Tamaractam, a New Bioactive Lactam from Tamarix ramosissima, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Chemical investigation of Tamarix ramosissima Ledeb, a traditional herbal medicine used for rheumatoid arthritis (RA) treatment in northwest China, led to the discovery of a new phenolic aromatic rings substituted lactam, tamaractam (1), together with the previously reported compounds cis-N-feruloyl-3-O-methyldopamine (2) and trans-N-feruloyl-3-O-methyldopamine (3). The structures of the compounds were determined by high resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D and 2D-NMR experiments, as well as comparison with the literature data. The effects of the three compounds on the viability of RA fibroblast-like synoviocytes (RA-FLS) were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Pro-apoptosis effect of compound 1 in RA-FLS was further investigated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, activated caspase-3/7 level assessment using luminescence assay, and sub-G1 fraction measurement using flow cytometry. It was found that these three compounds displayed variable proliferation inhibitory activity in RA-FLS, and compound 1 exhibited the strongest effect. Compound 1 could remarkably induce cellular apoptosis of RA-FLS, increase activated caspase-3/7 levels, and significantly increase sub-G1 fraction in the cell cycle. The results suggested that compound 1 may inhibit the proliferation of RA-FLS through apoptosis-inducing effect, and these compounds may contribute to the anti-RA effect of T. ramosissima.

Congestive heart failure. Drug therapy: central or peripheral approach?

Although prevention of heart failure recently has become a realistic issue, management of heart failure once the syndrome has developed, is mainly supportive, based on the various cardiac and peripheral changes which occur in the course of heart failure. Of these, abnormal neurohormonal activation is of major pathophysiologic and prognostic significance. Consequently, modulation of neuroendocrine activation is now recognized a prime target in the treatment of heart failure, besides diuretic therapy. In this respect, the value of converting enzyme inhibition is well established. Future developments in this area include dopaminergic agents, vasopressin antagonists, angiotensin II receptor antagonists, renin inhibitors, spironolactone and, possibly, ANF peptidase inhibitors. Besides diuretics, necessary when signs of fluid retention are present, the approach to heart failure management involves other pharmacologic issues. In view of abnormal vascular control with vasoconstriction prevailing during progressive heart failure, it clearly makes sense to vasodilate. However, of available vasodilators, only the combination of relatively high dose nitrates and hydralazine has proven to be of clinical significance, in terms of hemodynamics, exercise capacity and survival. It is possible, though, that novel generation dihydropyridine derivatives may prove beneficial as well. Thus far, there has been much debate concerning the usefulness and particularly the safety of positive inotrope therapy and inodilator treatment. Taken together, this concern relates to presence and predominance of cAMP-dependent mechanisms to induce these effects. Thus, sympathomimetic agents and phosphodiesterase inhibitors, such as milrinone or enoximone, are without beneficial effects, but instead shorten survival during long-term therapy. This may be different where compounds which act through cAMP-independent mechanisms, i.e., calcium sensitization or sodium channel stimulation, are concerned, but needs to be confirmed yet.(ABSTRACT TRUNCATED AT 250 WORDS)

Invasive pharmacodynamic characterization of combined ibopamine and calcium blocker therapy for heart failure.

