P. Fitscha

Isradipine: A potent calcium blocker with beneficial effects on platelet function and vascular prostacyclin production

Calcium blockers inhibit platelet aggregation induced in vitro by various stimuli, such as ADP and collagen. In this study the in vitro effects of isradipine, a new dihydropyridine-derivative, and of nifedipine on platelet aggregation and malondialdehyde-production were tested. The lowest concentrations affecting ADP-induced platelet aggregation were 1.0 micrograms/ml isradipine and 12.5 micrograms/ml nifedipine. Both drugs exhibited an inhibitory action on malondialdehyde-production in concentrations 2 to 3 times lower than those affecting platelet aggregation. In vitro, PGI2-formation by rat aortic rings incubated with calcium blockers was increased in a dose-dependent manner. The lowest concentration of isradipine which increased PGI2-generation amounted 0.5 micrograms/ml. The corresponding value for nifedipine was 10 micrograms/ml. The findings demonstrate isradipine to be more potent than nifedipine in affecting in vitro platelet aggregation and enhancing PGI2-formation.

Comparable effect of prostaglandin E1 in decreasing in vivo platelet deposition on human lesion sites after intravenous and intraarterial application

It had been claimed that prostaglandin E1 is degraded during first lung passage to a major extent. Clinical results, however, as well as various platelet function tests and coagulation parameters revealed no apparent difference after i.v. and i.a. infusion. Thus, we examined the question what the quantitative difference between i.v. and i.a. PGE1-application would be upon in-vivo platelet function assessed by platelet uptake over active lesion sites as well as platelet half-life monitoring after autologous 111-In-oxine platelet labelling. In patients suffering from peripheral vascular disease stage II according to Fontaine PGE1 was able to decrease platelet uptake after i.v. and i.a. therapy to a comparable extent; similarily, a significant prolongation in platelet half-life was noted, again revealing no difference. As the decrease in platelet uptake is assumed to be predominantly a vascular effect, it is hypothetized that more stable derivatives of PGE1 are active, counterbalancing a lower biological activity with a longer half-life.

Successful Eradication of Helicobacter pylori as Determined by 13C-Urea Breath Test Does Not Alter Fibrinogen and Acute Phase Response Markers

In this study we examined in 100 patients testing positive for Helicobacter pylori infection whether successful eradication therapy with pantoprazole, clarithromycin, and metronidazole alters fibrinogen and other acute phase response markers. Of 100 patients, only 11 showed a fibrinogen level above 300 mg/dL. Successful eradication proven by the 13C-urea breath test does not alter acute phase response markers. These findings indicate that Helicobacter pylori infection is unlikely to affect atherosclerosis unfavourably via acute phase response.

Modification of platelet function by isosorbide dinitrate in patients with coronary artery disease

The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.

Platelet Half-Life, Plasma Thromboxane B2 and Circulating Endothelial-Cells in Peripheral Vascular Disease

We studied platelet half-life (T/2), plasma thromboxane B2-levels (TXB2) and circulating endothelial cells in 107 patients with a mean age of 63 ± 6.8 years and angiographically proven peripheral vascular disease (PVD). Patients were divided into 4 groups according to Fontaine but also according to additional clinical manifestations of atherosclerosis like coronary heart disease (CHD) and cerebrovascular disease (CVD). Furthermore, the influence of sex and smoking was investigated. Compared to patients without atherosclerotic manifestations we could detect an enhanced platelet consumption measured as shortended platelet half-life time (79.2 ± 9.1 vs 100.9 ± 5.6 hours, p < 0.001 and an increased platelet activity measured as increased TXB2-plasma levels (51.6 ± 20.9 vs 23.2 ± 11.2 ng/ml, p < 0.001). Correspondingly, the amount of circulating endothelial cells was increased 45.2 ± 25.7 vs 20.3 ± 23.4, p < 0.001). Patients with PVD who smoked had the shortest actual platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to non-smok ing patients and controls. Patients with clinical stage IV according to Fontaine had the shortest platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to the other clinical stages. Analyzing the influence of additional clinical manifestations of atherosclerosis we could detect only in patients with PVD and CHD significant differences compared to the other groups.

Beneficial effect of long-term PGE1-treatment in left ventricular heart failure.

Five male patients aged 34-47 years with congestive heart failure showed an improvement of left ventricular ejection fraction (LVEF) at rather low PGE1-doses (10-30 ng/kg/min) without affecting blood pressure or heart rate. LVEF was estimated by means of radionuclide ventriculography (RNV) prior to and during i.v.-infusion of PGE1 at increasing dose rates (10-100 ng/kg/min). Therefore, we administered to these responders PGE1 at a rate of 20 ng/kg/min i.v. continuously on a long-term basis by means of a portable infusion pump. Until up to 4 months the remarkable benefit in LVEF induced by PGE1 was still present to a comparable extent in all the patients. No rebound desensitization phenomenon occurred either on platelet activity or on LVEF. PGE1, via a more practical route of application or by a stable analogue, may be a promising therapy at this stage of cardiomyopathy (CMP).

Platelet kinetics in patients with atherosclerosis.

