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PubMed1987

Monoclonal antibodies to ethanol-induced rat liver cytochrome P-450 that metabolizes aniline and nitrosamines.

Hybridomas were prepared from mouse myeloma cells and spleen cells derived from female BALB/c mice that had been immunized with a partially purified ethanol-induced rat liver cytochrome P-450 (P-450et). Monoclonal antibodies (MAbs) produced by the hybridomas were screened for binding to P-450et with a radioimmunoassay. Thirty-one independent hybrid clones produced MAbs that had a high affinity for P-450et. Each clone produced MAbs of a single subclass of the mouse immunoglobulins IgG1, IgG2a, IgM, or IgA. Ten of the 31 MAbs also immunoprecipitated P-450et as determined by Ouchterlony double-immunodiffusion analyses. One of the MAbs was tested for cross-reactivity with other rabbit and rat liver cytochromes P-450 and was found not to cross-react with rat liver P-450 induced by either phenobarbital, beta-naphthoflavone, or rabbit liver P-450LM2 or P-450LM4. Nine of the MAbs were tested for cross-reactivity with rat liver clofibrate-induced P-450, rat liver pregnenolone-16-alpha-carbonitrile-induced P-450, and a human liver P-450. All the MAbs showed no cross-reactivity except for one MAb which cross-reacted with both pregnenolone-16-alpha-carbonitrile and human P-450 and three MAbs which cross-reacted with human P-450. Three antigen-precipitating MAbs and four nonprecipitating MAbs were tested for their effects on the aniline p-hydroxylase activity of liver microsomes of untreated rats and from rats treated with acetone, pyrazole, methylpyrazole, or imidazole. One of the seven MAbs tested, 1-91-3, inhibited enzyme activity of acetone-, pyrazole-, or methylpyrazole-induced microsomes by 54, 47, and 48%, respectively. This indicates that at least 50% of microsomal cytochrome P-450 aniline p-hydroxylase activity in the latter is a function of a P-450 enzyme that contained the epitope to which the MAb 1-91-3 is directed. With untreated and imidazole-induced microsomes, 32 and 21% inhibition of the enzyme activity was observed. In reconstituted systems containing phospholipid and NADPH-cytochrome P-450 reductase, MAb 1-91-3 inhibited aniline p-hydroxylase activity of purified ethanol-induced P-450et and acetone-induced P-450 by more than 90%. Nitrosodimethylamine demethylase activity of acetone-induced rat microsomes was inhibited by the various MAbs up to 77% and the activity of the purified acetone-induced P-450 was inhibited up to 92%.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetone↗
PubMed1988

Leukemia L1210 cell lines resistant to ribonucleotide reductase inhibitors.

Leukemia L1210 cell lines, ED1 and ED2, were generated which were resistant to the cytotoxic effects of deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine and deoxyadenosine/erythro-9-(2-hydroxyl-3-nonyl)adenine plus 2,3-dihydro-1H-pyrazole[2,3a]imidazole/Desferal, respectively. The ED1 and ED2 were characterized to show that these cell lines had increased levels of ribonucleotide reductase as measured by CDP reduction. The reductase activity in crude cell-free extracts from the ED1 and ED2 cells was not inhibited by dATP. For CDP reductase, the activation by adenylylimido diphosphate and inhibition by dGTP and dTTP in these extracts from the ED1 and ED2 cells were the same as for the wild-type L1210 cells. The ED1 and ED2 cells were highly cross-resistant, as measured by growth inhibition, to deoxyguanosine/8-aminoguanosine, 2-fluorodeoxyadenosine, and 2-fluoroadenine arabinoside. While the ED2 cells showed resistance to 2,3-dihydro-1H-pyrazole-[2,3a]-imidazole/Desferal (6-fold), the ED1 and ED2 cell lines showed less resistance to hydroxyurea, 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, and the dialdehyde of inosine. These data indicate that the mechanisms of resistance to the ribonucleotide reductase inhibitors are related to the increased level of ribonucleotide reductase activity and to the decreased sensitivity of the effector-binding subunit to dATP.

Adenosine Deaminase↗
PubMed1986

Comparative pharmacology of 'non-opioid' analgesics.

