In this randomized, placebo-controlled, double-blind, single-centre, dose escalation study, we report the first evaluation of the pharmacokinetics and safety of recombinant activated factor VII (rFVIIa) in healthy Caucasian and Japanese subjects. Thirty-two healthy subjects were stratified according to sex and ethnic group to receive single bolus intravenous injections of three different doses of rFVIIa (40, 80, 160 microg/kg rFVIIa) or placebo, each separated by a 7-day wash-out period. Blood samples were taken up to 24 h after dosing. The factor VII clotting activity appeared to be dose dependent, but independent of sex and ethnic group. Statistical analyses demonstrated no significant effect of dose, sex or ethnicity on the dose-normalized mean area under the plasma concentration-time curve AUC0-t, indicating dose proportionality. No serious adverse events or thromboembolic events were reported. Analyses of coagulation parameters did not suggest induction of systemic coagulation when dosing rFVIIa up to 160 microg/kg. In conclusion, the pharmacokinetics of rFVIIa in Caucasian and Japanese subjects are similar, and no safety issues were identified.

Aim Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods This was a double‐blind, randomized, placebo‐controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK−PD modelling. Results The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half‐life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [−26.70% [90% confidence interval (CI) −40.9, −12.6%]; −7.10%, (90%CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively] and TM38837 500 mg [−22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.

Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause the type 3 form of maturity-onset diabetes of the young (MODY3), which is characterized by a severe impairment of insulin secretion. In addition to disease-associated mutations, three common amino acid polymorphisms have been identified in the HNF-1alpha gene: Ile/Leu27, Ala/Val 98, and Ser/Asn487. We have addressed the question of whether these variants of the HNF-1alpha gene are associated with altered glucose-induced C-peptide and insulin responses or late-onset NIDDM. Among 245 NIDDM patients, the allelic frequency of the Val 98 variant was 3.7% (95% CI 2.0-5.4%) vs. 4.4% (2.6-6.2%) among 240 glucose tolerant control subjects (NS). Studies of genotype-phenotype interactions in 240 middle-aged control subjects showed, however, that heterozygous subjects (i.e., genotype Ala/Val 98) had an 18% decrease in 30-min serum C-peptide level (P = 0.004) as well as a 23% decrease in 30-min serum insulin level (P = 0.03) during an oral glucose tolerance test. One Val 98 homozygote subject had a more severe reduction in stimulated insulin and C-peptide levels. The impact of the homozygous carrier status was similar in a study of 377 healthy young subjects. In contrast, the Ile/Leu27 and Ser/Asn487 polymorphisms were not associated with altered C-peptide and insulin release or NIDDM. In conclusion, 8% of white subjects of Danish ancestry are heterozygous for the Ala/Val 98 polymorphism in the HNF-1alpha gene, which in middle-aged subjects is associated with a approximately 20% reduction in serum C-peptide and insulin responses 30 min after an oral glucose challenge. Val 98 homozygotes may exhibit a more severe defect in the early glucose-induced insulin response.