Initial experience with paclitaxel-coated stents

Local delivery of immunosuppressive or antiproliferative agents using a drug-eluting stent is a new technology that is supposed to inhibit in-stent restenosis, thus providing a biological and mechanical solution. This technique is a very promising. To date, several agents have been used, including paclitaxel, QP-2, rapamycin, actinomycin D, dexamethason, tacrolimus, and everolimus. Several studies, published recently or still ongoing, have evaluated these drugs as to their release kinetics, effective dosage, safety in clinical practice, and benefit. These studies include: SCORE (paclitaxel derivative), TAXUS I-VI, ELUTES, ASPECT, DELIVER (paclitaxel), RAVEL, SIRIUS (sirolimus), ACTION (actinomycin), EVIDENT, PRESENT (tacrolimus), EMPEROR (dexamethason), and FUTURE (everolimus). Paclitaxel was one of the first stent-based antiproliferative agents under clinical investigation that provided profound inhibition of neointimal thickening depending on delivery duration and drug dosage. The randomized, multicenter SCORE trail (Quanam stent, paclitaxel-coated) enrolled 266 patients at 17 sites. At 6-month's follow-up, a drop of 83% in stent restenosis using the drug-eluting stent could be achieved (6.4% drug-eluting stent vs 36.9% control group), which was attributable to a remarkable decrease in intimal proliferation. Unfortunately, due to frequent stent thrombosis and side-branch occlusions, the reported 30-day MACE rate was 10.2%. The randomized TAXUS-I safety trial (BSC, NIRx, paclitaxel-coated) also demonstrated beneficial reduction of restenotic lesions at 6-month's follow-up (0% vs 10%) but was associated with the absence of thrombotic events presumably due to less drug dosage. The ongoing TAXUS II-VI trials are addressing additional insight regarding the efficacy of the TAXUS paclitaxel-eluting stent. ASPECT and ELUTES evaluated paclitaxel-coated stents (i.e., Cook and Supra G), including subgroups with different drug dosages. With respect to stent restenosis and neointimal proliferation, both studies demonstrated a clear dose response. The RAVEL and the SIRIUS trials evaluated sirolimus-coated stents (i.e., Cordis, Johnson & Johnson, and Bx VELOCITY stents). Results confirmed the beneficial findings regarding reduction of renarrowing using a drug-eluting stent without any major adverse effects. Although parameters such as drug toxicity, optimal drug dosage, or delayed endothelial healing still need to be evaluated, today's clinical experience indicates that drug-coated stents are extremely beneficial in the interventional treatment of coronary lesions.     

A further case with a small supernumerary marker chromosome (sSMC) derived from chromosome 1--evidence for high variability in mosaicism in different tissues of sSMC carriers

A prenatally ascertained case with a de novo small supernumerary marker chromosome (sSMC) derived from chromosome 1 is reported. Due to a fetal heart defect the parents decided in favour of an induced abortion. Postmortem, a molecular cytogenetic study on eleven formalin fixed, paraffin-embedded tissues of the fetus was performed, to further characterize the levels of mosaicism of the sSMC(1). sSMC presence varied between 13 and 62% within different tissues of sSMC carriers. This finding is something common in sSMC carriers and could explain why up to the present no clinical correlations for sSMC mosaicism and clinical outcome in the corresponding carriers could be established.     

Ischemia increases the angiogenic potency of basic fibroblast growth factor (FGF-2)

The aim of this study was to investigate the angiogenic response to exogenously administered basic fibroblast growth factor (FGF-2) in normal and ischemic skin, using the hairless mouse ear microcirculatory model. The hairless mouse ear is a well-established model for in vivo studies of skin microcirculation. Using this model, angiogenesis- and angiogenesis-associated changes in the microcirculation can be directly and continuously viewed and quantified in a variety of different experimental settings. To create ischemia in the mouse ear, all but one of the three to four feeding vessels nourishing the ear were ligated 3 days prior to a local subdermal injection of FGF-2 (9.3 + 1–0.5 mm/mm²) or saline into the dorsum of the ears. Angiogenesis was quantified by direct observation, at high magnification, of the injection site where increases in total vessel length (TVL) were measured repeatedly over 18 days following injection. We found a significant (P < 0.01) increase in TVL in normal and ischemic ears injected with FGF-2. Saline injection also induced a significant increase in TVL in ischemic ears. However, the angiogenic response to FGF-2 in ischemic ears was significantly stronger than saline alone in ischemic ears or saline or FGF-2 in normal ears. This response could be used clinically to accelerate angiogenesis and thus increase perfusion in ischemic tissue. © 1997 Wiley-Liss, Inc. MICROSURGERY 17:452–456 1996     

Long-term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate-containing liposomes

Objective. To determine whether systemic elimination of macrophages by means of clodronate-containing liposomes counteracts inflammation and joint destruction in rats with established adjuvant arthritis (AA). Methods. Rats with AA received a total of 2.7 mg of clodronate encapsulated in liposomes in 3 intravenous doses on days 10, 11, and 12 of arthritis. Phosphate buffered saline (PBS), PBS-laden liposomes, or free clodronate were used as negative controls. Clinical, hematologic, and histopathologic signs of AA were monitored, and depletion of macrophages by clodronate-liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MPS). Results. Clodronate-laden liposomes led to significant, long-term amelioration of the clinical signs of AA, a reduction in the erythrocyte sedimentation rate (ESR), and counteraction of joint destruction, not only immediately after treatment, but also for 2 weeks thereafter. Free clodronate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA. Drug-free vesicles even aggravated the joint destruction. Clodronate-laden liposomes did not induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the liver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. Conclusion. Clodronate-laden liposomes induce long-term amelioration of AA, even if administered for a brief period during the florid phase of the disease. The amelioration is paralleled by the elimination of macrophages in immunocompetent areas of the spleen and draining lymph nodes, but not locally in the SM. This suggests an influence of the treatment on the immunoregulatory rather than effector, functions of macrophages.