Absorption, first-pass metabolism, and disposition of itraconazole in rats

This study examined the pharmacokinetic disposition, oral absorption and hepatic extraction of itraconazole and its active metabolite, hydroxyitraconazole, in rats. After i.v. injection, serum itraconazole concentrations decreased biexponentially, with an average terminal elimination half-life, volume of distribution and systemic clearance of 4.9 h, 6.0 l/kg and 14.2 ml/min/kg, respectively. When given orally, its absorption was low, with a mean absolute bioavailability of 16.6%. The metabolite to parent drug area under the curve (AUC) ratio was higher after oral administration compared with i.v. injection (mean ratio, 2.7 vs. 0.9). The hepatic drug extraction ratio determined after femoral and portal vein administration averaged 18.5%. When hydroxyitraconazole was injected i.v., the elimination half-life, volume of distribution and systemic clearance of itraconazole averaged 10.0 h, 2.4 l/kg and 3.4 ml/min/kg, respectively. The fraction of the systemically available itraconazole that was metabolized to hydroxyitraconazole was 21.0% and 76.0% after i.v. and oral administration, respectively. In summary, this study is the first reporting the hepatic extraction of itraconazole and the i.v. disposition characteristics of hydroxyitraconazole in rats. Itraconazole is a drug with a low hepatic extraction ratio and its systemic clearance appears to be largely accounted for by hepatic metabolism.     

Structure Sensitivity in the Hydrodechlorination of Chlorophenols

The gas phase hydrodechlorination of methanolic and mixed methanol/water solutions of 2-chlorophenol, 2,6-dichlorophenol, 2,4,5-trichlorophenol and pentachlorophenol has been studied at 573 K over nickel/silica catalysts of varying (1.5–20.3 wt.% Ni) nickel loading. Each catalyst was 100% selective in promoting hydrodechlorination: the variation of catalytic activity and selectivity with time-on-stream is illustrated and catalyst deactivation is addressed. Dechlorination is quantified in terms of specific rate constants, phenol selectivity/yield and chlorine removal efficiencies. Increasing the nickel loading resulted in a marked increase in dechlorination efficiency while the introduction of water into the feed lowered the activity.     

Chemical Oxidative Degradation of Acridine Orange Dye in Aqueous Solution by Fenton's Reagent

Degradation of acridine orange (AO) in aqueous solution by Fenton's reagent (Fe²⁺ and H₂O₂) was investigated. The effects of different reaction parameters such as initial AO concentration, pH value of solution, ferrous concentration, hydrogen peroxide concentration, and the presence of chloride ion on the oxidative degradation of AO were investigated. Under optimum conditions, 2 mM H₂O₂, 0.4 mM Fe²⁺ and pH 3.0, the initial 0.2 mM AO solution was reduced by 95.8% within 10 min. The primary intermediates of the degradation reaction of AO were identified. The analytical results indicated that the N‐de‐methylation degradation of AO dye took place in a stepwise manner to yield mono‐, di‐, tri‐, and tetra‐N‐de‐methylated AO species generated during the Fenton process. The probable degradation pathways were proposed and discussed.     

Tuning Local Coordination Environments of Manganese Single-Atom Nanozymes with Multi-Enzyme Properties for Selective Colorimetric Biosensing

Single-atom nanozymes (SAzymes) are promising in next-generation nanozymes, nevertheless, how to rationally modulate the microenvironment of SAzymes with controllable multi-enzyme properties is still challenging. Herein, we systematically investigate the relationship between atomic configuration and multi-enzymatic performances. The constructed Mn_SA−N₃-coordinated SAzymes (Mn_SA−N₃−C) exhibits much more remarkable oxidase-, peroxidase-, and glutathione oxidase-like activities than that of Mn_SA−N₄−C. Based on experimental and theoretical results, these multi-enzyme-like behaviors are highly dependent on the coordination number of single atomic Mn sites by local charge polarization. As a consequence, a series of colorimetric biosensing platforms based on Mn_SA−N₃−C SAzymes is successfully built for specific recognition of biological molecules. These findings provide atomic-level insight into the microenvironment of nanozymes, promoting rational design of other demanding biocatalysts.     

Development and validation of a sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method for quantitative analysis of bambermycin in livestock and aquatic products: Implications for food safety control and regulatory enforcement

A sensitive and accurate analytical method was developed and validated to detect bambermycin, a commonly used antibiotic in animal feed and livestock. The presence of bambermycin residues in food products can pose health risks to consumers, emphasizing the need for a sensitive and accurate analytical method. A reversed-phase analytical column was utilized with a mobile phase comprising 0.005 mol/L ammonium acetate in 5% acetonitrile (A) and 0.005 mol/L ammonium acetate in 95% acetonitrile (B) to achieve effective chromatographic separation. Quantitative determination of bambermycin in various samples, including beef, pork, chicken, milk, eggs, flatfish, eel, and shrimp, was performed using ultra-high-performance liquid chromatography-tandem mass spectrometry. Sample extraction involved a mixture of methanol and a 25% ammonium hydroxide solution, followed by low-temperature purification and phospholipid removal utilizing a Phree cartridge. The method exhibited a satisfactory recovery rate ranging from 69% to 100%. Validation results demonstrated the reliability, robustness, and accuracy of the method, exhibiting good linearity, precision, and recovery. This validated method can be applied for routine analysis of bambermycin residues, assisting in the development of effective monitoring and control measures to ensure the safety of livestock and aquatic products.     

