Influência do genótipo do citocromo P450 (CYP2C9) na eficácia clínica do tenoxicam após cirurgias de terceiros molares inferiores / Influence of cytochrome P450 (CYP2C9) genotype on clinical efficacy of tenoxicam after lower third molars surgeries

Atualmente, com os avanços da Farmacogenética, estudos estão demonstrando que a resposta individual de medicamentos pode ser diretamente afetada pela alteração da farmacocinética induzida pela genética de cada paciente, e isto pode induzir à ausência, redução, alteração ou aumento da atividade enzimática associada. Esse fato pode modificar a eficácia clínica de determinados medicamentos e, nos casos de anti-inflamatórios não esteroidais (AINEs), alterar sua capacidade de lidar com a dor e até aumentar a frequência e a gravidade dos efeitos adversos. Este estudo teve como objetivo genotipar e fenotipar o gene CYP2C9 em 89 pacientes saudáveis submetidos à cirurgia de terceiro molar inferior, sob medicação de 20 mg de tenoxicam por dia durante 4 dias, comparando a influência do gene na dor pós-operatória, edema, trismo, quantidade de medicamentos de socorro consumidos pelos pacientes, avaliação global e satisfação do paciente em relação à ingestão do medicamento. Trata-se de um ensaio clínico randomizado, desenvolvido no Departamento de Cirurgia e Traumatologia Bucomaxilofacial da Faculdade de Odontologia de Araçatuba (FOA/UNESP) e na Disciplina de Farmacologia do Departamento Ciências Biológicas da Faculdade de Odontologia de Bauru (FOB/USP). Foi realizado o sequenciamento genético dos participantes do estudo, a fim de verificar polimorfismos do gene CYP2C9, e estes dados foram cruzados com as características pós-operatórias acima mencionadas. Oitenta e nove participantes foram selecionados: 64 (74%) foram incluídos no grupo "Metabolizadores Normais" (CYP2C9 * 1 / * 1) e 25 participantes no grupo "Metabolizadores Intermediários/Lentos" (CYP2C9 * 1 / * 2, * 1 / * 3 e CYP2C9 * 2 / * 3, * 3 / * 3). Não foram encontradas diferenças estatisticamente significantes em todos os parâmetros avaliados. Em relação à dor, apesar dos dois grupos referirem baixos níveis de dor durante o pós-operatório, o grupo "Metabolizadores Normais" apresentou mais dor (p<0,05) nos períodos de 4, 5, 6, 7, 8, 10, 48 e 72 horas de pós-operatório, quando comparado ao ponto de tempo "zero", diferente do grupo "Metabolizadores Intermediários/Lentos" que relatou dor significativa apenas em 6 horas de pós-operatório, quando comparados com o tempo "zero". Na prática clínica, isso significa que indivíduos com atividade anormal do CYP2C9 (metabolizadores intermediários e lentos) apresentam uma exposição aumentada ao tenoxicam e provavelmente mostram níveis mais baixos de dor, mas também mostram provavelmente um risco maior de efeitos colaterais, que incluem sangramento gastrointestinal, distúrbios hemorrágicos e cardiovasculares, sendo provavelmente necessário que a dose habitual do medicamento seja revisada(AU)

One of the most accepted pharmacological protocols on third molar extraction surgeries involves the use of the non-steroidal anti-inflammatory drugs, as tenoxicam. Many studies present that the individual drug response could be directly affected by genetics induced pharmacokinetics alteration. Our study aimed to genotype and phenotype CYP2C9 gene in 89 health patients that were submitted to wisdom teeth surgical removal under medication of tenoxicam, comparing the gene influence on postoperative pain, edema, trismus, amount of rescue medication consumed, global evaluation and patient satisfaction regarding the medication. CYP2C9 gene was screened to evaluate polymorphisms and the genetic characteristics were crossed to aforementioned postoperative findings on a randomized clinical trial. 89 volunteers were splitted in two groups: 64 (74%) Normal Metabolizers (NM) group and 25 (26%) Intermediate/Slow Metabolizers (ISM) group. There were not found statistically significant difference between groups. The NM group referred more pain (p<0,05) at 4, 5, 6, 7, 8, 10, 48 and 72 postoperative hours time points when compared to time zero. In clinical practice it means that individuals with CYP2C9 abnormal activity (ISM) presented an augmented exposition to tenoxicam and referred lower pain levels, but also, they were probably more susceptible to adverse effects(AU)

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).

