Potentiometric investigation of the stability of palladium(II) complex of pralidoxime chloride in aqueous solution

The formation of a complex between palladium(II) chloride and pralidoxime chloride (PAM-2Cl) has been studied by means of potentiometric pH measurements. The real stability constant of the complex in aqueous medium of ionic strength 0.3 M (KCl) at 25.0°C was log K_s = 7.29. This value was close to that (log K_s = 7.02) obtained previously by spectrophotometric methods after appropriate correction with respect to the corresponding value of the acidic constant of PAM-2Cl (pK^c_a = 8.05), which was also determined under the same experimental conditions.     

Reactivating and protective effects of Pro-2-PAM in mice poisoned with paraoxon

Acute toxicity of N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride (Pro-2-PAM) in mice, its concentrations in blood and brain and its protective and reactivating effects in diethyl p-nitrophenyl phosphate (paraoxon) poisoning were determined. Comparative studies with N-methylpyridinium-2-aldoxime chloride (PAM-2 Cl) and a mixture of two oximes were also performed. Pro-2-PAM was much less toxic than was PAM-2 Cl. In contrast to this, the Pro-compound penetrates well into central nervous system (CNS), and effectively reactivates brain acetylcholinesterase (AChE) in vivo inhibited by paraoxon. The two oximes were equally effective in reactivating blood AChE. However, protective effects of Pro-2-PAM were unexpectedly lower than those of PAM-2 Cl. The observation suggests that there is no correlation between brain AChE reactivating power and protective effects of Pro-2-PAM. Contrary to the present belief, it seems that Pro-2-PAM undergoes slow conversion in vivo into its active form PAM-2 Cl. The possible use of Pro-2-PAM as a model oxime for penetration into CNS requires further evaluation with regard to therapy of organophosphorus poisoning.     

Use of palladium(II) chloride as colour-forming reagent in determination of pralidoxime chloride in water and tablets

Pralidoxime chloride (PAM-2Cl) has been determined spectrophotometrically in Britton—Robinson buffer solution at pH = 6.45; the method is based on measurement of the absorbance of the Pd(II)-pralidoxime complex at 327 nm. Studies of the composition of the complex by Job's continuous variation method, the molar ratio method and Bent—French's method yielded a Pd(II):pralidoxime ratio of 1:1. The conditional stability constant (K′) of the complex at the optimum pH of 6.45 and an ionic strength (μ) of 0.3 M was found to be 10^5.2. The molar absorptivity was 1.05 × 10⁴ 1 mol⁻¹ cm⁻¹. Beer's law was obeyed at concentrations up to 60 μM. The detection limit was 0.55 μg ml⁻¹. The relative standard deviation (N = 10) was 0.28–1.03%. The method was accurate and sensitive for the analysis of PAM-2Cl in water and tablets.     

Effect of PAM-2 Cl,HI-6, and HGG-12 in poisoning by tabun and its thiocholine-like analog in the rat

It has been shown that HI-6 was the most potent oxime so far known in poisoning by sarin, VX, and soman, but its protective effect in tabun poisoning, allegedly due to poor reactivation of inhibited ChE, was much less pronounced. We have found that the thiocholine-like analog of tabun, O-ethyl, N-N-dimethyamino-S-(2-diethylaminoethyl)-thiophosphatemethylsulfomethylate (Ta-S-N+), was very useful in resolving this problem and established the relationship between reactivating and protective effects of PAM-2 Cl, HI-6, and HGG-12 in rats. PAM-2 Cl (protective ratio (PR) = 22.1) and HI-6 (PR = 24.8), combined with atropine, were very effective against Ta-S-N+ poisoning and reactivating inhibited RBC AChE in vitro and rat blood ChE in vivo. The inefficiency of PAM-2 Cl (PR = 1.6) and HI-6 (PR = 2) in tabun poisoning was due to their inadequacy to reactivate tabun-inhibited ChEs. The protective effects of HGG-12 in tabun (PR = 2.8) and Ta-S-N+ poisoning (PR = 2.6) were low, and in the absence of any reactivation of inhibited ChEs, have been atributed to its direct pharmacological effects, which were much more potent in the comparison with PAM-2 Cl or HI-6. It is concluded that the reactivation of inhibited ChE is of decisive importance in the efficient protection in poisoning by tabun and other known chemical warfare nerve agents, whereas their direct pharmacological effects are of limited value, allowing survival of animals only against a few LD50s.     