Pain is the most prominent symptom of disease in man and analgesics are the most widely used drugs. More than 90% of the analgesics used belong to the so-called peripherally acting, non-opioid (non-narcotic) or mild analgesics. They all derive from 3 types of compounds: aspirin and other acidic non-steroidal anti-inflammatory drugs (NSAIDs), aniline derivatives such as paracetamol (acetaminophen) and non-acidic pyrazole drugs like propyphenazone and dipyrone (metamizole). These compounds and all of their derivatives differ in their analgesic activity and their typical profile of side effects. While NSAIDs are particularly useful in the treatment of pain related to inflammation these compounds are well known to cause gastrointestinal, haematological and kidney side effects. Aniline derivatives such as paracetamol are not very effective analgesics, but reasonably good antipyretics. These compounds, unlike aspirin-like drugs, do not interfere with inflammatory pain. Their main side effects are allergic but, particularly at overdose, they cause liver and kidney damage. Rarely, they have also been associated with kidney damage and malignomas of the urinary system after long term administration. Non-acidic pyrazole drugs are supposedly particularly active in pain originating from spasms of smooth muscles. They are not very effective anti-inflammatory drugs but are good antipyretics. Their major side effects consist of mild allergic reactions. They have also rarely been associated with agranulocytosis and shock. In addition to these differences in therapeutic application and side effect profile the major representatives of the groups of analgesics mentioned differ in their pharmacokinetic behaviour in the human body. Aspirin shows non-linear pharmacokinetics not seen with ibuprofen, a more modern NSAID.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1986

Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures.

We are engaged in a selective breeding program developing lines of mice which differ in severity of withdrawal convulsions after ethanol treatment. Withdrawal seizure prone (WSP) mice show greater handling-induced convulsion scores than withdrawal seizure resistant (WSR) mice after 3 days of ethanol intoxication. In the present experiments, we sought to characterize these mice further as a model of genetic susceptibility to ethanol dependence and withdrawal. During withdrawal after chronic treatment with ethanol, WSP mice displayed more severe handling-induced convulsions and tremor than WSR mice, and tended to show greater reduction of exploratory activity. WSP and WSR mice did not differ in ethanol metabolism after acute treatment with ethanol alone or after chronic treatment with ethanol and pyrazole, an alcohol dehydrogenase inhibitor. Six to 10 hr after an acute injection of ethanol, WSP and WSR mice showed elevated handling-induced convulsions. This elevation was more pronounced in WSP mice than in WSR mice. WSP mice also showed slightly more severe convulsions than WSR mice when treated with saline or pyrazole alone. In summary, WSP and WSR mice treated with identical doses of ethanol differ in several symptoms of withdrawal, whereas not differing in ethanol metabolism. These mice constitute a useful population in which to study the molecular mechanisms of ethanol dependence and withdrawal.

Alcohol Withdrawal Delirium↗
PubMed1984

Effects of antifeins (memory affecting agents) on behavior, brain infraslow activity and temperature.

Four imidazole- and pyrazoledicarboxylic acid derivatives: 1-ethyl-4,5-di-(N-methylcarbamoyl)-imidazole (aethimizol), 1-allyl-4,5-di(N-methylcarbamoyl)-imidazole (allylnorantifein), 1-ethyl-4,5-di-(N-methylcarbamoyl)-pyrazole (IEM-476), and 1-allyl-4,5-di-(N-methylcarbomyol)-pyrazole (IEM-474) were investigated for their ability to abolish in rats the amnesia of passive avoidance response induced by electroconvulsive shock and to alter the infraslow activity and temperature of the brain in rabbits. IEM-476 10 mg/kg did abolish (P less than 0,05) the amnesia in rats, while the other agents did not. The experiments in rabbits with brain indwelling golden electrodes and thermocouples revealed a shift in the amplitude and frequency of multiminute waves of infraslow activity and a decrease in the temperature of hippocampus, hypothalamus and neocortex after aethimizol (1,5 mg/kg) and IEM-476 (3 mg/kg). Allylnorantifein and IEM-474 (both 3 mg/kg) shifted the amplitude and frequency of multiminute waves of infraslow activity in the reticular formation of the mesencephalon, in the medial group of thalamic nuclei, and the neocortex, i. e. the structures of the nonspecific ascending brain system, and failed to affect the brain temperature. The effects of IEM-476 and IEM-474 were shorter in duration, than those of aethimizol and allylnorantifein.

Animals↗
PubMed1993

Synthesis and cardiodepressant activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pentatomic-heteroaryl)-3,5-pyridine-dicarbo xylates. 2.

