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PubMed2004

Evaluation and validation of a commercially available enzyme-linked immunosorbent assay for the neonicotinoid insecticide imidacloprid in agricultural samples.

The performance of a commercially available microtiter plate ELISA kit for the determination of the neonicotinoid insecticide imidacloprid was evaluated for sensitivity, selectivity, influence of organic solvent used for extraction procedure, matrix interference originated from agricultural sample, accuracy, and method comparison with conventional HPLC analysis. The limit of detection for the kit (0.1 or 0.5 ng/mL) was determined. The working range (1-39 ng/mL) experimentally calculated on the basis of a criterion, which is determined as the range from I(20) to I(80), was comparable to that established by the manufacturer (1-50 ng/mL). The linearity of the standard curve based on the kit-assembled standard solutions agreed with the one based on the self-made standard solutions. Specificity studies indicate that the imidacloprid monoclonal antibody can readily distinguish the target compound from other structurally related neonicotinoid analogues and some metabolites, with the exception of clothianidin, the cross-reactivity of which was approximately 12%. To extract imidacloprid from an agricultural sample (apple) as simply and rapidly as possible, some extraction methods were examined. Consequently, the extraction method with hand-shaking for 5 min was the best among the examined methods. For the analysis of imidacloprid in apple samples, it was extracted directly with methanol and the extracts were diluted 10-fold (100-fold in the well) with water prior to ELISA analysis. No significant matrix interference was observed with the dilution factor. Recoveries of imidacloprid from fortified apple samples ranged from 87.7 to 112.0%. The results obtained with the ELISA kit correlated well with those by the reference method (conventional HPLC analysis) for apple samples (r > 0.998). These findings strongly indicate that the ELISA kit may be employed routinely for an on-site imidacloprid residue analysis of apple samples.

Antibodies, Monoclonal↗

PubMed1993

The nitrovasodilators. New ideas about old drugs.

The nitrovasodilators are a diverse group of pharmacological agents that produce vascular relaxation by releasing nitric oxide. The mechanisms by which these compounds release nitric oxide vary, depending on their chemical structure. Compounds with lower oxidation states of nitrogen such as nitroprusside, nitrosamines, and nitrosothiols release nitric oxide nonenzymatically. In the case of nitroprusside, this involves a one-electron reduction that may occur upon exposure to a variety of reducing agents and tissues such as vascular smooth muscle membranes. In the case of the organic nitrates, which have higher oxidation states of nitrogen, the release of nitric oxide in vascular tissue occurs predominantly by a poorly understood enzymatic process. This interesting property of nitroglycerin is important because it "targets" its effect to vascular tissues that are capable of this enzymatic process. In the case of the coronary circulation, nitroglycerin predominantly dilates the larger coronary arteries while having a minimal effect on coronary resistance vessels < 100 microns in diameter. This prevents the development of coronary steal, which is often encountered with agents that produce intense vasodilation of the coronary resistance vessels. In this review, the mechanisms by which the nitrovasodilators (particularly nitroglycerin) release nitric oxide will be considered, and recent studies of nitroglycerin bioconversion in various-sized coronary vessels will be discussed in detail.

Animals↗

PubMed1999

Generation of nitric oxide and possibly nitroxyl by nitrosation of sulfohydroxamic acids and hydroxamic acids.

Diazeniumdiolates (NONOates) and sulfohydroxamic acids are chemical entities that spontaneously generate nitric oxide (NO) and nitroxyl (HNO), respectively, at physiological pH and temperature. By combining the functional aspects of the NONOates with the hydroxamic acids and sulfohydroxamic acids, hybrid NONOate-type compounds that could theoretically generate nitroxyl or nitric oxide can be rationalized. Although the instability of these compounds, viz., the N-nitrosohydroxamic acids and the N-nitrososulfohydroxamic acids, precluded their chemical characterization by actual isolation, their transient existence was deduced by identification of the products of their decomposition. Thus, treatment of benzohydroxamic acid (BHA) with limiting or excess nitrous acid (from NaNO(2) and H(3)PO(4)) gave rise to quantitative generation of N(2)O, possibly via HNO, based on the limiting reactant. Nitrosation of N-t-butyloxycarbonyl hydroxylamine gave similar results. The organic acid produced from BHA was identified as benzoic acid. No nitric oxide was detected from these reactions. In contrast, treatment of Piloty's acid (benzenesulfohydroxamic acid) and methanesulfohydroxamic acid (MSHA) with nitrous acid under the same conditions as above gave 36% of the theoretical quantity of NO from Piloty's acid and 47% of NO from MSHA, although finite quantities of HNO (measured as N(2)O) were also formed. The organic acid produced from Piloty's acid was identified by reverse-phase HPLC as the redox product, benzenesulfinic acid.

