In vitro antigenotoxic activity, in silico ADME prediction and protective effects against aflatoxin B1 induced hepatotoxicity in rats of an Erythrina latissima stem bark extract.

Stem bark of Erythrina latissima E. Mey (Leguminosae) contains a wide range of prenylated flavonoids able to counteract the genotoxic properties of aflatoxin B1 (AFB1). Thus, the hypothesis was raised that E. latissima stem bark extracts (ELBE) may counteract the in vivo hepatotoxic effects of aflatoxins, contaminants in food and feed. An HPLC-DAD method was developed and validated to determine the level of flavonoid aglycones (11.82%) and glycosides (16.17%). ADME, pharmacokinetic and drug-likeness assessment of major flavonoids of ELBE, using the web tool SwissADME, showed good oral bioavailability. The protective effect of ELBE against AFB1 induced genotoxicity in the Vitotox assay after metabolic activation was confirmed (IC50 of 44.32 µg/ml), followed by evaluation of its inhibitory effect on hepatotoxicity in rats induced by the same agent. Male Wistar rats were orally treated with ELBE (20 mg/kg, 50 mg/kg and 100 mg/kg) or curcumin (500 mg/kg) combined with piperine (20 mg/kg) - positive control, for 8 days prior to AFB1 exposure (1 mg/kg). The ELBE group showed a decreased activity of ALP and γ-GT compared to the AFB1 group. Histopathological examination of the liver demonstrated ameliorative effects of ELBE. Thus, ELBE could have a protective effect against hepatotoxins such as AFB1.

Dermal absorption of inorganic germanium in rats.

So-called germanium 'health' products including dietary supplements, cosmetics, accessories, and warm bath service containing germanium compounds and metalloid are popular in Japan. Subchronic and chronic oral exposure of germanium dioxide (GeO(2)), popular chemical form of inorganic germanium causes severe germanium toxicosis including death and kidney dysfunction in humans and experimental animals. Intestinal absorption of neutralized GeO(2) or germanate is almost complete in humans and animals. However, it is not known whether germanium is cutaneously absorbed. We tested dermal absorption of neutralized GeO(2) or germanate using male F344/N rats. Three groups of rats were treated with a 3-h topical application of hydrophilic ointment containing graded level of neutralized GeO(2) (pH 7.4): 0, 0.21 and 0.42 mg GeO(2)/g. Germanium concentration in blood and tissues sampled from rats after topical application of inorganic germanium was measured by inductively coupled plasma-mass spectrometry. Animals topically applied 0.42 mg GeO(2)/g ointment had significantly higher germanium concentrations in plasma, liver, and kidney than those of rats that received no topical germanium. The results indicate that skin is permeable to inorganic germanium ion or germanate and recurrent exposure of germanium compounds may pose a potential health hazard.

A bioassay using intestinal organoids to measure CFTR modulators in human plasma.

Treatment efficacies of drugs depend on patient-specific pharmacokinetic and pharmacodynamic properties. Here, we developed an assay to measure functional levels of the CFTR potentiator VX-770 in human plasma and observed that VX-770 in plasma from different donors induced variable CFTR function in intestinal organoids. This assay can help to understand variability in treatment response to CFTR potentiators by functionally modeling individual pharmacokinetics.

Sugar-linked dithiocarbamates as modulators of metabolic and genotoxic properties of N-nitroso compounds.

A series of putative anticarcinogenic and antimutagenic compounds was synthesized on the basis of tetraethylthiuram disulfide (disulfiram) and its metabolite, diethyldithiocarbamate (DDTC). Diallyldithiocarbamate was synthesized in order to combine the anticarcinogenic properties of diallyl sulfide, a known inhibitor of chemical carcinogenesis from Allium species, and those of DDTC. Several sugar-linked dithiocarbamates (SDTCs) were prepared using glucose, cellobiose, and lactose as glycosyl donors and DDTC and diallyldithiocarbamate as acceptors. All the S--glycoside bonds of SDTCs were very stable under physiological conditions in vitro. At low nitrosamine concentrations, glucose-DDTC inhibited microsomal nitrosamine dealkylases in vitro. In vivo these enzymes were also inhibited 4 h after i.p. administration of glucose-DDTC or lactose-DDTC to rats (1.7 mmol/kg); after 24 h, the values had returned to control levels. Glucose-DDTC induced the activity of glutathione-related enzymes. Concomitant treatment of rats with glucose-DDTC and N-nitrosodiethylamine (NDEA) led to a depression of the oxidative metabolism of [14C]NDEA to 14CO2 but increased the elimination of unchanged [14C]NDEA in the urine. Furthermore, glucose-DDTC totally inhibited the formation of DNA single-strand breaks induced by NDEA. All these effects may contribute to possible antimutagenic and anticarcinogenic actions of the dithiocarbamates investigated.

