Comparative bioavailability study on naproxen betainate sodium salt monohydrate and naproxen sodium salt in healthy volunteers.

The S-naproxen betainate sodium salt monohydrate (naproxen-betaNa, CAS 104124-26-7, Aprenin, test drug), and the sodium salt of S-naproxen (reference), were administered to twelve healthy volunteers of both sexes according to a crossover design, in a single dose of one 575 mg capsule of test, containing 342 mg of S-naproxen and two 275 mg tablets of reference, containing 502 mg of S-naproxen. Blood samples were drawn off over a 24-h period before (time 0) and after administration at foreseen time intervals. Naproxen was measured in plasma by a validated HPLC assay with UV detection which was able to detect 1 microgram/ml and proved to be linear in the range 1-100 micrograms/ml. The non-compartmental pharmacokinetic parameters obtained were statistically processed according to the EU guidance note on bioavailability and bioequivalence Cmax, AUC0-24h and AUC0-infinity were normalized to the dose of 502 mg of naproxen and log-transformed before statistical analysis to assess bioequivalence. Dose-normalized values of plasma concentrations encountered with the two formulations proved to overlap, with the exception of the first sampling time which showed naproxen concentrations that were higher with test drug than with reference. The specific test for bioequivalence led to 90% confidence intervals within the 80-125% range with target pharmacokinetic parameters, whereas the time to peak (tmax) observed with the test and reference drugs did not differ to any statistically significant degree when analysed with Wilcoxon's non-parametric test. It is concluded that the test drug should be declared bioequivalent with the reference drug in terms of dose-normalized concentrations, despite the more rapid increase in plasma concentrations of naproxen observed at the first sampling time with test drug.

Dobutamine echocardiography: usefulness of digital image processing.

The present study was undertaken in order specifically to evaluate the usefulness of digital image processing so as to enhance the diagnostic power of dobutamine stress echocardiography. For this purpose 44 dobutamine echocardiographic tests, routinely performed in our echo laboratory, were analysed blindly by two observers using traditional videotape recording and digitized image acquisition. The results obtained from both observers show a trend which suggests that the traditional videotape approach provides more true-positive tests than the digitized approach (27/38 vs 23/38 and 24/38 vs 22/38 for the first and second observer, respectively). True-negative test detection was 6/6 with the videotape and 5/6 with the digitized method for both observers. As a consequence of the discrepancies observed between the two modalities, the videotape indicates that it can provide higher diagnostic accuracy than the digitized approach (72 +/- 9% vs 63 +/- 10%). The tests results concordance (positive or negative) between the two modalities of analysis was 66% for both the observers. The inter-observer agreement on the test results was 84% and 80% for the videotape analysis and the digitized analysis, respectively. On the basis of the results, we consider that digitized analysis applied to dobutamine stress echocardiography does not afford significant diagnostic advantages and should not be considered as an alternative option to traditional videotape analysis. However, it may be considered an extremely useful integrative tool since it produces the on-line image evaluation more easily and faster and allows a more practical form of stress test storage.

["Incomplete closure" of the mitral valve: the relationships to valvular regurgitation and to the morphofunctional characteristics of the left ventricle]. / "Chiusura incompleta" della mitrale: rapporti con il rigurgito valvolare e con le caratteristiche morfofunzionali del ventricolo sinistro.

