Phase I study of SM-5887, a new anthracycline derivative

SM-5887, a new totally synthetic anthracycline derivative, was studied in a phase I setting. Twenty-nine evaluable courses of treatment were conducted in groups at doses increasing from 10 to 130 mg/m2. At 130 mg/m2 the median lowest WBC count was 0.7 x 10(3)/mm3 (range 0.3-1.8) and the median lowest platelet count was 57 x 10(3)/mm3 (range 4-176). Nonhematological side effects were mild gastrointestinal symptoms and hair loss. The recommended dose and schedule for a phase II setting is 100 mg/m2 every 3 weeks.     

Effects of cisapride on lower esophageal sphincter pressure and gastroduodenal motor activity in man

Manometric study was performed to investigate the effects of cisapride, a new non-antidopaminergic gastrointestinal prokinetic compound, on interdigestive lower esophageal sphincter pressure (LESP) and gastroduodenal motility using infused catheter technique. The subjects consisted of 9 healthy volunteers and 29 patients with progressive systemic sclerosis (19), reflux esophagitis (8) and others (2). 4 mg of cisapride was given by bolus injection, continuous infusion or oral administration. The following results were obtained: Intravenous and oral cisapride increased LESP compared with basal pressure. Especially, bolus injection of cisapride caused a significant elevation of LESP during 30 minutes after administration. After administration of cisapride, gastroduodenal motility was accelerated gradually, then inducing IMC-like contractions. By bolus injection, IMC-like contractions were induced in healthy subjects more frequently than in patients group. On the other hand, motility index of stomach and duodenum showed persistent increase in patients group compared with healthy subjects. Cisapride-induced IMC-like contractions initiated from LES and upper part of stomach and mediated to duodenum, though aborad migration was not confirmed in the present study.     

Fractal Dimension Analysis of the Oscillated Blood Flow with a Vibrating Flow Pump

Abstract: To analyze the hemodynamic parameters during circulation with oscillated blood flow, nonlinear mathematical analyzing techniques, including fractal theory, were utilized. Vibrating flow pumps (VFP) were implanted as a left heart bypass, and the ascending aorta was clamped to constitute the total left heart circulation with oscillated blood flow in acute animal experiments using 7 adult goats. Using nonlinear mathematical analyzing techniques, reconstructed attractors of the arterial blood pressure waveform in the phase space during natural circulation and oscillated circulation were analyzed.
Using the Grassberger-Procaccia correlation dimension analyzing technique, fractal dimension analysis of the reconstructed attractor was performed. During VFP bypass, lower fractal dimensions of the reconstructed attractor were shown compared with those during natural heart circulation. The results suggest that lower dimensional chaotic dynamics contributed to the circulation with oscillated blood flow.     

Frequent expression of mucin core protein MUC1 in non-neoplastic gallbladder mucosa from patients with pancreaticobiliary maljunction

Abstract: Background: Gallbladder carcinoma is known to develop frequently in patients with pancreaticobiliary maljunction, though the causal relationship remains speculative. Methods: Histopathologic changes, expression of mucin core protein MUC1 and MUC2, and cell proliferative activities in the gallbladder mucosa from 27 patients with panceaticobiliary maljunction and 21 control gallbladders were examined. Three cases of pancreaticobiliary maljunction were associated with gallbladder carcinoma. Results: The lining epithelia of the non-neoplastic gallbladder mucosa of pancreaticobiliary maljunction showed frequently papillary hyperplasia and higher proliferative activities, when compared to the control. In 3 cases with carcinoma, MUC1 was expressed on the luminal border and in the cytoplasm of carcinoma cells, particularly in de-differentiated and invasive areas. MUC1 was variably expressed on the luminal surface of the lining epithelia of non-neoplastic gallbladder mucosa in babies, children, youths and adults with pancreaticobiliary maljunction. However, such expression was focally seen in 2 of the 21 control cases (p<0.01). MUC2 was scattered in the hyperplastic and carcinomatous epithelial cells appearing as goblet cells in pancreaticobiliary maljunction and control groups. Conclusions: This study suggests that persistent MUC1 expression and increased cell proliferative activities of non-neoplastic gallbladder epithelium of the patients with pancreaticobiliary maljunction after birth reflect an altered phenotype of epithelial cells and these abnormalities may be related to carcinogenesis in such patients.     

