The efficacy and safety of once-daily nifedipine: the coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate diastolic hypertension. Nifedipine Study Group.

The efficacy and safety of two sustained-release formulations of nifedipine, the coat-core system (NIF CC) and the gastrointestinal therapeutic system (NIF GITS), were examined in 228 patients with mild-to-moderate essential hypertension in this 16-week, multicenter, randomized, double-blind study. The coadministration of food affects the nifedipine pharmacokinetics with differing magnitudes for the two formulations. To evaluate drug safety under the most rigorous circumstances, all medication was given with food. After a 4-week placebo lead-in period, eligible patients were randomized to a parallel-group treatment period of either NIF CC or NIF GITS. 30 mg daily with food for 4 weeks, followed by forced titration to nifedipine 60 mg daily for an additional 4 weeks. For the final 4-week period, half of the patients receiving each formulation were switched to the alternate formulation at a dose of 60 mg daily. Within treatment groups, all four blood pressure variables (systolic and diastolic measurements for both trough and 24-hour periods) demonstrated significant reductions (P < 0.05) from baseline (established after the placebo lead-in period) for both formulations at every subsequent visit and end point. When comparing the two formulations, the mean change from baseline in 24-hour systolic and diastolic blood pressure measurements, determined by using ambulatory monitoring, was not statistically different for both doses (P > 0.05). The mean change in trough blood pressure from baseline during the parallel-group treatment period was statistically significant in favor of NIF GITS for both the 30-mg and 60-mg doses (P < 0.05). The treatment-emergent adverse-event rates for both formulations were similar during the parallel-group period, with the exception of dizziness, which was higher for patients receiving NIF CC. Both formulations were well tolerated and reduced blood pressure over the 24-hour dosing interval even when coadministered with food. When half of the patients receiving NIF GITS 60 mg daily were randomly crossed over to NIF CC 60 mg daily, there were no significant changes in either the trough or 24-hour mean blood pressure measurements (P > 0.05), adverse events, or dropout rates. When patients receiving NIF CC 60 mg were crossed over to NIF GITS 60 mg daily, they exhibited no significant change in diastolic blood pressure (P > 0.05). This study demonstrated that when given with food, both NIF CC and NIF GITS reduce 24-hour mean blood pressure measurements similarly.(ABSTRACT TRUNCATED AT 400 WORDS)

The ABCD (Appropriate Blood Pressure Control in Diabetes) trial. Rationale and design of a trial of hypertension control (moderate or intensive) in type II diabetes.

OBJECTIVE: The primary objective of the ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is to determine the efficacy of intensive versus moderate antihypertensive control on the outcome of type II diabetic end-organ complications in normotensive and hypertensive populations. The secondary objective is to determine whether any differential effect on end-organ complications exists between an angiotensin converting enzyme inhibitor (enalapril) and a calcium channel blocker (nisoldipine). DESIGN: The ABCD Trial is a prospective, controlled, randomized, double-blind trial, with a planned follow-up of 5 years. SETTING: All patients are seen at the Colorado Prevention Center, site of the ABCD Trial, for follow-up visits. PATIENTS: Patients are type II diabetic males and females between the ages of 40 and 74 years with entry diastolic blood pressures > or = 80 mmHg. Patients were recruited from University of Colorado-affiliated hospitals, several health maintenance organizations, and mailing lists from the Colorado affiliate of the American Diabetes Association. INTERVENTIONS: Patients were randomized to intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients were also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control was necessary. MAIN OUTCOME MEASURES: The primary outcome measure is glomerular filtration rate as assessed by 24-hour creatinine clearance. Secondary outcome measures are microalbumin urinary excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. CONCLUSION: Given the data showing the impact of hypertension on diabetic complications, the ABCD Trial was designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of these complications. Results from the ABCD Trial are expected to lend interpretable and clinically relevant findings with regards to the treatment of hypertension in type II diabetes.

Effectiveness of once-daily monotherapy with a new nifedipine sustained release calcium antagonist.