Is man helpless against cancer? An environmental approach: antimutagenic agents from Egyptian food and medicinal preparations.

Sixty-two Egyptian food and medicinal preparations were extensively examined for antimutagenic/anticarcinogenic activity using short-term and host-mediated assays. The antimutagenic activity of the substances examined was ranked as follows: thirteen (strong), seven (mild) and five (weak) after metabolic activation. Metabolic activation seems to be necessary for most antimutagenic substances in this study, e.g. radish inhibits 29% of mutagenicity produced in direct antimutagenic assay and inhibits 89% of mutagenicity induced in host-mediated assay.

Antimutagenicity of cyclohexanol towards 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone and N-nitrosodiethylamine in Salmonella typhimurium strain TA100.

The ability of cyclohexanol to inhibit the mutagenicity of tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and of N-nitrosodiethylamine (NDEA) was tested on Salmonella typhimurium strain TA100. Cyclohexanol produced a dose-dependent decrease in the number of revertants induced by a single dose of NNK (24 mumoles) or NDEA (59 mumoles). Nevertheless, this inhibitory effect was not observed with other premutagenic agents such as benzo[a]pyrene and 2-aminoanthracene nor with direct mutagens such as ethyl methanesulfonate and methyl methanesulfonate. These results suggest that cyclohexanol interferes with the 'bioactivation' of the tested nitrosamines in a similar way that other alcohols such as ethanol or isopropanol interfere with N-nitro-sodimethylamine and NDEA metabolism.

Antimutagenic activity of phenylpropanoids from clove (Syzygium aromaticum).

Phenylpropanoids that possess antimutagenic activity were isolated from the buds of clove (Syzygium aromaticum). The isolated compounds suppressed the expression of the umu gene following the induction of SOS response in the Salmonella typhimurium TA1535/pSK1002 that have been treated with various mutagens. The suppressive compounds were mainly localized in the ethyl acetate extract fraction of the processed clove. This ethyl acetate fraction was further fractionated by silica gel column chromatography, which resulted in the purification and subsequent identification of the suppressive compounds. Electron impact mass spectrometry, IR, and (1)H and (13)C NMR spectroscopy were then used to delineate the structures of the compounds that confer the observed antimutagenic activity. The secondary suppressive compounds were identified as dehydrodieugenol (1) and trans-coniferyl aldehyde (2). When using 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (furylfuramide) as the mutagen, compound 1 suppressed 58% of the umu gene expression as compared to the controls at a concentration of 0.60 micromol/mL, with an ID(50) (50% inhibitory dose) value of 0.48 micromol/mL, and compound 2 suppressed 63% of the umu gene expression as compared to the controls at a concentration of 1.20 micromol/mL, with an ID(50) value of 0.76 micromol/mL. Additionally, compounds 1 and 2 were tested for their ability to suppress the mutagenic activity of other well-known mutagens such as 4-nitroquinolin 1-oxide (4NQO) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which do not require liver metabolizing enzymes, and aflatoxin B(1) (AfB(1)) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which require liver metabolizing enzymes and activated Trp-P-1 and UV irradiation. Compounds 1 and 2 showed dramatic reductions in their mutagenic potential of all of the aforementioned chemicals or treatment. For the search of the structure-activity relationship, the derivatives of 1 and 2 (1a and 2a-c) were also assayed with all mutagens. Finally, the antimutagenic activities of compounds 1, 1a, 2, and 2a-c against furylfuramide, Trp-P-1, and activated Trp-P-1 were assayed by the Ames test using the S. typhimurium TA100 strain.

Fronts movement as a useful tool for hydrophilic matrix release mechanism elucidation.

The purpose of this study was to modify the fronts movement method proposed by Colombo et al. in order to apply it to uncoloured drugs and hydrophilic non-swellable matrices. Matrix tablets were prepared using theophylline as a model drug and sodium carboxymethylcellulose (NaCMC) or a new graft copolymer, hydroxypropylcellulose methylmethacrylate dried by lyophilization (HCMMAL), as polymer carriers. Drug release experiments were performed from the whole tablets. Radial drug release and fronts movement were also evaluated using special devices consisting of two Plexiglass(R) discs joined by means of four stainless steel screws. Release kinetics were determined by means of Higuchi, Korsmeyer and Peppas equations and were related to the fronts movement data. The analysis of drug release and fronts movement kinetics revealed a different release mechanism for both matrices. Drug release from NaCMC matrices was mostly controlled by relaxation, whereas drug diffusion through the porous network regulated drug release from HCMMAL matrices. A reduction in the surface exposed to the dissolution medium led to a decrease in the drug release rate, but the release mechanism was not essentially modified. Fronts movement was shown as a useful tool for matrix release mechanism elucidation. A new denomination for the different fronts observed in HCMMAL matrices was proposed.