Hydrazines↗

PubMed1995

Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity.

Cytochrome P4501A2 (CYP1A2) has been identified as a key factor in the metabolic activation of numerous chemical carcinogens, including aflatoxin B1, various heterocyclic and aromatic amines, and certain nitroaromatic compounds. In addition, CYP1A2 contributes to the inactivation of several common drugs and dietary constituents, including acetaminophen and caffeine. Two xenobiotic-responsive-element (XRE)-like sequences and an antioxidant response element (ARE) have been identified in the regulatory region of the CYP1A2 gene; however, the functionality of the ARE remains to be demonstrated. Based on in vivo phenotyping assays, substantial interindividual variability in CYP1A2 activity has been reported. Some population-based studies have reported either bi- or tri-modal distributions in CYP1A2 phenotype, suggesting a genetic basis for the large interindividual differences in CYP1A2 activity. However, despite the polymodal distributions reported for CYP1A2 activity, a distinct functional genetic polymorphism in the gene has not been identified. Potential mechanisms contributing to the large interindividual variability in CYP1A2 activity are discussed. A thorough understanding of the functions and regulation of the CYP1A2 gene may ultimately lead to new methods for preventing or intervening in the development of certain chemically-related human cancers.

Aflatoxin B1↗

PubMed2005

Arvanil, a hybrid endocannabinoid and vanilloid compound, behaves as an antihyperkinetic agent in a rat model of Huntington's disease.

The present study was designed to examine whether arvanil (N-arachidonoyl-vanillyl-amide), an endocannabinoid/vanilloid structural "hybrid", might provide symptom relief in the rat model of Huntington's disease (HD) generated by bilateral intrastriatal application of 3-nitropropionic acid (3-NP), where previous evidence suggests that hybrid cannabinoid/vanilloid compounds might be effective. As expected, arvanil did reduce ambulation, stereotypic activity, and number of hole entries, and increased the inactivity, in control rats. It was also active in 3-NP-lesioned rats, where, despite its lowering effects on stereotypic activity and number of hole entries, arvanil reduced the hyperkinesia (increased ambulation) typical of these rats, and also increased the inactivity, these two effects being more moderate than those found in control rats. Arvanil caused its antihyperkinetic effects in 3-NP-lesioned rats presumably by enhancing excitatory transmission at the globus pallidus, since it increased glutamate content in this region. This contrasts with its effects in control rats where arvanil enhanced GABA transmission at the globus pallidus. In summary, arvanil does alleviate hyperkinesia typical of HD, although it also affects locomotion in normal rats. Nevertheless, considering the lack of efficacious pharmacological treatments in this basal ganglia disorder, our findings might provide the basis for the development of more specific drugs against HD.

Animals↗

PubMed2006

Nitric oxide-dependent suppression of thioredoxin-interacting protein expression enhances thioredoxin activity.

