Local and systemic delivery of low molecular weight heparin stimulates the reendothelialization after balloon angioplasty.

OBJECTIVE: Recent investigations revealed the importance of endothelial cell integrity and function in the pathogenesis of restenosis after angioplasty. Agents which stimulate reendothelialization may prevent restenosis after interventional procedures. The results of in vitro studies suggested that heparin and low molecular weight heparin administration may enhance the recovery of the endothelium. In this study the extent of endothelial denudation and the occurrence and time course of endothelial regeneration after experimental balloon angioplasty followed by subcutaneous or local delivery of low molecular weight heparin was investigated. METHODS: A total of 102 rabbits were included in the study. An atheromatous plaque was induced by electrical stimulation in the right carotid artery of the animals. All animals underwent balloon angioplasty. Thirty-two rabbits received no further medical treatment. Twenty-five rabbits received subcutaneous low molecular weight heparin reviparin (400 anti-Xa-units/day) during the following 7 days. In 25 animals the dilated arterial segments were treated locally with reviparin (1500 anti-Xa-units/4 ml, 2 atm) using a porous balloon (2.5 mm, 35 holes, diameter 75 microns). Twenty animals served as control group without intervention. The vessels were excised 3, 7, 14, 28 and 56 days following intervention. Sections were stained with an antibody against von Willebrand factor and PECAM 1 to confirm the endothelial origin of the lining cells. After bromodeoxyuridine labeling, the extent of proliferation was determined by using a monoclonal antibody. In addition, morphometric analysis of the intimal and medial area was performed. RESULTS: Three days after balloon angioplasty histomorphological analysis showed a reduction of about 60% of the preinterventional endothelial cell number in all three groups. Already one week after intervention there was a significantly higher number of endothelial cells in both groups of low molecular weight heparin treated animals compared to the untreated group (s.c. group 144 +/- 33, local group 142 +/- 32 versus untreated 79 +/- 17 endothelial cells, p < or = 0.05). This significant difference was maintained during the following four weeks and demonstrated a 2-fold increase in endothelial proliferation in the heparin treated animals compared with the untreated group. In addition, immunohistological examination showed a significant decrease in smooth muscle cell proliferation in the s.c. and local reviparin treated animals and a subsequent reduction of intimal thickening. CONCLUSION: Local delivery of low molecular weight heparin promotes reendothelialization and contributes to the inhibition of smooth muscle cell proliferation.

[Urinary concentration and antibacterial effect of short and long acting tetracycyline]. / Concentration urinaire et effet antibactérien de tétracyclines à courte et longue durée d'action

Forty-one hospitalized patients, of whom the majority had asymptomatic bacteriuria, were randomly divided into 4 treatment groups. They were given either tetracycline HCl 1 g, or tetracycline HCl + terpenes 100 mg, or minocycline 200 mg, or cotrimoxazole (sulfamethoxazole 1.6 g + trimethoprim 320 mg), daily for one week. A large number of bacteria were resistant to tetracyclines. The urine was sterilized in 14 out of 24 patients receiving tetracyclines and in all of the 17 patients receiving cotrimoxazole. The mean urinary concentration of tetracycline was 20 times higher than that of minocycline. The 24-h urinary excretion of tetracyclines was slightly higher in patients receiving the combination of terpenes and tetracycline, but these differences in urinary excretion did not appear to have any influence on the antibacterial effect of tetracyclines.

Efficacy of low-molecular-weight heparin delivery with the Dispatch catheter following balloon angioplasty in the rabbit iliac artery.

Local drug delivery can be achieved with active injection systems or passive contact of a compound with the arterial wall. The Dispatch catheter allows for passive diffusion of drugs from drug compartments while preserving blood flow through the central conduit. The aim of this study was to investigate whether a reduction in neointima formation can be achieved by local delivery of a limited amount of a highly concentrated solution of the low-molecular-weight heparin Reviparin. In 16 New Zealand white rabbits, successful balloon dilatation was performed in both iliac arteries, followed by local delivery of 4 ml Reviparin (1,000 IU/ml). The arteries were harvested at 7, 28, or 56 d following the procedure. The intimal cell layers increased substantially between 7 and 28 d following balloon dilatation with or without local drug delivery. The medial cell layers showed only a little increase. Proliferation of smooth muscle cells reached an early peak after 7 d, with a significantly higher proliferation index following local delivery. The maximum amount of macrophages in the intima and media was detected after 28 d. The lumen area decreased with time and was 0.6 +/- 0.7 mm2 in the local delivery group at 56 d compared with 0.5 +/- 0.5 mm2 in the control group. In conclusion, local delivery of Reviparin with the Dispatch catheter is safe and feasible. However, the infusion of highly concentrated low-molecular-weight heparin over a short period of time did not result in a reduction of neointima formation and restenosis following balloon dilatation in the rabbit iliac artery.

Local and systemic delivery of low molecular weight heparin following PTCA: acute results and 6-month follow-up of the initial clinical experience with the porous balloon (PILOT-study). Preliminary Investigation of Local Therapy Using Porous PTCA Balloons.

The purpose of this study was to assess safety and feasibility of intracoronary delivery of reviparin using a porous balloon following percutaneous transluminal coronary angioplasty. The 2.7 mm porous balloon used in this study had 35 holes arranged in a spiral pattern. Eighteen patients (male n = 10, female n = 8, age 63 +/- 9 years) undergoing successful PTCA in coronary arteries with a vessel diameter of 2.5 to 3.0 mm determined by online QCA (LAD = 11, RCX = 3, RCA = 4) were included. They received a bolus of 7,000 anti-Xa-IU reviparin followed by local delivery of 1,500 anti-Xa-IU in 4 ml with an injection pressure of 2 atm. The patients received additionally 10500 anti-Xa-units intravenously during the following 24 hours and a daily dose of 7000 anti-Xa-units reviparin subcutaneously for the following 28 days. Angiograms were obtained before and after PTCA, directly after local delivery, at 24 hours postintervention and after 6 months. The primary success rate was 100%. Quantitative coronary angiography showed a minimum luminal diameter of 0.42 +/- 0.14 mm before PTCA, 1.87 +/- 0.45 after PTCA, 1.67 +/- 0.43 after LDD, 1.63 +/- 0.46 after 24 hours, and 1.06 +/- 0.6 after 6 months. Angiographic follow-up was obtained in all patients. No major complications occurred during the 6-month follow-up period. The angiographic restenosis rate was 28% (5/18) at follow-up. This study demonstrates safety and feasibility of local intracoronary delivery of reviparin with a porous balloon following PTCA even in smaller diameter coronary arteries.