A new series of 1,4-dihydropyridine bearing substituted pyrazole and imidazole at C-4 position was synthesized and characterized as inotropic, chronotropic and calcium antagonist agents, in order to evaluate the effect on pharmacological activity of replacement of the 4-aryl group of nifedipine-like drugs by pyrazole and imidazole moieties. All compounds were tested on myocardial muscle and vascular smooth muscle of guinea-pigs. The new compounds showed both significant selective negative inotropic activity and fairly good negative chronotropic effects. All compounds elicited weak calcium antagonist activity, except compound 9 which is a selective bradycardic agent.

Animals↗
PubMed1993

[Antimicrobial activity of diazole-(N-salicylidene-L-alpha- alaninato)-copper complexes].

The antimicrobial activities of a group of copper(II) chelates with the composition [Cu(TSB)(L)] or [Cu(TSB)(L')]. (TSB = N-salicylidene-L-alpha-alaninate dianion, L = imidazole and its alkyl derivatives, L' = pyrazole and 3,5-dimethylpyrazole) were studied. Bis-diazole complexes with L' = pyrazole and 3,5-dimethylpyrazole were found to be the most active against S. aureus (MIC = 78 and 20 micrograms.cm-3), less effective against C. albicans (156 micrograms.cm-3), T. terrestre and M. gypseum (100 micrograms.cm-3). The observed biological properties of complexes are discussed in relation to their proposed structures.

Anti-Bacterial Agents↗
PubMed1993

Inhibition and induction of cytochrome P450 isoenzymes in rat lung.

The O-dealkylation of pentoxyresorufin, a substrate for P450 2B1, was decreased in lung microsomes from rats dosed with O,O,S-trimethylphosphorodithioate, O,O,O-trimethylphosphorothioate, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine. This activity was decreased by antibodies to P450 2B1 but unaffected by antibodies to P450 1A1 or 4B1. This reduction reflected both inactivation and destruction of P450 2B1; destruction of this protein was particularly marked after bromophos and fenitrothion. Pyrazole was the only compound in this study to induce the O-dealkylation of pentoxyresorufin. None of these compounds altered the rate of ethoxyresorufin O-dealkylation, an indicator of P450 1A1 activity, but this activity was induced greatly by both Aroclor and beta-naphthoflavone, p-Xylene was the only compound to decrease P450 4B1 activity, as determined by the N-hydroxylation of 2-aminofluorene. In the liver, bromophos, fenitrothion, p-xylene and 2,4-dichloro-(6-phenylphonoxy)ethylamine all had marked effects on the O-dealkylation of ethoxyresorufin and pentoxyresorufin but, at the dose used, O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate had minimal effects in this tissue. Thus, both O,O,O-trimethylphosphorothioate and O,O,S-trimethylphosphorodithioate are exquisitely selective inhibitors of pulmonary P450 2B1 activity. Their use, together with pyrazole, will facilitate future studies of the pulmonary activation of toxins by P450 2B1.

Animals↗
PubMed1996

Biotransformation of allyl chloride in the rat. Influence of inducers on the urinary metabolic profile.

Allyl chloride (AC) is used as intermediate in the synthesis of epichlorohydrin (ECH). We investigated the biotransformation of AC in rats to select potential urinary biomarkers of exposure. For this purpose, we developed analytical methods to measure different selected urinary metabolites of AC. The earlier described urinary metabolites of AC [allyl mercapturic acid (ALMA) and 3-hydroxypropyl mercapturic acid (HPMA)], as well as two urinary metabolites of ECH [alpha-chlorohydrin (alpha-CH) and 3-chloro-2-hydroxypropyl mercapturic acid (CHPMA)], were determined in this study. After intraperitoneal administration of AC, in doses ranging from 66 to 590 mumol/kg, control rats excreted 30 +/- 6.5% of the AC dose as ALMA. HPMA was a minor urinary metabolite of AC (< 3% of the AC dose), and, for this metabolite, no clear dose-excretion relationship was found. Two other minor urinary metabolites were also found as well, namely CHPMA and alpha-CH, suggesting the formation of ECH. CHPMA excretion was linear from 66 to 330 mumol/kg AC and amounted to 0.21 +/- 0.08% of the AC dose. alpha-CH excretion was linear in the dose range used and was excreted for 0.13 +/- 0.02% of the AC dose. In addition, we investigated the influence of three different enzyme inducers on the urinary metabolite profile of AC, namely pyrazole, beta-naphthoflavone, and phenobarbital. Pyrazole only increased the urinary excretion of alpha-CH. beta-Naphthoflavone induction only enhanced the ALMA excretion significantly. Phenobarbital inducted both the excretion of CHPMA and alpha-CH. From these studies, we conclude that urinary excretion of ALMA, CHPMA, and alpha-CH can be used as biomarkers in humans potentially exposed to AC. However, ALMA seems to be the more appropriate biomarker, because enzyme induction may play a confounding role if CHPMA or alpha-CH is used.