Data from 2 separate multicenter, double-blind clinical studies following the same protocol, except for the selection of doses, were pooled to evaluate the efficacy and tolerability of fixed doses of a new sustained-release (SR) formulation of nifedipine compared with placebo in 388 patients with mild to moderate uncomplicated essential hypertension. After a 3-6 week placebo washout period, the patients were randomized to receive either placebo or nifedipine SR-20 mg (study I only), 50 mg, 100 mg, or 150 mg (study II only). Among the 278 patients who completed 6 weeks of active therapy, mean supine diastolic blood pressure reductions from pretreatment baseline were 5.9, 9.3, 9.2, 11.1, and 13.2 mm Hg in the placebo, 20-, 50-, 100-, and 150-mg groups, respectively. The reductions achieved in each of the nifedipine SR groups were statistically significant versus baseline values (p less than 0.001). All nifedipine-SR doses reduced supine systolic blood pressure significantly more than placebo (p less than 0.001). In addition, there was a significant linear relationship between the log of the dose and the blood pressure reduction (p less than 0.05). Automated ambulatory blood pressure recordings performed in 221 of the patients showed that the blood pressure was lowered evenly through the entire 24-hour dosing period. The doses that were effective and associated with the fewest adverse reactions were 20 mg and 50 mg once daily.

A comparison of the safety of therapeutically equivalent doses of isradipine and diltiazem for treatment of essential hypertension.

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.

Effect of 1,25-dihydroxyvitamin D3 on mesangial cell proliferation.

We have studied the effect of 1,25-dihydroxyvitamin D3 (1,25, (OH)2D3) on mesangial cell growth. Previous studies have shown that the monocyte-macrophage is the principal effector cell in immune-mediated nephritis; this cell infiltrates the glomerular mesangium, and its products may have important effects on the physiology of the mesangial cell. One of the substances produced by the activated macrophage is 1,25,(OH)2D3. We have investigated the effect of 1,25,(OH)2D3 on mesangial cell growth and found that this vitamin D metabolite suppresses the proliferation of mouse mesangial cells as assessed by mesangial cell tritiated thymidine uptake and by cell counts; this substance also antagonizes the mitogenic effect of epidermal growth factor on mesangial cell growth. By comparison, the vitamin D metabolite 25 hydroxyvitamin D3 has no significant suppressive effect on the proliferation of mesangial cells. It has also been possible to demonstrate that 1,25,(OH)2D3 could suppress the growth of mesangial cells that had been committed to proliferate by the prior addition of epidermal growth factor. The results of these studies are relevant to our understanding of the pathogenesis of the cellular abnormalities that occur in immune-mediated nephritis, and especially in subjects who have concurrent hypertension, because a segment of subjects with hypertension have demonstrable abnormalities in the levels of circulating 1,25,(OH)2D3.

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial.

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.

Lisinopril dose-response relationship in essential hypertension.

1. This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2. After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5.20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3. There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-1 groups. 4. Lisinopril, at doses up to 80 mg day-1, was well tolerated.

The effect of transforming growth factor-beta on mouse mesangial cell proliferation.

The factors which regulate mesangial cell growth are of importance in determining the cellular lesions of nephritis. In this communication, we report that transforming growth factor-beta (TGF-beta) exerts a suppressive effect on mesangial cell 3H-thymidine uptake. Furthermore, TGF-beta antagonizes the mitogenic effect of epidermal growth factor (EGF) on DNA synthesis. The concomitant presence of TGF-beta in the cell cultures is not required for its effect since cells pretreated with the substance and rinsed of it showed suppressed 3H-thymidine uptake and did not respond to EGF. The effect of TGF-beta can also be demonstrated on cells committed to proliferate by the prior addition of EGF. The results of the study have relevance to the mechanisms underlying the histologic lesions of immune-mediated nephritis.

Dihydropyridines and beta-adrenoceptor antagonists as combination treatment in hypertension.

The combination of one of the dihydropyridine class of calcium channel antagonists with a beta-adrenoceptor blocker has particular therapeutic advantages in the management of hypertension. The beta-blocker reduces the effects of the dihydropyridine-induced reflex increases in sympathetic nervous system and renin-angiotensin system activity, while the dihydropyridine reduces the peripheral effects of beta-blockade. Numerous studies have documented additional antihypertensive effects when these two classes of agents are used as combination therapy in hypertension. This therapeutic combination is well tolerated and produces minimal alterations in clinical laboratory tests. Initial concerns that the combination may impair atrioventricular conduction and left ventricular function have not been substantiated in widespread clinical trials.

