RESUMEN
Severely-debilitating or life-threatening (SDLT) diseases include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT diseases is comparable to advanced cancer and the benefit vs. risk assessment and development of SDLT disease therapeutics should be similar to that of advanced cancer therapeutics. A streamlined development approach would allow patients with SDLT conditions earlier access to therapeutics and increase the speed of progression through development. In addition, this will likely increase the SDLT disease therapeutic pipeline, directly benefiting patients and reducing the economic and societal burden of SDLT conditions. Using advanced-stage heart failure (HF) as an example that illustrates the concepts applicable to other SDLT indications, this article proposes a streamlined development paradigm for SDLT disease therapeutics and recommends development of aligned global regulatory guidance.
Asunto(s)
Progresión de la Enfermedad , Descubrimiento de Drogas/métodos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Animales , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/tratamiento farmacológico , Enfermedades Transmisibles/epidemiología , Descubrimiento de Drogas/tendencias , Evaluación de Medicamentos/métodos , Evaluación de Medicamentos/tendencias , Insuficiencia Cardíaca/epidemiología , Humanos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/epidemiologíaAsunto(s)
Hígado Graso/cirugía , Trasplante de Hígado/normas , Cirugía Bariátrica , Medicina Basada en la Evidencia/métodos , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Monitoreo Fisiológico/métodos , Enfermedad del Hígado Graso no Alcohólico , Selección de Paciente , Atención Perioperativa/métodosRESUMEN
BACKGROUND: The STEPP group was established to investigate factors that affect long-term transplant outcomes including quality of life and other patient-reported outcomes between different transplant centers and patients. METHODS: Data were collected for 2,650 patients whose first renal transplant took place between 1992 and 2003 in five UK centers. Univariable and multivariable survival analyses were performed using eleven candidate explanatory variables. RESULTS: Graft survival was worse in Black (B) patients (HR B v W 1.57 95% CI 1.10, 2.24), and in South Asian (A) patients (HR A v W 1.39 95% CI 1.03, 1.85) compared to Whites (W) after adjusting for other factors including HLA mismatch, and time on dialysis. Time spent on dialysis pre-transplantation was non-linearly associated with patient, but not death-censored graft survival. Losing a functioning graft was a strong predictor of patient death. One site had both the best graft and the worst patient survival. CONCLUSIONS: Differences in patient and graft survival between ethnic groups cannot be explained by currently recognized factors. These, and the complex balance between optimum patient and graft survival which differs between sites in this study require further investigation.
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Supervivencia de Injerto , Trasplante de Riñón/etnología , Adolescente , Adulto , Pueblo Asiatico/estadística & datos numéricos , Población Negra/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Calidad de Vida , Diálisis Renal/estadística & datos numéricos , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Reino Unido/epidemiología , Población Blanca/estadística & datos numéricosRESUMEN
We describe a patient with loin pain hematuria syndrome who required bilateral nephrectomy because of intractable pain and urological complications. After bilateral nephrectomy, his pain disappeared for the first time in 40 years. He subsequently received a cadaveric renal transplant which, at 4-year follow-up, is working well. Although he has developed intermittent microscopic hematuria, there has been no significant recurrence of pain over the kidney. This is the first reported case of transplantation after bilateral nephrectomy for loin pain hematuria syndrome. It provides insight tnto the possible pathogenic mechanisms underlying the condition.
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Hematuria/cirugía , Trasplante de Riñón , Dolor/cirugía , Adulto , Hematuria/etiología , Hematuria/fisiopatología , Humanos , Riñón/fisiopatología , Masculino , Nefrectomía , Dolor/etiología , Dolor/fisiopatología , SíndromeAsunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antirreumáticos/administración & dosificación , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vasculitis/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Femenino , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Infliximab , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among Louisiana women. The incidence data from Louisiana Tumor Registry were used to calculate breast cancer incidence rates, which were compared with the combined rates from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program. Breast cancer mortality rates for Louisiana were compared with the US death rates from the National Center for Health Statistics (NCHS). Our data revealed that Louisiana women were not at a higher risk for developing breast cancer than women in the SEER areas, but that mortality rates in Louisiana were not correspondingly low. Although the percentage of cases diagnosed at an early stage (in situ and localized) increased in Louisiana from 1988 through 1997, the average in Louisiana was still below the level for the SEER areas (65.9% and 71.6%) in 1993-1997. The rates of in situ breast cancer significantly increased (on average 5.3% for whites per year and 7.1% for blacks), and localized breast cancer also significantly increased (2.6% for whites and 2.5% for blacks), while the incidence of distant stage breast cancer significantly decreased (3.4% for whites and 2.0% for blacks). Compared with white women, black women still were less likely to be diagnosed with early stage breast cancer in 1993-1997 (56.4% and 68.9%). Women residing in the parishes with high percentages of persons in poverty were less likely to be diagnosed with early stage of disease.
