Effects of 100 mg of controlled-release metoprolol and 100 mg of atenolol on blood pressure, central nervous system-related symptoms, and general well being.

Central nervous system (CNS)-related symptoms and quality of life during treatment with controlled-release (CR) metoprolol and a standard formulation of atenolol were compared in a double-blind crossover study in 60 patients with mild to moderate hypertension. After a 4-week placebo run-in period, each beta 1-adrenoceptor blocker was administered at a dosage of 100 mg once daily for 6 weeks. Quality of life was assessed regularly during the active treatment phases by use of two standardized self-administered questionnaires, the minor symptom evaluation (MSE) profile, and the psychologic general well-being (PGWB) index. Both questionnaires have previously been shown to be effective in detecting CNS symptoms and changes in well being produced by beta-blockers. Blood pressure and heart rate were monitored to assess the antihypertensive efficacy of the two drugs. Metoprolol CR and atenolol produced equivalent, clinically effective reductions in systolic and diastolic blood pressures measured 24 hours after administration. The drugs were found to exert similar effects on general well being, as assessed by the PGWB index, and there were no significant differences between the two treatments with regard to the three dimensions of the MSE profile, contentment, vitality, and sleep. Thus, at equivalent antihypertensive dosages, metoprolol CR and atenolol are clinically comparable with regard to the degree of CNS-related symptoms produced and effects on general well being. Because these agents differ markedly in lipophilicity, other factors, such as beta 1-selectivity/nonselectivity, may be more important determinants of whether these subjective symptoms occur during therapy with beta-blockers.

Controlled release metoprolol. Clinical pharmacokinetic and therapeutic implications.

Metoprolol is a relatively beta 1-selective beta-blocker used extensively to treat hypertension and angina and as a prophylaxis after myocardial infarction. Conventional formulations are usually administered twice daily and the drug has a tendency to lose its selectivity of action at higher plasma concentrations. Two controlled release formulations, metoprolol CR and metoprolol 'Oros', have made it possible to achieve sustained beta 1-blockade over an entire 24h period and to minimise the loss of selectivity associated with higher plasma concentrations. The CR formulation has been extensively investigated and is the major subject of this review. The 'Oros' formulation is pharmaceutically different from the CR, yet both produce similar plasma concentration profiles and comparable beta 1-blocking effects. The availability of these preparations occurs at a time when increasingly persuasive data are becoming available on the cardioprotective or coronary preventive action of metoprolol.

The efficacy of low dose metoprolol CR/ZOK in mild hypertension and in elderly patients with mild to moderate hypertension.

In two separate but similarly designed placebo-controlled studies, the efficacy of metoprolol CR/ZOK 50 mg once daily was evaluated in 64 patients (mean age 53 years) with mild hypertension (Study I) and in 34 elderly patients (mean age 68 years) with mild to moderate hypertension (Study II). Both studies were of randomized, double-blind, parallel-group design, the entry criteria for diastolic blood pressure being greater than or equal to 90 less than 105 mm Hg in Study I and greater than or equal to 95 less than 110 mm Hg in Study II. Study I: The impact of metoprolol CR/ZOK 50 mg once daily for 4 weeks compared with placebo 24 hours post dosing was to produce a significant reduction in supine (P = .0001), and standing (P less than .0001) systolic blood pressures and the standing diastolic pressure (P = .035). The supine diastolic pressure was lower after metoprolol CR/ZOK but not significantly so. Study II: Metoprolol CR/ZOK 50 mg daily given to elderly hypertensives when compared with placebo 24 hours post dosing produced a significant fall in supine (P = .022) and standing (P = .022) diastolic pressure. Systolic pressure and heart rate were not significantly reduced. One patient in Study II had a nonfatal myocardial infarct whilst receiving placebo. There were no other serious adverse effects in either study and no patients were withdrawn from the trial because of drug related unwanted events. The studies indicate that 50 mg metoprolol CR/ZOK may be an effective antihypertensive agent which may prove useful in the treatment of mild to moderate hypertension, particularly in the elderly.