Studies on trans-cinnamaldehyde. 1. The influence of dose size and sex on its disposition in the rat and mouse.

The metabolism of trans-[3-14C]cinnamaldehyde was investigated in male and female Fischer 344 rats and CD1 mice at doses of 2 and 250 mg/kg body weight given by ip injection and in males at 250 mg/kg by oral gavage. Some 94% of the administered dose was recovered in the excreta in 72 hr in both species with most (75-81%) present in the 0-24-hr urine. Less than 2% of the administered dose was found in the carcasses at 72 hr after dosing. Urinary metabolites were identified by their chromatographic characteristics. In both species the major urinary metabolite was hippuric acid accompanied by 3-hydroxy-3-phenylpropionic acid, benzoic acid and benzoyl glucuronide. The glycine conjugate of cinnamic acid was formed to a considerable extent only in the mouse. The oxidative metabolism of cinnamaldehyde essentially follows that of cinnamic acid, by beta-oxidation analogous to that of fatty acids. Apart from the metabolites common to cinnamic acid and cinnamaldehyde, 7% of 0-24-hr urinary 14C was accounted for by two new metabolites in the rat and three in the mouse, which have been shown in other work to arise from a second pathway of cinnamaldehyde metabolism involving conjugation with glutathione. The excretion pattern and metabolic profile of cinnamaldehyde in rats and mice are not systematically affected by sex, dose size and route of administration. The data are discussed in terms of their relevance to the safety evaluation of trans-cinnamaldehyde, particularly the validity or otherwise of extrapolation of toxicity data from high to low dose.

Disposition, toxicity, and intestinal absorption of cobaltous chloride in male Fischer 344 rats.

The absorption and disposition of inorganic cobalt salts after oral administration have not been well characterized. The objectives of this study were to compare in vivo results with cobalt transport through the in vitro everted small intestine and to relate the disposition results to a biochemical indicator of cobalt toxicity. Cobalt chloride was given to male Fischer 344 rats orally at 33.3 mg Co(II)/kg or intravenously at 4.16 mg Co(II)/kg. By 36 h, 74.5% of the oral dose was eliminated in the feces. The liver, kidney, and heart accumulated cobalt to the greatest extent. Following the single oral dose, the blood cobalt concentration-time curve was triphasic, peaked at 3.2 h, and had an absorptive half-life of 0.9 h, an elimination phase half-life of 3.9 h, and a terminal elimination half-life of 22.9 h. Following intravenous administration, 10.1% of the dose was excreted in the feces, indicating that cobalt can be secreted in the bile. Following a single intravenous injection, the concentration-time curve displayed three segments. The first segment, which occurred during the first 4 h, had a rapid half-life of 1.3 h. The second phase, from 4 to 12 h, demonstrated a slower clearance rate with a half-life of 4.3 h. The final and slowest phase, from 12 to 36 h, had a half-life of 19 h. Intestinal jejunal ring experiments indicated that cobalt transport has both active and passive components; however, cobalt transport through the in vitro rat everted duodenum indicated that cobalt transport had almost exclusively passive components with facilitated diffusion. The finding that uptake was saturable may explain the small extent of absorption following oral dosing. Heme oxygenase studies following subcutaneous and intravenous administration resulted in an increase in activity (twofold) over controls, while oral administration did not. We concluded that the extent of cobalt absorption across the gastrointestinal tract is incomplete, and that the concentration administered and the route of exposure may determine its systemic toxicity.

Metabolism and pharmacokinetics of S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine in rats.

The metabolism and pharmacokinetics of a mixed disulfide S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC) were studied in rats. Two metabolites of AC-DDTC following i.v. and p.o. administration were identified in plasma and liver by HPLC and GC, namely N,N-diethyldithiocarbamate (DDTC) and the methyl ester of DDTC (Me-DDTC). AC-DDTC was very unstable in vivo and could not be detected neither in plasma nor in urine. Pharmacokinetic parameters of DDTC following intravenous administration of AC-DDTC (20 mg/kg) were calculated. DDTC has a low affinity to rat tissue and the total body clearance was 9.0 +/- 3.4 ml/min/kg. The mean residence time (MRT) was 111.5 +/- 16.3 min. After oral administration of 20 mg/kg AC-DDTC, maximal plasma concentration (Cmax) was 3.8 +/- 0.2 nmol/ml and the bioavailability was 7.04%. Cmax for DDTC at a dose of 120 mg/kg AC-DDTC was 40.1 +/- 2.2 nmol/ml. MRT was 47.1 +/- 2.8 min at a dose of 20 mg/kg and 110.5 +/- 6.0 min at 120 mg/kg.

