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PubMed1978

[New methods of chemotherapy also for extrapulmonary tuberculosis?].

The chemotherapy of all forms of tuberculosis is basically performed according to homogeneous principles. Different opinions exist within the extrapulmonary forms particularly with regard to the duration of the treatment. Here, the so-called long-term therapy is frequently still postulated with 18--24 months. But newly developed, highly effective antituberculotic medicaments do not only allow but actually demand a shortening of the time of treatment in interest of the patient. Apparantly rifampicin and also pyrazin amide are able to effect on the germs in rest -- the persisters. Up to now the last mentioned gave the actual rise for the long-term application. Under the notion short-term therapy on the one hand by the application of the preparations mentioned and on the other hand basing on the experiences in the medicamentous treatment of the pulmonary tuberculosis now in the same measure the possiblity of a total duration of the therapy of on an average twelve months develops for the extrapulmonary manifestations of tuberculosis. Here, the two-phase regime is preferred with a continuous application of medicaments lasting for three months and following controlled phase with intermitting application of antituberculotics twice a week. The duration of application for rifampicin in these cases should neither trandgress nor be below three months.

Female↗

PubMed1994

Effects of cytotoxic factors of Helicobacter pylori on superoxide generation in situ in the rabbit stomach.

OBJECTIVE: To evaluate the effect of certain cytotoxic products of Helicobacter pylori on superoxide generation in situ and on the infiltration by polymorphonuclear cells into the gastric mucosa. The agents studied were ammonia, a culture supernatant of H. pylori, and N-formyl-methionyl-leucyl-phenylalanine (FMLP), a chemotactic factor. METHODS: One or two of these agents were dripped onto rabbit gastric epithelium. The number of polymorphonuclear cells in gastric mucosa were counted histologically. Superoxide generation was measured by a chemiluminescence method, using a Cypridina luciferin analog, 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2-alpha]pyrazin-3-one , a chemiluminescence probe that responds to the generation of superoxides and singlet oxygen radicals. Bovine erythrocyte copper zinc superoxide dismutase was dripped to confirm that the increase in photon counts was a direct consequence of the generation of superoxides. RESULTS: The greatest infiltration of polymorphonuclear cells into the gastric mucosa was observed with the administration of 1 mmol/l FMLP followed by 5.9 mmol/l ammonia, and 10 mmol/l FMLP followed by 59 mmol/l ammonia. There was no increase in the number of polymorphonuclear cells in the other experiments. Increased chemiluminescence was observed in conjunction with the infiltration of polymorphonuclear cells and was inhibited by superoxide dismutase. CONCLUSIONS: Acute gastritis and superoxide generation in situ were induced by ammonia after pretreatment with FMLP.

Ammonia↗

PubMedDate not supplied

Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules.

The cytochrome P450 isoenzyme P4502E1 is constitutively expressed in human liver and catalyzes the oxidation of many known or suspected carcinogens of low molecular weight. In this structure-metabolism study, the role that heteroatoms in heterocyclic compounds play in determining their affinity for P4502E1 was investigated. The ability of 16 six-membered and 10 five-membered compounds to inhibit the hydroxylation of p-nitrophenol, which is specifically catalyzed by P4502E1, was studied in suspensions of microsomes from rat livers in which P4502E1 had been induced by inclusion of acetone in the drinking water. Apparent Ki values were extrapolated from kinetic models of Dixon or Cornish-Bowden plots for enzyme inhibition. Enzyme inhibition was generally of the non-or uncompetitive type. Pyridine was the most potent and benzene one of the least potent inhibitors, with Ki values of 0.4 microM and 8,400 microM, respectively. Pyridazine was less inhibitory than 1,3,5-triazine, which inhibited P4502E1 to a lesser degree than pyrazine and pyrimidine. Among the unsubstituted unsaturated five-membered ring molecules, pyrrole was a better inhibitor than furan or thiophene. 4-Methylimidazole was a much stronger inhibitor than imidazole or 1-and 2-methylimidazole. The ability of compounds to inhibit P4502E1 seems to depend in the main on the presence of a nitrogen atom in the molecule and on the ability of the nitrogen lone pair of electrons to ligand to the heme.

Animals↗

PubMed1993

[In vitro studies of the metabolism of paraquat and diquat using rat liver homogenates--isolation and identification of the metabolites of paraquat and diquat].

