RESUMEN
BACKGROUND: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC). METHODS: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured. RESULTS: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin. CONCLUSIONS: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Indoles/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Adenocarcinoma/sangre , Adenocarcinoma/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Proteínas Angiogénicas/sangre , Antineoplásicos Fitogénicos/uso terapéutico , Docetaxel , Resistencia a Antineoplásicos , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico por imagen , Inhibidores de Proteínas Quinasas/efectos adversos , Pirroles/efectos adversos , Radiografía , Sunitinib , Taxoides/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Several N-benzylpiperazino derivatives of [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-one and its 5-methyl homologue have been prepared and evaluated for H1-antihistamine activity on guinea pig ileum. The most potent compounds were also evaluated for their ability to stabilize mast cells in the rat passive peritoneal anaphylaxis (PPA) system and were shown to inhibit histamine release at concentrations below those required to inhibit extravasation, suggesting that this might be relevant to their antianaphylactic activity in this system. The compound tested with the most potent H1-antihistamine activity was 6-[3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy][1]benzopyrano[2,3- d]-1,2,3-triazol-9(1H)-one, 28, which had a pA2 of 9.1 against histamine on guinea pig ileum, comparable to that of mepyramine, and inhibited histamine release in the rat PPA system with an IC50 value of 5.4 X 10(-6) M.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/síntesis química , Mastocitos/efectos de los fármacos , Triazoles/síntesis química , Anafilaxia/prevención & control , Animales , Cobayas , Antagonistas de los Receptores Histamínicos H1/farmacología , Liberación de Histamina/efectos de los fármacos , Técnicas In Vitro , Ratas , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
Twenty-four substituted 4-hydroxy-3-nitrocoumarins have been prepared for nitration of the corresponding 4-hydroxycoumarins. All were found to possess antiallergic activity as measured by the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.
Asunto(s)
Cumarinas/síntesis química , Hipersensibilidad/tratamiento farmacológico , Animales , Reacciones Antígeno-Anticuerpo , Cumarinas/uso terapéutico , Inmunidad Celular , Isoanticuerpos , Nitrocompuestos/síntesis química , Nitrocompuestos/uso terapéutico , Anafilaxis Cutánea Pasiva , RatasRESUMEN
The synthesis and biological activity of a number of 4-hydroxy-3-nitro-2-quinolones are discussed and compared with their related hydroaromatic analogs. Antiallergic activity has been assessed by their ability to inhibit the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.
Asunto(s)
Hidroxiquinolinas/síntesis química , Hipersensibilidad/tratamiento farmacológico , Nitroquinolinas/síntesis química , Animales , Hidroxiquinolinas/uso terapéutico , Masculino , Nitroquinolinas/uso terapéutico , Anafilaxis Cutánea Pasiva , Ratas , Pruebas CutáneasRESUMEN
A short series of the title compounds was prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. All but the two N-methylated derivatives were active in this screen by the intravenous route, the most potent being the symmetrical dimethyl compound, 4,9-dihydro-6,7-dimethyl-4,9-dioxo-1H-naphtho[2,3-d]-v-triazole, and its 5-nitro derivative. The latter two compounds were noticeably more potent than disodium cromoglycate, and one of these, the unnitrated material, was selected for further evaluation as a potential antiasthmatic drug.
Asunto(s)
Hipersensibilidad/tratamiento farmacológico , Triazoles/farmacología , Animales , Masculino , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Ratas , Ratas Endogámicas , Triazoles/síntesis químicaRESUMEN
A number of 2-cyanoindan-1,3-diones and 3-cyano-4-hydroxycoumarins have been prepared and assessed for potential antiallergy activity as measured by their ability to inhibit passive cutaneous anaphylaxis in the rat, mediated by rat serum containing antigen specific IgE. The structural requirements for activity were similar not only for both series of compounds but also for the analogous 2-nitroindan-1,3-diones and 4-hydroxy-3-nitrocoumarins previously reported. The most active compounds were 2-cyano-5,6-diethylindan-1,3-dione (4e) and 3-cyano-6,7-diethyl-4-hydroxycoumarin (11h).
Asunto(s)
4-Hidroxicumarinas/síntesis química , Hipersensibilidad/tratamiento farmacológico , Indanos/síntesis química , Indenos/síntesis química , 4-Hidroxicumarinas/farmacología , Animales , Cromolin Sódico/farmacología , Inmunoglobulina E , Indanos/farmacología , Ovalbúmina/inmunología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that of disodium cromoglycate, the most potent being 6,7-dimethyl-9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole and its 4,4-dioxide.
