 48 e 144h. Nos mesmos momentos, avaliou-se a as funções de produção de espécies reativas de oxigênio (ERO) e de fagocitose por granulócitos sanguineos em citometria de fluxo. Notou-se aumento dos indicadores de dor (FR, de V e de EP), da porcentagem dos granulócitos sanguíneos e redução da eficiência de fagocitose em ambos os grupos as 6h. As 48h, os animais do grupo cetoprofeno ainda apresentava mais tempo em postura de dor que os demais grupos e as 144h, apresentou redução da produção ERO por granulócitos. Tais achados permitem concluir que tanto o flunexin meglumine como o cetoprofeno não preveniram dor/desconforto agudo promovido pela elastração, pois os dois grupos manifestaram comportamento de dor e redução da resposta imune inata. Ainda, o analgésico flunixin meglumine foi efetivo em controlar a dor mais tardia e seus efeitos na função de granulócitos sanguíneos em comparação ao cetoprofeno.

Effect of flunixin or ketoprofen in caudectomy by elastration in lambs: pain and neutrophil function / Efeito de flunixin ou cetoprofeno em cordeiras submetidas a caudectomia por elastração: dor e função neutrofílica

Painful procedures can affect the function of innate immune cells, such as neutrophils and macrophages, increasing the risk of infectious diseases. The present work aimed to verify if the analgesics flunixin meglumine or ketoprofen can attenuate the pain/discomfort of newborn lambs submitted by elastration tail docking and thereby avoid the impairment of blood granulocytes function. Twenty-one neonate lambs were divided into three treatments: the control group (n=7), not subjected to caudectomy; the flunixin group (n=7), subjected to caudectomy under local anesthesia and analgesia with two doses of flunixin meglumine; and the ketoprofen group (n=7), subjected to caudectomy under local anesthesia and two doses of ketoprofen. Pain indicators were observed by pain posture score (PS), the number of vocalizations (V), frequency of the movement of the ears (EF), and respiratory rates (RR), observed by a 10 minutes videos for each time points: -15min, 6h, 48h, and 144h. At the same time points, the reactive oxygen species (ROS) production and phagocytosis of blood granulocytes were measured by flow cytometry. At 6h after caudectomy, there was a pain indicator increase (RR, V, and PS), a blood granulocyte percentage increase, and a granulocytes phagocytosis reduction for both groups. At 48h, the ketoprofen group spend more time in pain posture and, at 144h, they exhibited a ROS production granulocyte reduction without signs of pain. We conclude the flunixin meglumine and ketoprofen did not prevent the acute pain/discomfort caused by caudectomy, because the groups showed a pain behavior and impaired of the innate immune response however, the flunixin meglumine was effective in controlling the chronic pain and their effects on blood granulocytes function in compare ketoprofen.(AU)

Procedimentos dolorosos podem afetar a função das células imunes inatas como neutrófilos e macrófagos, aumentando o risco de ocorrer doenças infeciosas. Desta maneira, o presente trabalho pretendeu verificar se os analgésicos flunixin meglumine ou cetoprofeno conseguem atenuar a dor/desconforto de cordeiros neonatos submetidos a caudectomia por elastração, evitando assim o comprometimento da função dos granulócitos sanguíneos. Para tanto 21 cordeiras foram aleatoriamente divididas em três tratamentos: grupo controle (n=7) não submetido a caudectomia, grupo flunixin (n=7) submetido a caudectomia precedida por anestesia local e duas doses de flunixin meglumine, e cetoprofeno (n=7) submetido a caudectomia precedida por anestesia local e duas doses de cetoprofeno. Mensurou-se os indicadores de dor/desconforto após caudectomia por observações de escore de postura de dor (EP), número de vocalizações (V), frequência de movimentar as orelhas (FO) e frequência respiratória (FR), observados em vídeos de 10 minutos nos momentos -15 min e 6, 48 e 144h. Nos mesmos momentos, avaliou-se a as funções de produção de espécies reativas de oxigênio (ERO) e de fagocitose por granulócitos sanguineos em citometria de fluxo. Notou-se aumento dos indicadores de dor (FR, de V e de EP), da porcentagem dos granulócitos sanguíneos e redução da eficiência de fagocitose em ambos os grupos as 6h. As 48h, os animais do grupo cetoprofeno ainda apresentava mais tempo em postura de dor que os demais grupos e as 144h, apresentou redução da produção ERO por granulócitos. Tais achados permitem concluir que tanto o flunexin meglumine como o cetoprofeno não preveniram dor/desconforto agudo promovido pela elastração, pois os dois grupos manifestaram comportamento de dor e redução da resposta imune inata. Ainda, o analgésico flunixin meglumine foi efetivo em controlar a dor mais tardia e seus efeitos na função de granulócitos sanguíneos em comparação ao cetoprofeno.(AU)

