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N Frank

Publications and source records attributed to N Frank.

At least 19 recordsLinked to original sources
PubMed1992

Proline dithiocarbamate inhibits N-nitrosodiethylamine induced liver carcinogenesis.

A study was conducted to determine the toxicity of different dithiocarbamates and of disulfiram. In an experiment showing the cytotoxicity against murine spleen lymphocytes, proline dithiocarbamate (PDTC) and thioproline dithiocarbamate showed the lowest toxicity. Therefore one of them was selected and different doses of the hydrophilic PDTC were checked for their ability to affect the development of liver and oesophagus tumours induced in BD-6 rats by N-nitrosodiethylamine (NDEA). Rats were injected i.p. with 80 mg/kg NDEA once weekly for 10 weeks. Administration of PDTC, 1 h before and 24 h after the carcinogen, markedly decreased the number of rats developing NDEA-induced hepatocellular carcinoma and liver haemangioendothelioma. A 59%-77% reduction in the incidence of liver tumours was found in the different groups when the carcinogen was administered in combination with the inhibitor. For least 40 weeks after the start of the experiment PDTC protected the liver from NDEA carcinogenesis and did not shift the tumour development to any other organ. PDTC did not significantly affect the weight gain of the experimental animals. We conclude that parenteral administration of PDTC seems to represent a promising approach in chemoprevention of liver carcinogenesis.

Animals↗
PubMed1991

Newly synthesized dithiocarbamates inhibit the metabolism and toxicity of N-nitrosodimethylamine.

Several dithiocarbamates (DTC) of secondary amines and secondary amino acids were tested for their stability in aqueous solution and for their effect on nitrosamine metabolizing enzymes and on the acute toxicity of N-nitrosodimethylamine (NDMA) in rats. The following results were found: (i) All DTC tested were stable in alkaline solution; in acidic milieu, only DTC derived from secondary amino acids were moderately stable. (ii) The activity of NDMA-demethylase in rat liver microsomes was inhibited completely by all DTC tested. (iii) The excretion of unmetabolized NDMA in rat urine over 24 h increased from 0.1% without pretreatment to 3.6% of the given NDMA dose when combined with a single dose of DTC. (iv) The acute toxicity of NDMA was reduced by dihydroxyethyldithiocarbamate; when the sulfur compound was administered simultaneously and 24 h after the nitrosamine, lethality was almost completely inhibited. (v) The stability of a compound in aqueous solutions did not affect its activity in the enzyme tests.

Animals↗
PubMed1991

[The laboratory animal management system--an animal housing management data-processing system].

The Laboratory Animal Management System (LAMS) is a flexible, multi-purpose animal house management tool. It has a decentralized structure and was developed using UNIFACE and Oracle-database software. The multiuser LAMS system runs on a Micro-Vax computer and can be accessed from several workstations. LAMS has been designed to manage the following functions: animal study details; animal procurement; book keeping and follow-up; amendments; update of data; inquiries; statistics and numerous additional tasks. LAMS is a user-friendly interactive system which does not allow input of incorrect data and can be operated by staff with very little computer experience. The system fully complies with German legal requirements and is becoming an increasingly important tool for routine management of animal house facilities and animal experimentation.

Animals↗
PubMed1990

Detoxifying potential of thioproline against N-nitroso compounds, N-nitrosodimethylamine and N-nitrosocimetidine.

Thioproline (TPRO), an effective nitrite trapping agent in vivo, was examined for its detoxifying ability in rats against N-nitrosodimethylamine (NDMA) and N-nitrosocimetidine (NCIM). When NDMA (37-101.5 mg/kg) was administered with TPRO (532 mg/kg), no influence of TPRO on NDMA-induced lethality and histological results in liver were observed. NDMA oxygenase activity measured by formaldehyde formation was not affected either. Denitrosation is a route of detoxication of N-nitroso compounds. When NCIM (100 mg/kg), a direct acting mutagen but not carcinogen, was given by gavage with TPRO, urinary excretion of N-nitrosothioproline (NTPRO) in rats apparently increased compared with TPRO alone. This result shows that TPRO is a trapping agent in vivo for nitrosating (NO) species originating from N-nitroso compounds, e.g., NCIM, which are denitrosated non-enzymatically in stomach acidic conditions. Transnitrosation from NDMA to TPRO, where enzymatic denitrosation is required, did not occur in measurable amount after oral administration of NDMA and TPRO.

