RESUMO
BACKGROUND AND OBJECTIVE: There is a paucity of data regarding tolerability of alkaline drugs administered subcutaneously. The aim of this study was to assess the tolerability of alkaline preparations of human albumin delivered subcutaneously to healthy humans. METHODS: We compared the tolerability of neutral versus alkaline (pH 10) formulations of human albumin in ten volunteers. With an intent to minimize the time required to reach physiological pH after injection, the alkaline formulation was buffered with a low concentration of glycine (20 mmol/L). Each formulation was given at two rates: over 5 seconds and over 60 seconds. A six-point scale was used to assess discomfort. RESULTS: For slow injections, there was a significant difference between pH 7.4 and pH 10 injections (0.4 ± 0.2 vs 1.1 ± 0.2, mean ± SEM; p = 0.025), though the degree of discomfort at pH 10 injections was only 'mild or slight'. For fast injections, the difference between neutral and alkaline formulations was of borderline significance. Inflammation and oedema, as judged by a physician, were very minimal for all injections, irrespective of pH. CONCLUSION: For subcutaneous drug administration (especially when delivered slowly), there was more discomfort associated with alkaline versus neutral formulations of albumin, though the discomfort was mild. This study suggests that there is little discomfort and inflammation resulting from subcutaneous administration of protein drugs formulated with weak buffers at alkaline pH.
Assuntos
Albuminas/administração & dosagem , Adulto , Albuminas/efeitos adversos , Albuminas/química , Soluções Tampão , Química Farmacêutica , Método Duplo-Cego , Edema/etiologia , Eritema/etiologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Inflamação/etiologia , Injeções Subcutâneas/efeitos adversos , Masculino , Oregon , Dor/diagnóstico , Dor/etiologia , Medição da Dor , Fatores de TempoRESUMO
To be effective in type 1 diabetes, algorithms must be able to limit hyperglycemic excursions resulting from medical and emotional stress. We tested an algorithm that estimates insulin sensitivity at regular intervals and continually adjusts gain factors of a fading memory proportional-derivative (FMPD) algorithm. In order to assess whether the algorithm could appropriately adapt and limit the degree of hyperglycemia, we administered oral hydrocortisone repeatedly to create insulin resistance. We compared this indirect adaptive proportional-derivative (APD) algorithm to the FMPD algorithm, which used fixed gain parameters. Each subject with type 1 diabetes (n = 14) was studied on two occasions, each for 33 h. The APD algorithm consistently identified a fall in insulin sensitivity after hydrocortisone. The gain factors and insulin infusion rates were appropriately increased, leading to satisfactory glycemic control after adaptation (premeal glucose on day 2, 148 ± 6 mg/dl). After sufficient time was allowed for adaptation, the late postprandial glucose increment was significantly lower than when measured shortly after the onset of the steroid effect. In addition, during the controlled comparison, glycemia was significantly lower with the APD algorithm than with the FMPD algorithm. No increase in hypoglycemic frequency was found in the APD-only arm. An afferent system of duplicate amperometric sensors demonstrated a high degree of accuracy; the mean absolute relative difference of the sensor used to control the algorithm was 9.6 ± 0.5%. We conclude that an adaptive algorithm that frequently estimates insulin sensitivity and adjusts gain factors is capable of minimizing corticosteroid-induced stress hyperglycemia.
Assuntos
Algoritmos , Diabetes Mellitus Tipo 1/complicações , Hiperglicemia/prevenção & controle , Estresse Psicológico/sangue , Corticosteroides/efeitos adversos , Corticosteroides/sangue , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Hidrocortisona/efeitos adversos , Hidrocortisona/sangue , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: Administration of small, intermittent doses of glucagon during closed-loop insulin delivery markedly reduces the frequency of hypoglycemia. However, in some cases, hypoglycemia occurs despite administration of glucagon in this setting. METHODS: Fourteen adult subjects with type 1 diabetes participated in 22 closed-loop studies, duration 21.5±2.0 h. The majority of subjects completed two studies, one with insulin + glucagon, given subcutaneously by algorithm during impending hypoglycemia, and one with insulin+placebo. The more accurate of two subcutaneous glucose sensors was used as the controller input. To better understand reasons for success or failure of glucagon to prevent hypoglycemia, each response to a glucagon dose over 0.5 µg/kg was analyzed (n=19 episodes). RESULTS: Hypoglycemia occurred in the hour after glucagon delivery in 37% of these episodes. In the failures, estimated insulin on board was significantly higher versus successes (5.8±0.5 versus 2.9±0.5 U, p<.001). Glucose at the time of glucagon delivery was significantly lower in failures versus successes (86±3 versus 95±3 mg/dl, p=.04). Sensor bias (glucose overestimation) was highly correlated with starting glucose (r=0.65, p=.002). Prior cumulative glucagon dose was not associated with success or failure. CONCLUSION: Glucagon may fail to prevent hypoglycemia when insulin on board is high or when glucagon delivery is delayed due to overestimation of glucose by the sensor. Improvements in sensor accuracy and delivery of larger or earlier glucagon doses when insulin on board is high may further reduce the frequency of hypoglycemia.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucagon/administração & dosagem , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Pâncreas Artificial , Adulto , Algoritmos , Automação , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Infusões Subcutâneas , Insulina/efeitos adversos , Monitorização Fisiológica , Fatores de TempoRESUMO