STUDY OBJECTIVE: To determine the acute hemodynamic response of single-dose coadministration of ibopamine plus nifedipine or diltiazem in patients with New York Heart Association functional class (NYHA FC) II-III congestive heart failure. DESIGN: A single-blind, placebo-controlled, two-paired, crossover study. SETTING: Cardiology clinics at two large teaching hospitals. PATIENTS: Eight patients with NYHA FC II-III congestive heart failure who met the inclusion criteria were selected randomly. INTERVENTIONS: All patients underwent right heart catheterization. Day 1 consisted of concomitant calcium channel blocker plus placebo, with cardiac and peripheral hemodynamic recordings from 30 minutes-24 hours. The design was equivalent on day 2, with single-dose administration of ibopamine plus calcium channel blocker. MEASUREMENTS AND MAIN RESULTS: Single-dose nifedipine-diltiazem augmented cardiac output and stroke volume secondary to decreasing systemic vascular resistance. The nifedipine-ibopamine and diltiazem-ibopamine subgroups demonstrated relatively equal hemodynamics, augmenting cardiac index (nifedipine 43%, p < 0.05; diltiazem 40%, p < 0.05 vs baseline) while decreasing systemic vascular resistance (nifedipine 41%, p < 0.05; diltiazem 28%, p NS vs baseline) 30 minutes after the dose. In contrast to single-dose diltiazem, the diltiazem-ibopamine subgroup exhibited an increased left ventricular filling pressure (122%, p < 0.05 vs baseline) and mean pulmonary artery pressure (43%, p < 0.05 vs baseline) at 30 minutes after the dose. One patient experienced a transient episode of chest pain associated with increased heart rate and blood pressure with diltiazem-ibopamine. CONCLUSION: Diltiazem and ibopamine should be coadministered with caution in patients with coronary artery disease and left ventricular dysfunction.

Hemodynamic comparison of combined therapy by nitroglycerin tape and ibopamine with combination of nitroglycerin tape and nifedipine.

Fifteen congestive heart failure patients (NYHA: class III or IV) were enrolled in the study and were classified into two groups. Six patients (group I) received combined therapy by nitroglycerin tape (5 mg) and ibopamine (100 mg), while the remaining 9 patients (group II) were given nitroglycerin tape (5 mg) and nifedipine (10 mg). The effects of the combined treatments on hemodynamics were compared between the two groups using Swan-Ganz catheter method. No significant differences were noted in the hemodynamic baseline values of the two groups before treatment. In group I mean pulmonary arterial pressure (mPA) and systemic vascular resistance (SVR) decreased and the cardiac index (CI) increased, while the heart rate (HR) and mean blood pressure (mBP) remained unchanged. In group II mBP, mPA and SVR were lowered, whereas CI and HR were augmented. There were no significant differences between the two groups with respect to mPA and CI. However, mBP decreased in group II, while it remained unchanged in group I, with significant difference between the two groups (p less than 0.01). Preload and afterload, on the base of mPA and SVR, respectively, decreased in both groups, while cardiac output increased, suggesting that both treatments were useful for the improvement of cardiac output. Mean BP decreased in group II, although it remained unchanged in group I. These results suggest that the combination of nitroglycerin and ibopamine may be more useful in hypotensive patients with heart failure.

Extracardial effects of oral ibopamine versus furosemide in patients with mild or moderate heart failure. A double-blind, randomized trial.

Ibopamine is a novel oral dopamine analogue with vasodilatory, positive inotropic and diuretic effects. In a double-blind, randomized study, the drug was investigated in 12 patients (mean age 49 +/- 10 years, 8 male, 4 female) with mild or moderate heart failure (NYHA classes II:8 patients, III:4 patients). Effects of single oral doses of 200 mg ibopamine, of 40 mg furosemide and of 200 mg ibopamine + 40 mg furosemide were compared in each patient at 3-day intervals. 1 h after administration, systolic and diastolic blood pressure increased from 120 +/- 11 to 124 +/- 9 and from 76 +/- 5 to 81 +/- 6 mm Hg in the ibopamine group. During 4 h after drug ingestion, urinary flow was significantly raised from 124 +/- 81 to 228 +/- 166 ml/2 h in the ibopamine group (p less than 0.05), while the administration of furosemide (with or without ibopamine) resulted in several folds increases of urinary flow. After ibopamine, the 2-h creatinine clearance rose from 123 +/- 73 to 131 +/- 85 ml/min (not significant). Sodium and potassium excretion remained essentially unchanged by ibopamine, while effects of furosemide were several folds of those of ibopamine. Plasma renin activity was lowered to 65% by ibopamine (p less than 0.01). No additive effects of ibopamine in the presence of furosemide were observed for all parameters tested. These results indicate that ibopamine has smaller renal effects than furosemide with regard to water diuresis and kaliuresis. These effects of ibopamine could reflect direct changes of renal function or secondary effects of neurohumoral origin. Ibopamine does not produce undesirable renal side effects, but affects the neurohumoral status favourably. This drug, thus, could be useful as an adjuvant therapy in mild heart failure.

