Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: Relation to intestinal hypermotility

Background and Aim:  We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes.
Methods:  Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results:  Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE₂ content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE₂ was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE₂ and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions.
Conclusion:  These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

Improvement of Transdermal Delivery of Tetragastrin by Lipophilic Modification with Fatty Acids

The in-vitro permeability of chemically modified tetragastrin with fatty acids through the rat skin was studied. The permeability of these compounds through intact skin and stripped skin of rat was determined with a Franz-type diffusion cell. The permeation of tetragastrin across the intact skin was improved by chemical modification with acetic acid and butyric acid. However, tetragastrin and caproyl-tetragastrin did not permeate across the intact skin up to the end of experiment. The permeation of tetragastrin across the stripped skin was improved by chemical modification, the skin flux of these acyl derivatives being in the order: acetyl > butyroyl > caproyl. The stability of tetragastrin in skin homogenate was also significantly improved by chemical modification with fatty acids. These results suggest that chemical modification of tetragastrin with fatty acids increases its lipophilicity, which makes it permeable across the stratum corneum. Moreover, the chemical modification reduced the degradation of tetragastrin in the viable skin, resulting an increase in permeation of tetragastrin across the skin.     

Prostaglandin E1‐effective,transient‐type ischemic colitis developed after surgical resection of sigmoid colon cancer. A case report

A 55‐year‐old‐man had a laparoscopic resection of the sigmoid colon due to colon cancer with submucosal invasion. After the surgery he suffered ileus and had a laparotomy. Six months later he complained of frequent defecation. Colonoscopy confirmed a circular ulcer extending from the anal side of the anastomosis in the sigmoid colon to the mid rectum. Endoscopic ultrasound demonstrated thickening of all layers of the diseased colon and rectum. We diagnosed ischemic colitis. After intravenous drip infusion of prostaglandin, symptoms and colonic stricture gradually improved. Although abdominal angiography revealed a narrowing of the peripheral sigmoid branch of the inferior mesenteric artery, blood flow was unrestricted. Colonoscopy performed 84 days after discharge revealed an ulcer scar.     

Diagnostic value of serum prostate-specific antigen in hemodialysis patients

BACKGROUND: The value of serum prostate-specific antigen (PSA) screening was examined to detect prostate cancer in men receiving hemodialysis. METHODS: Forty-one male patients age 60-95 (median age, 70 years) receiving hemodialysis were investigated for PSA levels. We set the cut-off point at 4 ng/mL (the usual reference range). Digital rectal examination (DRE) and transrectal ultrasonography (TRUS) of the prostate were performed in patients whose PSA was more than 4 ng/mL and/or who expected further examination of the prostate. When prostate cancer was suspected, biopsy of the prostate was performed. In patients with prostate cancer, magnetic resonance imaging, computed tomography and bone scintigraphy were performed to diagnose the clinical stage. RESULTS: The mean serum level of PSA was 2.10 +/- 0.49 ng/mL. In this screening study, four of 41 men required further examinations for prostate cancer. Two of four refused further examinations. The other two were diagnosed with prostate cancer. The incidence of prostate cancer was at least 5% in our hemodialysis patients. One man, whose clinical stage was T2aN0M0, was treated with radical retropubic prostatectomy. Another man, whose clinical stage was T2bN0M0, was treated with luteinizing hormone-releasing hormone analogue. CONCLUSION: In our preliminary study, prostate cancer screening with PSA was useful for the early detection of prostate cancer in hemodialysis patients. If possible, DRE and TRUS should be performed in conjunction with PSA tests.     

Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C

Interferon (IFN) therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and is often limited by side effects. Cyclosporine A (CsA) is a potent immunosuppressant widely used in organ transplantation. We conducted a pilot study to determine whether CsA therapy could affect aminotransferase activity and hepatitis C virus RNA levels in patients with chronic hepatitis C. Cyclosporine A was administered to 10 patients (mean age of 59 years; male: female = 9:1) who did not respond to IFN therapy previously and who had elevated serum alanine aminotransferase (ALT) values for at least 6 months. All patients were positive for HCV-RNA by RT-PCR with genotype 1b. Their mean duration of hepatitis was 15 years. Oral CsA was given for 3 months in a dose that was increased at 1 month intervals from 1.5–2.0 to 2.0–3.0 and 3.0–4.0 mg/kg per day. All patients completed the treatment schedule, although two patients developed mild non-symptomatic hypertension. Serum ALT levels gradually decreased in all but one patient. The mean percentage decrease was 59.5% at the end of therapy (from 153 ± 82 to 62 ± 48 IU/L; P < 0.02). The ALT levels fell to the normal range in five patients, although once therapy was discontinued the enzyme levels tended to return to pretreatment levels. Serum aspartate aminotransferase and g-glutamyl transpeptidase levels similarly decreased. The serum HCV-RNA titre, determined by competitive RT-PCR, did not change in any patient throughout the study period. There were no appreciable alterations in other laboratory tests, such as serum creatinine levels and lymphocyte subsets, except for an increase in serum alkaline phosphatase levels. These findings suggest that CsA, even in a relatively low dose, reduces serum aminotransferase levels without serious side effects in patients with chronic-hepatitis C, although an antiviral effect was not noted.     