Asunto(s)
Óxidos S-Cíclicos/farmacología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Triazoles/farmacología , Animales , Fenómenos Químicos , Química , Óxidos S-Cíclicos/síntesis química , Masculino , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Triazoles/síntesis químicaRESUMEN
In a small range finding study a number of N-benzylpiperazino derivates of 3-nitro-4-hydroxycoumarin have been shown to combine potent H1-antihistamine activity with that of mast cell stabilization as demonstrated by their activity as antagonists of histamine on guinea pig ileum and by their inhibition of the release of histamine in rat passive peritoneal anaphylaxis (PPA). The most potent compound, 1-[2-hydroxy-3-[(4-hydroxy-3-nitrocoumarin-7-yl)oxy]propyl]-4- (4-chlorobenzyl)piperazine, 30, had a pA2 of 9.0 against histamine on guinea pig ileum and inhibited histamine release in the rat PPA test with a potency similar to that of disodium cromoglycate.
Asunto(s)
4-Hidroxicumarinas/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Mastocitos/efectos de los fármacos , Piperazinas , Piperazinas/síntesis química , 4-Hidroxicumarinas/farmacología , Anafilaxia/fisiopatología , Animales , Líquido Ascítico , Cobayas , Liberación de Histamina/efectos de los fármacos , Íleon/efectos de los fármacos , Piperazinas/farmacologíaRESUMEN
Selected omega-nitroacetophenones, formed by the alcoholic cleavage of 2-nitroindandiones, have been shown to inhibit the homocytotropic antibody-antigen induced passive cutaneous analhylaxis reaction in the rat. The enzymatic cyclization of these derivatives to the parent nitroindandione has been demonstrated both in vivo and in vitro and this process is suggested as a possible prerequisite to biological activity.
Asunto(s)
Acetofenonas/síntesis química , Hipersensibilidad/tratamiento farmacológico , Acetofenonas/sangre , Acetofenonas/uso terapéutico , Animales , Ciclización , Técnicas In Vitro , Hígado/metabolismo , Nitrocompuestos/sangre , Nitrocompuestos/síntesis química , Nitrocompuestos/uso terapéutico , Anafilaxis Cutánea Pasiva , Ratas , Espectrofotometría UltravioletaRESUMEN
A series of the little compounds was prepared by cyclization of the appropriate 5-(aryloxy)-v-triazole-4-carboxylic acids and evaluated for antiallergic activity by the rat passive cutaneous anaphylaxis (PCA) screen. The most potent compounds were 6-(mesyloxy)-9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazole and its 5-methyl homologue, which were some tenfold more potent than disodium cromoglycate. Dialkyl derivatives, especially those substituted at C-5 and C-6 or C-6 and C-7, and 6-methoxy compounds were also among the more potent compounds. One compound, 6,7-dimethyl-9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazole, was further evaluated and shown to be a potent inhibitor of rat PCA when given orally.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Triazinas/síntesis química , Animales , Benzopiranos/uso terapéutico , Indicadores y Reactivos , Masculino , Anafilaxis Cutánea Pasiva , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Triazinas/uso terapéuticoRESUMEN
A selection of novel 2-hydroxy-3-nitro-1,4-naphthoquinones are shown to be potent inhibitors of rat passive cutaneous anaphylaxis (PCA) and to have highest potency with alkyl substitution at both C-6 and C-7. The most potent compounds were 7c and 7e which produced a 50% inhibition in the rat PCA test at doses of about 10 micrometerM/kg following subcutaneous administration and showed activity after oral administration. Related 4-hydroxy-3-nitro-2(1H)-naphthalenones had no effect on rat PCA in doses up to 500 micrometerM/kg.
Asunto(s)
Naftoquinonas/síntesis química , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Animales , Depresión Química , Masculino , Naftoquinonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The syntheses and structure--activity relationships of a number of 4-hydroxy-3-nitrocoumarins, which are both antagonists of a slow reacting substance of anaphylaxis and potent inhibitors of antigen-induced histamine release in the rat, are described. Most active among these are 7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy(-2-hydroxypropoxy] derivatives having hydrogen or lower alkyl substituents at the C-8 position of the coumarin ring, 168, 171, 173, and 174.
