Influence of tart cherry juice on indices of recovery following marathon running.

This investigation determined the efficacy of a tart cherry juice in aiding recovery and reducing muscle damage, inflammation and oxidative stress. Twenty recreational Marathon runners assigned to either consumed cherry juice or placebo for 5 days before, the day of and for 48 h following a Marathon run. Markers of muscle damage (creatine kinase, lactate dehydrogenase, muscle soreness and isometric strength), inflammation [interleukin-6 (IL-6), C-reactive protein (CRP) and uric acid], total antioxidant status (TAS) and oxidative stress [thiobarbituric acid reactive species (TBARS) and protein carbonyls] were examined before and following the race. Isometric strength recovered significantly faster (P=0.024) in the cherry juice group. No other damage indices were significantly different. Inflammation was reduced in the cherry juice group (IL-6, P<0.001; CRP, P<0.01; uric acid, P<0.05). TAS was ~10% greater in the cherry juice than the placebo group for all post-supplementation measures (P<0.05). Protein carbonyls was not different; however, TBARS was lower in the cherry juice than the placebo at 48 h (P<0.05). The cherry juice appears to provide a viable means to aid recovery following strenuous exercise by increasing total antioxidative capacity, reducing inflammation, lipid peroxidation and so aiding in the recovery of muscle function.

Cardiac transplantation in a patient with hereditary hemochromatosis: role of adjunctive phlebotomy and erythropoietin.

We describe the case of a 36-year-old woman with hereditary hemochromatosis (HH) resulting in end-stage cardiomyopathy and treated successfully with orthotopic cardiac transplantation. Before and after transplantation, the patient underwent aggressive treatment with frequent phlebotomy. We used erythropoietin concomitantly to maintain adequate hematocrit to support continued phlebotomy. We believe that aggressive use of phlebotomy provided the patient hemodynamic benefit and hastened the return of endocrine function post-transplantation. We also believe that the patient's history of high-dose vitamin C usage may have accelerated iron deposition in the heart and other vital organs.

Role of metabolically active drugs in the management of ischemic heart disease.

This article reviews the fundamentals of myocardial energy metabolism and selectively outlines the use of several metabolically active drug therapies in the treatment of ischemic heart disease. These drugs - ranolazine, trimetazidine, dichloroacetate (DCA), glucose-insulin-potassium (GIK) solutions, and L-carnitine - have mechanisms of action distinct from traditional anti-ischemic drugs. These agents work by shifting myocardial energy metabolism away from fatty acids toward glucose as a source of fuel. Because these agents are well tolerated and do not affect heart rate or blood pressure, they conceivably could supplement traditional anti-ischemic drug therapy with little risk. The background, rationale for use, and published literature on each agent is reviewed, and the outcomes of pertinent clinical trials are discussed. In the case of ranolazine, data suggest benefit in the treatment of stable angina pectoris, particularly with sustained release formulations. Trimetazidine appears to have similar physiologic effects to ranolazine, and it is effective as monotherapy and as additive therapy in patients with chronic ischemic heart disease. DCA improves acidosis in critically ill patients and, likewise, improves myocardial hemodynamics in those with chronic coronary artery disease and congestive heart failure; however, its metabolism is variable and clinical data on its use in chronic ischemic heart disease are limited. GIK solutions have been shown to be beneficial in animal and human models of ischemia and acute myocardial infarction, and they offer an inexpensive means by which to improve the oxidation of glucose in the heart. Lastly, a large body of literature suggests a benefit with L-carnitine in a number of cardiovascular illnesses, including ischemic heart disease. Clinical trial data in acute myocardial infarction are promising and have prompted the initiation of a large-scale mortality trial.

Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study).

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001).

Modulation of human granulosa cell steroid production in vitro by tumor necrosis factor alpha: implications of white blood cells in culture.