In 12 patients (8 males, 4 females; 59.4 +/- 6.2 years) with clinically manifest atherosclerosis (peripheral vascular disease stage II according to Fontaine and coronary heart disease) without any risk factor and 6 controls (4 males, 2 females; 58.5 +/- 7.06 years) autologous platelets were labelled using 100 microCi 111-In-oxine. In parallel, serum- and plasma-thromboxane (TX) B2 and conversion of exogenous radiolabelled arachidonic acid towards TXB2 were determined. No difference in labelling efficiency and recovery was noted. Platelet half-life was significantly (p less than 0.01) shortened in the atherosclerotics. Gamma-camera images were obtained during the first 64 minutes after reinjection as well as 2, 6, 18, 24 and daily up to 1 week after reinjection of autologous radiolabelled platelets. No difference between the patients suffering from atherosclerosis--having either visible atherosclerotic lesions or not--could be discovered. Serum-TXB2 was comparable, whereas plasma-TXB2 showed a trend towards an increase and the conversion from exogenous 14C-AA to 14C-TXB2 was increased in atherosclerosis.

A double blind placebo controlled trial of intravenous prostacyclin (PGI2) in 108 patients with ischaemic peripheral vascular disease

108 patients with ischemic peripheral vascular disease were randomly allocated to receive infusion of either PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days) or placebo in a double-blind manner. All patients had Stage II disease (Fontaine classification). One month after infusion the absolute and relative walking times were significantly (p less than 0.05) longer in the PGI2- than in the placebo-treated group. Patients were further classified as treatment responders or non-responders on the basis of increase of absolute and relative walking times. After one month 44% (24 out of 54) of the PGI2- and 15% (8 out of 54) of the placebo-treated patients were positive treatment-responders (p less than 0.01).

Prostaglandin E1-therapy reduces circulating adhesion molecules (ICAM-1, E-selectin, VCAM-1) in peripheral vascular disease.

BACKGROUND It has been postulated that adhesion molecules (AM) may be involved in development and progression of human atherosclerosis. We examined whether prostaglandin (PG) E1 affects circulating levels of the AM (ICAM-1, VCAM-1 and E-selectin) in peripheral vascular disease (PVD) patients. METHODS AND RESULTS AM are significantly (p < 0.01) increased in PVD (n = 65) as compared to controls (n = 31). There was no influence of risk factors. 26 PVD-patients received 2 different schemes of PGE1-therapy (group A [n = 17]; 5 ng PGE1/kg/min x 6 h x 5 d x 4 wk; group B [n = 9]; 60 micrograms PGE1/2 h x 5 d x 2 wk). PGE1 decreases all the AM significantly (p < 0.01) using both therapeutic schemes. Stopping PGE1-therapy reverses values within about 4 weeks. Details on therapeutic regimens (dose, duration, route, etc.) and individual response still need to be assessed. CONCLUSION Our results indicate that PGE1-treatment of PVD is associated with a significant benefit on circulating AM. These findings are in line with the described anti-inflammatory actions of PGE1 and may represent a further contributing factor to the great variety of beneficial actions of PGE1 on human atherosclerosis.Background: It has been postulated that adhesion molecules (AM) may be involved in development and progression of human atherosclerosis. We examined whether prostaglandin (PG) E1 affects circulating levels of the AM (ICAM-1, VCAM-1 and E-selectin) in peripheral vascular disease (PVD) patients. Methods and results: AM are significantly (p < 0.01) increased in PVD (n = 65) as compared to controls (n = 31). There was no influence of risk factors. 26 PVD-patients received 2 different schemes of PGE1-therapy (group A [n = 17]; 5 ng PGE1/kg/min × 6 h × 5 d × 4 wk; group B [n = 9]; 60 mug PGE1/2 h × 5 d × 2 wk). PGE1 decreases all the AM significantly (p < 0.01) using both therapeutic schemes. Stopping PGE1-therapy reverses values within about 4 weeks. Details on therapeutic regimens (dose, duration, route, etc.) and individual response still need to be assessed. Conclusion: Our results indicate that PGE1-treatment of PVD is associated with a significant benefit on circulating AM. These findings are in line with...

Isradipine, a calcium-entry blocker, decreases vascular (125-I)low-density lipoprotein entry in hypercholesterolemic rabbits

In 72 male rabbits aged 6 months, the endothelium of the abdominal aorta was abraded by a Fogarthy catheter. The animals were then fed a cholesterol-supplemented diet for 4 weeks. In addition, half of the animals were treated for the entire period with isradipine (0.3 mg kg daily dihydropyndine calcium antagonist: the other 36 aminuals served as controls. One hour and 3.6 12. 24. and 48 hours before the animals were killed. [125-I]low-density lipoprotein (1.1)1.10 μ was administered intravenously (i.v. to siv animals in each group. The [125-I]LDL entry was quantified in the abdominal aorta according to the type and presence of endothelial lining. Isradipine significantly reduced the {125-I]LDL entry at most time intervals. In parallel, an increase in vascular prostaglandin (PGL) synthesis was noted, which might be the underlying mechanism for the decreased LDL entry.