A new imidazole derivative, DP-1904, produces a selective, potent and long-acting inhibition of thromboxane A2 (TXA2) syntheses and platelet aggregation. This study was designed to investigate the pharmacokinetics and pharmacodynamics (PK/PD) of DP-1904. DP-1904 disappeared from plasma with a half-life of 20 min after i.v. dosing, and the bioavailability after oral dosing was approximately 70%. The level of serum TXB2, which is a pharmacological marker for thromboxane synthetase inhibition, was measured to characterize the pharmacodynamics of DP-1904. A marked reduction of serum TXB2 was exhibited within 1 h after both i.v. and oral doses, reflecting the rapid onset of action of DP-1904. Serum TXB2 returned to the basal level much more slowly after oral dosing than after i.v. dosing, due to the longer half-life after oral dosing. An Emax model was employed to fit the pharmacological data after oral dosing, and IC50 and Emax values were estimated to be 5.0 ng/ml and 81%, respectively. In order to test its predictability, the PK/PD model was then used to predict a pharmacological profile after i.v. dosing; good agreement between the observed and predicted values was achieved. Thus, the present modelling procedure may be useful for optimizing the therapeutic regimens of DP-1904.

Administration, Oral↗

PubMedDate not supplied

The WDHA syndrome: clinical and laboratory data on 28 Japanese cases.

During the period between 1967 and 1983, there were 28 WDHA patients in Japan. Clinically, these patients were not very different from those reported in western countries, but we have been able to add a few observations as follows. First, the WDHA patients with pancreatic endocrine tumors and those with neuroblastic tumors were present in almost equal numbers. Second, fluctuating hypercalcemia was often observed in patients with this syndrome, but it was not observed in any watery diarrhea due to the other etiologies. Third, the WDHA patients who have multiple endocrine neoplasia (MEN) type 1 have multiple tumors in the pancreas, indicating that the patients with MEN should be managed in a different manner in regard to determining tumor location as well as applying surgical treatment. When various types of tumors were examined for VIP content, it was found that many tumors have the potential to produce VIP, and when VIP is produced in large amounts, plasma VIP levels become elevated, resulting in the WDHA syndrome.

Achlorhydria↗

PubMedDate not supplied

Heterogeneity of myocardial wall motion and thickening in the left ventricle evaluated with quantitative gated SPECT.

BACKGROUND: Global and regional ventricular function may be evaluated by using gated myocardial perfusion single photon emission computed tomography (SPECT). This study investigated two parameters of regional contraction of the left ventricle, segmental wall motion (WM) and wall thickening (WT), to determine their similarity and disparity in each myocardial segment in patients with normal myocardial perfusion. METHODS AND RESULTS: Thirty-five patients with normal myocardial perfusion and cardiac function (mean left ventricular ejection fraction, 62.6%+/-8.8%) were included in this study. A 1-day stress/rest protocol was used as a means of acquiring technetium 99m (Tc-99m) sestamibi gated SPECT protocol for each patient. A commercially available software package for quantitative gated SPECT (QGS) was used to generate cine loop three-dimensional surface display and SPECT images. The left ventricle was divided into 9 segments to score WM and WT (on a scale of 0 to 4, with 0 being normal and 4 being severely reduced) by 6 independent observers. The WM score was significantly higher than the WT score in the septum, whereas the WM score was lower than the WT score in the inferior segment. Similar WM and WT scores were observed in the remaining segments. CONCLUSIONS: Heterogeneous myocardial WM and WT were observed by using QGS software. These findings suggest that different criteria are required in each segment to evaluate segmental WM and WT by means of gated myocardial perfusion SPECT.

Adenosine Triphosphate↗

PubMedDate not supplied

Topographical relation between serotonin-containing paraneurons and peptidergic neurons in the intestine and urethra.

