Pharmacological Properties of β-Amyrin Palmitate,a Novel Centrally Acting Compound,Isolated from Lobelia inflata Leaves

Abstract— Effects of β-amyrin palmitate isolated from the leaves of Lobelia inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, β-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg^?1). β-Amyrin palmitate (5, 10 and 20 mg kg^?1) or mianserin (5, 10 and 20 mg kg^?1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg^?1) increased locomotor activity and potentiated methamphet-amine-induced hyperactivity. β-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg^?1) and imipramine (10 and 20 mg kg^?1) antagonized the reserpine-induced effect. Unlike imipramine, β-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. β-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg^?1) decreased it in a dose-dependent manner. A potentiating effect of β-amyrin palmitate (5, 10 and 20 mg kg^?1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg^?1) but weaker than that of mianserin (2·5, 5 and 10 mg kg^?1). These results suggest that β-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action. We suggest that β-amyrin palmitate has antidepressant activity with a mianserin-like profile of action.     

Relationship between cellular ATP content and cellular functions of primary cultured rat hepatocytes in hypoxia

The importance of oxygen in maintaining the functional integrity of hepatocytes has been well established in a variety of experimental models, such as in vivo , perfused liver and isolated hepatocytes. However, one of the shortcomings of these systems is their short life span. Therefore, we have examined the effects of long-term hypoxia on cellular adenine nucleotide content and cellular functions, such as albumin production, urea production and DNA synthesis, in adult rat hepatocytes in primary culture. Hepatocytes were cultured at a density of 11 × 10⁴ and 5 × 10⁴ cells/0.18 mL per cm² for the study of albumin and urea production and DNA synthesis, respectively, at various oxygen tensions (20, 12, 8 and 5%) for 24 h. Cellular ATP content in cultured hepatocytes in hypoxia gradually declined, corresponding to the decrease in oxygen tension, and the cellular ATP level at 5% oxygen was approximately 20% of that at 20% oxygen. Albumin production also decreased in parallel with the decrease in cellular ATP content in cultured hepatocytes in hypoxia. However, even when cellular ATP content gradually declined corresponding with the decrease in oxygen tension in cultured hepatocytes in hypoxia, such as at 8 or 5% oxygen, urea production remained at a high level; in contrast, DNA synthesis was completely suppressed. These results suggest that the cellular ATP content decreases in cultured hepatocytes during long-term hypoxia in relation to oxygen tension and that the relationship between decreased ATP levels and liver function in cultured hepatocytes during hypoxia differs for albumin production, urea production and DNA synthesis.     

Cytotoxin and urease activities of Helicobacter pylori isolates from Japanese patients with atrophic gastritis or duodenal ulcer

The vacuolating cytotoxin and urease secreted by Helicobacter pylori are thought to be virulent factors. Because vacuolation is potentiated by the presence of ammonium ion, which is produced by urease in vitro, it is of interest to examine whether cytotoxin and urease work reciprocally in the development of atrophic gastritis or duodenal ulcer. In the present study, patients (all H. pyloripositive) were divided into four groups: mild atrophic gastritis (group 1; nine patients), severe atrophic gastritis (group 2; 36 patients), duodenal ulcer with mild atrophic gastritis (group 3; 19 patients) and duodenal ulcer with severe atrophic gastritis (group 4; 12 patients). Cytotoxin production and urease activity of H. pylori isolated from these patients were analysed. Cytotoxin production was observed in four of nine (44.4%), 28 of 36 (77.8%), 11 of 19 (57.9%) and eight of 12 (66.7%) isolates from groups 1, 2, 3 and 4, respectively. Cytotoxin-producing H. pylori isolates were found significantly more in patients with severe atrophy than in patients with mild atrophy (P= 0.048). The mean of relative activity of cytotoxin in H. pylori isolate was 1. 6. ± 2. 3, 7. 9. ± 7. 4, 5. 8. ± 6. 0 and 9. 0 ± 9. 1 in groups 1, 2, 3 and 4, respectively. Helicobacter pylori isolates from severe atrophy or duodenal ulcer patients in groups 2 or 4 possessed significantly higher activity than those from non-ulcer patients in group 1 (P= 0.017 and 0.030, respectively). The mean of urease activity was 8. 6 ± 4. 6, 10. 0 ± 5. 9, 10. 0 ± 8. 5 and 11. 2 ± 7. 7 IU/mg in groups 1, 2, 3 and 4, respectively. These differences indicated no statistical significance. In each H. pylori isolate, the production of cytotoxin and urease were independent, which indicated that there was no reciprocal effect between them in vivo. Thus, cytotoxin-producing H. pylori isolates were more prevalent in patients with severe atrophic gastritis and the cytotoxin activities of H. pylori isolates from the patients with severe atrophic gastritis or duodenal ulcer were much higher than those from the patients with mild atrophic gastritis, which suggested that vacuolating cytotoxin may be a disease-inducing factor.     