Quantification of a novel PPARγ partial agonist (<Emphasis Type="Italic">S</Emphasis>)-2-ethoxy-3-(4-{3-methyl-5-[4-(3-methyl-isoxazol-5-yl)-phenyl]thiophen-2-ylmethoxy}-phenyl)-propionic acid (PAM-1616) in rat plasma using liquid chromatography-tandem mass spectrometry

(S)-2-ethoxy-3-(4-{3-methyl-5-[4-(3-methyl-isoxazol-5-yl)-phenyl]thiophen-2-ylmethoxy}-phenyl)-propionic acid (PAM-1616) is a novel peroxisome proliferators-activated receptor γ (PPARγ) partial agonist with excellent antihyperglycemic activity. It is a promising new drug candidate for the treatment of type-2 diabetes with reduced possibility of edema in vitro/in vivo. In order to evaluate the pharmacokinetics of PAM-1616, a reliable, selective and sensitive highperformance liquid chromatography/electrospray ionization tandem mass spectrometry was developed for the quantification of PAM-1616 in rat plasma. The analytes were extracted from rat plasma with ethyl acetate, separated on an Atlantis dC₁₈ column with a mobile phase of 75% acetonitrile in 10 mM ammonium formate (pH 4.5), and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r ² = 0.999) over the concentration range of 0.05–20.0 μg/mL and the lower limit of quantification was 0.05 μg/mL. The coefficient of variation and relative error at four QC levels were 1.8% to 14.3% and −10.0% to 6.5%, respectively. The present method was successfully applied to the pharmacokinetic study of PAM-1616 after intravenous administration of PAM-1616 potassium at a dose of 1 mg/kg in rats.     

Limited reactivity of formyl chloride with glutathione and relevance to metabolism and toxicity of dichloromethane

Formyl chloride has been indirectly implicated as an intermediate in the oxidation of CH(2)Cl(2) and proposed to be a product of the oxidation of some other compounds. Formyl chloride was synthesized and added to aqueous solutions, with CO formed as a product. The presence of glutathione (GSH) did not reduce the yield of CO at any of the pH values tested. At pH >or= 9, a small amount of S-formyl GSH was detected (相似文献   

PAM-1616, a selective peroxisome proliferator-activated receptor γ modulator with preserved anti-diabetic efficacy and reduced adverse effects

Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAM-1616 is a novel, non-thiazolidinedione small molecule compound synthesized in Dong-A Research Center. In this study, we characterized the pharmacological and safety profiles of PAM-1616 as a selective PPARγ modulator. PAM-1616 selectively binds to human PPARγ (IC(50), 24.1±5.6 nM) and is a partial agonist for human PPARγ with an EC(50) of 83.6±43.7 nM and a maximal response of 24.9±7.1% relative to the full agonist, rosiglitazone. PAM-1616 was selective for human PPARγ than for human PPARα (EC(50), 2658±828 nM) without activating human PPARδ, which makes it a selective modulator of PPARγ. Treatment of high fat diet-induced obese C57BL/6J mice with PAM-1616 for 21 days improved HOMA-IR. Furthermore, PAM-1616 significantly improved hyperglycemia in db/db mice with little side effect when orally administered at a dose of 1 mg/kg/day for 28 days. Intriguingly, PAM-1616 was seen to increase the gene expression of inducible glucose transporter (GLUT4), while it partially induced that of a fatty acid carrier, aP2 in 3T3-L1 adipocytes, and it also showed partial recruitment of an adipogenic cofactor, TRAP220 as compared to rosiglitazone. PAM-1616 did not cause a significant increase in plasma volume of ICR mice when orally administered at a dose of 10 mg/kg/day for 9 days. PAM-1616 increased the expression of fluid retention-inducing genes such as serum/glucocorticoid-regulated kinase (SGK)-1 to a lesser extent as compared to rosiglitazone in human renal epithelial cells. These results suggest that PAM-1616 acts as a selective modulator of PPARγ with excellent antihyperglycemic property. The differential modulation of target gene by PAM-1616 might contribute to the improved side effect profiles.     

