RESUMEN
We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Cetoprofeno/análogos & derivados , Dolor/tratamiento farmacológico , Trometamina/análogos & derivados , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/farmacocinética , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Biotransformación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Flurbiprofeno/administración & dosificación , Flurbiprofeno/farmacología , Inyecciones Intraventriculares , Cetoprofeno/farmacología , Cetoprofeno/toxicidad , Ketorolaco , Masculino , Morfina/administración & dosificación , Morfina/farmacología , Dolor/inducido químicamente , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Tolmetina/administración & dosificación , Tolmetina/análogos & derivados , Tolmetina/farmacología , Trometamina/farmacología , Trometamina/toxicidad , Ácido ÚricoAsunto(s)
Lesión Renal Aguda/inducido químicamente , Antiinflamatorios no Esteroideos/efectos adversos , Tolmetina/análogos & derivados , Adolescente , Antiinflamatorios no Esteroideos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ketorolaco , Tolmetina/administración & dosificación , Tolmetina/efectos adversosRESUMEN
The pharmacokinetics of 2 doses of intravenous ketorolac (0.5 and 0.9 mg x kg-1) were studied in 14 children (age 2-8 years). A single dose of the drug was injected into the dorsum vein of one hand. Blood samples were collected at regular time intervals for 6 hours. Serum ketorolac concentrations were assayed using a high pressure liquid chromatography method. Pharmacokinetic values were estimated by a nonlinear computer program. The distribution volume (Vdarea), the total clearance (Cltotal), and elimination half-life (t1/2 beta) were similar in both groups of children who either received 0.5 or 0.9 mg x kg-1 of ketorolac. The estimated geometric mean Vdarea, Cltotal, and t1/2 beta ratios (95% CI in parentheses) for 0.9 mg x kg-1:0.5 mg x kg-1 were 1.24 (0.82, 1.50), 1.14 (0.88, 1.23), and 1.083 (0.40, 1.81), respectively. The pharmacokinetic parameters found in this study are different from those found by other authors in adult subjects.
Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Tolmetina/análogos & derivados , Abdomen/cirugía , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/uso terapéutico , Análisis de Varianza , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Humanos , Inyecciones Intravenosas , Ketorolaco , Masculino , Dolor Postoperatorio/prevención & control , Programas Informáticos , Tolmetina/administración & dosificación , Tolmetina/sangre , Tolmetina/farmacocinética , Tolmetina/uso terapéuticoRESUMEN
OBJECTIVE: To determine the incidence of side effects with the short-term use of intravenously administered ketorolac in children and the overall cost savings with a unit dosing system. STUDY DESIGN: We prospectively examined the incidence of complications arising from the intravenous administration of ketorolac to 1747 children (14,810 doses) during a 3-year, 3-month period and assessed cost savings resulting from dividing 60 mg syringes into 7.5, 15, 30, and 60 mg unit doses. Complications were recorded prospectively into a computerized database. Estimated drug costs to the pharmacy were calculated on the basis of the total numbers of each drug fraction administered, with allowance for 1O% wastage as a result of drug expiration. RESULTS: Side effects occurring with ketorolac administration were rare. Four patients (0.2%) had hypersensitivity reactions to the drug, two of them possibly on the basis of latex allergy. Two patients (O.1%) had renal complications but were subsequently found to have underlying causes that could account for their renal symptoms. One patient (0.05%) had massive gastrointestinal bleeding in the postoperative period. With fractionation of 60 mg syringes, total drug cost to the pharmacy was $34,786, rather than the $86,639 that would have been spent had a single syringe been used for each dose. CONCLUSION: Ketorolac proved safe for short-term intravenous use in children more than 1 year of age when patients with known contraindications to the use of non-steroidal antiinflammatory drugs were excluded. A considerable reduction in drug costs can be achieved with fractionation of premixed syringes into unit doses.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Tolmetina/análogos & derivados , Adolescente , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/economía , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/economía , Niño , Preescolar , Ahorro de Costo , Costos de los Medicamentos , Hipersensibilidad a las Drogas/etiología , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Hipersensibilidad/etiología , Incidencia , Lactante , Sistemas de Información , Inyecciones Intravenosas , Ketorolaco , Enfermedades Renales/etiología , Látex/efectos adversos , Sistemas de Medicación/economía , Servicio de Farmacia en Hospital/economía , Hemorragia Posoperatoria/inducido químicamente , Estudios Prospectivos , Seguridad , Jeringas , Tolmetina/administración & dosificación , Tolmetina/efectos adversos , Tolmetina/economía , Tolmetina/uso terapéuticoRESUMEN
The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.
