In vivo metabolic investigation of cetilistat in normal versus pseudo-germ-free rats using UPLC-QTOFMS/MS and in silico toxicological evaluation of its metabolites

Cetilistat (CET) is a pancreatic lipase inhibitor approved for management of obesity after the serious adverse effects exhibited by its analogue orlistat. Exhaustive literature review reveals lack of comprehensive reports on its biotransformation. With a view to study the same, the present study reports the identification and characterization of metabolites of CET in rats using UPLC–MS/MS. As the small intestine is the site of action for CET, it is important that the role of microbial flora in the metabolism of CET be explored. To achieve this, the metabolic profile of CET was compared between normal and pseudo-germ-free rats. The study involved the administration of a drug suspension to male Sprague–Dawley pseudo-germ-free and normal untreated rats followed by collection of urine, feces, and blood at specific intervals. Sample preparation was performed using liquid–liquid extraction and concentration of samples followed by analysis using LC–MS/MS. Finally, an in silico study was performed on the drug and metabolites to predict their toxicological properties using ADMET Predictor^TM software. Four metabolites of CET were observed in in vivo matrices. As expected, significant changes were observed both qualitatively and quantitatively, implying that formation of metabolites was both CYP enzymes and gut microflora mediated.     

l-Asparaginase as Potent Anti-leukemic Agent and Its Significance of Having Reduced Glutaminase Side Activity for Better treatment of Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is one of the leading types of malignant disorder seen in children. Viral infections, genetic factors and exposure to chemical carcinogens are some of the factors responsible for causing ALL. Treatment strategies followed for curing ALL include chemotherapy or radiation therapy, wherein, chemotherapy involves the use of the enzymatic drug l-Asparaginase. The enzyme can be produced from various plants, animals, bacterial and fungal sources but, among them, bacterial sources are widely used for production of this enzyme. The enzyme is non-human in origin having certain bottle necks with l-Asparaginase therapy in the form of side effects such as pancreatitis, thrombosis which are mainly due to glutaminase side activity. Hence, present-day research is mainly focussed on minimizing or completely eliminating the glutaminase activity of the enzyme l-Asparaginase. This review is focussed on the complications associated with glutaminase side activity and use of glutaminase free enzymatic drug l-Asparaginase in treating ALL and the other developments related to the modification of the drug for quality treatment.     

Glycol modified titanosiloxane as molecular precursor for homogenous titania–silica material: synthesis and characterization

Ti(OPrⁱ)₄ reacts with HOSi(O^tBu)₃ in anhydrous benzene in 1:1 and 1:2 molar ratios to afford alkoxy titanosiloxane precursors, [Ti(OPrⁱ)₃{OSi(O^tBu)₃}] (A) and [Ti(OPrⁱ)₂{OSi(O^tBu)₃}₂] (B), respectively. Further reactions of (A) or (B) with glycols in 1:1 molar ratio afforded six complexes of the types [Ti(OPrⁱ)(O–G–O){OSi(O^tBu)₃}] (1A–3A) and [Ti(O–G–O){OSi(O^tBu)₃}₂] (1B–3B), respectively [where G = (CH₂)₂ (1A, 1B); (CH₂)₃ (2A, 2B) and {CH₂CH₂CH(CH₃)} (3A, 3B)]. Both (A) and (B) are liquids while all the other products are viscous liquids which get solidified on ageing. Cryoscopic molecular weight measurements of the fresh products indicate their monomeric nature. FAB mass studies of (A) and (B) also indicate monomeric nature. However, FAB mass spectra of the two representative solids (1A) and (2B) suggest dimeric behavior of the glycolato derivatives. (A) distills at 85 °C/5 mm while other products get decomposed even under reduced pressure. TG analyses of (A), (B), (1A), and (1B) suggest formation of titania–silica materials at 200 °C for (A) and (B) and 350 °C for (1A) and (1B). The products have been characterized by elemental analyses, FTIR and ¹H, ¹³C & ²⁹Si-NMR techniques. All these products are soluble in common organic solvents indicating a homogenous distribution of the components on the molecular scale. The Si/Ti ratio of the oxide may be controlled easily by the composition of the starting precursors. Hydrolysis of the glycol modified derivative, (1A) by the Sol–Gel technique affords the desired homogenous titania–silica material, TiO₂·SiO₂ in nano-size while, the precursor (A) yields a non-stiochiometric silica doped titania material. However, pyrolysis of (A) yields nano-sized crystallites of TiO₂·SiO₂. All these materials were characterized by FTIR, powder XRD patterns, SEM images, and EDX analyses.     

Regulatory Aspects in Development of Stability-Indicating Methods: A Review

Poly(N-vinylcaprolactam) (PVCL) connected to aminopropyl silica is a new stationary phase for temperature responsive liquid chromatography (TR-LC). PVCL shows a transition from hydrophilic to hydrophobic interaction between 30 and 40 °C. The synthesis is described in detail. The temperature responsive characteristic of the phase is illustrated with a mixture of steroids using pure water as mobile phase. An increase in retention is observed when raising the temperature. H–u plots at different temperatures were constructed. Below the lower critical solution temperature (LCST), no optimal velocity could be measured because of substantial resistance to mass transfer. Above the LCST, u _opt was ca. 0.3 mm s^?1 with reduced plate heights from 4 at 45 °C to 3 at 65 °C. The temperature responsive nature of the polymer is lost in green chromatography with ethanol as modifier in concentrations above 5%.     