Manejo farmacológico del dolor en la odontología actual / Pharmacological management of pain in today´s dentistry

Una de las principales preocupaciones de los pacientes que van a ser sometidos a un procedimiento odontológico es el dolor que dicho procedimiento pueda ocasionar. Por lotanto, lograr un control eficaz y seguro de ese dolor es una parte esencial de la práctica odontológica diaria. Los fármacos de primera elección para el tratamiento del dolor y el edemason, sin lugar a dudas, los antiinflamatorios no esteroideos(AINEs). Principios activos como el ibuprofeno (y sus congéneres) o sus derivados permiten controlar simultáneamente el dolor y el edema posquirúrgicos de una forma eficaz y segura. En muchas ocasiones, el AINE prescrito para mantener al paciente asintomático o con síntomas tolerables es suficiente. Sin embargo, cuando esto no ocurre, debemos recurrir a otrosfármacos, o realizar asociaciones con fármacos que complementen el efecto analgésico y trabajen logrando un sinergismo de potenciación que incremente el efecto buscado y disminuya los efectos adversos de cada una de las sustancias por separado, utilizando menores dosis. Un ejemplo comprobado de esas asociaciones es la de ibuprofeno con paracetamol. En el presente artículo se sugieren diversas estrategias pre- y posoperatorias para el manejo del dolor de origen inflamatorio, y un protocolo para su tratamiento.

Effective method for the detection of piroxicam in human plasma using HPLC

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de São Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers.

Natural product and drugs interactions, its clinical implication in drug therapy management

The interaction of natural products and drugs is a common hidden problem encountered in clinical practice. The interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Clinically important interactions appear to involve effects on drug metabolism via cytochrome P-450 isoenzymes, impairment of hepatic or renal function, and other possible mechanisms. To effectively counsel patients on interactions involving natural products, physicians, and pharmacists should be familiar with the most commonly used products, and have access to information on more obscure products. In this review, we describe details of drugs interaction with natural products and its impact on drug therapy management

In vitro interaction studies of diltiazem with NSAID's using UV spectrophotometry and RP-HPLC techniques

Diltiazem [DTZ] is a well-known cardiovascular drug used clinically in the treatment of angina pectoris and hypertension. Present paper deals with the in vitro available studies of DTZ in presence of commonly used nonsteroidal anti-inflammatory drugs [NSAID's] like diclofenac sodium, flubiprofen, mefenamic acid and meloxicam. Simultaneous administration of both types of drugs may alter the antihypertensive effect of DTZ. These studies were carried out using BP 2005 dissolution test apparatus in simulated human body environments at body temperature and at elevated temperature in order to study the kinetics and energitics of these interactions. Both the drug in each case were analyzed either by measuring the absorbance of aliquots on a UV/VIS spectrophotometer, or by RP-HPLC method. Present study clearly indicated that most of the NSAID's studied bind to DTZ forming charge transfer complexes, evident from the high availability of DTZ. Hence, concurrent administration of NSAID's with DTZ is not recommended

Design and optimization of nsaid loaded nanoparticles

The objective of the study was to design and evaluate NSAID loaded Nanoparticles drug delivery system, where Flurbiprofen [model drug] Nanoparticles with suitable size range are envisaged to concentrate at inflammation sites due to increase fragility of blood vessels at those sites and increased aggregation and prostaglandin synthesis. Materials used were surfactant [pluronic F 68] and polymer [poly lactic co glycolic acid; PLGA]. The flurbiprofen loaded nanoparticles were prepared by solvent diffusion nano-precipitation method. Experiment was carried out following 32 factorial designs, where drug-polymer ratio was varied to optimize the formulation. From I.R studies no drug-polymer interaction was found. Particles size analysis was done using Malvern Mastersizer. Two parameters, namely, drug-polymer ratio and solvent-nonsolvent ratio were chosen for optimization following the factorial design. Amount of drug loading and surfactant were kept constant, and only polymer load was varied. The in-vitro drug release profile from nanoparticles was found to follow Higuchi square root kinetics implying a diffusion dependent release as is expected of an insoluble, non-swellable nature of PLGA. It indicated that nanoparticles formed were matrix in nature, in which flurbiprofen dispersed uniformly. Suitable polynomial models were generated and statistically validated using ANOVA for the different responses, namely drug release [maximization] and particle size [minimization]. Those models were solved numerically and simultaneously to optimize the required formulation. Optimized formulation were found to have a polymer-drug ratio of 18.89:1 and manufactured at a nonsolvent-solvent ratio of 4:1 to maximized release after 8 hrs and minimized particle size. The methodology avoids the use of organic solvent and thus provides a safe, reproducible and fast method of production of nanoparticles. The study collaborates on the feasibility and suitability of aqueous polymeric drug delivery system, employing statistical design to develop a clinically useful Nanoparticle system with targeting potential

