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Two types of multiple controlled release dosage forms, hydroxypropylmethyl cellulose acetyl succinate (HPMC-AS) coated granules and double layer coated granules with HPMC-AS and ethyl cellulose (EC), were prepared for the newly developed antihistaminergic drug, TA-5707F, using a centrifugal fluidizing granulator. The in vitro dissolution rate of TA-5707F in the second fluid from the former granules could be altered by changing the grade (HPMC-AS-M, AS-H, AS-V) or coating amount. However, the plasma concentration determined in fasted dogs was not markedly affected by the HPMC-AS grades. From the granules coated with 30% (w/w) AS-V (the polymer with the highest pH required for dissolution), little TA-5707F was released into the second fluid, but a fairly high plasma concentration was detected although a constant plasma level was not maintained in the fasted dogs. The dissolution rates from the double layer coated granules were changed by the coating percent of EC. The plasma concentration of TA-5707F in dogs correlated well with the in vitro dissolution rate and was not markedly affected by food. Thus, two kinds of double layer coated granules (coated 0.75% EC and 1% EC) were administered to humans, and showed sustained-releasing plasma profiles; that is, the plasma concentration increased gradually and reached a Cmax 5 and 8 h after administration, respectively. The amount of urinary excretion of TA-5707F and its metabolite was 70% of the dose. This value was almost equal to that of the rapid release tablet. In dogs the in vivo absorption rate was similar to the in vitro dissolution rate, but in humans it was only about half.

Aim: Ammonia is a cytotoxic factor of Helicobacter pylori that is involved in gastric mucosal injury. This study was designed to show whether ammonia has an effect on the cell-cycle progression in human gastric cells in vitro., Materials and Methods: We studied the effects of ammonia and ammonium chloride on cell growth and cell-cycle progression of the human gastric cancer cell line HGC-27. We cultured HGC-27 cells and counted viable cells by trypan blue dye exclusion 24 h after the addition of various concentrations of ammonia or ammonium chloride. DNA contents of nuclei were analysed by flow-cytometry., Results: Ammonia and ammonium chloride inhibited the proliferation of HGC-27 cells dose-dependently. Flow-cytometric analysis showed S-phase accumulation of HGC-27 cells treated with ammonia and ammonium chloride at cytostatic doses., Conclusions: These results suggest that ammonia and ammonium chloride inhibit the growth of gastric cells in S phase. This mechanism may make a significant contribution to the pathogenesis of Helicobacter pylori-associated gastric mucosal atrophy.

A 68-year-old woman had been complained of xerostomia since she was 30 years old. Further symptoms of polyuria, polyposia and insomnia had been developed since she was 35 years old. The biopsy material from a minor salivary gland demonstrated the infiltration of lymphocytes into mesenchyme which was compatible with Sjögren's syndrome. She admitted to our hospital because of myalgia in bilateral gastrocnemius and petechiae in both lower extremities in addition to the complaints described above. Complete blood cell counts on admission revealed hemoglobin 9.7 g/dl, platelet count 12.5 x 10(4)/microliters, and white blood cell count 3,300/microliters. Marked polyuria, polyposia (more than 5,000 ml/day, respectively) and low urine gravity (1.005) were observed, although the serum creatinine level showed normal value. Serologic examination showed that the elevation of total serum protein concentration (9.5 g/dl) with marked elevation of serum IgG level (6,190 mg/dl). Her immunoglobulins contained cryoglobulin (cryocrit 20%), and immunoelectrophoresis demonstrated the existence of IgG-kappa monoclonal protein. A positive anti-nuclear antibody at 1:320 dilution, a positive rheumatoid factor and a positive antibody to SS-A (Ro) were also observed. The serial studies of blood gas analysis could not demonstrated the presence of metabolic acidosis. Together with the result of elevated plasma antidiuretic hormone level and results of vasopressin test, Fishberg's concentrating test and the tests of the overload of NH4Cl or bicarbonate, she was diagnosed Sjögren's syndrome with both diabetes insipidus and subclinical renal tubular acidosis. She was initially medicated with prednisolone (40 mg/day, orally), then she was given six courses of intravenous cyclophosphamide (750 mg/body/month).(ABSTRACT TRUNCATED AT 250 WORDS)