Asunto(s)
4-Hidroxicumarinas/síntesis química , Liberación de Histamina/efectos de los fármacos , SRS-A/antagonistas & inhibidores , 4-Hidroxicumarinas/farmacología , Animales , Métodos , Ratas , Relación Estructura-ActividadRESUMEN
1. The pA2 anti-acetylcholine activity in vitro for benapryzine was 6.55 compared with 9.02 for benzhexol.2. In vivo, the anti-acetylcholine activity of benapryzine relative to benzhexol was 0.038 as assessed by the mydriatic response of mice after subcutaneous administration. The relative activity assessed by the inhibition of pilocarpine-induced salivation was 0.13 after oral administration and 0.056 following subcutaneous administration of the drugs.3. Benapryzine had the same order of activity as benzhexol in inhibiting oxotremorine-induced tremors in mice.4. Benapryzine had anticonvulsant properties but no analgesic activity, whilst in high doses it antagonized the extrapyramidal symptoms induced by perphenazine in rats.5. In patients benapryzine was effective in reducing the symptoms of Parkinson's disease without overt anti-cholinergic effects or central hallucinogenic actions.6. Benapryzine abolished the excess tremor and reduced the rigidity and akinesia induced by physostigmine in Parkinsonian subjects.
Asunto(s)
Antiparkinsonianos/farmacología , Bencilatos/farmacología , Parasimpatolíticos/farmacología , Acetilcolina/antagonistas & inhibidores , Anciano , Animales , Antiparkinsonianos/uso terapéutico , Bencilatos/uso terapéutico , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Etilaminas/farmacología , Etilaminas/uso terapéutico , Tractos Extrapiramidales/efectos de los fármacos , Femenino , Cobayas , Humanos , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Midriáticos/farmacología , Oxotremorina/antagonistas & inhibidores , Enfermedad de Parkinson/tratamiento farmacológico , Perfenazina/antagonistas & inhibidores , Propilaminas/farmacología , Propilaminas/uso terapéutico , Ratas , Salivación/efectos de los fármacos , Factores de Tiempo , Trihexifenidilo/uso terapéuticoRESUMEN
1. Rats given an intravenous injection of Sephadex particles (0.5 mg of G200 in 1 ml of saline) on days 0, 2 and 5 had a blood eosinophilia which was maximal on day 7. 2. On day 7, broncho-alveolar lavage (BAL) fluids taken from the rats contained an increased number of eosinophils and fewer mononuclear cells but there was no change in the small number of neutrophils. In addition the rats were hyper-sensitive to the increase in resistance to artificial respiration produced by 5-hydroxytryptamine (5-HT), given intravenously, with a shift to the left of the log dose-response curve. Lung parenchymal strips, taken from the rats on days 6, 7 and 8, were hyper-reactive to 5-HT with an increase in slope of the log dose-response curve. 3. Compounds with a wide variety of activities were evaluated for their effects on the blood eosinophilia on day 7 when given before each injection of Sephadex. The eosinophilia was reduced by glucocorticosteroids, beta-adrenoceptor agonists, aminophylline, dapsone and phenidone. 4. Dexamethasone, isoprenaline, dapsone and phenidone at doses that reduced the blood eosinophilia also reduced the changes in number of leucocytes in the BAL fluids and the hyper-responsiveness to 5-HT in vivo and in vitro, except that the effects of dapsone on the hyper-sensitivity to 5-HT in vivo did not reach significance. Aminophylline was the least effective of the drugs at reducing the blood eosinophilia and its effects on the other changes did not reach significance. Sodium cromoglycate reduced the BAL eosinophilia but had no effect on the other changes produced by Sephadex. 5. The correlation coefficients between blood eosinophil numbers and reactivity to 5-HT in vitro and sensitivity in vivo were r = 0.76, (n = 88; P < 0.001) and r = 0.53, (n = 61; P < 0.001) respectively. 6. Doses of dexamethasone, isoprenaline, dapsone and phenidone that reduced the blood eosinophilia when given before each injection of Sephadex were inactive when given up to 8 h after the Sephadex. 7. These data show an association between blood eosinophilia and hyper-responsiveness of the lung. The blood eosinophilia in the rats was triggered within the first few hours of injecting the Sephadex and drugs have been identified which inhibit this trigger.
