Biological components in a standardized derivative of bovine colostrum.

Products of different origin, time of collection, and activities fall under the general term of colostrum and, therefore, great variability in composition as well as in the concentration of its components has been reported in the literature. In the present study, we describe the standardization of a bovine colostrum derivative and the characterization of its bioactive components. Evaluation of the most representative agents (lactoferrin, transferrin, IL-2, IFN-γ, tumor necrosis factor, IgG, and IgA) showed that a marked decrease in active components occurs after the first few hours. Bovine colostrum was, therefore, collected up to the fifth hour after delivery from Holstein cows, in the presence of preservatives, and immediately frozen. A protocol of centrifugation, filtration, and lyophilization was then applied to pools of colostrum from at least 30 cows to obtain a stable, sterile, standardized product. Preservatives were removed by dialysis. Evaluation of the active biological components of colostrum showed that the final product of colostrums contained significant and reproducible amounts of bioactive factors, including cytokines, immunomodulating factors, growth factors, and immunoglobulins. The final product appeared, therefore, as a sterile, pyrogen-free, standardized derivative of bovine colostrum with a high concentration of bioactive components.

Superior efficacy of propranolol versus nifedipine in double-component angina, as related to different influences on coronary vasomotility.

PURPOSE: In 24 patients with stable spontaneous and effort-related angina, ischemic episodes at rest were not preceded by changes in circulatory variables (heart rate, systemic and pulmonary arterial pressures) that may raise the myocardial oxygen consumption. We interpreted these episodes as caused by critical and reversible coronary flow reduction at the site of a stenotic lesion, and evaluated the clinical efficacy of nifedipine and propranolol in the treatment of this condition. PATIENTS AND METHODS: The study was randomized, placebo-controlled, and crossover in design. Nineteen of the 24 subjects were men (mean group age, 59 years; range, 47 to 65 years). The study consisted of four four-day periods. The first and the fourth periods, during which patients received placebo, were single-blind. The treatment consisted of 80 mg of propranolol or 20 mg of nifedipine administered four times daily. The second and the third periods, during which patients received propranolol or nifedipine crossing over to the alternative drug in the next period, were double-blind and separated by a 24-hour interval. RESULTS: Propranolol fully abolished or reduced the number of spontaneous ischemic episodes in a significantly larger proportion of patients than did nifedipine; it was also effective in several cases in which nifedipine had failed or had even caused a paradoxic effect. Quantitative angiographic evaluation of the influences of nifedipine (Group 1, 12 patients, 10 mg sublingually) and propranolol (Group 2, 12 patients, 0.1 mg/kg intravenously) on the residual lumen diameter of one significant coronary stenosis in each patient showed that (1) after nifedipine, the lumen was unchanged in one, augmented in seven, and reduced in four cases; (2) variations ranged between +1.59 and -1.2 mm, and their direction correlated closely with the influence of oral nifedipine on the episodes of spontaneous ischemia; and (3) in no case did treatment with propranolol vary the stenosis lumen by more than 0.3 mm. CONCLUSION: In this form of angina, a number of lesions seem to offer a compliant substrate for vasomotion and, possibly, for critical changes in flow. The vasomotor influences of nifedipine on these lesions are variable as well as the efficacy of the drug on the manifestations of ischemia at rest. Propranolol produces no important variations of the coronary stenotic lesions, causes a decrease of heart rate that facilitates coronary flow in diastole, and reduces the baseline metabolic demand of the heart so that the threshold of ischemia during critical reduction of coronary flow may become elevated.

Different coronary vasomotor effects of nifedipine and therapeutic correlates in angina with spontaneous and effort components versus Prinzmetal angina.

Flow impedance, probably of vasomotor origin, superimposed on severe coronary stenosis has been considered a trigger for the spontaneous component of angina occurring both on effort and at rest. To investigate more thoroughly this pathophysiologic aspect we evaluated (by means of quantitative coronary angiography) the acute vasomotor reaction to nifedipine (10 mg sublingually) of significant (greater than 50%) stenotic lesions in 22 patients with double-component angina. We also correlated this reaction with the clinical response (daily number of ischemic episodes evaluated by means of 48-hour Holter ambulatory monitoring) to treatment with nifedipine (20 mg four times a day); calcium channel blockade, in fact, is considered a specific remedy in cases of altered coronary vasomotility. Patients with Prinzmetal angina, who were known to have homogeneous coronary vasodilating reactions and favorable clinical responses to nifedipine, were studied by means of the same methods and served as the control group (14 patients). In double-component angina the residual lumen diameter of significant lesions was unchanged in two patients, enhanced in 10, and reduced in 10 after sublingual nifedipine; lumen variations from baseline values ranged from +1.29 to -1.56 mm. Acute changes in stenosis correlated closely with results obtained with oral treatment. In the group with Prinzmetal angina, coronary stenoses invariably responded with dilatation (the residual coronary lumen increased by an average of 69% of baseline); 100% of the patients in this group responded favorably to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Different vasomotor action of nifedipine on dynamic coronary obstructions and therapeutic response in effort and prinzmetal angina.