OBJECTIVES: The present study was designed in order to evaluate the prevalence of mitral regurgitation in patients with the "incomplete mitral leaflet closure" echocardiographic pattern, to verify whether the amount of "incomplete mitral leaflet closure" is related to the severity of mitral regurgitation and, last, to verify the relation between the "incomplete mitral leaflet closure" and left ventricular morphology and function. METHODS: We studied 80 patients (14 patients with dilatative cardiomyopathy, 26 patients with coronary artery disease, and 40 patients with hypertensive heart disease or aortic valve disease) showing the "incomplete mitral leaflet closure" pattern, retrospectively selected from a population composed of 1700 consecutive patients routinely examined in our echocardiographic laboratory. In all patients we evaluated the presence and the severity of mitral regurgitation, the morphological and functional parameters of the left ventricle, the systolic diameter of the mitral annulus, the distance between the point of mitral leaflet coaptation and the annular plane, and the incomplete mitral closure area, assuming the last two parameters as indexes of the severity of incomplete closure of the mitral valve. RESULTS: We observed the presence of mitral regurgitation in 51 out of 80 patients (64%). The valvular insufficiency was considered mild in 78% of the patients. We observed no significant difference between patients with mitral regurgitation and without, as regards the diameter of the mitral annulus, the distance between the point of mitral leaflet coaptation and the annular plane, and the incomplete mitral closure area in different types of heart diseases. The incomplete mitral closure area and the diameter of the mitral annulus showed a significant, although not elevated, correlation with the severity of the mitral regurgitation (r = 0.36 and r = 0.32, respectively). The severity of mitral regurgitation showed significant correlations with all of the left ventricular morphological and functional parameters evaluated. Finally, we observed significant correlations between the incomplete mitral closure area and all of the morphological and functional parameters of the left ventricle. CONCLUSIONS: On the basis of the results obtained we can conclude that: 1) the "incomplete mitral leaflet closure" pattern does not appear to be a highly specific marker of mitral regurgitation, 2) this pattern appears to be related to the morphology and function of the left ventricle, and 3) the severity of the incomplete mitral valve closure is more easily evaluated by a parameter that takes into account the numerous factors acting on the mitral apparatus, that is the incomplete mitral closure area.

[Myocardial response to ischemia produced by repeated coronary occlusions: an experimental study]. / Risposta miocardica all'ischemia prodotta da occlusioni coronariche ripetute: studio sperimentale.

BACKGROUND: The fact that brief repeated episodes of ischemia may induce prolonged functional depression of the left ventricle is still a matter of debate. During an angioplasty several brief (20-90 sec) coronary occlusions are performed, with the potential risk of inducing myocardial jeopardy. METHODS: We performed 4 repeated LAD occlusions in 7 open chest pigs under general anesthesia and controlled ventilation. The following parameters were evaluated: mean systemic arterial pressure (MAP), left ventricular peak systolic pressure (LVPSP), heart rate (HR), and peak negative and positive dP/dt (dP/dt- and +). Each parameter was measured in the basal state and every 4 sec, in the expiratory phase, during the coronary occlusion, the first min and after 10 min of reperfusion. The percent change from control values for each parameter was also calculated and, by means of the ANOVA test, the differences among the 4 consecutive occlusions for each parameter were tested. RESULTS: The results showed that: 1) coronary occlusions significantly depressed dP/dt + and -, MAP and LVPSP, while HR did not change; 2) each variable returned to control values within 1 min of reperfusion; 3) the response to ischemia (percent change) was the same in each of the 4 consecutive occlusions for all parameters at every recording time. CONCLUSIONS: We can conclude that: 1) each experimental coronary occlusion induces a depression of myocardial function that is reversible in 1 min of reperfusion; 2) four repeated 2 minutes coronary occlusions do not induce cumulative effects on myocardial response to ischemia.

Does aortic regurgitation affect transmitral flow? An echo-Doppler study.

Recent studies suggest that the presence of aortic regurgitation can interfere with Doppler measurement of mitral pressure half-time in patients with mitral stenosis. Amongst the factors affecting the transmitral flow in aortic regurgitation a putative role may be played by the mechanical hit of the aortic regurgitant jet impinging on the anterior mitral leaflet, as is very often seen with Doppler Color Flow examination. This study was designed to evaluate the effects of pure aortic regurgitation on the transmitral flow in patients with normal mitral valves. We studied 35 patients affected by pure chronic aortic regurgitation but with a normal mitral valve and compared them with 30 normal subjects. In all the patients the aortic regurgitant jet was directed toward the anterior mitral leaflet. In all the patients and control subjects a standard echo-Doppler examination was performed, sampling the transmitral flow at the level of the tip of the mitral leaflets. In 7 patients and 11 normal subjects the transmitral flow was also sampled at the level of the mitral annulus. Patients with aortic regurgitation showed significantly higher values of the mitral pressure half-time (61.04 +/- 15.14 vs 50.59 +/- 7.07 ms, P < 0.05) and of the time-velocity integral of the total transmitral flow, while the other parameters of transmitral flow, the mitral annulus diameter and the mitral stroke volume didn't show statistically significant differences. The comparison of the pressure half-time and time-velocity flow values measured at the level of the mitral annulus between patients and normal subjects didn't show significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative evaluation of three dosages of slow-release isosorbide dinitrate (60, 80, 100 mg) in chronic angina of the aged.

