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PubMed1985

The pathologic response of the liver and thyroid of the rat to potassium prorenoate (SC-23992).

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone- 16-alpha-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4 elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.

Animals↗
PubMed1989

[Pathologic response of the retinal pigment epithelium. The effect of mucopolysaccharide in the subretinal space to phagocytosis. Part 5].

Previously we reported that retinal pigment epithelial cells (RPE) showed different phagocytotic activity according to the charge characteristics of the surface of polystyrene particles which were injected into the subretinal space of albino rats. In this study we examined whether subretinal mucopolysaccharide controls RPE phagocytosis or not, using positive or negative charged particles (3 microns in diameter). The technique of ruthenium red staining, a cationic dye, was employed with special efforts to detect the relationship between acid mucopolysaccharide and particles at the electron microscopic level. Six hours after injection of the positive charged particles, the ruthenium red staining revealed fine granular electron-dense materials, coating the surfaces of many small substances surrounding polystyrene particles which were not yet phagocytized by RPE. On the other hand, there was no staining of negative ones which were already phagocytized by RPE. At 24 hours, no staining was observed on the surface of either particles. These findings suggest that an anionic property of mucopolysaccharide in the subretinal space controls the phagocytosis of RPE.

Animals↗
PubMed1989

[Pathologic response of the weak damaged retinal pigment epithelium (RPE)--affected by sodium iodate (NaIO3)].

We examined the cellular responses of the retinal pigment epithelium (RPE) damaged by sodium iodate. RPE was damaged by intravenous administration of sodium iodate, 10mg per kg body weight, in rats. This dose of the agent damaged RPE weakly. Twenty-four hours after the administration of sodium iodate, polystyrene particles were injected into the subretinal space trans-sclerally. Rats were sacrificed at 6 hours to 4 days after injection of particles. Twenty four hours after injection of sodium iodate, RPE were weakly damaged. The cell organelles were swollen and ruptured, but cell structures were not destroyed. Then particles were injected into the subretinal space, RPE did not phagocytize the particles until 24 hours after the injection of particles. After 48 hours, RPE showed proliferation. After 4 days, RPE formed thick multilayers in the subretinal space and transformed to spindle shapes, and RPE underwent metaplasia to fibroblast-like cells. However proliferation of RPE was not marked. RPE cells weakly damaged by sodium iodate showed delay in phagocytosis of the particles and decrease in proliferation and metaplasia to fibroblast-like cells.

Animals↗
PubMed1989

[Pathologic response of the regenerated retinal pigment epithelium (RPE)--affected by sodium iodate (NaIO3)].

Phagocytosis, proliferation and metaplasia to fibroblast-like cells in the regenerated retinal pigment epithelial cell (RPE) were examined after damage caused by administration of sodium iodate. The solution of sodium iodate (40 mg/kg) was given in a single intravenous injection in rats. Three days after injection, RPE showed marked necrotic damage, but in 2 weeks flat regenerated RPE with short microvilli and no basal infolding were seen on Bruch's membrane. Polystyrene particles were then injected into the subretinal space. The rats were sacrificed 6 hours to 4 days after injection of the particles. The regenerated RPE showed phagocytosis within 6 hours. After 48 hours, they showed multilayer proliferation. After 4 days RPE transformed to spindle-shaped fibroblast-like cells. However proliferation and metaplasia of RPE markedly decreased. The results showed significant decrease in the function of regenerated RPE-cells as a result of their damage.

Animals↗
PubMed1986

Systemic pathologic responses in experimental Psoroptes ovis infestation of Hereford calves.

Nine Hereford calves were infested with Psoroptes ovis and were allowed to develop clinical mange during a 9-week period. Blood, serum, and urine samples were obtained before and after calves were infested and were compared with those from 3 noninfested control calves. All calves were euthanatized and necropsied 9 weeks after they were infested. Gross and microscopic anatomic changes occurred only in the skin. Calves developed typical exudative dermatitis, the extent of which was dependent on population density of mites. Severely infested calves (50% to 70% of skin with dermatitis) developed a mild anemia and lymphopenia with marked neutropenia and variable eosinophilia. There were also increases in fibrinogen, gamma-globulin, and in vitro lymphocyte response to mitogen stimulation and decreases in anion gap cortisol, albumin, albumin/globulin ratio, and fractional Na clearance values. The severity of many of the changes could be correlated with the extent of dermatitis.

Animals↗
PubMed1989

High-dose platinum consisting of combined carboplatin and cisplatin in previously untreated ovarian cancer patients with residual disease.

A phase II trial of carboplatin, 300 mg/m2 day 1, and cisplatin, 50 mg/m2 days 2 and 3 every 4 weeks for six cycles, was performed in 42 previously untreated patients with residual disease after primary laparotomy. Overall, 79% of patients had primary residual tumor larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 37 evaluable patients was 62%, and in PCRs was 22%. Of the responding patients, 78% had primary residual tumor larger than 2 cm. The toxicity was cumulative but manageable, with thrombocytopenia being the main reason for dose reduction. Dose-limiting nephrotoxicity and neurotoxicity occurred in 22% and 7% of the patients, respectively. Combined high-dose platinum as a "single agent" appears to be as active as combination chemotherapy containing cisplatin, and the treatment is feasible. Further clinical trials of this combination alone or combined with other drugs are warranted.

