RESUMEN
The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 µg) and 0.12% (36 µg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 µg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.
Asunto(s)
Antihipertensivos/farmacología , Dinoprost/agonistas , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Hipertensión Ocular/tratamiento farmacológico , Prostaglandinas F Sintéticas/farmacología , Administración Tópica , Animales , Antihipertensivos/farmacocinética , Humor Acuoso/enzimología , Línea Celular , Cuerpo Ciliar/metabolismo , GMP Cíclico/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Femenino , Glaucoma/metabolismo , Guanilato Ciclasa/metabolismo , Iris/metabolismo , Latanoprost , Macaca fascicularis , Masculino , Donantes de Óxido Nítrico/farmacocinética , Hipertensión Ocular/metabolismo , Prostaglandinas F Sintéticas/farmacocinética , Conejos , Ratas , Tonometría OcularRESUMEN
A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Donantes de Óxido Nítrico/química , Nitrocompuestos/química , Inhibidores de Agregación Plaquetaria/química , Ácido Salicílico/química , Vasodilatadores/química , Animales , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacología , Aorta Torácica/efectos de los fármacos , Aspirina/farmacología , Carragenina , Evaluación Preclínica de Medicamentos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Hidrólisis , Masculino , Estructura Molecular , Donantes de Óxido Nítrico/clasificación , Donantes de Óxido Nítrico/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/clasificación , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Wistar , Ácido Salicílico/clasificación , Ácido Salicílico/farmacología , Soluciones/química , Estereoisomerismo , Vasodilatadores/clasificación , Vasodilatadores/farmacología , Agua/químicaRESUMEN
The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.
Asunto(s)
Envejecimiento/efectos de los fármacos , Aspirina/farmacología , Óxidos N-Cíclicos/farmacología , Flurbiprofeno/análogos & derivados , Masoprocol/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Flurbiprofeno/farmacología , Masculino , Ratones , Proyectos de Investigación , Análisis de SupervivenciaRESUMEN
Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Cardiomiopatía Dilatada/complicaciones , Enalapril/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico/metabolismo , Remodelación Ventricular/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Aorta , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/genética , Cricetinae , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Enalapril/análogos & derivados , Enalapril/farmacología , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Hemodinámica/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Mesocricetus , Contracción Miocárdica/efectos de los fármacos , Nitratos/sangre , Donantes de Óxido Nítrico/farmacología , Nitritos/sangre , Oxadiazoles/farmacología , Quinoxalinas/farmacología , Conejos , Sarcoglicanos , Ultrasonografía , Vasoconstricción/efectos de los fármacosRESUMEN
1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.