In a single-blind, placebo-controlled study the acute and chronic antianginal effects of three slow-release (SR) new formulations of isosorbide dinitrate (ISDN 60, 80, 100 mg) have been comparatively evaluated in a group of aged affected by chronic stable effort-induced angina. Compared to placebo, overall the active dose paritetically improved the effort tolerance up to 24 h after the first assumption. In the time course of the trial (2 and 4 weeks) the resting hemodynamic changes induced by the first dose were partially blunted without affecting the exercise related-parameters. Also if plasma levels of ISDN and of its metabolites did not correlate to the degree of physical improvement, the peak increase in effort tolerance was observed under 100 mg treatment. Mild to moderate transient headache was experienced by 50% of actively treated and by 20% of placebo treated patients and no other serious adverse effects have been noted. One may conclude that ISDN in slow-release formulations of 60-100 mg isan effective, safe and well tolerated medication in the management of angina in the aged.

[Pharmacokinetics of defibrotide in uremic patients undergoing hemodialysis]. / Farmacocinetica di defibrotide in pazienti uremici sottoposti ad emodialisi.

Defibrotide pharmacokinetics were studied in 6 voluntary healthy subjects and in 10 uremic patients undergoing dialysis during which (instead of heparin) defibrotide was administered to prevent fibrino-formation in the circuit. Blood concentrations of the drug were assessed (expressed with reference to the residual glycidic deoxyribose) during a standard dialysis using defibrotide, 3.5, 15, 30, 45, 60 and 90 minutes after the defibrotide bolus (200 mg) had been injected into the arterial channel. The half-lives of the alpha and beta plasmatic phases were found to be equal at 3.79 and 41.4 min in dialysed subjects and at 1.13 and 16.54 in healthy volunteers. These results indicate that in uremic patients undergoing dialysis at intervals using defibrotide, a longer time is required to eliminate the drug from the circulation. This variation does not however appear to be significant in terms of the therapeutic use of the drug during dialysis.

[Effects of low-dose diltiazem on isovolumetric relaxation and contraction]. / Effetti del diltiazem, a basse dosi, su rilasciamento e contrazione isovolumetrica.

Calcium entry blockers are commonly believed to have a direct negative inotropic effect, but systolic function of the left ventricle (LV) can be improved when the peripheral vasodilator activity of the drug is present. The aim of our study was to evaluate the effect of diltiazem (D) on isovolumic contraction (IC) and relaxation (IR) at a dosage which is not effective on the peripheral vascular bed. We infused 10 micrograms/Kg/min i.v. of D for a 30 min period in to 12 pigs, anesthetized with ethyl urethane (1250 mg/Kg) and under artificial ventilation. The following variables were evaluated: left ventricular systolic (LVSP) and end-diastolic (LVEDP) pressure, peak - and + dP/dt, mean arterial pressure (MAP), heart rate (HR) and double product. The recordings were obtained in the control condition and 5, 10, 15, 20, 25 and 30 minutes after beginning the infusion. The statistical analysis was performed using the one-way ANOVA test. Our results show: 1) a maximal increase in the peak + dP/dt from 2228 +/- 501 to 2448 +/- 576 mmHg/sec (p less than or equal to 0.01) and of the peak . dP/dt from 1262 +/- 260 to 1348 +/- 272 mmHg/sec (p less than or equal to 0.05); 2) and increase in LVSP from 86 +/- 13 to 90 +/- 10 mmHg (p less than or equal to 0.01) and 3) no changes in HR, PAM, LVEDP and double product. As the indices representing afterload and preload (PAM and LVEDP) remained unchanged during the infusion, we suggest that the increase in dP/dt + and - are due to a direct effect of diltiazem on myocardial function.(ABSTRACT TRUNCATED AT 250 WORDS)

[A comparison between mitral and aortic outputs evaluated by Doppler echocardiography in a group of healthy subjects: false regurgitation]. / Confronto tra portata mitralica ed aortica valutate con eco-Doppler in un gruppo di soggetti sani: il falso rigurgito.