OBJECTIVE: Cellular redox balance is regulated by enzymatic and nonenzymatic systems and freely diffusible nitric oxide (NO) promotes antioxidative mechanisms. We show the NO-dependent transcriptional regulation of the antioxidative thioredoxin system. METHODS AND RESULTS: Incubation of rat pulmonary artery smooth muscle cells (RPaSMC) with the NO donor compound S-nitroso-glutathione (GSNO, 100 micromol/L) suppressed thioredoxin-interacting protein (Txnip), an inhibitor of thioredoxin function, by 71+/-18% and enhanced thioredoxin reductase 2.7+/-0.2 fold (n=6; both P<0.001 versus control). GSNO increased thioredoxin activity (1.9+/-0.5-fold after 4 hours; P<0.05 versus control). Promoter deletion analysis revealed that NO suppression of Txnip transcription is mediated by cis-regulatory elements between -1777 and -1127 bp upstream of the start codon. Hyperglycemia induced Txnip promoter activity (3.9+/-0.2-fold; P<0.001) and abolished NO effects (-37.4+/-1.0% at 5.6 mmol/L glucose versus 12.4+/-2.1% at 22.4 mmol/L glucose; P<0.05). Immunoprecipitation experiments demonstrated that GSNO stimulation and mutation of thioredoxin at Cys69, a site of nitrosylation, had no effect on the Txnip/thioredoxin interaction. CONCLUSIONS: NO can regulate cellular redox state by changing expression of Txnip and thioredoxin reductase. This represents a novel antioxidative mechanism of NO independent of posttranslational protein S-nitrosylation of thioredoxin.

Animals↗

PubMed2006

Nitrocompound activation by cell-free extracts of nitroreductase-proficient Salmonella typhimurium strains.

A characterization of nitrocompounds activation by cell-free extracts (CFE) of wild-type (AB(+)), SnrA deficient (B(+)), Cnr deficient (A(+)) and SnrA/Cnr deficient (AB(-)) Salmonella typhimurium strains has been done. The Ames mutagenicity test (S. typhimurium his(+) reversion assay) was used, as well as nitroreductase (NR) activity determinations where the decrease in absorbance generated by nitrofurantoin (NFN) reduction and NADP(H) oxidation in the presence of NFN, nitrofurazone (NFZ), metronidazole (MTZ) and 4-nitroquinoline-1-oxide (4NQO) were followed. Different aromatic and heterocyclic compounds were tested for mutagenic activation: 2-nitrofluorene (2-NF); 2,7-dinitrofluorene (2,7-DNF); 1-nitropyrene (1-NP), 1,3-dinitropyrene (1,3-DNP); 1,6-dinitropyrene (1,6-DNP); and 1,8-dinitropyrene (1,8-DNP). Differential mutagenicity was found with individual cell free extracts, being higher when the wild type or Cnr containing extract was used; nevertheless, depending on the nitrocompound, activation was found when either NR, SnrA or Cnr, were present. In addition, all nitrocompounds were more mutagenic after metabolic activation by CFE of NR proficient strains, although AB(-) extract still showed activation capacity. On the other hand, NR activity was predominantly catalyzed by wild type CFE followed by A(+), B(+) and AB(-) extracts in that order. We can conclude that results from the Ames test indicate that Cnr is the major NR, while NFN and NFZ reductions were predominantly catalyzed by SnrA. The characterization of the residual NR activity detected by the mutagenicity assay and the biochemical determinations in the AB(-) CFE needs further investigation.

Biotransformation↗

PubMed2006

Neonicotinoid insecticides display partial and super agonist actions on native insect nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors (nAChRs) are present in high density in insect nervous tissue and are targeted by neonicotinoid insecticides. Improved understanding of the actions of these insecticides will assist in the development of new compounds. Here, we have used whole-cell patch-clamp recording of cholinergic neurons cultured from the central nervous system of 3rd instar Drosophila larvae to examine the actions of acetylcholine (ACh) and nicotine, as well as the neonicotinoids imidacloprid, clothianidin and P-CH-clothianidin on native nAChRs of these neurons. Dose-response data yield an EC(50) value for ACh of 19 microm. Both nicotine and imidacloprid act as low efficacy agonists at native nAChRs, evoking maximal current amplitudes 10-14% of those observed for ACh. Conversely, clothianidin and P-CH-clothianidin evoke maximal current amplitudes up to 56% greater than those evoked by 100 microm ACh in the same neurons. This is the first demonstration of 'super' agonist actions of an insecticide on native insect nAChRs. Cell-attached recordings indicate that super agonism results from more frequent openings at the largest (63.5 pS) conductance state observed.

