Continuous intravenous insulin therapy with a miniaturized open-loop system.

For the continuous intravenous application of insulin, a portable open-loop system was developed consisting of a delivery unit with a miniaturized pump and an insulin reservoir which is connected with an electronic control unit. The infusion rates were either preprogrammed or patient-controlled. Blood glucose control with both systems was tested in eight juvenile-type diabetics, among them two of the brittle type. Diabetic control during a 1-2-day pre-infusion period was compared with 2-3 days of continuous insulin infusion; as judged by the mean blood glucose value (MBG), the mean amplitude of glycemic excursions (MAGE), and glucosuria, all patients were significantly better controlled by the open-loop systems than by conventional therapy with subcutaneous insulin. The use of portable open-loop systems offers a promising approach to an improvement of metabolic control in insulin-requiring diabetics.     

An open-loop insulin delivery device for the control of experimental diabetes.

A new insulin delivery device has been developed and tested. It includes a reservoir, a pump, and a power pack. The reservoir holds 75 ml and is coupled to a precision peristaltic pump whose delivery can be set to any one of 128 different flow rates from 0 to 80 microliter/min (+/- 1.6% over 10 months) using the flow rate controller included in the battery power pack. The system weighs 525 g, consuming 50 mW at the maximum pumping rate, proportionately less at lower rates. Ten pumps have undergone bench tests for 30 days. One has been subjected to an extended life test of 16 months without change of tubing while seven complete systems have been used on dogs to demonstrate their capability for precise long-term (up to 16 months) intravenous insulin therapy. With this system, experimental diabetes has been controlled in 7 dogs for periods now extending beyond 16 months. This device now qualifies for-long term studies on hospitalized patients with diabetes mellitus.     

The external artificial pancreas: an instrument to induce remissions in severe recent juvenile diabetes. Comparison with a preprogrammed insulin infusion system.

Remission of juvenile insulin-dependent diabetes is a rare, temporary, and partial phenomenon which seems to be related to an improvement of the residual insulin secretion supported by prompt and rigorous insulin therapy. Thus, remissions allowing the replacement of insulin by oral drugs were attempted in 23 insulin dependent ketotic juvenile diabetics (age 10 +/- 2 years) of recent onset (apparent duration of diabetes 71 +/- 5 days) treated by an external artificial pancreas during 5 +/- 1 days and compared with 10 control diabetics treated by a less effective technique (preprogrammed insulin pump without feedback control) during 6 +/- 1 days. 18 (78%) remissions of long duration (1-26 months) occurred after artificial pancreas compared with 3 (30%) in the control group. Measurement of daily urinary C-peptide excretion confirmed the improvement of the residual insulin secretion in patients with insulin-induced remissions. Thus, the excellent blood glucose control given by an artificial pancreas seems necessary to lead to much more frequent remissions of diabetes than usually reported.     

High antigenicity of intraperitoneal insulin infusion via implantable devices: preliminary rat studies.

Intraperitoneal insulin infusion of Genapol stabilized insulin via implantable devices significantly improves diabetes control and hypoglycemia frequency in type 1 diabetes while it increases insulin antibody levels. Causes for this particular antigenicity remain unknown. The role of insulin modifications occurring in the reservoir on the antigenicity observed was assessed by comparing the antigenicities of the insulin coming from the vial or from the pump reservoir. Rats were injected intraperitoneally with insulin sampled either from a vial (group 1) or from a pump reservoir during a refill of a clinical trial (group 2). Two control groups, one without insulin, the second one receiving a mixture of silicone and insulin were also studied. Human insulin antibody levels were assessed by RIA 10 days after 4 weekly immunizations. AIA levels were higher in group 1 compared to group 2 (P = 0.003 for the first experiment, P = 0.04 in the second experiment). The increased antigenicity of the insulin sampled from the implanted pump might be due to the insulin modifications occurring during the storage in the device. Insulin aggregates could be involved in this antigenicity since they are known to be antigenic and their concentration was shown to be related to the amplitude of the antigenic response.     

