Effect of XKJ-001, a crude drug preparation, on body water distribution and water excretion in mice

The effect of XKJ-001, a crude drug preparation based on Seisho-ekki-to, was investigated on the hematocrit, plasma volume, extracellular and interstitial fluid volumes as well as water excretion in mice. Mice were housed in an animal room maintained at 34 degrees C for 3 d with water and food freely available. While the hematocrit, extracellular and interstitial fluid volumes increased, the plasma volume decreased. These results suggest that the distribution of body water in mice housed at high environmental temperature exhibit the state of water metabolism disorders (Suitai) described in Kampo medicine. After the administration of XKJ-001 (3 g/kg, once a day) for 5 d, mice were housed in an animal room maintained at 34 degrees C for 3 d. The administration of XKJ-001 was allowed to continue on the day 0, day 1 and day 2. XKJ-001 inhibited the increase in hematocrit and the changes in body water distribution of mice induced by high environmental temperature. An effect of XKJ-001 on water excretion in mice was investigated in comparison with hydrochlorothiazide (HTZ). Distilled water (D.W., 100 ml/kg) or bicarbonate saline (B.S., 100 ml/kg) was intraperitoneally injected immediately after the oral administration of XKJ-001 (1.5 g/kg) or HTZ (15 mg/kg). The water excretion was enhanced after 3 h for XKJ-001 and after 6 h for HTZ after the intraperitoneal injection of D.W. As for the intraperitoneal injection of BS, HTZ enhanced the water excretion, however, XKJ-001 exhibited no effect. These results suggest that XKJ-001 has activities on water maldistribution and facilitates the water excretion.     

Factors modifying the prognosis of Wilson's disease in childhood

The prognosis of Wilson's disease was investigated in 96 patients, in whom the disease had presented before 15 years of age and had begun between 1965 and 1983 (when D-penicillamine was widely available in Japan). In the activities of daily living, the prognosis was poor in those patients presenting with neurological symptoms. Interruption of D-penicillamine treatment was seen in one third of the patients, and it worsened the prognosis. Toxic side effects were seen in about half of the patients, being more frequent in the patients with initial neurological symptoms. A disappointing 17% of patients with slight or no side effects discontinued the drug. Death occurred in eight patients of whom seven had had initial hepatic symptoms. Not only early diagnosis and treatment before the appearance of hepatic failure or neurological symptoms, but also treatment throughout life without interruption is important for improving the prognosis of Wilson's disease.     

A case of emergency surgery for acute mitral regurgitation due to complete papillary muscle rupture as complication of acute inferior myocardial infarction

We experienced a case with acute mitral regurgitation caused by complete posterior papillary muscle rupture as complication of acute inferior myocardial infarction, who underwent successfully emergency operation of mital valve replacement and coronary revascularization in acute stage. A 64-year-old woman developed sudden cardiogenic shock shortly after the onset of acute inferior myocardial infarction. The diagnosis of acute inferior myocardial infarction was based on the electrocardiographic findings. Under IABP support, preoperative coronary angiography visualized total occlusion of segment 3 of the right coronary artery, and preoperative left ventriculography showed akinesis of inferior wall and severe mitral regurgitation. At 6 hours after onset of papillary muscle rupture, emergency operation was performed. At operation, posterior papillary muscle was found to be totally ruptured. Coronary artery revascularization and mitral valve replacement were performed. Postoperative course was uneventful, with 4 days of IABP and 5 days of ventilatory support. She was discharged on the twentieth postoperative day in NYHA class I. Reports of successful emergency operation for total papillary muscle rupture following acute myocardial infarction are rare. Early diagnosis and surgical treatment are mandatory to save this group of patients.     

Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation

Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/− cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The k_M value for the CYP3A4 expressed in the cells was 69.7 μmol · l⁻¹, and the V_max was 4.87 pmol · min⁻¹ · pmol⁻¹ P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k_i value of 24.9 and 1390 μmol · l⁻¹, respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k_i value of 4.3 μmol · l⁻¹. Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 μmol · l⁻¹, whereas higher concentrations of the compound (>10 μmol · l⁻¹) inhibited the hydroxylase activity. Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity. Received: 10 April 1997 / Accepted in revised form: 16 December 1997     

Epileptic seizure of El mouse initiates at the parietal cortex: depth EEG observation in freely moving condition using buffer amplifier

The initiation site of seizure discharges and the relationship between behavioral manifestations and electroencephalography were investigated in the El mouse, a hereditary epilepsy model. The chronic depth electrodes were implanted stereotaxically into the frontal cortex, parietal cortex, temporal cortex, hippocampus, striatum, amygdaloid complex, non-specific nuclei of thalamus and substantia nigra. Electrical activities were recorded in freely moving condition with use of the buffer amplifier devised in the laboratory and behaviors were monitored simultaneously. Seizure spike discharges started in the parietal cortex and spread out into other brain areas. When the hippocampus was involved, the tonic convulsion occurred behaviorally. The paper describes the first direct evidence of the initiation and propagation of seizure discharges in the brain of El mouse.     

