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1.
J Pharmacol Exp Ther ; 345(1): 125-38, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23318470

RESUMEN

There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration.


Asunto(s)
Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Administración Oral , Animales , Antiinflamatorios/química , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Indoles/química , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Fármacos Neuroprotectores/química , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Espectrometría de Masas en Tándem
2.
Front Physiol ; 14: 1112906, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37275221

RESUMEN

Introduction: Cannabidiol (CBD) extract from the cannabis plant has biomedical and nutraceutical potential. Unlike tetrahydrocannabinol (THC), CBD products produce few psychoactive effects and pose little risk for abuse. There is emerging preclinical and clinical evidence that CBD is stress modulatory and may have anti-inflammatory properties. People across the United States legally ingest CBD-rich hemp extracts to manage mental and physical health problems, including stress and inflammation. Preclinical studies have revealed potential mechanisms for these effects; however, the impact of this prior work is diminished because many studies: 1) tested synthetic CBD rather than CBD-rich hemp extracts containing terpenes and/or other cannabinoids thought to enhance therapeutic benefits; 2) administered CBD via injection into the peritoneal cavity or the brain instead of oral ingestion; and 3) failed to examine potential sex differences. To address these gaps in the literature, the following study tested the hypothesis that the voluntary oral ingestion of CBD-rich hemp extract will attenuate the impact of stressor exposure on plasma and tissue inflammatory and stress proteins in females and males. Methods: Adult male and female Sprague Dawley rats (10-15/group) were randomly assigned to be given cereal coated with either vehicle (coconut oil) or CBD-rich hemp extract (L-M0717, CBDrx/Functional Remedies, 20.0 mg/kg). After 7 days, rats were exposed to a well-established acute model of stress (100, 1.5 mA, 5-s, intermittent tail shocks, 90 min total duration) or remained in home cages as non-stressed controls. Results: Stressor exposure induced a robust stress response, i.e., increased plasma corticosterone and blood glucose, and decreased spleen weight (a surrogate measure of sympathetic nervous system activation). Overall, stress-induced increases in inflammatory and stress proteins were lower in females than males, and oral CBD-rich hemp extract constrained these responses in adipose tissue (AT) and mesenteric lymph nodes (MLN). Consistent with previous reports, females had higher levels of stress-evoked corticosterone compared to males, which may have contributed to the constrained inflammatory response measured in females. Discussion: Results from this study suggest that features of the acute stress response are impacted by oral ingestion of CBD-rich hemp extract in female and male rats, and the pattern of changes may be sex and tissue dependent.

3.
Bioorg Med Chem Lett ; 22(6): 2338-42, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22342142

RESUMEN

The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.


Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Antiasmáticos/síntesis química , Asma/tratamiento farmacológico , Benzamidas/síntesis química , Inhibidores Enzimáticos/síntesis química , Pirroles/síntesis química , Enfermedad Aguda , Aldehído Oxidorreductasas/metabolismo , Animales , Antiasmáticos/administración & dosificación , Antiasmáticos/uso terapéutico , Asma/inducido químicamente , Asma/enzimología , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Ratones , Ovalbúmina , Pirroles/administración & dosificación , Pirroles/uso terapéutico , S-Nitrosoglutatión/metabolismo , S-Nitrosotioles/metabolismo , Relación Estructura-Actividad
4.
Regul Toxicol Pharmacol ; 62(1): 115-24, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22210450

RESUMEN

S-nitrosoglutathione reductase is the primary enzyme responsible for the metabolism of S-nitrosoglutathione (GSNO), the body's main source of bioavailable nitric oxide. Through its catabolic activity, GSNO reductase (GSNOR) plays a central role in regulating endogenous S-nitrosothiol levels and protein S-nitrosation-based signaling. By inhibiting GSNOR, we aim to increase pulmonary GSNO and induce bronchodilation while reducing inflammation in lung diseases such as asthma. To support the clinical development of N6022, a first-in-class GSNOR inhibitor, a 14-day toxicology study was conducted. Sprague-Dawley rats were given 2, 10 or 50 mg/kg/day N6022 via IV administration. N6022 was well tolerated at all doses and no biologically significant adverse findings were noted in the study up to 10 mg/kg/day. N6022-related study findings were limited to the high dose group. One male rat had mild hepatocellular necrosis with accompanying increases in ALT and AST and several male animals had histological lung assessments with a slight increase in foreign body granulomas. Systemic exposure was greater in males than females and saturation of plasma clearance was observed in both sexes in the high dose group. Liver was identified as the major organ of elimination. Mechanistic studies showed dose-dependent effects on the integrity of a rat hepatoma cell line.


Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Benzamidas/farmacocinética , Benzamidas/toxicidad , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Pirroles/farmacocinética , Pirroles/toxicidad , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Asma/tratamiento farmacológico , Benzamidas/sangre , Benzamidas/orina , Bilis/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/orina , Heces/química , Femenino , Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Pirroles/sangre , Pirroles/orina , Ratas , Ratas Sprague-Dawley
5.
Bioorg Med Chem Lett ; 21(19): 5849-53, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21855338

RESUMEN

The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious S-nitrosoglutathione reductase (GSNOR) inhibitor and is currently undergoing clinical development for the treatment of acute asthma. GSNOR is a member of the alcohol dehydrogenase family (ADH) and regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). Reduced levels of GSNO, as well as other nitrosothiols (SNOs), have been implicated in the pathogenesis of many diseases including those of the respiratory, cardiovascular, and gastrointestinal systems. Preservation of endogenous SNOs through GSNOR inhibition presents a novel therapeutic approach with broad applicability. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on removal of cytochrome P450 inhibition activities. We identified potent and novel GSNOR inhibitors having reduced CYP inhibition activities and demonstrated efficacy in a mouse ovalbumin (OVA) model of asthma.


Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Benzamidas/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Pirroles/farmacología , Animales , Asma/tratamiento farmacológico , Asma/enzimología , Benzamidas/química , Benzamidas/toxicidad , Inhibidores Enzimáticos del Citocromo P-450 , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/toxicidad , Humanos , Imidazoles/farmacocinética , Imidazoles/toxicidad , Pulmón/patología , Pulmón/fisiopatología , Ratones , Estructura Molecular , Terapia Molecular Dirigida , Nivel sin Efectos Adversos Observados , Pirroles/química , Pirroles/toxicidad , Receptores Opioides delta/metabolismo , S-Nitrosoglutatión/metabolismo , Relación Estructura-Actividad
6.
Bioorg Med Chem Lett ; 21(6): 1670-4, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21324685

RESUMEN

There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 21(12): 3671-5, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21570838

RESUMEN

S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach.


Asunto(s)
Aldehído Oxidorreductasas/antagonistas & inhibidores , Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Propionatos/química , Propionatos/farmacología , Pirroles/química , Pirroles/farmacología , Benzamidas/síntesis química , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Concentración 50 Inhibidora , Estructura Molecular , Propionatos/síntesis química , Pirroles/síntesis química , Estereoisomerismo , Relación Estructura-Actividad
8.
Int J Toxicol ; 30(5): 466-77, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21868767

RESUMEN

To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period. Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds.


Asunto(s)
S-Nitrosoglutatión/farmacocinética , S-Nitrosoglutatión/toxicidad , Pruebas de Toxicidad/métodos , Administración por Inhalación , Animales , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Determinación de Punto Final , Eritrocitos , Femenino , Masculino , Nitratos/sangre , Nitratos/farmacocinética , Nitratos/orina , Nivel sin Efectos Adversos Observados , Ratas , Ratas Wistar , Ovinos
9.
Regul Toxicol Pharmacol ; 55(1): 28-32, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19497343

RESUMEN

The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.


Asunto(s)
Antibacterianos/efectos adversos , Diaminas/efectos adversos , Irritantes/efectos adversos , Mucosa Nasal/efectos de los fármacos , Tiofenos/efectos adversos , Administración Intranasal , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Disponibilidad Biológica , Diaminas/administración & dosificación , Diaminas/sangre , Diaminas/farmacocinética , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Edema/inducido químicamente , Eritema/inducido químicamente , Femenino , Irritantes/administración & dosificación , Irritantes/farmacocinética , Masculino , Mupirocina/administración & dosificación , Mupirocina/efectos adversos , Mupirocina/sangre , Mupirocina/farmacocinética , Mucosa Nasal/patología , Nariz , Pomadas/efectos adversos , Pomadas/farmacocinética , Conejos , Tiofenos/administración & dosificación , Tiofenos/sangre , Tiofenos/farmacocinética
10.
Cell Rep ; 6(1): 56-69, 2014 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-24388745