Biochemical and histopathological effects of diclofenac and ketoprofen administration on bone regeneration / Efeitos bioquímicos e histopatológicos da administração de diclofenaco e cetoprofeno na regeneração óssea

Objetivo: Avaliar os efeitos bioquímicos e histopatológicos da administração de diclofenaco e cetoprofeno na regeneração óssea em modelo de defeito calvarial em ratos. Material e Métodos: A amostra foi composta por 108 ratos Wistar que foram distribuídos aleatoriamente em três grupos, aos quais foi realizada osteotomia de 6 mm de diâmetro na calvária. O grupo A (controle) recebeu solução salina; O Grupo B recebeu 2 mg / kg de cetoprofeno e o Grupo C recebeu 2 mg / kg de diclofenaco. Todos os tratamentos foram administrados intraperitonealmente a cada 12 horas durante 3 dias. A regeneração óssea foi avaliada pelas características bioquímicas (fosfatase alcalina e cálcio sérico) e histopatológicas (contagem de osteócitos e células de osteoblastos) aos 15 e 30 dias. Resultados:Na avaliação bioquímica, os níveis de fosfatase alcalina no grupo cetoprofeno foram significativamente menores em comparação com o grupo diclofenaco em 15 e 30 dias (p= 0.015 e p= 0.001; respectivamente). No entanto, os níveis séricos de cálcio não mostraram diferença entre os grupos de estudo aos 15 e 30 dias (p= 0.42 p= 0.81; respectivamente). Na análise histopatológica, a contagem de osteoblastos e osteócitos foi significativamente menor no grupo cetoprofeno em comparação ao grupo diclofenaco aos 15 e 30 dias (p< 0,05). Conclusão: A administração de cetoprofeno tem efeitos bioquímicos e histopatológicos negativos de maior intensidade na regeneração óssea em comparação com a administração de diclofenaco. (AU)

Objective: To evaluate the biochemical and histopathological effects of diclofenac and ketoprofen administration on bone regeneration in a calvarial defect model in rats. Material and Methods: The sample consisted of 108 Wistar rats that were randomly distributed in three groups, to which an osteotomy of 6 mm in diameter was performed in the calvaria. Group A (control) was given saline solution; Group B received ketoprofen 2 mg/kg and Group C received diclofenac 2 mg/kg. All treatments were administered intraperitoneally every 12 hours for 3 days. Bone regeneration was evaluated by biochemical (alkaline phosphatase and serum calcium) and histopathological (osteocyte and osteoblast cell count) characteristics at 15 and 30 days. Results: In the biochemical evaluation, alkaline phosphatase levels in the ketoprofen group were significantly lower compared to the diclofenac group at 15 and 30 days (p= 0.015 and p= 0.001; respectively). However, serum calcium levels did not show the difference between the study groups at 15 and 30 days (p= 0.42 and p= 0.81; respectively). In the histopathological analysis, the count of osteoblasts and osteocytes was significantly lower in the ketoprofen group compared to the diclofenac group at 15 and 30 days (p< 0.05). Conclusion: The administration of ketoprofen has negative biochemical and histopathological effects of greater intensity on bone regeneration compared to the administration of diclofenac (AU)

Morphometric analysis and pattern of protein and gene expression of apoptosis in focal cerebral ischemia in rats and the neuroprotetive action of hypothermia and ketoprofen / Análisis morfométrico y modelo de expresión de proteína y genes de apoptosis en isquemia cerebral focal en ratas y la acción neuroprotectora de hipotermia y ketoprofeno

This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.

Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.

Screening of Ketoprofen-Poloxamer and Ketoprofen-Eudragit solid dispersions for improved physicochemical characteristics and dissolution profile

The aim of the present study was to enhance the dissolution rate of an NSAID drug Ketoprofen by formulating it into solid dispersions with water soluble carrier Poloxamer 188 and Eudragit S 100. The solid dispersions of Ketoprofen with Poloxamer 188 were prepared at 1:1, 1:1.5 and 1:2 (Ketoprofen: Poloxamer 188) ratio by Solvent evaporation methods. The same concentration ratio was used for the preparation of solid dispersion with Eudragit S 100 by melting/fusion technique. Further, solid dispersions were investigated by solubility, ATR-FTIR, XRD, DSC, surface morphology, in-vitro dissolution and accelerated stability study. Results demonstrated that both Poloxamer 188 and Eudragit S 100 improve solubility of drugs by 8­10 folds. The result of ATR-FTIR study showed the slight shifting/broadening of principle peaks. In vitro dissolution studies showed that in the solid dispersion system containing Ketoprofen: Poloxamer 188 batch P2 (1:1.5) gives faster dissolution rate of Ketoprofen than the physical mixtures. The solid dispersion with Eudragit S 100, batch E1 (1:1) gives faster dissolution rate of Ketoprofen than the physical mixtures. In phase solubility study with Poloxamer 188 showed concentration dependent solubilization of drug but Eudragit S 100 produced opposite result. The effect of pH on solubility of Eudragit S 100 was carried out which showed solubility at pH 7.4. The dissolution profile of solid dispersion with Eudragit S 100 at pH 7.4 gives excellent result. The Accelerated stability of solid dispersions & its physical mixtures were studied at 400±2 °C/75 ± 5% RH for a period of 1 month. In these studies, Solid Dispersion batches produced an unstable formulation. The Ketoprofen solid dispersions with Poloxamer 188 and Eudragit S 100 could be introduced as a suitable form with improved solubility

Preparation and Formulation Optimization of Ketoprofen Microemulsion-based Gel / 中国药学杂志

OBJECTIVE: To prepare the ketoprofen microemulsion-based gel in order to expand its drug loading and increase the transdermal permeability. METHODS: The proportion range of oil phase/surfactant in ketoprofen microemulsion were screened by the pseudo-ternary phase diagram. Optimization of formulation for microemulsion gels was conducted by central composite design-response surface methodology with the cumulative permeation quantity across in vitro rat skin and time-lag as evaluation indexes.The transdermal performance of self prepared gel was compared with the commercially available gel. RESULTS: The optimal oil phase, surfactant and cosurfactant of ketoprofen microemulsion were oleic acid, polyoxy ethylene castor oil (EL-35) and ethanol, respectively.The optimal microemulsion formulation was 1.35% oleic acid, 10.8% EL-35, and 9% ethanol by central composite design experiment. The cumulative penetration quantity in 24 h reached 562.82 μg•cm-2 in vitro rat skin was 1.35 times as much as commercially available gel. CONCLUSION: The ketoprofen microemulsion-based gel prepared in this study has good permeability, which lay the foundation for development of the gel.

Effects of ketoprofen in spermatogenesis of mice exposed to continuos hypobaric hypoxia / Efecto del ketoprofeno en la espermatogénesis de ratones expuestos a hipoxia hipobárica continua