Epstein-Barr Virus-induced Lymphoblastoid Cell Lines from Patients with Primary Immunodeficiency Diseases

Peripheral lymphocytes from eight patients with congenital immunodeficiency diseases were infected with Epstein-Barr virus (EBV) in an attempt to establish B lymphoblastoid cell lines (LCL). These patients included three boys with congenital agammaglobulinaemia, two girls with hypogammaglobulinaemia, one boy with common variable immunodeficiency, one boy with severe combined immunodeficiency with adenosine deaminase deficiency, and one boy with DiGeorge syndrome. Five of the patients bore no surface immunoglobulins (slg) on their peripheral lymphocytes. LCL were established from seven of the eight patients. All the LCL established formed rosettes with EAC3 and had the ability to produce cytoplasmic immunoglobulins (clg) of various classes. Culture supernatants concentrated up to 100-fold developed precipitin bands by Ouchterlony's method with antisera to human Ig in all the established LCL. These results suggested that both slg^-, clg^- and C3⁺ cells and slg⁺, clg^- and C3⁺ cells might be the target cells for EBV and that slg^-, clg^- and C3⁺ cells might be the precursor cells of B lymphocytes.     

Diagnosis of Small Pancreatic Carcinoma

A retrospective analysis was performed to evaluate the clinicalsymptoms and abnormal test findings in small pancreatic carcinoma.Five hundred and thirty-six cases of pancreatic carcinoma withthe histology of duct cell carcinoma were collected from 14medical centers in Japan. In 440 of the cases, tumor size wasmeasured at the time of laparotomy or from the resected specimen.Three hundred and seventy-seven patients (86%) had a carcinomalarger than 3.0 cm; only 30% of these were resectable. Sixty-threepatients (14%) had a carcinoma of 3.0 cm or less, with resectabilityof 97%. Detecting a tumor of "3 cm or less" with a high probabilityof resectability is the objective of early diagnosis with theresulting possibility of a cure. In most cases these small carcinomaswere found easily when obstructive jaundice was present (73%).However, the estimated occurrence of obstructive jaundice associatedwith carcinomas of 3 cm or less was only 10% among the totalcases of pancreatic carcinoma studied. Therefore, it is necessaryfor early diagnosis to detect carcinomas of 3 cm or less presentingwithout jaundice. The symptoms of small carcinoma without jaundiceare weight loss, anorexia, upper abdominal pain, back pain anda palpable abdominal mass. Among the various available examinations,endoscopic retrograde cholangiopancreatography, computerizedtomography and ultrasonography were valuable in diagnosing thesesmall carcinomas.     