Evaluation of Mini Mental State Examination and Brief Psychiatric Rating Scale on aged schizophrenic patients

Abstract  Mini Mental State Examination (MMSE), Brief Psychiatric Rating Scale (BPRS) and subscales of the BPRS were performed on 73 elderly inpatients (mean age: 67.9 years; standard deviation: 7.2; range: 60–89) diagnosed with DSM-III-R chronic schizophrenia. Forty of the subjects were men and 33 were women. A significant negative correlation was observed between MMSE and the age, factor negative, factor depressive, and total score of BPRS. We believe, however, that it is relatively sufficient to screen for demented illness of schizophrenics using MMSE when considering the age and the psychiatric symptoms (especially negative or depressive symptoms). Forty-eight (66%) of the 73 patients were categorized as 'demented' by MMSE. These results suggest that the aged inpatients with schizophrenia in a hospital showed certain kinds of cognitive deficits (including senile dementia) more frequently than the general population.     

Growth Kinetics of Hepatocellular Carcinoma

We measured the size of 17 semispherical hepatocellular carcinomatumor nodules in 13 patients repeatedly by either computed tomographyor ultrasonography for 10 to 291 days. At the initial examinationthe diameter of these tumors was 30 ± 15 mm (mean ±SD).When the doubling time of these tumor volumes was calculatedby the formula proposed by Schwartz, it was 119 ± 96days (mean ± SD). There was no correlation between thedoubling time of the tumors and the degree of impairment ofliver function in any case. There was also no correlation betweenthe doubling time of the tumors and the alpha-fetoprotein level.However, in patients with hepatitis B surface antigen, the doublingtime was short (48 ± 8 days), when compared with theantigen-negative cases (140 ± 98 days). Based on the shortest doubling time of the smaller tumors, itwas revealed that the diameter was duplicated in four months.Since the minimum tumor diameter that was detected by ultrasonographyand/or computed tomography was considered to be 1 cm, we recommendthat ultrasonography and/or computed tomography should be performedat least every four months to detect so-called "small hepatocellularcarcinoma," which has a diameter of less than 2 cm, in patientsat high risk for hepatocellular carcinoma.     

Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test (OECD): Familiarization Using Cyclophosphamide

Combined Repeat Dose and Reproductive/Developmental ToxicityScreening Test (OECD): Familiarization Using Cyclophosphamide.TANAKA, S., KAWASHIMA, K., NAITO, K., USAMI, M., NAKADATE, M.,IMAIDA, K., TAKAHASHI, M., HAYASHI, Y., KUROKAWA, Y., AND TOBE,M. (1992A, Y., AND TOBE, M. (1992). Fundam. Appl. Toxicol. 18,89–95. A familiarization study was conducted on the "Combined RepeatDose and Reproductive/Developmental Toxicity Screening Test(ReproTox)" proposed by the OECD. Cyclophosphamide (CP) at dosesof 6.7, 4.5, 3, 2, and 0 mg/kg body wt was given daily by gavageto groups of 12 male and 12 female Sprague-Dawley rats. As aresult, anemia and leukopenia were evident in treated males.The absolute and relative thymus and spleen weights were decreasedin treated rats. Histopathologically, atrophy of the thymus,spleen, and bone marrow was observed. With respect to the reproductive/developmentaltoxicity, dose-dependent increases in postimplantation lossof fetuses and postnatal death were found in dams given CP.The body weight of pups treated with CP was significantly loweredin a dose-related manner. Thus the results demonstrated mostof the known toxicological properties of CP, except the adverseeffects on spermatogenesis and fertility. Therefore ReproToxcan be considered as a useful screening test for assessing repeatdose and reproductive/developmental toxicity of existing chemicalsof high production volume.