Doppler echocardiography is a potentially useful tool for the non invasive evaluation of cardiac output and, therefore, for the quantitative assessment of valvular regurgitation. The aim of our study was to establish the presence of possible pitfalls in the evaluation of mitral and aortic regurgitant fraction obtained by Doppler echocardiography comparing the cardiac output measured at the level of the mitral and aortic valve. For this purpose 19 healthy volunteers, aged between 14-68 years, were studied. Stroke volume and cardiac output were calculated at the level of the mitral and aortic valve. The methods we used for the measurement of both the mitral and aortic cardiac output had already been validated and presumes that the shape of the valve annulus, is circular. No statistically significant differences were found between the parameters obtained at the two different valvular levels. Furthermore, cardiac output values correlated fairly well (r = 0.83, ESS = 0.78 l/min). In 9 subjects the aortic cardiac output was greater than the mitral one, while in the others mitral cardiac output was greater. The average of the differences between the two cardiac outputs was 0.58 +/- 0.48 l/min with a regurgitation fraction of 9.5 +/- 7.9%. Our results show that the mitral and aortic stroke volume and cardiac output, as measured by Doppler echocardiography (considering a circular shaped valve annulus, are not statistically different and correlate fairly well in our normal subjects. Nevertheless, we observed a certain degree of variability between the mitral and the aortic cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

[First seconds after acute experimental ischemic: changes in isovolumic contraction and relaxation]. / Primi secondi dopo ischemia acuta sperimentale: modificazioni della contrazione e rilasciamento isovolumetrici.

The purpose of this study was to answer the following questions: 1) are isovolumic contraction and relaxation affected in a different way by LAD occlusion? 2) Does proximal and distal LAD coronary occlusion induce different changes in isovolumic contraction and relaxation? In 22 pigs, LAD coronary artery was dissected free right after the first or third diagonal branch and occluded by ligation. The following variables were evaluated: left ventricular systolic and end-diastolic pressure; peak - and + dP/dt, mean arterial and pulmonary pressure. All our data were obtained in the first minute following the occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of food on the absorption of flurithromycin in man.

Oral absorption of flurithromycin, a new fluorinated macrolide, has been evaluated on eight healthy volunteers on fasting and after a standard meal. Serum levels from 0 to 8 hours, peak serum concentrations, times to peak and areas under the curves were compared using a balanced sequence cross-over design. The highest mean concentration was reached after 3 h from administration on fasting (1.36 +/- 0.31 mcg/ml) and after 1 h following a meal (1.36 +/- 0.30 mcg/ml). All the pharmacokinetic parameters considered showed no statistical change. Therefore a meal does not reduce or delay the absorption of flurithromycin, while in the presence of food other macrolides may behave differently. Moreover the tolerability to the drug was good, lacking any report of side-effects, either on fasting or after the food.

Gas chromatographic evaluation of trapidil and its desethyl metabolite in biological fluids for pharmacokinetic and bioavailability investigations.

This paper describes a suitable and cost-saving method for quantitative analysis of trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-a]pyrimidine) and its desethyl metabolite in plasma and urine for pharmacokinetic and bioavailability investigations. Trapidil and desethyl-trapidil were extracted from plasma, concentrated and injected into the gas chromatography without any derivatization process. The authors suggest a series of internal standards. A thermoionic specific detector enables high sensitivity to be achieved, i.e. 20 ng/ml, and good specificity. The method is cost-saving in that it allows about 30 analyses a day to be performed without automatic integrators, and about 50 analyses a day with these integrators.

[Functional evaluation of the autonomic regulation in mitral valve prolapse]. / Valutazione funzionale della regolazione neurovegetativa nel prolasso valvolare mitralico.

We examined fifty patients aged from 15 to 35 years, mean 23 +/- 5, with mitral valve prolapse (MVP) documented by two-dimensional echocardiography in the apical 4-chamber view as well as in the parasternal-long axis. The patients have been submitted to 4 tests: Valsalva maneuver, standing and exercise test and 24 hours ambulatory ECG monitoring. Fourty-five healthy subjects of similar age and sex served as controls. During the standing test the patients with MVP showed a significantly faster heart rate than the control subjects both in resting and in the standing position; during the exercise test they exhibited higher prevalence of ST segment and T wave abnormalities disappearing at the peak of the exercise. These observations support the hypothesis of a hyperadrenergic state. The greater bradycardia showed during the Valsalva maneuver, the lower heart rate and the higher incidence of bradyarrhythmias and A-V blocks during the sleeping period suggest an increased vagal tone. Our results suggest therefore that in subjects with MVP a dysfunction of both, sympathetic and parasympathetic nervous system is present.