The metabolism of paraquat and diquat was studied in vitro using rat liver homogenates, and the resulting metabolites were identified. Rat liver was homogenized with three volumes of isotonic buffer, and aliquots of the homogenate were preheated in a boiling water bath for 5 min prior to use. One milliliter of a mixture including both paraquat and diquat in an isotonic buffer solution (10 micrograms ion/ml) was incubated with an equal volume of fresh or preheated homogenate for 1 to 60 min at 37 degrees C. Quantification of paraquat and diquat was carried out by high-performance liquid chromatography (HPLC). In the fresh homogenate, a gradual decrease of paraquat concentration (about a 30% decrease over 60 min of incubation) and a rapid decrease of diquat concentration (not detectable after 10 min of incubation) were observed, but the same phenomenon was not evident with the preheated homogenate. Analysis of the incubated mixture of fresh liver homogenate with paraquat and diquat revealed three unknown peaks on the HPLC chromatograms; these seemed to be breakdown products of paraquant and diquat. The products were isolated and purified from the mixture by Sep-Pak C18 cartridge extraction, HPLC, silica gel column chromatography and Sephadex LH-20 column chromatography. Analysis of the chemical structure of the purified compounds was performed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. These analyses determined that paraquat-monopyridone (1',2'-dihydro-1,1'-dimethyl-2-oxo-4,4'-bipyridylium ion) was derived from paraquat, and that diquat-monopyridone (6,7-dihydro-4-oxodipyrido [1,2-a':2',1'-c] pyrazinium ion) and diquat-dipyridone (6,7-dihydrodipyrido [1,2-a:2',1'-c] pyrazine-4,9-dione) were derived from diquat. These results indicate that paraquat and diquat are metabolized by rat liver homogenate, diquat more readily so than paraquat. As the toxicity of these metabolites has been reported to be much lower than those of the parental compounds, it would seem that there is a system capable of detoxifying paraquat and diquat in rat liver.

Animals↗

PubMed1993

Increase in thermosensitivity of tumor cells by lowering intracellular pH.

We previously reported that the thermosensitivity of tumor cells can be increased when the intracellular pH is lowered by inhibiting Na+/H+ exchange through the plasma membrane with amiloride (3,5-diamino-6-chloro-N-(diamino methylene)pyrazinecarboxamide) or its analogues and HCO3-/Cl-exchange with 4,4-diiothiocyanato-stilbene-2,2'-disulfonic acid. In this study, we investigated the effects of (3-amino-6-chloro-5- (1-homopiperidyl)-N-(diaminomethylene)pyrazine-carboxamide) (HMA), an analogue of amiloride and a potent inhibitor of Na+/H+ exchange, and R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7- yl)oxy]acetic acid [B-3(+)], a potent inhibitor of HCO3-/Cl- exchange, on the thermosensitivity of SCK tumor cells in vitro. We observed that 10 microM of HMA could effectively increase the cell death by heating at 43 degrees in pH 6.6 medium but not in pH 7.5 medium. The B-3(+) at 50 microM alone had no effect on the thermosensitivity of cells, but it increased the thermosensitizing effect of HMA in acidic medium. Our results strongly suggested that a combination of HMA and B-3(+) may preferentially thermosensitize tumors in vivo since the interstitial environment in tumors is acidic relative to that in normal tissues.

Amiloride↗

PubMed1996

Mechanism of oxidative DNA damage induced by delta-aminolevulinic acid in the presence of copper ion.

Delta-Aminolevulinic acid (ALA) is a heme precursor accumulated in lead poisoning and acute intermittent porphyria. ALA-induced DNA damage in the presence of metal ions was investigated with a DNA sequencing technique and a high-performance liquid chromatograph equipped with an electrochemical detector. ALA caused damage to DNA fragments obtained from c-Ha-ras proto-oncogene in the presence of Cu(II), but only slightly in the presence of Fe(II). ALA + Cu(II) induced piperidine-labile sites at thymine residues, especially in the 5'-GTC-3' and 5'-CTG-3' sequences of double-stranded DNA. Catalase and bathocuproine inhibited DNA damage induced by ALA + Cu(II). Typical .OH scavengers did not inhibit DNA damage, suggesting that active species other than .OH play a more important role in DNA damage. 8-Hydroxy-2'-deoxyguanosine formation by ALA increased with ALA concentration in the presence of Cu(II). Electron spin resonance studies using alpha-(1-oxy-4-pyridyl)-N-tert-butylnitrone as spin trap showed that carbon-centered radicals were generated during Cu(II)-catalyzed autoxidation of ALA. The major pathway of ALA autoxidation consists for the formation of 4,5-dioxovaleric acid and NH(4)+. Formation of a pyrazine derivative through ALA autocondensation was also observed. Concomitantly, O2- and H2O2 were generated during the Cu(II)-catalyzed ALA autoxidation. These results indicate that H2O2 reacts with Cu(I) to form a crypto-OH radical, such as the Cu(I)-peroxide complex, causing DNA damage. The possible mechanism for metal-dependent DNA damage by ALA is discussed in relation to the carcinogenicity of lead compounds and the increased frequency of liver cancer in acute intermittent porphyria.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1997

