Antihypertensive effect of isradipine on ambulatory and casual blood pressure.

The antihypertensive effect of isradipine was studied in 35 mild-to-moderate hypertensive patients (mean age 57 years) using casual and ambulatory 24-h blood pressure measurement. After the placebo phase, oral treatment was started with 1.25 mg isradipine twice daily for 4 weeks, which was increased to 2.5 mg twice daily if blood pressure was not normalized [in one patient, the new angiotensin-converting enzyme (ACE) inhibitor spirapril was added at a dose of 3 mg daily after 4 weeks]. The active-treatment period lasted 24 weeks. At the end of therapy, casual blood pressure decreased significantly (P < .001) from 174/103 to 151/86 mm Hg, and mean ambulatory blood pressure from 145/88 to 139/84 mm Hg (P < .05). The total number of hypertensive systolic and diastolic blood pressure values also decreased. When patients were divided into normotensives and hypertensives according to their initial ambulatory blood pressure, no effect of treatment was detected in the normotensive group. Casual blood pressure was higher than the 24-h ambulatory pressure.

Antihypertensive effects of isradipine and captopril as monotherapy or in combination.

The antihypertensive effects of isradipine and captopril were studied in 140 patients (70 men) with mild-to-moderate hypertension, aged 26 to 74 years, in a double-blind, randomized, between-patient comparative trial. Initial treatment started with 1.25 mg isradipine twice daily or 12.5 mg captopril twice daily. If normotension was not achieved after four weeks, doses were increased to 2.5 mg twice daily or 25 mg twice daily, respectively. If the maximum dose as monotherapy did not result in normotension, captopril (12.5 mg or, if necessary, 25 mg twice daily) was added to regimens of the isradipine-treated patients or isradipine (1.25 mg or, if necessary, 2.5 mg twice daily) was given in addition to the captopril-treated patients. After 24 weeks of active treatment, systolic blood pressure was significantly reduced (P less than .001) with isradipine (from 168 +/- 18 to 144 +/- 14 mm Hg) and with captopril (from 168 +/- 20 to 143 +/- 10 mm Hg). Diastolic blood pressure also fell significantly (P less than .001) in both groups (isradipine: from 105 +/- 5 to 84 +/- 5 mm Hg; captopril; from 105 +/- 4 to 85 +/- 4 mm Hg). With isradipine as monotherapy, diastolic blood pressure was normalized in 49% of patients compared with 56% with captopril as monotherapy (P = NS). Combining both drugs resulted in an increased rate of normalization (to 87%). The results indicate that combined treatment with a calcium antagonist and an angiotensin-converting enzyme inhibitor is effective in lowering blood pressure and is well tolerated during long-term therapy.

A multicenter study using causal readings, self-recordings, and ambulatory blood pressure monitoring to assess isradipine effects. AMICUS Study Group.

The antihypertensive efficacy of isradipine has been widely studied. In most studies, however, blood pressure values were assessed by causal readings (CR) only. Furthermore, whether or not such blood pressure readings are sufficient proof of efficacy is still under discussion. Thus, a multicenter study was devised wherein blood pressure were recorded by CR, self-recordings, and noninvasive ambulatory monitoring (ABM). A total of 595 patients with mild-to-moderate hypertension were treated for 6 months starting with 1.25 mg of isradipine twice daily. If, after 4 weeks of treatment, CR-determined diastolic blood pressure (DBP) was still > 90 mm Hg, this dosage was doubled (n = 327) and, at week 8, pindolol at 5 mg or spirapril at 3 mg daily was added if necessary for blood pressure control. On the basis of CR, the results confirmed that low dosages of isradipine twice daily are safe and effective in the treatment of mild-to-moderate hypertension. The mean decrease in CR-determined blood pressure was 28.5/19.0 mm Hg at week 24, and the normalization rate (DBP < or = 90 mm Hg) for all patients treated was 78.2%. However, SR-determined blood pressure reduction was 20.0/13.0 mm Hg, with a normalization rate of 42%, whereas ABM-determined blood pressure reduction was 7.0/4.2 mm Hg. On the basis of ABM recordings, 66% of the patients had a DBP < 90 mm Hg on entry into the study and their blood pressures did not decrease with treatment. Thus, it appears that CR-determined blood pressures bias study results by including normotensives and thereby overestimating efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of isradipine on platelet function in hypertension at rest and during exercise.

The effects of eight weeks of treatment with isradipine (1.25 mg twice daily for four weeks, followed by 2.5 mg twice daily for four weeks) on ex vivo platelet function were investigated in ten male patients with hypertension. Systolic and diastolic blood pressures, platelet aggregation in response to adenosine diphosphate (ADP), serum thromboxane B2, and beta-thromboglobulin levels were significantly decreased (P less than .05) at rest before exercise ergometry, during exercise, and at rest after exercise. The platelet count and plasma levels of 6-oxo-prostaglandin F1 alpha (PGF1 alpha) were not affected by isradipine. It is concluded that treatment of hypertension with a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit when routinely applied in hypertensive patients.

Glucocorticoid-treatment does not influence the synthesis of thromboxane B2 and bicyclo-PGE2 in humans.

It has been reported that the anti-inflammatory action of glucocorticoids is due to the inhibition of phospholipases. Consequently, after high-dose steroid treatment in humans a decrease in cyclooxygenase products should be expected. In 15 patients (10 males, 5 females, 29-62 y) undergoing 6-methyl-prednisolone-treatment (40-80 mg daily) for various clinical reasons and in 5 healthy volunteers (4 male, 1 female, 28-37 y) receiving 500 mg 6-methyl-prednisolone daily for 3 days plasma- and serum-thromboxane B2 (TXB2), as well as bicyclo-prostaglandin E2 (bicyclo-PGE2) were monitored over 3 weeks. In the entire follow-up period, however, no significant change in either serum- or plasma-TXB2 or bicyclo-PGE2 could be measured in either, patients and volunteers, under glucocorticoid-treatment. These findings indicate that even high-dose glucocorticoid-treatment does not affect the serum- and plasma-metabolites of the eicosanoids examined. It is concluded that in humans a significant inhibition of phospholipases by glucocorticoids and subsequently reduced formation of cyclooxygenase products seems to be rather unlikely.

Effects of bopindolol on platelet function in hypertension at rest and during exercise.

The effects of bopindolol, a new nonselective beta-blocking agent, on platelet function have been studied in 10 male hypertensive patients given the drug (1 mg/day) in turn for eight weeks. Bopindolol significantly (p less than 0.01) decreased the bicycle exercise- (1.5 W/kg body weight for 6 minutes) induced increase in platelet aggregation. During bopindolol-treatment both the slope and the height of the platelet aggregation response curve were moderately decreased at rest before exercise and significantly (p less than 0.05) decreased at rest after exercise. During exercise the slope amounted to 75.4 +/- 44 degrees before and to 70.8 +/- 5.3 degrees after therapy (p less than 0.01), the height to 64.0 +/- 11.9% before and to 58.1 +/- 14.7% (p less than 0.05) after therapy. Furthermore, bopindolol significantly increased the exercise-induced decrease in platelet sensitivity to PGI2 (p less than 0.05; IC-50-value: 2.10 +/- 0.47 vs 1.88 +/- 0.31 ng/ml) and PGD2 (p less than 0.05; IC-50-value: (19.88 +/- 2.10 vs 18.57 +/- 1.63 ng/ml). Bopindolol also significantly (p less than 0.05) decreased the exercise-induced elevation in serum-TXB2 (244.9 +/- 35.2 vs 237.3 +/- 27.2 ng/ml) and plasma-TXB2 (15.7 +/- 6.3 vs 13.1 +/- 3.7 pg/ml). The platelet count, the plasma levels of 6-oxo-PGF1 alpha, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were not affected by bopindolol. It is concluded that bopindolol favourably affects platelet function, in that it lowers exercise-induced platelet aggregation and TXB2-formation in therapeutical doses and increases platelet sensitivity to antiaggregatory prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of taprostene, a chemically stable prostacyclin analogue, in patients with ischaemic peripheral vascular disease: a placebo controlled double-blind trial.

Thirty patients with ischaemic peripheral vascular disease and intermittent claudication were randomly allocated to receive either placebo or taprostene, a chemically stable prostacyclin analogue, intravenously at a rate of 25 ng/kg/min for 6 hours daily on 5 consecutive days. Taprostene produced a significant (p less than 0.05) increase in absolute walking time compared to placebo on one day after infusion and at 1, 4 and 8 weeks (14% vs 2.8%) later. Taprostene also produced a significant (p less than 0.05) increase in the pain-free walking time compared to placebo in the follow-up period (8 weeks after infusion: 23% vs 3.8%). During the infusion period systolic and diastolic blood pressure decreased (p less than 0.05) and heart rate was accelerated (p less than 0.05) in the taprostene treated group whereas no change was monitored in the placebo group. The ankle/brachial Doppler index was unaffected by taprostene. The platelet half-life was significantly (p less than 0.05) prolonged following taprostene-infusion (72.6 +/- 9.35 vs 77.9 +/- 7.44 hours). However, no change on platelet half-life was found in the placebo group (p less than 0.05). Various measures of platelet function parameters followed in vitro (ADP-induced aggregation, platelet sensitivity to PGI2, PGE1, PGD1 and taprostene, concentrations of platelet factor 4 and beta-thromboglobulin) showed no change with taprostene. Measures of circulating platelet aggregates and endothelial cells count showed no changes during the 2 months follow-up period too. It is assumed that taprostene may be of clinical benefit in patients with ischaemic peripheral vascular disease. However, future investigations have to be carried out to assess the optimal dose regime.

Diminished platelet residence time on active human atherosclerotic lesions in-vivo--evidence for an optimal dose of aspirin?

Although aspirin is an old drug, its optimal dose for the treatment of human atherosclerosis has not been finally proven. Various in-vitro and ex-vivo platelet function tests revealed a dose range from 1 to 3000 mg as being optimal. It was thus the goal to examine its in-vivo efficacy in human suffering from peripheral vascular disease in 7 different doses ranging from 1 mg to 1000 mg a day. All these patients have been treated for 3 months. Platelet half-life and platelet uptake ratio show an in part significant improvement being most pronounced at the daily doses of 20 and 1000 mg respectively. No change occurs in the placebo treated controls. These findings indicate, that 20 or 1000 mg aspirin taken daily per os, are superior to the other doses examined concerning the in-vivo platelet function (as measured by platelet half-life) and rendering the arterial surface less thrombogenic (as reflected by platelet uptake ratio-measurements).

Epoprostenol in patients with Raynaud's disease.

Prostaglandin metabolism and the clinical effect of epoprostenol (prostacyclin, PGI2) infusions were studied in thirteen patients with Raynaud's disease. Epoprostenol was infused at 5 ng/kg/min for six hours daily for two consecutive five day periods, separated by a two day interval. No beneficial effects either during or after infusion could be detected in terms of frequency of severity of attacks or on skin temperature measurement. Raynaud's patients had significantly lower serum thromboxane B2 levels than normal controls though plasma levels of thromboxane B2, 6-oxo-PGF1 and the bicyclic metabolite of PGE2 did not differ between the two groups. Platelets from Raynaud's patients had a significantly lower conversion rate of arachidonic acid into thromboxane B2 and HHT and a significantly higher rate of HETE production than platelets from controls.

The diminished extracellular matrix production induced by isradipine, a calcium channel blocker, is completely abolished by cyclooxygenase inhibition.

Collagen and glycosaminoglycan synthesis are well known to be enhanced during early atherogenesis. In this experimental study the synthesis of collagen was determined using 14C proline incorporation, the glycosaminoglycan production by means of 35S-sulphate incorporation and subsequent quantification by means of autoradiography. Isradipine, a new calcium channel blocker of the dihydropyridine family at a dose of 0.3 mg/kg significantly (p less than 0.01) decreased the incorporation of both the radioactive precursors. This effect was abolished by a concomitant aspirin treatment, while aspirin alone did not exert any significant effect on the precursor incorporation. These data suggest that isradipine, which is known to stimulate PGI2 synthesis, may exert this antiatherosclerotic inhibitory action on extracellular matrix production via the endogenous liberation of PGI2.

Isradipine lowers human arterial low density lipoprotein retention in vivo.

During the recent past it has been discussed that calcium antagonists may exert antiatherosclerotic actions at the vessel wall. Apolipoprotein B containing lipoproteins were isolated by immunoaffinity chromatography and radiolabeled with 123-iodine. The effect of 2 x 2.5 mg isradipine on the low density lipoproteins (LDL) entry into the carotid and femoral arteries of 12 hypertensive patients with primary hyperlipoproteinemia (total cholesterol >6.5 mmol/l [250 mg/dL) was examined. Cholesterol -1.7% (P< 0.05 664), high density lipoprotein (HDL) cholesterol +4.5% (P< 0.01 123), and LDL cholesterol -1% (P< 0.01 563) did not change, nor did any of the safety parameters. The types of entry kinetics reflecting vascular surface lining did not change while the LDL retention 20 h after tracer application was depressed by up to 23.5%. The data were comparable in the carotid and femoral artery segments, the significance level ranging up to 0.0009. These results indicate a decreased LDL retention in the arterial wall of hypertensive patients induced by isradipine. The clinical implications of the findings ought to be pursued in properly designed clinical trials.

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).

Decreased prostaglandin-I2 stability in acute myocardial infarction.

It has been demonstrated that under certain conditions the in-vitro half-life of biologically active PGI2 in plasma is extremely shortened, which may result in-vivo in a local haemostatic imbalance. In 36 patients suffering from acute myocardial infarction a sequential change in in-vitro half-life of synthetic PGI2 was therefore studied during 3 weeks. 21 patients admitted turning out not to develop myocardial infarction served as follow-up controls. During and shortly after the acute episode the plasmatic half-life of PGI2 in-vitro was shortened by about 40%, improving continuously thereafter. No certain influence of either risk factors, sex or age could be discovered. A possible influence of various drugs administered in the hospital period has been excluded in 43 patients with proven coronary artery disease. No such changes occurred during acute angina pectoris attack in 12 patients. It remains to be established, whether the short-lasting destabilisation of PGI2 may be an acute disease-associated finding, or an important pathogenetic factor.

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.

Successful eradication of Helicobacter pylori as determined by ((13))C-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.

Effects of Hydergine on platelet deposition on "active" human carotid artery lesions and platelet function.

Effects of co-dergocrine mesylate (Hydergine), a drug widely used for the therapy of cerebral vascular disease on local platelet accumulation in the carotid artery region was studied by means of the platelet uptake ratio (PUR) and on the systemic platelet-vascular wall interaction as calculated from platelet half-life were investigated. A placebo controlled, double blind, randomised protocol was used, 18 patients were treated with co-dergocrine and compared to placebo (n = 18). Co-dergocrine treatment resulted in a significant decrease in platelet deposition, PUR decreased from 1.28 +/- 0.05 before treatment to 1.25 +/- 0.06 on day 5 of therapy with a statistically significant (p less than 0.001) in the paired comparison. In the control group the corresponding changes from 1.29 +/- 0.04 before to 1.28 +/- 0.04 did not show a p-value of less than 0.05 in paired comparison. Platelet half-life (72 +/- 11 before vs. 76 +/- 11 hours after 5 days of co-dergocrine treatment) showed a statistically significant (p less than 0.001) prolongation, whereas in the placebo group no relevant change of T/2 was observed (71 +/- 10 before vs. 72 +/- 10 hours on day 5, p greater than 0.10). No relevant effects on ADP-induced platelet aggregation, platelet-release reaction, platelet aggregate ratio, TXB2 plasma levels and thrombin-induced MDA-formation could be detected. These results indicate that co-dergocrine decreased in-vivo platelet residence time to atherosclerotic lesions of the carotid artery. Co-dergocrine may thereby be of benefit in prevention of mural thrombus formation and prevention of transient ischemic attacks, but also of atherosclerosis in man.

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.

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.

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.

Isradipine decreases arterial thrombogenicity in rabbits. A morphometric and radioisotopic study.

The effect of isradipine, a calcium antagonist, on aortic and iliac wall thrombogenicity was examined in rabbits. After one week of dosing, the abdominal aortic and iliac artery endothelium was abraded using a Fogarthy catheter. One group of animals (n = 8) was dosed for one week with isradipine 0.3 mg/kg. A second group of animals received 10 mg acetylsalicylic acid (ASA)/kg daily in addition, while a third group received the vehicle only. Finally, a fourth group of animals (n = 8) was treated with ASA only. The percentage denuded surface covered with contact (unspread) platelets decreased significantly (p < 0.01) from 14.7 +/- 2.0 to 9.3 +/- 2.1 (6.2 +/- 0.8 to 3.7 +/- 0.4). The amount of contact and spread platelets was diminished from 84.9 +/- 5.6 to 71.4 +/- 4.4 (91.8 +/- 5.3 to 75.2 +/- 4.6). Platelet thrombi decreased from 7.4 +/- 0.9 to 4.6 +/- 1.4 (9.4 +/- 1.9 to 5.2 +/- 0.7) in the aortic and the iliac artery, respectively. In-platelet deposition decreased by 39.9 and 41.9%. Concomitant ASA therapy not only abolished the effect of isradipine but enhanced thrombogenicity, probably as a result of almost complete blockade of vascular PGI2-production.