Synthesis and characterization of glycol-modified vanadium(V) oxoisopropoxide and their oximato derivatives: sol–gel transformations of [VO(OPr i )3], [VO{OCH2CH2OCH2CH2O}{OPr i }] and [VO{OCH2CH2OCH2CH2O}{ON=C(CH3)(C4H3S-2)}] to vanadia

Reaction of [VO(OPr ⁱ )₃] (1) with [O(CH₂CH₂OH)₂] in 1:1 molar ratio in anhydrous benzene yield glycol-modified precursor, [VO{OCH₂CH₂OCH₂CH₂O}{OPr ⁱ }] (2). Further reactions of (2) with internally functionalized oximes in anhydrous benzene yield heteroleptic complexes of the type [VO{OCH₂CH₂OCH₂CH₂O}{ON=C(R)(Ar)}] (3–8) {where R=CH₃, Ar=C₄H₃O-2 (3), C₄H₃S-2 (4), C₅H₄N-2 (5); and when R=H, Ar=C₄H₃O-2 (6), C₄H₃S-2 (7), C₅H₄N-2 (8)}. All these derivatives have been characterized by elemental analyses, molecular weight measurements and spectroscopic techniques. The crysoscopic molecular weight measurement as well as FAB mass study suggests dimeric nature of (2). However, FAB mass spectrum of (4), and the crysoscopic molecular weight measurements of (3), (4), (5) and (6) indicate the monomeric behavior of the oximato derivatives (3–8). Hexa-coordination around vanadium(V) has been proposed for both monomeric and dimeric derivatives. Sol–gel transformations of (1), (2) or (4) to vanadia [(a), (b) or (c), respectively] have been carried out at low sintering temperature (600 °C). The XRD patterns of (a), (b) or (c) indicate formation of a single orthorhombic phase in all the three cases. The SEM images suggest grain like [for (a) and (b)] and rod like [for (c)] morphology of the crystallites. IR, Raman spectra as well as EDX analyses indicate formation of pure vanadia. Absorption spectra of the vanadia (b) and (c) suggest energy band gaps of 2.53 and 2.65 eV, respectively.     

Thermal,XRD, and magnetization studies on ZnAl<Subscript>2</Subscript>O<Subscript>4</Subscript> and NiAl<Subscript>2</Subscript>O<Subscript>4</Subscript> spinels,synthesized by citrate precursor method and annealed at 450 and 650 °C

Two aluminate spinel materials (ZnAl₂O₄ and NiAl₂O₄) were synthesized by the citrate precursor method. The citrate precursors consisting of coprecipitated citrates of Zn²⁺ or Ni²⁺ and aluminum were first subjected to thermal analysis (TG-DSC) for determining the optimum temperature for annealing. Two step decomposition was observed incorporating dehydration and formation of the aluminate. The second step gives an endo peak (−2937 J/g) at 356 °C in the DSC curve of the coprecipitated nickel(II) citrate–aluminum citrate gel in O₂ atmosphere. Kinetic/mechanistic analysis of the TG data has also been carried out and values of E _a, ΔS ^#, ΔG ^#, and A were approximated. On the basis of the findings, 450 °C has been chosen for annealing of the gels. Annealing has also been done at 650 °C for 1 h in muffle furnace in an attempt to obtain nanometric particles of aluminates (MAl₂O₄) {M = Ni, Zn} and to find out their magnetic properties which could render them useful for chemical sensing applications, etc. The TG-DSC curves of various powders which were obtained on annealing at the two temperatures did exhibit thermal instability when carried out in N₂ atmosphere. NiAl₂O₄ and ZnAl₂O₄ spinels (particle size 17 and 34 nm, respectively) are obtained in pure crystalline phase at 650 °C. ZnAl₂O₄ prepared this way shows coercivity values of 470 and 58.37 G and NiAl₂O₄, 107 and 23.24 G when annealed at 450 and 650 °C, respectively. ZnAl₂O₄ prepared by a polymer precursor method and annealed at 1000 °C, has earlier been reported to have coercivity value of 469 G. Thus, the citrate precursor method is good for the synthesis of ZnAl₂O₄, producing single phase nanocrystalline powder of high quality and crystallinity. The value of magnetization was found to be small in the present case for the NiAl₂O₄ spinel obtained at 450 °C.     

Solgel synthesis and structural characterization of silver-silica nanocomposites

The solgel process has been successfully used to prepare silver/silica nanocomposites. After drying in air at 50°C for 30 min, samples were heat treated in air, at 100, 200, 400 and 500°C for the formation of silver nanoparticles. Evolution of silver nano-particles in the amorphous SiO₂ matrix as a function of annealing temperature has been studied. Characterizations were made by X-ray diffraction, ultraviolet-visible, and infrared spectroscopy. Mechanisms of silver clusters formation in the densified silica matrix with respect to thermal treatment are discussed.     

On the Bödewadt–Rosenblat flow

Fluid motion induced by the torsional oscillations (of angular velocity bΩcosω T) of an infinite disk in contact with an incompressible viscous rotating (with angular velocity aΩ) fluid of semi-infinite extent is analysed when the amplitude parameter α( = b/a) varies from zero to infinity. Composite solutions valid over the whole of the flow regime and specific expressions for the shearing stress components at the disk and for the axial flow in the far region are obtained for low and high frequencies of torsional oscillations. Using the method of matched asymptotic expansions, we find that the region of the mean flow increases with α and reaches a maximum before settling down to the Rosenblat profile. Series expressions (for α < 1) are deduced for physical quantities of interest when the fluid in the far field and the disk are rotating with different angular velocities (in the same or in the opposite sense), which agree well with the known numerical results. (Received: April 7, 2003; revised: September 29, 2005)