Determination of gliclazide minimum concentration in type 2 diabetes mellitus patients.

Type 2 diabetes mellitus is a worldwide health problem. Many drugs can be used in its treatment. One of them is gliclazide - the sulfonylurea derivative. It is dosed in modified release tablets. The study aimed to determine the minimum steady-state concentration of gliclazide at patients taking modified release tablets. Fasting plasma glucose, insulin level, and glycated hemoglobin were also assayed in this study. Ten patients of the primary care physician clinic took 30-90 mg of gliclazide daily. The statistical analysis proved that there is a statistically significant correlation between insulin level and body weight (p = 0.044) as well as between the dose and gliclazide concentrations (p = 0.015) and also between insulin level and minimum concentration of the drug (p = 0.0074). The linear correlation between dose and gliclazide's minimum steady state concentration proved its linear pharmacokinetics. The correlation between the minimum concentration of gliclazide and insulin level might be a potential predictor of patients compliance.

Photostabilization of papaverine hydrochloride solutions.

Abstract: The stability of aqueous and non-aqueous papaverine hydrochloride solutions exposed to the UV radiation is poor. In order to enhance its photo-stability suitable light absorbers may be used. There werefour photo-protectors considered in this work: 4-aminobenzoic acid, sodium benzoate, methyl 4-hydroxybenzoate and propyl 4-hydroxybenzoate, whose UV absorption spectra characteristics match to some extent with the UV spectrum of papaverine. Approximately 20 mg/mL papaverine chloroform solutions with the above non-toxic additives in the concentrations 0.01; 0.05; 0.10% were exposed to the UV light of 254 nm. High performance capillary electrophoresis was used to determine the papaverine hydrochloride concentration loss as a function of time exposition to the light. It was found that papaverine hydrochloride photolysis proceeds according to the first-order kinetics. Methyl 4-hydroxybenzoate was found to be the best UV radiation-protective agent, and at the concentration 0.10%, the reaction rate constant decreases from 0.143 h(-1) to 0.028 h(-1). Both 4-hydroxybenzoate esters develop a more efficient UV radiation-protective activity than sodium benzoate, because the latter additive molar extinction coefficient is less significant. However, in spite of a high value of 4-aminobenzoic acid molar absorptivity coefficient, it is an unsuitable photo-protector for papaverine hydrochloride solutions, because its UV absorption spectrum does not match with that of papaverine.

The biological activity of G-quadruplex DNA binding papaverine-derived ligand in breast cancer cells.

It was shown previously that the papaverine oxidation products 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (ligand 1) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinium chloride (ligand 2) bind to guanine-quadruplexes (G4) of single stranded G-rich 3'-overhangs of mammalian telomeric DNA. Here we show the biological activity of ligand 1. This compound exhibit antiproliferative activity in MCF-7 cells (IC(50) for ligand 1 = 14.16 +/- 0.01 microM, 24 h, 1.158 +/- 0.056 microM, 72 h. PCNA levels were not altered after treatment of MCF-7 cells with concentrations of ligand 1 which, however, led to alterations in the cell cycle. 5 and 10 microM of the ligand 1 arrested cells in the G0/G1 phase of the cell cycle and this led to a decrease of cells in the S phase. Intracellular accumulation of ligand 1 was observed even after a cell passage and medium exchange in fluorescence microscopy while low concentrations of ligand 1 (0.001 to 0.1 microM) inhibited telomerase activity as shown by TRAP assay.

Spectroscopic study and G-quadruplex DNA binding affinity of two bioactive papaverine-derived ligands.

The interactions of G-quadruplex DNA with two oxidation products of papaverine, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (1) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinium cation (2) were investigated. Their activity against telomerase was assessed using the conventional telomeric repeat amplification protocol (TRAP) assay. Effect of TRAP buffer and oligonucleotide length on the DNA-binding affinity of 1 and 2 were also studied. Three quadruplex-forming oligonucleotides with human telomeric sequence: dG(3)(T(2)AG(3))(3) (htel21), dAG(3)(T(2)AG(3))(3) (htel22), and d(T(2)AG(3))(4) (htel24) were used in these investigations. Both ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex, which agrees with the binding model of end-stacking on terminal G-tetrads. Circular dichroism spectra revealed that preferences of quadruplex-forming oligonucleotide to adopt a particular topological structure may be also affected by the external ligand that binds to quadruplex. Telomerase activity was suppressed at very low ligand 1 and ligand 2 concentrations with an appreciable selectivity comparing with inhibition of Taq polymerase.