Synthesis and in vitro trypanocidal activity of some novel iron chelating agents.

This report describes the syntheses and in vitro trypanocidal activity of a number of iron (III) chelators against epimastigotes of Trypanosoma cruzi. The compounds examined included a number of lipophilic N-alkyl derivatives of 2-ethyl- and 2-methyl-3-hydroxypyrid-4-ones, N,N'-bis(o-hydroxybenzyl)-(+/-)-trans-1,2-diaminocyclohexane, cyclotetrachromotropylene and four commercially available carboxy derivatives of pyridine, pyrazine, and pyarazole. Benznidazole, the drug clinically used in the treatment of Chagas' disease in humans, served as standard. All compounds were screened in vitro against Trypanosoma cruzi epimastigotes at 50 and 100 micrograms/ml for 72 h of exposure. At 100 micrograms/ml dosage, at least 4 compounds exhibited high epimastigote growth inhibition (65-69%) comparable to benznidazole (72%), whereas 9 compounds showed moderate to fair activity (53-64%) in the in vitro assay. At the lower concentration (50 micrograms/ml), the inhibitory activity of the best of these compounds was reduced significantly (39-48%) compared to the standard drug (59%). The activity of all the carboxylic acids remained in the lower range (4-25%). It is hypothesized that the enhanced activity of some of the compounds is due to their increased lipophilicity which enables them to successfully pass through the cellular membrane of Trypanosoma cruzi epimastigotes. The trypanocidal activities of the most effective compounds were significantly reduced when tested in the presence of added ferric ion.

Animals↗

PubMedDate not supplied

[Gas chromatographic analysis of volatile nitrogen bases in boiled beef; possible N-nitrosamine precursors].

The composition of nitrogen-containing organic bases in the volatile substances of boiled beef has been studied. For the first time 30 compounds have been identified, including primary, secondary, and tertiary aliphatic amines, pyrazines, pyridine, piperidine and their alkyl substituted derivatives. The content of trimethyl-, diethyl-, diisopropyl-amines, and piperidine, possible precursors of N-nitrosamines, has been quantitated.

Amines↗

PubMed1998

The glycine site on the NMDA receptor: structure-activity relationships and possible therapeutic applications.

L-glutamate is the most important fast excitatory neurotransmitter in the mammalian central nervous system. Glutamate receptors are classified into two main categories: ionotropic and metabotropic. The N-methyl-D-aspartate (NMDA) receptor, which is associated with an ion channel, seems to play an important role in glutamate excitotoxicity, a process thought to be involved in a number of neurodegenerative disorders such as focal cerebral ischaemia (stroke), Parkinsonís, Huntingtonís, Alzheimerís disease, schizophrenia and epilepsy. The unique glycine site on the NMDA receptor, discovered by Johnson and Ascher in 1987, represents an interesting target for the development of neuroprotective compounds. Glycine antagonists may offer advantages over other NMDA antagonists in terms of their side-effect profile, especially in the long-term treatment of chronical neurodegenerative disorders but also in the treatment of serious medical emergencies with a significant morbidity and mortality like status epilepticus or stroke. So far it is not clear whether NMDA receptor antagonists including glycine antagonists would be suitable for chronic administration because of their effects on cognition, learning and motor function. High-affinity, in vivo potent, glycine antagonists of great structural diversity (i. e. pyrido[2,3-b]pyrazine-N-oxides, indole-2-carboxylates, 4-substituted-3-phenylquinoline-2(1H)-ones and alkyl-substituted 1,4-dihydro-quinoxaline-2,3-diones) are now available and their suitability for long-term treatment of chronical neurodegenerative disorders has to be investigated in clinical trials.

