Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women.

OBJECTIVE: To determine the effects of metformin on blood pressure, left ventricular mass, and some metabolic and endocrine parameters in nondiabetic, obese, hypertensive women. RESEARCH DESIGN AND METHODS: Twelve obese, nondiabetic, hypertensive women received 850 mg metformin 2 times/day for 12 wk and placebo for another 12 wk, according to a double-blind, cross-over, randomized design. All patients were hospitalized 4 times, i.e., before randomization and after each treatment (metformin or placebo), to conduct metabolic and cardiovascular investigations (oral glucose tolerance test, euglycemic clamp associated with indirect calorimetry, and echocardiography). RESULTS: Fasting glucose, HbA1c, fasting and glucose-stimulated insulin, blood pressure and left ventricular mass, cholesterol, triglycerides, and fibrinogen decreased significantly after metformin treatment, whereas high-density lipoprotein cholesterol increased. The improvement in glucose metabolism resulted from increased sensitivity to insulin. CONCLUSIONS: These findings suggest that metformin treatment in obese, nondiabetic, hypertensive women produces a more favorable cardiovascular risk profile.

Hemorheological and cardiovascular responses to beta-endorphin and naloxone in healthy subjects and in patients with essential hypertension.

The purpose of the present study was to determine if opioid agonism (beta-endorphin) and antagonism (Naloxone) exert rheological and cardiovascular effects in normal humans and in patients with essential hypertension. Eight hypertensive patients were matched for age, sex, and body habitus (body mass index, waist to hip ratio) with eight normotensive healthy subjects. In all subjects, heart rate and blood pressure (continuous automatic recording), blood and plasma viscosity, fibrinogen, hematocrit, and platelet aggregation to ADP were evaluated during an infusion of human synthetic beta-endorphin (0.5 mg/h). On a different day and in randomized order, the subjects were submitted to another beta-endorphin infusion preceded by an i.v. naloxone bolus (5 mg in 5 min). beta-Endorphin and naloxone failed to significantly alter heart rate or blood pressure in both normotensive and hypertensive subjects. In hypertensive patients, beta-endorphin significantly increased blood viscosity and ADP-induced platelet aggregation, but only the former effect was naloxone-sensitive. In normotensive subjects, beta-endorphin caused a transient but significant decrease of platelet aggregation that was reversed by naloxone. These data suggest that beta-endorphin may play some role in the inhibitory control of platelet aggregation in normal subjects. An altered responsiveness of some rheological determinants to beta-endorphin seems to be present in human hypertension.

Trough:peak ratio of nifedipine gastrointestinal therapeutic system and nifedipine retard in essential hypertensive patients: an Italian multicentre study.

OBJECTIVE: To evaluate the antihypertensive effect of nifedipine gastrointestinal therapeutic system and retard in terms of trough:peak ratio efficacy. METHODS: According to a double-blind, randomized, crossover design, 58 patients with mild-to-moderate essential hypertension, after 1 month placebo washout, received 30 mg/day nifedipine gastrointestinal therapeutic system, 20 mg nifedipine retard twice a day and the corresponding placebos for 1 month. At the end of each treatment period, blood pressure was measured by using a mercury sphygmomanometer at trough and 1, 2, 3 and 4 h after the last dosing. The peak effect was identified as the maximum decrement induced by the three randomized treatments with respect to the value at the end of the placebo washout period during the 4 h interval. The trough:peak ratios of systolic and diastolic blood pressure were calculated as group ratios and individual ratios from decrements induced by nifedipine gastrointestinal therapeutic system and retard, corrected for those induced by randomized placebo. Patients were defined as responders to each randomized treatment if their diastolic blood pressure at trough time was reduced by at least 10 mmHg relative to that at the corresponding time at the end of placebo washout. RESULTS: Nifedipine gastrointestinal therapeutic system and retard significantly reduced blood pressure to a similar extent both at trough and at peak. Systolic and diastolic group trough:peak ratios in responders to nifedipine gastrointestinal therapeutic system (n = 41) were 0.80 and 0.88, respectively, and those in responders to nifedipine retard (n = 30) 0.84 and 0.93, respectively. The percentage of patients with trough:peak ratios > 0.50 was > 80% (systolic trough:peak ratios) and above 90% (diastolic trough: peak ratios) for both nifedipine formulations. CONCLUSIONS: Our data show that 30 mg/day nifedipine gastrointestinal therapeutic system and 20 mg nifedipine retard twice a day have a favourable trough:peak ratios efficacy when given as monotherapy to essential hypertensive patients.

