Baricitinib is a drug used for the treatment of rheumatoid arthritis. It is a selective and reversible inhibitor of Janus kinases 1 and 2, which play an important role in signalling the pro-inflammatory pathway activated in autoimmune disorders such as rheumatoid arthritis. The pH-spectrophotometric and pH-potentiometric titrations allowed the measurement of three or four successive dissociation constants of Baricitinib. Baricitinib neutral LH2 molecule was able to protonate into two soluble cations LH42+, LH3+ and dissociate into two soluble anions LH- and L2- in pure water. The graph of molar absorption coefficients of differently protonated species versus wavelength indicated that the spectra εL, εLH, εLH2 were the nearly the same for these species and that the spectra εLH4 and εLH3 were also similar. In the pH range from 2-13, four pKa´s of spectra analysis were reliably estimated by REACTLAB at I =0.0020 mol. dm-3 values pKTa1 = 3.07, pKTa2 = 3.87, pKTa3 = 6.27, pKTa4 = 12.78 at 25 °C and pKTa1 = 3.00, pKTa2 = 3.79, pKTa3 = 6.12, pKTa4 = 12.75 at 37 °C. Potentiometric pH-titration analysis for a higher concentration of 1 × 10-3 mol. dm-3 estimated with ESAB at I =0.0001 mol. dm-3 values pKTa1 = 3.69, pKTa2 = 3.81, pKTa3 = 4.73 at 25 °C and pKTa1 = 3.62, pKTa2 = 3.73, pKTa3 = 4.43 at 37 °C. Molar enthalpy ΔH°, molar entropy ΔS° and Gibbs free energy ΔG° were calculated from the spectra using a dependence ln K to 1/T.

• MeSH
• azetidiny * MeSH
• entropie MeSH
• koncentrace vodíkových iontů MeSH
• puriny MeSH
• pyrazoly MeSH
• sulfonamidy MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH

Cílem publikace je pochopení principu statistických metod a správná interpretace výsledků.

• MeSH
• interpretace statistických dat MeSH
• statistické modely MeSH
• statistika jako téma MeSH
• Publikační typ
• studijní příručka MeSH

• Konspekt
• Statistika
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• statistika, zdravotnická statistika
• NLK Publikační typ
• učebnice vysokých škol

Učební text pojednává o měření, průzkumových analýzách dat a numerických testech normality. Další kapitoly jsou věnovány bodovým odhadům, testování statistických hypotéz, analýze rozptylu, metodě regrese a diagnostice lineární a nelineární regrese. V závěru publikace se pojednává o plánování experimentů. Cílem publikace je pochopení principu statistických metod a správná interpretace výsledků. Učební text předpokládá základní znalosti statistiky.

• MeSH
• interpretace statistických dat MeSH
• statistické modely MeSH
• statistika jako téma MeSH
• Publikační typ
• studijní příručka MeSH

• Konspekt
• Statistika
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• statistika, zdravotnická statistika
• NLK Publikační typ
• učebnice vysokých škol

Potentiometric and spectrophotometric pH-titration of the multiprotic cytostatics bosutinib for dissociation constants determination were compared. Bosutinib treats patients with positive chronic myeloid leukemia. Bosutinib exhibits four protonatable sites in a pH range from 2 to 11, where two pK are well separated (ΔpK>3), while the other two are near dissociation constants. In the neutral medium, bosutinib occurs in the slightly water soluble form LH that can be protonated to the soluble cation LH4(3+). The molecule LH can be dissociated to still difficultly soluble anion L(-). The set of spectra upon pH from 2 to 11 in the 239.3-375.0nm was divided into two absorption bands: the first one from 239.3 to 290.5nm and the second from 312.3 to 375.0nm, which differ in sensitivity of chromophores to a pH change. Estimates of pK of the entire set of spectra were compared with those of both absorption bands. Due to limited solubility of bosutinib the protonation in a mixed aqueous-methanolic medium was studied. In low methanol content of 3-6% three dissociation constants can be reliably determined with SPECFIT/32 and SQUAD(84) and after extrapolation to zero content of methanol they lead to pKc1=3.43(12), pKc2=4.54(10), pKc3=7.56(07) and pKc4=11.04(05) at 25°C and pKc1=3.44(06), pKc2=5.03(08) pKc3=7.33(05) and pKc4=10.92(06) at 37°C. With an increasing content of methanol in solvent the dissociation of bosutinib is suppressed and the percentage of LH3(2+) decreases and LH prevails. From the potentiometric pH-titration at 25°C the concentration dissociation constants were estimated with ESAB pKc1=3.51(02), pKc2=4.37(02), pKc3=7.97(02) and pKc4=11.05(03) and with HYPERQUAD: pKc1=3.29(12), pKc2=4.24(10), pKc3=7.95(07) and pKc4=11.29(05).

• MeSH
• aniliny analýza   chemie   MeSH
• chinoliny analýza   chemie   MeSH
• cytostatické látky analýza   chemie   MeSH
• koncentrace vodíkových iontů MeSH
• metoda nejmenších čtverců MeSH
• nelineární dynamika * MeSH
• nitrily analýza   chemie   MeSH
• potenciometrie MeSH
• spektrofotometrie metody   MeSH
• Publikační typ
• časopisecké články MeSH

The resolving power of multicomponent spectral analysis and the computation reliability of the stability constants and molar absorptivities determined for five variously protonated anions of physostigmine salicylate by the SQUAD(84) and SPECFIT/32 programs has been examined with the use of simulated and experimental spectra containing overlapping spectral bands. The reliability of the dissociation constants of drug was proven with goodness-of-fit tests and by examining the influence of pre-selected noise level s(inst)(A) in synthetic spectra regarding the precision s(pK) and also accuracy of the estimated dissociation constants. Precision was examined as the linear regression model s(pK)=β(0)+β(1)s(inst)(A). In all cases the intercept β(0) was statistically insignificant. When an instrumental error s(inst)(A) is small and less than 0.5 mAU, the parameters' estimates are nearly the same as the bias ΔpK=pK(a,calc)-pK(a,true) is quite negligible. In all four dissociation constants the bias seems to be quite small even though for pK(a4) it is a little bit higher, i.e., +0.05 for s(inst)(A) about 1.0 mAU. In the interval of s(inst)(A) from 0.1 to 1.0 mAU all four dissociation constants pK(i) are accurate enough. Of the various regression diagnostics considered, the goodness-of-fit is the most efficient criterion of whether the parameters found adequately represent the data. The magnitude of instrumental error s(inst)(A) only slightly affects the shape of a Cattel's scree graph s(k)(A)=f(k) to determine the true number of light-absorbing species in the equilibrium mixture.

• MeSH
• absorpce MeSH
• chemické modely MeSH
• fysostigmin analýza   chemie   MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• počítačová simulace MeSH
• povrchové vlastnosti MeSH
• protony MeSH
• regresní analýza MeSH
• reprodukovatelnost výsledků MeSH
• software MeSH
• spektrofotometrie metody   MeSH
• termodynamika MeSH
• titrace metody   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH