Efficacy and safety of losartan/hydrochlorothiazide in patients with severe hypertension.

This 12-week, open-label, multicenter study assessed the efficacy and safety of losartan/hydrochlorothiazide (HCTZ), alone or in combination with other antihypertensive agents, in the treatment of patients with severe systemic hypertension. Treatment began with once-daily losartan/HCTZ 50/12.5 mg. The dose was increased to 100/25 mg, if required, to achieve blood pressure (BP) control (sitting diastolic BP <95 mm Hg); felodipine (extended release) and/or atenolol could be added if target sitting diastolic BP was not achieved with losartan/HCTZ alone. Mean sitting systolic BP of the 131 patients enrolled was 165.3 mm Hg at baseline and 139.8 mm Hg at final visit (reduction -25.4 mm Hg; p < or =0.01). Mean sitting diastolic BP was 111.9 mm Hg at baseline and 93.6 mm Hg at final visit (reduction -18.4 mm Hg; p < or =0.01). After 2 weeks of treatment, 63.8% of patients (83 of 130) were taking losartan/HCTZ 50/12.5 mg alone. By the final visit, one third of patients (35.1%; 46/131) were still only taking losartan/HCTZ. Most patients (48.1%; 63 of 131) were taking losartan/HCTZ 100/25 mg plus felodipine (extended release) at the final visit. Losartan/HCTZ was well tolerated. Drug-related adverse experiences occurred in 30 patients (22.9%). Only 2 patients (1.5%) had a serious adverse experience; 6 patients (4.6%) discontinued the drug because of an adverse experience. In conclusion, losartan/ HCTZ, alone or as part of a regimen with other standard antihypertensive agents, is effective and well tolerated in the treatment of patients with severe hypertension.

Effect on collagen metabolism of thrombolytic therapy with tissue-plasminogen activator. A randomized, placebo-controlled study.

This paper assesses alterations in collagen metabolism following thrombolytic therapy of acute myocardial infarction with tissue-plasminogen activator. Sequential serum measurements of the amino-terminal propeptide of type III procollagen (S-PIIINP) and the carboxyterminal propeptide of type I collagen (S-PICP) in patients suspected of acute myocardial infarction randomized to tissue-plasminogen activator or placebo were used. S-PIIINP increased at 3 h in patients with acute myocardial infarction treated with tissue-plasminogen activator (P < 0.05). S-PIIINP was higher in patients treated with tissue-plasminogen activator compared with placebo-treated patients at 3 and 6 h (P < 0.05). S-PICP decreased independently of therapy and diagnosis. Tissue-plasminogen activator, therefore, induces breakdown of collagen, some of which is located in the wall of atheromatous arteries. Vascular patency following thrombolytic therapy may partly be mediated by breakdown of thrombogenic collagen in the vessel wall. The findings may suggest a role for S-PIIINP as a non-invasive indicator of the risk of reocclusion.

Influence of oral magnesium supplementation on cardiac events among survivors of an acute myocardial infarction.

OBJECTIVE: To investigate the effect of long term oral magnesium treatment on incidence of cardiac events among survivors of an acute myocardial infarction. DESIGN: Double blind, placebo controlled parallel study in which patients were randomised to treatment or placebo. SETTING: Two coronary care units and corresponding outpatient clinics. SUBJECTS: 468 survivors of an acute myocardial infarction (289 men and 178 women) aged 31-92. INTERVENTIONS: One tablet of 15 mmol magnesium hydroxide or placebo daily for one year. MAIN OUTCOME MEASURES: Incidences of reinfarction, sudden death, and coronary artery bypass grafting in one year. RESULTS: There was no significant difference between treatment and placebo groups in the incidence of each of the three cardiac events, but when the events were combined and drop outs were excluded from calculations there was a significantly higher incidence of events in the treatment group (56/167 v 33/153; relative risk 1.55 (95% confidence interval 1.07 to 2.25); p = 0.02). When the timing of events was incorporated by means of a Kaplan-Meier plot the treatment group showed a significantly higher incidence of events whether drop outs were included or excluded (p < 0.025). CONCLUSION: Long term oral treatment with 15 mmol magnesium daily doses not reduce the incidence of cardiac events in survivors of an acute myocardial infarction and, indeed, seems to increase the risk of developing a cardiac event. Consequently, this treatment cannot be recommended as secondary prophylaxis for such patients.

The prevalence of myocardial ischemia six months after thrombolytic treatment of acute coronary episodes. A subset of a placebo controlled, randomised trial, the ASSET Study.