OBJECTIVE: To test the hypothesis that the macrophage cytokine, tumor necrosis factor-alpha (TNF-alpha), directly inhibits progesterone, estrone (E1), and estradiol (E2) synthesis by human granulosa cells in vitro in the presence and absence of white blood cells. METHODS: Granulosa cells from follicle aspirates of patients undergoing in vitro fertilization (IVF) were separated from red blood cells on 50% Percoll columns. Such preparations contained numerous white blood cells (lymphocytes, 40-52%, and macrophages, 6-14%) as determined with immunocytochemistry. In some studies, anti-CD45 magnetic beads followed by an additional adherence step and media change were used to remove white blood cells from granulosa cell cultures. Granulosa cells with and without associated white blood cells were cultured in basal and hCG-supplemented media. Androstenedione (40 ng/mL) and/or recombinant TNF-alpha (0.5-50 ng/mL) were added to triplicate wells. Media were harvested for radioimmunoassay of progesterone, E1, and E2 after 24 and 48 hours of incubation. RESULTS: The effects of TNF-alpha on progesterone production in white blood cell-associated cultures were inconsistent when 0.5 ng/mL TNF-alpha was added under basal conditions. At higher TNF-alpha doses (5-50 ng/mL) and under hCG-stimulated conditions, there was a consistent decrease in progesterone production, but the effect was not clearly dose-dependent. It was possible to remove white blood cells effectively from granulosa cell cultures. In granulosa cell cultures without associated white blood cells, 0.5 ng/mL of TNF-alpha at 48 hours produced an increase in progesterone, whereas 50 ng/mL of TNF-alpha decreased progesterone (P < .001). Estrone and E2 were both decreased by TNF-alpha regardless of whether white blood cells were present in culture, without clear evidence of dose-dependency. Granulosa cell viability and proliferation were unaffected by TNF-alpha as demonstrated by direct cell counts, trypan blue exclusion, and tetrazolium salt viability assays. CONCLUSIONS: In the normal ovary, TNF-alpha may influence the development of the dominant follicle by inhibiting aromatase activity. It may also mediate oocyte maturation disorders and ovarian endocrine dysfunction in some pathologic states. White blood cells can be effectively removed from granulosa cell cultures. Application of this removal technique will facilitate future granulosa cell studies by allowing more precise determination of direct granulosa cell function.

Hysterosalpingography contrast media and chromotubation dye inhibit peritoneal lymphocyte and macrophage function in vitro: a potential mechanism for fertility enhancement.

OBJECTIVE: To determine the effects of hysterosalpingography (HSG) contrast media (CM) and chromotubation dye on peritoneal lymphocyte proliferation and macrophage phagocytosis in vitro. DESIGN: Peritoneal fluid (PF) lymphocytes and macrophages were isolated from 40 subfertile women undergoing diagnostic laparoscopy and 12 fertile women having laparoscopic tubal ligation. Dilutions of renografin, ethiodol, methylene blue, and indigo carmine were added to peritoneal lymphocyte and macrophage cultures. Tissue culture media alone served as control. Lymphocyte proliferation was assessed by hemocytometer counts and 3H-thymidine incorporation. Macrophage function was determined by phagocytosis of fluorescent microspheres. RESULTS: Peritoneal lymphocyte proliferation and macrophage phagocytosis were significantly inhibited by renografin, ethiodol, methylene blue, and indigo carmine in a dose-dependent manner. CONCLUSION: Inhibition of PF immune cell function by HSG CM and chromotubation dye may provide a potential mechanism for fertility enhancement after these diagnostic procedures.

Effects of atenolol alone, nifedipine alone and their combination on ambulant myocardial ischemia.

The effects of atenolol (100 mg/day) and nifedipine (20 mg 3 times daily) and their combination on ambulant myocardial ischemia were investigated using a randomized, double-blind, placebo-controlled, crossover trial. Eighteen men with symptomatic coronary artery disease, exercise-induced ischemia and minimal symptoms, underwent 4 blinded treatment periods of 2 weeks' duration (2 placebo, 1 atenolol, 1 nifedipine). Those that did not have ischemia eliminated by monotherapy received combination therapy with both drugs. Forty-eight-hour ambulatory electrocardiographic monitoring was used to quantitate ischemic parameters at the end of each period. Both nifedipine and atenolol as monotherapy reduced the number of ischemic episodes and the average duration of each episode compared with placebo (p less than 0.05). Compared with placebo, nifedipine reduced the total duration of ischemia (p less than 0.05) but the effect of atenolol on ischemia duration was of borderline significance (p = 0.066). There were no differences in reduction of ischemic parameters when atenolol was compared with nifedipine (difference not significant). In the 9 patients who continued to have ischemia with monotherapy, combination therapy eliminated it in 2 and reduced the duration by greater than 50% in the remaining patients compared with placebo. In conclusion, monotherapy with nifedipine or atenolol is similarly effective in eliminating or reducing ambulant ischemia. Combination therapy can provide additional benefit in those with continued ischemia.

Comparison of diltiazem and nifedipine alone and in combination in patients with coronary artery spasm.