Influence of acidic beverage (Coca-Cola) on pharmacokinetics of ibuprofen in healthy rabbits.

The study was aimed at determining the effect of Coca-Cola on the pharmacokinetics of ibuprofen in rabbits. In a cross-over study, ibuprofen was given orally in a dose of 56 mg/kg, prepared as 0.5% suspension in carboxymethyl cellulose (CMC) and blood samples (1 ml) were drawn at different time intervals from 0-12 hr. After a washout period of 7 days, Coca-Cola in a dose of (5 ml/kg) was administered along with ibuprofen (56 mg/kg) and blood samples were drawn from 0-12 hr. To these rabbits, 5 ml/kg Coca-Cola was administered once daily for another 7 days. On 8th day, Coca-Cola (5 ml/kg) along with ibuprofen (56 mg/kg), prepared as a suspension was administered and blood samples (1 ml each) were drawn at similar time intervals. Plasma was separated and assayed for ibuprofen by HPLC technique and various pharmacokinetic parameters were calculated. The Cmax and AUC0-alpha of ibuprofen were significantly increased after single and multiple doses of Coca-Cola, thereby indicating increased extent of absorption of ibuprofen. The results warrant the reduction of ibuprofen daily dosage, frequency when administered with Coca-Cola.

Pharmacoknetic Study of Diclofenac and Its Interaction with Enrofloxacin in Buffalo Calves

A comparative pharmacokinetic study of diclofenac (1 mg/kg, i.v.) when given alone or in combination with enrofloxacin (4 mg/kg, i.v.) in five buffalo calves was carried out by using HPLC. The study revealed that the plasma concentrations of diclofenac were significantly lower (p<0.05) in combined administration of diclofenac with enrofloxacin (0.042 to 3 h), whereas significantly higher (p<0.05) levels of plasma drug concentrations were observed in later period (8 to 24 h). In urine, significantly lower (p<0.05) drug concentrations of diclofenac were observed from 0.167 to 1.5 h, whereas significantly higher (p<0.01) urine drug concentrations were observed in later period (4 to 48 h) when diclofenac was given in combination with enrofloxacin as compared to when diclofenac was given alone. Various kinetic parameters like A, Cpo and beta were significantly lower (p<0.05) whereas t1/2 beta, AUMC, MRT and various volume of distribution (VdC, VdB, Vdarea and VdSS) were significantly higher in combined administration of diclofenac with enrofloxacin as compared to when diclofenac was given alone (p<0.05).

Effect of preservative, antioxidant and viscolizing agents on in vitro transcorneal permeation of ketorolac tromethamine.

The influence of formulation additives, e.g. preservative, antioxidant and viscolizing agents on in vitro transcorneal permeation of ketorolac tromethamine from 0.5%(w/v) aqueous drop was studied using goat cornea. Permeation characteristics of drug, from selected formulations, through excised rabbit cornea were also evaluated. Aqueous solution of ketorolac tromethamine (0.5% w/v), pH 6.5 or 7.0 having ionic strength 0.2, was prepared. To this solution perservatives either alone or in combination with other additives were added to have drops of various composition. Permeation studies with goat cornea showed maximum permeation of ketorolac tromethamine from formulation containing benzalkonium chloride and disodium edetate. Increase in viscosity of drop resulted in decreased permeation of drug. Formulation containing benzalkonium chloride and disodium edetate also increased permeation of drug through rabbit cornea. Cumulative permeation of drug through rabbit cornea was found to be 2.3-2.4 fold higher than that observed with goat cornea.