Cell therapy for ischaemic stroke

While acute neuroprotection in acute stroke has proven difficult and ended in many failures, there is increasing interest in restorative therapies that target brain remodelling. Cell therapy (transplantation of cells) shows promise, with a growing body of pre-clinical evidence demonstrating improved functional outcomes in animal models; however, questions still remain concerning mechanisms of action. Clinical trials are already underway and will increase in the next few years; their appropriate design and execution along with continued pre-clinical work are necessary for the field to advance and satisfy a large unmet clinical need.     

Technological problems of miniaturized insulin dosing devices and some approaches to clinical trials.

With the long-term goal of developing implantable insulin dosing devices, we have since 1971 developed various types of programme-controlled units for clinical research. In the initial stage, a 24-hour, fixed-programme bed-side device has been in clinical use since 1973. The good results with even labile diabetics has supplied the basis for the further development of sensorless units. Via intermediate stages, two types of miniaturized portable devices were constructed: fixed-programme and demand-programme devices. The essential equipment components have been optimized with a view to later implantability: hermetically sealed capsule for the dosing device, refilling membrane for the insulin reservoir, bubble-free drawing off of the insulin via a wick from a collapsible silicone reservoir, the stepping motor-driven roller pump of approx. 9 cm3 volume, an energy consumption of about 50 mu W, and electronic safety and alarm circuits. Because of stability problems of the insulin, the neutral insulin U-1000 used initially was changed to acid insulin U-100 (both from Hoechst).     

Impaired insulin secretion in the neonatal rhesus monkey after chronic hyperinsulinemia in utero

The secretion of insulin by the pancreas of the newborn rhesus monkey that had been made experimentally hyperinsulinemic in utero was studied in 18 animals. Chronic in utero hyperinsulinemia was produced by the continuous subcutaneous delivery of 4.75 units of insulin per day for 18 +/- 1 days. After delivery, the insulin-containing pump was removed to allow neonatal insulin levels to drop to normal levels. By 6.5 +/- 1.0 hr after pump removal, plasma glucose, insulin, and C-peptide immunoreactivity (CPIR) were comparable in the control and experimental animals. At that point 300 micrograms of glucagon/kg body weight was given iv to stimulate insulin secretion. After 30 min a significant elevation (expressed as the percentage of basal levels) in plasma glucose by 250%, insulin by 200%, and CPIR by 200% was observed in the control animals. In contrast, no changes in plasma insulin or CPIR concentrations occurred, with an attenuated glucose response that was only one-fifth of the control response, in the experimental animals. These results along with the observed lowered concentrations of CPIR in the plasma and insulin in the pancreas at birth can be interpreted as evidence that insulin is an inhibitor of its synthesis and secretion in utero and that this abnormal intrauterine environment causes changes that persist into extrauterine life.     

Severe hyperkalaemia and ketoacidosis during routine treatment with an insulin pump.

During a feasibility study of the use of insulin pumps to treat diabetes ketoacidosis occurred at a rate of 0.14 episodes/patient/year in the first year but was lower in subsequent years. A case of cardiac arrest secondary to hyperkalaemia during ketoacidosis occurred in a patient treated with a pump. The mean (SD) serum potassium concentration on presentation to hospital with ketoacidosis was significantly higher in patients treated with a pump (5.7 (1.1) mmol(mEq)/l) than those treated with conventional injections of insulin (4.9(0.9) mmol/l; p less than 0.01). The high rate of ketoacidosis and raised serum potassium concentrations during treatment with the pump creates doubt about the use of this treatment as an alternative regimen for large numbers of patients in a busy diabetic clinic.     

