Unique binding pocket for KW-4679 in the histamine H1 receptor.

The histamine H1 receptor has an aspartate (Asp) residue in transmembrane helix 3 (TM3), which is well-conserved among biogenic amine receptors. The Asp residue is one of the most crucial amino acids for ligand binding. The tested histamine H1 receptor antagonists with tri- and tetracyclic structures were not selective for histamine H1 receptors and showed affinity for several other biogenic amine receptors. In contrast, KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b, e]oxepin-2-acetic acid hydrochloride), a tricyclic compound, was a selective histamine H1 receptor antagonist. [3H]KW-4679 had high affinity (Kd value of 2.5 +/- 0.12 nM) for wild-type human histamine H1 receptors. In the [3H]KW-4679 binding assay, replacement of Asp107 by alanine by site-directed mutagenesis greatly reduced the affinities (280-2100-fold) of tri- and tetracyclic compounds, whereas this mutation led to a comparatively small reduction (14-fold) in KW-4679 affinity. These results demonstrate that the tested tri- and tetracyclic histamine H1 receptor antagonists which have a tight interaction with the Asp residue are not selective for the histamine H1 receptor. Furthermore, the high selectivity of KW-4679 might be explained by a unique binding pocket, which consists of the Asp residue and other acceptor sites, in the histamine H1 receptor.

Severe hypertension and cardiac failure associated with neuroblastoma: a case report.

The authors report on 3-year-old-girl with neuroblastoma complicated by severe hypertension and cardiac failure. She had cardiomegaly and pleural and pericardial effusions. Echocardiogram showed left ventricular hypertrophy and decrease of the left ventricular ejection fraction to 0.36 (normal > .40). Abdominal computed tomographic scan indicated a 7 x 7-cm tumor in the left suprarenal area. There was a marked increase in catecholamines and metabolites in her body fluids. After hypertension was controlled with doxazosin (a long-acting alpha 1 adrenergic blocker), her cardiac function gradually improved. A tumor was surgically removed and diagnosed as a poorly differentiated ganglioneuroblastoma. Preoperative differentiation between neuroblastoma and pheochromocytoma was not possible on the basis of catecholamine analysis or imaging studies including computed tomography scan and magnetic resonance imaging. It is important to control hypertension quickly in the patients with catecholamine-induced cardiomyopathy to facilitate surgical intervention for diagnosis and treatment.

[Experimental study on the effect of injection with anticancer agent-oil suspension].

Local injection of an anticancer agent guided by endoscopy is thought to be effective for cancerous lesion associated with lymph node metastasis, if the anticancer drugs are drained into the lymph nodes. In the experimental study, anticancer drug-oil (nimustine-Lipiodol) (N-L) suspension (5 mg/ml) was injected into the tumor (Lewis lung cancer) that had been implanted sub dorsally in mice (57 black/6 mice) for the purpose of finding out the antitumor effect on the primary lesion. Then it was injected into sarcoma-180 that had been implanted into hind feet of mice (ICR mice) for the purpose of finding out the antitumor effect on metastatic lymph nodes. The results showed that the N-L suspension was effective for the primary cancerous lesion and metastatic lesions.

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

Estimation of right ventricular pressure in children by thallium-201 myocardial imaging using single-photon emission computed tomography.

Thallium-201 myocardial imaging using single-photon emission computed tomography was performed to estimate right ventricular (RV) systolic pressure in 34 children (aged 4.1 to 16.1 years, mean 7.9 +/- 2.9). Acquisition of the images was performed using a semicircular arc of 180 degrees. On a short-axis slice, a line drawn perpendicular to the ventricular septum so as to cross the RV free wall showing maximum uptake was defined as the region of interest. Thallium-201 counts in regions of interest over both RV and left ventricular (LV) free walls were measured. The ratio of RV-to-LV peak thallium-201 counts was compared with RV peak systolic pressure and the ratio of RV-to-LV peak systolic pressure measured at cardiac catheterization. Both RV peak systolic pressure and the ratio of RV-to-LV peak systolic pressure correlated well with the ratio of RV-to-LV peak thallium-201 counts (r = 0.95 and 0.96, respectively). The ratio of RV-to-LV peak thallium-201 counts greater than or equal to 0.45 could predict RV pressure overloading with a sensitivity of 92%, and a specificity of 88%. Thus, the quantitative analysis of thallium-201 myocardial imaging using single-photon emission computed tomography permits the noninvasive and accurate estimation of RV systolic pressure in children.