N-Chlorotaurine and ammonium chloride: an antiseptic preparation with strong bactericidal activity

The bactericidal activity of the endogenous antiseptic N-chlorotaurine (NCT) is significantly enhanced in the presence of ammonium chloride which induces the formation of monochloramine (NH(2)Cl) whose strong bactericidal activity is well known. In this study the properties of NCT plus ammonium chloride have been investigated. The reaction of active chlorine compounds like chloramine-T (N-chlorotoluene-sulfonamide sodium), chloroisocyanuric acid derivatives, hypochlorites (NaOCl, CaOCl(2)) with ammonium chloride did not stop at the stage of monochloramine, and the pungent smelling by-products di- and trichloramine, NHCl(2) and NCl(3), were also formed. This was not the case with NCT where only monochloramine was generated. The equilibrium constant of the reaction of NCT with ammonium was found to be [Formula: see text] , which allows to estimate the equilibrium concentration of monochloramine in aqueous solutions of NCT and ammonium chloride. At concentrations each ranging between 0.01% and 1.0% it comes to [NH(2)Cl]=3.5-254 ppm. As an unexpected result the monochloramine containing formulation turned out to be most stable in plain water without buffer additives. Quantitative killing assays revealed complete inactivation of 10(6) to 10(7)CFU/mL of seven bacterial strains by 0.1% NCT plus 0.1% ammonium chloride within 5 min, while with plain 0.1% NCT an incubation time of 2-4h was needed to achieve the same effect. The highly significant increase of bactericidal activity (200-300-fold) could be assigned to the presence of monochloramine which could be isolated by vacuum distillation. Aqueous solutions of NCT and ammonium chloride provide a highly effective and well tolerable antiseptic preparation appropriate to a treatment cycle of at least 1 month if stored in the refrigerator.     

Synthesis of new 1,3-oxazolyl-7-chloroquinazolin-4(3H)ones and evaluation of their antimicrobial activities

2-[2-(2,6-Dichlorophenyl)amino]phenylmethyl-3-{4-[(substituted phenyl)amino]-1,3-oxazol-2-yl)-7-chloroquinazolin-4(3H)ones 5a-o have been prepared from 2-[(2,6-dichloro phenyl)amino]phenyl acetic acid 1, which was converted to acid chloride 2 and cyclized with anthranilic acid afforded benzoxazin-4(H)ones 3. Further reaction with urea gave carboxamide-7-chloroquinazolin-4(3H)ones 4 cyclized with substituted phenyl acetamide a-o. All the compounds have been confirmed by elemental analysis, IR, NMR spectral data and evaluated for antimicrobial activity. Compounds 5o, 5k, and 5m (R = 1-H, 2,5-(Cl), and 2-Cl, 4-NO2) showed good activity, compared with the standard drugs.     

Efficient use of the iron ortho-nitrophenylporphyrin chloride to mimic biological oxidations of dimethylaminoantipyrine

Major metabolites of dimethylaminoantipyrine have been synthesized using iron ortho-nitrophenylporphyrin chloride as biomimetic catalyst. Reactivity of iron tetrakis-ortho-nitrophenylporphyrin chloride [Fe(TNO2PP)Cl] has been compared with iron tetrakis-pentafluorophenylporphyrin chloride and iron tetrakis-2,6-dichlorophenylporphyrin chloride using various oxidants such as hydrogen peroxide, iodosobenzene, and cumene hydroperoxide in either protic or aprotic solvent. Effect of imidazole has been showed on the reactivity of Fe(TNO2PP)Cl/cumene hydroperoxide system.     

PAM-2 Cl,HI-6, and HGG-12 in soman and tabun poisoning

Acute sc toxicity of soman increased in the order, mice → rats → guinea pigs → dogs, being 12.6 times more toxic to dogs (LD50 = 0.05 μmol/kg) than to mice. It was 2.8 times more toxic than tabun to mice and 35 times more toxic to dogs. HI-6 was the least toxic and had similar toxicity values to the four animal species studied and HGG-12 the most toxic of the three oximes used. HGG-12 has shown the greatest interspecies variation (rats:dogs = 1:19.5). HI-6, HGG-12, and PAM-2 Cl (in conjunction with atropine and diazepam) revealed the best protective effect in soman-poisoned dogs, with the respective protective indices of 9, 6.3, and 3.5, followed by guinea pigs. In tabun poisoning the best, but relatively low, protective effect was found only in guinea pigs. The introduction of diazepam increased the protective effects of atropine-oxime combination in soman and tabun poisoning by 10 to 80%. We suggest that the high toxicity of soman and low toxicity of HI-6 may be anticipated in man. The inefficiency of HI-6, HGG-12, and PAM-2 Cl in tabun poisoning points either to the search of new compounds or to the use of the mixture of the oximes found to be effective against the known chemical warfare nerve agents.     