Acetylcholine↗

PubMed2005

A novel azulenyl nitrone antioxidant protects against MPTP and 3-nitropropionic acid neurotoxicities.

Oxidative stress plays an important role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Animal models of PD or HD, produced by administration of the mitochondrial toxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3NP), respectively, show increased free radical generation. Free radicals generated in biological systems can react with spin-trapping compounds, such as nitrones, to form stable adducts. In recent years, the utility of nitrones has moved beyond analytical applications and into the realm of neuroprotection as antioxidants in both brain ischemia and models of neurodegenerative diseases. In the present study, we administered a new nitrone antioxidant, stilbazulenyl nitrone (STAZN), with either MPTP or 3NP. STAZN attenuated MPTP-induced striatal dopamine depletion by 40% and showed a tendency to dose-dependent neuroprotection. STAZN dose-dependently protected against loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. STAZN reduced the striatal lesion volume caused by systemic 3NP administration from 44 +/- 9 to 20 +/- 6 mm(3). The lipid peroxidation marker, malondialdehyde(MDA), was significantly increased in the striatum, cortex, and cerebellum of rats after administration of 3NP. These increases were blocked by co-injection of STAZN. Our data provide further evidence that STAZN is a neuroprotective free radical spin trap, and suggest that the development of new antioxidants will broaden our therapeutic strategies for neurodegenerative diseases.

Animals↗

PubMed2006

Aminolyses of 4-nitrophenyl phenyl carbonate and thionocarbonate: effect of modification of electrophilic center from C=O to C=S on reactivity and mechanism.

A kinetic study is reported for nucleophilic substitution reactions of 4-nitrophenyl phenyl carbonate (5) and 4-nitrophenyl phenyl thionocarbonate (6) with a series of primary amines. The thiono compound 6 is less reactive than its oxygen analogue 5 toward strongly basic amines but is more reactive toward weakly basic CF3CH2NH2. The Brønsted-type plots obtained from the aminolyses of 5 and 6 are curved downwardly. The reactions are proposed to proceed through a stepwise mechanism with a change in the RDS on the basis of the curved Brønsted-type plots. The microscopic rate constants (k(1) and k(2)/k(-1) ratio) associated with the current aminolyses are consistent with the proposed reaction mechanism. The replacement of the C=O bond in 5 by a polarizable C=S group results in a decrease in the k(1) value but an increase in the k(2)/k(-1) ratio. Besides, such a modification of the electrophilic center causes a decrease in pKa degrees , defined as the pK(a) at the curvature center of curved Brønsted-type plots, but does not alter the reaction mechanism. The larger k(2)/k(-1) ratio for the reactions of 6 compared to those of 5 is proposed to be responsible for the decreased pK(a) degrees value.

Carbonates↗

PubMed2001

Acute poisoning with the neonicotinoid insecticide imidacloprid in N-methyl pyrrolidone.

BACKGROUND: Imidacloprid [1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine, CAS 138261-41-3] belongs to a relatively new class of insecticidal chemistry, the chloronicotinyl neonicotinoid compounds. Animal studies indicate relatively low toxicity to mammals because they have resistant nicotinic receptor subtypes compared to insects, as well as protection of the central nervous system by the blood brain barrier. Despite wide usage, human exposure experience resulting in toxicity is quite limited. CASE REPORT: Here, we report a case of acute ingestion of an insecticide formulation containing 9.7% imidacloprid, <2 % surfactant, and the balance as solvent, N-methyl pyrrolidone. Clinical manifestation included drowsiness, disorientation, dizziness, oral and gastroesophageal erosions, hemorrhagic gastritis, productive cough, fever, leukocytosis, and hyperglycemia. The patient recovered without complication with supportive treatment and was discharged 4 days after ingestion. Follow-up barium upper gastrointestinal examination 1 month later was normal. Because moderate to high dose imidacloprid in animals causes central nervous system activation similar to nicotine, including tremors, impaired pupillary function, and hypothermia, it is unclear whether imidacloprid had a causal role in the patient's initial drowsiness and dizziness. It is more likely that the formulation ingredients, particularly N-methyl pyrrolidone, caused most of the clinical symptoms including minor central nervous system depression, gastrointestinal irritation, and hyperglycemia.

