Investigation of the enantioselectivity and enantiomeric elution order of some piperidine-2,6-dione drugs on chiralcel OD column

The enantioselectivity and enantiomeric separation of five racemic piperidine-2,6-dione compounds, on the cellulose tris(3,5-dimethylphenyl carbamate) chiral stationary phase Chiralcel OD-CSP were investigated under the same chromatographic conditions. This class of drugs includes glutethimide, aminoglutethimide, cyclohexylaminoglutethimide, pyridoglutethimide, and phenglutarimide. The results revealed that chiral recognition and the binding sites of these drugs on the Chiralcel OD column are similar, regardless of the absolute configuration of the individual enantiomers. A possible chiral recognition mechanism(s) for this class of drugs and the CSP is presented. © 1994 Wiley-Liss, Inc.     

The effects of calcium channel blocking drugs on the thermotropic behavior of dimyristoylphosphatidylcholine

The effects of four calcium channel blocking drugs, diltiazem, verapamil, nimodipine and nisoldipine, on the main phase transition of dimyristoylphosphatidylcholine have been studied by high resolution differential scanning calorimetry. In all cases, the phase transition temperature is lowered, though much more effectively by nimodipine and nisoldipine than by the other two drugs. Nimodipine and nisoldipine markedly reduce the enthalpy of transition while diltiazem and verapamil have no significant effect on the enthalpy within the drug concentration range studied. Analysis of the data in terms of ideal solution theory is presented. X-ray and neutron scattering studies indicate that nimodipine and verapamil differ significantly with respect to their location within a lipid bilayer, and this difference suggests a partial rationalization of the experimental results presented here.     

A simple high performance liquid chromatography assay for monitoring plasma concentrations of tipranavir in HIV infected patients

A simple HPLC assay to determine plasma concentration of tipranavir is presented. A liquid/liquid extraction of the drugs in ethyl acetate/hexane from 250 microL of plasma is followed by a reversed phase isocratic HPLC assay with UV detection at 205 nm. The imprecision and inaccuracy are lower than 10%, the low limit of quantitation is 0.4 mg/L. Thus, this method can be used for therapeutic drug monitoring of tipranavir in HIV infected patients.     

Numerical analysis of flow in an elastic artery model.

Oscillatory and pulsatile flows of Newtonian fluids in straight elastic tubes are simulated numerically with the aid of Ling and Atabek's "local flow" assumption for the nonlinear convective acceleration terms. For the first time, a theoretical assessment of the local flow assumption is presented, and the range of validity of the assumption is estimated by comparison with perturbation solutions of the complete flow problem. Subsequent simulations with the local flow model indicate that the flow field and associated wall shear stress are extremely sensitive to the phase angle between oscillatory pressure and flow waves (impedance phase angle). This phase angle, which is a measure of the wave reflection present in the system, is known to be altered by arterial disease (e.g., hypertension) and vasoactive drugs. Thus, the paper elucidates a mechanism by which subtle changes in systemic hemodynamics (i.e., phase angles) can markedly influence local wall shear stress values.     

Critical Interval Hypotheses for Depression

Two chronobiologic models are presented for the etiology of depression. The internal coincidence model suggests that a phase advance of the strong oscillator in reference to the weak oscillator causes depression. An external coincidence model suggests that depression is caused when the light/dark cycle or photoperiod provides too little illumination during a critical photosensitive interval, which might in turn occur early due to a phase advance. Thus, depression might be treated by drugs or other manipulations which delay the phase of internal circadian rhythms. Depression might also be treated with bright illumination during the critical photosensitive interval. Preliminary experiments suggest that bright artificial light does have antidepressant effects. The optimal times for light exposure and the most responsive patient groups have not yet been identified.     

Lipid bilayer position and orientation of novel carprofens,modulators of γ-secretase in Alzheimer's disease

γ-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-β peptides. Amyloid-β peptides are considered causative agents for Alzheimer's disease and drugs targeted at γ-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed γ-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to γ-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner.     

Phase behavior of an intact monoclonal antibody

Understanding protein phase behavior is important for purification, storage, and stable formulation of protein drugs in the biopharmaceutical industry. Glycoproteins, such as monoclonal antibodies (MAbs) are the most abundant biopharmaceuticals and probably the most difficult to crystallize among water-soluble proteins. This study explores the possibility of correlating osmotic second virial coefficient (B(22)) with the phase behavior of an intact MAb, which has so far proved impossible to crystallize. The phase diagram of the MAb is presented as a function of the concentration of different classes of precipitants, i.e., NaCl, (NH4)2SO4, and polyethylene glycol. All these precipitants show a similar behavior of decreasing solubility with increasing precipitant concentration. B(22) values were also measured as a function of the concentration of the different precipitants by self-interaction chromatography and correlated with the phase diagrams. Correlating phase diagrams with B(22) data provides useful information not only for a fundamental understanding of the phase behavior of MAbs, but also for understanding the reason why certain proteins are extremely difficult to crystallize. The scaling of the phase diagram in B(22) units also supports the existence of a universal phase diagram of a complex glycoprotein when it is recast in a protein interaction parameter.     