Acetylcysteine↗
PubMed1998

Non-steroidal anti-inflammatory agents: synthesis of novel benzopyrazolyl, benzoxazolyl and quinazolinyl derivatives of 4(3 H)-quinazolinones.

Four novel series of 4(3 H)-quinazolinone derivatives have been synthesized by cyclization of the intermediate 3-aryl-2-(6-aryl-2-cyclohexen-1-on-5-yl)-4(3 H)-quinazolinones 3a-f with hydrazine, phenylhydrazine, hydroxylamine and thiourea. The products are 3-aryl-2-(6-aryl-3-methyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4a-f; 3-aryl-2-(6-aryl-3-methyl-1-phenyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4g-1; 3-aryl-2-(6-aryl-3-methyl-4,5-dihydrobenzo[d]-1,2-oxazol-4-yl)-4(3 H)-quinazolinones 5a-f, and 3-aryl-2-(7-aryl-4-methyl-5,6-dihydro-2(1 H)thioxoquinazolin-5-yl)-4(3 H)-quinazolinones 6a-f. Some of these compounds showed anti-inflammatory activity comparable to or higher than that of the reference compound proquazone.

Animals↗
PubMed1984

Therapeutic reduction of ongoing carrageenin-induced inflammation by lipoxygenase, but not cyclooxygenase inhibitors.

A variety of steroidal and nonsteroidal antiinflammatory agents (NSAs) were compared for their effectiveness against a developing acute inflammatory reaction. Only BW 755C [3-amino-1-(m-trifluoromethyl)-phenyl-2-pyrazole] was immediately effective when administered 2 h after carrageenin, as the 3-h swelling was significantly reduced. Dexamethasone, a steroidal antiinflammatory agent, produced a delayed reduction. When administered at 2 h postcarrageenin, there was no effect at 3 h; but at 6 h, dexamethasone significantly reduced the swelling. In contrast, neither of the classic NSAs, aspirin or indomethacin, were effective when administered after the carrageenin. The results demonstrating a postcarrageenin effectiveness by BW 755C and dexamethasone are discussed as a possible reflection of an action on the lipoxygenase pathways of the arachidonic cascade that is not shared by the classic NSA.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Inhibition of leukotriene C4 and B4 generation by human eosinophils and neutrophils with the lipoxygenase pathway inhibitors U60257 and BW755C.

Human eosinophils and neutrophils have the capacity to generate leukotriene C4 (LTC4) and leukotriene B4 (LTB4) respectively when stimulated by calcium ionophore A23187. Leukotriene production by mixtures of these cell types was measured by radioimmunoassay for LTC4 and LTB4, and the specificities of the assays determined by assessing cross-reactivities with a number of other arachidonic acid metabolites. The IC50S for LTC4 and LTB4 in their respective assays were 1.76 +/- 0.04 nmol and 3.00 +/- 0.08 nmol. Cross-reactivity for anti-LTC4 was shown by leukotriene D4 (LTD4) (70%) and leukotriene E4 (LTE4) (8%), when compared to LTC4, whereas in the radioimmunoassay for LTB4, only the 5(S), 12(R) 6-trans isomer of LTB4 showed appreciable interaction (12%). LTC4 production by eosinophil enriched cell fractions obtained from metrizamide gradients was inhibited in a dose-dependent fashion by the prostacyclin analogue, 6,9-deepoxy-6,9-phenylimino-delta 6,8-prostaglandin I, (U60257) and by 3-amino-1-(3-trifluoromethyl phenyl)-2-pyrazole (BW755C). The ID50 values for U60257 and BW755C were 2 X 10(-6) and 5 X 10(-6) M respectively. This demonstration of LTC4 production by human eosinophils, which are known to be important cells in clinical asthma, provides an in vitro model to assess 5-lipoxygenase inhibitors in human tissue.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1999

3-Amino- and 5-aminopyrazoles with anticonvulsant activity.