Evidence that a substance P-like peptide mediates the non-cholinergic excitatory response of the carp intestinal bulb (Cyprinus carpio)

Summary The participation of substance P in the noncholinergic contraction induced by transmural stimulation (TMS) of the carp intestinal bulb was examined. In the presence of atropine, substance P caused the contraction of carp intestinal bulb smooth muscle in a concentration dependent manner (1 nmol/1 – 1 mol/l). The EC50 value was 28 ± 7 nmol/l (n = 6). Substance P-induced desensitization (1 mol/l for 15 min), decreased the response to substance P and the atropine-resistant contraction induced by TMS (20 Hz) selectively. In contrast, in the absence of atropine, the contraction induced by TMS (20 Hz) was slightly attenuated with the substance P-induced desensitization. The acid extract obtained from the carp intestinal bulb contained a smooth muscle excitatory material whose pharmacological properties were consistent with those of substance P. The present results indicate that a substance P-like peptide is present in the carp intestinal bulb which is involved in the non-cholinergic contraction induced by TMS.Send offprint requests to T. Kitazawa at the above address     

Fine structure of the mouse portal vein in relation to its peristaltic movement

The hepatic portal vein has been known to make a spontaneous peristaltic movement in some mammals, including the mouse and rat. To investigate the fine structure of the portal vein in relation to its physiological characteristics, we observed the mouse portal vein by using various histological techniques including conventional light microscopy, videomicroscopy, transmission and scanning electron microscopy, and real-time confocal laser scanning microscopy. The mouse hepatic portal vein was provided with a spiral fold which was produced by the inner layer, i.e. the endothelium and smooth muscles of the wall protruding into the lumen. Longitudinal smooth muscle cells spanned the interval of the fold, like a spirally arranged palisade around the vessel wall. The longitudinal muscle fibers ended at the spiral fold, being partly connected with a network of irregularly shaped smooth muscle cells. This network, hitherto unknown, was recognized to be restricted to the fold in distribution and characterized by numerous gap junctions connecting the muscle cells. Real-time confocal laser scanning microscopy using a Ca2+ sensitive fluorescent dye revealed that a transient and periodic increase in Ca2+ concentration occurred in the longitudinal smooth muscle cells and was transmitted spirally from the intestinal to the hepatic side. These findings indicate that, during the peristaltic movement, the contraction of smooth muscle cells is transmitted along the longitudinal smooth muscles of the portal vein wall toward the liver, presumably controlled by the network of the irregularly-shaped smooth muscle cells in the fold of the portal vein. Light microscopic observation in some specimens indicated an occurrence of cardiac muscle cells outside the smooth muscle layer. Restricted to the site of the porta hepatis in distribution, their involvement in the peristaltic contraction of the portal vein seemed unlikely.     

Case of minocycline-induced pneumonitis with bilateral pleural effusion]

A 51-year-old man was admitted to our hospital with fever, dry cough and dyspnea. He had taken minocycline for 11 days because of urinary tract infection. Chest X-ray on admission showed diffuse reticular shadows in bilateral lung fields with bilateral pleural effusion. Cessation of minocycline led to spontaneous improvement of symptoms and radiographic findings. The lymphocyte stimulation test for minocycline with peripheral blood and pleural effusion were negative. After provocation test with minocycline, he developed fever and dry cough and bilateral ground glass opacity appeared on his chest X-ray. He was diagnosed as minocycline-induced pneumonitis and recovered rapidly following corticosteroid therapy.     

Influence of acute-phase proteins on the activity of natural killer cells

The effects of ₁-antitrypsin ( ₁,-AT), ₁,-acid glycoprotein ( ₁AGP), and haptoglobin (Hp), the main constituents of-globulin and which belong to acute phase proteins, on NK activity were examined using K562 cells as the NK target cells. Among the three proteins, ₁,-AT and ₁AGP had inhibitory effects on NK activity for fast target K562 cells. The,-AT preparations having the same protein concentration and a different trypsin inhibitory capacity (TIC) had an equal effect. Although ₁AT and ₁,-AGP equally reduced the NK activity, the mechanism involved in the reduction differed, in that the effect of ₁,-AT directed toward NK cells reduced their binding capacity with the target cells, ₁,-AGP probably interacts with a cytotoxic factor secreted from NK cells following effector-target interaction. These studies suggest that each of the acute-phase proteins, which increase following inflammation, inhibits NK cell function by two distinct mechanisms.