Effect of ibopamine and the active metabolite epinine on the catecholamine content of rat hypothalamus and brainstem in vitro.

The effect of ibopamine (IBO) (SB 7505, SK&F 100168-A), a new drug for the treatment of congestive heart failure, and its active metabolite epinine (EPN) (N-methyldopamine), on the catecholamine content of hypothalamus and brainstem was studied in vitro after monoamine oxidase inhibition with pargyline. IBO and EPN increased levels of epinephrine (EPI) in a concentration- and time-dependent manner in both brain areas without significantly affecting the concentration of other catecholamines. Inhibition of either dopamine beta-hydroxylase, the neuronal EPI and norepinephrine uptake system, or esterase hydrolysis of IBO prevented the increase of EPI, whereas inhibition of phenylethanolamine N-methyltransferase, enzymatic dealkylation or the neuronal dopamine or serotonin uptake system had no influence on the increase of EPI levels. These results suggest that IBO after hydrolysis to EPN can be converted enzymatically to EPI by dopamine beta-hydroxylase in hypothalamus and brainstem. EPN seems to be accumulated into adrenergic and noradrenergic neurons by the high affinity uptake system. Changes in the EPI content of the central nervous system neurons might be responsible for some of the pharmacologic effects of IBO.

Effects of digoxin, placebo and ibopamine on exercise tolerance and cardiac rhythm of patients with chronic post-infarct left ventricular failure.

This study compares the effects of digoxin, placebo and ibopamine (SB-7505), the orally active 3,4-diisobutyryl ester of N-methyl-dopamine, on exercise tolerance and cardiac rhythm of 14 patients whose left ventricular heart failure (end-diastolic pressure, 26.3 +/- 5.9 mmHg; ejection fraction, 0.42 +/- 0.10%) depended on a previous myocardial infarction. Patients were admitted to the study while on chronic oral digoxin treatment (serum levels between 1.1 and 1.9 ng/ml). Placebo instead of digoxin was given for the following month. Thereafter ibopamine 50 mg t.i.d. for one month was given. A sequence of one-month treatments with digoxin, placebo and ibopamine was repeated, then ibopamine was administered continuously for the next two months. The concurrent treatment (diuretics in all patients, nitroderivates in twelve, calcium antagonists in two) remained unchanged during the observation period. Symptoms-limited exercise tests and 24-h Holter recordings were obtained at admission, at the end of each one-month treatment and at the end of the observation period. Two patients developed unstable angina without increase of serum creatine phosphokinase while on ibopamine and were withdrawn. Out of the 12 patients that concluded the trial, one required supplementary doses of diuretic at the end of the second period on placebo. The results obtained during the trial suggest that: a) therapeutic plasma levels of digoxin have no deleterious effect on cardiac rhythm nor significantly increase exercise tolerance as compared with placebo; b) diuretics and nitrates appear to sustain the clinical stability of these patients as a group.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of carbidopa to alpha-methyldopamine and alpha-methylnorepinephrine in rats.

Recent observations on the central and peripheral actions of carbidopa (CD) combined with our own results with the compound led us to examine its metabolism and effects on brain catecholamines in rats. CD was found to undergo a two-stage N-deamination process in vivo giving rise to alpha-methyldopa (AMD) and alpha-methyldopamine respectively. Further, beta-hydroxylation yielded alpha-methylnorepinephrine. These metabolic products were demonstrated in rat brain with reductions in norepinephrine and 3-methoxy-4-hydroxyphenylglycol, and little effect on dopamine. These results are consistent with the alpha-2 agonist effects of alpha-methylnorepinephrine. The relative formation of alpha-methyldopamine from CD was about 26% of an equivalent dose of AMD. It is concluded that some of the central effects of CD may be mediated by its metabolism to AMD, which readily crosses the blood-brain barrier. Possible implications of the findings are discussed.