Kinetics of photooxidation of papaverine hydrochloride and its major photooxidation products.

HPCE methodology was modified to be used in kinetic experiments on photooxidation reactions of papaverine hydrochloride 1 and its oxidation products (papaverinol 2 and papaveraldine hydrochloride 3) chloroform solutions exposed to UV254 light in aerobic conditions. On photooxygenation of the above compounds is formed the final degradation product, a brown compound X 4, 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinylim chloride. The rate of 4 formation from the above compounds can be given as 2>3>1>1 HCl. The photooxidation reactions of 1 and 2 proceed with pseudo first-order kinetics and that reaction for 3 follows zero-order kinetics. The most labile compound is 2 whose half-life time is 2.4 times shorter than that one of 1 HCL. The most stable product is 3 whose half-life time is 31-fold longer than of 2. The specific quantum yields are equal 0.28, 0.30 and 0.10 for 1 HCl, 2 and 3, respectively which confirm the above stability pattern of the compounds concerned.

Modeling of purine derivatives transport across cell membranes based on their partition coefficient determination and quantum chemical calculations.

Mercaptopurine (6-MP), thioguanine (6-TG), and azathioprine (AZA) are purine antimetabolites introduced as anticancer or immunosuppressive drugs decades ago. Methylated AZA, called MAZA, is among the investigational drugs. The present study compares MAZA to the widely recognized drugs AZA, 6-MP, and 6-TG with respect to the ability of being transported across cell membranes. The obtained octanol/water phases partition coefficients and results of quantum chemical calculations predict the following sequence of hydrophobicity: MAZA > AZA > 6-TG > 6-MP.

Pharmaceutical availability of gliclazide from selected matrix formulation tablets.

BACKGROUND: Immediate release and modified release gliclazide formulation tablets are available on the market. We decided to measure the kinetics of gliclazide release from these tablets, and to propose our own technique for producing gliclazide matrix tablets, comparing their release kinetic profile with the gliclazide tablets available on the market. MATERIAL/METHODS: A BP 2001 dissolution test was performed for selected gliclazide formulation tablets, and the water solubility of authentic gliclazide samples from different manufacturers was determined by UV spectrometry. RESULTS: Diabezidum (Jelfa) and diabrezide (Molteni) tablets are classic gliclazide oral formulations, releasing the drug very rapidly in vivo and in vitro according to BP 2001 (approximately 99% at 100 min). However, diaprel tablets (Servier) are modified release formulations (67% released in in vitro conditions at 8 h). The matrix tablets (C) produced according to our own formula demonstrated a release profile similar to diaprel tablets. The MDT, calculated in order to classify the tablets we studied, ranged from 4.6 to 76.4 minutes for immediate release (IR) tablets (diabrezide, diabezidum, I and F), and from 279.6 to 701.2 minutes for sustained-release (SR) tablets (E, G, C, diaprel, J, B, D, H, K, A). CONCLUSIONS: The dissolution process of immediate release gliclazide formulation tablets (diabrezide, diabezidum, F, I) obeys a first-order equation. However, the process for modified release formulation tablets (diaprel, diaprel MR, A, B, C, D G, H, J, K) proceeds according to a zero-order equation.

Aggregation and G-quadruplex DNA-binding study of 6a,12a-diazadibenzo-[a,g]fluorenylium derivative.

The aggregation and DNA binding behavior of a new G-quadruplex selective ligand, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative, was studied by UV-vis absorption and fluorescence spectroscopy. The formation of ligand aggregates with different spectral characteristics was observed at low and high concentration of NaCl, respectively. The ligand binds to G-quadruplex with much higher affinity than to single- and double-stranded DNA.