Variations induced by nifedipine (10 mg sublingually) in the residual lumen diameter of significant (greater than 50%) coronary lesions were assessed angiographically in 58 patients with effort angina (group 1) and in 19 patients with Prinzmetal angina (group 2). A relationship was sought between these acute variations of the stenotic lumen and the clinical response to treatment with the same drug (20 mg four times daily). Treatment efficacy was evaluated with exercise testing in group 1 and Holter monitoring in group 2. In group 1 the residual segment of stenotic diameter showed an increase, decrease, or no change with the calcium antagonist. Nifedipine failed to improve 40% of the cases (21% unchanged and 19% worsened) in group 1. In the same group of patients, the responses to exercise tests were dissociated from the acute vasomotor pattern. Changes in the pressure-rate product also did not explain the clinical results. In group 2 the majority of lesions had compliant portions, which invariably reacted to nifedipine with dilatation. All patients with the Prinzmetal form had relief of the anginal episodes with treatment. These data suggest that the therapeutic efficacy of nifedipine in classic effort angina probably is the net result of influences on the myocardial oxygen consumption and supply, and the acute coronary vasomotor pattern does not allow to predict the clinical response. Stenotic lesions in the Prinzmetal form possess a distinct sensitivity to the relaxant action of calcium channel blockade, which reasonably explains the highly positive response to treatment.

Coronary vasomotor and therapeutic influences of propranolol and nifedipine on the spontaneous component of mixed angina.

In 24 patients with spontaneous and effort-related angina (mixed angina), propranolol (80 mg q.i.d.) was significantly more beneficial than nifedipine (20 mg q.i.d.) on the number, duration and severity of the spontaneous manifestations. In some cases nifedipine elicited a paradoxical response. These patterns are unlikely to have resulted from different influences on the myocardial oxygen demands, since heart rate was steady before the occurrence of ischaemia and systemic arterial pressure was equally reduced in all patients. Sublingual nifedipine (10 mg) was tested in 12 patients and the residual lumen diameter of significant (greater than 50%) coronary stenoses (quantitative angiography) was unchanged in one, enhanced in seven and reduced in four of them. Lumen variations ranged from +1.59 to -1.2 mm and correlated closely with the results of oral nifedipine treatment. Propranolol (0.1 mg kg-1 i.v.) was tested in the other 12 cases and in none did variations of stenosis lumen diameter exceed 0.3 mm. These observations indicate that: in a number of lesions a portion of pliable wall may offer a compliant substrate for vasomotor influences; this may be the major factor whereby coronary obstructions cause spontaneous, besides effort-related angina; nifedipine is effective on the former manifestation provided that it does not promote stenosis constriction; propranolol may result in benefit through bradycardia facilitating coronary flow in diastole and reducing the baseline metabolic demands, to elevate the threshold of ischaemia during transient impedance to flow.

Nifedipine and angina pectoris. Short-term changes in quantitative coronary angiography with nifedipine and clinical response to treatment in effort-induced, mixed, and spontaneous angina pectoris.

Changes induced by nifedipine (10 mg sublingually) in the residual luminal diameter of significant (greater than 50 percent) coronary lesions were assessed angiographically in 69 patients with effort-induced angina (group 1), in 22 patients with mixed angina (group 2), and in 14 patients with Prinzmetal's angina (group 3). These changes were related to the clinical response to treatment with the same drug, as evaluated through diary records and Holter monitoring in the mixed (spontaneous component) and Prinzmetal forms and through exercise testing in effort-induced and mixed (effort-associated component) angina. In groups 1 and 2, segments of stenotic vessels showed either an increase or decrease or no change in diameter with the calcium antagonist; in group 3, the majority of the lesions had compliant portions which invariably responded with dilatation. Nifedipine failed to improve cases with exertional (20 percent [14/69] unchanged; 19 percent [13/69] worsened) and mixed (41 percent [9/22] exacerbated) forms; 100 percent of the 14 patients with the Prinzmetal form had relief of the anginal episodes. In group 1, the response to exercise tests was dissociated from the short-term vasomotor pattern, and the pressure-rate product failed to explain the clinical results. Forty-five percent (ten) of the patients in group 2 showed significant short-term widening of critical stenoses, as well as obvious improvement; patients who did worse with treatment in this group had reacted to nifedipine with narrowing of critical stenoses. These data suggest that the response to nifedipine of classic effort-induced angina is probably the net result of an interaction of changes in myocardial oxygen consumption and supply; coronary vasomotion has a role in mixed angina, and influences of nifedipine may be either favorable or unfavorable; stenotic lesions in the Prinzmetal form are quite sensitive to the relaxant action of calcium blockade, and this probably represents a background to the highly positive clinical response to treatment.

Coronary vasomotor and clinical effects of nifedipine in effort, mixed and Prinzmental angina.