Animals↗
PubMed1990

Sacrosine- and prolinedithiocarbamate pretreatment increases the therapeutic efficacy of doxorubicin, methotrexate, teniposide, mitoxantrone or cyclohexylchloroethylnitrosourea in leukemia L1210.

The influence of different doses of the hydrophilic sarcosine- or prolinedithiocarbamate on the chemotherapeutic efficacy of doxorubicin, teniposide, methotrexate, mitoxantrone or cyclohexylchlorethylnitrosourea was evaluated in female B6D2F1 mice bearing leukemia L1210, implanted intraperitoneally. The simultaneous administration of these dithiocarbamates and the drugs used induced no increase of the therapeutic efficacy of the combinations compared to the corresponding dose of the drug and simultaneously applied saline. The results indicate that the subcutaneous pretreatment with sarcosine- or prolinedithiocarbamate increased the therapeutic efficacy of the drugs used compared to the corresponding monotherapy, in which saline was applied in the same interval as the dithiocarbamate and the antineoplastic agents. Sarcosine- or prolinedithiocarbamate applied alone did not influence leukemia L1210. The increase of the efficacy of the drugs used by sequential combination with sarcosine- or prolinedithiocarbamate seems to be influenced predominantly by diminishing the toxicity as well as by modulating the chemotherapeutic action.

Animals↗
PubMed1990

N-nitrosamino phosphates are unlikely transport forms for activated nitrosamines.

Some of the target organs for nitrosamine carcinogenicity have a low activating capacity but many carcinogenic nitrosamines can be activated in the liver. Conjugates, such as phosphates, are chemically accessible reaction products of 1-OH-nitrosamines, and are either potential detoxication products or potential transport forms for activated nitrosamines. 14C-labeled 1-(N-ethyl-N-nitrosamino)ethyl phosphate was tested for its ability to enter primary rat hepatocytes but no uptake was detectable. No uptake was observable into fibroblasts and human leukocytes. N-Nitrosomethylbenzylamine is efficiently 1-C-hydroxylated by hepatocytes but the corresponding 1-C-phosphate was detectable neither in the cells nor in the surrounding medium. N-Nitrosamino-1-phosphates, unlike 1-glucuronides, therefore, do not seem to be important for nitrosamine toxicokinetics.

Animals↗
PubMed1990

Alterations in dimethylnitrosamine-induced lethality and acute hepatotoxicity in rats during dietary thiamin, riboflavin and pyridoxine deficiencies.

The effects of dietary thiamin, riboflavin and pyridoxine deficiencies on dimethylnitrosamine-induced lethality and hepatotoxicity were investigated in the rat. Development of deficiencies was monitored by growth rate, food intake, ratio of liver weight to body weight and the biochemical parameters (thiamin diphosphate effects for thiamin deficiency, glutathione reductase activity coefficient for riboflavin deficiency and erythrocyte glutamate-oxaloacetate transaminase activity for pyridoxine deficiency). Thiamin deficiency slightly increased the acute toxicity of dimethylnitrosamine as observed by the lowering of the LD50 dose and the greater increase in the serum glutamate-oxaloacetate transaminase and serum glutamate-pyruvate transaminase levels. Riboflavin deficiency, on the other hand, slightly increased the LD50 dose of dimethylnitrosamine and resulted in less dimethylnitrosamine-induced damage to the liver. Pyridoxine deficiency did not affect the lethal dose nor significantly alter the transaminases levels.

Alanine Transaminase↗
PubMed1990

Influence of dithiocarbamates on the metabolism and toxicity of N-nitrosodimethylamine in rats.

