Double-blind comparison of tiapamil and atenolol in patients with mild to moderate hypertension: a multicenter trial.

The efficacy and safety of tiapamil, a new calcium-channel blocker, was compared with the cardio-selective beta-blocker atenolol in a 16-week double-blind, multicenter trial with an initial 4-week placebo run-in period. Eighty-one outpatients with WHO stage I or II hypertension, 55 men and 26 women, entered the study. There was a total of nine drop-outs, six in the tiapamil group and three in the atenolol group. Five were due to side effects (four in the tiapamil group and one in the atenolol group). Sixty-one patients performed a graded exercise test sitting on a ergometer bicycle before and after completion of the therapy. Patients eligible for the study after the placebo period received either tiapamil 450 mg b.i.d. or atenolol 100 mg daily. Both drugs lowered systolic and diastolic blood pressure significantly. After 12 weeks of therapy, supine blood pressure in the tiapamil group fell from 167/104 mmHg to 154/91 mmHg (p less than 0.005), and in the atenolol group from 166/102 mmHg to 151/89 mmHg (p less than 0.005). A satisfactory reduction in diastolic blood pressure, defined as a reduction of more than 10 mmHg and/or values below or equal to 90 mmHg at the end of the study, was achieved in 29 of 35 patients in the tiapamil group and in 27 of 37 in the atenolol group. No changes in heart rate were observed in the tiapamil group, whereas there was a significant fall in heart rate in the atenolol group. The maximal exercise workload tolerated increased equally in both groups, from 135 to 147 watts.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved blood pressure control with isradipine in hypertensive patients treated with pindolol.

Isradipine is a new calcium antagonist of the dihydropyridine type with marked vasodilator activity and minimal negative inotropic effects. It is a potent antihypertensive drug when given as monotherapy. This was a randomized double-blind crossover study of 16 weeks' duration, including 80 hypertensive patients with diastolic blood pressures of at least 95 mm Hg who had shown clinically relevant antihypertensive responses, but no normalization of blood pressure during pindolol 10 to 15 mg once daily as monotherapy. Either isradipine or placebo was added to the beta-blocker at doses of either 2.5 mg or 5 mg twice daily, which was doubled after four weeks if the diastolic blood pressure remained more than 90 mm Hg. The addition of isradipine (in either dose regimen) caused a pronounced reduction of blood pressure with no changes in heart rate. Five patients were withdrawn from the study because of adverse events while receiving isradipine compared with three taking placebo. A further three patients withdrew from the study because of adverse events (one patient) or lack of efficacy (two patients) during placebo treatment. These results indicate that isradipine is an effective and well-tolerated adjunct to beta-blockers in hypertensive patients.

Serum lipid changes in a one-year, multicenter, double-blind comparison of doxazosin and atenolol for mild to moderate essential hypertension.

Proatherogenic changes in serum lipid concentrations have been implicated as one of the major risk factors in the development of coronary artery disease. In a double-blind study, the new alpha 1-adrenoceptor inhibitor, doxazosin, was compared with atenolol for effects on the serum lipid profile. Ninety-six hypertensive patients were treated for up to 1 year with either doxazosin or atenolol once daily. There were statistically significant differences (p less than or equal to 0.01) between doxazosin and atenolol after 20 to 52 weeks of treatment in changes from baseline total triglyceride levels, high density lipoprotein (HDL) cholesterol levels and HDL/total cholesterol ratio. The percentage of change from baseline and the statistical significance of the difference between treatment groups were: total triglycerides, doxazosin -5.9%, atenolol +32.4% (p = 0.01); HDL cholesterol, doxazosin +7.2%, atenolol -5.6% (p = 0.007) and HDL/total cholesterol ratio: doxazosin +8.7%, atenolol -6.2% (p = 0.006). All mean changes were in favor of doxazosin therapy. In addition, doxazosin treatment beneficially decreased total serum cholesterol levels (-1.6%) compared with atenolol (+0.6%), although not to a significant degree. The differences were maintained in the cohort of 67 patients treated for a full year. The favorable change exerted by doxazosin on the lipid profile suggests that it may have a beneficial influence on the lipid risk factor. These results, together with the sustained decrease in blood pressure achieved for up to 1 year of therapy, suggest that doxazosin may reduce the risk of coronary artery disease in susceptible patients.