Changes induced by nifedipine (10 mg s.l.) in the residual lumen diameter of significant (greater than 50%) coronary lesions were assessed angiographically in 69 patients with effort angina (Group 1), in 22 patients with mixed angina (Group 2), and in 14 patients with Prinzmental angina (Group 3). These changes were related to the clinical response to treatment with the same drug (diary records, exercise testing, Holter monitoring). In Groups 1 and 2 segments of stenotic vessels showed either increase, decrease or no change in diameter with the calcium antagonist; in Group 3 the majority of the vessels showed compliant portions which invariably responded with dilatation. Nifedipine failed to improve cases with exertional (21% unchanged, 19% worsened) and mixed (41% exacerbated) forms; all patients with the Prinzmental form had relief of the anginal episodes. In Group 1, the response to exercise tests were dissociated from the acute vasomotor pattern and the pressure-rate product failed to explain the clinical results. Fifty-two percent of the patients in Group 2 showed significant acute widening of critical stenoses as well as obvious improvement; patients in this group who did worse with treatment had reacted to nifedipine with narrowing of their critical stenoses. These data suggest that: the response to nifedipine of classic effort angina is probably the net result of an interaction of changes in myocardial oxygen consumption and supply; coronary vasomotion has a role in mixed angina and influences of nifedipine may be either favorable or unfavorable; stenotic lesions in the Prinzmental form are quite sensitive to the relaxant action of calcium blockade and this probably represents a background to the highly positive clinical response to treatment.

Calcium channel blockade with nifedipine reduces the systemic and the pulmonary vascular reactivity to adrenergic activation in hypertension.

In hypertension the systemic and the pulmonary circulation show exaggerated vascular tone and responsiveness to adrenergic stimuli. In 22 hypertensive men we tested whether the regulation of the two vascular beds is improved by calcium entry blockade with nifedipine. Mental arithmetic raised epinephrine plasma concentration (by 80%), cardiac output (CO) and blood pressure in both circuits, and caused systemic vasodilatation and pulmonary vasoconstriction. After the drug the epinephrine reaction was diminished (+20%), variations in CO and systemic blood pressure were almost unchanged and pulmonary vasoconstriction was abolished. A cold pressor test increased norepinephrine plasma concentration (by 24%), systemic and pulmonary pressure and resistance and did not alter CO. The norepinephrine response to cold was enhanced (+35%) by nifedipine, while systemic and pulmonary resistance rises were importantly attenuated (from +24% to +7% and from +41% to +1%, respectively), and greatly diminished the pressure reactivity. A sympatho-adrenal modulation by calcium blockade, per se, might have restrained the vasomotion during arithmetic. The impressive attenuation of the constrictor responses to cold, which was possibly associated with a potentiated sympathetic drive, prospects that the two circuits share a vascular contractile disorder in which calcium ions are involved.

Calcium-channel blockade with nifedipine and angiotensin converting-enzyme inhibition with captopril in the therapy of patients with severe primary hypertension.

Nifedipine (10 mg qid) and captopril (25 mg qid) were tested alone and in combination in 14 patients suffering from severe primary hypertension. Each study period was of 1 week's duration. Circulatory response was evaluated through hourly pressure and pulse rate readings. The fall in pressure after oral nifedipine was maximal within 1 hr or less and was generally accompanied by palpitation and increase in pulse rate; with a six hourly dosing regimen the tendency of blood pressure to recover after each dose was interrupted by the next dose, so that values remained significantly reduced throughout the 24 hr, although pressure fluctuations were evident. Promptness of the antihypertensive action of captopril was similar, but the magnitude and the duration of the fall in pressure were less pronounced. When the converting-enzyme inhibitor was combined with the calcium-channel blocker, pressure fluctuations were not abolished, but the antihypertensive response was definitely enhanced, so that normal blood pressure was maintained for several hours during the day. Additional positive effects of captopril were mitigation of the heart rate reaction and prevention of the ankle pitting or edema elicited by nifedipine. A balance in arteriolar and venular dilatation promoted by captopril is the suggested mechanism for these effects. With the two-drug combination the function of the left ventricle was not reduced and possibly improved; blood urea nitrogen and serum electrolyte and creatinine concentration were not affected. Plasma renin activity increased with captopril and reverted toward baseline with the addition of nifedipine, suggesting an interference of the calcium-channel blocker with the release of renin.

Treatment of hypertension with calcium antagonists. Review.

Calcium channel blockers have a selective action on the cardiovascular system. They reduce the energy requirement of the heart, reduce vascular smooth muscle tone, and increase systemic blood flow. Vasodilatation occurs in both the systemic and the pulmonary systems to an extent proportional to the baseline level of vascular resistance, and results in reduction of blood pressure when it is elevated. Thus, these blockers are useful in patients with high blood pressure. Clinical experience of calcium channel blockers in hypertension is so far confined almost exclusively to verapamil and nifedipine. This article reviews the advantages and limitations of these two compounds, their acute hemodynamic effects in hypertensive subjects, and their use in the treatment of hypertensive emergencies, hypertensive encephalopathy, and pheochromocytoma, and as ventricular afterload reducing agents in hypertensive left ventricular failure. Similarities in the effects of nifedipine on systemic and pulmonary vascular tone are presented as evidence that altered intracellular Ca++ concentration is involved in the vasoconstriction seen in both systems in systemic high blood pressure. They also provide support for the hypothesis that inappropriate Ca++ handling may be involved in maintaining elevated blood pressure in human hypertension.