Blood Cell Count↗

PubMed2002

DNA adducts from nitroreduction of 2,7-dinitrofluorene, a mammary gland carcinogen, catalyzed by rat liver or mammary gland cytosol.

Nitrofluorenes are mutagenic and carcinogenic environmental pollutants arising chiefly from combustion of fossil fuels. Nitro aromatic compounds undergo nitroreduction to N-hydroxy arylamines that bind to DNA directly or after O-esterification. This study analyzes the DNA binding and adducts from the in vitro nitroreduction of 2,7-dinitrofluorene (2,7-diNF), a potent mammary carcinogen in the rat. Potential adduct(s) of 2,7-diNF was (were) generated by reduction of 2-nitroso-7-NF with ascorbate/H(+) in the presence of calf thymus DNA. The major adduct was characterized by HPLC/ESI/MS and (1)H NMR spectrometry as N-(deoxyguanosin-8-yl)-2-amino-7-NF, and a minor one was determined by HPLC/ESI/MS to be a deoxyadenosine adduct of 2-amino-7-NF. Products from enzymatic nitroreduction were monitored by HPLC and DNA adduct formation by (32)P-postlabeling. Xanthine oxidase/hypoxanthine-catalyzed nitroreduction of 2,7-diNF, 2-nitrofluorene (2-NF), and 1-nitropyrene (1-NP) yielded the respective amines to similar extents (30-50%). However, the level of the major adducts ( approximately 0.15/10(6) nucleotides) from 2-NF [N-(deoxyguanosin-8-yl)-2-aminofluorene] and 2,7-diNF [N-(deoxyguanosin-8-yl)-2-amino-7-NF] was < or = 2% that from 1-NP. In the presence of acetyl CoA, nitroreduction of 2-NF catalyzed by rat liver cytosol/NADH yielded the same adduct at a level of 2.2/10(6) nucleotides. Liver or mammary gland cytosol with acetyl CoA yielded mainly N-(deoxyguanosin-8-yl)-2-amino-7-NF from 2,7-diNF at >30 adducts/10(6) nucleotides, levels comparable to those from 1,6-dinitropyrene and 4- or 49-fold greater than the respective levels without acetyl CoA. Recovery of 2-nitroso-7-NF and 2-amino-7-NF from cytosol-catalyzed reduction of 2,7-diNF indicated nitroreduction and an N-hydroxy arylamine intermediate. Likewise, the presence of 2-acetylamino-7-NF indicated that reactivity with acyltransferase(s) was not prevented by the nitro group at C7. These data are consistent with activation of 2,7-diNF via nitroreduction to the N-hydroxy arylamine and acetyl CoA-dependent O-acetylation of the latter to bind to DNA. Enzymatic nitroreduction of 2,7-diNF was greatly enhanced by 9-oxidation. The nitroreduction of either 9-oxo-2,7-diNF or 9-hydroxy-2,7-diNF catalyzed by liver cytosol with acetyl CoA yielded two adducts (>2/10(6) nucleotides). Differences in the TLC migration of these adducts, compared to those from 2,7-diNF, and the lack of 2,7-diNF formation in the incubations suggested retention of the C9-oxidized groups. The relative ratios of the amine to amide from nitroreductions of 9-oxo-2,7-diNF and 2,7-diNF catalyzed by liver cytosol suggested that the 9-oxo group decreased reactivity with acyltransferase and, thus, the amount of N-acetoxy arylamine that binds to DNA. The mammary gland tumorigenicity of 2,7-diNF and the extent of its activation by the tumor target tissue shown herein suggest relevance of this environmental pollutant for breast cancer.

Animals↗

PubMed2005

Nitrated lipids decompose to nitric oxide and lipid radicals and cause vasorelaxation.