The pharmacokinetics and pharmacodynamics of doxazosin compared with atenolol during long-term double-blind treatment.

The pharmacodynamics of doxazosin and atenolol were compared on single study days in 39 patients with mild to moderate hypertension receiving long-term double-blind treatment. The pharmacokinetics of doxazosin were investigated in the 20 patients receiving doxazosin. Individually titrated once daily doses of doxazosin were 1, 2, 4, 8 or 16 mg and of atenolol 50 or 100 mg. Patients were first investigated after at least one month on constant dose and then again after at least a further three months. Mean plasma concentrations of doxazosin were proportional to dose and the plasma half-life was 11.5 h and independent of dose. There was low variability of doxazosin plasma concentrations between patients receiving the same dose. Concentrations and half-life were unchanged during the period between investigations. Mean reductions of AUC (0-12 h) blood pressure during the 12-h period post-dose and of blood pressure at 24 h post-dose were not statistically different between doxazosin and atenolol. There was effective control of blood pressure by both drugs at all time points of the day. The pharmacokinetic and pharmacodynamic results obtained in this study are compatible with the use of doxazosin in a once daily dose regimen for the treatment of essential hypertension.

Diflunisal in the treatment of low back pain in a multicentre study.

An open trial with diflunisal (500 mg twice daily) in 766 outpatients consulting their doctor for low back pain, was carried out as part of the project "Back Pain 1981" in Finland. Of the patients (mean age 41 years), 460 had acute lumbago, 144 sciatica and 162 had chronic low back pain as a clinical diagnosis. In each diagnostic group there was a control group of patients receiving no drug therapy. Of the patients 65 percent were men and 35 percent women and the groups did not differ from this distribution in any diagnosis. The efficacy of the treatment was evaluated using four criteria: change of pain at rest and during exercise, patient's evaluation of the efficacy of the treatment, and the need for any supportive treatment. Side-effects of the drug therapy were registered. In all diagnostic groups the relief of pain both at rest and during exercise was greater in patients receiving diflunisal than in the controls. The greatest difference was found in lumbago. The patient's evaluation did not differ between the groups. The drug therapy diminished the need for supportive physical therapy. The frequency of side-effects was 8.6%. They led to the discontinuation of medication in 14 cases (3%). No severe side-effects were found. Diflunisal therapy for the relief of low back pain is therefore considered to be indicated in outpatient care.

A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension.

The efficacy and safety of doxazosin and atenolol were compared following once-daily administration for up to 1 year, with a minimum of 20 weeks' active treatment. According to response, patients received doxazosin 1-16 mg day-1 or atenolol 50-100 mg day-1. Mean daily doses at the final efficacy assessment (between 20 weeks and 1 year) were doxazosin 11.8 mg and atenolol 94.2 mg. Atenolol produced somewhat greater falls in blood pressure than doxazosin. The differences were statistically significant in the supine but not in the standing position. A small mean reduction in heart rate was produced by doxazosin whereas atenolol produced a marked bradycardia. Analysis of the same patient group at 20 weeks revealed similar overall profiles of activity except that atenolol produced greater falls in blood pressure than in the longer term analysis. Serum concentrations of HDL/total cholesterol ratio were raised in the doxazosin treatment group and lowered in the atenolol group. Triglyceride concentrations fell in the doxazosin group and rose in the atenolol group. Significant differences (P less than 0.001) were observed between treatment groups for these parameters, all differences being in favour of doxazosin. Pharmacokinetics of doxazosin, measured at steady state in 36 patients, showed dose-related plasma concentrations, a mean half-life of about 12 h and relatively low intersubject variation. The incidence of side-effects was slightly greater for patients in the doxazosin group. Drug-related side-effects were mostly mild to moderate in severity with no serious drug-related occurrences in either treatment group. No serious drug-related abnormalities in laboratory biochemistry and haematology tests were observed in either treatment group.

Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins.