Comparison of CNS-related subjective symptoms in hypertensive patients treated with either a new controlled release (CR/ZOK) formulation of metoprolol or atenolol.

The present study evaluated and compared subjective symptoms in hypertensive patients (N = 83) at therapeutically comparable dosages of a new controlled release (CR/ZOK) formulation of metoprolol (100 mg od) and atenolol (50 mg od). The trial was a 4-week randomized double-blind study preceded by a placebo run-in period. Blood pressure (BP) was recorded 24 hours after intake of last dose. In subpopulations, 24-hour ambulatory BP was recorded and exercise tests performed. Subjective symptoms were evaluated with a previously documented questionnaire (MSE-profile) which has been shown to be sensitive in detecting CNS-related symptoms caused by beta blockers. The MSE-profile includes three dimensions: Contentment, Vitality and Sleep. The results showed that there were no significant differences between the groups in BP reduction either at 24 hours or over the entire 24-hour dose interval. Furthermore, the degree of beta 1-blockade (reduction in exercise-induced tachycardia) 24 hours after last dose did not differ between the groups. There were no significant differences regarding subjective symptoms (Contentment, Vitality, Sleep) between the two treatment groups. An a posteriori power analysis showed that the power to detect a true difference was of an acceptable magnitude. In conclusion, there was no difference in CNS-related symptoms between metoprolol and atenolol at therapeutically comparable dosages indicating that the degree of lipophilicity may be of minor importance for the occurrence of such symptoms.

Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects--a comparison with atenolol.

In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects. The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2-4 h. All three active treatments produced significant beta 1-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of beta 1-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg. The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.

The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis.

This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselen in vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.

Controlled-release metoprolol compared with atenolol in asthmatic patients: interaction with terbutaline.

The beta 2-adrenoceptor mediated effects on ventilatory capacity, forced expiratory volume in one second (FEV1), forced ventilatory capacity (FVC), heart rate, and skeletal muscle tremor of a new controlled-release (CR) formulation of metoprolol, 100 mg and 200 mg, and of atenolol tablets, 100 mg, were studied in eight asthmatic patients. The effects of single-dose treatment, including placebo as reference, were studied in a randomized, double-blind, cross-over design. Starting 2 h after drug intake, four intravenous infusions containing increasing doses of terbutaline were given at 30-min intervals, followed by three doses of terbutaline inhalations. Maximum plasma concentrations for both metoprolol and atenolol were achieved within the study period. The FEV1 measurements after terbutaline infusions and inhalations were significantly lower after atenolol than after either dose of metoprolol CR. This indicates less blockade of beta 2-adrenoceptors with metoprolol CR than with atenolol at maximum plasma concentrations. The terbutaline-induced skeletal muscle tremor and increase in heart rate were less after atenolol than after either dose of metoprolol CR, also suggesting less interaction of metoprolol CR with beta 2-receptors. Thus, the new CR formulation of metoprolol caused fewer adverse effects on beta 2-adrenoceptor mediated bronchodilatation than a clinically equivalent dose of atenolol.

Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: a comparison with atenolol.

Pharmacokinetic and pharmacodynamic properties of a new controlled-release (CR) formulation of metoprolol have been compared with those of atenolol. Metoprolol CR (100 mg and 200 mg), atenolol (50 mg and 100 mg) and placebo were each given once daily for four days in a double-blind, cross-over study to ten healthy men. The plasma concentration-time profiles were more even with metoprolol CR than with atenolol over the 24-h dose interval, shown by the lower fluctuation ratio and the longer time period during which the plasma concentration exceeded 50% of the maximum concentration. All four active treatment regimens reduced exercise heart rate over the 24-h period compared with placebo. However, the reduction in both exercise heart rate and systolic blood pressure (SBP) was more even with metoprolol CR than with atenolol. The remaining beta 1-blockade after 24 h, expressed as the percentage reduction in exercise heart rate in relation to placebo, was significantly greater after the administration of metoprolol CR, 200 mg, than after either dose of atenolol. At this time the beta 1-blockade with metoprolol CR, 100 mg, was similar to that with atenolol, 100 mg. At peak plasma concentrations, 4 h after the dose, the subjects experienced less fatigue during exercise with metoprolol CR than with atenolol.