Nitric oxide-derived oxidants such as nitrogen dioxide and peroxynitrite have been receiving increasing attention as mediators of nitric oxide toxicity. Indeed, nitrated and nitrosated compounds have been detected in biological fluids and tissues of healthy subjects and in higher yields in patients under inflammatory or infectious conditions as a consequence of nitric oxide overproduction. Among them, nitrated lipids have been detected in vivo. Here, we confirmed and extended previous studies by demonstrating that nitrolinoleate, chlolesteryl nitrolinoleate, and nitrohydroxylinoleate induce vasorelaxation in a concentration-dependent manner while releasing nitric oxide that was characterized by chemiluminescence-and EPR-based methodologies. As we first show here, diffusible nitric oxide production is likely to occur by isomerization of the nitrated lipids to the corresponding nitrite derivatives that decay through homolysis and/or metal ion/ascorbate-assisted reduction. The homolytic mechanism was supported by EPR spin-trapping studies with 3,5-dibromo-4-nitrosobenzenesulfonic acid that trapped a lipid-derived radical during nitrolinoleate decomposition. In addition to provide a mechanism to explain nitric oxide production from nitrated lipids, the results support their role as endogenous sources of nitric oxide that may play a role in endothelium-independent vasorelaxation.

Animals↗

PubMed2003

Incubation of porcine iris-ciliary bodies to study the mechanisms by which nitric oxide donors lower intraocular pressure.

BACKGROUND: We previously reported that several nitric oxide (NO) donors, guanylate cyclase activators, and cyclic GMP lower intraocular pressure (IOP) in rabbits. MATERIAL/METHODS: This study evaluated a novel method for studying cGMP production in the iris-ciliary body after the administration of different NO donors and guanylate cyclase activators. Tissue samples of porcine iris-ciliary body were incubated for 30 or 60 minutes with the test compounds and with or without the phosphodiesterase inhibitor zaprinast. The concentration of cGMP in the iris-ciliary body as an indicator of soluble guanylate cyclase activation was measured by radioimmunoassay. RESULTS: The tested NO donors - SNOG, NONOate, NOR-3, and SNAP - were shown to release NO in incubation medium, and clearly increase cGMP concentration in the iris-ciliary body. Cyclic GMP production was 2-5 times higher with nitrosocaptopril and about 10 times higher with SNP than in the unstimulated control tissue incubation. Captopril, the reference for nitrosocaptopril, did not induce cGMP production in the porcine iris-ciliary body. ODQ, a guanylate cyclase inhibitor, shut down the production of cGMP after the administration of nitrosocaptopril and SNP. The guanylate cyclase activators YC-1 and atriopeptin III increased cGMP dose-dependently. CONCLUSIONS: In this novel tissue incubation method, several NO donors and guanylate cyclase activators increased cGMP production in the porcine iris-ciliary body. This method can be used to screen new molecules in terms of cGMP production, since the ciliary body is important in lowering intraocular pressure.

Animals↗

PubMed2004

Metabolism of imidacloprid in Apis mellifera.

Biotransformation of imidacloprid and the appearance of olefin and 5-hydroxyimidacloprid metabolites in the honeybee were studied by HPLC-MS/MS analysis. Honeybees were treated orally with imidacloprid at 20 and 50 microg kg(-1) bee. Imidacloprid was metabolised relatively quickly and thoroughly. Twenty minutes after the beginning of imidacloprid ingestion, the sum of the residues from the three compounds amounted to only 70% of the actual given dose. Imidacloprid, 5-hydroxyimidacloprid and olefin represented, respectively, 50%, 9% and 8% of the actual ingested dose. Six and 24 h, respectively, after ingestion of imidacloprid at 20 and 50 microg kg(-1) bee, imidacloprid could no longer be detected in the honeybee. Imidacloprid had a half-life ranging between 4.5 and 5 h and was rapidly metabolised into 5-hydroxyimidacloprid and olefin. Except 5-hydroxyimidacloprid in the 20 microg kg(-1) treatment, these two metabolites presented a peak value 4 h after ingestion of the 20 and 50 microg kg(-1) doses. This time fully coincided with the appearance of mortality induced by imidacloprid after acute oral intoxication. These results suggested that the immediate neurotoxicity symptoms are due to the action of imidacloprid, whereas 5-hydroxyimidacloprid and/or olefin are involved in honeybee mortality. In addition, it was likely that the 30% of residues undetected 20 min after intoxication were imidacloprid metabolites, although not 5-hydroxyimidacloprid or olefin. Thus, 5-hydroxyimidacloprid and olefin could not be the major metabolites in the worker bees.