The effects on plasma lipids and apoproteins A-I and B of oral administration of doxazosin and atenolol over a 20-week period were studied in 42 patients with mild to moderate essential hypertension. Total plasma cholesterol decreased by 8.9% (P less than 0.01) and LDL cholesterol by 16.9% (P less than 0.01) after 20 weeks' treatment with doxazosin. Total HDL cholesterol and HDL2 cholesterol concentrations increased slightly during doxazosin treatment and the increase in HDL2 level at 4 weeks was statistically significant (P less than 0.05). At 20 weeks, the levels of total HDL cholesterol and HDL2 were significantly (P less than 0.05) lower with atenolol than with doxazosin. The ratio HDL/total cholesterol increased during doxazosin treatment (P less than 0.05 at 4, 12 and 20 weeks). The HDL/total cholesterol ratio was significantly higher after 20 weeks with doxazosin than with atenolol (P less than 0.05). The levels of VLDL cholesterol and triglycerides increased significantly (P less than 0.01) during atenolol treatment. The concentrations of apoproteins A-I and B did not change significantly during treatment with doxazosin or with atenolol but at 20 weeks the ratio of apo A-I to apo B was significantly (P less than 0.05) lower with atenolol than with doxazosin. On the basis of these results, doxazosin would seem to have significant favourable effects on the serum lipid profile.

Effect of the short-term beta-adrenoceptor blockade on exercise metabolism in cold weather.

Carbohydrate and lipid metabolism at rest and after 1 h submaximal physical exercise in cold weather (between -1 and -6 C) were studied in ten healthy male subjects treated in a randomized double-blind fashion for 2 days with either placebo, the non-selective beta-adrenoceptor antagonist with high ISA pindolol (10 mg), or the cardioselective drug atenolol (100 mg). Four subjects, on both atenolol and pindolol, complained of muscular fatigue during exercise on beta blockade; four other subjects perceived some fatigue. There were no significant differences in blood glucose or insulin levels between treatments and placebo period. Post-exercise growth hormone levels increased on placebo (p less than 0.01), on pindolol (p less than 0.01), and on atenolol (p less than 0.05), but the alteration was more prominent on pindolol than on placebo (p less than 0.05). The plasma free fatty acid concentrations increased during exercise on placebo and pindolol (p less than 0.05) and on atenolol (p less than 0.01). Serum triglyceride concentrations decreased significantly during exercise on placebo or pindolol (p less than 0.01). Triglyceride levels before exercise were significantly higher on beta blockade than on placebo (p less than 0.05). The metabolic parameters taken before and after exercise did not explain the muscle fatigue experienced by many subjects during exercise.

Binding of folic acid to serum proteins. V. Tritiated folic acid in the liver.

Sephadex G-200 chromatographies of the liver cell sap of rabbits, 1, 3 and 6 days after an injection of 3H-folic acid activity (FAA) into the circulation, were used in an attempt to study the binding of this labelled FAA to liver proteins. The labelled FAA was quickly accumulated in the liver, and in the cell sap it was grouped chromatographically to two maxima, which corresponded to the two maxima of microbiological FAA (L. casei). The maxima were eluated in the chromatography together with cell sap proteins. The possible coupling of FAA to proteins in the liver is discussed.

Pentose phosphate pathway inhibition in blood cells during anticonceptive hormone therapy.

PIP: The transketolase activity (TKA) of the white and red blood cells of oral contraceptive users was studied in an unselected sample population. Compared with healthy controls of corresponding age, the white cell TKA in the oral contraceptive groups was lowered in about 30%. The red cell TKA was lowered in about 15% of the subjects studied. The most pronounced TKA inactivation was observed in the group taking pills that contained mestranol and megestrol acetate. The glucose tolerance tests were normal. Discontinuing the hormones normalized the white cell TKA.^ieng

Serum folic acid activity (L. casei) in Sephadex gel chromatography.

The folic acid activity (FAA) of the protein zone in DEAE Sephadex A-50 chromatography of normal serum showed the following distribution: most (about 40%) was eluted with protein zone IV (alpha-2-macroglobulin), about 33% with protein zones II-III (transferrin), and the balance with zone V (albumin). In healthy human subjects the variations were relatively small. The repeatability of the chromatography in an individual was good.Towards the end of pregnancy the binding of FAA to protein zones II-III increased, while that to zone IV decreased. The return to normal started a few days after delivery. The binding to zones II-III was greatly increased in patients with pernicious anaemia but no neuropathy. It became normal during B(12) therapy. If the patient had neuropathy, his FAA chromatogram was close to normal. During therapy the amount of unbound FAA decreased rapidly. The use of diphenylhydantoin increased the binding of FAA to protein zone I and to zones II-III. In these patients the binding to protein zone IV was slighter than normal.