Insulin: a new era for an old hormone.

All forms of diabetes have been treatable since insulin became medically available in 1921. While insulin alone produces a substantial reduction in blood-glucose levels and is thus the mainstay of treating type-1 diabetes, today's peroral agents used in treating type-2 diabetes struggle to achieve satisfactory clinical results in the absence of endogenous or exogeneous insulin. Emerging evidence suggests that insulin may not only produce symptomatic effects; recent data suggest that insulin may stimulate beta-cell recovery. In fact, short-term insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in early stages of type-2 diabetes. During the last decade the pharmaceutical industry has largely failed to introduce new agents that can fundamentally improve the course of diabetes and the safety of artificial insulin analogs is undergoing thorough investigation. In contrast, new delivery approaches that present natural recombinant insulin to the enterohepatic circulation holds the promise of radically improving the treatment of type-2 diabetes.

Accelerator mass spectrometry offers new opportunities for microdosing of peptide and protein pharmaceuticals.

Accelerator Mass Spectrometry (AMS) is an ultra-sensitive analytical method which has been instrumental in developing microdosing as a strategic tool in early drug development. Considerable data is available for AMS microdosing using typical pharmaceutical drugs with a molecular weight of a few hundred Daltons. The so-called biopharmaceuticals such as proteins offer interesting possibilities as drug candidates; however, experimental data for protein microdosing and AMS is scarce. The analysis of proteins in conjunction with early drug development and microdosing is overviewed and three case studies are presented on the topic. In the first case study AMS experimental data is presented, for the measured concentration of orally administered recombinant insulin in the blood stream of laboratory rabbits. Case study 2 concerns minimum sample size requirements. AMS samples normally require about 1 mg of carbon (10 microL of blood) which makes AMS analysis unsuitable in some applications due to the limited availability of samples such as human biopsies or DNA from specific cells. Experimental results are presented where the sample size requirements have been reduced by about two orders of magnitude. The third case study concerns low concentration studies. It is generally accepted that protein pharmaceuticals may be potentially more hazardous than smaller molecules because of immunological reactions. Therefore, future first-in-man microdosing studies might require even lower exposure concentrations than is feasible today, in order to increase the safety margin. This issue is discussed based on the current available analytical capabilities.