A 30-year-old woman with systemic lupus erythematosus (SLE) developed ectopic calcinosis. She had been receiving prednisolone since 1980 with the addition of vitamin D3 in 1986. Despite this therapy, her renal function had gradually deteriorated. Right gonalgia was noted in September 1991. X-ray findings revealed calcinosis of the arteries of the femur, poplitea, cubitus, hands, and feet. Her finger pads and joint sacs were also involved. Calcinosis seen in SLE has only rarely been reported, and that observed in association with vitamin D intoxication or arteriosclerosis has a different distribution of calcium deposits. The use of vitamin D3 in our patient with renal disability may have induced calcinosis with a unique distribution.

Flavonoids are pigments of edible plants. We have recently reported that most flavonoids induce G1 arrest in human cancer cells, and that genistein (an isoflavone) specifically inhibits their cell cycle at G2-M phase. In the present study, apigenin (a flavone) was found to inhibit the proliferation of B104 rat neuronal cells, and flow-cytometric analysis showed that apigenin arrested their cell cycle at G2-M phase. This effect was dose-dependent and reversible when apigenin was removed from the culture medium. Microscopic observation showed that apigenin did not significantly increase the mitotic index compared with the control. Further, apigenin induced morphological differentiation, that is, elongation and arborization of neurites in B104 cells. This is the first report to show that apigenin inhibited the proliferation of malignant tumor cells by G2-M arrest and induced morphological differentiation.

Despite many suicidal cases in patients with systemic lupus erythematosus (SLE), literature on this subject is lacking. To elucidate and prevent this phenomenon, we re-evaluated the clinical records of seven suicidal patients with SLE. Six patients had photosensitivity and insomnia. At the time of the suicide attempt, hypocomplementemia was observed in five of six patients. Diffuse slowing on electroencephalograms were observed in four of five patients. One patient successfully committed suicide while on no therapy while five patients made their attempts under the tapering courses of steroids. Five patients manifested psychoses whereas two patients displayed no psychotic findings. All patients attempted suicide shortly after admission (mean time 20 days). The subsequent courses of the survivors who received more medication were favorable. Therefore, it appears that disease activity was not fully controlled in these patients. Furthermore, signs of an imminent suicide attempt were missed in some cases. Psychosis, insomnia, history of photosensitivity, an incompletely controlled disease state, receiving tapering steroid dose, diffuse slowings on electroencephalograms and the presence of hypocomplementemia appeared to be risks for attempting suicide in SLE. We would recommend that such patients be under psychiatric care for at least 2 months to prevent suicide. When the patient is still psychotic or unstable, further medical care will be required.

We estimated the concentration of soluble IL-2R (sIL-2R) in the serum of patients with systemic lupus erythematosus (SLE) and examined the relationship between the serum levels of sIL-2R and clinical features or laboratory data. We found that elevated levels of sIL-2R were present in the serum of SLE patients with discoid rash, and sIL-2R concentrations were correlated with the soluble CD4 and soluble CD8 concentrations but not with classical serological marker, anti-DNA antibody or complement titer.

Genistein, an isoflavone, is a specific inhibitor of tyrosine kinase and topoisomerase II. However, its effect on cell growth is unknown. Therefore, we examined the effects of genistein on cell growth and cell cycle progression and compared its effects with other flavonoids. Genistein inhibited in a dose-dependent manner the growth of HGC-27 cells derived from human gastric cancer. Flow-cytometric analysis showed that genistein almost completely arrested the cell cycle progression at G2-M. This effect was reversible when genistein was removed from the culture medium. In contrast, other flavonoids such as flavone, luteolin, and the structurally similar daidzein arrested the cell cycle at G1. Consistent with the flow-cytometric analysis, microscopic observation showed that genistein did not increase the mitotic index, which supposes that genistein may arrest the cell cycle at G2 or early M. These results suggest that the G2-M arrest by genistein is a unique effect among flavonoids.