Effect of controlled-release metoprolol on blood pressure and exercise heart rate in hypertension: a comparison with conventional tablets.

In a double-blind study with parallel groups a new controlled-release (CR) formulation of metoprolol, 100 mg once daily, was compared with conventional metoprolol tablets, 100 mg once daily, in 27 patients with primary hypertension. Exercise tests on a bicycle ergometer were undertaken 24 h after intake of the last dose of the drug following a four-week placebo run-in period and after four weeks of active treatment. Heart rate, measured in the supine position and during exercise at the highest comparable workload, was reduced significantly more by metoprolol CR (p less than 0.05), thus indicating a higher degree of beta 1-blockade at the end of the dose interval with metoprolol CR. There was a greater reduction in supine systolic pressure (p less than 0.05) but not in supine diastolic pressure after metoprolol CR than after conventional tablets at 24 h. There was no significant difference between the two groups with respect to reduction in systolic blood pressure during exercise. The 24-h plasma concentrations of metoprolol CR and conventional tablets correlated with the effects on heart rate, but not with blood pressure. The tolerability of metoprolol CR was comparable with that of metoprolol administered as conventional tablets. In conclusion, there was significantly greater beta 1-blockade 24 h after the intake of drug after metoprolol CR compared with conventional tablets.

Efficacy and tolerability of a new controlled-release formulation of metoprolol: a comparison with conventional metoprolol tablets in mild to moderate hypertension.

In a double-blind study with parallel groups 195 hypertensive patients were randomly allocated to treatment with either conventional tablets of metoprolol, 100 mg once daily, or a new controlled-release (CR) formulation of metoprolol, 100 mg once daily. The dose was doubled if the patient's diastolic blood pressure remained greater than or equal to 95 mmHg after six weeks on 100 mg, whereas well-controlled patients continued on 100 mg once daily for a further six-week period. In the metoprolol tablet group the 200 mg dose was administered in the form of Durules. There was a significant reduction from the placebo baseline in systolic and diastolic blood pressure and heart rate at 24 h after both six weeks and 12 weeks of active treatment; no significant difference in the mean reduction from baseline between the two groups was demonstrated. However, significantly more patients responded to treatment with metoprolol CR when compared with those patients taking metoprolol tablets. After six weeks of active treatment 61% of the metoprolol CR group and 56% of the conventional metoprolol tablet group had a diastolic blood pressure less than 95 mmHg. After another six weeks the corresponding figures were 83% and 69% respectively. Between week 6 and 12, 36% of patients in the metoprolol CR group and 42% of patients in the conventional metoprolol tablet group were receiving a 200 mg dose. All formulations of metoprolol were well-tolerated. Fewer subjective symptoms were reported during active treatment than during the placebo phase. There were no differences between the groups with regard to changes in laboratory variables from baseline, changes in all combined symptoms, or changes in any one symptom.

Some applications of the indium-113m-transferrin technique for gamma-radiation detection of microvascular effects of serotonin and ischemia.

The distribution of systematically injected In-113m (t1/2 = 100 min) in organs of the rat was analyzed, and the use of the isotope for in vivo and in vitro gamma-radiation detection studies of blood plasma protein extravasation was demonstrated in skin, muscle, and tumor. In-113m was slowly excreted from rats. One to 6 h after injection the blood held 3% and 2%, respectively, of injected radioactivity/g tissue wet weight; skin and muscle held 0.1%-0.2%/g; liver, colon, and spleen held approximately 1%/g; lungs 1.5%-1.3%/g and kidneys 2.8%-3.3%/g. Scintillation camera technique revealed 40%-80% extraaccumulation of In-113m in a control extremity upon local administration of serotonin and 20%-40% in an extremity with a transplanted tumor, thus indicating a lower effect of serotonin in tumor microvascular circulation than in muscle and skin. In vitro detection of In-113m radiation by a well-counter in dissected tissues showed no effects of serotonin in the tumor and a four- to five-fold increase of radioactivity in muscle and skin, thus confirming blood protein extravasation upon serotonin treatment in these tissues. External analyses of In-113m in the vascular system using one miniaturized probe directed toward an area of interest showed that the method was too sensitive to movements of the animal, and second probe directed toward a control area is needed.

