Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment.

The pharmacokinetics of the low-molecular-weight heparin enoxaparin were evaluated in 12 healthy volunteers and 36 patients with mild, moderate or severe renal impairment. Enoxaparin was administered once daily by subcutaneous injections at a dose of 40 mg for 4 days and venous blood samples were taken over a 5-day period to determine antifactor Xa and antifactor IIa activity and the activated partial thromboplastin time. Adverse events were also recorded. The results for anti-Xa activity showed that the rate of absorption of enoxaparin was similar across the four groups of study participants. The elimination half-life increased with the degree of renal impairment, and this relationship was more evident after repeated dosing. Anti-Xa exposure was not significantly different between healthy volunteers and patients with mild or moderate renal impairment, but was significantly increased in patients with severe renal impairment (creatinine clearance < or =30 ml/min). Anti-Xa clearance decreased with the degree of renal impairment after repeated dosing, but only the difference between patients with severe renal impairment and healthy volunteers was statistically significant, the clearance on Day 4 being 39% lower in patients with severe renal impairment than in healthy volunteers (P=.0001). Anti-IIa activity was low in all study participants, and the activated partial thromboplastin time was not significantly different between the study groups. In conclusion, the clearance of enoxaparin is reduced in patients with severe renal impairment. Dose adjustment of enoxaparin may need to be recommended in these patients, but no recommendation can be made in patients with mild or moderate renal impairment.

Analogues of human parathyroid hormone (1-31)NH(2): further evaluation of the effect of conformational constraint on biological activity.

A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.