THE IMPACT OF DIABETES MELLITUS ON THE PROGNOSIS OF ALCOHOLICS

In this study, the mortality of clinically treated Japanesealcoholics with diabetes mellitus was analysed. Fifty-one diabeticalcoholics without liver cirrhosis (DM), 23 diabetic and cirrhoticalcoholics (DM LC), 44 cirrhotic alcoholics without diabetes(LC), and 354 alcoholics without either complication (AL) admittedto the National Institute on Alcoholism in 1985 were studied.Thirty-seven diabetics required insulin treatment, and 12 oralhypoglycemic agents. The 4.4-year survival and drinking statusafter discharge were studied in 1990. Stepwise logistic regressionanalysis showed that the estimated odds for death increased8.10, 4.38, 3.70, and 3.27 times for the subjects with the alcoholmisuse after discharge, DM, DM LC, and LC, respectively. The4.4-year survival rate of alcoholics who continued misusingalcohol was much lower in DM (26%, P < 0.0005) and LC (35%,P < 0.0001) than in AL (73%). The survival rate of thosewho stopped misusing alcohol was significantly higher in DM(90%, P < 0.0001), LC (88%, P < 0.0001) and AL (94%, P< 0.0005) than those who continued misusing alcohol. Therewas no significant difference in the survival rate between thealcoholics with DM LC who continued misusing alcohol (50%) andthose who stopped misusing alcohol (73%). In the dead patients,56% of DM died unexpectedly or suddenly, whereas 71% of LC diedof liver failure after hospitalization. These results suggestthat diabetic alcoholics should be intensively educated forabstinence.     

Differences in the Mode of Lethality Produced through Intravenous and Oral Administration of Organophosphorus Insecticides in Rats

Differences in the Mode of Lethality Produced through Intravenousand Oral Administration of Organophosphorus Insecticides inRats. TAKAHASHI, H., KOJIMA, T., IKEDA, T., TSUDA, S. and SHIRASU,Y. (1991). Fundam. Appl. Toxicol. 16, 459–468. This studywas undertaken to investigate the possibility that mechanismsother than cholinesterase (ChE) inhibition account for the acutetoxicity of organophosphorus insecticide. Both the PO type insecticide(direct ChE inhibitors: chlorfenvinphos and dichlorvos) andthe PS type insecticide (indirect ChE inhibitors: diazinon andfenthion) were employed. Rats treated with lethal doses of intravenousand oral PO type insecticides and oral PS type insecticidesexhibited typical signs of anti-ChE poisoning along with markedinhibition of brain and erythrocyte ChE activity. In contrast,rats given lethal doses of intravenous PS type insecticidesexhibited tonic convulsions and opisthotonos, with only slightinhibition of ChE activities. When PO type insecticides wereintravenously administered to anesthetized and conscious rats,animals exhibited typical anti-ChE poisoning signs in cardiorespiration:hypertension and apnea which were antagonized by atropine. Afteradministration of lethal doses of PO type insecticides, breathingdisappeared before the cessation of heart beats. Rats receivinglethal doses of intravenous PS type insecticides did not showhypertension, but exhibited transient cessation of breathingand heart beats. Breathing was observed after the disappearanceof heart beats. The electroencephalogram (EEG) was characterizedby spike and wave complexes. The EEG and cardiorespiratory changeswere not antagonized by atropine. It was concluded that lethalityfollowing intravenous PS type insecticides may be independentof ChE inhibition.     

Benign Tumors and Tumor-Like Lesions (Excluding Adenomas) of the Lung: Radiological and Clinicopathological Analysis of 48 Cases

Forty-eight cases of surgically resected benign tumors and tumor-likelesions of the lung were analyzed, with the following results:1) Hamartoma and sclerosing hemangioma have well defined borders,compressing bronchi and blood vessels, and are loosely boundto the surrounding lung parenchyma. 2) Hamartomas, in 90% ofthe cases, showed "nodularity" on film tomograms. Histologically,nodularity at the edge was produced by lobules of cartilage.3) Fifty-three percent of the patients with sclerosing hemangiomawere middle-aged females and asymptomatic. Only two patientscomplained of hemosputum. Routine roentgenograms showed a roundshadow with homogeneous density. Cut surfaces were solid withvarious degrees of hasemorrhage. 4) Roentgenograms of benignmesothelioma showed large tumors more than 4 cm in diameter,in which extrapleural signs could be observed. 5) "Calcification"was seen on the roentgenograms of seven out of 27 hamartomasand one out of 15 sclerosing hemangiomas. Pleural retractioncould not be seen in our series. Xerotomography was superiorto film tomography in showing calcification. 6) One of the sclerosinghemangiomas was double, and the other 47 benign tumors and tumor-likelesions were solitary; the lesions were peripheral in 45 casesand central in three. All of the patients were free of localrecurrence and distant metastasis.