New 3-amino- and 5-aminopyrazoles were synthesised. 3-Aminopyrazoles exert a strong anticonvulsant effect, 4-Chlorophenyl-3-(morpholin-4-yl)-1 H-pyrazole 2 distinctively blocks sodium channels and is strongly effective in the Maximal Electroshock Seizure (MES) test.

Animals↗
PubMed2000

Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281.

The goals of this study were to examine the relationship between intravenous doses of the cannabinoid CB1 receptor antagonist AM281 (N-(morpholin-4-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and the degree of occupancy of this receptor, and to relate occupancy to the ability of this compound to antagonize the sedative effects of the cannabinoid receptor agonist WIN 55,212-2. Occupancy was determined by measuring the ability of intravenous doses of AM281 to inhibit in vivo binding of [(131)I]AM281 in brain areas, and locomotor activity was assessed by measuring the rate of beam crossings in a photocell apparatus. As previously documented, WIN 55,212-2 (1 mg/kg, i.v.) significantly reduced locomotor activity at early times after administration. Co-injection of AM281 (0.3 mg/kg i/v) and WIN 55, 212-2 restored the rate of beam crossings to that seen on injection of vehicle. In addition, AM281 (0.3 mg/kg i/v) approximately doubled locomotor activity between 60-120 min when injected alone. The IC(50) value for displacement of [(131)I]AM281 by AM281 was 0.45 mg/kg. These observations confirm earlier indications that AM281 is a CB1 receptor antagonist or inverse agonist and suggest the existence of an endogenous cannabinoid tone that moderates exploratory locomotor activity.

Animals↗
PubMed2006

A pyrazolato-bridged dinuclear platinum(II) complex induces only minor distortions upon DNA-binding.

The cytotoxic, pyrazolato-bridged dinuclear platinum(II) complex [(cis-{Pt(NH3)2})2(mu-OH)(mu-pz)]2+ (pz=pyrazolate) has been found to cross-link two adjacent guanines of a double-stranded DNA decamer without destabilizing the duplex and without changing the directionality of the helix axis. A 1H NMR study of the oligonucleotide d(CTCTG*G*TCTC)-d(GAGACCAGAG), cross-linked at the two G* guanines by [(cis-{Pt(NH3)2})2(mu-pz)]3+, and molecular dynamics simulations of the explicitly solvated duplex were performed to characterize the structural details of the adduct. The dinuclear platinum cross-link unwinds the helix by approximately 15 degrees , that is, to a similar extent as the widely used antitumor drug cisplatin, but, in contrast to the latter, induces no significant bend in the helix axis. The Watson-Crick base-pairing remains intact, and the melting temperature of the duplex is unaffected by the cross-link. The helical twist is considerably reduced between the two platinated bases, as becomes manifest in an unusually short sequential H1'-H1' distance. This unwinding also affects the sugar ring of the guanosine in the 3'-position to the cross-link, which presents an N<-->S equilibrium. This is the first cytotoxic platinum complex that has been successfully designed by envisioning the structural consequences of its binding to DNA.

Base Pairing↗
PubMed1981

Studies in potential organo-fluorine antibacterial agents. Part 6: Synthesis and antibacterial activity of some new fluorine containing 1,3,4,5,7-pentasubstituted dipyrazolo[3,4-b,; 4,3-3]pyridines.

Ten new fluorine containing dipyrazolo [3,4-b;4,3-3]pyridines have been synthesized as possible antibacterial agents. The synthesis involves the condensation of 5-amino-1,3-disubstituted pyrazoles with an appropriate arylaldehyde at 220-240 degrees C. The synthesized compounds have been characterized by their m. p.'s elemental analysis, TLC, IR, 1H-NMR and 19F-NMR. A representative number of compounds have also been screened for their antibacterial activity and most of them were found to inhibit the growth of different bacteria.

Anti-Bacterial Agents↗
PubMed1986

[N-pyrazolyl-2-nitrobenzamides with antifungal activity].

Novel N-pyrazolyl-2-nitrobenzamides variously substituted on the pyrazole nucleus were prepared. The products obtained together with some other N-substituted 2-nitrobenzamides were tested for their antifungal activity against Cryptococcus neoformans and Candida albicans. The results of the antimicrobial assay showed different behaviours of the organisms used with regard to the derivatives tested.

Antifungal Agents↗