Synergistic mechanisms by which sirolimus and cyclosporin inhibit rat heart and kidney allograft rejection

The studies presented herein examined the mechanism(s) whereby sirolimus (SRL) and cyclosporin (CsA) act synergistically to block allograft rejection. Combination index (CI=1 reflects additive, CI<1 antagonistic, and CI<1 synergistic, effects) analysis documented potent synergism between SRL and CsA to block allograft rejection. Combinations of the two drugs produced synergistic prolongation of heart (CI=0.001–0.2) or kidney (CI=0.03–0.5) allograft survival at SRL/CsA ratios ranging from 1:12.5 to 1:200. Pharmacokinetic analysis of the individual drugs showed that CsA does not affect the blood levels of SRL, and SRL mildly increases the levels of CsA in SRL/CsA-treated rats. Quantitative polymerase chain reaction analysis was used to document that both subtherapeutic (1.0 mg/kg) and therapeutic (2.0 or 4.0 mg/kg) CsA doses inhibited the expression of interferon-gamma (IFN-γ) (P<0.03) and IL-2 (P<0.003) mRNA produced by T helper (Th) 1 cells, as well as IL-10 (P<0.001), but not IL-4 (NS) mRNA produced by Th2 cells. Contrariwise, all tested SRL doses (0.02, 0.04 or 0.08 mg/kg) did not affect cytokine mRNA expression. However, heart allografts from rat recipients treated with synergistic SRL/CsA doses displayed reduced levels of IFN-γ (P<0.01), IL-2 (P<0.001) and IL-10 (P<0.001) mRNA. Thus, because subtherapeutic doses of CsA reduce Th1/Th2 activity, thereby facilitating the inhibition of signal transduction by low does of SRL, the two agents act synergistically to inhibit allograft rejection.     

Nifedipine and alpha1-adrenergic blockade in Raynaud's phenomenon

The efficacy of nifedipine and prazosin in the treatment ofRaynaud's phenomenon was assessed in a prospective double-blindrandomized cross-over trial in 15 patients. Each patient receivedone week of nifedipine 20 mg TID, one week of prazosin 1 mgTID, and 2 weeks of placebo. Nifedipine was shown to be effectivein reducing both the frequency and the severity of Raynaud'sphenomenon, whereas prazosin was ineffective. Before initiationof therapy in the 15 patients, pressor responses to the intravenousalpha₁-agonist phenylephrine were assessed in the basal state,30 min after 20 mg oral nifedipine, and 30 min after 1 mg oralprazosin; the shift to the right of the log dose-vasopressorresponse curves to phenylephrine was similar with nifedipineand prazosin.     

LIBMAN-SACKS ENDOCARDITIS: THE DIAGNOSTIC IMPORTANCE OF TWO-DIMENSIONAL ECHOCARDIOGRAPHY

In 1980, a 44-year-old woman with the diagnosis of systemiclupus erythematosus presented with fever and mitral and aorticvalvular insufficiency Blood cultures were sterile. M-mode echocardiogramsof the mitral valve revealed an image resembling vegetationsof infective endocarditis. The diagnosis was rejected aftertwo-dimensional echocardiography which failed to demonstratevegetation. Two-dimensional echocardiography should thereforebe systematically utilized in the diagnosis of valvular lesionsin patients with systemic lupus erythematosus KEY WORDS: Systemic lupus erythematosus, Libman-Sacks endocarditis, Echocardiography