The electroencephalograms (EEGs) of 120 patients with systemic lupus erythematosus (SLE), were evaluated with regard to clinical manifestations and laboratory findings. On the initial 120 records, abnormal EEGs were observed in 109 patients (90.8%). Epileptiform patterns were also observed in 33 patients (27.5%). Diffuse alpha wave, theta wave, and delta wave appeared to be unique findings of basic wave activity in EEGs of SLE patients. Paroxysmal abnormalities of spike and wave complex, spike, and sharp wave were frequently observed. These paroxysmal abnormalities appeared to be easily exaggerated by hyperventilation or sleep. Focal abnormal discharges were also observed. The incidence of abnormal EEGs of the patients with central nervous system involvement (CNS lupus), did not differ from that of non-CNS lupus i.e. 24/30 (80.0%) vs 82/93 (88.2%). On the other hand, regarding the severity of abnormal EEGs, CNS lupus manifested severer findings than those of non-CNS lupus. As to the EEG abnormality, female patients, younger patients less than 30 years old, flared patients, and patients receiving prednisolone more than 30 mg/day had severer EEG findings than those of each counterparts. The patients who had once manifested neuropsychiatric disorders and/or immunologic abnormalities (anti-deoxynucleic acid antibody, anti-DNA antibody), showed severe findings on EEG. Epileptiform patterns were frequently observed in patients receiving lower prednisolone doses (30 mg/day or less), although they did not correlate with disease activity. Patients with arteriosclerosis obliterans or aortitis syndrome, demonstrated only mild abnormalities on EEGs and they had not shown any epileptiform patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

A 41-year-old patient with chronic myelogenous leukemia in the accelerated phase was treated with mitoxantrone. She developed pyrexia 7 days after receiving the third administration of mitoxantrone. After 3 more days, she experienced dry cough and dyspnea. Bilateral fine crackles were audible, but no signs of heart failure were found. A chest X-ray film revealed diffuse reticulogranular infiltrates bilaterally. An increase in the prednisolone dosage led to an improvement. Specimens of the bronchoalveolar lavage revealed an increase in CD4-/CD8- lymphocytes. The peripheral lymphocytes also expressed neither CD4 nor CD8. Specimens of a transbronchial lung biopsy disclosed thickening of the alveolar wall with infiltration of lymphoid cells.

The authors report a case with esophageal cancer who had undergone a non-curative resection and showed a recurrence. Treatment with only oral 5'-DFUR resulted in complete response. This was followed by oral ftorafur, and the case has remained complete response for 40 months. It is rare to obtain such an effect in esophageal cancers by oral and sole administration of a drug in the 5-FU class. Our experience with this case is described.

We examined the effect of famotidine, a histamine-type 2 receptor antagonist, on the immunocompetent cells. The number of DR(+) cells were significantly decreased in patients with systemic lupus erythematosus (P less than 0.05) by parenteral administration of famotidine (40 mg/days for 4 weeks). However, total lymphocyte number and monocyte number did not change. Immunoglobulin levels of patients with rheumatoid arthritis and normal male did not change. Furthermore, phytohemagglutinin induced lymphocyte proliferation was increased by addition of famotidine (10 ng/ml). Nonetheless, famotidine did not have mitogenic function itself to lymphocyte and did not affect IL-2 production.

Delayed diagnosis in two cases of congenital duodenal obstruction was discussed. Case 1. Ten-month-old baby girl with Down's syndrome was admitted to the hospital because of vomiting of milk. Wall-like obstruction was found in the second part of duodenum. Case 2. One-year-old boy infant with Down's syndrome showed a stack of coin in the duodenum on admission. Wall-like obstruction was found in the second part of duodenum. Diagnosis of duodenal obstruction is sometimes delayed in Down's syndrome. Symptom such as vomiting and growth retardation might be ignored in a child with Down's syndrome. A large hole was found in the center of the obstruction in both cases; 4 mm in diameter in case 1, 3 mm in case 2. Papilla of Vater opened at the anal side of the obstruction. These structural particularities played a role in making symptom of duodenal obstruction obscure. Mural obstruction of duodenum was observed in both cases. The obstructions were, in shape, similar to the membraneous stenosis of the duodenum. However, they were not membranes but walls as thick as 4-5 mm. Wall-like duodenal obstruction has not been reported in the literature. It can not be concluded whether mural obstruction in our cases is a new subtype of duodenal obstruction or not.

