Pharmacokinetics of continuous subcutaneous insulin infusion

Summary One of the reasons for the variability of blood glucose regulation in Type 1 (insulin-dependent) diabetic patients is the huge variation in subcutaneous absorption of intermediate-acting insulin. We have investigated the variation in insulin absorption during continuous subcutaneous insulin infusion in eight such patients. The content of insulin in the subcutaneous tissue was measured using ¹²⁵I-labelled insulin. The concentration of free serum insulin and blood glucose was followed from 1 h before and from 7 h after breakfast on two consecutive days. The amount of insulin absorbed during 24 h differed in all cases by less than 3% from the daily insulin dose given by the pumps. Mean insulin absorption rates and mean free insulin concentration showed peak values 30–90 min after meal bolus injections; this was sufficient to maintain near-normal blood glucose. Mean free serum insulin correlated strongly with disappearance of insulin from the subcutaneous tissue (r=0.98). From the insulin absorption rates and free insulin concentrations during basal constant insulin infusion, the half-time of serum insulin was calculated as 6 min. Compared with the known large variability in the absorption of intermediate-acting insulin, continuous subcutaneous insulin infusion offers a precise and reproducible way of insulin administration resulting in post-prandial serum insulin peaks sufficient to maintain near-normal blood glucose levels. The half-time of serum insulin during subcutaneous infusion corresponds to values for intravenous infusion given in the literature, indicating that local degradation of insulin in subcutaneous tissue is of minor importance.     

Radioiodinated anti-hepatocellular carcinoma (HCC) ferritin Targeting therapy,tumor imaging and anti-antibody response in HCC patients with hepatic arterial infusion

Summary Radioimmunoimaging and radioimmunotherapy with radioiodinated anti-(hepatocellular carcinoma ferritin) antibody (¹³¹I-or¹²⁵I-FtAb) have been applied in patients with primary liver cancer. A total of 41 patients with surgically unresectable hepatocellular carcinoma (HCC) and receiving hepatic artery ligation and cannulation during exploratory laparotomy were treated with this regimen by intrahepatic arterial infusion. Compared with the control group, a decline of serum -fetoprotein (65.7% versus 42.9%) and shrinkage of tumor (68.3% versus 33.9%) were observed in the treated group, and a higher second-look resection rate (31.7% versus 5.1%) and longer survival (1-year: 61.0% versus 37.3%, 3-year: 25.0% versus 6.9%) resulted. The administration of antibody through a hepatic arterial catheter (n=16) was compared with intravenous injection (n-17) in terms of the tumor-imaging sensitivity in 33 patients with liver cancer. The results indicated that hepatic arterial infusion was superior to intravenous injection. The sensitivity 7 days after the administration was 100% in the i.a. group and 76.5% in the i.v. group, the uptake ratio of tumor to liver being 1.74±0.57 in the former and 1.34±0.29 in the latter. Furthermore, intrahepatic arterial infusion revealed a lower anti-antibody detection rate than intravenous injection (0/14 versus 4/11).Abbreviations AFP -tetoprotein - FtAb ferritin antibody     

Peripherally inserted central venous catheters for treatment of cystic fibrosis

Patients who have cystic fibrosis (CF) are frequently hospitalized for long-term intravenous (IV) treatment. We evaluated clinical effectiveness of the Drum-Cartridge Catheter (Abbott Laboratories) for such patients. The catheter is placed peripherally under local anesthesia via an antecubital vein into the superior vena cava or right atrium. Patients who were more than 10 years of age and who were hospitalized for IV antibiotic therapy and/or IV hyperalimentation were studied. All but 2 patients had CF. Using an aseptic technique the catheters were inserted into the basilic or cephalic vein. Chest radiographs were used to confirm the final location of the catheter. Catheters were used to administer IV antibiotics, hyperalimentation, and lipids. There were 38 catheterizations in 23 patients; several patients had repeated insertions at later admissions. The success rate of insertion was 86% with 31 of the 38 insertions initially located either in the superior vena cava or right atrium. Mean duration of catheterization was 15.4 days (range 5-49 days). No major complications such as sepsis, catheter or clot embolism, pneumothorax, vascular perforation, or hemorrhage occurred in the patients who had DF. Complications that required displacement of catheter into the axillary vein (1 patient), and cracked catheter hub (1 patient). This study shows that the Drum-Cartridge Catheter can be used easily for IV therapy of patients who have CF for a long duration, repeatedly, and with no major complications.     

Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: sustained molecular remission after early and dose-escalating infusion of donor leucocytes

We present a patient who underwent sibling allogeneic BMT because of refractory Ph+ve ALL and remained BCR-ABL-positive after marrow grafting. Haemopoietic precursor cells were predominantly BCR-ABL-negative and of donor origin. In T cells an exclusively donor genotype was demonstrated. Despite donor leucocyte infusion (DLI), 20 weeks after BMT BCR-ABL fusion mRNA increased in semiquantitative polymerase chain reaction and leukaemic infiltration of the patient's bone marrow was seen. After a second course of DLI the patient achieved sustained molecular remission but he developed severe graft-versus-host disease (GvHD) and died from bacterial sepsis 9 months after DLI.     