RESUMEN

Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hígado/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , S-Nitrosotioles/farmacología , Acetaminofén/toxicidad , Aldehído Oxidorreductasas/metabolismo , Animales , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/uso terapéutico , S-Nitrosotioles/uso terapéutico , Pez Cebra , Proteínas de Pez Cebra/metabolismo
12.
ACS Med Chem Lett ; 2(5): 402-6, 2011 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-24900320

RESUMEN

S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal function. In GSNOR knockout mice, basal airway tone is reduced and the response to challenge with bronchoconstrictors or airway allergens is attenuated. Consequently, GSNOR has emerged as an attractive therapeutic target for several clinically important human diseases. As such, small molecule inhibitors of GSNOR were developed. These GSNOR inhibitors were potent, selective, and efficacious in animal models of inflammatory disease characterized by reduced levels of GSNO and bioavailable NO. N6022, a potent and reversible GSNOR inhibitor, reduced bronchoconstriction and pulmonary inflammation in a mouse model of asthma and demonstrated an acceptable safety profile. N6022 is currently in clinical development as a potential agent for the treatment of acute asthma.

13.
Reprod Toxicol ; 30(4): 619-24, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20708074

RESUMEN

We determined the toxicity of faropenem medoxomil (FPM) in neonatal/juvenile dogs following 28 days of administration. The puppies received vehicle or FPM beginning on Postnatal Day (PND) 22 at respective dose levels of 0, 100, 300, 600, or 1400 mg/kg-d (four daily doses (QID) of 25, 75, 150, or 350 mg/kg/dose), respectively, at a dose volume of 5 mL/kg/dose. Body weight, food consumption, clinical observation, clinical pathology, urine analysis and TK were evaluated. Body weight in males and kidney findings at 1400 mg/kg-d were considered adverse. Comparison of Day 27 TK values with Day 1 parameters showed a change in FPM pharmacokinetic behavior over time with an apparent increase in the rate of clearance characterized by a decrease in AUC(0-6) and T(max) values on Day 27 with little to no change in C(max) values. Based on these results, the No Observed Adverse Effect Level was 600 mg/kg-d.


Asunto(s)
Antibacterianos/toxicidad , beta-Lactamas/toxicidad , Envejecimiento , Animales , Antibacterianos/sangre , Antibacterianos/química , Antibacterianos/farmacocinética , Desarrollo Óseo/efectos de los fármacos , Creatinina/orina , Perros , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Riñón/crecimiento & desarrollo , Riñón/patología , Masculino , Tasa de Depuración Metabólica , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/patología , Insuficiencia Renal/orina , Pruebas de Toxicidad Crónica , Aumento de Peso/efectos de los fármacos , beta-Lactamas/sangre , beta-Lactamas/química , beta-Lactamas/farmacocinética
14.
Int J Toxicol ; 25(2): 119-26, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16597550

RESUMEN

4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.


Asunto(s)
Antineoplásicos/toxicidad , Arabinonucleósidos/toxicidad , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/sangre , Arabinonucleósidos/farmacocinética , Recuento de Células Sanguíneas , Perros , Evaluación Preclínica de Medicamentos , Femenino , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Testículo/efectos de los fármacos , Testículo/patología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Tiroxina/sangre
15.
J Pharmacol Exp Ther ; 309(3): 894-902, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-14982966

RESUMEN

OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] is a liposomal formulation of the highly specific, noncompetitive, thymidylate synthase inhibitor OSI-7904 (also known as GW1843, 1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. The studies presented here were conducted to determine the antitumor efficacy, distribution, pharmacokinetics, and safety of OSI-7904L in mice. In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior antitumor efficacy compared with OSI-7904 or 5-fluorouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 although still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904-treated animals. Tumor exposures, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional consistent with saturation of plasma clearance mechanisms. OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration.


Asunto(s)
Antineoplásicos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Indoles/farmacocinética , Quinazolinas/farmacocinética , Timidilato Sintasa/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Radioisótopos de Carbono , Modelos Animales de Enfermedad , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/sangre , Indoles/uso terapéutico , Isoindoles , Liposomas , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/sangre , Quinazolinas/uso terapéutico , Distribución Tisular , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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