The purpose of this prospectively conducted study was to determine the prevalence of transient myocardial ischemia, evaluated from 24 h continuous ECG monitoring and exercise test, 6 months after inclusion in the Anglo Scandinavian Study of Early Thrombolysis (the ASSET trial, a randomised, placebo controlled study of alteplase for survival in patients with suspected acute myocardial infarction (AMI)), and to relate these findings to development of cardiac events. Of the 58 consecutively studied patients ischemic responses were found in 13 (45%) of 29 patients initially treated with placebo, and in 21 (72%) of 29 alteplase treated patients (P = 0.03). After another 6 months, i.e. 12 months after the acute event, two patients were dead, two had non-fatal reinfarctions and three had coronary artery by-pass surgery in the group with ischemic response; no events were recorded in patients without ischemia (P < 0.05). Alteplase treated patients more often had late myocardial ischemia, and cardiac events were found in patients with ischemia. Since the ASSET trial has demonstrated significantly higher short- and long-term survival rate in the alteplase treated group, it was indicated (1) that alteplase treated patients were better positioned for sustaining subsequent ischemia and thus cardiac events due to preservation of viable myocardial tissue, and (2) that late ischemia in the setting of initial alteplase treatment may convey other information than ischemia occurring in placebo treated patients.

[Serotonin and cardiovascular control]. / Serotonin og kardiovaskulaer kontrol.

Serotonin is a monoamine and is widely distributed in the human organism. Serotonin is synthesized from the amino acid tryptophane and is broken down via mono-amino-oxydase enzymes to 5-hydroxy-indol-acetic acid and by acetylizing and methylizing to melantonin. In 1986, a consensus concerning the classification of the serotonergic receptors was established. Three main classes were determined, viz: 5-HT1, 5-HT2 and 5-HT3. 5-HT1 receptors were further subdivided into A, B, C and D-receptors and, of these, the 5-HT1A-receptor is involved in the centrally mediated blood pressure control via reduction in the pre- and postganglionic sympathetic activity. The 5-HT2 receptors are primarily involved in control of peripheral blood pressure where agonizing results in vascular contraction of the large arteries and veins and thrombocyte aggregation. The 5-HT1 receptors are also involved peripherally in connection with release of relaxing factors derived from endothelium. In vitro and in animal experiments, it has been demonstrated that serotonin is capable of inducing arrhythmia and myocardial dysfunction via 5-HT3 receptors. Several preparations with effects on both the central and peripheral serotonergic receptors are already marketed for treatment of hypertension and other conditions.

Influence of magnesium substitution therapy on blood lipid composition in patients with ischemic heart disease. A double-blind, placebo controlled study.

In a double-blind, placebo-controlled study, 47 patients with ischemic heart disease and acute myocardial infarction were allocated to 3 months' treatment with peroral magnesium (15 mmol/d) or placebo. Before, during, and after treatment, blood samples were taken to determine serum concentrations of cholesterol; triglyceride; high-density, low-density, and very-low-density lipoprotein; apolipoprotein A1 and B; and magnesium. We found a 13% increase in molar ratio of apolipoprotein A1:apolipoprotein B after magnesium treatment, as compared with a 2% increase in the placebo group (for mean differences between changes of the magnesium and the placebo groups). This increase was caused by a decrease in apolipoprotein B concentrations, which were reduced by 15% from 1.44 to 1.23 mmol/L in the magnesium group as compared with a slight increase in the placebo group. Triglyceride, and thereby very-low-density lipoprotein concentrations decreased by 27% after magnesium treatment (from 2.41 to 1.76 mmol/L, and from 1.1 to 0.79 mmol/L, respectively) as compared with much smaller decrements in the placebo group. Likewise, we found tendencies toward an increase in high-density lipoprotein cholesterol and in high-density lipoprotein cholesterol ratio/(low-density lipoprotein cholesterol:very-low-density lipoprotein cholesterol) after magnesium treatment. The observed findings support the hypothesis that magnesium deficiency might be involved in the pathogenesis of ischemic heart disease by altering the blood lipid composition in a way that disposes to atherosclerosis.

The effect of intravenous magnesium therapy on serum and urine levels of potassium, calcium, and sodium in patients with ischemic heart disease, with and without acute myocardial infarction.

Serum concentrations of magnesium, potassium, calcium, and sodium were determined on admission of 224 patients to the hospital and after 2, 4, and 6 days in hospital; all were admitted to the hospital with suspected acute myocardial infarction (AMI). On admission, the patients were randomly allocated to 48 hours of treatment with magnesium intravenously or placebo. One hundred twenty-three patients had AMI (of whom 53 [43%] were treated with magnesium) and 101 had their suspected AMI disproven (of whom 51 [50%] were treated with magnesium). In a supplementary study, serum and urine levels of magnesium, potassium, calcium, and sodium, together with serum levels of parathyroid hormone, were determined before and after intravenous magnesium treatment in six patients with AMI and six patients with ischemic heart disease but without AMI. In both studies, magnesium therapy was associated with significant alterations in extracellular ion homeostasis. Serum concentrations of potassium decreased during the initial days of hospitalization in the patients treated with placebo, but increased slightly in the patients treated with magnesium infusions. These increments in the serum concentrations of magnesium and potassium correlated significantly. The increase in the serum concentration of potassium after magnesium infusions was due to a reduced renal potassium excretion level (from 71.3 to 49.4 mmol/24 h), indicating the existence of a divalent-monovalent cation exchange mechanism in the nephron. This hypothesis was supported by the observation that renal sodium excretion likewise decreased after magnesium infusions (from 83.2 to 59.2 mmol/24 h). Serum concentration of calcium decreased significantly after magnesium treatment (from 2.35 mmol/L on admission to 2.15 mmol/L after 24 hours in the hospital) in the AMI group, in contrast to the placebo-treated patients, where no significant fluctuations in serum concentration of calcium were detected during the initial six days. This decrease in serum concentration of calcium was due to a marked increase in renal calcium excretion (from 3.43 mmol/24 h before to 6.59 mmol/24 h after magnesium infusion). A correlation between increments in serum magnesium concentration and decrements in serum calcium concentration was detected. No change in serum levels of parathyroid hormone was found before and after magnesium infusions. Both serum and urine levels of magnesium significantly increased after magnesium treatment to levels above the upper normal limits (serum magnesium concentration increased from 0.81 to 1.21 mmol/L, urine magnesium excretion levels from 3.57 to 16.57 mmol/24 h for both serum and urine changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial contractility and performance capacity after magnesium infusions in young healthy persons: a double-blind, placebo-controlled, cross-over study.