Oxidation and degradation products of papaverine. Part II[1]: investigations on the photochemical degradation of papaverine solutions.

The structure of the final degradation product formed in papaverine solutions in either water or chloroform was found to be a 2, 3, 9, 10-tetramethoxy-12-oxo-12H-indolo [2, 1-a] isoquinolinylium salt (a dibenzo [b, g] pyrrocolonium derivative). Its formation from papaverine oxidation products that is papaverinol, papaveraldine, and papaverine-N-oxide chloroform solutions under the influence of UV light, was investigated and possible reaction pathways are discussed.

Comparative kinetics of azathioprine and metazathioprine mercaptolysis in presence of physiological thiols.

Kinetic parameters of mercaptolysis of azathioprine (AZA) and metazathioprine (MAZA) to 6-mercaptopurine in phosphate buffer, pH 7.4, under the influence of physiological thiols (glutathione and cysteine) at 25 degrees, 30 degrees and 37 degrees C were determined and compared. It comes out that the mercaptolysis of MAZA is significantly faster under the influence of both mentioned thiols if compared to that reaction of AZA. Furthermore, the mercaptolysis of MAZA and AZA proceeded significantly faster under the influence of cysteine than on the glutathione heterolysis.

[Clinical value of hypoxanthine concentration assays in diagnosis of hypoxia in newborns]. / Wartosc kliniczna oznaczania stezen hipoksantyny w diagnostyce niedotlenienia u noworodka.

The purpose of this study was to asses the usefulness of hypoxanthine (HYP) concentration as an indicator of hypoxia. Concentration of HYP (HPLC method) in the umbilical arterial cord blood was determined in 145 newborns. Newborns were studied in four groups: premature asphyxiated, term asphyxiated, premature non-asphyxiated, term non-asphyxiated. Newborns were classified as hypoxic if they had: pH < 7.15, BE < -7.0 mmol or PaO2 < 10 mmHg. Reduced umbilical arterial pH, PaO2 and BE correlated directly with increased concentrations of HYP. The highest correlations were observed for HYP and PaO2. The levels of HYP for asphyxiated and non-asphyxiated newborns were different. The results show that HYP concentration is an important indicator in detection of asphyxia in newborns. Strong correlation between parameters of acid base balance and HYP concentration was observed in the studied groups. Increased concentration of HYP confirms intrauterine hypoxia independently of maturity.

Oxidation and degradation products of papaverine. Part I: Gadamer and Schulemann's papaverinol synthesis revisited.

In 1915 Gadamer published in this journal [1] a procedure for the synthesis of papaverinol 2 from papaverine 1 in excellent yield. However, he did not investigate the formation of a violet fluorescence produced upon crystallization of papaverinol 2 from ethanol. The compound responsible for this fluorescence was isolated and identified as the yet unknown quaternary ammonium ion 4, a 6a, 12a-diazadibenzo-[a, g]fluorenylium derivative. The isolation of 4 and its structure determination by spectroscopic methods are described. However, its formation mechanism is unknown.

Photooxidation of papaverine, papaverinol and papaveraldine in their chloroform solutions.

Papaverine hydrochloride, papaverinol, and papaveraldine chloroform solutions were exposed to UV light of 254 nm in atmospheric, aerobic and anaerobic (helium) conditions. The same degradation products appear (TLC) in the above papaverine hydrochloride chloroform solutions. However, the rate of papaverine hydrochloride degradation processes is enhanced as a function of oxygen pressure. Papaverinol and papaveraldine photooxidation products are essentially not different from those observed in the above papaverine hydrochloride solutions. However, the amount of an unknown brown degradation product (X) is the greatest in the papaverinol chloroform solution degraded. That brown compound was previously observed in papaverine either hydrochloride or sulfate injection solutions on their storage even when protected from daylight. The preliminary X product structure development was undertaken (TLC, molecular weight, elemental analysis, UV/VIS, IR and 13C MAS NMR spectroscopy).