Bioequivalência de comprimidos de nimesulida do mercado nacional / Bioquivalence of nimesulide tablets of the national market

A nimesulida, é um fármaco sintético, pouco solúvel em água (0,01 mg/mL), classificado como antiinflamatório não esteróide, com atividade analgésica e antipirética. No Brasil são comercializadas várias especialidades farmacêuticas orais, contendo nimesulida, na dosagem de 100 e 200 mg. Em termos de saúde pública tais produtos, prescritos pelo médico como similares intercambiáveis, deveriam apresentar, a mesma eficácia clínica, sendo a bioequivalência um requisito fundamental. Um estudo em que se verifique a qualidade biofarmacotécnica de uma amostragem destes produtos torna-se bastante útil para que se possa avaliar a situação atual...

Role of volatile oil pretreatment and skin cholesterol on permeation of ion-paired diclofenac sodium.

This study was designed to investigate the influence of volatile oil pretreated skin on in vitro permeation from films containing ionized and dodecylamine ion-paired diclofenac sodium (DS). The involvement of skin cholesterol was investigated to determine its possible role in enhancing the permeation of ion-paired DS. Cardamom oil produced the maximum (10 x) in vitro permeation enhancement for ion-paired DS. The carrageenan induced rat paw oedema reduction (up to 12 hr) by cardamom oil was comparable to that of diclofenac injection (s c). Leaching of cholesterol from excised skin in addition to increased partition coefficient following volatile oil skin pretreatment appears to be responsible for in vitro permeation enhancement of DS. Whereas, a mild barrier perturbation effect due to altered cholesterol levels following pretreatment with volatile oils appears to increase the permeation of ion-paired DS across viable skin, thereby producing significant reduction of carrageenan induced paw oedema.

Efecto de la quinacrina con agentes antiinflamatorios sobre el desarrollo del tumor TA3 en ratón AJ / Quinacrine effects with antiinflamatory agents over TA3 tumor development in AJ mice

Objetivo: analizar la eventual potenciación mutua del efecto antineoplásico que presentan la quimacrina, los glucocorticoides y los antiinflamatorios no esteroidales (AINEs). Material y método: se utilizaron trasplantes de tumor TA3 en ratones machos AJ. Se establecieron 29 grupos con diferentes combinaciones terapéuticas, y se hizo un análisis estadístico de la sobrevida y del diámetro tumoral promedio en cada grupo. Resultados: la quimacrina combinada con betametasona y un agente AINE, permite obtener una alta tasa de regresión completa y definitiva de los tumores TA3. Discusión: la betametasona y los AINEs, forma separada no modifican la curva de crecimiento de los tumores TA3. La administración simultánea de quimacrina con betametasona o con un AINE, y su administración triple demuestra poseer una potente acción antitumoral, con regresiones totales que llegan a 50 o 70 por ciento de los tumores, variando en forma inversamente proporcional al lapso de días previos al inicio del tratamiento. El mecanismo de acción puede relacionrse con la apoptosis de células endoteliales de los capilares intratumorales que se observa en los animales tratados

DAINEs en el tratamiento del dolor postoperatorio / NSAIDs for the tratment of postoperative pain

En el presente trabajo se realizó una revisión de los artículos publicados en los últimos años sobre el tema, poniendo especial atención en la eficacia de estos agentes según el tipo de cirugía en que se emplean y la vía y el momento de administración más conveniente. Las DAINEs (drogas antiinflamatorias no esteroides) son los fármacos más utilizados en el mundo occidental. Son un grupo de drogas efectivas, y, en general, de bajo costo para el tratamiento del dolor postoperatorio. En los últimos años se produjo un gran avance en el conocimiento de su mecanismo de acción al descubrirse su acción central y la existencia de dos tipos de ciclooxigenasa: una constitutiva y otra inducida por la noxa, cuya inhibición es la que produce los efectos terapéuticos de las DAINEs. Esto permitió comprender más a fondo el mecanismo de producción de efectos adversos y permitirá el desarrollo de nuevas DAINEs con mayor especificidad tisular. Las DAINEs son efectivas como analgésicos únicos en cirugías de pequeña y mediana magnitud y como ahorradores de opioides en las de mayor envergadura. Las vías de elección para administrarlos son la endovenosa y la oral en cuanto es posible, comenzando antes del estímulo quirúrgico y continuando durante el postoperatorio para maximizar su eficacia y evitar el fenómeno de wind-up. Es de vital importancia identificar a los pacientes de riesgo para desarrollar efectos adversos, que pueden ser muy graves, y prevenir su aparición.