Induction of mouse monocyte-macrophage replication by a mesangial cell-derived factor.

Conditioned media of cultured mouse mesangial cells (possessing microfilaments) were shown to contain a factor that stimulated splenic monocytes-macrophages and blood monocytes to replicate. Replicated cells were shown to express MAC-1 antigen as demonstrated by immunofluorescence with anti-MAC 1 and to possess Fc receptors as evidenced by their capacity to ingest sensitized erythrocytes. Preliminary characterization revealed the following characteristics: by Amicon ultrafiltration, fractions greater than 100,000 daltons were shown to have biologic activity; chromatofocusing of these active fractions revealed a peak of activity associated with fractions having pH 4; heating to 100 degrees C for 10 minutes abolished almost all activity, whereas trypsin treatment was without effect. The observations suggest a mechanism by which mesangial cells may modulate the proliferation of monocytes-macrophages that infiltrate the glomerulus in glomerulonephritis.

Beta-endorphin amplifies the effect of interleukin-1 on mouse mesangial cell proliferation.

We report experiments that show that beta-endorphin, a neuropeptide, enhances the effect of interleukin-1 on mouse mesangial cell proliferation. Met-enkephalin, which comprises the first five amino acids of the beta-endorphin molecule, can also be shown to possess similar biologic activity. This action of beta-endorphin and met-enkephalin is mediated through naloxone-insensitive receptors on the mesangial cell, because naloxone treatment of the kidney cells does not abrogate this activity. The studies delineate a novel mechanism by which a neuropeptide may influence the development of immune-mediated cellular pathology.

Diltiazem and propranolol in mild to moderate essential hypertension as monotherapy or with hydrochlorothiazide.

We compared the safety and efficacy of diltiazem and propranolol, and examined demographic factors influencing responses to these agents. One hundred ninety-six patients with supine diastolic blood pressures of 95 to 114 mm Hg were treated with propranolol (80 to 240 mg twice a day) or a sustained-release preparation of diltiazem (60 to 180 mg twice a day) in a double-blind, randomized, parallel group protocol for 6 months. Hydrochlorothiazide was added for patients not achieving the treatment goal. Both agents produced nearly identical and highly significant (p less than 0.001) reductions in supine blood pressure. There were no significant differences at the end of the optional combination therapy phase, although additional reduction with hydrochlorothiazide was slightly greater in the propranolol group. Blood pressure responses in relation to age, gender, race, and smoking history showed that diltiazem produced greater changes in older subjects and women, whereas propranolol was less effective in blacks. However, these differences were not critical.

Sodium-calcium exchange exists across the cell membrane of intact vascular smooth muscle cells.

Ouabain stimulated Ca2+ uptake in rat aortic smooth muscle cells in culture. The maximum uptake of Ca2+ was observed at about 200 mumol/l ouabain. Na+K+-ATPase activity of these cells was also maximally inhibited at about 200 mumol/l ouabain. The ouabain-stimulated Ca2+ uptake was not inhibited by the calcium antagonist diltiazem. The cells treated with ouabain also showed increased steady-state cytosolic Ca2+ concentration as measured by the fluorescent dye indicator Fura 2/AM. The ouabain stimulated Ca2+ uptake and increased cytosolic Ca2+ is explained as follows: ouabain inhibits Na+K+-ATPase with subsequent increase in cytosolic Na+, which is then exchanged with external Ca2+ through the Na+-Ca2+ exchange in intact vascular smooth muscle cells.

Guanabenz: a centrally acting, natriuretic antihypertensive drug.