An evaluation of antimutagenic properties of vitamin E.

The influence of vitamin E on the mutagenic activities of aflatoxin and adriamycin was studied. The results indicate that vitamin E shows antimutagenic activity towards aflatoxin B1 only when homogenized with liver tissue.

[The pharmacological problems of searching for and using antimutagens]. / Farmakologicheskie problemy poiska i primeneniia antimutagenov.

To design protectants of human genomic structures against mutagenic effects is defined as a new pharmacological problem; the perspectives of its solution are outlined. The experimental evidence that formed the biological basis for searching for pharmacological correctors of the mutagenic effects produced by xenobiotics is analysed, the basic principles for designing pharmacological protectants of genetic structures are formulated. Great emphasis is laid on the antimutagenic properties of antiradical agents. Evidence is provided for that there are no prospects of searching for pharmacological protectants among natural and synthetic phenol compounds. It is noted that the informative value of microbiological tests is poor. To design a corrector of the damaging action of each particular mutagen is shown to be an independent scientific problem which can be solved only by employing eukaryotic test systems. The areas of possible application of antimutagens are defined and some known examples of their use to protect human genetic structures are presented.

[Absolute and relative bioavailability of germanium in the rabbit]. / Biodisponibilités absolue et relative du germanium chez le lapin.

The debated consumption of germanium suggested the authors to compare biopharmaceutical parameters of germanium oxide and germanium sesquioxide. A first evaluation, in rabbit, has been based on Germanium blood levels determined by atomic absorption spectrometry, after cross administration of both products by the I.V. and oral routes. When given orally, the apparent oxide bioavailability is very low (about 10%) but better than that of the sesquioxide. That difference could result from differences of disposition parameters of both products, which have to be studied late.

Preliminary assessment of mutagenic and anti-mutagenic potential of some aminoalkanolic derivatives of xanthone by use of the Vibrio harveyi assay.

The Vibrio harveyi assay was used to evaluate mutagenic and anti-mutagenic effects of four new aminoalkanolic derivatives of xanthone with anticonvulsant activity, to select the potentially safe compounds for further in vivo studies in animal models. The study showed that at a concentration of 40 ng/ml the test compounds were not mutagenic. Additionally, two of the investigated compounds, namely the (R,S)-N-methyl-1-amino-2-propanol derivative of 6-methoxyxanthone (compound III) and the (R)-N-methyl-2-amino-1-butanol derivative of 7-chloroxanthone (compound IV) were strong inhibitors of the mutagenicity induced by 4-nitroquinoline-N-oxide (4-NQO) in V. harveyi strains BB7M and BB7XM. The inhibition percentages for compound IV were 49 (in BB7M) and 69 (in BB7XM), whereas for compound III these percentages were 47 (in BB7M) and 42 (in BB7XM), respectively. The present study demonstrates that four bioactive derivatives of xanthone display no mutagenic activity in the V. harveyi assay. In addition, compounds III and IV demonstrated considerable anti-mutagenic activity in this test. Based on the results obtained here, these compounds could be selected for further studies in animal models, while compounds III and IV should be tested further for their anti-mutagenic properties.

Phenolic contribution of South African herbal teas to a healthy diet.

South African herbal teas, rooibos and honeybush, are increasingly enjoyed as healthy alternatives to Camellia sinensis teas. They contribute to the diet with bioactive phytochemicals not commonly found in foods. Major compounds of rooibos are the unique dihydrochalcone, aspalathin, and its flavone isomers, orientin and isoorientin. Honeybush contributes the xanthones, mangiferin and isomangiferin and the flavanones, eriocitrin, narirutin and hesperidin. All these compounds are either C-glucosides or O-rhamnoglucosides, which are poorly absorbed. Phase II metabolism and degradation by intestinal bacteria are important factors in their absorption. Modulation of drug metabolising enzymes is indicated which not only could affect the therapeutic window of drugs, but also the bioavailability of other dietary flavonoids.

Treating patients with respiratory disease who smoke.

The high prevalence of cigarette smoking in patients with respiratory disease puts them at risk of developing clinically important drug interactions. Cigarette smoking reduces the therapeutic response to certain drugs such as theophyllines through the induction of hepatic cytochrome P450 isoenzymes. Smokers with asthma and patients with COPD have reduced sensitivity to corticosteroids, possibly due to non-eosinophilic airway inflammation, altered glucocorticoid receptor activity or reduced histone deacetylase activity. Although all smokers should be encouraged to stop smoking, there is limited information on the influence of smoking cessation on the therapeutic and anti-inflammatory effects of a number of the drugs used in the treatment of respiratory disease.