Five secondary amines and secondary amino acids were reacted with carbon disulfide to yield dithiocarbamates. These compounds were tested for their influence on biochemical parameters and on some biological effects of N-nitrosodimethylamine (NDMA). The following results were found. (i) All dithiocarbamates tested reduced the activity of N-nitrosodiethylamine-deethylase and completely inhibited the N-nitrosodimethylamine-demethylase in the rat liver. A striking influence on the glutathione content and on the activity of glutathione-S-transferase and glutathione-reductase was not observed. (ii) The excretion of unmetabolized N-nitrosodimethylamine in rat urine during 24 h increased from 0.1% without pretreatment to 3.6% of the given dose on combination with a single dose of dithiocarbamate. (iii) The acute toxicity of NDMA could be reduced with diethanol-dithiocarbamate. After a single simultaneous application of the inhibitor with NDMA, the LD50 was increased from 40 to 66 mg/kg. When the sulfur compound was administered twice, both simultaneously and 24 h after the nitrosamine, lethality was almost completely inhibited. We conclude from these results that dithiocarbamates may be suitable compounds for chemoprevention of nitrosamine-induced tumors.

Animals↗
PubMed1989

Metabolism of N-nitroso-hydroxyethyl-alkylamine phosphate esters in the rat.

The metabolism of 1-(N-methyl-N-nitrosamino)-ethylphosphate and 1-(N-ethyl-N-nitrosamino)-ethylphosphate in the rat was investigated. The determination of blood clearance, organ clearance, excretion of parent compounds in the urine and the exhalation of radiolabeled CO2 originating from a nitrosaminophosphate demonstrated a rapid metabolism of the compounds. The high activity of alkaline phosphatase in kidney caused a very rapid degradation of the nitrosamino phosphates in kidney homogenate, whereas the compounds were relatively stable in liver homogenate and serum. We, therefore, suggest a rapid degradation of such nitrosamino conjugates, if they are formed at all, in vivo.

Animals↗
PubMed1989

Right ventricular dysfunction in septic shock: assessment by measurements of right ventricular ejection fraction using the thermodilution technique.

Right ventricular ejection fraction (RVEF) was measured by the thermodilution technique in a series of 127 consecutive critically ill patients monitored with a modified pulmonary artery (PA) catheter equipped with a fast response thermistor. Thermodilution RVEF was significantly lower in septic shock (23.8 +/- 8.2%, 93 measurements) than in sepsis without shock (30.3 +/- 10.1%, 118 measurements) or in the absence of sepsis or cardiopulmonary impairment (32.5 +/- 7.1%, 62 measurements). Both myocardial depression and pulmonary hypertension could account for this impairment of RV function. RVEF decreased from 35.1 +/- 9.8 to 24.2 +/- 10.4% (P less than 0.01) during development of septic shock and increased from 25.0 +/- 7.6 to 29.8 +/- 8.5% (P less than 0.05) during recovery (14 patients). Initial RVEF in septic shock was 27.8 +/- 8.6% in 11 patients who survived but only 20.9 +/- 6.7% (P less than 0.02) in the 23 patients who eventually died. Thus, RV dysfunction is common during septic shock, is directly related to its severity, and can easily be recognized in patients monitored with a PA catheter.

Adult↗
PubMed1988

Marked increase in the urinary level of N-nitrosothioproline after ingestion of cod with vegetables.

When five volunteers were given food containing cod and vegetables (a traditional Japanese food, called tara-chiri), their urinary excretion of N-nitrosothioproline increased from 7.9 +/- 4.2 (SD) micrograms/day to 110 +/- 64.5 micrograms/day. This increase was accounted for by in vivo nitrosation of of thioproline by nitrite formed from nitrate in the vegetables. This finding was confirmed by results on a volunteer who ate boiled cod and Japanese radish (daikon) (a simple version of the food containing cod and vegetables). Boiled cod was found to contain 300-500 micrograms/100 g of thioproline, and the level nearly doubled when the cod was boiled with Japanese radish. This increase occurred during the cooking of cod with Japanese radish by the reaction of formaldehyde in the cod with cysteine in the Japanese radish. The nitrosation of thioproline was estimated to be 1000-fold that of proline in the human body. Thus thioproline is a very sensitive probe of in vivo nitrosation. Thioproline formation either in vivo or in vitro may have the following two roles in reducing tumorigenesis in humans: (a) detoxication of formaldehyde, which is genotoxic; and (b) blocking the formation of carcinogenic N-nitroso compounds by trapping nitrite and then being excreted in the urine.