A 64-year-old man with ethanol intoxication, ingested a bottle of Herbiace (100 ml, 32 w/v% of bialaphos, CAS #35597-43-4, Meiji Seika Kaisha, Tokyo, Japan). He had severe metabolic acidosis and was treated with infusions of sodium bicarbonate and furosemide, plus gastric lavage and enema. The metabolic acidosis improved 15 hours after treatment but nystagmus, apnea and convulsions were progressive. Although his sensorium was clear, spontaneous respirations were not observed for 64 hours. The electroencephalographic findings of atypical triphasic waves and slow waves suggest a unique response to bialaphos poisoning. His clinical course indicates that the management of apnea is critically important to recovery from bialaphos poisoning.

We are presenting a patient with primary myelofibrosis who responded to the High-Dose methylprednisolone therapy (1 g/day for 3 days). Three and a half years ago, a 55-year-old male was admitted to our hospital because of severe erythroblastic anemia, thrombocytopenia, splenomegaly and "dry tap" of bone marrow aspiration. Bone marrow biopsy revealed a marked fibrosis without any blastoid cell proliferations. Since a thrombocytopenia was progressive and refractory to the ordinary therapy, high-dose methylprednisolone therapy was performed which was followed by an administration of activated vitamin D3. After the therapy, hematologic improvements were achieved within a month (RBC: 284 x 10(4)/microliters----413 x 10(4)/microliters, WBC: 3,000/microliters----11,500/microliters, Plat.: 7,000/microliters----20,000/microliters). Three months after the therapy, the bone marrow biopsy and 113In scintigraphy were performed. These tests also proved marked improvement of histological features of the bone marrow and a decrease of uptake of 113In to the spleen, respectively. The patient continues to be in good condition and he is free from any medications at present time.

A 22-year-old female patient with severe aplastic anemia was treated by ATG.bolus methylprednisolone therapy. After the therapy, anemia and thrombocytopenia began to recover within a month. The frequency of blood transfusion decreased thereafter. Since anemia due to splenomegaly was certified, bolus methylprednisolone therapy was performed in good response. Suppressor T-cells towards hemopoiesis were confirmed in this case, and hemopoietic potential was augmented by ATG.bolus methylprednisolone therapy. In spite of discontinuation of any therapy in 1986, she is being in good health more than five years.

The binding of alpha-human atrial natriuretic polypeptide (alpha-hANP) to brush border and basolateral membranes isolated from the rat renal cortex was studied at 0 degree C by a rapid filtration technique. Specific binding of 125I-alpha-hANP to basolateral membranes reached a steady state at 4 hr. The binding to brush border membranes was maximal at 5-15 min and then rapidly decreased. The analysis of incubation mixtures with basolateral membranes revealed little degradation of 125I-alpha-hANP during the 4-hr incubation, while there was extensive degradation of the ligand with brush border membranes during the 30-min incubation. High affinity binding of 125I-alpha-hANP was demonstrated on basolateral membranes but not on brush border membranes. These data suggest that specific receptors for alpha-hANP are localized on basolateral membranes of the renal cortex.

Receptor binding activities and cyclic GMP responses by alpha-human atrial natriuretic polypeptide (alpha-hANP) and its fragments were studied in a kidney epithelial cell line (LLC-PK1). Binding of 125I-alpha-hANP to the cells at 0 degrees C was saturable, time-dependent and reversible, indicating the presence of a single class of binding sites. alpha-hANP (7-23)NH2 fragment inhibited most effectively the specific binding of 125I-alpha-hANP to the LLC-PK1 cells, followed by alpha-hANP (17-28) and alpha-hANP (8-22), while alpha-hANP (1-6) and alpha-hANP (24-28) did not. alpha-hANP stimulated the formation of cyclic GMP in the LLC-PK1 cells dose-dependently. Although no fragments of alpha-hANP used were effective for cyclic GMP formation in the LLC-PK1 cells, alpha-hANP (7-23) NH2 antagonized the action of alpha-hANP on cyclic GMP formation. These data suggest that the LLC-PK1 cells retain specific receptors for atrial natriuretic polypeptide (ANP) and respond to ANP by stimulating cyclic GMP formation, and therefore this cell line may be useful for studying the mechanism of action for ANP in renal tubular cells.