Fifteen patients with coronary artery spasm completed a double-blind placebo-controlled trial comparing diltiazem and nifedipine. Increasingly, higher daily doses (diltiazem, 90 to 360 mg; nifedipine, 30 to 120 mg) were administered to achieve optimal clinical effects. Daily diaries and ambulatory electrocardiographic recordings were used to assess efficacy and side effects. Both drugs significantly decreased angina frequency compared with that in the preceding placebo period (diltiazem 1.4 +/- 0.4 [mean +/- SEM] to 0.4 +/- 0.2 episodes per day; nifedipine 1.4 +/- 0.3 to 0.4 +/- 0.1 episodes per day; both p less than 0.05). Ambulatory electrocardiographic recordings showed fewer ST shifts than were expected during all treatment periods (0.02/h recorded during placebo, none during diltiazem and 0.02/h during nifedipine therapy). Although some patients responded better to one drug than the other, neither drug resulted in a clearly superior clinical response. Diltiazem was discontinued in one patient because of urticaria, but the total number of side effects was higher with nifedipine (12 of 15 patients) than with diltiazem (5 of 15, p less than 0.01). Nine patients remained symptomatic on single drug treatment and entered open label treatment with the combination of diltiazem and nifedipine. Three patients did not tolerate the combination because of important side effects; the other six also had side effects, but these were relatively minor. Four patients received no more benefit from the combination than from a single agent; the condition of two patients improved. Both diltiazem and nifedipine provide effective antianginal therapy for coronary spasm, but diltiazem has fewer side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nicardipine on left ventricular function and energetics in man.

The effects of nicardipine, a new dihydropyridine calcium antagonist, on left ventricular function and energetics were studied in 13 patients. Nicardipine was administered as a 2 mg bolus (i.v.) followed by an infusion titrated to maintain a 10-20 mm Hg decrease in systolic pressure. Nicardipine increased heart rate 19% (P less than 0.001) while left ventricular end-diastolic pressure was not significantly changed and stroke volume (ml) increased 13% (P less than 0.01). Peak values for the first and second time derivatives of left ventricular pressure were increased by 26% (P less than 0.01) and 50% (P less than 0.02) respectively. Peak aortic blood flow, peak aortic blood acceleration, and the peak rate of change of ejection power were increased 86% (P less than 0.001), 123% (P less than 0.01), and 113% (P less than 0.001), respectively. Stroke work was not changed during nicardipine infusion. External power increased by 40% (P less than 0.01); however, the ratio of oscillatory to total power was not significantly different. Although the product of heart rate and systolic aortic pressure was not significantly altered with nicardipine, myocardial oxygen consumption increased 18% (P less than 0.02) with a disproportionate increase in coronary blood flow of 41% (P less than 0.001) and decrease in coronary resistance of 39% (P less than 0.001). The time constant for left ventricular isovolumic relaxation decreased 22% (P less than 0.001) during nicardipine infusion while the minimum value of dP/dt was unchanged. Thus, when administered intravenously in man, nicardipine is a potent coronary and systemic vasodilator producing reflex tachycardia, increased indices of myocardial contractile state, and improved isovolumic relaxation with an associated increase in myocardial oxygen consumption.

Isosorbide dinitrate and nifedipine in variant angina pectoris.

The efficacy of isosorbide dinitrate (ISDN) in variant angina is enhanced by the addition of a calcium antagonist. A prospective double-blind, crossover trial of ISDN, 40 to 120 mg/day, and nifedipine, 40 to 120 mg/day, in 19 patients with variant angina and various degrees of coronary atherosclerosis showed that although both agents were equally effective in controlling angina of vasospastic origin, some patients responded better to one or the other drug. Such response could not be predicted by demographic factors, ECG changes, or degree of coronary atherosclerosis. Since quantitative angiography done in a similar group of patients showed that intracoronary nitroglycerin, 200 micrograms, was a more potent vasodilator than sublingual nifedipine, 10 mg (p less than 0.01), the calcium antagonists may have a different mechanism of preventing variant angina attacks and may act in an additive or synergistic fashion when administered in combination with long-acting nitrates. Such a combination will increase coronary blood flow, reduce ventricular volume and end-diastolic pressure, and reduce systemic arterial resistance. Coronary vasospasm may be directly prevented by a general inhibition of smooth muscle contraction by the calcium antagonist. Clinical studies suggest that combination therapy significantly improves the long-term prognosis of patients with variant angina and reduces the need for bypass surgery. Thus combining ISDN with a calcium antagonist is a rational and effective treatment for variant angina.

Calcium antagonists.

