Controlled release alginate-chitosan microspheres of tolmetin sodium prepared by internal gelation technique and characterized by response surface modeling

Tolmetin sodium (TS) is a powerful non-steroidal mitigating drug for the treatment of rheumatoid joint inflammation, osteoarthritis, and adolescent rheumatoid joint pain. In addition to its gastrointestinal (GIT) problems, TS has a short biological half-life (1 hr). In a trial to overcome these side effects and control the rate of (TS) release, chitosan coated alginate microspheres are recommended. A Box-Behnken experimental design was employed to produce controlled release microspheres of TS in the sodium alginate and chitosan copolymers (Alg-Ch) by emulsification internal gelation methodology. The effect of critical formulation variables namely, drug to polymer ratio (D:P ratio), speed of rotation and span 80% on drug encapsulation efficiency (% EE), drug release at the end of 2 hours (Rel2) and drug release at the end of 8 hours (Rel8) were analyzed using response surface modeling. The parameters were assessed using the F test and mathematical models containing only the significant terms were generated for each parameter using multiple linear regression analysis. The produced microspheres were spherical in shape with extensive pores at D:P ratio 1:1 and small pores at a drug to polymer ratio (D:P ratio) 1:3. Differential scanning calorimetry (DSC) affirmed the steady character of TS in microspheres and revealed their crystalline form. All formulation variables examined exerted a significant influence on the drug release, whereas the speed emerged as a lone factor significantly influencing % EE. Increasing the D: P ratio decreases the release of the drug after two and 8 hours. The increase in speed results in an increase in drug release after two and eight hours. The drug release from the microspheres followed zero order kinetics. TS Alg-Ch microspheres exhibited a significant anti-inflammatory effect on incited rat paw edema after eight hours. These results revealed that the internal gelation technique is a promising method to control TS release and eradicate GIT side effects using Alg-Ch copolymers.

Comparison of oral tramadol and tolmetin in relieving pain of knee osteoarthritis

The aim of this double blind crossover study was to compare the efficacy of oral tramadol with that of tolmetin [NSAID] in relieving pain of patients with chronic pain due to osteoarthritis of the knee. After baseline observation, 44 patients were assigned to one of the two treatment sequences and 40 patients completed the study. During the two treatment periods, the patients daily ratings of pain on a 0- 10 numeric rating scale throughout baseline and double blind treatment periods served as the primary outcome measure. Their ratings for pain were not significantly different between tramadol and tolmetin. It was concluded that though tolmetin was little more effective in relieving the pain and was of less side effects, both tramadol and tolmetin relieved pain due to knee osteoarthritis

Glucuronoconjugación: consecuencias toxicológicas y clínicas / Glucuronidation: toxicological and clinical consequences

La glucuronoconjugación es un proceso de gran importancia en el metabolismo de xenobióticos y sustancias endógenas, facilitando su excreción por parte del organismo. Durante mucho tiempo ha sido aceptado que los metabolitos derivados de esta vía no poseían carácter activo o reactivo. Sin embargo, en los últimos años han surgido evidencias que ponen en duda aquella creencia, con especial referencia a los acilglucurónidos de los ácidos aril 2-propiónicos, cuya inestabilidad in vivo bajo condiciones fisiológicas ha demostrado tener implicancias inmunotoxicológicas potenciales a través de su unión irreversible a las proteínas (aductos). Esta revisión considera los aspectos que han modificado la percepción de la glucuronoconjugación como una vía sin importancia toxicológica y clínica para el organismo. Por lo tanto, la pregunta que debería ser contestada podría ser: es la glucuronoconjugación una vía de producción de sustancias tóxicas tanto como un mecanismo de detoxificación?

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.

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.

Topical ketorolac 0.5% solution for the treatment of vernal keratoconjunctivitis.

The efficacy of topical ketorolac 0.5% in treatment of vernal keratoconjunctivitis (VKC) was evaluated in a randomised double-blind prospective trial in 21 patients. Ketorolac treated eyes showed 50.7% reduction in main symptoms of itching compared to 33.3% relief in placebo treated eyes after 2 weeks of treatment (p < 0.01). Photophobia, ropy discharge, and conjunctival injection also lessened by 39.9%, 31.6%, and 39.1%, respectively, in ketorolac treated eyes compared to 23.8%, 17.3%, and 20.3% in placebo group. Transient stinging sensation was observed in 3 (14.3%) patients on ketorolac therapy. This study shows efficacy of ketorolac 0.5% solution in controlling symptoms in VKC.