Impaired glucose metabolism and reduced insulin clearance in elderly hypertensives.

Diabetes mellitus and essential hypertension are characterized by a continuous rise of prevalence with aging and this association may not be casual. Thirty nonobese nondiabetic elderly patients with primary hypertension and 28 healthy normotensives matched for age, sex, and body weight were evaluated for insulin secretion (oral glucose tolerance test, day-long glycemic and insulinemic profiles), action (euglycemic moderately hyperinsulinemic glucose clamp associated with 3H-3-glucose dilution technique), and clearance (120 min insulin/glucose infusion at two prefixed doses). Compared with normotensives, hypertensive elderly patients were characterized by the following: 1) plasma insulin and C-peptide were similar in basal conditions but significantly enhanced in response to both oral glucose and a mixed meal; 2) insulin-stimulated glucose uptake was significantly impaired with a similar rate of hepatic glucose production; 3) exogenous insulin metabolic clearance rate was significantly lower at both insulin infusion rates. The multiple alterations of insulin secretion, action and metabolism found in nonobese nondiabetic elderly hypertensives seem to support a role for this hormone in the regulation of arterial blood pressure.

Antihypertensive effect of oxprenolol and chlorthalidone in fixed combination, given once daily.

In a multicentre, single-blind, within-patient study, the effectiveness and tolerability of the fixed combination oxprenolol 80 mg + chlorthalidone 10 mg per tablet given once daily, compared to the well established b.i.d. schedule, has been investigated in forty out-patients with mild to moderate hypertension. After a two-weeks placebo wash-out, twenty patients were given 1 tablet b.i.d. of the fixed combination for 4 weeks and thereafter 2 tablets once-daily for a further 4 weeks; the remaining twenty patients were given the fixed combination in the reverse order. There was no significant difference in clinical response between the two treatment regimes, which were equally effective and well tolerated. However, patient compliance might be considerably improved with the once-daily dosage schedule of the fixed combination.

[Efficacy and tolerability of nicardipine retard and captopril in hypertension in the aged. Results of a multicenter study]. / Efficacia e tollerabilità della nicardipina retard e del captopril nell'ipertensione dell'anziano. Risultati di uno studio multicentrico.

The efficacy and tolerability of nicardipine retard and captopril were assessed in 174 over-60-year-olds suffering from slight or moderate essential hypertension. After 2-3 weeks of wash out the patients were randomly assigned to calcium antagonist (40 mg twice a day) or ace-inhibitor (25 mg twice a day) treatment which continued for 180 days. Monotherapy was combined with hydrochlorothiazide (12.5 mg/day) after 2 months in the event of an unsatisfactory reduction of arterial pressure in relation to basal values. Systolic and diastolic blood pressure was measured (1st and 5th Korotkoff's tone) at monthly intervals while lying and standing; heart rate was also measured using a palpatory method. Both nicardipine retard (no. 86) and captopril (no. 88) caused a significant reduction of clino- and orthostatic systolic and diastolic arterial pressure during the first two months of treatment. Respectively 70% and 51% of patients responded to treatment and the blood pressure reductions achieved using monotherapy remained unchanged during the course of the study. The association of hydrochlorothiazide resulted in a significant decrease in arterial pressure in non-responders, an effect which was observed with both nicardipine retard and captopril. No significant variation in heart rate was recorded between the two groups. Twenty-one patients in the nicardipine retard group and 16 in the captopril group suffered from slight to moderate side effects. Six patients dropped out of the nicardipine retard group and 15 patients out of the captopril group, an event for which side-effects were responsible in 1 and 3 cases respectively. In conclusion, nicardipine retard and captopril represent an efficacious form of treatment for geriatric hypertension and possess a satisfactory level of tolerability.

