RESUMEN
AIMS: Development of inhaled insulin has increased the need to understand its pulmonary safety. This study evaluated pulmonary function changes in diabetes patients receiving inhaled Technosphere Insulin (TI) or usual antidiabetes treatment (usual care). METHODS: This randomized, open-label study was conducted at 220 sites (25 July 2005 to 29 August 2008). Pulmonary function tests [forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), total lung capacity (TLC) and lung diffusion capacity for carbon monoxide (DL(CO))] were prospectively followed over 2 years in patients with type 1 or type 2 diabetes receiving TI (n = 730) or usual care (n = 824), along with a cohort without diabetes not receiving any specific therapy (n = 145). RESULTS: Baseline demographics and pulmonary function were similar between diabetes treatment groups. Lung function declined from baseline in all groups. TI was non-inferior to usual care for mean change in FEV(1) from baseline to month 24 [mean (s.e.m.) 0.037 (0.0119) l; 95% CI 0.014 to 0.060] using mixed-model repeated-measure with a pre-specified non-inferiority margin of 50 ml/year. After a greater initial decline at month 3 with TI, rate of change (slope) in FEV(1), FVC and DL(CO) (months 3-24) was not statistically different between treatment groups. TI was well tolerated; no serious safety concerns emerged. The most common respiratory event associated with TI was mild, transient cough, occurring within minutes of inhalation. CONCLUSIONS: Observed changes in lung function with TI were small, occurred early after therapy initiation, remained non-progressive over 2 years and were unlikely to be clinically meaningful.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Administración por Inhalación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Líquido del Lavado Bronquioalveolar , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Hipoglucemiantes/administración & dosificación , Inyecciones Subcutáneas , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Capacidad Pulmonar Total/efectos de los fármacos , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacos , Adulto JovenRESUMEN
The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.
Asunto(s)
Péptido C/sangre , Hipoglucemiantes/farmacocinética , Insulina/sangre , Insulina/farmacocinética , Disponibilidad Biológica , Glucemia , Diabetes Mellitus Tipo 2/sangre , Péptido 1 Similar al Glucagón/sangre , Péptidos Similares al Glucagón/administración & dosificación , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Insulina/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/sangreRESUMEN
MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Péptido 1 Similar al Glucagón/farmacocinética , Hipoglucemiantes/farmacocinética , Fragmentos de Péptidos/farmacocinética , Administración por Inhalación , Adulto , Anciano , Glucemia/metabolismo , Péptido C/metabolismo , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Ingestión de Energía , Femenino , Glucagón/sangre , Péptido 1 Similar al Glucagón/administración & dosificación , Péptido 1 Similar al Glucagón/efectos adversos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina/sangre , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/efectos adversosAsunto(s)
Difosfonatos/administración & dosificación , Osteítis Deformante/tratamiento farmacológico , Anciano , Fosfatasa Alcalina/sangre , Esquema de Medicación , Humanos , Hidroxiprolina/orina , Infusiones Intravenosas , Osteítis Deformante/sangre , Osteítis Deformante/diagnóstico por imagen , Osteítis Deformante/orina , Pamidronato , Cintigrafía , Inducción de Remisión , Índice de Severidad de la EnfermedadRESUMEN
A method of analysing the factors which contribute to the length of stay in England as an acute medical in-patient has been developed, and applied in both real-time and cross-sectional studies. The major factors delaying discharge were found to be the time taken to respond to treatment and the actions of agencies other than the acute medical unit of the hospital. Areas where improvement could be made have been identified and some changes implemented. The system can be applied to monitor the effect of such changes.
Asunto(s)
Ocupación de Camas/estadística & datos numéricos , Investigación sobre Servicios de Salud/métodos , Hospitales/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Recolección de Datos , Inglaterra , Episodio de Atención , Recursos en Salud/estadística & datos numéricos , Auditoría Administrativa/métodos , Auditoría Médica/métodos , Medicina Estatal/estadística & datos numéricosRESUMEN
AIDS patients (2 groups) had a blood deficiency (p less than 0.001) of coenzyme Q10 vs. 2 control groups. AIDS patients had a greater deficiency (p less than 0.01) than ARC patients. ARC patients had a deficiency (p less than 0.05) vs. control. HIV-infected patients had a deficiency (p less than 0.05) vs. control. The deficiency of CoQ10 increased with the increased severity of the disease, i.e., from HIV positive (no symptoms) to ARC (constitutional symptoms, no opportunistic infection or tumor) to AIDS (HIV infection, opportunistic infection and/or tumor). This deficiency, a decade of data on CoQ10 on the immune system, on IgG levels, on hematological activity constituted the rationale for treatment with CoQ10 of 7 patients with AIDS or ARC. One was lost to follow-up; one expired after stopping CoQ10; 5 survived, were symptomatically improved with no opportunistic infection after 4-7 months. In spite of poor compliance of 5/7 patients, the treatment was very encouraging and at times even striking.