First-pass metabolism of acetaminophen in thyroxine treated rats

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.     

Stimulation by gastrin-releasing peptide, neurotensin and DN1417, a novel TRH analog, of dopamine and norepinephrine release from perifused rat hypothalamic fragments in vitro

Both dopamine (DA) and norepinephrine (NE) release from perifused rat hypothalamic fragments was increased by depolarizing concentrations of potassium (K+, 20 mM and 56 mM) in a dose-related and Ca2+-dependent manner. DA and NE release induced by high K+ (20 mM) was further enhanced by gastrin-releasing peptide (GRP, 10(-5)-10(-6) M) and DN 1417 (10(-5) M), a thyrotropin-releasing hormone (TRH) analog. GRP (10(-5) M), neurotensin (NT, 10(-5) M) and DN 1417 (10(-5) M) also stimulated spontaneous release of DA and NE from the hypothalamus. These results suggest that GRP, NT and DN 1417 act at the hypothalamic catecholamine nerve terminals and stimulate the release of DA and NE in the rat.     

Identification of thalamic neurons with vasoactive intestinal polypeptide-like immunoreactivity in the rat

Cell bodies with vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) were found in the thalamus of the rat. They were distributed throughout the ventrolateral nucleus (VL) and in the whole extent of the thalamic reticular nucleus (R) except for its most rostral part. On the basis of soma diameters, VIP-LI cells in the VL and R were assumed to be projection neurons.     

Phorbol ester binding sites in human brain: Characterization,regional distribution,age-correlation,and alterations in Parkinson’s disease

We have characterized and localized phorbol ester binding sites in human autopsied brains, using [³H]phorbol 12,13-dibutyrate ([³H]PDBu). When the tissue was homogenized in the absence of Ca²⁺ chelator (10 mM EGTA/2 mM EDTA), Scatchard analysis of the specific [³H]PDBu bindings to both particulate and soluble fractions yielded a single class of high-affinity binding site (K _d = 7.1 and 7.4 nM:B _max = 45.4 and 3.1 pmol/mg protein, respectively). The particulate fraction retained the majority of [³H]PDBu binding (98% of total binding activity), while the soluble fraction was almost devoid of binding activity (2%). In the presence of Ca²⁺ chelator, more of the activity was found in the soluble fraction (30%). The binding of [³H]PDBu was potently inhibited by active phorbol esters and related diterpenes withK _i of nanomolar concentration but not by inactive ones. Diolein (OAG), a synthetic diacylglycerol, and polymixin B, an inhibitor of protein kinase C (PKC), inhibited the binding moderately (K _i = 5.8 and 1.3 μM, respectively). H-7, an inhibitor of PKC and cyclic nucleotides-dependent kinase, did not compete with [³H]PDBu for the binding sites (K _i > 100,000 nM). The regional distribution of specific [³H]PDBu binding in the human brain was rather uneven and resembled that of [³H]PDBu autoradiograms and PKC-like immunoreactivities in the rat brain. The binding capacities were generally in the order: rhinencephalon > basal ganglia > cerebral cortex > diencephalon > cerebellum > mesencephalon. Age-related loss of binding sites was observed in the prefrontal cortex of the subjects 33–81 years of age. In Parkinson’s disease, the phorbol ester binding showed a significant reduction in the substantia nigra, caudate putamen, and pallidum, whereas it was unchanged in the prefrontal cortex and caudate nucleus of schizophrenics, when compared with the relevant controls. This work was supported by a Grant-in-Aid for Special Project Research of Selected Intractable Neurological Disorders from the Ministry of Education, Science and Culture, Japan.     

Neuropathologic abnormalities of the brain in the Wistar ataxic rat

The neuropathologic findings of the Wistar ataxic rat brain were reported after making serial sections of the brain and studying the cerebellum with an electron microscope. Twenty-five adult Wistar rats from a mutant strain were used: 14 were ataxic and 11 were normal. In the brains of the Wistar ataxic rats, neuropathologic abnormalities were present only in the Purkinje cells. The possibility of a new model animal with autosomal recessive cerebellar ataxia is discussed.