PubMed Health⌕ Search

Biomedical subjects

J L Skibba

Publications and source records attributed to J L Skibba.

At least 37 records · Page 2Linked to original sources
PubMed1983

Altered hepatic functions and microsomal activity in perfused rat liver by hyperthermia combined with alkylating agents.

Livers of fasted rats were perfused for one hour in the presence of cyclophosphamide (CP), mechlorethamine (HN2), or melphalan (L-PAM) at 37 degrees and 42 degrees C. Hepatic biosynthetic function was assessed by determining gluconeogenesis from lactate, ureogenesis from NH4Cl, and O2 consumption. Antipyrine (AP) metabolism was employed to assess microsomal mixed function oxygenase enzyme activity at elevated temperatures. The t 1/2 of AP increased 2.8-fold in a temperature-dependent manner between 37 degrees and 43 degrees C. In the presence of biosynthetic substrates, the t 1/2 of AP increased 1.8-fold between 37 degrees and 43 degrees C. CP activation was suppressed (27% at 125 micrograms/ml, 49% at 500 micrograms/ml) at 42 degrees C. The presence of biosynthetic substrates significantly attenuated the suppression of CP activation by hyperthermia. A dose-dependent decrease in biosynthetic function occurred in the presence of CP at 37 degrees and 42 degrees C suggesting hepatotoxicity and/or competition for biochemical intermediates. The t 1/2 of HN2 at 50 micrograms/ml was slightly decreased by 11% at 42 degrees C (19.6 min vs. 17.4 min). The half-lives of 10 micrograms/ml HN2 and 5 micrograms/ml L-PAM were not altered at 42 degrees C (17.1 min vs. 16.4 min and 44.6 min vs. 44.1 min, respectively). The adverse effects of HN2 and L-PAM on hepatic biosynthetic functions were minimal suggesting that alkylating agents not requiring metabolism by the liver would be most useful for hepatic thermochemotherapy. The data indicate that hyperthermia depresses hepatic microsomal drug metabolizing enzyme function and alters the perfusate pharmacokinetics of alkylating agents. Moreover, manipulation of the hepatic biochemical environment may modify the adverse effects of hyperthermia on microsomal activity.

Alkylating Agents↗
PubMed1983

Azathioprine induction of lymphomas and squamous cell carcinomas in rats.

The carcinogenicity of azathioprine was evaluated in weaning female noninbred Sprague-Dawley rats by feeding it in the diet. Due to toxicity, the dose had to be changed during the course of the experiments and ranged from 0.015 to 0.04% of the diet by weight. In the first experiment, the estimated maximal cumulative consumption of azathioprine was 1.5 g/rat. Of the 14 rats evaluated, six developed thymic lymphomas, and four developed squamous cell carcinomas of the ear duct. When the experiment was repeated with a slightly lower daily consumption but with a cumulative total dose of 2.2 g/rat, there were seven of 19 rats with thymic lymphoma and two rats with ear duct carcinoma. These data support the hypothesis that azathioprine is a carcinogen.

Animals↗
PubMed1982

Altered hepatic disposition of doxorubicin in the perfused rat liver at hyperthermic temperatures.

The perfused rat liver was used to study the effects of heat on hepatic functions and on the metabolism and biliary excretion of doxorubicin (Ad). Livers were perfused for 1 hour at 37 degrees C and 42 degrees C in the presence of biosynthetic substrates with or without Ad. Gluconeogenesis was decreased at both temperatures in the presence of Ad. Bile flow and excretion of Ad ceased at 42 degrees C. Perfusate levels of Ad were not significantly different in the 1-hour perfusions. Livers were then perfused at 37 degrees C and 41 degrees C for 3 hours in the presence of 10 mM glucose and amino acids. The beta half-life of Ad measured as total fluorescence and as parent drug was prolonged at 41 degrees C. The area under the plasma concentration-time curve was unchanged for parent drug but increased from 2010 micrograms/ml . min at 37 degrees C to 4477 micrograms/ml . min at 41 degrees C for total drug equivalents. Biliary excretion of total Ad equivalents was 7.39% +/- 1.35% of the total dose at 37 degrees C and 2.56% +/- 2.08% of the total dose at 41 degrees C (P less than 0.05). Biliary excretion of Ad was 2.07% +/- 0.37% of the total dose at 37 degrees C and 1.31% +/- 0.84% of the total dose at 41 degrees C (P less than 0.05). Hepatic tissue levels of total Ad equivalents were 288.7 +/- 21.2 micrograms/g at 37 degrees C and 322.7 +/- 10.6 micrograms/g at 41 degrees C (P less than 0.05). Tissue levels of Ad were 57.5 +/- 14 micrograms/g at 37 degrees C and 23.0 +/- 10.7 micrograms/g at 41 degrees C (P less than 0.05). Bile flow at the two temperatures decreased after 2 hours of perfusion. The greatest decrease in bile flow occurred during the third hour of perfusion at 41 degrees C. The data indicate that at elevated temperatures there was a significant alteration in the pharmacokinetics of Ad in the perfused rat liver system. Since the liver plays a primary role in the metabolism and elimination of Ad, the observed changes might also occur during wholebody hyperthermia.

Animals↗
PubMed1980

Effect of palmitate on hepatic biosynthetic functions at hyperthermic temperatures.