Luminal stimulation of enterochromaffin (EC) cells is known to cause their release of serotonin which in turn may induce a variety of reflexes via mucosal intrinsic neurons. To morphologically support this idea, the present study demonstrates a close topographical relationship between EC cells and nerves, using whole-mount preparations. Beaded nerve fibers containing vasoactive intestinal polypeptide (VIP) were observed in close proximity to serotonin-immunoreactive EC cells in the small and large intestines of the rat and guinea pig; in whole-mount preparations, the VIP nerve fibers appeared to underlie EC cells. This finding correlates with the physiological datum that the intra-arterial infusion of serotonin causes VIP release from the intestine. Canine urethral serotonin cells, a counterpart of the intestinal EC cells, were shown to contact intraepithelial nerves immunoreactive for calcitonin gene-related peptide. The neuroparaneuronal connection in the urethra may play an important role in the serotonin-evoked urethrogenital reflex. Intestinal and urethral serotonin-containing paraneurons, which are sensory in nature, may release serotonin in response to luminal stimuli, and directly activate adjacent peptidergic neurons to initiate the reflex arcs.

Animals↗

PubMedDate not supplied

Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia.

The clinical usefulness of incadronate was compared with elcatonin in 26 patients with malignancy-associated hypercalcaemia. Data from 21 and 24 patients could be used to assess efficacy and safety, respectively. Eleven patients were given a single 10-mg intravenous infusion of incadronate and 10 received twice-daily intramuscular injections of 40 IU of elcatonin for 7 consecutive days. After treatment, corrected serum calcium levels decreased significantly in both groups. The anti-hypercalcaemic effect of elcatonin was characterized by its rapid onset, with serum calcium levels reduced 1 day after administration. In contrast, the anti-hypercalcaemic effect of incadronate was more sustained but only became apparent a few days after infusion. Evaluation of symptoms revealed significantly greater improvement rates in the incadronate group compared with the elcatonin group. Adverse drug reactions were observed in three patients in the incadronate group, i.e. mild and transient fever in two cases and exacerbation of disturbance of consciousness in one case. These findings suggest that incadronate produces more marked and sustained hypocalcaemic effects than elcatonin, and that co-administration of these two drugs may yield both rapid and sustained control of malignancy-associated hypercalcaemia.

Adolescent↗

PubMedDate not supplied

Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma.

Serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-2 and IL-6 were determined by enzyme-linked immunosorbent assay or chemiluminescent enzyme immunoassay in 46 Japanese patients with metastatic breast cancer. No IL-2 activity was detectable, only two patients had a detectable TNF-alpha level, and 4 had detectable IL-1 beta concentrations. No correlations were found between TNF-alpha and IL-1 beta levels and clinicopathological parameters. Twenty-two patients (48%) showed higher serum IL-6 levels than the cut-off value of 4 pg/ml. Significantly higher IL-6 levels were detected in patients with more than one metastatic site and with dominant metastatic visceral disease than in those with one metastatic site (median, 6.9 vs 1.1 pg/ml, P < 0.0001) or with dominant metastatic bone or soft tissue disease (median, 7.1 vs 2.4, P < 0.05). The patients with liver metastasis and pleural effusion showed significantly higher serum IL-6 levels than those without liver metastases (median, 17.2 vs 2 pg/ml, P = 0.0006) or pleural effusion (median, 12.1 vs 2.1 pg/ml, P = 0.02). A strong correlation was observed between IL-6 levels and C-reactive protein levels (r = 0.47, P = 0.0006). Patients unresponsive to chemo-endocrine therapy showed significantly higher serum IL-6 levels than those who responded to chemo-endocrine therapy (P = 0.0007). Moreover, the patients with high IL-6 levels showed significantly poorer survival than patients with low IL-6 levels. Multivariate analysis revealed that IL-6, as well as disease-free interval, is an independent prognostic factor of metastatic breast cancer. These results suggest that IL-6 levels are elevated and may be an aggressive parameter in patients with metastatic breast cancer. Higher IL-6 serum levels are found to predict a poorer response to chemo-endocrine therapy, and to represent a poorer prognostic predictor in metastatic breast cancer.

Adult↗