Cefsulodin (CFS), a new antipseudomonas cephalosporin, was clinically evaluated for treatment of the Pseudomonas aeruginosa infections in the surgical field to obtain the following results. 1. CFS was administered to total 11 cases of the surgical infections caused by P. aeruginosa, comprising of 5 cases with wound infections, 3 cases with infected burn and 1 case each with muscular abscess, decubitus and postoperative pneumonia in 0.5 approximately 1 g twice a day by intravenous bolus or drip infusion. Good clinical responses were obtained in 9 out of 11 cases (81.8%). 2. Bacteriological responses were observed in all cases. P. aeruginosa was eradicated in 9 cases and suppressed in 2 cases by CFS treatment. However, replacement of pathogens with the other organisms was observed in 6 out of 8 cases caused by P. aeruginosa only. 3. Neither objective and subjective side effects nor abnormalities of laboratory tests associated with CFS treatment were observed. 4. It can be, therefore, concluded that CFS is one of the useful drugs for treatment of the surgical infections caused by P. aeruginosa.

The relapse of icterus may be a sign of serious postoperative complication after hepatic portoenterostomy for biliary atresia. To analyse the cause of such icteric flare-up, a retrospective study was made on 27 patients. A total of 38 episodes of icteric flare-up occurred in 19 patients. An accompanying disease, which had not directly involved the biliary tract, was assumed to be the cause in 11 episodes (29%). Fourteen episodes (37%) were due to biliary tract infection caused by the cyst formed at the porta hepatis (5 episodes) or so-called ascending cholangitis (9 episodes). The other 13 episodes (34%) were free from both accompanying disease and signs of biliary infection. Among them, the cause of icteric flare-up was the cyst at the porta hepatis in one episode, scar tissue formation at the porta hepatis in 9 episodes and undetermined in 3 episodes.

After hepatic portoenterostomy for biliary atresia, granulation that formed at the porta hepatis caused biliary obstruction in seven out of 27 patients (26%). Six of the seven developed the complication during the first 6 weeks after surgery. The mortality rate was 29% (2/7). Among the same group, the incidence and mortality rate of ascending cholangitis was 19% (5/27) and 20% (1/5), respectively. The features characteristic of biliary obstruction caused by granulation, as compared with those of ascending cholangitis, were the absence of signs of infection and the lack of response to medical treatment. Quantitative analysis of the healing process of an experimental hepatoenterostomy in the rat showed that the mean thickness of the granulation formed at the anastomotic site (area, 5 x 20 mm) decreased almost constantly--from 1.49 mm on day 7 to 0.64 mm on day 42. Mucosa covered 20% of the granulation on day 7, 55% on day 14, 63% on day 21, 76% on day 28, and 92% on day 42. The increase in coverage was greatest during the second postoperative week. The results suggested that the healing of the hepatoenteostomy should be almost complete within 6 weeks. The operative method and postoperative management to prevent excessive granulation should be chosen so as to decrease the incidence of postoperative biliary obstruction.

The binding of alpha-human atrial natriuretic polypeptide (alpha-hANP) to basolateral membranes isolated from renal cortex of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHR-SP) was measured at 0 degree C and compared with that of Wistar-Kyoto rats (WKY). The binding of 125I-alpha-hANP in SHR and SHR-SP at 14-15 weeks old demonstrated different binding profiles compared with that in WKY, though there were no apparent differences of the profiles among WKY, SHR and SHR-SP at 5 weeks old. For the high affinity binding sites, the apparent dissociation constant and the maximal binding capacity in SHR and SHR-SP were significantly decreased in comparison with those in WKY. The present data suggest that the altered characteristics of specific receptors for atrial natriuretic polypeptide in SHR and SHR-SP may be involved in the development or maintenance of genetic hypertension.