Prognostic significance of the size of coronary artery aneurysms in Kawasaki disease.

The prognosis of coronary artery aneurysms complicating Kawasaki disease was assessed by serial coronary angiography in 33 patients. They underwent initial angiography with four months, and one or two follow-up angiographies between 11 months to 6.3 years after the onset of the illness. These patients had 69 coronary aneurysms at the initial study. The maximal diameter of the aneurysms was expressed as a percent of the normal value. Of 44 aneurysms with a diameter less than 300% of normal, 43 were found to have regressed on follow-up. Of 13 aneurysms with a diameter 300 to 400% of normal, four were proved to have regressed, eight persisted and one stenosed. Of 12 aneurysms with a diameter 400% of normal or more, one was found to have regressed, four persisted, two stenosed and five obstructed. Thus, the prognosis of aneurysms less than 300% of normal in diameter is excellent, whereas that of aneurysms 400% of normal or more in diameter is serious.

Prediction of peak pulmonary artery pressure by continuous-wave Doppler echocardiography in infants and children.

Continuous-wave Doppler echocardiography was used to estimate peak pulmonary artery (PA) pressure in 104 infants and children, aged 4 days to 16 years, with normal hearts (control group) and 43, aged 29 days to 13 years, with various kinds of heart disease (patient group). The Doppler transducer was directed toward the right ventricular outflow tract and angled until the maximal velocity signal was reached. Doppler velocity time intervals were measured as follows: acceleration time (AT), from the onset to the peak of the velocity curve; and ejection time (ET), from the onset to the termination of the velocity curve. In the control group, AT corrected through dividing by the RR interval of the electrocardiogram (ATc), and AT/ET by dividing by the square root of the RR interval (AT/ETc), were independent of body surface area. In the patient group, peak PA pressure had a significant inverse correlation with both ATc (r = -0.78) and AT/ETc (r = -0.87). Thus, AT/ETc derived from continuous-wave Doppler echocardiography is a good quantitative predictor of peak PA pressure in infants and children.

Angiocardiographic estimation of left ventricular mass in normal infants and children.

Left ventricular mass data were obtained from biplane cineangiocardiograms in 37 normal infants and children. Left ventricular mass calculated by using thickness of anterior wall (left ventricular mass-anterior) and posterior wall (left ventricular mass-posterior) of the free left ventricular wall were studied in relation to body surface area and left ventricular end-diastolic volume. Both of left ventricular mass-anterior and mass-posterior were expressed as a function of body surface area with exponential relationship; left ventricular mass-anterior = 68.5 (body surface area) g (r = 0.98, p less than 0.01), left ventricular mass-posterior = 84.6 (body surface area) g (r = 0.97, p less than 0.01). Left ventricular mass-anterior/left ventricular end-diastolic volume averaged 0.73 +/- 0.01 g/ml, and left ventricular mass-posterior/left ventricular end-diastolic volume 0.89 +/- 0.02 g/ml, respectively. Thus, left ventricular mass can be predicted from body surface area by using the exponential equations. In addition, normal values for left ventricular mass-posterior must be discriminated from those for left ventricular mass-anterior.

Echocardiographic measurements of left ventricle in normal infants and children.