BACKGROUND: For automated prevention of hypoglycemia, there is a need for glucagon (or an analog) to be sufficiently stable so that it can be indwelled in a portable pump for at least 3 days. However, under some conditions, solutions of glucagon can form amyloid fibrils. Currently, the usage instructions for commercially available glucagon allow only for its immediate use. METHODS: In NIH 3T3 fibroblasts, we tested amyloid formation and cytotoxicity of solutions of native glucagon and the glucagon analog MAR-D28 after aging under different conditions for 5 days. In addition, aged native glucagon was subjected to size-exclusion chromatography (SEC). We also studied whether subcutaneous aged Novo Nordisk GlucaGen® would have normal bioactivity in octreotide-treated, anesthetized, nondiabetic pigs. RESULTS: We found no evidence of cytotoxicity from native glucagon or MAR-D28 (up to 2.5 mg/ml) at a pH of 10 in a glycine solvent. We found a mild cytotoxicity for both compounds in Tris buffer at pH 8.5. A high concentration of the commercial glucagon preparation (GlucaGen) caused marked cytotoxicity, but low pH and/or a high osmolarity probably accounted primarily for this effect. With SEC, the decline in monomeric glucagon over time was much lower when aged in glycine (pH 10) than when aged in Tris (pH 8.5) or in citrate (pH 3). Congo red staining for amyloid was very low with the glycine preparation (pH 10). In the pig studies, the hyperglycemic effect of commercially available glucagon was preserved despite aging conditions associated with marked amyloid formation. CONCLUSIONS: Under certain conditions, aqueous solutions of glucagon and MAR-D28 are stable for at least 5 days and are thus very likely to be safe in mammals. Glycine buffer at a pH of 10 appears to be optimal for avoiding cytotoxicity and amyloid fibril formation.
Assuntos
Glicemia/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Glucagon/farmacologia , Amiloide/química , Animais , Glicemia/metabolismo , Soluções Tampão , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Cromatografia em Gel , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Glucagon/administração & dosagem , Glucagon/análogos & derivados , Glucagon/química , Glucagon/toxicidade , Concentração de Íons de Hidrogênio , Injeções Subcutâneas , Camundongos , Células NIH 3T3 , Octreotida/farmacologia , Concentração Osmolar , Suínos , Fatores de TempoRESUMO
BACKGROUND: A cause of suboptimal accuracy in amperometric glucose sensors is the presence of a background current (current produced in the absence of glucose) that is not accounted for. We hypothesized that a mathematical correction for the estimated background current of a commercially available sensor would lead to greater accuracy compared to a situation in which we assumed the background current to be zero. We also tested whether increasing the frequency of sensor calibration would improve sensor accuracy. METHODS: This report includes analysis of 20 sensor datasets from seven human subjects with type 1 diabetes. Data were divided into a training set for algorithm development and a validation set on which the algorithm was tested. A range of potential background currents was tested. RESULTS: Use of the background current correction of 4 nA led to a substantial improvement in accuracy (improvement of absolute relative difference or absolute difference of 3.5-5.5 units). An increase in calibration frequency led to a modest accuracy improvement, with an optimum at every 4 h. CONCLUSIONS: Compared to no correction, a correction for the estimated background current of a commercially available glucose sensor led to greater accuracy and better detection of hypoglycemia and hyperglycemia. The accuracy-optimizing scheme presented here can be implemented in real time.
Assuntos
Automonitorização da Glicemia/métodos , Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Adulto , Algoritmos , Inteligência Artificial , Técnicas Biossensoriais , Calibragem , Interpretação Estatística de Dados , Feminino , Glucagon/administração & dosagem , Glucagon/uso terapêutico , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system. RESEARCH DESIGN AND METHODS: Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement. RESULTS: Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 +/- 6 vs. 40 +/- 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 +/- 0.6 vs. 2.1 +/- 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 +/- 0.8 vs. 4.0 +/- 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05). CONCLUSIONS: During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucagon/uso terapêutico , Hormônios/uso terapêutico , Hipoglicemia/prevenção & controle , Adulto , Glicemia/análise , Feminino , Glucagon/efeitos adversos , Hormônios/efeitos adversos , Humanos , Masculino , Resultado do TratamentoRESUMO
Chronically implanted biosensors typically lose sensitivity 1-2 months after implantation, due in large part to the development of a collagen-rich capsule that prevents analytes of interest from reaching the biosensor. Corticosteroids are likely candidates for reducing collagen deposition but these compounds have many serious side effects when given over a prolonged period. One method of assessing whether or not locally released corticosteroids have a systemic effect is to measure cortisol concentrations in venous serum. We hypothesized that a very low release rate of the potent corticosteroid, dexamethasone, would lead to a localized anti-inflammatory effect without systemic effects. We found that reduction in subcutaneous granulocytes (primarily eosinophils), and to a lesser extent, reduction of macrophages served as a good local indicator of the steroid effect. When released over a 28-day period, a total dexamethasone dose of < or =0.1 mg/kg led to a consistent reduction in the number of granulocytes and macrophages found in the local vicinity of the implant without a reduction of these cells at distant tissue locations. The lack of suppression of serum cortisol with these doses confirmed that low-release rates of dexamethasone can lead to consistent local anti-inflammatory effects without distant, systemic effects. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.