Pharmacokinetics and tolerability of a novel long-acting glucagon-like peptide-1 analog, CJC-1131, in healthy and diabetic subjects.

OBJECTIVE: The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated. METHODS: CJC-1131 was subcutaneously injected in 8 groups (1.5 - 20.5 microg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 - 12 microg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3. RESULTS: CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in Cmax. The half-life of CJC-1131 varied from 8.9 - 14.7 days in healthy subjects and from 9.1 - 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 microg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients. CONCLUSIONS: Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.

Methodological aspects of glucose monitoring with a slow continuous subcutaneous and intravenous ultrafiltration system in rats.

A method for the continuous ultrafiltration of venous blood or subcutaneous fluid is demonstrated with glucose monitoring in the living rat. Ultrafiltrate was withdrawn at a constant flow rate of approximately 100 nl/min. Glucose content of the ultrafiltrates was electrochemically determined with a flow injection analysis method and a bi-enzyme reactor. After glucose loading, the time course of glucose in the ultrafiltrate from the jugular vein was virtually identical, whereas that from the subcutaneous compartment was attenuated and the peaks blunted as compared to glucose levels in concomitantly assayed arterial blood. Our study demonstrates the potential of low rate ultrafiltration for monitoring metabolism with biosensor technology in vivo.

An ultrafiltration catheter for monitoring of venous lactate and glucose around myocardial ischemia.

Early detection of myocardial ischemia is of major importance in critical-care medicine. Changes of lactate or glucose levels in the cardial venous efflux may be useful parameters. We succeeded in integrating an ultrafiltration membrane in a cardiac catheter for continuous sampling. The ultrafiltrate was analyzed outside the body, resulting in a lag-time of about 24 min. Biosensors in a flow-injection analysis system were used for minute by minute sample analyses. The coronary sinus of pigs was catheterized to monitor the effects of 5, 15 or 45 min ischemia by coronary artery obstruction or myocardial stress by dobutamine infusion. A total of 27 h was monitored. The intravascular response time was 1.33+/-0.61 min (10-90%). Linear regression in vivo of blood and ultrafiltrate samples was 0.977 for lactate and 0.994 for glucose. Lactate levels rose 0.38+/-0.10 mM above baseline within 5 min after ischemia. Reperfusion was clearly marked by a promptly peaking lactate release (maximum 9.27 mM). Myocardial stress by dobutamine increased glucose but not lactate levels. Once, a wall effect was noted at the catheter tip. In vivo semi-continuous myocardial monitoring of absolute lactate and glucose concentrations was thus achieved by an ultrafiltration catheter. Ischemia and reperfusion can be detected very early by a lactate level rise. Further, development of the ultrafiltration catheter will be focused on the diagnostic potential of lactate monitoring for patients.

Development of a potentially wearable glucose sensor for patients with diabetes mellitus: design and in-vitro evaluation.

A potentially wearable glucose sensor was developed, consisting of an oxygen electrode as detector and a dynamic enzyme perfusion system as selector. The selector is a hollow fibre, which can be placed subcutaneously and dialyses glucose from tissue fluid. In this design the problems of enzyme instability and oxygen limitation might be circumvented. The sensor measures glucose reliably for over two weeks, provided a new 10 ml syringe containing a glucose oxidase solution is connected to the system each day.

[Biosensors for continuous glucose and lactate monitoring]. / Biosensoren voor continue glucose- en melkzuurmetingen.

Biosensors, and in particular glucose and lactate sensors, are being widely developed and a few have been registered for continuous and semi-continuous use. Three glucose sensors, a transcutaneous sensor (GlucoWatch), a needle sensor (MiniMed) and microdialysis sensor (GlucoDay) have recently been evaluated among diabetes patients. The precise relationship between the biosensor signal and blood glucose is still a problem. For example, the utility of the subcutaneously placed needle sensor to detect nocturnal hypoglycaemia has been shown to be limited. The best subcutaneous site for placing the sensor needs to be systematically investigated. The three types of sensors have only been tested for a 3-5 day period. The utility of the microdialysis (separate from a direct link to biosensors) sensors among diabetes patients was established over a 3-week period following subcutaneous implantation. Furthermore, biosensors are being developed to monitor lactate in preterm babies, and patients with ischaemia, sepsis, or threatened organ damage (e.g. heart and brain infarction). In view of the current progress it is expected that within 5 years biosensor technology will have developed far enough to be used in the management of diabetes and in intensive care units.

A fetus with a parvovirus B19 infection and congenital anomalies.

A fetus with multiple structural defects was seen at prenatal ultrasound examination. After termination of the pregnancy a bilateral cleft lip, alveolus, and palate; micrognathia; and webbed joints were seen. Fetal tissues showed indications of infection, intranuclear inclusion bodies, chronic stress, haemolysis, arterial wall damage, and profuse haemorrhage. Parvovirus B19 DNA was detected in fetal tissues by dot hybridization after polymerase chain reaction. The possibility of parvovirus B19 infection leading to congenital malformations is discussed.