Echocardiographic studies were performed on 110 normal infants and children ranging in age from 2 days to 15 years. The following parameters of the left ventricle were measured: left ventricular end-diastolic and end-systolic diameters (LVEDd and LVESd), shortening fraction (LVSF), end-diastolic volume (LVEDV), ejection fraction (LVEF), posterior wall thickness in end-diastole (LVPWED) and end-systole (LVPWES), mass (LVM), LVEDd/LVPWED, LVESd/LVPWES and mean velocity of circumferential fiber shortening (LV mean Vcf). Each parameter was compared with body surface area (BSA). LVEDd, LVESd, LVEDV, LVPWED, LVPWES and LVM were expressed as a function of body surface area with exponential equations: LVEDd = 41.4 (BSA)0.49 mm, LVESd = 28.1 (BSA)0.49 mm, LVEDV = 74.1 (BSA)1.48 ml, LVPWED = 4.4 (BSA)0.45 mm, LVPWES = 9.2 (BSA)0.44 mm and LVM = 46.4 (BSA)1.48 g. LVSF, LVEDd/LVPWED, LVESd/LVPWES and LV mean Vcf were independent of body surface area: LVSF averaged 32 +/- 1 (mean +/- standard error of the mean)%, LVEF 68 +/- 1%, LVEDd/LVPWED 10.0 +/- 0.2, LVESd/LVPWES 3.1 +/- 0.1 and LV mean Vcf 1.08 +/- 0.02 circ/sec. Thus, normal values of these parameters can be applied to estimate them in pediatric patients with heart diseases.

Assessment of cardiac performance by first pass radionuclide angiocardiography in infants and children with normal heart and endocardial fibroelastosis.

Peak to peak time from the right and to the left ventricle (PPT), left ventricular ejection fraction, left ventricular peak ejection rate and left ventricular peak filling rate were measured by first pass radionuclide angiocardiography in 27 infants and children with normal heart and in 8 patients (18 studies) with endocardial fibroelastosis. In normal subjects, the PPT significantly correlated with heart rate (r = -0.87, p less than 0.001). A PPT corrected by the heart rate (cPPT) was calculated by rotation of the regression equation relating the variables: cPPT = PPT + 0.018 X (heart rate)-2.1. The cPPT averaged 3.0 +/- 0.0 (mean +/- S.E.) sec. Consequently, there was no significant correlation between the cPPT and heart rate, but the cPPT and body surface area are significantly correlated (r = 0.41, p less than 0.05). Left ventricular ejection fraction, peak ejection rate and peak filling rate averaged 68 +/- 2%, 4.2 +/- 0.3/sec and 4.8 +/- 0.3/sec, all of which were independent of the heart rate and body surface area. In patients with endocardial fibroelastosis, the cPPT was prolonged (4.7 +/- 0.4 sec), and left ventricular ejection fraction, peak ejection rate and peak filling rate were all reduced (28 +/- 4%, 1.7 +/- 0.2/sec and 1.8 +/- 0.2/sec). These results indicate that parameters obtained from the radionuclide angiocardiography are useful for evaluating cardiac performance in patients with endocardial fibroelastosis.

Angiocardiographic estimation of left and right ventricular volume characteristics in normal infants and children.

Left (LV) and right ventricular (RV) volume data were obtained from biplane cineangiocardiograms in 31 patients with Kawasaki disease who showed normal coronary arteries in selective coronary arteriograms. LV and RV volumes were calculated by using Simpson's rule method. Both of end-diastolic (EDV) and stroke volume (SV) were excellently expressed as a function of body surface area (BSA) with exponential relationship: LVEDV = 104.3 (BSA)1.61 ml (r = 0.93, p less than 0.001), RVEDV = 109.7 (BSA)1.68 ml (r = 0.90, p less than 0.001), LVSV = 68.1 (BSA)1.60 ml (r = 0.89, p less than 0.001) and RVSV = 66.8 (BSA)1.76 ml (r = 0.86, p less than 0.001). LV ejection fraction (LVEF) averaged 66 +/- 1% (mean +/- S.E.) and RVEF 58 +/- 1%. Both of them showed no significant correlations with BSA. The normal values of EDV and SV in infants and children can be predicted from their BSA by using the exponential equations demonstrated by the present study. Thus, these values in pediatric patients with heart diseases could be evaluated in terms of percentage of normal.