Animals↗
PubMed1988

Influence of thiocompounds on the metabolism of N-nitrosodiethylamine.

Diethyldithiocarbaminate (DDTC), mercaptoethanesulfonate (MESNA) and ethylxanthate (PEX) were tested for their influence on N-nitrosodiethylamine (NDEA) metabolism. The exhalation rate of 14CO2 released from [14C]NDEA was decreased by PEX, but not by MESNA or DDTC. The sulfur compounds led to an increased excretion of unchanged NDEA in urine in the order PEX greater than DDTC much greater than MESNA. The activity of NDEA-deethylase in liver microsomal system was decreased only after DDTC or PEX treatment. Glutathione content and glutathione-S-transferase activity were not affected significantly by any of the tested compounds. NDEA-induced single-strand breaks in liver cell DNA were inhibited after PEX treatment.

Animals↗
PubMed1988

pH-dependent degradation of nitrosocimetidine and its mechanisms.

The degradation of nitrosocimetidine (NC) and its mechanism were found to be strongly dependent upon pH by monitoring NC and its degradation products by high-performance liquid chromatography (HPLC). NC was relatively stable at neutral pH, but it degraded rapidly under both acidic and alkaline conditions. In a strongly acidic solution, the degradation was shown to be entirely by denitrosation, but under alkaline conditions scarcely any denitrosation was observed and various other degradation products were found. At neutral pH, both these degradation mechanisms were observed. In neutral solution, the presence of thiol compounds greatly shortened the half life of NC, and enhanced its denitrosation. The high degradation rate in acidic solution, the strong influence of thiol groups, and the preference of denitrosation at pH 0.3-5 can explain the discrepancy between the in vitro genotoxicity and the lack of carcinogenicity of NC.

Acetylcysteine↗
PubMed1988

Effects of potassium ethylxanthogenate on nitrosodiethylamine-induced DNA damage and on liver carcinogenesis.

BD-6 rats were injected with 80 mg/kg N-nitroso-diethylamine weekly for 10 weeks. Addition of 270 mg/kg potassium ethylxanthogenate weekly reduced significantly the number of rats developing NDEA-induced malignant liver tumors. Ethylxanthogenate decreased the total number of liver tumors induced by the carcinogen to 6 as compared to a total of 29 neoplasms in animals treated only with NDEA. In acute experiments potassium ethylxanthogenate markedly decreased the exhalation of 14CO2 derived from 14C-NDEA. The amount of the nonmetabolized carcinogen increased in the urine of ethylxanthogenate protected rats only 4% of the given dose. Initial DNA damage, single strand breaks and alkali-labile sites, was determined by alkaline sucrose gradients and in protected animals was minimal for at least 24 hours after NDEA administration. It appears that the production of less initial DNA damage may be important for the further course of liver carcinogenesis induced by relatively large doses of nitrosodiethylamine.

Animals↗
PubMed1987

Locoregional application of 5-fluorouracil to the liver: alteration of pharmacokinetics and bone marrow toxicity in rats with thioacetamide-induced cirrhosis.

Pharmacokinetics and toxicity of 5-fluorouracil (5-FU) applied intra-arterially into the liver were studied in control and cirrhotic rats. Cirrhosis was induced by administering thioacetamide (4.5 mg/rat X day) over 6 months. 5-FU was administered into the hepatic artery at 30 mg/kg b.w. by bolus injection followed by infusion of 0.63 mg/kg X min for 40 min. Pharmacokinetics of 5-FU in plasma was studied by HPLC analysis. 5-FU induced toxicity was examined in a second group of control and cirrhotic rats at 48 and 168 hours after treatment with 5-FU (31.4 mg/kg b.w.) infused into the liver artery for 1 h. Analysis of toxicity was carried out by determining liver enzymes in plasma, bone marrow cellularity and colony forming units in vitro (CFU-C) and in vivo (CFU-S). The results indicate that during the period investigated (85 min) 5-FU was not eliminated from the plasma of cirrhotic rats in contrast to controls. The constant level of 5-FU in the plasma of cirrhotic rats induced a considerably higher myelosuppression in these animals, than the short-lived 5-FU peak in controls.

Alanine Transaminase↗