Asunto(s)
Analgésicos/farmacología , Cafeína/farmacología , Óxido Nítrico/antagonistas & inhibidores , Tolmetina/análogos & derivados , Animales , Cafeína/administración & dosificación , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Ketorolaco , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , Tolmetina/farmacologíaRESUMEN
The pharmacokinetics of ketorolac, a potent analgesic agent used for relief of moderate to severe pain, has been studied in rats who received oral doses of 1, 3.2 or 5.6 mg/kg of ketorolac tromethamine. Blood samples were obtained at selected times during 24 h after medication, and ketorolac concentrations were determined by high performance liquid chromatography. After administration of ketorolac, blood concentrations increased rapidly reaching a dose-dependent maximal concentration in about 20 min. Then, concentrations decayed with a half-life of about 6 h. A linear increase in Cmax and AUC as a function of the dose was observed, and not statistically significant difference was observed in AUC/dose or Cmax/dose between doses, indicating that pharmacokinetics of ketorolac is linear in the range of doses studied.
Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Tolmetina/análogos & derivados , Trometamina/análogos & derivados , Administración Oral , Animales , Femenino , Ketorolaco Trometamina , Cetosas , Ratas , Ratas Wistar , Tolmetina/administración & dosificación , Tolmetina/farmacocinética , Trometamina/administración & dosificaciónRESUMEN
The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.
Asunto(s)
Analgesia , Analgésicos no Narcóticos/farmacología , Arginina/análogos & derivados , Óxido Nítrico/antagonistas & inhibidores , Tolmetina/análogos & derivados , Analgésicos no Narcóticos/administración & dosificación , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Arginina/farmacología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Dipirona/farmacología , Femenino , Miembro Posterior , Ketorolaco , NG-Nitroarginina Metil Éster , Dimensión del Dolor , Ratas , Ratas Wistar , Tolmetina/administración & dosificación , Tolmetina/farmacología , Ácido Úrico/toxicidadRESUMEN
A new method for determination of ketorolac in blood or plasma samples by reversed-phase high-performance liquid chromatography has been developed. The method includes a double extraction with diethyl ether and detection by absorbance at 313 nm. Quantitation was performed by height ratios of ketorolac and the internal standard (sodium tolmetin). Detection limit of the method was 3 ng/ml using 1 ml of plasma and 10 ng/ml using 0.2 ml of blood. The method is linear in the range of concentrations typically obtained after therapeutic doses of the drug, has the advantages of using low volume of body fluid and the internal standard used is commercially available. Those characteristics allow us to conclude that this method is suitable for pharmacokinetic or drug monitoring studies.
Asunto(s)
Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Tolmetina/análogos & derivados , Animales , Cromatografía Líquida de Alta Presión , Humanos , Ketorolaco , Ratas , Espectrofotometría Ultravioleta , Tolmetina/sangre , Tolmetina/farmacocinéticaRESUMEN
This study shows that the nonsteroidal anti-inflammatory drug. Ketorolac, has an ionophore-like action for calcium, such a drug may transfer calcium through an hydrophobic phase. This property does not affect the respiratory rate of mitochondria. These results indicate that the ionophoretic effect is not due to an uncoupling action of Ketorolac. The effect of this compound was tested in a reperfusion model where it was observed that Ketorolac (1 mg/Kg weight) administered 30 min before an ischemic period was induced, reverts the arrhythmic effect of reperfusion. These results are in agreement with the analysis of the plasmatic concentrations of the enzymes creatine kinase and lactic dehydrogenase. It was found that the levels of such enzymes were lower in Ketorolac treated group, than in the untreated one. The results clearly indicate that Ketorolac prevents from the myocardial damage induced by reperfusion, probably by avoiding calcium overload in myocytes.
Asunto(s)
Ionóforos/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Tolmetina/análogos & derivados , Animales , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ionóforos/farmacología , Ketorolaco , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Wistar , Tolmetina/farmacología , Tolmetina/uso terapéuticoRESUMEN
The bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol and Dolac, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma-concentration-against-time curves were constructed. Maximal plasma concentration and AUC0-24 values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for Cmax and from 85 to 118% for AUC0-24. It is concluded that the two assayed formulations are bioequivalent.