Livers of fasted rats were perfused for 80 min at 37 degrees-43 degrees C, supplemented with lactate, NH4Cl, and ornithine in the presence or absence of palmitate. Hepatic functional integrity was maintained from 37 degrees to 42 degrees C as assessed by gluconeogenesis, ureogenesis, and O2 consumption. Between 42 degrees and 43 degrees C a sharp decline in biosynthetic function occurred. The sharp decline in biosynthetic function occurred. The ratio of lactate disappearance to glucose formation increased progressively with increasing temperature when compared with the ratio obtained at 37 degrees C. Exogenous palmitate significantly decreased the ratio of lactate disappearance to glucose formation at 43 degrees C. Furthermore, palmitate attenuated the detrimental effects of hyperthermia on gluconeogenesis, ureogenesis, and O2 consumption found in the absence of palmitate. The 3-hydroxybutyrate/acetoacetate ratio progressively decreased as the liver temperature was increased in the presence or absence of palmitate, indicating a more oxidized mitochondrial redox state. Palmitate significantly increased the 3-hydroxybutyrate/acetoacetate ratio in the presence of gluconeogenic and ureogenic substrates at all temperatures examined. The data suggest that provision of fatty acid has a protective effect in thermally stressed liver. Moreover, palmitate may substitute for the increased energy requirements of the hyperthermic state.

Ammonium Chloride↗
PubMed1980

Modification of the 4-(p-nitrobenzyl) pyridine assay for measurement of melphalan and mechlorethamine in plasma.

A sensitive, reproducible spectrophotometric assay for mechlorethamine and melphalan was developed through modifications in the use of 4-(p-nitrobenzyl) pyridine as the chromogenic reagent. Key factors that led to enhanced color development and consistency of results were: (1) protein precipitation with 4 degrees C perchloric acid; (2) control of the pH of the reaction with acetate buffer; (3) precise timing of color development in alkali; and (4) sample reading at the appropriate wavelength. The modifications allowed measurement of mechlorethamine and melphalan levels in perfusate samples obtained from isolated rat liver perfusions. Half-lives calculated from perfusate decay curves after addition of mechlorethamine at 50 microgram/ml and 10 microgram/ml were 15.9 min and 15.0 min respectively. The perfusate half-life after addition of melphalan at 5 microgram/ml was 44.2 min. Plasma levels of mechlorethamine were not detectable by this assay after intrapleural administration of 15 mg to one patient but were detectable after intravenous administration of 20 mg to a second patient.

Animals↗
PubMed1980

Inhibition of hepatic macromolecular processes in normal and regenerating liver by hyperthermia.

Incorporation of radioactive precursors into DNA, RNA and protein fractions isolated from perfused normal and 22 h regenerating rat livers were measured at temperatures between 37 and 43 degrees C. Compared to the 37 degrees C control levels of precursor incorporation, significant inhibition of precursor incorporation into nucleic acids and protein from slowly and rapidly proliferating livers occurred from 41 degrees to 43 degrees C. The time course of release of newly labeled protein into the perfusate was determined during 1.5 h of perfusion at supranormal temperatures in normal and regenerating liver. Release of radioactive labeled protein into the perfusate was significantly suppressed between 41 degrees and 43 degrees C in a time- and temperature-dependent manner. In both experimental models, the sharpest drop in the rates of precursor incorporation was found between 42 degrees C and 43 degrees C. It is concluded that hyperthermic perfusion (41 degrees to 43 degrees C) significantly suppresses precursor incorporation into hepatic DNA, RNA and protein in normal and regenerating liver. Moreover, the data indicate that macromolecular processes in regenerating liver are no more sensitive to the stress of hyperthermia than those found in normal liver.

Animals↗
PubMed1976

Effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide and its metabolites on Novikoff hepatoma cells.

Studies were undertaken to determine the effects of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) and its metabolites on the growth and macromolecular synthesis of Novikoff hepatoma cells in culture. DTIC (3.0 mM) in light decreased the viable cell count by 90% within 96 hr. DTIC protected from light, 2-azahypoxanthine, dimethylamine, and 5-aminoimidazole-4-carboxamide, all at 3.0 mM, reduced the rate of cellular proliferation. 5-Diazoimidazole-4-carboxamide (1.0 mM) and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (3.0 mM) decreased the viable cell count by 99%. Effects on macromolecular synthesis were determined by the rate of incorporation of the appropriate 3H-labeled precursor. Results after 6 hr are given as percentage of controls. DTIC (1.0 mM) in light inhibited DNA (8%), RNA (41%), and protein (63%) synthesis. DTIC (1.0 mM) protected from light inhibited DNA (12%) and RNA (57%) synthesis. 5-Diazoimidazole-4-carboxamide (0.1 mM) inhibited DNA (1%), RNA (9%), and protein (1%) synthesis. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (1.0 mM) inhibited DNA (72%) and protein (65%) synthesis but stimulated RNA (127%) synthesis. 2-Azahypoxanthine (1.0 mM) inhibited DNA (43%), RNA 82%) and protein (28%) synthesis. 5-Aminoimidazole-4-carboxamide (3.0 mM) stimulated DNA (354%) and RNA (266%) synthesis. These data show that DTIC is able to generate several toxic metabolites that may be responsible for its biological effects.

Animals↗
PubMed1975

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.

Adenofibroma↗
PubMed1975

Urinary bladder effects of levodopa in hamsters.

Levodopa (3,4-dihydroxyphenyl-L-alanine) was fed at 1.0% of the diet to 60 male weanling Syrian golden hamsters for 48 weeks, followed by control diet for an additional 38 weeks. The incidence of tumors were: three of 60 hamsters with forestomach squamous cell papillomas, one of 60 with leiomyosarcoma of the skin, and one of 60 with cortical adrenal adenoma. Two of 30 control animals developed adrenal adenomas. Hyperplasia of the urinary bladder epithelium occurred in 33 of the treated group, and hyperplasia was not found in the bladders of the control group.

Administration, Oral↗