Recent advances in liposomal drug-delivery systems

Liposomal drug-delivery systems have come of age in recent years, with several liposomal drugs currently in advanced clinical trials or already on the market. It is clear from numerous pre-clinical and clinical studies that drugs, such as antitumor drugs, packaged in liposomes exhibit reduced toxicities, while retaining, or gaining enhanced, efficacy. This results, in part, from altered pharmacokinetics, which lead to drug accumulation at disease sites, such as tumors, and reduced distribution to sensitive tissues. Fusogenic liposomal systems that are under development have the potential to deliver drugs intracellularly, and this is expected to markedly enhance therapeutic activity. Advances in liposome design are leading to new applicants for the delivery of new biotechology products, such as recombinant proteins, antisense oligonucleotides and cloned genes.     

Gene delivery methods in cardiac gene therapy

Gene therapy for the treatment of heart failure is emerging as a multidisciplinary field demonstrating advances with respect to identifying key signaling pathways, modernized vector creation and delivery technologies. Although these discoveries offer significant progress, selecting optimal methods for the vector delivery remains a key component for efficient cardiac gene therapy to validate the targets in rodent models and to test clinically relevant ones in pre-clinical models. Although the goals of higher transduction efficiency and cardiac specificity can be achieved with several delivery methods, the invasiveness and patient safety remain unclear for clinical application. In this review, we discuss various features of the currently available vector delivery methods for cardiac gene therapy.     

A multiscale mathematical model of avascular tumor growth to investigate the therapeutic benefit of anti-invasive agents

With the aim of inhibiting cancer growth and reducing the risk of metastasis, pharmaceutical companies in the early 1990s developed anti-metastatic agents called inhibitors of metalloproteinases (MMPi). Despite the promising results obtained in pre-clinical studies, results of Phase III trials have been somewhat disappointing for late stage cancer patients. With the aim of mathematically investigating this therapeutic failure, we developed a mechanistically based model which integrates cell cycle regulation and macroscopic tumor dynamics. By simulating the model, we evaluated the efficacy of MMPi therapy. Simulation results predict the lack of efficacy of MMPi in advanced cancer patients. The theoretical model may aid in evaluating the efficacy of anti-metastatic therapies, thus benefiting the design of prospective clinical trials.     

Bioengineered 3D Human Kidney Tissue,a Platform for the Determination of Nephrotoxicity

The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug–induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs.     

Hybrid Closed-Loop Insulin Pump Technology Can Be Safely Used in the Inpatient Setting

BackgroundHybrid closed-loop (HCL) systems, also known as automated insulin delivery systems, are a rapidly growing technology in diabetes management. Because more patients are using these systems in the outpatient setting, it is important to also assess inpatient safety to determine whether HCL use can be continued when those patients become hospitalized.MethodsThe records of patients using HCL technology on admission to our hospital between June 1, 2020, and June 30, 2021, were analyzed.ResultsThe final analysis included 71 patients divided into 3 categories based on their pump use as an inpatient: (1) HCL users; (2) manual pump users; and (3) pump removed. All cohorts were similar in age, sex, race, hemoglobin A1C at admission, and in Medicare Severity Diagnosis Related Group. Pairwise comparisons indicated that patient-stay mean glucose levels, frequency of patient-specific hyperglycemic measurements, and frequency of hypoglycemic events were similar between all groups. No adverse events, particularly occurrences of diabetic ketoacidosis, pump site complications or infection, or equipment malfunction, were reported.ConclusionThis preliminary case series review indicates that continued use of HCL technology in the hospital is safe. Moreover, glycemic control in HCL users was comparable with that in those using insulin pump with manual settings and those converted to basal-bolus insulin therapy.     