Hypoxia hypobaric (HH) can cause alterations at testicular level, with temperature increase, intrascrotal alteration and deterioration of spermatogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen have anti-angiogenic properties, and can decrease testicular abnormalities. The objective of the study was to evaluate the effect of ketoprofen on spermatogenesis of mice exposed to continuous hypobaric hypoxia. 78 Mus musculus CF-1 male mice 3 to 4 months old were used and subjected to HH in chamber at 4200 m. They were divided into 13 groups (G) of 6 animals: 10 with HH cycles (1, 2, 3, 4 and 8, lasting 8.3 days each cycle, two groups each) and 3 in normoxia (Nx). Intraperitoneal ketoprofen 25 mg/kg was administered every 4 days. Euthanasia of these animals was performed at the end of each cycle and in the case the Nx groups at the end of cycles 1, 4 and 8. Percentage of microhematocrit and reticulocytes were measured in blood smears and a morphometric and histopathological analysis of the height of the epithelium, the tubular diameter and the diameter of the tubular lumen was made. It was shown that hematocrit increases continuously up to 8 cycles, while reticulocytes increase up to 3 cycles. Continuous HH decreases the tubular diameter in a sustained manner and proportional to HH cycles, and the height increased only in the groups subjected to 8 cycles. The groups treated with ketoprofen saw a decrease in angiogenesis, presenting some degree of protection at the testicular level.

La hipoxia hipobárica (HH) puede provocar alteraciones a nivel testicular, con aumento de la temperatura, alteración intraescrotal y deterioro de la espermatogénesis. Los antiinflamatorios no esteroidales (AINEs) como el ketoprofeno tienen propiedades antiangiogénicas, pudiendo disminuir las alteraciones testiculares. El objetivo de estudio fue evaluar el efecto del ketoprofeno en la espermatogénesis de ratones expuestos a hipoxia hipobárica continua. Se utilizaron 78 ratones macho Mus musculus CF-1 de 3 a 4 meses de edad y se sometieron a HH en cámara a 4200 m. Se dividieron en 13 grupos (G) de 6 animales: 10 con ciclos de HH (1, 2, 3, 4 y 8, con duración de 8,3 días cada ciclo, dos grupos cada uno) y 3 en normoxia (Nx). Se administró ketoprofeno intraperitoneal 25 mg/kg cada 4 días. La eutanasia de estos animales se realizó al final de cada ciclo y en el caso los grupos Nx al final de los ciclos 1, 4 y 8. Se midió porcentaje de microhematocrito y reticulocitos en frotis de sangre y se hizo un análisis morfométrico e histopatológico de la altura del epitelio, el diámetro tubular y el diámetro de la luz tubular. Se evidenció que el hematocrito aumenta de manera continua hasta los 8 ciclos, en cambio los reticulocitos aumentan hasta los 3 ciclos. La HH continua disminuye el diámetro tubular de forma sostenida y proporcional a los ciclos de HH, y la altura aumentó sólo en los grupos sometidos a 8 ciclos. Los grupos tratados con ketoprofeno se vio una disminución de la angiogénesis, presentando algún grado de protección a nivel testicular.

A Comparative Study to Evaluate Efficacy of Fentanyl Transdermal Patch VS Ketoprofen Patch in Pain Control after Mandibular Third Molar Surgery

Background: Surgical removal of impacted lower third molars is a common oral surgical procedure, generally followed by moderate to severe postoperative pain. Transdermal drug delivery as a concept offers interesting possibilities for postoperative pain control. Aims and Objectives: to evaluate and compare the degree of post-operative analgesia, patient compliance and frequency of adverse events between transdermal ketoprofen patch and transdermal fentanyl patch following third molar extraction. Methods: Total 7 patients aged 18-65 years with impacted mandibular third molar teeth were included in the study. The study drugs transdermal patches of fentanyl and ketoprofen was applied one hour before the surgical procedure on the skin, preferably in an area devoid of any hair. The selected mandibular third molar tooth of either of the side was extracted in the first appointment using an aseptic protocol. Every patient was given a Verbal Pain Intensity and Pain Relief chart ( both 5- point scales with values 0-4 ) for assessing pain intensity and pain relief for all the three post-operative days. Results: During the first four hours of operative day, the difference observed between the two groups was not found to be statistically significant (p=0.881). Whereas during the first eight hours of operative day the difference observed between the two groups was not found to be statistically significant (p=0.141). During the first twelve hours of operative day, the difference observed between the two groups was not found to be statistically significant (p=0.276). At the end of operative day, the difference observed between the two groups was found to be statistically significant (p=0.048). Conclusion: Transdermal fentanyl patch was more effective for immediate pain relief than transdermal ketoprofen patch for pain control following removal of mandibular impacted third molars.

Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study / Avaliação dos efeitos neurotóxicos da administração intratecal do (S)-(+)-cetoprofeno em medula espinhal de rato: estudo experimental randômico e controlado

Abstract Background and objectives Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats. Methods A randomized placebo-controlled experimental study was conducted. Sprague-Dawley rats (250-300 g) aged 12-16 weeks were randomly divided into 2 treatments [100 and 800 µg (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis. Results Rats in all the groups exhibited normal pinch-toe testing response (score = 0) and normal gait at each observed time (motor function evaluation score = 1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p = 0.044; 2, 5, 0, p = 0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800 µg group than those in the 100 µg and Control Groups (5, 3, 0, p = 0.048, respectively). Conclusion Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.

Resumo Justificativa e objetivos A administração intratecal de anti-inflamatórios não esteroides é mais eficaz no tratamento da dor pós-operatória. Anti-inflamatórios não esteroides, como o (S)-(+)-cetoprofeno, pode ser eficaz em doses intratecais inferiores às parenterais. A segurança pré-clínica relativa à possível neurotoxicidade associada ao (S)-(+)-cetoprofeno intratecal não foi avaliada. Neste estudo avaliamos a neurotoxicidade do (S)-(+)-cetoprofeno administrado por via intratecal em ratos. Métodos Conduzimos um estudo experimental randomizado e controlado por placebo em ratos Sprague-Dawley (250-300 g) com idades entre 12 e 16 semanas. Eles foram randomicamente divididos em dois grupos de tratamento [100 e 800 µg de (S)-(+)-cetoprofeno] e um de controle (água estéril). Cateteres intratecais foram colocados através do espaço atlantoaxial nos ratos anestesiados. Testes de pinça, avaliações da função motora e exames histopatológicos da medula espinhal e das raízes nervosas foram realizados nos dias 3, 7 e 21 do estudo. Os cortes da medula espinhal foram avaliados por microscopia de luz para vacuolização do funículo axonal dorsal, perda de mielina axonal, cromatólise neuronal, neurite, inflamação, aderências e fibrose das meninges. Resultados Em todos os grupos, os ratos exibiram resposta normal ao teste de pinça (pontuação = 0) e marcha normal em cada tempo observado (escore de avaliação da função motora = 1). A neurotoxicidade foi maior com os tratamentos nos dias 3 e 7 do que no dia 21 (2, 3, 0, p = 0,044; 2, 5, 0, p = 0,029, respectivamente). No dia 7, os escores totais refletindo o dano neuronal foram maiores no grupo com 800 µg que nos grupos com 100 µg e controle (5, 3, 0, p = 0,048, respectivamente). Conclusão A administração intratecal de (S)-(+)-cetoprofeno causou alterações neuro-histopatológicas dose-dependentes em ratos nos dias 3 e 7 após a aplicação e sugerindo que o (S)-(+)-cetoprofeno não deve ser administrado por via intratecal.

Predicting complexation performance between cyclodextrins and guest molecules by integrated machine learning and molecular modeling techniques

Most pharmaceutical formulation developments are complex and ideal formulations are generally obtained after extensive experimentation. Machine learning is increasingly advancing many aspects in modern society and has achieved significant success in multiple subjects. Current research demonstrated that machine learning can be adopted to build up high-accurate predictive models in drugs/cyclodextrins (CDs) systems. Molecular descriptors of compounds and experimental conditions were employed as inputs, while complexation free energy as outputs. Results showed that the light gradient boosting machine provided significantly improved predictive performance over random forest and deep learning. The mean absolute error was 1.38 kJ/mol and squared correlation coefficient was 0.86. The evaluation of relative importance of molecular descriptors further demonstrated the key factors affecting molecular interactions in drugs/CD systems. In the specific ketoprofen-CD systems, machine learning model showed better predictive performance than molecular modeling calculation, while molecular simulation could provide structural, dynamic and energetic information. The integration of machine learning and molecular simulation could produce synergistic effect for interpreting and predicting pharmaceutical formulations. In conclusion, the developed predictive models were able to quickly and accurately predict the solubilizing capacity of CD systems. Current research has taken an important step toward the application of machine learning in pharmaceutical formulation design.

