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Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0 ± 1.2 vs. 10.1 ± 1.1; diabetic mice with 180 mg/kg 55P0110, 23.1 ± 0.9 vs. 11.1 ± 1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49 ± 0.27; 55P0110, 2.99 ± 0.35; gliclazide, 8.97 ± 0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53 ± 0.41; 55P0110, 3.80 ± 0.46; gliclazide, 3.99 ± 0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus.

Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0 plus or minus 1.2 vs. 10.1 plus or minus 1.1; diabetic mice with 180 mg/kg 55P0110, 23.1 plus or minus 0.9 vs. 11.1 plus or minus 1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49 plus or minus 0.27; 55P0110, 2.99 plus or minus 0.35; gliclazide, 8.97 plus or minus 0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53 plus or minus 0.41; 55P0110, 3.80 plus or minus 0.46; gliclazide, 3.99 plus or minus 0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of fully synthetic substituted quinazolidines with an attractive pharmacological profile that recommends the structures for further evaluation as candidates for the treatment of diabetes mellitus.

White blood cell counts are routinely measured with automated hematology analyzers, by flow cytometry, or by manual counting. Here, we introduce an alternative approach based on DNA methylation (DNAm) at individual CG dinucleotides (CpGs). We identified candidate CpGs that were nonmethylated in specific leukocyte subsets. DNAm levels (ranging from 0% to 100%) were analyzed by pyrosequencing and implemented into deconvolution algorithms to determine the relative composition of leukocytes. For absolute quantification of cell numbers, samples were supplemented with a nonmethylated reference DNA. Conventional blood counts correlated with DNAm at individual CpGs for granulocytes ( = -0.91), lymphocytes ( = -0.91), monocytes ( = -0.74), natural killer (NK) cells ( = -0.30), T cells ( = -0.73), CD4+ T cells ( = -0.41), CD8+ T cells ( = -0.88), and B cells ( = -0.66). Combination of these DNAm measurements into the \"Epi-Blood-Count\" provided similar precision as conventional methods in various independent validation sets. The method was also applicable to blood samples that were stored at 4 °C for 7 days or at -20 °C for 3 months. Furthermore, absolute cell numbers could be determined in frozen blood samples upon addition of a reference DNA, and the results correlated with measurements of automated analyzers in fresh aliquots ( = 0.84). White blood cell counts can be reliably determined by site-specific DNAm analysis. This approach is applicable to very small blood volumes and frozen samples, and it allows for more standardized and cost-effective analysis in clinical application.

Objective of the study To analyse the off-label use of drugs on a paediatric ward in Germany, and to identify domains of pharmacotherapy with the highest need for research concerning off-label use in children. Setting A prospective observational study was conducted on a paediatric ward in Duesseldorf in Germany between January and June 2006. Method Data about patients, diagnoses and prescribed drugs were collected from the prescription records and the discharge letters. Diagnoses were classified in groups by means of the International Classification of Diseases. Drugs were grouped according to the Anatomical Therapeutic Chemical Classification system. We compared the off-label prescriptions with those on the list of paediatric needs and priority list established by the European Medicines Agency (EMEA). Main outcome measure Off-label use was defined due to age, indication, route of application and dose. Results The study included 417 patients. We analysed 1,812 prescriptions representing 211 different drugs. In total, 253 patients (61%) received at least one off-label prescription. Of all analysed prescriptions, 553 (31%) were off-label. The percentage of off-label prescriptions among the five most frequently prescribed drug groups were as follows: 60% cardiovascular drugs (CV: 129/216), 42% anti-infectives (AI: 190/449), 30% drugs for respiratory system (RS: 100/335), 25% drugs for alimentary tract and metabolism (AM: 67/269) and 3% analgesics and antipyretics (AA: 8/264); with 17 drugs, the cardiovascular drugs also showed the highest number of different off-label prescribed drugs due to age: AI: 14; AM: 11; RS: 5; AA: 1. In addition, there was a nearly complete overlap between the identified off-label prescriptions in cardiovascular drugs and those listed by the EMEA to be prioritized for urgent research in Europe. Conclusion C ardiovascular drugs are a domain of pharmacotherapy, with a large need for research in paediatrics. The results of our study can guide the researcher to future trials on off-label prescriptions such as cardiovascular drugs, especially due to the fact that the identified off-label prescribed drugs in this group are also mentioned by the EMEA to be prioritized for paediatric research.

The composition of white blood cells is usually assessed by histomorphological parameters or flow cytometric measurements. Alternatively, leukocyte differential counts (LDCs) can be estimated by deconvolution algorithms for genome-wide DNA methylation (DNAm) profiles. We identified cell-type specific CG dinucleotides (CpGs) that facilitate relative quantification of leukocyte subsets. Site-specific analysis of DNAm levels by pyrosequencing provides similar precision of LDCs as conventional methods, whereas it is also applicable to frozen samples and requires only very small volumes of blood. Furthermore, we describe a new approach for absolute quantification of cell numbers based on a non-methylated reference DNA. Our Epi-Blood-Count facilitates robust and cost effective analysis of blood counts for clinical application.