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Biomedical subjects

J Pausch

Publications and source records attributed to J Pausch.

52 records · Page 3Linked to original sources
PubMed1985

The glutamine analog acivicin as antipyrimidine. Studies on the interrelationship between pyrimidine and urea synthesis in liver.

The inhibition of cytosolic carbamoyl-phosphate synthetase II by acivicin was used to study the role of the cytosolic carbamoyl phosphate pool as the exclusive substrate source for de novo pyrimidine synthesis in rat hepatocytes. De novo pyrimidine synthesis was stimulated: 1. by uridine triphosphate deficiency (incubation with D-galactosamine) leading to a stimulation of cytosolic carbamoyl phosphate synthesis, and 2. by accumulation and efflux of mitochondrial carbamoyl phosphate (incubation with ammonium ions and L-norvaline). The stimulated orotate formation from cytosolic carbamoyl phosphate in UTP depleted cells was completely blocked by acivicin. It was not influenced by an inhibition of mitochondrial carbamoyl phosphate synthesis mediated by 4-pentenoate, since mitochondrial carbamoyl phosphate did not participate in cytosolic pyrimidine synthesis even in the presence of ammonium ion concentrations maintaining physiological rates of urea synthesis. An excess of ammonium ions led to an artificial accumulation and efflux of mitochondrial carbamoyl phosphate, which could be avoided by 4-pentenoate. The non-regulated stimulation of pyrimidine synthesis from surplus mitochondrial carbamoyl phosphate was not inhibited by acivicin. Utilization of mitochondrial carbamoyl phosphate for de novo pyrimidine synthesis presumably does not occur under physiological conditions because mitochondrial CP efflux depends on the accumulation of this metabolite in the mitochondria under experimental or pathological circumstances. Acivicin inhibition of CPS II thus cannot be bypassed by mitochondrial CP. It is suitable as inhibitor of the physiological de novo pyrimidine synthesis.

Animals↗
PubMed1985

First clinical experiences with a selective chemotherapy of hepatocellular carcinoma with 5-fluorouridine in combination with other antipyrimidines.

Sixteen unselected patients with non-resectable hepatocellular carcinoma were treated in a phase I study with 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine. Thirty % of the patients survived for more than one year without signs of tumor progression and with an unchanged performance status. The compatibility of this chemotherapeutical method was quite satisfactory. The only extrahepatic side effect was a leucopenia and/or thrombocytopenia which was reversible upon reduction of the 5-fluorouridine dose. The heterogeneity of the 16 patients treated to date does not allow a definite statistical evaluation of the reported clinical observations and results. A final decision about the clinical applicability of this concept of a selective chemotherapy of hepatocellular carcinoma requires further experience.

Adult↗
PubMed1982

[Systemic disease closely related to Cogan's syndrome (author's transl)].

In a 51-year-old patient with non-syphilitic interstitial keratitis and disturbances of inner ear function (Cogan's syndrome) the course of the disease could be followed for 8 years. Organ manifestations which indicated generalised vascular disease were present in accordance with reports in the literature of this rare syndrome. In addition to multiple digital arterial occlusions, recurrent pulmonary infiltrations were observed which have not previously been described in connection with this syndrome. With the exception of the inner ear hearing loss the symptoms could be improved by systemic administration of corticosteroids and azathioprine. The patient remained free of recurrence for over three years.

Arterial Occlusive Diseases↗
PubMed1981

[Approaches to a selective chemotherapy of hepatocellular carcinoma (author's transl)].

1. An improvement of the chemotherapy of hepatocellular carcinoma with adriamycin or 5-fluorouracil and a reduction of side effects has been achieved by intra-arterial administration of the drugs. This treatment provides a somewhat extended survival but no cure. 2. The treatment of hepatocellular carcinoma in patients by reduction of an inactive precursor of a cytocidal alkylating agent by azoreductase of the tumor showed no therapeutic effect. 3. A selective hepatocellular uptake of drugs coupled to asialoglycoproteins has been described. An application of this concept for the chemotherapy of hepatocellular carcinoma seems doubtful since a loss of binding proteins for desialylated glycoproteins during experimental hepatocarcinogenesis has been demonstrated. 4. The increased uptake of 5-fluorouridine in hepatomas after induction of a tissue-specific depletion of uridine 5'-triphosphate and cytidine 5'-triphosphate provides an effective experimental chemotherapy with limited side effects. A clinical use of this new concept for the chemotherapy of hepatocellular carcinoma may serve as a useful approach.

Antineoplastic Agents↗
PubMed1977

[Biochemical and pathophysiological aspects of hyperammonaemia (author's transl)].

1. Ammonia liberated continuously in large amounts in muscle, kidney and brain is used immediately for the synthesis of mainly glutamine because of the toxic effects of elevated ammonia concentrations. After glutamine hydrolysis in the liver ammonia serves as substrate for the urea biosynthesis. In ureotelic animals urea is the quantitatively most important product for the elimination of surplus nitrogen. 2. The rate of urea biosynthesis depends on the amount of surplus nitrogen and acts as regulatory factor for the nitrogen balance of the adult organism. 3. Urea cycle abnormalities in liver diseases or inborn enzymatic defects are important factors leading to hyperammonaemia in patients. 4. The hyperammonaemia induces an increase of the rate of hepatic pyrimidine nucleotide biosynthesis as a consequence of an ineffective feedback inhibition of the glutamine-dependent carbamoyl phosphate synthetase. 5. The distribution of ammonia between intra- and extracellular space and the amount of ammonium ions excreted in the urine depend on the pH value. An alkalosis induces an intracellular ammonia load and inhibits the urinary ammonium ion excretion, which is increased in acidosis as one mechanism of protein elimination. 6. The ammonia-induced inhibition of the citric acid cycle by an alpha-ketoglutarate deficiency is one important reason for the neurotoxicity of ammonia, which is the main point in the pathogenesis of hepatic coma.

Ammonia↗
PubMed1975

Control of pyrimidine biosynthesis in the perfused liver. Feedback inhibition of glutamine-dependent carbamoyl phosphate synthetase.

The site of feedback inhibition of the biosynthesis of pyrimidine nucleotides de novo was investigated in the isolated perfused rat liver. Hepatic uridine phosphate contents were specifically depleted by use of D-galactosamine. The effective activities of enzymes involved in the synthetic pathway were deduced from the rats of incorporation of labeled precursors into the acid-soluble uracil nucleotide pool and into some intermediates of the pathway. The labeling of hepatic urea was also monitored. When the uridine phosphate contents were less than 20% of controls, the incorporation of [14-C]-bicarbonate was stimulated about 20-fold. Label from [U-14C]oxaloacetate used as permeable precursor of intrace-lular aspartate was introduced into the uridylates to the same extent in normal and UTP-depleted livers. Similar results were obtained with labeled carbamoyl phosphate although the uptake of this compound by the liver was rather low. The lack of labeling of urea from exogenous carbamoyl phosphate does not indicate a free exchange of extra- and intramitochondrial carbamoyl phosphate. [ureido-14C]Ureidosuccinate produced in normal and D-galactosamine-treated livers almost identical labeling patterns of dihydroorotate, orotate and orotidine 5'-phosphate. The steady state concentrations of these intermediates were all below 15 nmol/g liver wet weight.

Adenosine Triphosphate↗