A Comparative Study of Inhibition of Postsurgical Adhesion Formation in the Rat Model by Nonsteroid Antiinflammatory Drugs , Heparin , Hyskon , and TC-7 / 대한산부인과학회잡지

The purpose of this study was to evaluate and compare the effect of inhibition of postsurgical adhesion formation in the rat model by meclofenamate, tolmetin, TC-7, Hyskon, and heparin. Laparotomies were performed on grossly healthy, mature nonpregnant female rats, and proximal 1 cm of each uterine horn was traumatized with unipolar electrocautery. Each rat was randomly assigned to one of six different groups(control, meclofenamate, tolmetin, heparin, TC-7, and Hyskon group), and different solutions or an adhesion barrier were placed into traumatized uterine horn before closure. One week later adhesion formation was scored according to percent involvement of each traumatized uterine horn(0 to 4), and adhesion density(0 to 2), and compared using one-way analysis of variance and Fishers exact test. Compared with the control group, postsurgical adhesion formation was significantly decreased in the TC-7 group(average adhesion score, 1.72), the meclofenamate group(2.19), the Hyskon group(2.53), and the tolmetin group(2.93). The TC-7 group was also significantly decreased in adhesion formation compared with the Hyskon, tolmetin, heparin groups, and meclofenamate group was significantly decreased in adhesion formation compared with tolmetin and heparin groups. There were no significant differences between groups in adhesion density. So we suggest that meclofenamate is a cost-effective agent in inhibition of postsurgical adhesion formation.

Wound healing profiles of ketorolac, metronidazole and tinidazole administered post-surgically.

On dead space wounds, drugs (ketorolac, metronidazole and tinidazole) caused a significant (P < 0.01) decrease in breaking strength, granulation tissue weight and hydroxyproline content in male rats. Both the parameters of excision wound were significantly (P < 0.01) hastened by metronidazole and tinidazole only. Post operative management of wounds with ketorolac (a potent analgesic), metronidazole and tinidazole (for anaerobic infections) may be dealt with the risk of a delay in healing. Both metronidazole and tinidazole promote the epithelization process.

Effect of tolmetin and its copper complex on wound healing.

Dose matched comparison between copper complex of tolmetin(Tol-Cu) and tolmetin(Tol) was carried out in male albino rats bearing either sutured incision, dead space or excision wounds. Results showed that Tol significantly decreased tesile strength of incision and dead space wound. This effect was totally reversed by copper present in Tol-Cu. Tol-Cu shared the significant suppressant effect of Tol on granulation formation and its collagen content. Tol suppressed wound contraction and epithelization and copper complex of Tol antagonised the suppressant effect of Tol on wound contraction and epithelization.

A multiple dose comparison of ketorolac tromethamine with ibuprofen for analgesic activity.

This study was done to compare a new analgesic ketorolac with ibuprofen in post-operative and post-laparoscopy pain. A total of 40 patients were recruited for the study of which 20 were post-operative and 20 were post-laparoscopy cases. Medication was given over a period of 48 hours after surgery and a pain score based on subjective symptoms was monitored at fixed intervals after each dose. The analgesic efficacy of ketorolac was found to be comparable to that of ibuprofen and the drug was well tolerated in the doses used without any extra medication being required.

Comparative evaluation of tolmetin & tolmetin-zinc on wound-repair & inflammation.

