RESUMEN
PURPOSE: Cancer patients are a particularly vulnerable population group, facing an increase in physical, mental, logistical and financial difficulties. This, as well as Ireland's increased focus on primary care with the Sláintecare health plan, led to the development of the Community Oncology Nursing Programme, where community nurses are trained to provide cancer care in the community. This paper sought to explore the lived experiences of the patients and nurses involved in this programme in order to examine its impact as well as determine facilitators and roadblocks for future development. METHODS: A qualitative examination of the service was carried out by interviewing cancer patients receiving care as part of the programme as well as the nurses delivering care, both in the community and hospital day-ward. Thematic analysis was used. RESULTS: Themes of improved patient experience, nurse-patient relationship, the importance of location and roadblocks to further implementation of the programme emerged. There was a universal belief that the programme offered benefits to the patient and improved their care in some manner. CONCLUSIONS: The Community Oncology Nursing Programme has been well received by both nurses and patients. The service provided by community nurses as part of this programme offers benefits to patients and an improved cancer service.
Asunto(s)
Enfermería en Salud Comunitaria , Neoplasias/enfermería , Servicio de Enfermería en Hospital , Enfermería Oncológica , Servicio de Oncología en Hospital , Adulto , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Investigación en Evaluación de Enfermería , Investigación CualitativaRESUMEN
PURPOSE: Ireland's Sláintecare health plan is placing an increased focus on primary care. A community oncology nursing programme was developed to train community nurses to deliver care in the community. While the initial pilot was proven to be clinically safe, no cost evaluation was carried out. This study aims to compare the costs of providing cancer support services in a day-ward versus in the community. METHODS: 183 interventions (40 in day-ward and 143 in community) were timed and costed using healthcare professional salaries and the Human Capital method. RESULTS: From the healthcare provider perspective, the day-ward was a significantly cheaper option by an average of 17.13 (95% CI 13.72 - 20.54, p < 0.001). From the societal perspective, the community option was cheaper by an average of 2.77 (95% CI -3.02 - 8.55), although this was a non-significant finding. Sensitivity analyses indicate that the community service may be significantly cheaper from the societal perspective. CONCLUSIONS: Given the demand for cost-viable options for primary care services, this programme may represent a national option for cancer care in Ireland when viewed from the societal perspective.
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Enfermería de Cuidados Críticos/economía , Hospitales Comunitarios/economía , Hospitales Comunitarios/estadística & datos numéricos , Hospitales/estadística & datos numéricos , Neoplasias/enfermería , Enfermería Oncológica/economía , Atención Primaria de Salud/economía , Adulto , Anciano , Anciano de 80 o más Años , Costos y Análisis de Costo , Enfermería de Cuidados Críticos/estadística & datos numéricos , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Enfermería Oncológica/estadística & datos numéricos , Atención Primaria de Salud/estadística & datos numéricosRESUMEN
BACKGROUND AND OBJECTIVE: The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man. METHODS: 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations. RESULTS: Single oral doses of 5-300 mg and repeated oral doses of 50-500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6-18.3 h (Day 7; Part B). V158866 reached steady state within 2-3 days of administration, with an accumulation ratio, based on AUC0-24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs. CONCLUSIONS: V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300-500 mg/day.
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Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Resultado del Tratamiento , Administración Oral , Adolescente , Adulto , Amidohidrolasas/análisis , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/sangre , Amidohidrolasas/orina , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Semivida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Piridonas/farmacología , Animales , Apoptosis/efectos de los fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Diseño de Fármacos , Sinergismo Farmacológico , Femenino , Humanos , Irinotecán , Ratones , Ratones Desnudos , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
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Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirimidinas/química , Pirroles/química , Agua/química , Administración Oral , Animales , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HCT116 , Proteínas HSP90 de Choque Térmico/metabolismo , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Relación Estructura-ActividadRESUMEN
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
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Amidohidrolasas/antagonistas & inhibidores , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , Urea/farmacología , Amidohidrolasas/metabolismo , Animales , Azetidinas/síntesis química , Azetidinas/química , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/químicaRESUMEN
PURPOSE: The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. METHODS: We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. RESULTS: VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. CONCLUSION: These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.
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Apoptosis/efectos de los fármacos , Proteínas del Choque Térmico HSC70/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Nucleósidos de Purina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Sistemas de Liberación de Medicamentos , Sinergismo Farmacológico , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Nucleósidos de Purina/farmacocinéticaRESUMEN
We have examined the role of age on the continuous positive airway pressure (CPAP) levels required to treat two groups of elderly (n=70) and young (n=70) sleep apneic patients, matched for disease severity (apnea/hypopnea index), body mass index and neck circumference. Elderly patients required lower CPAP levels compared to young [mean (sd): 6.9(1.9)cm H(2)O and 9.4(3.5)cm H(2)O, respectively; P<0.0001]. To investigate this finding, we studied the effects of CPAP and its components (inspiratory and expiratory positive airway pressure) on lung volume and upper airway resistance in two groups of elderly [n=9, age 71.7(3.3) years] and young [n=9, age 36.7(4.4)] patients with sleep apnea during wakefulness. CPAP produced a greater decrease in airway resistance (P=0.009) and a greater increase in lung volume (P=0.008) in the elderly compared to young patients. We conclude that both the greater lung inflation and the greater direct splinting of the upper airway contributed to the lower CPAP level required by the elderly. Ageing may be an important determinant of therapeutic CPAP levels in clinical practice, especially in older sleep apneic patients.
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Presión de las Vías Aéreas Positiva Contínua/métodos , Síndromes de la Apnea del Sueño/terapia , Adulto , Factores de Edad , Anciano , Resistencia de las Vías Respiratorias , Antropometría , Femenino , Humanos , Mediciones del Volumen Pulmonar , Masculino , Cuello/patología , Índice de Severidad de la Enfermedad , Síndromes de la Apnea del Sueño/patología , Síndromes de la Apnea del Sueño/fisiopatologíaRESUMEN
The antitumor and metabolic activities of 2-(4-aminophenyl)benzothiazoles and their fluorinated analogues cannot be explained or predicted by conventional chemical means. Their mode of anti-cancer action involves metabolism of the benzothiazoles to an as yet unidentified reactive species. This species then forms DNA adducts which provoke cell death. The electronic structures and possible intermediates of these compounds have been computed quantum mechanically. The counter-intuitive patterns of metabolism can only be explained by considering the active intermediate to be a nitrenium ion. The distribution of the highest occupied molecular orbital for the nitrenium species derived from each fluorinated analogue correlates perfectly with the production, or otherwise, of an exportable metabolite. Further related compounds have been analyzed by this method and the predictions of their metabolism have subsequently been verified experimentally.