超声介导镇痛药物透皮吸收研究进展

现阶段,临床中常用的镇痛药物多采用口服或注射给药的方式,具全身不良反应多,患者依从性差等缺点,透皮给药作为一种非侵入性给药方式,相对于这些有很多显著的优势,如使用方便,患者痛苦少等。但是,如何克服皮肤的低渗透性一直是该种给药方式发展的瓶颈。近年来,使用超声能量增强镇痛药物在皮肤上的的渗透性成为新的研究热点,各项研究发现,低频超声对药物的增透效果尤为显著。本文通过检索各国文献,对超声介导镇痛药物透皮吸收的原理,临床前试验和临床试验进行综述。     

Factors Associated With Insulin Pump Discontinuation in Adults With Diabetes: A Time-to-Invent Analysis and Prediction Model

ObjectiveInsulin pump discontinuation has mostly been studied in children and adolescents living with diabetes. We aimed to assess the rate of insulin pump continuation in a population of adult patients with diabetes, at 18 months after initiation; determine the factors associated with pump discontinuation; and develop a simple prediction model.MethodsThis single-center, retrospective study included all adult patients with type 1 diabetes or type 2 diabetes who started insulin pump treatment between January 2015 and June 2018. The exclusion criteria were pregnancy, short-term pregnancy plans, and insulin pump discontinuation within the previous 6 months. The probability of insulin pump continuation after 18 months was estimated using the Kaplan-Meier method. Factors associated with insulin pump discontinuation were studied using a Cox regression model, and an exponential model was built for prediction purposes.ResultsThe study included 315 patients. The mean age was 41 years, the mean duration of diabetes was 16 years, 50% were men, 74% had type 1 diabetes, and the mean hemoglobin A1c level was 9.1% (76 mmol/mol). After 18 months, the rate of insulin pump continuation was 0.80 (95% Confidence Interval (CI), 0.76-0.85). By multivariate analysis, the occurrence of severe hypoglycemia in the previous year was associated with insulin pump discontinuation (hazard ratio, 2.42; 95% CI, 1.30-4.51), while other factors did not reach statistical significance.ConclusionInsulin pump discontinuation occurred in 20% of patients at 18 months after initiation and was mainly associated with a recent history of severe hypoglycemia. The type of diabetes and glycemic control at baseline were not associated with treatment discontinuation.     

A Bridge to Insulin Pump Therapy: Twice-Daily Regimen with NPH and Detemir Insulins During Initial Treatment of Youth with Type 1 Diabetes Mellitus

ObjectiveTo describe clinical outcomes in youth with new-onset type 1 diabetes mellitus (TlDM) treated with a modified, twice-daily regimen of a mixture of NPH insulin and rapid-acting insulin analogue at breakfast and separate injections of rapid-acting insulin analogue and insulin detemir at dinner.MethodsOur clinic database was used to describe changes in insulin doses, hemoglobin A_1c (A1C) levels, and frequency of severe hypoglycemia during the first year of therapy in young patients with T1DM diagnosed between September 2006 and April 2009. Data are presented as median values (25%, 75%).ResultsOverall, 108 patients (62 girls; mean age, 10.0 ± 0.4 years) were eligible for inclusion. Total daily insulin doses at 3, 6, and 12 months were 0.6 (0.4, 0.8), 0.7 (0.4, 0.9), and 0.8 (0.6, 0.9) U/kg, respectively. A1C levels were 9.8% (8.5%, 10.8%) at 2 weeks (baseline). Of the 108 patients, 19 had switched to insulin pump therapy by 3 months and 49 had switched by 12 months after initial diagnosis of T1DM. The 49 pump-treated patients had an A1C of 6.9% (6.6%, 7.3%), whereas the 59 injection- treated patients had an A1C of 7.2% (6.7%, 7.7%) by 12 months. There were only 6 severe hypoglycemic events in 5 patients; none occurred during the first 3 months, none occurred during the night, and all occurred in patients receiving insulin injection treatment.ConclusionA twice-daily insulin regimen that uses insulin detemir for overnight basal replacement and morning NPH insulin to avoid lunch and afternoon snack doses is an effective initial treatment for young patients with new-onset T1DM that can provide a smooth transition to intensive basal/bolus insulin pump therapy. (Endocr Pract. 2011;17:862-866)     