Adult↗
PubMed1990

Combined high-dose carboplatin and cisplatin, and ifosfamide in previously untreated ovarian cancer patients with residual disease.

Carboplatin 200 mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3, ifosfamide 1,500 mg/m2 days 1 to 3, and mesna 900 mg/m2 days 1 to 3 every 4 weeks for six cycles were given to 37 previously untreated ovarian cancer patients with residual disease after the primary laparotomy. The median observation time was 17+ months (range, 9+ to 24+ months). Of all the patients, 81% had primary residual disease larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 36 assessable patients was 58%, PCR was 42%. Of the PCR patients, 53% had primary residual tumor larger than 5 cm. The substantial hematologic toxicity was manageable, but also the main reason for dose modifications. During treatment, 92% and 100% of the patients developed WBC and platelet nadir values corresponding to World Health Organization (WHO) grades 3 to 4. Dose-limiting encephalopathy, nephro- and neurotoxicity each occurred in 6% of the patients. The high PCR rate warrants further investigations of combined high-dose platinum and ifosfamide.

Adult↗
PubMed1992

A European Organization for Research and Treatment of Cancer--Genitourinary Group phase 2 study of chemotherapy in stage T3-4N0-XM0 transitional cell cancer of the bladder: evaluation of clinical response.

From 1986 to 1990 the European Organization for Research and Treatment of Cancer--Genitourinary Group conducted a phase 2 trial of neoadjuvant chemotherapy in patients with stage T3-4N0-XM0 transitional cell carcinoma of the bladder. The objectives were to evaluate the clinical response in relation to the pathological response, and to measure the side effects of chemotherapy. Of 171 patients entered 136 were fully evaluable: 18% had clinical complete remissions, 36% had clinical partial remissions, 39% had no clinical remissions and 10% had unknown response. A selected subgroup of 76 patients underwent cystectomy after 2 or 4 courses of chemotherapy: 2 were not evaluable for pathological response because of preoperative radiotherapy after neoadjuvant chemotherapy, 16 had a pathological complete remission, 7 had a pathological partial remission and 51 had no pathological remission. Comparison of the clinical response or T category only after 2 courses of chemotherapy with the pathological response after 2 or 4 courses of chemotherapy showed that in a number of patients the disease status could be downstaged to pathological complete or partial remission by additional courses of chemotherapy. If the discrepancies between clinical and pathological responses, or between T and P categories, induced by further downstaging after additional chemotherapy were left out, it was shown that clinical complete and partial remissions were a heterogeneous group but nonresponders could be delineated with a 100% accuracy by clinical response evaluation and transurethral resection biopsy only. Furthermore it seems important to establish the number of chemotherapy courses to induce a maximal response of the primary tumor.

Adult↗
PubMed1989

Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin.

The aim of this multicenter randomized trial was to compare carboplatin (400 mg/m2) and cisplatin (100 mg/m2) in patients with untreated advanced epithelial ovarian cancer. Toxicity and treatment efficacy assessed by pathological response rate, progression-free survival, and survival were the endpoints of the study. One hundred seventy-three patients with advanced epithelial ovarian cancer, F.I.G.O. (International Federation of Gynecology and Obstetrics) stage III and IV were accrued in the trial. The median follow-up time was 15 months (maximum, 34); three patients in each treatment arm were not eligible (four, nonepithelial ovarian cancer type; one, no data, and one, stage II). Patient characteristics were similar in the two groups. In the carboplatin-treatment arm, the overall pathological response rate was 57.3% and the complete pathological response rate was 26.8%. In the cisplatin-treatment arm, the overall pathological response rate was 71.6% and the complete pathological response rate was 24.7%. There was no statistical difference in the two arms in survival or progression-free survival. Cisplatin was more nephrotoxic while carboplatin induced a higher degree of myelosuppression, especially thrombocytopenia; however, severe hematological toxicity was seldom observed. Carboplatin is a cisplatin analog with definite activity in ovarian cancer, but it is more active than the parent compound. Because of less nonhematological toxicity, carboplatin is undoubtedly a useful substitute in patients who cannot be given cisplatin. Further experience is needed to indicate whether or not carboplatin should completely displace cisplatin in the clinical treatment of ovarian cancer.

Adult↗
PubMed1987

Autonomic disturbances and cardiovascular reflexes in idiopathic Parkinson's disease.

A total of 22 patients suffering from idiopathic Parkinson's disease and 20 age-matched volunteers were questioned about autonomic disturbances and all underwent four non-invasive tests examining cardiovascular reflexes. Significantly more autonomic disturbances were reported by the patients than by the controls. Resting blood pressure was significantly decreased in patients taking dopamine agonists, whereas it was normal in those patients who only received levodopa and anticholinergics. Resting heart rate and resting beat-to-beat variation were normal in the patients, as were the blood pressure response to standing and the postural heart rate response. No pathological response to the Valsalva manoeuvre could be detected. On the other hand, the heart rate variation evoked by deep breathing as well as the blood pressure response and the heart rate response to sustained isometric exercise were significantly diminished in the patients with idiopathic Parkinson's disease. These findings indicate a central disturbance of cardiovascular reflex control, whereas the corresponding peripheral pathways seem to be normal.

Aged↗