A Case of Gastric Ulcer Caused by NSAIDs Patches / 日本プライマリ・ケア連合学会誌

In general, when topical non-steroidal anti-inflammatory patches (hereinafter NSAIDs patches) are prescribed in clinical practice, adverse events, such as gastroduodenal ulcers, are not considered. However, patients often increase the number of NSAIDs patches they use in a single day even though they should only use 1 or 2 for local administration. Daily use of many NSAIDs patches (more than 4 large patches) may maintain the blood concentration of NSAIDs at a significantly level and cause adverse events similar to those by oral administration of standard-dose NSAIDs.We present a case of prolonged gastric ulcer caused by the daily use of many NSAIDs patches. In this case, Helicobacter pylori infection was negative and no oral NSAIDs were administered, and the discontinuation of NSAIDs patches resulted in the rapid healing of a gastric ulcer that was present for 2 years.

Efficacy of ketoprofen with or without omeprazole for pain and inflammation control after third molar removal

Abstract In view of the gastrointestinal problems generated by the ketoprofen use, the ketoprofen association with omeprazole is available on the market. However, this association efficacy in acute pain control has not been established. Bilateral extraction of lower third molars in similar positions is currently the most used model for the evaluation and investigation of the efficacy and pharmacological effects of new compounds for the treatment of acute postoperative pain. The randomized and crossover study consisted in evaluating the clinical efficacy of therapy performed by ketoprofen 100 mg (twice daily-b.i.d.) versus ketoprofen 200 mg + omeprazole 20 mg (once daily-q.d.) to pain, swelling and trismus control in the bilateral extraction model of lower third molars in similar positions in two different appointments, in 50 volunteers. Volunteers reported significantly less postoperative pain at various post-operative periods and consumed less rescue analgesic medication (acetaminophen 750 mg) throughout the study when they took the combination of ketoprofen 200 mg + omeprazole 20 mg (q.d.). Following administration of both study drugs, no gastrointestinal adverse reactions were reported by volunteers. Furthermore, the evaluations of the drugs in pain control by the volunteers were significantly favorable to ketoprofen 200 mg + omeprazole 20 mg (q.d.). For swelling and trismus control, the treatments presented similar results. In conclusion, when volunteers took ketoprofen 200 mg + omeprazole 20 mg (q.d.), they reported significantly less postoperative pain at various post-surgical periods and consumed less rescue analgesic medication throughout the study compared with ketoprofen 100 mg (b.i.d).

Resumo Em vista dos problemas gastrointestinais gerados pelo uso do cetoprofeno, a associação do cetoprofeno com o omeprazol está disponível no mercado. No entanto, esta eficácia de associação no controle da dor aguda não foi estabelecida. A extração bilateral de terceiros molares inferiores em posições semelhantes é atualmente o modelo mais utilizado para a avaliação e investigação da eficácia e efeitos farmacológicos de novos compostos para o tratamento da dor aguda pós-operatória. O estudo randomizado e cruzado consistiu na avaliação da eficácia clínica da terapia com cetoprofeno 100 mg (duas vezes ao dia-b.i.d.) versus cetoprofeno 200 mg + omeprazol 20 mg (uma vez ao dia-q.d.) para o controle da dor, do edema e do trismo no modelo bilateral de terceiros molares inferiores em posições semelhantes em duas consultas diferentes, em 50 voluntários. Os voluntários relataram significativamente menos dor pós-operatória em vários períodos pós-operatórios e consumiram menos medicação analgésica de socorro (acetaminofeno 750 mg) durante todo o estudo quando tomaram a combinação de 200 mg de cetoprofeno + 20 mg de omeprazol (q.d.). Após a administração de ambas as drogas do estudo, nenhuma reação adversa gastrointestinal foi relatada pelos voluntários. Além disso, as avaliações das drogas no controle da dor pelos voluntários foram significativamente favoráveis ​​ao cetoprofeno 200 mg + omeprazol 20 mg (q.d.). Para o controle do edema e do trismo, os tratamentos apresentaram resultados semelhantes. Em conclusão, quando os voluntários tomaram 200 mg de cetoprofeno + 20 mg de omeprazol (q.d.), eles relataram significativamente menos dor pós-operatória em vários períodos pós-cirúrgicos e consumiram menos medicação analgésica de socorro durante o estudo comparado com 100 mg de cetoprofeno (b.i.d).

