Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial / Efeito da pré‐ administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado

Abstract Background and objectives Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. Methods Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg−1, 0.75 mg.kg−1 and 1 mg.kg−1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL−1-lower (or -higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation and 15 minutes after intubation. Results The EC50 of propofol was lower in Group C (2.32 µg.mL−1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL−1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL−1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL−1, 95% CI 2.33-2.71) and Group A (p > 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). Conclusion High-dose FA (0.75 mg.kg−1 or 1 mg.kg−1) reduces the EC50 of propofol, and 1 mg.kg−1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Resumo Justificativa e objetivos A administração pré‐operatória de Flurbiprofeno Axetil (FA) é amplamente usada para a modulação da analgesia. No entanto, a relação entre FA e fármacos sedativos permanece obscura. Neste estudo, nosso objetivo foi investigar os efeitos de diferentes doses de FA na Concentração Efetiva mediana (CE50) do propofol. Métodos Noventa e seis pacientes (ASA I ou II, com idades de 18-65 anos) foram alocados aleatoriamente em quatro grupos na proporção de 1:1:1:1. Dez minutos antes da indução, o Grupo A (grupo controle) recebeu 10 mL de Intralipid, enquanto os grupos B, C e D receberam FA na dose de 0,5 mg.kg‐1; 0,75 mg.kg‐1 e 1 mg.kg‐1, respectivamente. A profundidade da anestesia foi medida pelo Índice Bispectral (BIS). O método up‐and‐down foi usado para calcular a CE50 do propofol. Durante o período de equilíbrio, se o valor do BIS fosse ≤ 50 ou BIS > 50, o próximo paciente tinha a infusão de propofol ajustada para uma concentração alvo‐controlada 0,5 µg.mL‐1 inferior ou superior, respectivamente. Os dados hemodinâmicos foram registrados no início do estudo, 10 minutos após a administração de FA, após a indução, após a intubação e 15 minutos após a intubação. Resultados A CE50 do propofol foi menor no Grupo C (2,32 µg.mL‐1, Intervalo de Confiança de 95% [95% IC] 1,85-2,75) e D (2,39 µg.mL‐1, 95% IC 1,91-2,67) do que no Grupo A (2,96 µg.mL‐1; 95% IC 2,55-3,33) (p = 0,023, p = 0,048, respectivamente). Não houve diferenças significantes na CE50 entre o Grupo B (2,53 µg.mL‐1, 95% IC 2,33-2,71) e o Grupo A (p > 0,05). Não houve diferenças significantes na Frequência Cardíaca (FC) entre os grupos A, B e C. A FC foi significantemente menor no grupo D do que no grupo A após a intubação (66 ± 6 vs. 80 ± 10 bpm, p < 0,01) e 15 minutos após a intubação (61 ± 4 vs. 70 ± 8 bpm, p < 0,01). Não houve diferenças significantes entre os quatro grupos na Pressão Arterial Média (PAM) em qualquer momento. A PAM dos quatro grupos foi significantemente menor após a indução, após a intubação e 15 minutos após a intubação do que na linha de base (p < 0,05). Conclusão FA em altas doses (0,75 mg.kg‐1 ou 1 mg.kg‐1) reduz a CE50 do propofol, e 1 mg.kg‐1 de FA reduz a FC durante níveis adequados de anestesia em pacientes não estimulados. Embora esse resultado deva ser investigado na presença de estimulação cirúrgica, sugerimos que a pré‐administração de FA pode reduzir a necessidade de propofol durante anestesia cuja profundidade seja monitorada pelo BIS.

Formulation, Evaluation and Pharmacokinetics of Flurbiprofen Fast Dissolving Tablets.

Aim: The intent of present study is to formulate fast dissolving tablets of flurbiprofen using different superdisintegrants to improve the dissolution and bioavailability. Place and Duration of Study: Jyothishmathi Institute of Pharmaceutical Sciences, Karimnagar, Andhra Pradesh, India, between January 2011 and December 2012. Methodology: Flurbiprofen fast dissolving tablets were prepared using different superdisintegrants and characterized for different physical parameters, DSC, FTIR studies, in vitro dissolution studies and in vivo pharmacokinetics to prove the enhancement of bioavailability. Results: From the in vitro dissolution studies, the percent drug release in 15 min (Q15) was found to be 91.46±1.42% in case of optimized formulation where as the conventional tablets prepared by similar manner showed 22.92±0.47% in 15 min. The initial dissolution rate and dissolution efficiency for optimized formulation was 6.10%/min and 53.44 but it was 1.53%/min and 10.96 in conventional tablets. They increased by 4.0 folds when compared to conventional tablets. From the pharmacokinetic evaluation, the optimized fast dissolving tablets produced peak plasma concentration (Cmax) as 11433.32 ng/ml at 2 h Tmax, but they were found to be 8792.64 ng/ml at 3 h Tmax, in case of conventional tablets. The area under the curve for the optimized fast dissolving and conventional tablets were found to be 42691.23 and 30727.14 ng-h/ml. Conclusion: In summary, formulation of fast dissolving tablets using superdisintegrants was a good approach to enhance the dissolution and absorption rates of flurbiprofen.

Intracrevicular application of 0.3% Flurbiprofen gel and 0.3% Triclosan gel as anti inflammatory agent. A comparative clinical study.