In view of the reported healing-suppressant activity of some NSAIDs and absence of this adverse effect in their zinc-complexes, tolmetin (Tol), a recently introduced NSAID and its zinc-complex (Tol-Zn) were compared for their wound healing and antiinflammatory profiles in male albino rats. Tolmetin-zinc (Tol-Zn) significantly reversed (P less than 0.01) the suppressant effect of Tol on gain in breaking strength of skin incisions and dead space wounds (breaking strength, g: for control, Tol and Tol-Zn were: 313 +/- 7, 250 +/- 11, 294 +/- 16 in skin wounds; 244 +/- 7, 137 +/- 18, 195 +/- 16 in dead space wounds). Tol-Zn shared the significant (P less than 0.001) suppressant effect of Tol on granuloma formation (granuloma weight, mg: control - 69 +/- 3, Tol - 36 +/- 3.03, Tol-Zn - 37 +/- 2.75) and its collagen content (total hydroxyproline per tissue, microgram: control - 1955 +/- 55, Tol - 1400 +/- 200, Tol-Zn - 1410 +/- 150). Rat paw edema induced by carrageenin was significantly (P less than 0.001) reduced by Tol as well as Tol-Zn. In the chronic model both the agents suppressed significantly (P less than 0.001) granuloma formation by 50 per cent. Zinc sulphate by itself reduced the rat paw edema by 39 per cent (P less than 0.02) and did not affect the other parameters. Zinc-complex appears to be an improved version of tolmetin as an antiinflammatory agent with no adverse effect on the healing process. Tolmetin-zinc promotes gain in breaking strength, not by increasing the collagen content, but by favouring better maturation of available collagen at the wound site.

Valoración de tolmetín sódico en niños con faringoamigdalitis aguda en comparación con naproxén sódico / Sodiun tolmetin in children with acute pheryngo-tonsilitis

Se valoró la eficacia antinflamatoria de tolmetín jarabe en dosis de 100 mg tres veces al día (TID) y naproxén sódico suspensión en dosis de 125 mg TID, durante seis días, mediante un estudio simple ciego en pacientes pediátricos con faringoamigdalitis aguda. Se valoró la evolución del cuadro clínico por la presencia de hiperemia, edema y exudado con controles al tercero y sexto días, obteniéndose con ambos fármacos una regresión de los signos, que fue altamente significativa (P<0.01) al tercer día de tratamiento, desapareciendo al sexto día. Los dos fármacos fueron bien tolerados. Se concluye que tometín sódico es un antinflamatorio eficaz, útil en el tratamiento de faringoamigdalitis y con una actividad antiflogística equipotente comparable a la de naproxén sódico

Analgesia con pirprofén en el posoperatorio de cirugía general / Postoperative analgesia with pirprofen in the postoperative period of general surgery

Se valoró, por medio de método doble ciego, el efecto analgésico de la administración en dosis única de pirprofén, diflunisal y zomepirac en el posoperatorio de cirugía general de 90 pacientes distribuidos en tres grupos. Las valoraciones se realizaron mediante una escala visual análoga al momento de tomar el medicamento, a los 15 y 30 minutos, y a la una, dos, tres y cuatro horas después. El efecto analgésico inmediato de pirprofén fue satisfactorio y estadísticamente superior a diflunisal y zomepirac (p=<0.01). Al final del estudio los tres medicamentos tuvieron resultados semejantes entre sí. En cuanto a la tolerancia, fue satisfactoria para los tres medicamentos

Pirprofén en cirugía bucal / Pirprofen in oral surgery

Se valoró, mediante estudio doble ciego, el efecto analgésico de pirprofén, diflunisal y zomepirac, comparando los efectos de la administración en dosis única en 60 pacientes adultos sometidos a cirugía bucal. Los resultados demuestran que pirprofén tuvo acción más rápida que diflunisal, con efecto similar casi al final del estudio, y que tanto pirprofén como diflunisal resultaron más eficaces que zomepirac

Evaluacion doble ciego de la eficacia analgesica y tolerancia de zomepirac sodico y dipirona, a dosis unica en dolor posoperatorio. / Double blind evaluation of the analgesic efficacy and tolerance of zomepirac sodium and dipyrone, in a single dose during post-operative pain

En un estudio doble ciego se trataron 90 pacientes de ambos sexos, y mayores de 18 anos, que presentaban dolor posoperatorio de intensidad moderada o severa, para valorar la eficacia analgesica de zomepirac sodico en comparacion con dipirona y placebo. Los medicamentos y el placebo fueron administrados en dosis unica, en forma de capsulas identicas, conteniendo 100 mg de zomepirac sodico o 500 mg de dipirona o placebo y se valoro la evolucion del dolor tanto en intensidad como en disminucion, inicialmente, 1/2 hora despues de la administracion y despues a la 1, 2, 3, 5 y 6 horas subsecuentes. Cien mg de zomepirac sodico demostraron poseer mayor eficacia que 500 mg de dipirona, con una accion analgesica mas rapida que empieza a manifestarse desde la 1/2 hora de su administracion, logrando su maxima actividad entre la primera y la cuarta hora