Casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) lower blood pressure (BP) in long-term clinical studies. Their acute effects on BP and vascular function, important for daily dosing scheme, were studied in a placebo-controlled double-blind crossover study using a single oral dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro as well as plant sterols. Twenty-five subjects with untreated mild hypertension received in random order 250 g of study product (25 mg peptides and 2 g plant sterols) or placebo. Ambulatory BP was monitored for 8 h post-dose and arterial stiffness measured by pulse wave analysis at 2, 4, and 8 h. Blood and urine samples were analyzed for markers of the renin-angiotensin system (RAS) and endothelial function. Baseline adjusted treatment effect for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP was -2.1 mmHg (95% CI: -4.1 to -0.1, p = 0.045), -1.6 mmHg (95% CI: -3.1 to -0.1, p = 0.03), and -1,9 mmHg (95% CI: -3-3 to -0.4, p = 0.0093), respectively, in favor of the active treatment for 8 h post- dose. No significant differences between the treatments were seen in brachial or aortic augmentation index, pulse wave velocity, or markers of RAS. Urinary excretion of cGMP, the second messenger of endothelial nitric oxide, was higher in the active group vs. placebo (p = 0.01). The results indicate that a single dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols acutely lowers brachial SBP and DBP in mildly hypertensive subjects.

GPs should be aware of barriers to statin therapy and useful approaches to overcome them. They could be supported by guideline recommendations that are more closely aligned to primary care as well as comprehensible patient information about lipid-lowering therapy. Future studies, exploring patients' specific needs and involving them in improving adherence behaviour, are recommended.

Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed. Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested. Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.

BackgroundThe CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis (RA). Blocking this pathway may be a promising new treatment for RA-patients. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody, free of agonistic activity and without antibody-dependent cellular- or complement-dependent cytotoxicity. BI 655064 binds human CD40 on B cells in whole blood with an EC90 of 6.85±0.74 nM.ObjectivesBI 655064 was investigated in healthy volunteers to assess safety, tolerability, PK and PD after single and multiple dosing.MethodsIn a single-blinded randomized, placebo-controlled trial in healthy subjects, BI 655064 was administered to 72 male subjects in increasing single doses of 0.2-120 mg i.v. and 40-120 mg s.c. A double-blinded multiple rising dose study was conducted in 40 male and female subjects at doses of 80-240 mg q1w s.c. for 4 weeks. Blood samples were analyzed for PK, CD40-receptor occupancy (RO) and inhibition of CD40L-induced CD54-upregulation throughout the entire trial duration.ResultsAll doses of BI 655064 were well tolerated in both studies. There was no-drug related serious adverse event (AE) or significant AE reported. Reported AEs were mainly of mild intensity and did not show a dose-relationship. There was no significant difference in the total number of subjects with AE [BI 655064: 47/86 (54%) vs. placebo: 16/26 (61%)] or category of reported AEs between subjects treated with BI 655064 or placebo (combined data from both studies). The most frequently reported AEs were headache (BI 655064 23% vs. placebo 19%) and upper respiratory tract infection (BI 655064 13% vs placebo 12%) in both studies (combined data). There was no evidence of thromboembolism or bleeding, no hypersensitivity reaction, no cytokine release and no relevant change in safety laboratory tests including coagulation parameters. BI 655064 plasma exposure increased in a supra-proportional manner indicating target mediated drug clearance with a terminal half-life ranging between 6 and 13 days. At single i.v. doses of 20 mg and higher, there was >90% RO and >90% inhibition of CD40L-induced CD54 upregulation for 24 hours after dosing. Single doses of 120 mg i.v. or s.c resulted in >90% RO and >90% inhibition of CD54 upregulation for at least one week. After multiple dosing, persistent >90% RO and >90% inhibition of CD40L-induced CD54 upregulation was maintained for the entire treatment period and for 3 weeks after the last dose for all doses of 120 mg q1w and above.ConclusionsEarly trials with BI 655064 show a favorable clinical safety profile and high potential to block the CD40-CD40L pathway supporting clinical trials with BI 655064 in RA-patients.Disclosure of InterestC. Schwabe Employee of: Auckland Clinical Studies, F. Wagner Employee of: Charité Research Institute, I. Filler Employee of: Charité Research Institute, M. Albulescu Employee of: Boehringer-Ingelheim, P. Rose Employee of: Boehringer-Ingelheim, B. Emerson Employee of: Boehringer-Ingelheim, T. Doan Employee of: Boe...