Effects of pH on the stability of the indium-113m blood protein complex and the selective binding of indium-113m to transferrin.

Indium-113m (t1/2 = 100 min; gamma-emission of 393 keV) in trace amounts was injected i.v. in rats. Blood was collected by heart puncture 15 min after the injection, and blood plasma was separated by centrifugation. Gel filtration of plasma on Sephadex G-25M equilibrated with glycine/HCl (pH 2.2-3.6), NaHCO3/CO2 (pH 4.0-11.0) glycine/NaOH (pH 8.6-10.6) or sodium acetate/acetic acid (pH 3.0-5.0) was used to separate free indium from indium bound to macromolecular proteins. Determination of radioactivity in eluted fractions showed that more than 85% of the plasma indium was bound to macromolecules at pH values between 5.0 and pH 10.6. However, dissociation of the indium plasma protein complexes occurred at pH values below 5.5, and more than 90% of the indium radioactivity was found in the low molecular weight fraction at pH 2.2. Affinity chromatography using immobilized antibodies to rat transferrin was used to isolate transferrin at pH 7.4 and 5.5. Immunodiffusion and electrophoresis were used to identify the proteins in fractions obtained by affinity chromatography. It was found that the indium-113m activity was correlated with the content of transferrin and that 80%-90% of this activity was found in fractions that had affinity to antitransferrin. These fractions contained transferrin exclusively at pH 7.4, but additional protein fractions of albumin and alpha1-globulin mobility at pH 5.5. At pH 7.4 and 5.5, 10%-20% of the indium activity was detected in molecular fractions that had no affinity to antitransferrin. Immunologic analyses showed that these fractions contained transferrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive treatment with metoprolol or hydrochlorothiazide in patients aged 60 to 75 years. Report from a double-blind international multicenter study.

In a randomized double-blind study (N = 562), a traditional treatment schedule, starting antihypertensive treatment in elderly hypertensive patients (60 to 75 years old) with 25 mg of hydrochlorothiazide once daily and doubling the dose if a satisfactory response was not achieved, was compared with antihypertensive treatment of 100 mg of metoprolol once daily, adding 12.5 mg of hydrochlorothiazide for patients whose response was not satisfactorialy achieved with metoprolol alone. Systolic and diastolic blood pressure was significantly reduced with both regimens. The frequency rates of responders (diastolic blood pressure, less than or equal to 95 mm Hg) in the metoprolol group and the hydrochlorothiazide group were 50% and 47% after four weeks and 65% and 61% after eight weeks, respectively. There were no significant differences in total symptom score or single symptoms between the regimens, but significantly more patients had hypokalemia and hyperuricemia with the hydrochlorothiazide regimen. Thus, we conclude that beginning antihypertensive treatment with 100 mg of metoprolol once daily and adding a small dose of hydrochlorothiazide (12.5 mg) in patients whose response is not satisfactory with metoprolol alone appears to be effective and safe in elderly hypertensive patients.

Persistence and spread of the orally-implanted bacterium Streptococcus sanguis between persons.

Transformant strains of streptomycin-resistant Streptococcus sanguis persisted 2.5 years after oral implantation in 6 out of 11 subjects. Natural transmission of these bacteria to spouses had occurred in 5 of the 6 infected subjects. At follow-up examinations, the median value of streptomycin-resistant Strep. sanguis per ml saliva was 226,000 c.f.u. in the infected subjects and 352,000 c.f.u. in their spouses. The median values of streptomycin-resistant Strep. sanguis as a percentage of the total Strep. sanguis c.f.u. count were 3.6 and 4.8 per cent in samples from vestibular mucosa, and 18.2 and 7.8 per cent in samples from the teeth of the infected subjects and their spouses, respectively.

Oral implantation in humans of Streptococcus mutans strains with different degrees of hydrophobicity.