Antitumor effect of Pt(II) amine phosphonate complexes on sarcoma sa-180 in mice. Crystal structure of cis-dichlorobis(diethyl-4-pyridylmethylphosphonate-kappaN)platinum(II) hydrate, cis-[PtCl2(4-pmpe)2].H20

The cisplatin analogoues platinum (II) complexes of the general formula cis-[PtL2Cl2], where L is monodentate diethyl 2-, 3- or 4-pyridylmethylphosphonate (2-, 3- or 4-pmpe) ligand, have been synthesized and characterized by means of IR and NMR (1H, 31P, 195Pt) spectroscopy. The crystal and molecular structure of cis-[Pt(4-pmpe)2 Cl2].H2O (A3) shows a square planar geometry of PtL2Cl2, with two organic molecules and two chloride leaving ligands in a cis configuration. The antitumor activity of the platinum (II) complexes was examined against Sarcoma Sa-180 in mice. The obtained results indicate a marked anticancer effect of platinum phosphonate complexes, and moderate nephrotoxicity evaluated in the BUN and creatinine levels in comparison with cisplatin (CDDP).     

Oxaliplatin Degradation in the Presence of Chloride: Identification and Cytotoxicity of the Monochloro Monooxalato Complex

PURPOSE: To study the degradation of oxaliplatin in chloride media and evaluate the cytotoxicity of oxaliplatin in normal and chloride-deficient medium. METHODS: The products of the reaction of oxaliplatin with chloride were separated on a Hypercarb S column with a mobile phase containing 40% methanol in 0.05 M ammonia and subjected to electrospray ionization mass spectrometry. The cytotoxicity of oxaliplatin in normal and chloride-deficient medium was evaluated by 30-min incubations on human colon adenocarcinoma cells (HT-29). RESULTS: We identified a new intermediate degradation product, the monochloro monooxalato complex ([Pt(dach)oxCl]-) and the final product. the dichloro complex (Pt(dach)Cl2), by liquid chromatography-mass spectrometry. [Pt(dach)oxCl]- was found as the negative ion, M-, at m/z 431, and the positive ion, [M+2H]+, m/z 433. Pt(dach)Cl2 was found as the negative ion, [M-H]-, m/z 377, and the positive ion, [M+NH4]+, m/z 396. The fast initial degradation of oxaliplatin can be coupled to the fast formation of [Pt(dach)oxCl]-. In the cytotoxic assay, the cell survival was not affected by the chloride levels. CONCLUSIONS: [Pt(dach)oxCl]-, a new transformation product of oxaliplatin, has been identified. Its in vitro cytotoxic effect does not appear to exceed that of oxaliplatin.     

Biomimetic oxidation of diphenyl sulfide with electrochemical P-450 model system in CH2Cl2 treated with alkaline solution]

Dichloromethane containing metalloporphyrins [meso-tetraphenylporphyrinatomanganese(III) chloride (1) or meso-tetraphenylporphyrinatoiron(III) chloride (2)] and Bu4NClO4 was treated with an aqueous solution of NaOH (5%), and subjected to controlled potential electrolysis at -1.0 V (vs. S.C.E. (saturated calomel electrode)) in a divided cell after addition of diphenyl sulfide (3). Diphenyl sulfoxide (4) and diphenyl sulfone (5) were found in an electrolyzed solution as the reaction products. Results obtained from cyclic voltammetry and visible spectrometry suggested that the treatment of dichloromethane containing metalloporphyrins with the aqueous solution of NaOH did not change the fifth ligand of metalloporphyrins from Cl to OH. On the electrode, dissolved dioxygen was reduced to hydrogen peroxide. Compounds 1 and 2 catalyze the oxidation of 3 by hydrogen peroxide without imidazole. Compound 2 showed higher selectivity than compound 1.     

