Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

Background and purpose:

The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model.

Experimental approach:

Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg⁻¹·day⁻¹; dalcetrapib 100, 300 or 500 mg⁻¹·kg·day⁻¹; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days'' treatment with torcetrapib 40 mg·kg⁻¹·day⁻¹, dalcetrapib 500 mg·kg⁻¹·day⁻¹ or vehicle was measured by quantitative polymerase chain reaction.

Key results:

Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg⁻¹·day⁻¹ at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas.

Conclusions and implications:

In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.     

Treatment of infected total hip arthroplasty with a 2-stage reimplantation protocol: update on "our institution's" experience from 1989 to 2003

Infection is a devastating complication of total hip arthroplasty (THA). This study aimed to determine whether 2-stage reimplantation is still effective for treating contemporary pathogens, including multidrug-resistant organisms. Records of all cases of infected THAs from 1989 to 2003 were reviewed for data on organism, presence of drug resistance, use of an antibiotic-impregnated spacer, type of reimplant, and success of treatment. Of the 87 protocol patients with 2 years of follow-up, 94.3% (82) underwent reimplantation. The original infection was eradicated in 80 of the 84 hips (78/82 patients), a success rate of 95%. All 21 multidrug-resistant infections were eradicated. There were no major differences in eradication rates when the period was split into 3 sections. These results support previous studies from our institution which demonstrated the effectiveness of a 2-stage reimplantation protocol with a standard 1:8 minimal bactericidal titer for treating infections after THA, including those due to methicillin-resistant organisms.