Investigación de la resolución cinética eco-compatible de R/S-ketoprofeno

Se llevó a cabo la esterificación de R/S-ketoprofeno empleando metanol, etanol, 1- y 2-propanol como reactivos y solventes catalizada con el biocatalizador comercial Novozym® 435. Se estudió la interacción de los alcoholes con el biocatalizador mediante diversas técnicas espectroscópicas. Los resultados evidenciaron la disolución del soporte polimérico, la pérdida de proteína activa, la fuerte adsorción de los alcoholes, la modificación de la estructura secundaria de la proteína y el alisado de la estructura interna de las esferas de biocatalizador.Facultad de Ciencias Agrarias y Forestale

Investigación de la resolución cinética eco-compatible de R/S-ketoprofeno

Se llevó a cabo la esterificación de R/S-ketoprofeno empleando metanol, etanol, 1- y 2-propanol como reactivos y solventes catalizada con el biocatalizador comercial Novozym® 435. Se estudió la interacción de los alcoholes con el biocatalizador mediante diversas técnicas espectroscópicas. Los resultados evidenciaron la disolución del soporte polimérico, la pérdida de proteína activa, la fuerte adsorción de los alcoholes, la modificación de la estructura secundaria de la proteína y el alisado de la estructura interna de las esferas de biocatalizador.Facultad de Ciencias Agrarias y Forestale

Investigación de la resolución cinética eco-compatible de R/S-ketoprofeno

Se llevó a cabo la esterificación de R/S-ketoprofeno empleando metanol, etanol, 1- y 2-propanol como reactivos y solventes catalizada con el biocatalizador comercial Novozym® 435. Se estudió la interacción de los alcoholes con el biocatalizador mediante diversas técnicas espectroscópicas. Los resultados evidenciaron la disolución del soporte polimérico, la pérdida de proteína activa, la fuerte adsorción de los alcoholes, la modificación de la estructura secundaria de la proteína y el alisado de la estructura interna de las esferas de biocatalizador.Facultad de Ciencias Agrarias y Forestale

Investigación experimental y teórica de la resolución cinética ecocompatible de R/S-ketoprofeno

Se llevó a cabo la esterificación de R/S-ketoprofeno empleando metanol, etanol y 1-propanol como reactivos y solventes catalizada con el biocatalizador comercial Novozym® 435. Se estudió la interacción de los alcoholes con el biocatalizador mediante diversas técnicas espectroscópicas. Los resultados evidenciaron la disolución del soporte polimérico, la pérdida de proteína activa, la fuerte adsorción de los alcoholes, la modificación de la estructura secundaria de la proteína y el alisado de la estructura interna de las esferas de biocatalizador. Sin embargo, ninguno de estos inconvenientes influye en la actividad del biocatalizador. Finalmente, los cálculos teóricos demostraron que el metanol ejerce impedimento estérico y electrónico en la etapa de coordinación del R/S-ketoprofeno con la tríada catalítica.Methanol, ethanol and 1-propanol were used as reactants and solvents in the esterification of R/Sketoprofen catalyzed with Novozym® 435. The interaction of the alcohols with Novozym® 435 was studied at a molecular level through various spectroscopic techniques. The results evidenced the dissolution of the polymeric support, loss of active protein, strong adsorption of the alcohols, modification of the secondary structure of the protein and smoothing of the inner structure of the biocatalyst’s beads. Nevertheless, none of those drawbacks influences the biocatalyst activity. Theoretical calculations demonstrated that methanol introduces steric and electronic hindrance from the step of the coordination of the R/S-ketoprofen with the catalytic triad.Centro de Investigación y Desarrollo en Ciencias Aplicada

Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer

Fil: Cura, Jorge E. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Blanzaco, Daniel P. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Brisson, Cecilia. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cura, Marco A. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cabrol, Rosa. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Larrateguy, Luis. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Mendez, Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Sechi, Jose Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Silveira, Jorge Solana. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Theiller, Elvira. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: de Roodt, Adolfo R. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.Fil: Vidal, Juan Carlos. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2)

Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer

Fil: Cura, Jorge E. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Blanzaco, Daniel P. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Brisson, Cecilia. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cura, Marco A. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cabrol, Rosa. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Larrateguy, Luis. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Mendez, Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Sechi, Jose Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Silveira, Jorge Solana. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Theiller, Elvira. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: de Roodt, Adolfo R. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.Fil: Vidal, Juan Carlos. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2)

Investigación de la resolución cinética eco-compatible de R/S-ketoprofeno

Se llevó a cabo la esterificación de R/S-ketoprofeno empleando metanol, etanol, 1- y 2-propanol como reactivos y solventes catalizada con el biocatalizador comercial Novozym® 435. Se estudió la interacción de los alcoholes con el biocatalizador mediante diversas técnicas espectroscópicas. Los resultados evidenciaron la disolución del soporte polimérico, la pérdida de proteína activa, la fuerte adsorción de los alcoholes, la modificación de la estructura secundaria de la proteína y el alisado de la estructura interna de las esferas de biocatalizador