DCPIB is a novel selective blocker of I(Cl,swell) and prevents swelling-induced shortening of guinea-pig atrial action potential duration.

1. We identified the ethacrynic-acid derivative DCPIB as a potent inhibitor of I(Cl,swell), which blocks native I(Cl,swell) of calf bovine pulmonary artery endothelial (CPAE) cells with an IC(50) of 4.1 microM. Similarly, 10 microM DCPIB almost completely inhibited the swelling-induced chloride conductance in Xenopus oocytes and in guinea-pig atrial cardiomyocytes. Block of I(Cl,swell) by DCPIB was fully reversible and voltage independent. 2. DCPIB (10 microM) showed selectivity for I(Cl,swell) and had no significant inhibitory effects on I(Cl,Ca) in CPAE cells, on chloride currents elicited by several members of the CLC-chloride channel family or on the human cystic fibrosis transmembrane conductance regulator (hCFTR) after heterologous expression in Xenopus oocytes. DCPIB (10 microM) also showed no significant inhibition of several native anion and cation currents of guinea pig heart like I(Cl,PKA), I(Kr), I(Ks), I(K1), I(Na) and I(Ca). 3. In all atrial cardiomyocytes (n=7), osmotic swelling produced an increase in chloride current and a strong shortening of the action potential duration (APD). Both swelling-induced chloride conductance and AP shortening were inhibited by treatment of swollen cells with DCPIB (10 microM). In agreement with the selectivity for I(Cl,swell), DCPIB did not affect atrial APD under isoosmotic conditions. 4. Preincubation of atrial cardiomyocytes with DCPIB (10 microM) completely prevented both the swelling-induced chloride currents and the AP shortening but not the hypotonic cell swelling. 5. We conclude that swelling-induced AP shortening in isolated atrial cells is mainly caused by activation of I(Cl,swell). DCPIB therefore is a valuable pharmacological tool to study the role of I(Cl,swell) in cardiac excitability under pathophysiological conditions leading to cell swelling.     

Effects of chloride channel blockers on hypotonicity-induced contractions of the rat trachea

1. We have investigated the inhibitory effects of blockers of volume-activated (Cl(vol)) and calcium-activated (Cl(Ca)) chloride channels on hypotonic solution (HS)-induced contractions of rat trachea, comparing their effects with those of the voltage-dependent calcium channel (VDCC) blocker nifedpine. 2. HS elicited large, stable contractions that were partially dependent on the cellular chloride gradient; a reduction to 41.45+/-7.71% of the control response was obtained when extracellular chloride was removed. In addition, HS-induced responses were reduced to 26.8+/-5.6% of the control by 1 microm nifedipine, and abolished under calcium-free conditions, indicating a substantial requirement for extracellular calcium entry, principally via VDCCs. 3. The established Cl(vol) blockers tamoxifen (相似文献   

New isomeric azine-bridged dinuclear platinum(II) complexes circumvent cross-resistance to cisplatin

Four new isomeric azine-bridged complexes ([(cis-Pt(NH(3))(2)Cl)(2)(mu-pzn)]Cl(2) (1a) (pzn = pyrazine) and its corresponding nitrate salt (1b), [(cis-Pt(NH(3))(2)Cl)(2)(mu-pmn)]Cl(2) (2) (pmn = pyrimidine), and [(cis-Pt(NH(3))(2)Cl)(2)(mu-pdn)](NO(3))(2) (3) (pdn = pyridazine) have been newly synthesized as potential anticancer compounds. These complexes have been characterized by (1)H and (195)Pt NMR spectroscopy, and also the X-ray crystal structure of 1b has been determined. The reactions of 1a, 2, and 3 with guanosine-5'-monophosphate (GMP) have been monitored and kinetically investigated in D(2)O solutions at 310 K using (1)H NMR spectroscopy. Both 1a and 2 react with 2 equiv of GMP to form 1:2 complexes. The reactions involve a stepwise direct substitution of chloride ligands by GMP, with similar reaction rates for both complexes. On the other hand, the reaction of 3 with GMP results in the cleavage of one of the Pt-N(pyridazine) bonds to form an N7,O6-platinated polymer. The reaction products have been separated and have been characterized by (1)H and (195)Pt NMR spectroscopy. A cytotoxicity assay of the azine-bridged complexes (1a, 1b, 2, and 3) has been performed on human tumor cell lines and two L1210 murine leukemia cell lines (one sensitive to and one resistant to cisplatin). In general, the complexes show lower cytotoxicity than cisplatin for the human tumor cell lines except for the IGROV cell line. Their cytotoxicity for the mouse cell lines is comparable to or higher than that of cisplatin. Furthermore, these complexes appeared to largely or partly overcome the cross-resistance to cisplatin. Implications of these findings are discussed in the context of a structure-activity relationship for this class of compounds.     