This study compared the anti-inflammatory efficacy of Triclosan and Flurbiprofen in a gel form on clinical parameters of moderate gingivitis cases. The study comprised of 100 sites from 16 volunteers and used split mouth technique. 0.3% Triclosan/0.3% Flurbiprofen gels applied intracrevicularly once daily for one week. Clinical parameters like Plaque index, Gingival index and Bleeding index scores were recorded at 0 day, 4th day and 8th day. The obtained results showed significant reductions in clinical parameters from baseline to 8th day. This indicates local delivery of 0.3% Triclosan/0.3% Flurbiprofen gel can be used as an anti-inflammatory agents either alone or as an adjunct to scaling in periodontal therapy.

Topical flurbiprofen therapy in vernal keratoconjunctivitis.

A clinical study of 90 cases of vernal keratoconjunctivitis was conducted to ascertain the efficacy of the local use of flurbiprofen and compare its effect with that of betamethasone. According to this study flurbiprofen was found to be effective in vernal keratoconjunctivitis, but less so than betamethasone. Because of the side effects due to prolonged use of steroids, it is recommended that topical flurbiprofen be tried first and in case it is ineffective, it should be replaced by betamethasone.

A comparative study of flurbiprofen and piroxicam in osteoarthritis.

In this single-blind, multiple-dose study the efficacy and tolerability of flurbiprofen was compared with that of piroxicam in 60 adult patients suffering from osteoarthritis of the knee. The patients were randomly allocated to receive either flurbiprofen 100 mg twice daily or piroxicam 20 mg once daily for a period of four weeks. Clinical assessments w.r.t. pain, tenderness, stiffness, swelling and general activity of patient were carried out prior to initiation of trial therapy and thereafter at weekly intervals for four weeks. The findings were graded. Though significant improvements as compared to baseline data occurred in both the treatment groups, flurbiprofen was found to be superior to piroxicam in improving pain on movement and at rest (p < 0.05). The incidence of side effects was less in the group receiving flurbiprofen (6% compared to 47% observed with piroxicam).

Preoperative topical flurbiprofen-Na+ in extracapsular lens extraction role in maintaining intraoperative pupillary dilatation.

Induction of intraoperative pupillary constriction, is predominantly a prostaglandin mediated process. The most potent antiprostaglandin NSAID, Flurbiprofen was used topically to study its efficacy against the above. In a prospective double blind clinical study, 50 brown eyes undergoing planned E.C.C.E., the pupils were dilated with 10% phenylephrine and 2% homatropine 1%/tropicamide. 25 eyes received 0.03% Flurbiprofen-Na+ eye drops 1/2 hourly starting two hours before surgery. The maintained intraoperative mydriasis in the two groups before anterior chamber entry (stage I) vs at the end of complete cortex wash (stage III) was: in control group (stage I) 8.46 +/- 0.48 mm vs (stage III) 3.56 +/- 0.43 mm (highly SS); in flurbiprofen group (stage I) 8.60 +/- 0.48 mm vs (stage III) 8.01 +/- 0.63 mm (NSS). The pupillary area available for surgical manipulation in the control group was significantly decreased from 56.18 mm2 in state I to 9.94 mm2 in stage III, while in flurbiprofen group it changed insignificantly from 58.05 mm2 in stage I to 50.24 mm2 in stage III. Postoperatively after cataract was observed in 44% eyes of control group as compared to only 8% of eyes of flurbiprofen group. Thus a maintained intraoperative mydriasis in flurbiprofen group led to better E.C.L.E. which is a mandatory prerequisite to preferred and better present day posterior chamber IOL implantation.

Doseamento do flurbiprofeno com hidróxido de sódio / Flurbiprofen assay with sodium hydroxide

Flubiprofeno, antiinflamatório näo-esteróide derivado de ácido fenilalcanóico, eficaz no tratamento de artrite reumatóide e enfermedades relacionadas, foi determinado quantitativamente por volumetria com hidróxido de sódio, usando-se fenolftaleína como indicador

Flurbiprofen em dose baixa comparado à dipirona ácido acetilsalicílico e placebo no tratamento da dor pós-extraçäo dentária / Flurbiprofen in low dosage compared to dipyrone, acetylsalicylic acid and placebo in the treatment of post tooth extraction pain

Este foi um estudo duplo-cego, randomizado, em dose única, com a finalidade de comparar o flurbiprofen, em dose baixa, com dipirona, ácido acetilsalicílico e placebo no tratamento da dor pós-extraçäo dentária. Foram tratados 159 pacientes, divididos em quatro grupos de tratamento: 40 pacientes receberam flurbiprofen (500mg), 39 receberam dipirona (500mg), 41 receberam ácido acetilsalicílico (650mg) e 39, placebo. Foram estudados pacientes com dor moderada ou intensa, os quais após a administraçäo do medicamento, eram avaliados em 1/2 hora, uma hora e a cada hora durante seis horas. A análise da diminuiçäo da intensidade da dor após o tratamento revelou pequenas diferenças entre os três agentes terapêuticos, os quais mostraram melhor desempenho em relaçäo ao grupo tratado com placebo. Da mesma forma, as drogas ativas foram superiores ao placebo em relaçäo ao alívio da dor, escores de alívio total, melhora de 50% da dor, bem como avaliaçäo global do investigador e do paciente e necessidade de analgésico suplementar. Os efeitos colaterais foram semelhantes em todos os grupos de tratamento