The more hydrophobic, rough-colony-forming, streptomycin-resistant Streptococcus mutans parent strains GW Smr and LK Smr and the less hydrophobic, smooth-colony-forming, streptomycin-resistant variant strains GW36 Smr and LK36 Smr were implanted in oral cavities. Strains GW Smr and LK Smr implanted significantly better than strains GW36 Smr and LK36 Smr. The hydrophobicity of and the colony morphology formed by the different S. mutans strains did not seem to be affected throughout the experiment.

Prevalence of transformable Streptococcus mutans in human dental plaque.

A total of 100 strains of Streptococcus mutans serotypes c/e/f and d/g, freshly isolated from dental plaque, were screened for their ability to undergo genetic transformation to streptomycin resistance. Of the serotype c/e/f strains, 28% were found to be transformable, whereas none of the serotype d/g strains could be transformed by donor DNA from streptomycin-resistant S. mutans strains of either serotype c or d/g. Two of the transformable serotype c/e/f strains were transformed by DNAs from a variety of oral streptococcal species commonly found in the microflora.

Hydrophobicity and adherence of oral streptococci after repeated subculture in vitro.

Fresh isolates of Streptococcus mutans, Streptococcus sanguis, and Streptococcus salivarius from human dental plaque were all highly hydrophobic. After repeated subculture in vitro on blood agar, strains of S. mutans serotype c showed decreased hydrophobicity, whereas serotype d/g strains did not. Parallel to the decreased hydrophobicity in the serotype c strains, an impaired ability to adhere to hydroxyapatite was observed. A similar but less pronounced decrease in hydrophobicity in one S. sanguis strain resulted in a marked decrease in adherence to hydroxyapatite.

Effect of SnF2, administered as mouthrinses or topically applied, on Streptococcus mutans, Streptococcus sanguis and lactobacilli in dental plaque and saliva.

Mouthrinsing with SnF2 reduced the Streptococcus mutans population in plaque and saliva and the proportion of Streptococcus sanguis in plaque. The effect was of short duration: 2 weeks after treatment the values of S. mutans in plaque and saliva were even higher than the pretreatment values. Topical SnF2 applications reduced the S. mutants population in plaque and saliva but did not reduce the proportion of S. sanguis in plaque. The effect was more prolonged : 4 weeks after treatment the S. mutans population in interproximal plaque remained significantly reduced and the salivary levels of the organism had not fully returned to pretreatment levels. Both SnF2 treatments significantly increased the salivary levels of lactobacilli. The values of lactobacilli in saliva remained significantly increased 4 weeks after the SnF2 mouthrinsing but had almost returned to pretreatment levels within 2 weeks after the topical SnF2 applications. The findings suggest that the cariogenic potential of dental plaque is differently affected depending on whether a drug is administered as a mouthrinse or is applied topically.

Implantation of transformant strains of the bacterium Streptococcus sanguis into adult human mouths.

Streptococcus sanguis strains isolated from dental plaque of 12 subjects were screened for their ability to undergo genetic transformation using a streptomycin-resistance marker. All subjects harboured at least one transformable strain. Eight of the subjects were implanted with transformant strains originally isolated from their own mouth, whereas four subjects received bacteria from other donors. The Strep. sanguis transformants became successfully implanted; their oral levels remained virtually unchanged during the 3-month experimental period. Their oral establishment did not seem to be related to whether the subjects were implanted with their own transformant strains or not. The implanted Strep. sanguis could be recovered both from teeth, oral soft tissues and throat.

Colonization and cariogenic potential in hamsters of the bacterium Streptococcus sanguis isolated from human dental plaque.

Strains of Strep. sanguis, freshly isolated from human dental plaque, were successfully implanted into albino hamsters. Transmission of the organisms from infected to uninfected animals occurred naturally. The transfer was as effective between unrelated hamsters as between dams and their offspring. Three of the strains tested did not cause caries in hamsters. Laboratory strains of Strep. sanguis did not colonize the hamsters. Two morphological variants of Strep. sanguis with different abilities to adhere to whale dentine in vitro, could infect hamsters; the more adhering phenotype was detected earlier and more frequently.