Tissue reaction to intraperitoneally implanted catheter materials

The limiting factor that introduces long-term complications of intraperitoneal (i.p.) catheters used, for example, with the Programable Implantable Medication System (PIMS) is the encapsulation of the catheter tip with tissues due to tissue reaction. The objective is the development of new catheters for PIMS or other systems for i.p. insulin delivery that allow continued insulin flow. The study is based on two hypotheses: (1) vascularized tissue will grow into a porous end plug mounted at the catheter tip (100–300 μm pore diameter), with sufficient blood supply to carry the insulin to the circulation; (2) use of a narrow pore diameter (25 μm or less) end plug will prevent tissue ingrowth yet allow insulin flow. The biological response to the following materials, all designed for use in catheters, were studied: polyurethane, segmented polyether-urethane, alumina coated on Teflon (proplast regular and micro-pore), pyrolytic carbon, high density polyethylene, ultra high molecular weight polyethylene, hydroxyapatite, bioglass, and expanded Teflon. Some of these materials also are used for several other applications: vascular grafts, in the cardiovascular system, and for dental, orthopaedic, and other purposes. The shape and size of the end plugs made from each of the materials were as similar as possible to minimize size effects. The test materials were implanted i.p. in 12 dogs for a period of 12 weeks. The cylindrical plugs were typically 1.5–2.5 cm long, with an inside diameter of 0.3 cm, and an outside diameter of 0.6 cm. When the explants were retrieved, thin capsules were observed, of varying thickness and blood supply, surrounding the end of the catheters. Pathological evaluation revealed the best large pore material to be proplast regular and the best small pore materials to be carbon and polyurethane.     

Device thrombogenicity emulation: a novel method for optimizing mechanical circulatory support device thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation--mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device--ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers--before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device 'thrombogenic footprint', indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops--before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology--demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization--indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.     

Pre-clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver,kidney and lung fibrosis

Fibrosis describes a dysregulated tissue remodelling response to persistent cellular injury and is the final pathological consequence of many chronic diseases that affect the liver, kidney and lung. Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) enzymes produce reactive oxygen species (ROS) as their primary function. ROS derived from NOX1 and NOX4 are key mediators of liver, kidney and lung fibrosis. Setanaxib (GKT137831) is a first-in-class, dual inhibitor of NOX1/4 and is the first NOX inhibitor to progress to clinical trial investigation. The anti-fibrotic effects of setanaxib in liver, kidney and lung fibrosis are supported by multiple lines of pre-clinical evidence. However, despite advances in our understanding, the precise roles of NOX1/4 in fibrosis require further investigation. Additionally, there is a translational gap between the pre-clinical observations of setanaxib to date and the applicability of these to human patients within a clinical setting. This narrative review critically examines the role of NOX1/4 in liver, kidney and lung fibrosis, alongside the available evidence investigating setanaxib as a therapeutic agent in pre-clinical models of disease. We discuss the potential clinical translatability of this pre-clinical evidence, which provides rationale to explore NOX1/4 inhibition by setanaxib across various fibrotic pathologies in clinical trials involving human patients.     

Critical path in cardiac stem cell therapy: an update on cell delivery

Despite optimal medical therapy, cardiovascular disease remains a leading cause of morbidity and mortality worldwide. One emerging therapeutic approach for treatment of cardiomyopathies is stem cell therapy. Use of stem cells for regenerative medicine has quickly evolved over the last decade. On the basis of encouraging pre-clinical results, stem cell therapy has developed rapidly into a potentially promising treatment for ischemic heart disease, myocardial infarction and congestive heart failure. In this review, we summarize the current state-of-the-art of stem cell therapy and compare collective experiences gleaned from trials using intravenous, intra-coronary and intra-myocardial delivery in exacting credible benefits. We discuss implications of clinical outcomes reported in relation to the delivered stem cells as probable destiny therapy for cardiovascular repair.