Asunto(s)
Neoplasias de la Mama/epidemiología , Población Negra , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Incidencia , Louisiana/epidemiología , Sistema de Registros/estadística & datos numéricos , Tasa de Supervivencia , Población BlancaRESUMEN
Mycophenolate mofetil (MMF) is an immunosuppressive agent that exerts relatively selective antiproliferative effects on T and B lymphocytes. Efficacy has been demonstrated in large-scale randomised studies, but the use of MMF is complicated by gastrointestinal upset and is associated with an increased incidence of tissue-invasive cytomegalovirus (CMV) disease. The gastrointestinal tract is a well recognised site for invasive CMV disease, and it has therefore been hypothesised that the abdominal pain commonly seen with MMF is related to CMV infection. This has only been tested in a single small uncontrolled study, where abdominal pain was associated with the presence of CMV on endoscopic biopsy. In contrast, the toxicity profile in 85 patients with psoriasis who had received relatively high dosages of mycophenolic acid, the active moiety of MMF, for up to 13 years showed that the incidence of gastrointestinal upset fell dramatically over time. We can find little evidence that CMV disease explains the gastrointestinal adverse event profile associated with MMF, and instead support the contention that high local concentrations of MMF have a direct toxic effect on cells of the small intestine. We do not recommend any changes to current policy on CMV prophylaxis in patients receiving MMF, although we recognise that some severe gastrointestinal adverse effects may be CMV-associated. The use of trough plasma concentration monitoring, divided doses and a gradually increasing dosage schedule may be of value in limiting toxicity.
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Infecciones por Citomegalovirus/inducido químicamente , Enfermedades Gastrointestinales/inducido químicamente , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Dolor/inducido químicamente , Humanos , Inmunosupresores/farmacología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Factores de RiesgoAsunto(s)
Paro Cardíaco , Trasplante de Riñón/mortalidad , Riñón/fisiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Causas de Muerte , Niño , Supervivencia de Injerto , Humanos , Trasplante de Riñón/fisiología , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the correlation between cisplatin sensitivity, intracellular glutathione, and platinum/DNA adduct formation (measured by atomic absorption spectroscopy) in a series of seven head and neck cancer cell lines, and to evaluate the effect of biochemical modulation of glutathione on platinum/DNA adduct formation and repair. METHODS: Cisplatin/DNA adducts were measured by atomic absorption spectroscopy. Glutathione content was measured by enzymatic assay and was modulated with buthionine sulfoximine. Apoptosis was measured by double-labeled flow cytometry. RESULTS: Intracellular glutathione concentration was strongly correlated with cisplatin resistance (P = 0.002, R2 = 0.7). There was also a statistically significant inverse correlation between cisplatin/DNA adduct formation and the IC50 for cisplatin in these cell lines. (P = 0.0004, R2 = 0.67). In addition, resistant cells were able to repair approximately 70% of cisplatin/DNA adducts at 24 h, while sensitive cells repaired less than 28% of adducts in the same period. However, despite the positive correlation between cellular glutathione and cisplatin resistance, there was no direct correlation between intracellular glutathione concentration and platinum/DNA adduct formation. Further, depletion of intracellular glutathione by buthionine sulfoximine did not dramatically alter formation of cisplatin/DNA adducts even though it resulted in marked increase in cisplatin cytotoxicity and was associated with increased apoptosis. CONCLUSIONS: These results suggest that glutathione has multiple effects not directly related to formation of cisplatin/DNA adducts, but may also be an important determinant of the cell's ability to repair cisplatin-induced DNA damage and resist apoptosis.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Aductos de ADN/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Células Escamosas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular , Aductos de ADN/genética , Reparación del ADN/efectos de los fármacos , Glutatión/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias de Células Escamosas/metabolismo , Neoplasias de Células Escamosas/patología , Platino (Metal)/química , Espectrofotometría Atómica , Células Tumorales CultivadasAsunto(s)
Inmunosupresores/efectos adversos , Trasplante de Riñón/inmunología , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/patología , Complicaciones Posoperatorias , Tacrolimus/efectos adversos , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/complicacionesRESUMEN
Rodent and nonrodent toxicology studies are currently expected to support Phase I trials of antineoplastic drugs in the United States. To determine the predictive value of these studies, we initiated a project to compare preclinical and clinical toxicity data within various drug classes. The first class analyzed was the platinum anticancer drugs. Twelve platinum analogues that had both preclinical (mice, rats and/or dogs) and clinical data from matching drug administration schedules were identified. The rodent LD10 (the dose that causes lethality in 10% of treated animals) or dog toxic dose high (a dose that when doubled causes lethality in dogs) correlated well with the human maximally tolerated dose on a mg/m2 basis. For every platinum analogue investigated, one-third the rodent LD10 or one-third the dog toxic dose high in mg/m2 gave a starting dose and a first escalation dose that did not exceed the clinical maximally tolerated dose. The dose-limiting toxicities in patients were previously observed in 7 of 7, 7 of 8, and 9 of 11 mouse, rat, and dog studies, respectively. Our data indicate that mice, rats, and dogs all had value in predicting a safe starting dose and the qualitative toxicities in humans for platinum anticancer compounds. The efficiency of Phase 1 trials could have been improved without sacrificing patient safety by allowing higher starting doses for this drug class than conventionally permitted.