Nucleobase-dependent reactivity of a quinone metabolite of pentachlorophenol

Pentachlorophenol (PCP) is a possible human carcinogen detected widely in the environment. A quinone metabolite of PCP, tetrachloro-1,4-benzoquinone (Cl4BQ), is a reactive electrophile with the capacity to damage DNA by forming bulky covalent DNA adducts. These quinone adducts may contribute to chlorophenol carcinogenesis, but their structures, occurrence, and biological consequences are not known. Previous studies have indicated that several DNA adducts are formed in vivo in rats exposed to Cl4BQ, but these adducts were not identified structurally. In the present study, we have elucidated the structure of new agent-specific DNA adducts resulting from the reaction of dGuo, dCyd, and Thd with Cl4BQ. These have been characterized chemically by liquid chromatography-electrospray ionization mass spectrometry, HPLC, UV, and NMR analysis. Two dGuo adducts and one dCyd adduct resulting from the reaction of double-stranded DNA with Cl4BQ have been identified. The results indicate that, in the structural context of DNA, Cl4BQ reacts most readily with dGuo compared to the other DNA bases and that the mode of Cl4BQ reactivity is dependent on the base structure; i.e., multiple types of adducts are formed. Finally, DNA adducts consistent with Cl4BQ reactions are observed when DNA or dGuo is treated with PCP and a peroxidase-based bioactivating system.     

Structure of aluminum hydroxide gel I: initial precipitate.

The initial aluminum hydroxide gel precipitate resulting from the reaction of aluminum chloride or aluminum sulfate with ammonium hydroxide is shown by potentiometric titration, chemical analysis, and the ratio of bound hydroxide to aluminum to fit a polymer model described previously. The formation of polynuclear hydroxyaluminum particles is treated as a stepwise process involving a deprotonation-dehydration mechanism, which results in the formation of six-membered rings; these rings may further coalesce by the same mechanism. The aluminum hydroxide gel precipitated from aluminum chloride can be represented by the formula Al(OH)2.55(Cl)0.45 and probably exists as a polymer of 10 fused six-membered rings. The aluminum hydroxide gel precipitated from aluminum sulfate can be represented by the formula Al(OH)2.30(SO4)0.35. This species probably exists as a polymer of three fused six-membered rings.     

Studies of the amplification of carbaryl toxicity by various oximes.

The administration of 2-pyridine aldoxime methyl chloride (2-PAM Cl) is a standard part of the regimen for treatment of human overexposure to many organophosphorus pesticides and nerve agents. However, some literature references indicate that poisoning by carbaryl (1-naphthyl N-methyl carbamate), an insecticide in everyday use, is aggravated by the administration of 2-PAM Cl. This effect has been reported in the mouse, rat, dog and man. We have found that the inhibition of both eel acetylcholinesterase (eel AChE, EC 3.1.1.7) and human serum cholinesterase (human BuChE, EC 3.1.1.8) by carbaryl was enhanced by several oximes. Based on 95% confidence limits the rank order of potentiation with eel AChE was TMB-4 = Toxogonin > HS-6 = HI-6 > 2-PAM Cl. By the same criterion, the rank order of potentiation with human BuChE was TMB-4 > Toxogonin > HS-6 = 2-PAM Cl. Carbaryl-challenged mice also reflected a potentiation since TMB-4 exacerbated the toxicity more than 2-PAM Cl. Our hypothesis is that certain oximes act as allosteric effectors of cholinesterases in carbaryl poisoning, resulting in enhanced inhibition rates and potentiation of carbaryl toxicity.