To evaluate the effect of intravenous magnesium (Mg) treatment on the inotropic state of the heart and maximal work capacity, 9 healthy volunteers were entered in a double-blind, placebo-controlled, cross-over study. Separated by an interval of three weeks, the volunteers were tested twice, each time randomly allocated to receive either an intravenous injection of 10 mmol magnesium chloride dissolved in 100 ml isotonic sodium chloride or placebo of isotonic sodium chloride only. Before and after each infusion myocardial inotropism was evaluated by echocardiography. Mitral-septal distance (MSA) was used as a measure for ejection fraction. On each test day an ergometer bicycle exercise test was performed, and maximal work capacity was calculated. Magnesium treatment reduced the MSA (from 4.2 to 2.9 mm, p = 0.07), while no difference was found after placebo treatment. Likewise, a tendency toward increasing fractional shortening after magnesium treatment was detected, although this difference was not statistically significant (p = 0.1). No difference in maximal work capacity between the magnesium and placebo periods was found. Serum magnesium concentrations and placebo periods was found. Serum magnesium concentrations rose significantly after the infusions (from 0.82 to 1.38 mmol/l, p less than 0.001). It is concluded that intravenous magnesium does not exert a negative inotropic effect on the myocardium as previously stated. On the contrary, we found a tendency toward a positive inotropic effect. However, the observed differences are of borderline statistical significance and a more extended study, employing invasive measurements of cardiac inotropism appears to be necessary.

Magnesium deficiency in patients with ischemic heart disease with and without acute myocardial infarction uncovered by an intravenous loading test.

An intravenous magnesium-loading test with 30 mmol/L of magnesium was used to evaluate the magnesium status in 38 patients with ischemic heart disease (IHD) admitted to the coronary care unit with suspected acute myocardial infarction (AMI), in ten healthy volunteers (control group), and in nine patients with chronic IHD in a stable phase of their disease (chronic IHD group). Sixteen of the patients admitted with acute disease proved to have AMI (AMI group) and 22 did not (non-AMI group). Patients with IHD both with and without AMI retained significantly more magnesium (9.3 and 10.7 mmol/L [22.6 and 26 mg/dL], respectively) than did the control group (1.4 mmol/L [3.4 mg/dL]). This 34% magnesium retention points to a state of magnesium deficiency in patients with IHD. However, since the patients with and without AMI did not differ, the observations do not indicate that AMI is associated with a more severe magnesium deficiency than that found in other IHD patients without AMI. When the patients with IHD were subgrouped according to long-term diuretic treatment, the patients (n = 19) receiving long-term diuretic treatment had a 39% retention of magnesium (11.6 mmol/L [28.2 mg/dL]) compared with a 29% retention (8.7 mmol/L [21.1 mg/dL]) observed in 19 patients who were not receiving long-term diuretic treatment. This observation was not influenced by the presence or absence of AMI. An even higher level of magnesium retention (17.1 mmol/L [41.6 mg/dL] equals 57% retention) was found when investigating patients with chronic ischemic heart disease in a stable phase of their disease. This indicates that patients with IHD may be severely magnesium deficient; that long-term diuretic treatment contributes to this deficiency, but that diuretic treatment per se is not the only cause of this condition.

Magnesium and acute myocardial infarction. Transient hypomagnesemia not induced by renal magnesium loss in patients with acute myocardial infarction.

Serum magnesium concentrations and the rate of urine magnesium excretion were studied in 24 patients with suspected acute myocardial infarction (AMI). Blood and urine samples were taken on admission, at three-hour intervals for the first 24 hours after admission, and every eight hours for the next 24 hours. Thirteen of the patients were found to have AMI, and the 11 who did not have AMI served as a control. During the first 32 hours, the AMI group had significantly low serum magnesium concentrations. The serum magnesium concentrations were unchanged in the control group. Results of the urine samples disproved our hypothesis that the drop in serum magnesium concentrations was due to an increased renal magnesium loss. These results indicate a magnesium migration associated with AMI, from extracellular to intracellular space.