Multicenter study on the clinical efficacy of chronic ibopamine administration.

The purpose of this multicenter study was to evaluate the therapeutic efficacy of ibopamine (SB-7505), the 3,4-diisobutyrylester of N-methyldopamine, chronically administered to patients with severe congestive heart failure (CHF) in whom traditional therapy had been ineffective. 55 patients chronically treated with cardiac glycosides and diuretics were assigned to an investigation covering three stages each lasting 7 days. Stage A: continuation of traditional therapy (glycosides and diuretics). Stage B: addition of ibopamine to the glycoside/diuretic therapy. Stage C: withdrawal of ibopamine. Heart rate, blood pressure, body weight, diuresis and 8 target symptoms of CHF (clinical scores) and hematochemical parameters were recorded throughout the three stages. The addition of ibopamine to traditional therapy led to a significant improvement. By contrast, after ibopamine had been withdrawn patients worsened. No hematochemical parameters were modified during the trial. None of the patients experienced any significant side-effects.

Monitored long-term treatment with ibopamine in patients suffering from severe congestive heart failure.

50 patients with congestive heart failure underwent monitored long-term treatment aimed at evaluating the effect of ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine, on their condition. Ibopamine was administered alone or in combination with traditional therapy mainly at a dose of 100 mg t.i.d. Clinical scores and NYHA (New York Heart Association) functional classes improved. Biochemical parameters showed no adverse modifications. Mild transient side-effects probably related to ibopamine occurred in two patients.

Single-dose pharmacokinetics of fenquizone in healthy volunteers.

A pharmacokinetic study of fenquizone (Idrolone), a thiazide-like diuretic, was conducted with single oral doses in 6 healthy volunteers. The substance thus administered was readily absorbed from the gut, with peak plasma levels being detected on average at 3 h after dosing; after that, plasma concentrations of fenquizone decreased biexponentially in a pattern fitting an open two-compartment model. Plasma half-life values were 1 h for phase alpha and 17 h for phase beta. The half-life calculated from urinary concentrations was 18 h. The apparent distribution volume for phase beta was 686 l; renal clearance was 220 ml/min, and the absorption constant (Ka) was 1055 h-1. Cumulative urinary excretion accounted for 53.1% of the administered dose in 72 h. Thus the pharmacokinetic profile of fenquizone was that of an "intermediate-acting" diuretic about half-way between the short-acting hydrochlorothiazide, chlorothiazide and furosemide and the long-acting chlorthalidone. In summation, fenquizone is described as a low-dosage diuretic apparently not conducive to accumulation; its pharmacokinetic profile qualifies the product particularly well for maintenance therapy, such as is needed for the management of essential hypertension, both as sole medication and in fixed-ratio combination with beta-blockers, and at any rate with once-a-day administration.

[Study of the regional contraction of the left ventricle in normal subjects using a two-dimensional echocardiographic technic]. / Studio della contrazione regionale del ventricolo sinistro nel soggetto normale con tecnica ecocardiografica bidimensionale.

The purpose of this study is to evaluate normal left ventricular regional wall motion pattern in order to answer the two following questions: does wall motion change at different levels of the left ventricle from the base to the apex? does wall motion change among different segments at the same level? Seventy-two normal subjects were submitted to a cross sectional echocardiographic examination and the tape recordings were analyzed by a computerized system. Parasternal short axis views at mitral valve and papillary muscles level were chosen and divided by the computer in 16 areas which were fitted to a more anatomical division, i.e. interventricular septum, anterior, lateral, posterior-lateral, inferior-posterior and inferior walls. From each segment, fractional area changes were obtained. Statistical analyses were carried out by the two way analysis of variance and two paired t test. Wall motion pattern of the normal left ventricle is not uniform either at different levels or among segments at the same level: we conclude that regional wall motion differences of the left ventricle are not necessarily due to abnormal conditions, but might be a normal left ventricular pattern.