Guanabenz is acutely natriuretic and diuretic in saline expanded animals. In man, guanabenz has not resulted in sodium retention as seen with other comparable antihypertensives. To directly define the action of guanabenz on sodium and water excretion in man, we performed clearance studies during water diuresis on eight hypertensive subjects under metabolic balance conditions. Each subject underwent three studies: 1) baseline study: no drug, a water diuresis study; this was followed by a saline load (= 2% BW); 2) acute study (24 hr after baseline): 16 mg guanabenz PO; and 3) chronic study: after one week of guanabenz 8 mg PO BID. In the acute guanabenz studies there were: 1) no changes in GFR or ERPF; 2) an increase in both sodium excretion and fractional sodium excretion; 3) a rise in free H2O clearance (CH2O) and (CH2O/GFR) X 100%. These findings were not sustained in the chronic guanabenz studies. We conclude that in man (preconditioned with prior saline loading) guanabenz is acutely natriuretic and water diuretic. These effects are due to decreased tubular sodium and water reabsorption, probably related to inhibition of alpha adrenergic activity. The data are consistent with selectively reduced renal sympathetic activity affecting sodium transport and provide a basis for the absence of edema and sodium retention associated with guanabenz therapy.

Modulation of mouse mesangial cell proliferation by macrophage products.

Mesangial hypercellularity is usually found in many models of nephritis characterized by monocyte/macrophage infiltration of the glomerulus. In order to examine the mechanism mediating these events, an in vitro model was used to study the effects of macrophage products on mouse mesangial cells, cultured under conditions which would render them relatively quiescent. Under these conditions, macrophage supernatants stimulated the proliferation of the mesangial cells. The stimulatory effect could be shown to be due in part to enhancement of endogenous mesangial cell PGE production. This was demonstrated by experiments which showed that macrophage supernatants stimulated mesangial cell PGE production, that the stimulatory effect of macrophage products was abrogated by pretreatment of mesangial cells with indomethacin, and finally that exogenous PGE2 stimulated mesangial cell proliferation.

Evidence for a mouse mesangial cell-derived factor that stimulates lymphocyte proliferation.

The functions of the glomerular mesangium are served by at least two populations of cells--a cell bearing microfilaments that regulates blood flow, and a phagocytic cell bearing Ia determinants and Fc receptors. We provide evidence that mouse mesangial cells (bearing microfilaments) produce a factor(s) that stimulates spleen cell proliferation. The factor(s) appears to act via monocytes/macrophages, since its stimulatory activity is abrogated by prior depletion of the responding mononuclear cell population of monocytes/macrophages. Confirmation of its action on macrophages was documented by experiments that showed that medium from macrophages incubated with mesangial cell supernatant contained greater amounts of a factor that stimulated [3H]thymidine uptake by macrophage-depleted spleen cell populations. By the cothymocyte proliferation assay, it could be shown that mesangial cell supernatant induced splenic macrophage production of interleukin-1-like activity. Preliminary characterization reveals the factor to have a molecular weight greater than 100,000. Thus, a novel function is delineated for this mesangial cell type that appears capable of modulating the local immune response by providing an amplification signal.

Evidence for an endothelial cell-derived factor which stimulates the growth of human peripheral blood mononuclear cells.

Evidence is provided which demonstrates that conditioned media of cultured endothelial cells derived from human umbilical veins contained a factor which stimulated peripheral blood mononuclear cell [3H]thymidine uptake. A dose-dependent response in peripheral blood mononuclear cell [3H]thymidine uptake was obtained when cells were incubated with increasing concentrations of supernatant of endothelial cell cultures. Studies on temporal kinetics demonstrated that stimulatory activity was evident when mononuclear cells had been incubated with endothelial cell supernatant for 120 hr or more. Preliminary characterization showed the growth immunoregulatory factor to have a molecular weight greater than 100,000 Da.

Abnormalities of fibrinolysis in essential hypertension.

A highly-standardized plate method was used to study fibrinolytic profiles in 14 patients with essential hypertension and 245 normotensive healthy control subjects. Compared with the normotensive group, the group with essential hypertension showed a defect in fibrinolysis, as evidenced by a significant increase in the mean level of inhibitor of plasminogen activation, and a subset of the hypertensive patients also showed a significant decrease in the mean level of vascular plasminogen activator. There were no significant differences between the two groups in relation to plasma fibrinogen level, total fibrinolytic activity and plasmin inhibitor. The alterations in inhibitor of plasminogen activation and vascular plasminogen activator in the patients with essential hypertension may reflect a defect in the fibrin-clearing mechanism and, perhaps, contribute to the vascular complications of hypertension.