Antihypertensive efficacy and tolerability of captopril in the elderly: comparison with hydrochlorothiazide and placebo in a multicentre, double-blind study.

In this study we compared the antihypertensive efficacy and tolerability of captopril at 25 mg twice daily, hydrochlorothiazide (HCTZ), 12.5 mg twice daily and placebo in a multicentre, double-blind, randomized study that included 152 essential hypertensive patients (77 males, 75 females, 87 WHO stage I, 65 WHO stage II, aged 69 +/- 4 years, mean +/- s.d.). Supine and standing blood pressure were similarly reduced by captopril and HCTZ (P less than 0.01 for both compared with placebo). The heart rate did not change. Captopril (25-30 mg twice daily) and HCTZ (12.5 mg twice daily), alone or in combination, maintained their antihypertensive effect during a 24-week single-blind follow-up study. During the follow-up, diastolic blood pressure remained less than 100 mmHg in seven essential hypertensives on placebo, in 45 on captopril and in 25 on HCTZ. Side effects were observed in seven essential hypertensives during placebo (treatment withdrawn in two), in eight during HCTZ and in three during captopril. Serum potassium was reduced (P less than 0.05) and uric acid was increased (P less than 0.01) only during HCTZ. We conclude that captopril and HCTZ have similar antihypertensive efficacy in the elderly; however, captopril appears to be better tolerated.

Antihypertensive activity of a new vasodilator, cadralazine, administered alone or in combination with a beta-blocker.

The antihypertensive activity of a new arterial dilator, cadralazine, was evaluated in 40 patients with mild-to-moderate arterial hypertension. Cadralazine was given once daily over 6 weeks, and blood pressure and heart rate were recorded 24-26 hours after dosing. Cadralazine dose was 10 mg daily initially, and 15 or 20 mg daily from the 3rd or 5th trial week according to a target diastolic pressure reduction to 95 mmHg or below. Slow-release metoprolol 200 mg once daily was added when heart rate increase exceeded 25% of the pretreatment value. Blood pressure showed a significant and progressive reduction throughout the study period, both in the patients receiving cadralazine as monotherapy (19 patients) and in those who added metoprolol (21 patients). The target diastolic pressure reduction was reached in 2 patients with the 10-mg dose, in 19 of the remaining 38 patients with the 15-mg dose, and in 13 of the other 19 patients with the 20-mg dose. Considering only those patients who did not add metoprolol, the target was reached in the 2 patients with the 10-mg dose, in 10 of the 19 patients with the 15-mg dose and in 7 of the 19 patients with the 20-mg dose. None of the laboratory tests showed clinically relevant changes. Neither LE cells nor antinuclear antibodies were found. In conclusion, cadralazine is a promising long-acting antihypertensive vasodilator. A clinically satisfactory antihypertensive effect is achieved mostly by a 15-mg or a 20-mg dose given once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of human calcitonin (hCT) on glucose- and arginine-stimulated insulin secretion.

Many studies have shown that in normal man salmon and porcine CT administration in bolus inhibits the release of TSH, LH, GH, and glucose- or arginine-induced insulin secretion. In the present study we investigated the effects of human synthetic calcitonin (hCT) on glucose- or arginine-induced insulin secretion in man. Twenty-two subjects were submitted to i.v. administration of hCT during glucose or arginine test. In our opinion, the most interesting results are those observed with arginine plus hCT at two different dosages (25 micrograms and 12.5 micrograms infused in 30 min). In fact arginine plus hCT (25 micrograms in 30 min) administration induced a significant increase of glycemia at 5, 10 and 20 min (p less than 0.01) and at 30 min (p less than 0.05) and a significant decrease of IRI at 5, 10, 20 and 30 min (p less than 0.001) and at 45 min (p less than 0.005). The highest plasma CT levels were observed at 15 and 30 min (490 and 540 pg X ml-1). Arginine plus hCT (12.5 micrograms in 30 min) infusion induced a similar significant increase in plasma glucose at 10, and 20 min (p less than 0.05) and at 30 min (p less than 0.01) and a significant decrease of plasma IRI at 10 min (p less than 0.05) at 20 min and 30 min (p less than 0.005). The highest plasma CT levels were reached at 20 min and 30 min (250 and 270 pg X ml-1, respectively). Our results clearly demonstrate that physiologic doses of hCT are able to inhibit arginine induced insulin secretion in normal man. Since insulin induces hypercalcemia and food ingestion increases both insulin and CT, one could hypothesize that CT inhibits insulin secretion thus controlling post-prandial hypercalcemia by its osteotrophic effect and by its action upon calcium redistributed within the cells.