Asunto(s)
Analgésicos/farmacocinética , Tolmetina/análogos & derivados , Trometamina/farmacocinética , Administración Oral , Adulto , Analgésicos/administración & dosificación , Analgésicos/sangre , Disponibilidad Biológica , Combinación de Medicamentos , Humanos , Ketorolaco Trometamina , Masculino , Comprimidos , Tolmetina/administración & dosificación , Tolmetina/sangre , Tolmetina/farmacocinética , Trometamina/administración & dosificaciónRESUMEN
Ketorolac is an analgesic drug known to induce its therapeutic effect by inhibiting prostaglandin synthesis. In this work we introduce the nonsteroidal antialgesic drug as a compound with ionophoretic properties for calcium ions, showing that ketorolac induces mitochondrial Ca++ release. This reaction did not depend on an uncoupler-like action, because the drug does not collapse the internal negative membrane potential nor does it affect oxidative phosphorylation. In addition, it is shown that ketorolac ferries calcium ions into energized liposomes and has a hydrophobic phase with an affinity constant of 4 x 10(-3). The therapeutic action of ketorolac is related to its ionophoretic properties in addition to its well known inhibitory effect on the cyclooxygenase enzyme.
Asunto(s)
Calcio/metabolismo , Ionóforos/farmacología , Tolmetina/análogos & derivados , Animales , Antiinflamatorios no Esteroideos/farmacología , Transporte Biológico , Calcio/farmacocinética , Concentración de Iones de Hidrógeno , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/fisiología , Ketorolaco , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiología , Membrana Dobles de Lípidos/metabolismo , Liposomas/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/fisiología , Fosforilación Oxidativa/efectos de los fármacos , Ratas , Rojo de Rutenio/farmacología , Sensibilidad y Especificidad , Tolmetina/farmacologíaRESUMEN
OBJECTIVE: To report a case of ketorolac tromethamine-induced acute renal failure and to discuss the risk factors that make patients more susceptible to the renal effects of nonsteroidal antiinflammatory drugs (NSAIDs). DATA SOURCES: Case reports and review articles identified by MEDLINE. Indexing terms included ketorolac, renal failure, and NSAIDs. DATA EXTRACTION: Data were abstracted from pertinent published English-language sources and were reviewed by all authors. DATA SYNTHESIS: Ketorolac is an intramuscularly administered NSAID with many of the same adverse effects associated with other oral NSAIDs. Although reversible depression of renal function has been associated with several NSAIDs, to date there have been no published reports of acute renal failure secondary to ketorolac administration. A 71-year-old woman received three doses of ketorolac to control the pain associated with pelvic and T11-T12 compression fractures. Over the next two days, the patient developed signs and symptoms of acute renal failure, including significant increases in blood urea nitrogen, serum creatinine, and peripheral edema. These signs and symptoms resolved over the next three to four days. Certain risk factors, several of which were present in this woman, make individual patients more susceptible to the renal affects of NSAIDs. These risk factors include advanced age, cirrhosis, volume depletion, congestive heart failure, gastrointestinal bleeding, and preexisting mild renal dysfunction. CONCLUSIONS: Caution should be taken when initiating ketorolac or any NSAID therapy with specific attention to risk factors that predispose a patient to renal dysfunction.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Fallo Renal Crónico/inducido químicamente , Tolmetina/análogos & derivados , Trometamina/efectos adversos , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Combinación de Medicamentos , Femenino , Humanos , Inyecciones Intramusculares , Ketorolaco Trometamina , Tolmetina/administración & dosificación , Tolmetina/efectos adversos , Trometamina/administración & dosificaciónRESUMEN
OBJECTIVE: To report a case of an anaphylactoid reaction to injectable ketorolac tromethamine in a patient with no prior history of allergies or risk factors associated with nonsteroidal anti-inflammatory drug-induced hypersensitivity reactions. CASE SUMMARY: A 37-year-old man without a significant medical history presented to an emergency department with vague, dull, left-sided chest pain. Myocardial infarction was ruled out based on an unremarkable electrocardiogram, chest X-ray, and laboratory data that were within normal limits. Sublingual nitroglycerin 0.4 mg, magnesium/aluminum hydroxide gel 30 mL, and intravenous ranitidine 50 mg were administered without resolution of symptoms. Ketorolac tromethamine 60 mg was administered intramuscularly with resolution of symptoms. The patient was discharged; however, within 30 minutes, he returned to the emergency department with facial swelling, shortness of breath, and chest tightness. Multiple doses of aerosolized albuterol and intravenous methylprednisolone and diphenhydramine were administered, resulting in a slight improvement of symptoms. The patient was admitted for a complete cardiac evaluation that proved negative. The allergic symptoms resolved and the patient was discharged without medication after a three-day hospitalization. DISCUSSION: Ketorolac tromethamine is the first injectable nonsteroidal antiinflammatory drug approved for short-term pain management. A review of the literature revealed no similar cases of anaphylactoid reaction. CONCLUSIONS: Healthcare professionals must be aware of the potential risks of anaphylactoid reactions, especially in light of the increased use of injectable ketorolac in the ambulatory setting and availability of the oral formulation.