Determination of breath alcohol using a differential-type amperometric biosensor based on alcohol dehydrogenase

A differential-type amperometric biosensor based on conventional thick-film technology has been developed for breath alcohol measurement. The amperometric breath alcohol biosensor utilizes the alcohol dehydrogenase (ADH) and nicotinamide adenine dinucleotide (NAD⁺) cofactor which produce reduced NADH as a product of the oxidation of alcohol. The biosensor was designed in a differential format consisting of a common Ag/AgCl reference electrode, an active working electrode containing the ADH, and the inactive working electrode containing only bovine serum albumin instead of the ADH. The differential signal between the active working electrode and the inactive working electrode minimized the interference from a large number of oxidizable species present in a person's breath. Prior to the amperometric measurement the biosensor was hydrated simply by dipping it into a phosphate buffer solution at pH 7.4. The NADH produced from the enzymatic reaction was oxidized at the working electrode biased at a potential of 470 mV vs. an on-board Ag/AgCl reference electrode. The biosensor can measure a person's breath alcohol over the concentration range 20–800 ppm routinely required in a test of drunken driving.     

A new fluorescent probe for zinc(II): an 8-hydroxy-5-N,N-dimethylaminosulfonylquinoline-pendant 1,4,7,10-tetraazacyclododecane

A new fluorescent probe for Zn2+, namely, 8-hydroxy-5-N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (L8), was designed and synthesized (cyclen=1,4,7,10-tetraazacyclododecane). By potentiometric pH, 1H NMR, and UV spectroscopic titrations, the deprotonation constants pKa1-pKa6 of L(8)4 HCl were determined to be <2, <2, <2 (for amino groups of the cyclen and quinoline moieties), 7.19+/-0.05 (for 8-OH of the quinoline moiety), 10.10+/-0.05, and 11.49+/-0.05, respectively, at 25 degrees C with I=0.1 (NaNO3). The results of 1H NMR, potentiometric pH, and UV titrations, as well as single-crystal X-ray diffraction analysis, showed that L8 and Zn2+ form a 1:1 complex [Zn(H-1L8)], in which the 8-OH group of the quinoline ring of L8 is deprotonated and coordinates to Zn2+, in aqueous solution at neutral pH. On addition of one equivalent of Zn2+ and Cd2+, the fluorescence emission of L8 (5 microM) at 512 nm in aqueous solution at pH 7.4 [10 mM HEPES with I=0.1 (NaNO3)] and 25 degrees C increased by factors of 17 and 43, respectively. We found that the cyclen moiety has the unique property of quenching the fluorescence emission of the quinolinol moiety when not complexed with metal cations, but enhancing emission when complexed with Zn2+ or Cd2+. In addition, the Zn2+-L8 complex [Zn(H-1L8)] is much more thermodynamically and kinetically stable (Kd{Zn(H-1L8)}=[Zn2+]free[L8]free/[Zn(H-1L8)]=8 fM at pH 7.4) than the Zn2+ complexes of our previous Zn2+ fluorophores ([Zn(H-1L2)] and [Zn(L3)]). Furthermore, formation of [Zn(H-1L8)] is much faster than those of [Zn(H-1L2)] and [Zn(L3)]. The staining of early-stage apoptotic cells with L8 is also described.     

Cyclic vinylogous triflate hemiacetals as new surrogates for alkynyl aldehydes

Cyclic vinylogous triflate hemiacetals can serve as ‘synthetic equivalents’ for alkynyl aldehydes: treatment of a vinylogous triflate hemiacetal with excess amounts of Grignard reagents produces acyclic alkynyl alcohols in good to high yields. This transformation likely involves the Grob-type C-C bond cleaving fragmentation to form the alkynyl aldehyde in situ. Subsequent nucleophilic attack of the Grignard reagent furnishes secondary alkynols. Vinylogous triflate hemiacetals are easily prepared by DIBALH reduction of vinylogous acyl triflates, which are derived from cyclic 1,3-diketones.     

Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas

Several molecular and genetic changes have been found in pituitary adenomas. We looked for correlations between these changes and the degree of invasiveness of the tumors. The invasiveness of 11 pituitary adenomas was graded by Hardy classification. We examined the retinoblastoma gene (RB1.20 on chromosome 13q) and the region around the MEN1 locus (chromosome 11q13.1-5) for loss of heterozygosity. Also examined are p53 mutations using single strain conformation polymorphism, p53 protein overexpression using immuno cytochemistry, homozygous deletions of p15 and p16 by polymerase chain reaction, and cellular proliferative activity using MIB-1 antibody. Six tumors (54.5%) had an LOH at either RB1.20 or the MEN1 locus. LOHs were found more frequently in Grade 4 and stage E tumors (72% and 67%) than in Grade 3 and stage D tumors (25% and 40%). However, no mutation or overexpression of p53 was found. No homozygous deletions of p15 or p16 were identified. The cell proliferative index ranged from 0 to 3%. LOH at 11q13 and 13q may be valuable in predicting the invasiveness of pituitary adenomas.