Asunto(s)
Complejo Relacionado con el SIDA/enzimología , Síndrome de Inmunodeficiencia Adquirida/enzimología , Ubiquinona/análogos & derivados , Complejo Relacionado con el SIDA/sangre , Síndrome de Inmunodeficiencia Adquirida/sangre , Adulto , Coenzimas , VIH , Humanos , Ubiquinona/deficiencia , Ubiquinona/uso terapéuticoAsunto(s)
Diseño de Equipo , Reología , Velocidad del Flujo Sanguíneo , Humanos , Ultrasonido/instrumentaciónRESUMEN
Six untreated hypertensive patients and ten on therapy, but having elevated blood pressures, were treated with coenzyme Q10(CoQ10); 14/16 patients showed reductions (p less than 0.05-less than 0.001) in systolic pressures; 11/16 showed reductions (p less than 0.05-less than 0.001) in diastolic pressure; 9/10 showed reductions of elevated pressures to a normal range. By impedance cardiography and electrocardiography, there were no changes in cardiac outputs, stroke volumes and Heather Indices except for a few patients with changes of doubtful biological significance. 3/16 patients had exceptionally low basal specific activities of the succinate dehydrogenase-coenzyme Q10 reductase in blood which increased to a normal range on treatment. A greater deficiency of CoQ10 in the vascular system than in blood is likely. We consider that (1) the mechanism of reduction of elevated blood pressures by CoQ10 is based upon normalization or autoregulation of peripheral resistance rather than cardiac regulation, and (2) that the therapeutic activity of CoQ10 is not pharmacodynamic, but results from a translational increase in levels of CoQ10-enzymes in vascular tissue during ca. 4-12 weeks.
Asunto(s)
Hipertensión/tratamiento farmacológico , Ubiquinona/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Volumen Sistólico/efectos de los fármacosAsunto(s)
Gasto Cardíaco , Neoplasias/fisiopatología , Ubiquinona/deficiencia , Deficiencia de Vitamina B 6/fisiopatología , Adulto , Anciano , Aspartato Aminotransferasas/sangre , Eritrocitos/enzimología , Frecuencia Cardíaca , Humanos , Persona de Mediana Edad , Neoplasias/complicaciones , Succinato Deshidrogenasa/sangre , Ubiquinona/sangre , Deficiencia de Vitamina B 6/complicacionesRESUMEN
This paper details our experience with the use of regression analysis and discriminant analyses, combined with a Bayes classifier, to evaluate the usefulness of a series of features derived in real time from a single channel of EEG. These features were 1) the number of zero crossings, 2) the number of zero crossings of the first derivative of the EEG, and 3) the number of zero crossings of the second derivative and five additional "histogram" measures. Each histogram measure represented the number of occurrences of a zero crossing interval falling within an arbitrarily selected range of values. The distributions of several measures conditioned on sleep stage are presented along with night-to-night and subject-to-subject variations in the measures. These details provide a basis for understanding effectiveness and limitations of zero crossing measures and the regression and discriminant analysis techniques. Our results permitted a range of 57-90% accurate classification with just zero crossing measures with the cross-correlation between computer- and hand-scored nightly sleep patterns ranging from 0.63-0.94. We consider these to be good and acceptable accuracies for this type of analysis.
Asunto(s)
Fases del Sueño/fisiología , Electroencefalografía , Humanos , Análisis de RegresiónAsunto(s)
Equipo Dental , Materiales Dentales , Resinas Compuestas , Matemática , Métodos , Reología , ViscosidadRESUMEN
Forty-five patients with chronic gastric ulcers were treated as out-patients in a double-blind comparison of gefarnate (geranyl farnesylacetate), 50 mg four times daily, with the same number of dummy capsules daily for five weeks. The mean percentage reduction in ulcer size assessed by radiography was 70-4 per cent in the gefarnate patients compared with 27-8 per cent in those receiving placebo capsules. This difference is statistically significant (p less than 0-05, with a two-tailed test). No change in the electrolyte balance occurred in any of the patients and no side-effects were reported. These results suggest that gefarnate promotes the healing of gastric ulcers in ambulant patients. Its apparent absence of side-effects makes it a safe ans useful drug.
Asunto(s)
Úlcera Gástrica/tratamiento farmacológico , Terpenos/uso terapéutico , Ensayos Clínicos como Asunto , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Fumar , Terpenos/administración & dosificaciónRESUMEN
The development of the Heart Beat Domain and the Fourier transform of the Heart Beat Domain (which we call the Beatquency Domain) has provided new and useful tools for the quantitative analysis of sleep level patterns. This method of analysis has produced remarkable intersubject as well as intra-subject consistency and the only physiologic parameter required in the analysis is beat-by-beat heart rate. This analytical tool was designed to aid in the detection of sleep cycles, or more specifically, the rhythmic transitions from REM+ (awake Stages 1 and REM combined) to NREM (Stage 2, 3 and 4 combined) over a normal night of sleep. Employing this method on minute-by minute sleep recordings from 9 normal sleep subjects, 2 complete nights each, we were able to distinguish between the REM+ and NREM stages with an average accuracy of approximately 80%. Considering that beat-by-beat heart rate was our only criteria, we felt that the algorithm performed with significant success.