Revisäo - O ibuprofeno e seu uso na dismenorréia primária / Review - Ibuprofen and its use in primary dysmenorrhea

Os autores apresentam uma revisäo sobre as propriedades farmacológicas do ibuprofeno, droga antiinflamatória-näo-esteroidal (AINE), e seu emprego na dismenorréia primária (DP), enfermidade de importante aspecto sócio-econômico devido a seus sintomas incapacitantes quando na forma severa. Säo abordados aspectos sobre farmacocinética, farmacodinâmica, indicaçöes clínicas, interaçöes medicamentosas e efeitos adversos da droga, revelando-se o ibuprofeno como o AINE que apresenta, na vigência de seu uso, a menor incidência de distúrbios gastrointestinais quando comparado aos demais AINE. Em relaçäo a seu uso na DP, säo analisados estudos onde compara-se a eficácia do ibuprofeno à eficácia de outros AINES em relaçäo ao alívio dos sintomas dismenorreícos. Conclui-se ser o ibuprofeno, devido à sua ótima eficácia no alívio da dor e sua baixíssima incidência efeitos adversos, e a droga de escolha no tratamento da DP, tendo nesta sua grande indicaçäo

Estudio doble ciego con ketoprofeno más clorzoxazona y diclofenaco en síndromes dolorosos de la columna vertebral / Double blind study of ketoprofen and chlorzoxazone versus diclofenac in spine painful syndromes

Con el objetivo de valorar la seguridad, tolerancia y eficacia de ketoprofeno más clorzoxazona vs diclofenaco en pacientes con síndrome doloroso de la columna vertebral, se realizó un estudio clínico doble ciego, prospectivo, longitudinal, controlados e inferencial. Para ellos, se incluyeron 50 pacientes que se distribuyeron en dos grupos: el A recibió dosis diaria de 50 mg de ketoprofeno más 250 clorzoxazona dos veces al día desde el inicio hasta el final del estudio, y el B 200 mg de diclofenaco al día. Se realizó examen clínico el día cero y 15 del tratamiento y luego periódicamente hasta un total de 12 semanas. Posterior a dicho periodo, en la primera evaluación se observó diferencia entre los grupos de tratamiento. En el grupo tratado con ketoprofeno más clorzoxazona disminuyó el dolor a la palpación, movimiento e inflamación y mejoró la función articular, no así con diclofenaco. Se observaron diferencias entre los dos grupos, tanto en el tratamiento como en respuesta sintomatológica que fueron significativas durante el estudio. Después de ocho semanas de tratamiento 70 por ciento del grupo con ketoprofeno más con diclofenaco. Estas sifras aumentaron hasta 95 por ciento de recuperacion casi completa en el grupo de ketoprofeno más clorzoxazona, mientras que 70 por ciento del grupo con diclofenaco no mejoró en absouluto como lodemuestran las estadísticas de respuesta. En ambos casos, la diferencia fue estadísticamente significativa. La tolerancia de ketoprofeno más clorzoxazona se consideró excelente. En ambos grupos se observaron incidencias similares de irritación gástrica en 4 por ciento de los casos. Estos resultados confirman la excelente seguridad, toleranacia y eficacia de ketoprofeno más clorzoxazona en el tratamiento del síndrome doloroso de la columna vertebral

In vitro transcorneal permeation of ketorolac from oil based ocular drops and ophthalmic ointment.