Plasma calcitonin variations in normal women and in women with family history of diabetes during pregnancy.

In eight normal pregnant women and in eighteen women with a family history of diabetes, plasma calcitonin (CT), parathyroid hormone (PTH), insulin and glucagon variations and total plasma calcium levels were investigated. Calcitonin, parathyroid hormone and glucagon were all increased during the 2nd and 3rd trimester of pregnancy in normal women (N.W.) and in women with a family history of diabetes (W.F.H.D.). Plasma calcitonin levels were statistically significantly different between the two groups only in the 3rd trimester (118 +/- 4.9 vs 139 +/- 3.6 pg/ml p less than 0.01 in N.W. and W.F.H.D. respectively). Total plasma calcium levels were decreased significantly in the 3rd trimester in both groups: 3rd vs 1st trimester p less than 0.005 and p less than 0.001 in N.W. and W.F.H.D. respectively. Statistically significant difference between the two groups in total insulinemic area (p less than 0.001), in the rapid phase area (p less than 0.01) and insulinogenic index (p less than 0.05) were observed in the 3rd trimester.

[Assessment of tolerability and antihypertensive efficacy of aceplus mite (captopril (CPT) 50 mg + hydrochlorothiazide (HCTZ) 15 mg): a double-blind study vs. HCTZ in diabetic hypertensive patients. A report on three treatments]. / Valutazione della sicurezza, tollerabilità ed efficacia anti-ipertensiva dell'aceplus mite [captopril (CPT) 50 mg + idroclorotiazide (HCTZ) 15 mg]: studio in doppio cieco vs. HCTZ in pazienti diabetici ipertesi. Rapporto a 3 mesi di trattamento.

Thirty hypertensive diabetic patients were randomly, double blindly, treated with Captopril (CPT) 50 mg + hydrochlorothiazide (HCTZ) 15 mg (No 19) or HCTZ 25 mg alone (No 11) for 3 months, to assess blood pressure control and some metabolic modifications. The results indicate that CPT + a low dose of HCTZ maintains the synergistic effect of the two drugs, minimizing the metabolic problems related to HCTZ in hypertensive diabetic patients.

Impaired insulin-mediated erythrocyte magnesium accumulation in essential hypertension.

1. This study was designed to investigate variations in erythrocyte magnesium in the presence of insulin (0.1 unit/l) in hypertensive subjects. 2. Plasma and erythrocyte magnesium levels were found to be significantly lower in hypertensive than in normotensive subjects. 3. The impaired response to insulin (0.1 units/l) of erythrocytes from hypertensive patients was not reversed by elevated extracellular Mg2+ (3.6 mmol/l). 4. Erythrocytes of hypertensive subjects showed an increased membrane microviscosity compared with normotensive subjects. 5. Lidocaine decreased erythrocyte membrane microviscosity and increased erythrocyte magnesium levels in the presence of insulin.

A multicenter trial of low dose captopril administered twice daily in patients with essential hypertension unresponsive to beta blocker-diuretic treatment.