Double blind randomized control trial to evaluate the efficacy of ketoprofen patch to attenuate pain during venous cannulation

BACKGROUND: Venipuncture pain is an uncomfortable suffering to the patient. It creates anxiety, fear and dissatisfaction. The ketoprofen transdermal patch is a proven treatment for musculoskeletal and arthritic pain. We planned this study to evaluate the efficacy of the ketoprofen patch to reduce venipuncture pain. METHODS: Two hundred adult patients, aged 18–60 years, of either sex, ASA grade I or II, were enrolled. Presuming that therapy would decrease venipuncture pain by 30%, a power calculation with α = 0.05 and β = 0.80 required enrollment of at least 24 patients into each group. However, 100 patients in each group were recruited. Group I (Control) received a placebo patch; Group II (Ketoprofen) received a 20 mg ketoprofen patch. A selected vein on the dorsum of the patient's non-dominant hand was cannulated with 18 g intravenous cannula 1 h after the application of the respective patch. Assessment of pain was done by a 10 cm visual analogue scale (VAS) of 0–10, where 0 depicts “no pain” and 10 is “the worst imaginable pain”. The venipuncture site was assessed for the presence of skin erythema, swelling and rashes at 12 h, 24 h and at the time of decannulation. RESULTS: Incidence of pain was 100% (94/94) in the control group as compared to 93% (85/91) in the ketoprofen group. The severity of the venipuncture pain was 6 (2) and 2 (2) for control and ketoprofen groups respectively (P < 0.05). CONCLUSIONS: Application of a ketoprofen patch at the proposed site of venipuncture one hour before the attempt is effective and safe for attenuating venipuncture pain.

Study on Drug Release from 25 Products of NSAIDs for External Use (4 Components) Using the Franz Diffusion Cell / 医薬品情報学

Objective: An evaluation index for drug release was measured in 25 currently used non‐steroidal anti‐inflammatory drugs (NSAIDs) for external use (4 components: indomethacin, diclofenac sodium, ketoprofen, and suprofen).Methods: All release tests were performed using the Franz diffusion cell with phosphate buffered saline (PBS) as the receptor phase and an artificial membrane to maintain uniform measurement conditions.　The receptor phase was collected over time and measured using high performance liquid chromatography (HPLC) to calculate the release rate.　The measurement time points were set over 0-4 h based on clinical use.　Furthermore, the additives were compared among the products.Results: The release profile of diclofenac sodium was similar among all 8 products.　On the other hand, the release rate of IN‐E (15.0% after 4 h) from indomethacin was higher than that from the other 6 products (6.2-9.1% after 4 h).　The release rate of KE‐D (39.2% after 4 h) from ketoprofen was higher than that from the cream, KE‐C (30.6 % after 4 h).　For suprofen, the release rate of SU‐E from the cream (18.1% after 4 h) was 1.6-1.7‐times higher than that of the other 2 products (10.9-11.3 %).　No release was detected from 3 suprofen ointments.Conclusion: Differences in the additives may have been a cause of the observed differences in release over 0-4 h.　This study may serve as a useful index for pharmacists to propose and select appropriate drugs.

Content Determination of Ketoprofen in Ketoprofen Enteric-coated Capsules by Improving HPLC / 中国药房

OBJECTIVE:To improve HPLC for content determination of ketoprofen in Ketoprofen enteric-coated capsules. METHODS:HPLC method was adopted. The determination was performed on Chiralpak IC column with mobile phase consisted of n-hexane (0.1% TFA)-isopropanol(90:10,V/V)at a flow rate of 0.8 mL/min. The detection wavelength was set at 268 nm,and column temperature was 25 ℃. The sample size was 10 μL. RESULTS:The linear range of ketoprofen were 0.025-0.5 mg/mL(r=0.9998). The limit of quantitation was 1.0 mg/L,and limit of detection was 0.2 mg/L. RSDs of precision,stability and reproduc-ibility tests were lower than 2%;recoveries were 96.36%-100.32%(RSD=1.87%,n=6). CONCLUSIONS:The method is sim-ple,accurate and rapid,and can be used for the content determination of ketoprofen in Ketoprofen enteric-coated capsules.

