Small, N‐ to C‐terminal cyclized peptides containing the leucyl‐aspartyl‐valine (LDV) motif from fibronectin connecting segment‐1 (CS‐1) have been investigated for their effects on the adhesion of human T‐lymphoblastic leukaemia cells (MOLT‐4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)‐4 (α4β1, CD49d/CD29). Cyclo(‐isoleucyl‐leucyl‐aspartyl‐valyl‐aminohexanoyl‐) (c(ILDV‐NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6±0.44 μM) than the 25‐amino acid linear CS‐1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV‐NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV‐NH(CH2)2CO), was inactive at 100 μM. c(ILDV‐NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA‐5 (α5,β1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule‐1 (LFA‐1, αLβ2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule‐1) at concentrations up to 300 μM. c(ILDV‐NH(CH2)5CO) inhibited ovalbumin delayed‐type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini‐pumps (0.1–10 mg kg−1 day−1). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg−1 i.v.) directed against the α4 integrin subunit. c(ILDV‐NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1–10 mg kg−1). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post‐dose (10 mg kg−1). Small molecule VLA‐4 inhibitors derived from c(ILDV‐NH(CH2)5CO) may be useful as anti‐inflammatory agents. British Journal of Pharmacology (1999) 126, 1751–1760; doi:

In this multicenter, double-blind study, the antihypertensive efficacy and safety of irbesartan were compared with those of atenolol in patients with mild-to-moderate hypertension. Following a 4- to 5-week placebo lead-in period, 231 patients with seated diastolic blood pressure (SeDBP) 95-110 mmHg were randomized to irbesartan 75 mg or atenolol 50 mg once daily for 24 weeks. Doses were doubled at Week 6 for SeDBP > or = 90 mmHg. At Week 12, or anytime thereafter, doses were doubled for SeDBP > or = 90 mmHg if not done at Week 6, and hydrochlorothiazide and then nifedipine were added. Efficacy was determined by change from baseline in blood pressure and by therapeutic response rates. Safety was assessed by monitoring adverse events (AEs). Both treatments significantly lowered blood pressure from baseline. There were no significant differences between treatment groups with respect to blood pressure changes or therapeutic response. Atenolol significantly reduced seated heart rate compared with irbesartan at Week 12. The incidences of serious AEs and discontinuations due to AEs were approximately twice as high in the atenolol group compared with the irbesartan group. Thus, in comparison to atenolol, irbesartan < or = 150 mg provided at least equivalent blood pressure control while demonstrating an excellent safety and tolerability profile.

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