Two hundred and one patients with essential hypertension, whose supine diastolic blood pressure (SDBP) was greater than or equal to 95 mmHg following 2 weeks of treatment with the optimal dose of a beta blocker-diuretic combination (Phase 1), were randomly assigned to the addition of either 25 or 50 mg captopril BID for 6 weeks (Phase 2). At the end of Phase 2, the dose of captopril was doubled in the patients not normalized (SDBP greater than or equal to 95 mmHg) and maintained in the others (SDBP less than 95) for an additional 4 weeks (Phase 3). At the end of Phase 3, the beta blocker was withdrawn in the normalized (SDBP less than 95 mmHg) patients, and captopril plus diuretic was given for 4 weeks (Phase 4). The addition of captopril at either dose level led to a significant fall (p less than 0.01) in standing and supine diastolic and systolic blood pressure after the first 2 weeks of treatment. There was no significant difference in response between the two dose levels of captopril. At the end of Phase 2, 59.4% and 55.8% of patients, respectively, assigned to 25 and 50 mg captopril BID, were normalized. Doubling the dose of captopril (Phase 3) led to approximately an additional 30% of patients being normalized. At the end of Phase 4 (captopril plus diuretic) the SDBP was still less than 95 mmHg in 63% of patients, whereas it was increased in the others. Side effects were noted in 10 patients (5%). The incidence was similar in each treatment group, and a total of four patients (2%) were withdrawn due to side effects.

[A comparative evaluation of metoprolol and methyldopa in hypertension therapy (author's transl)]. / Valutazione comparativa del metoprololo e della metildopa nella terapia dell'ipertensione arteriosa.

The antihypertensive effect and the tolerability of the cardioselective beta-blocking drug metoprolol, in comparison to methyldopa, were assessed in 119 hypertensive patients (73 WHO stage 1 and 46 WHO stage 2). After 2 weeks of placebo wash-out, the patients were randomly allocated to treatment with either of the two drugs: metoprolol up to 200 mg bid, and methyldopa up to 500 mg bid, for 6 weeks. Periodical clinical, biochemical, haematological, radiological and electrocardiographical measurements were performed. In respect to pre-treatment values, heart rate, both in lying and standing position, was significantly reduced (P less than 0.01) only in the metoprolol group, while systolic and diastolic blood pressures were significantly reduced (P less than 0.01) with both drugs in both positions. Asymptotic regression analysis showed that velocity of blood pressure reduction was comparable with both drugs. In the lying position, the diastolic blood pressure reduction obtained with metoprolol was significantly greater (P less than 0.05) in respect to that obtained with methyldopa. In general, side effects were few and of mild severity: mainly bradycardia in the metoprolol group and dizziness and fatigue in the methyldopa group. After the formal end of the double-blind trial, 36 patients, 14 in the metoprolol group and 22 in the methyldopa group, were treated in open conditions with metoprolol alone; after an average period of 6.5 weeks, diastolic blood pressure was significantly reduced (P less than 0.05) only in the group previously treated with methyldopa. In conclusion, metoprolol is a well tolerated and effective antihypertensive agent, which may be safely used in patients with mild to moderate hypertension.

A fixed combination of oxprenolol slow-release and chlorthalidone once daily in treatment of mild to moderate hypertension.

In a multicenter, single-blind, interpatient study, 103 outpatients with mild to moderate hypertension were given, after 2 weeks of placebo wash-out, 160 mg oxprenolol slow-release in fixed combination with chlorthalidone (20 mg per tablet) (SROC 160) once daily or conventional oxprenolol (80 mg) in fixed combination with chlorthalidone (10 mg per tablet) (COC 80) twice daily for 8 weeks. Throughout the study 22 of 51 patients on SROC 160 and 24 of 51 on COC 80 received 1 tablet once daily and, respectively, 1 tablet twice daily. The remaining patients of both groups double the corresponding dosage after the first 4 weeks. Systolic and diastolic blood pressure decreased on both treatments without and difference observed between the groups. Diastolic blood pressure normalization was achieved in both groups in the same number of patients (35). Minor side effects occurred on both treatments: only one patient on SROC 160 interrupted the study due to severe dizziness and fatigue. The advantages are discussed as regards patient's compliance with administration of fixed combination SROC 160 once daily in treatment of mild to moderate hypertension.