At present nitrates remain the initial treatment for relief or prevention of angina in patients with coronary artery disease. In cases where nitrates and beta blockers have been used and are ineffective for managing effort angina, calcium antagonists may be substituted or added to the beta-blocking treatment. When the predominant symptom is rest angina, and there is evidence suggesting coronary artery spasm, nitrates and a calcium antagonist can be effective therapy. In patients with heart block, bradyarrhythmias, heart failure, or hypertension nifedipine may be the drug of choice. In contrast verapamil merits choice when supraventricular tachycardia is present. Diltiazem appears intermediate between nifedipine and verapamil and may be particularly useful when hypotension or other side effects must be avoided.

Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil.

The clinical outcome after the initial year of therapy with either diltiazem (D), nifedipine (N), or verapamil (V) was examined in 45 patients with rest angina. Age, frequency of angina, duration of symptoms, and ejection fraction were similar in all three treatment groups. Coronary artery disease was present in 60% of patients (5 of 13 given D, 8 of 16 given N, and 14 of 16 given V). Coronary spasm was suspected (ST elevation with angina) or documented (angiographically) in 35 (78%) patients. Twenty-nine (64%) patients had greater than 50% decrease in angina without a coronary event (9 taking D, 11 taking N, and 9 taking V). Coronary events (sudden death, infarction, and hospitalization for unacceptable angina control or bypass surgery) occurred in 13 (29%) patients (two taking D, four taking N, and seven taking V). To achieve these responses, 20 (44%) patients required additional antianginal drugs (long-acting nitrates, beta blockers, or other calcium blockers). Four of these 20 patients were taking D, nine were taking N, and seven were taking V. Seventeen (38%) patients experienced a side effect (none taking D, 6 taking N, and 11 taking V). Although rest angina can be controlled in the majority of patients during the initial year of treatment with calcium blockers, additional therapy is often required. Furthermore, the clinical course of patients presenting with rest angina remains unpredictable, even during calcium blocker treatment. Morbid events continue to occur, related in part to the extent of coronary artery disease.

Long-term responses to nifedipine in patients with coronary spasm who have an initial favorable response.

Twenty-six patients with angina and coronary spasm participated in a randomized crossover trial comparing nifedipine with isosorbide dinitrate. Eighteen patients had a short-term beneficial response to nifedipine, and 14 of these were followed up for an average period of 9.4 months. During follow-up study, nifedipine was the primary therapy in these 14 patients, but other drugs were added when clinically necessary to control angina. There was an overall 86% beneficial response rate (greater than 50% decrease in angina frequency). However, 2 patients had a large increase (greater than 10 times) and 4 patients had a slight increase (transient) in angina frequency over the long term compared with the short-term response. The other 8 patients had a similar angina frequency compared with the short-term response. Of the 12 patients with a good response (transient slight increase or no change), 8 (67%) required additional drug therapy to maintain angina control. Nifedipine was discontinued in 2, and the dose was decreased in 3 of the 14 patients because of adverse effects. Three patients had a marked increase in angina at 9, 14, and 3 months, requiring hospitalization; 1 patient had coronary bypass for symptom control. Thus, patients with coronary spasm selected because of a favorable short-term response to nifedipine were effectively treated over the long term with nifedipine; however, additional therapy was often needed to control symptoms. Adverse effects were common, but simple reduction of nifedipine dose usually diminished the unwanted effects of the drug.

Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm.

The effects of nifedinpine and isosorbide dinitrate on the frequency of angina and consumption of nitroglycerin were studied in 19 patients with coronary arterial spasm. After a lead-in phase, the patients were randomized to treatment with either nifedipine or isosorbide dinitrate. After dose titration (40 to 120 mg/day) and evaluation, they were given the alternate therapy. During the initial segment of the double-blind phase, one patient died suddenly (nifedipine phase), one dropped out of the study (nifedipine phase) and another was unable to tolerate therapy (isosorbide dinitrate phase). In the other 16 patients, the mean frequency of angina was less during therapy with both nifedipine (0.69 episode/day, p less than 0.05) and isosorbide dinitrate (0.77 episode/day, p less than 0.05) phases than during the lead-in phase (1.71 episodes/day). The mean frequency of angina was similar in the nifedipine and isosorbide dinitrate phases. A 50 percent or greater decrease in frequency of angina compared with lead-in phase values occurred in 13 of 18 patients during treatment with nifedipine and in 10 of 16 during treatment with isosorbide dinitrate. Of the 16 patients who completed both double-blind phases, 7 showed greater improvement (that is, a 50 percent or greater decrease in frequency of angina) with nifedipine than with isosorbide dinitrate); 6 others showed greater improvement with isosorbide dinitrate, and the other 3 had a less than 50 percent difference in frequency of angina with the two drugs. These findings in a limited number of patients suggest that both nifedipine and isosorbide dinitrate are effective in certain patients with coronary spasm but that neither drug is clearly superior.