Analysis of labeling decisions regarding therapeutic indications during new drug application reviews in Japan.

We analyzed regulatory reviews in Japan to study the modifications made in drug labeling with respect to proposed therapeutic indications, and investigated factors associated with these changes so as to gain insight into the reasons behind the decisions. Of 220 new molecular entities (NMEs) approved in Japan from 2000 to 2009, 70 received more restricted indications and 14 received more expanded indications than those proposed by the applicants. Multinomial regression analysis suggested that the presence of competitive drugs in the market, higher estimated peak sales, and higher complexity of the proposed indication were factors that significantly increased the likelihood of the indications being restricted on review, in addition to factors related to adequacy of efficacy data. Our results give us a clue to how the approved therapeutic indications reflect the characteristics of the applicants, drugs, review areas (RAs), and clinical evidence in the submitted data package, as well as to the principle behind the decisions.

[Assessment of the practicability of coronary risk index as a screening method for ischemic heart disease in preoperative evaluation].

Coronary risk index (CRI) is our newly developed screening method for ischemic heart disease in preoperative evaluation. In this study, we assessed the practicability of CRI examining coronary angiograms (CAG) obtained in 106 patients scheduled for operations. CAG was rated with CAG score, then CRI and CAG score were statistically analyzed. These two parameters showed a significant positive relationship; the higher CRI, the higher CAG score (P < 0.0001). When the patients were divided into five groups by their CRI (0-9, 10-14, 15-19, 20-24, and more than 25), the group with higher CRI contained significantly more patients with severe multivessel coronary lesion (P < 0.0001). Similar results were obtained even in the patient with minimal change in ECG or exercise ECG, or those with minimal chest symptoms (P < 0.001). These results suggests that CRI works effectively as a screening method for ischemic heart disease regardless of abnormalities in ECG or the chest symptoms. More cautious perioperative management should be carried out in patients with higher CRI.

Hemodynamic assessment of radial-arterial pressure-wave contours in children.

A new classification system for the radial-arterial pressure-wave contour in children is proposed with respect to their hemodynamic parameters. The contour of the radial-arterial pressure wave was analyzed in 45 children who had undergone open heart surgery. Stroke volume and peripheral vascular resistance were calculated from the cardiac output by thermodilution. The arterial pressure-wave contours were classified into type I, II or III, with each wave type having three, two and one shoulders, respectively. Type I denoted a better cardiac index, with a lower heart rate and larger stroke volume than type II. Type III was symptomatic of low cardiac output. Type I was further classified into subgroups Ia and Ib according to the magnitude of the tidal wave, and type II was subdivided into IIa and IIb according to the magnitude of the dicrotic notch. The classification of subgroup types a and b in both types I and II was related to the degree of vascular contraction. It is concluded that monitoring of the arterial pressure-wave contours provides useful information regarding hemodynamics in children.

Assessment of left ventricular function after sublingual administration of nifedipine in patients with moderate to severe hypertension.

To evaluate the left ventricular functional changes induced by acute decreases in blood pressure in 15 patients with systemic hypertension and left ventricular hypertrophy, this study used Doppler and M-mode echocardiographic derived left ventricular indices. After 30 minutes of administration of sublingual nifedipine, both systolic and diastolic blood pressure decreased and heart rates increased. The left ventricular end-systolic dimension decreased but not the end-diastolic dimension, which suggests that sublingual nifedipine may decrease only afterload, not preload. Total peripheral resistance decreased from 2770 to 1960 dyne.sec.cm-5. The M-mode-derived peak rate of dimension changes improved both the systolic and diastolic phase, and Doppler-derived indices of atrial contribution to ventricular filling decreased. Because both the systolic and diastolic phase indices of LV function are sensitive to variations in both preload and afterload, the improvement of myocardial contractility per se cannot necessarily be attributed to the direct effect of the drug to myocardium. Though favorable effects on the myocardial oxygen supply-demand ratio or increased adrenergic tone stimulated by the decline in systemic arterial pressures may contribute to the augmentation of LV systolic and diastolic function observed after nifedipine in the present study, the apparent augmentation of LV function appears to be attributable primarily to afterload reduction.

[Assessment of alveolar bone changes with gamma-ray absorptiometry--on the analysis of detectability of a measuring system].

It is important to determine the changes in alveolar bone during periodontal treatments. At present, radiography is widely used to determine the changes. But small changes in alveolar bone cannot be detected on X-ray films. To detect these small changes, a direct observation system using gamma-ray from 133Ba was considered. Using a multi-channel analyzer, gamma-ray absorption through the bone was detected in this method. This method was compared with densitometric measurement on the films using sliced animal bone. The newly developed method detected the bone changes more accurately. To evaluate the influence of soft tissue, Mix-D was used in both measurements. 133Ba absorptiometry showed that soft tissue did not influence the measurement more than the densitometric method.

Modified Blalock-Taussig shunt operation without cardiac catheterization: two-dimensional echocardiographic preoperative assessment in cyanotic infants.

Between May 1981 and December 1983, 25 infants with cyanotic congenital heart defects underwent 26 Blalock-Taussig shunt operations without cardiac catheterization and angiocardiography. In these infants, the diagnosis was established by 2-dimensional echocardiography (2-D echo) supplemented with clinical findings, chest x-ray and electrocardiography. The right and left pulmonary artery measurements, a prerequisite for a shunt operation, determined by 2-D echo were compared with those at surgery and had an excellent correlation (r = 0.94). No infant died as a consequence of an early shunt failure, and only 1 died of postoperative pyothorax. In conclusion, 2-D echo may eliminate the need for invasive investigation in selected patients undergoing the Blalock-Taussig anastomosis.