Evaluation of insulin resistance during inhibition of endogenous insulin and glucagon secretion by somatostatin in non-obese subjects with impaired glucose tolerance

Summary Insulin resistance was studied in seven non-obese male subjects with impaired glucose tolerance and four healthy, age and body-weight matched male control subjects by means of a continuous intravenous infusion of somatostatin, glucose and insulin over 150 min. Glucose tolerance was evaluated by means of a 2-h glucose infusion test. Endogenous insulin (C-peptide), growth hormone, and glucagon secretion were suppressed by somatostatin in both groups. Steady-state plasma insulin and glucose levels were achieved between 90–135 min. Since similar steady-state levels of exogenous insulin were achieved, the resulting steady-state plasma glucose level provided a direct estimate of the ability of insulin to dispose of the infused glucose. The glucose levels were higher in subjects with impaired glucose tolerance with values of 14.6 ± 1.8 mmol/1 compared with 5.1 ± 1.2 mmol/1 in control subjects (p < 0.01), thus indicating insulin resistance. There was a direct correlation between the steady-state plasma glucose level and glucose tolerance suggesting that the degree of glucose intolerance is proportional to the degree of insulin resistance. These results revealed that decreased insulin sensitivity is found in non-obese subjects with impaired glucose tolerance.     

舒芬太尼靶控输注对非体外循环冠状动脉旁路移植术患者麻醉效果的影响

目的:比较不同效应室浓度的舒芬太尼靶控输注对非体外循环冠状动脉旁路移植术(OPCAB)患者麻醉效果的影响。方法:42例择期OPCAB的患者随机分为3组,分别在术中使用0.4ng/mL(组Ⅰ)、0.6ng/mL(组Ⅱ)和0.8ng/mL(组Ⅲ)固定效应室浓度的舒芬太尼靶控静脉麻醉。观察患者术中血流动力学及脑电双频普指数(BIS)值,记录术中舒芬太尼、丙泊酚、多巴胺用量,术后恢复时间及围手术期心肌酶谱[肌酸激酶(CK)与肌酸激酶同工酶(CK-MB)]。结果:3组患者术中都能维持满意的血流动力学。术中丙泊酚、多巴胺的用量,术后恢复时间和围手术期心肌酶谱差异无显著性(P>0.05)。但Ⅱ组与Ⅲ组患者舒芬太尼用量多于Ⅰ组(P<0.01),Ⅲ组患者心脏指数(CI)在手术开始时低于Ⅰ组(P<0.05),心率(HR)自搭桥开始后增快(与搭桥前比较P<0.01),Ⅰ组患者术中BIS值高于Ⅱ组与Ⅲ组(P<0.05)。结论:采用0.4ng/mL、0.6ng/mL或0.8ng/mL固定效应室浓度的舒芬太尼靶控静脉麻醉对OPCAB患者术中均可以维持满意的血流动力学,但0.6ng/mL为最合适的靶控浓度。     

The response to intravenous glucose infusion in normal and diabetic subjects

Summary Data from single injection studies on 23 normal subjects led to development of an intravenous primed — constant infusion test. The plasma glucose response to this test was determined in 48 normal and 24 diabetic subjects. Variation in plasma glucose concentration at equilibrium was minimal in normal and marked in diabetic subjects — assessed by the difference between maximum and minimum glucose concentration over the final 25 min of a 50 min infusion. This parameter was used successfully in predicting the course of 16 pregnant women with clinical suspicion of prediabetes unresolved by oral glucose tolerance tests.Submitted as part fulfillment of the requirements for Doctor of Medicine, Monash University, Melbourne, 1967.     

Blood glucose regulation using closed- and open-loop insulin delivery systems

Summary Glucose was infused into anaesthetized dogs before and after pancreatectomy. In the diabetics blood glucose was regulated first by closed-loop and then by open-loop insulin delivery schemes. Insulin requirements for the latter were determined by resolving the former into a sequence of 3 different infusion rates: during the baseline and recovery periods, basal insulin was delivered at 0.37±0.02 mU/kg/min, while during the 60 min glucose infusion (10 mg/kg/min) there was an 8 min infusion at 4.96±0.37 mU/kg/min and a 52 min component at 1.85±0.08 mU/kg/min. With the open-loop method under these highly standardized conditions glycaemia was similar to normal controls but IRI levels were significantly higher, 13.5 vs 8.0 U/ml (p<0.05) in the baseline and recovery periods and 74 vs 25 U/ml (p<0.05) during the glucose infusion. It was concluded that: constant normogly-caemia can be maintained in the basal state by a constant rate of peripheral insulin delivery but at rates resulting in peripheral hyperinsulinaemia; the glycaemic response to glucose infusion can be normalized by a two component waveform of insulin delivery; and the closed-loop method can serve as a useful guide in determining insulin requirements.