Transcorneal permeation of ketorolac from oil based ocular drops and ophthalmic ointments was studied in vitro, using goat cornea. Cumulative (%) permeation of ketorolac through cornea, was found to be maximum with 0.2% (w/v) ketorolac drops in sesame oil followed by formulations in corn oil and soyabean oil. Ketorolac 1% (w/v) drops in castor oil increased the quantity permeated but cumulative (%) permeation was less. Permeation profiles of ketorolac were in consistence with the partition characteristic of drug between oil and aqueous phase. Formulations favouring corneal permeation of ketorolac increased corneal hydration. Addition of benzyl alcohol, a preservative, to oil drops reduced permeation of ketorolac and corneal hydration indicating possible protective effect of benzyl alcohol against corneal damage. Permeation studies on ointment formulations containing either ketorolac acid or ketorolac tromethamine salt indicated better permeation for formulation containing ketorolac tromethamine aqueous solution. Thus for better transcorneal permeation, ketorolac 0.2% (w/v) drops, formulated in sesame oil, containing 0.5% v/v benzyl alcohol and ophthalmic ointment containing 0.5% (w/w) ketorolac tromethamine in dissolved state appear suitable.

Estudo comparativo dos efeitos biológicos do tenoxicam, indometacina, dexametasona e metotrexato em granulomas induzidos pela placa microbiana dental / Comparative study of biologic effects of tenoxicam, indometacin, dexamethazone and methotrexate in granulomas induced by microbial dental plaque

Estudamos o efeito antiinflamatório do tenoxicam, indometacina, dexametasona e metotrexato, em granulomas induzidos pela inoculaçäo da placa microbiana dental em uma bolsa de ar localizada no tecido subcutâneo de ratos aos 7, 14, 21 e 28 dias, por meio da avaliaçäo histomorfométrica da densidade de volume relativa (Vvi) ocupada pelo tecido granulomatoso, regiäo central de necrose, macrófagos e fibras colágenas. Os resultados revelaram que, até 14 dias, o tenoxicam apresentou vantagem comparativamente a indometacina, pois inibiu mais acentuadamente a regiäo central de necrose supurativa, demonstrando potência semelhante a da dexametasona, näo obstante, em relaçäo à inibiçäo da densidade de volume do tecido granulomatoso, os fármacos mais potentes terem sido a indometacina e a dexametasona. Após 14 dias näo foi constatada diferença estatisticamente significativa entre o efeito apresentado pelo tenoxicam e o da indometacina. A acentuada potência apresentada pelos NSAIDs, na inibiçäo da densidade de volume dos macrófagos, semelhante ao efeito de metrotexato, sugeriu que esses medicamentos apresentaram efeito antiproliferativo das células progenitoras dos monócitos/macrófagos. Os NSAIDs, também, apresentaram efeito estimulador (21 dias) e inibidor (28 dias) da densidade de volume das fibras colágenas, enquanto que a dexametasona apresentou efeito contrário. Tais resultados indicaram que a placa microbiana dental estimula a acentuada produçäo de LTs e PGs, de maneira que a administraçäo dos antiinflamatórios esteróides e näo esteróides foi vantajosa em relaçäo ao fármaco citostático

In vitro transcorneal permeation of ketorolac tromethamine from buffered and unbuffered aqueous ocular drops.

In vitro transcorneal permeation of ketorolac tromethamine from 0.5% w/v solutions containing equimolar (0.02 M) concentrations of citrate (pH 6.5), phosphate (pH 6.5 and 7), citrate-phosphate (pH 7) and borate (pH 7) buffers was studied using goat cornea. Cumulative % permeation was maximum with phosphate buffered drops of pH 6.5. The effect of pH and ionic strength on permeation of ketorolac tromethamine from buffered (phosphate) drops was next investigated. Cumulative % permeation of ketorolac tromethamine from buffered drops was pH dependent being maximum at pH 4.5. Adjustment of ionic strength of drops to 0.2 resulted in decreased permeation of drug. Permeation of ketorolac tromethamine from unbuffered drops of varying pH and ionic strength 0.2 was also pH dependent and was maximum at pH 4.5. Buffered drops of pH between 4.5-5.5, ionic strength 0.2, provided better permeation of drug compared to unbuffered drops of same pH and ionic strength. Above pH 6.5 unbuffered drops showed better permeation than buffered drops. Increase in molarity of phosphate buffer (pH 4.5) used in making drops, between 0 to 0.15 M increased permeation. Aqueous drops of ketorolac tromethamine formulated in 0.15 M phosphate buffer of pH 4.5 and ionic strength 0.2 showed maximum cumulative % permeation in vitro. Considering lacrimation induced drug loss in vivo, by buffer of high concentration, ketorolac tromethamine drops formulated in buffer of low molarity, pH 4.5 and ionic strength 0.2 appear suitable.