RESUMEN
This review presents the most relevant investigations concerning the biocatalytic kinetic resolution of racemic ketoprofen to dexketoprofen for the last 22 years. The advantages related to the administration of the dex-enantiomer in terms of human health, the so called "chiral switch" in the pharmaceutical industry and the sustainability of biotransformations have been the driving forces to develop innovative technology to obtain dexketoprofen. In particular, the kinetic resolution of racemic ketoprofen through enantiomeric esterification and hydrolysis using lipases as biocatalysts are thoroughly revised and commented upon. In this context, the biocatalysts, acyl-acceptors (alcohols), reaction conditions, conversion, enantiomeric excess, and enantiomeric ratio among others are discussed. Moreover, the investigations concerning scaling up processes in order to obtain an optically pure enantiomer of the profen are presented. Finally, some guidelines about perspectives of the technology and research opportunities are given.
Asunto(s)
Cetoprofeno/análogos & derivados , Trometamina , Biocatálisis , Química Farmacéutica , Esterificación , Humanos , Hidrólisis , Cetoprofeno/química , Cetoprofeno/metabolismo , Cinética , Lipasa , Estereoisomerismo , Trometamina/química , Trometamina/metabolismoRESUMEN
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common type of medication used in the treatment of acute pain. Ketorolac trometamol (KT) is a nonnarcotic, peripherally acting nonsteroidal anti-inflammatory drug with analgesic effects comparable to certain opioids. OBJECTIVE: The aim of this study was to compare the efficacy of KT and naproxen (NA) in the treatment of acute low back pain (LBP) of moderate-to-severe intensity. PATIENTS AND METHODS: In this 10-day, Phase III, randomized, double-blind, double-dummy, noninferiority trial, participants with acute LBP of moderate-to-severe intensity as determined through a visual analog scale (VAS) were randomly assigned in a 1:1 ratio to receive sublingual KT 10 mg three times daily or oral NA 250 mg three times daily. From the second to the fifth day of treatment, if patient had VAS >40 mm, increased dosage to four times per day was allowed. The primary end point was the reduction in LBP as measured by VAS. We also performed a post hoc superiority analysis. RESULTS: KT was not inferior to NA for the reduction in LBP over 5 days of use as measured by VAS scores (P=0.608 for equality of variance; P=0.321 for equality of means) and by the Roland-Morris Disability Questionnaire (P=0.180 for equality of variance test; P=0.446 for equality of means) using 95% confidence intervals. The percentage of participants with improved pain relief 60 minutes after receiving the first dose was higher in the KT group (24.2%) than in the NA group (6.5%; P=0.049). The most common adverse effects were heartburn, nausea, and vomiting. CONCLUSION: KT is not inferior in efficacy and delivers faster pain relief than NA.
Asunto(s)
Ketorolaco/administración & dosificación , Dolor de la Región Lumbar/tratamiento farmacológico , Naproxeno/administración & dosificación , Trometamina/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Método Doble Ciego , Humanos , Ketorolaco/química , Ketorolaco/metabolismo , Naproxeno/química , Naproxeno/metabolismo , Trometamina/química , Trometamina/metabolismoRESUMEN
This study evaluated the effect of the use of hypometabolic TRIS extenders in the presence or the absence of AMPK activators as well as the utilization of high cooling rates in the refrigeration step on the freezability of stallion sperm. Twelve ejaculates were cryopreserved using Botucrio® as a control extender and a basic TRIS extender (HM-0) separately supplemented with 10 mM metformin, 2mM 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), 2 mM Adenosine monophosphate (AMP), 40 µM compound C AMPK inhibitor or 2 mM AMP+40 µM compound C. Our results showed that the utilization of a hypometabolic TRIS extender supplemented or not with AMP or metformin significantly improves stallion sperm freezability when compared with a commercial extender. Additionally, high cooling rates do not affect stallion sperm quality after cooling and post-thawing. Finally, stallion spermatozoa present several putative AMPK sperm isoforms that do not seem to respond to classical activators, but do respond to the Compound C inhibitor.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Criopreservación/veterinaria , Crioprotectores/metabolismo , Caballos/fisiología , Preservación de Semen/veterinaria , Espermatozoides/citología , Trometamina/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Adenosina Monofosfato/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Criopreservación/métodos , Hipoglucemiantes/metabolismo , Masculino , Metformina/metabolismo , Ribonucleótidos/metabolismo , Preservación de Semen/métodos , Motilidad Espermática/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismoRESUMEN
Potentiometric titrations of the mixtures of lanthanide(III) perchlorates and bis-Tris propane (BTP) reveal formation of dinuclear hydroxo complexes M2(BTP)2(OH)n(6-n), where M = La(III), Pr(III), Nd(III), Eu(III), Gd(III), and Dy(III) and n = 2, 4, 5, or 6, in the pH range 7-9. ESI-MS data confirm the presence of dinuclear species. Kinetics of the hydrolysis of bis(4-nitrophenyl) phosphate (BNPP), mono-4-nitrophenyl phosphate (NPP), and 4-nitrophenyl acetate (NPA) in the lanthanide(III)-BTP systems has been studied at 25 degrees C in the pH range 7-9. The second-order rate constants for the hydrolysis of BNPP by individual lanthanide hydroxo complexes have been estimated by using the multiple regression on observed rate constants obtained at variable pH. For a given metal, the rate constants increase with increasing in the number n of coordinated hydroxide ions. In a series of complexes with a given n, the second-order rate constants decrease in the order La > Pr > Nd > Eu > Gd > Dy. Hydrolysis of NPP follows Michaelis-Menten-type "saturation" kinetics. This difference in kinetic behavior can be attributed to stronger binding of NPP dianion than BNPP monoanion to the lanthanide(III) species. Activities of lanthanide complexes in the hydrolysis of NPA, which is 10(6) times more reactive than BNPP in alkaline or aqueous hydrolysis, are similar to those in BNPP hydrolysis indicating unique capability of lanthanide(III) cations to stabilize the transition state of phosphate diester hydrolysis. Results of this study are analyzed together with literature data for other metal cations in terms of the Brønsted correlation and transition state-catalyst complexation strength.