Alkenes↗

PubMed1991

Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.

Angiotensin II↗

PubMed1994

The electron transfer reactions of NADPH: cytochrome P450 reductase with nonphysiological oxidants.

The steady-state kinetics of oxidation of rat liver NADPH: cytochrome P450 reductase (EC 1.6.2.4) by quinones, aromatic nitrocompounds, ferricyanide, Fe(EDTA)-, and cytochrome c has been studied. The logarithms of bimolecular rate constants of reduction (kcat/Km) of quinones and nitrocompounds increase with the increase in their single-electronreduction potential (E1(7)), reaching a maximum value at E1(7) > -0.15 V. The reactivities of nitroaromatics are about by an order of magnitude lower than the reactivities of quinones. For a series of nitroaromatics including the compounds with previously undetermined E1(7) values, an orthogonality was found between their reactivities toward cytochrome P450 reductase, flavocytochrome b2 (EC 1.1.2.3), and the NADPH: adrenodoxin reductase (EC 1.18.1.2)-adrenodoxin system. This indicates the absence of significant specific interactions during these reactions. The effects of ionic strength on reaction kinetics and the character of inhibition by a product of reaction, NADP+, are in accordance with the reduction of oxidants at the negatively charged site in the surroundings of FMN of P450 reductase. Quinones inactivate oxidized reductase modifying the NADP(H) binding site. The redox cycling of quinones markedly slows the inactivation. The kinetic data presented are consistent with an outer-sphere electron transfer mechanism. The analysis of kinetics of reduction of cytochrome c, ferricyanide, and Fe(EDTA)- using the model of Mauk et al. (A. G. Mauk, R. A. Scott, and H. B. Gray (1980) J. Am. Chem. Soc. 102, 4360-4363) gives calculated distances of FMN from the surface of protein globule, 0.33-0.63 nm. The data from nitroreductase reactions of cytochrome P450 reductase, flavocytochrome b2, and adrenodoxin were used for approximate evaluation of previously unknown E1(7) of nitrocompounds.

Animals↗

PubMed2006

Nitazoxanide for the treatment of Clostridium difficile colitis.

BACKGROUND: Clostridium difficile colitis has increased in incidence and severity, and treatment failure with metronidazole therapy has increasingly been documented. It is uncertain whether treatment with vancomycin is more effective than treatment with metronidazole, but concern over the emergence of vancomycin resistance has motivated the search for alternative therapy. Nitazoxanide, a nitrothiazolide, blocks anaerobic metabolism of eukaryocyes and effectively treats intestinal infestation due to Cryptosporidium or Giardia species. At low concentrations, this compound inhibits C. difficile in vitro. METHODS: We designed a prospective, randomized, double-blind study to compare nitazoxanide to metronidazole in treating hospitalized patients with C. difficile colitis. RESULTS: Thirty-four patients received metronidazole at a dosage of 250 mg 4 times per day for 10 days, 40 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 7 days, and 36 patients received nitazoxanide at a dosage of 500 mg 2 times per day for 10 days. After 7 days of treatment, 28 (82.4%) of 34 patients had responded to metronidazole therapy, compared with 68 (89.5%) of 76 who had received nitazoxanide therapy (difference, 7.1%; 95% confidence interval, -7.1% to 25.5%). Thirty-one days after beginning treatment, sustained responses were observed in 19 (57.6%) of 33 patients who had received metronidazole therapy for 10 days, compared with 25 (65.8%) of 38 who had received nitazoxanide for 7 days and 26 (74.3%) of 35 who had received nitazoxanide for 10 days (P = .34). CONCLUSION: Nitazoxanide is at least as effective as metronidazole in treating C. difficile colitis.

Aged↗