Alzheimer Disease↗

PubMedDate not supplied

Involvement of reactive oxygen species in human sperm arcosome reaction induced by A23187, lysophosphatidylcholine, and biological fluid ultrafiltrates.

Although recent evidence indicated that the production of reactive oxygen species (ROS) by human spermatozoa may be involved in the regulation of capacitation, very little is known about the role of ROS in the acrosome reaction. To address this issue, Percoll-washed spermatozoa were incubated in Ham's F-10 medium in the absence (no capacitation) or presence (capacitation) of fetal cord serum ultrafiltrate (FCSu) or progesterone. The effects of the ROS scavengers, superoxide dismutase (SOD), and catalase were then tested on the acrosome reaction induced by lysophosphatidylcholine (LPC), A23187, and ultrafiltrates from follicular fluid (FFu) and FCSu, as well as on the protein tyrosine phosphorylation associated with this process. 2-Methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo [1,2-a] pyrazin-3-one (MCLA)-amplified chemiluminescence was used to determine the extracellular superoxide (O2.-) production from spermatozoa. The observations that both SOD and catalase reduced (in the case of LPC) or totally prevented (in the other cases) the acrosome reaction of capacitated spermatozoa and that hydrogen peroxide (H2O2) or ROS generated by the combination of xanthine and xanthine oxidase (O2.-, which dismutates to H2O2) triggered the acrosome reaction indicated the involvement of ROS in this process. In fact, capacitated spermatozoa in which the acrosome reaction was induced by LPC, A23187, and FFu produced more O2.- than noncapacitated spermatozoa treated with the same agents. A23187 and LPC had minor effects on protein tyrosine phosphorylation of noncapacitated spermatozoa. However, these inducers caused a decrease in tyrosine phosphorylation of Triton-soluble proteins (mainly those of 37, 42, and 47 kDa) from capacitated spermatozoa, a decrease more pronounced in the presence of SOD. On the other hand, there was a marked increase in tyrosine phosphorylation of few proteins (70 to 105 kDa) from the Triton-insoluble fraction, which was partly reversed by SOD (in the case of LPC and A23187) or catalase (in the case of A23187), or abolished in the presence of the two antioxidants (in the case of A23187). These data indicate that the acrosome reaction is associated with an extracellular O2.- generation by spermatozoa and that both O2.- and H2O2 may be involved in the regulation of this process. The mechanism by which these ROS act is unknown but may involve tyrosine phosphorylation of sperm proteins.

Acrosome Reaction↗

PubMed1998

Taurine indirectly increases [Ca]i by inducing Ca2+ influx through the Na(+)-Ca2+ exchanger.

Recent studies in heart cells have shown taurine to induce a sustained increase of both intracellular Ca2+ and Na+. These results led us to believe that the increase in Na+ by taurine could be due to Na+ entry through the taurine-Na+ cotransporter which in turn favours transarcolemmal Ca2+ influx through Na(+)-Ca2+ exchange. Therefore, we investigated the effect of beta-alanine, a blocker of the taurine-Na+ cotransporter and low concentrations of CBDMB (a pyrazine derivative, 5-(N-4chlorobenzyl)-2',4'-dimethylbenzamil), a Na(+)-Ca2+ exchanger blocker on taurine-induced [Ca]i increase in embryonic chick heart cells. Using Fura-2 Ca2+ imaging and Fluo-3Ca2+ confocal microscopy techniques, taurine (20 mM) as expected, induced a sustained increase in [Ca]i at both the cytosolic and the nuclear levels. Preexposure to 500 microM of the blocker of the taurine-Na+ cotransporter, beta-alanine, prevented the amino acid-induced increase of total [Ca]i. On the other hand, application of beta-alanine did not reverse the action of taurine on total [Ca]i. However, low concentrations of the Na(+)-Ca2+ exchanger blocker, CBDMB, reversed the taurine-induced sustained increase of cytosolic and nuclear free calcium (in presence or absence of beta-alanine). Thus, the effect of taurine on [Ca]i in heart cells appears to be due to Na+ entry through the taurine-Na+ cotransporter which in turn favours transarcolemmal Ca2+ influx through the Na(+)-Ca2+ exchanger.

Amiloride↗

PubMedDate not supplied