Preparation and Evaluation of Solid Lipid Nanoparticles Containing Ketoprofen / 中国药师

Objective:To prepare ketoprofen-loaded solid lipid nanoparticles ( SLN) and evaluate the properties. Methods: The formula was optimized by orthogonal experiments with the encapsulation efficiency as the index. The optimal preparation was investiga-ted by the morphology, particle size, zeta potential and drug forms. The release property was characterized by a dialysis method and the release process was fitted. Results: The best formula was as follows: poloxamer 0. 1g, Tween-800. 2g, lecithin 0. 15g, glycerol monostearate 0. 05g and ketoprofen 50mg. The particles were spherical in shape with the encapsulation efficiency of 61. 95%, the par-ticle size was 151. 7 nm and the zeta potential was-30. 2 mV. The result of DSC indicated the drug dispersed in the lipid matrix was a-morphous and molecular state. The in-vitro release curve showed the release was rapid at the early stage and then slowed down with the accumulated amount up to (85. 11 ± 7. 62)% in 12h. The drug was released slowly from SLN with the matrix erosion. The release pro-file fitted well with a Higuchi equation. Conclusion: The solid lipid nanoparticles containing ketoprofen exhibit good quality and the preparation method is simple and feasible, therefore, it is valuable to be further studied.

Preparation and Evaluation of Solid Lipid Nanoparticles Containing Ketoprofen / 中国药师

Objective:To prepare ketoprofen-loaded solid lipid nanoparticles ( SLN) and evaluate the properties. Methods: The formula was optimized by orthogonal experiments with the encapsulation efficiency as the index. The optimal preparation was investiga-ted by the morphology, particle size, zeta potential and drug forms. The release property was characterized by a dialysis method and the release process was fitted. Results: The best formula was as follows: poloxamer 0. 1g, Tween-800. 2g, lecithin 0. 15g, glycerol monostearate 0. 05g and ketoprofen 50mg. The particles were spherical in shape with the encapsulation efficiency of 61. 95%, the par-ticle size was 151. 7 nm and the zeta potential was-30. 2 mV. The result of DSC indicated the drug dispersed in the lipid matrix was a-morphous and molecular state. The in-vitro release curve showed the release was rapid at the early stage and then slowed down with the accumulated amount up to (85. 11 ± 7. 62)% in 12h. The drug was released slowly from SLN with the matrix erosion. The release pro-file fitted well with a Higuchi equation. Conclusion: The solid lipid nanoparticles containing ketoprofen exhibit good quality and the preparation method is simple and feasible, therefore, it is valuable to be further studied.

Study on the Separation of Ketoprofen Enantiomer by Pre-column Derivation RP-HPLC / 中国药师

Objective:To establish a method for the separation and determination of ketoprofen enantiomer .Methods:A pre-col-umn derivation RP-HPLC method was used with L-alanine-β-naphthylamine ( L-Ala-β-NA) as the derivation reagent .The RP-HPLC conditions were as follows: a Hypersil ODS-2 column (250 mm ×4.6 mm,5 μm) was applied, the mobile phase was acetonitrile-0.025 mol· L-1 phosphate buffer solution (40∶60, v/v) and the flow rate was 1.0 ml· min-1 , the detection wavelength was set at 245 nm and the column temperature was 25℃.The injection volume was 10μl.Results:Base line separation was achieved for the sep-aration of enantiomer from ketoprofen , and the retention time for S-(+) -ketoprofen and the R-(-) -ketoprofen was 24.2 min and 26.0 min, respectively.Dexketoprofen within the range of 0.025-0.125 mg had a good linear relationship (r=0.998 1) and the aver-age recovery was 90.93%(RSD =4.10%, n=9 ).Conclusion:The method is simple, accurate and reliable, which can be applied in the separation and determination of ketoprofen .