Asunto(s)
Dextranos , Eosinofilia/sangre , Enfermedades Pulmonares/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar/química , Eosinofilia/inducido químicamente , Eosinofilia/prevención & control , Técnicas In Vitro , Recuento de Leucocitos , Pulmón/efectos de los fármacos , Enfermedades Pulmonares/fisiopatología , Neutrófilos/efectos de los fármacos , Tamaño de la Partícula , Ratas , Ratas Endogámicas , Respiración Artificial , Serotonina/farmacologíaRESUMEN
Professionals may become frustrated when caring for the Chinese palliative patient and family, as we may expect them to behave or act like us. This paper discusses two distinctive characteristics which may be unfamiliar to Western caregivers. The first pertains to the concept of family-based popular health care, where the family assumes the major role of decision-maker on behalf of the patient. The second relates to the Eastern belief of silence surrounding the discussion of dying and the impending death, versus our Western orientation, which advocates openness and honesty. By gaining a greater understanding of these cultural traditions and practices, we can deliver more culturally sensitive health care to the Chinese patient and family.
Asunto(s)
Actitud Frente a la Muerte/etnología , Características Culturales , Cuidados Paliativos/psicología , Cuidado Terminal/psicología , Actitud Frente a la Salud/etnología , Cuidadores/psicología , China/etnología , Toma de Decisiones , Familia/psicología , Humanos , América del Norte , Relaciones Profesional-Familia , Revelación de la VerdadAsunto(s)
Amino Alcoholes/farmacología , Broncodilatadores/farmacología , Amino Alcoholes/síntesis química , Animales , Broncodilatadores/síntesis química , Catecoles/síntesis química , Catecoles/farmacología , Estimulación Eléctrica , Cobayas , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Rotación Óptica , Anafilaxis Cutánea Pasiva , Propilaminas/síntesis química , Propilaminas/farmacología , Ratas , Receptores Adrenérgicos/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Tráquea/efectos de los fármacosAsunto(s)
Antagonistas de los Receptores Histamínicos H1/síntesis química , Indenos/síntesis química , Animales , Reacciones Antígeno-Anticuerpo , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Liberación de Histamina/efectos de los fármacos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/prevención & control , Indenos/farmacología , Indenos/uso terapéutico , Masculino , Nitrocompuestos/síntesis química , Nitrocompuestos/farmacología , Nitrocompuestos/uso terapéutico , Ovalbúmina , Anafilaxis Cutánea Pasiva , RatasAsunto(s)
Parasimpatolíticos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Glicolatos/uso terapéutico , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Ratones , Músculo Liso/efectos de los fármacos , Pilocarpina/antagonistas & inhibidores , Pirrolidinonas/antagonistas & inhibidoresRESUMEN
Antigen challenge of rats, sensitized by intraperitoneal injection with rat anti-serum, did not result in a detectable increase in the 5-hydroxytryptamine (5-HT) levels in their peritoneal fluids over the background level induced by sensitisation alone. The maximum amount of extravasation produced by intraperitoneal injection of 5-HT into passively sensitised rats was less than that produced by antigen or histamine, and the doses of 5-HT producing these levels of extravasation produced an produced an increase of 5-HT concentrations in the peritoneal fluids. Therefore, 5-HT is unlikely to make much direct contribution to the extravasation produced during rat passive peritoneal anaphylaxis. However, when given intraperitoneally to rats, 5-HT potentiates the extravasation produced by histamine.
Asunto(s)
Anafilaxia/inmunología , Serotonina/farmacología , Animales , Líquido Ascítico/inmunología , Colorantes , Relación Dosis-Respuesta Inmunológica , Histamina/farmacología , Masculino , Metisergida/farmacología , Ovalbúmina/farmacología , Ratas , SRS-ARESUMEN
Four compounds with H1 anti-histamine activity and four adrenoceptor stimulants, each given to rats prior to passive peritoneal anaphylaxis (PPA), inhibited extravasation of serum proteins into the peritoneal fluid at doses which had no effect on histamine release. In contrast, aminophylline and some non-steroidal anti-inflammatory agents inhibited extravasation only at doses which inhibited histamine releases they showed a similar type of avtivity to that of disodium cromoglycate (DSCG) and a nitroindanedione (BRL 10833), although they were much less potent. Predosing with DSCG reduced the potency of subsequent doses of DSCG, BRL 10833 and indomethacin, but not of aminophylline or phenylbutazone, and therefore DSCG, BRL 10833 and indomethacin may share a common pathway to produce activity. In the rat PPA system, no evidence was found for histamine 'feedback' inhibition of histamine release.