Simultaneous HPLC analysis of hydrophobic prodrugs and their hydrophilic metabolites in biological media without sample preparation. Application to the biotransformation studies of pronucleotides derived from 5-fluorouracil

Improvements of an "on-line cleaning" HPLC method for analysis of biological samples are presented: (i) the use of cleaning precolumns filled with hydrophobic stationary phases instead of the hydrophilic ones previously used to eliminate the biological matrix: (ii) the combination in the mobile phase of anionic and cationic pairing reagents in order to retain on the precolumn all the metabolites, whatever their hydrophilicity and ionicity are. Such modifications allowed to study the biotransformation of prodrugs of 5-Fluorouracil, designed to act as antitumoral pronucleotides.     

Comparison of synchronized Chinese hamster ovary cells obtained by mitotic shake-off, hydroxyurea, aphidicolin, or methotrexate

Synchronized cell populations are necessary to study many aspects of cell biology. We have developed a method to obtain highly synchronized Chinese hamster ovary cell populations in S phase or G2 phase by utilizing mitotic selection followed by incubation with either hydroxyurea, aphidicolin, or methotrexate for 12 h. Flow cytometry analysis shows that the coefficient of variation in the spread of the cell population in S phase is as low as 6%. Drug toxicity studies compare the effects of the various drugs on G1 and S phase cells. The use of aphidicolin or hydroxyurea results in the most highly synchronized cell populations, but methotrexate yields inadequate synchronization. These results demonstrate that both aphidicolin and hydroxyurea are useful drugs for obtaining highly synchronized cell populations after an initial synchrony in mitosis. Aphidicolin is perhaps the best choice because of less toxicity to S phase cells when used in low concentrations.     

Determination of loratadine and pheniramine from human serum by gas chromatography-mass spectrometry

In this work, a method for the determination of the antihistaminic drugs loratadine and pheniramine from human serum is presented. Serum samples are extracted under basic conditions with hexane-n-amyl alcohol (95:5, v/v), the analytes are reextracted into diluted hydrochloric acid and, after basification, are once again extracted into the organic phase. The samples are measured by GC-MS. The limits of detection of the assay are 0.5 ng/ml for loratadine and 2 ng/ml for pheniramine. The R.S.D.s in the day-to-day precision test for loratadine are 7.0% at 20 ng/ml and 12.4% at 2 ng/ml. For pheniramine, the R.S.D. are 6.4% at 300 ng/ml and 10.2% at 20 ng/ml.     

Study on the sorption properties of alpha1-acid glycoprotein (AGP)-based stationary phase modified by organic solvents

An alpha(1)-acid glycoprotein, immobilized on silica (Chiral-AGP) is one of the most widely used chiral stationary phases for the enantiomeric separation of a wide variety of chiral drugs with several applications in the biological and clinical field. The aim of this work was to study the sorption properties of the AGP-based stationary phase, which may have crucial importance for enantioselectivity. New binding data to the mechanism of the chromatographic separation are presented. The sorption of both organic solvents, i.e., acetonitrile and dioxane, shows remarkable pH dependency. A fluorescence quenching study was carried out to elucidate structural changes of AGP in the presence of acetonitrile using 2,2,2-trichloroethanol as fluorescence quencher.     

Bases sémantiques et pharmacologiques d’une nouvelle classification des antipsychotiques

The main stages involved in the development of drugs effective against psychotic manifestations are presented, as well as their mechanisms of action. Justification is given for the terms antipsychotic drugs, neuroleptic antipsychotic drugs, non-neuroleptic antipsychotic drugs, and non neuroleptic antipsychotic drugs, effective against negative expressions of schizophrenia. These constitute the basis of the new classification of antipsychotic drugs suggested. Finally, the term “atypical neuroleptic drugs”, frequently used in France, is described as badly constructed and unfortunate and should therefore be abandoned.     

全球免疫细胞治疗药物开发现状与趋势

目的:从产品开发角度分析免疫细胞治疗类药物的发展现状和未来趋势。方法:检索科睿唯安(Clarivate Analytics)的Cortellis数据库的数据,利用定量分析法和对比分析法对检索结果进行分析。结果:目前已有2种免疫细胞治疗类药物上市,1种免疫细胞治疗类药物处于预注册阶段,4种药物处于临床Ⅲ期,同时大量处于临床Ⅱ/Ⅰ期药物显示未来市场上将有更多免疫细胞治疗类药物。产品交易方面,目前在免疫细胞治疗类药物的商业交易也趋向频繁。通过列举分析目前已发生的交易金额前十的交易,发现其中药物开发及商业化许可是最主要的交易模式。结论:目前免疫细胞治疗类药物市场尚处于起步阶段,但随着未来技术的不断发展改进,相信未来有更多的药物进入商用市场,为癌症及其他疾病的治疗提供新的契机。     

Liquid chromatography–mass spectrometry in forensic and clinical toxicology

This paper reviews liquid chromatographic–mass spectrometric (LC–MS) procedures for the identification and/or quantification of drugs of abuse, therapeutic drugs, poisons and/or their metabolites in biosamples (whole blood, plasma, serum, urine, cerebrospinal fluid, vitreous humor, liver or hair) of humans or animals (cattle, dog, horse, mouse, pig or rat). Papers published from 1995 to early 1997, which are relevant to clinical toxicology, forensic toxicology, doping control or drug metabolism and pharmacokinetics, were taken into consideration. They cover the following analytes: amphetamines, cocaine, lysergide (LSD), opiates, anabolics, antihypertensives, benzodiazepines, cardiac glycosides, corticosteroids, immunosuppressants, neuroleptics, non-steroidal anti-inflammatory drugs (NSAID), opioids, quaternary amines, xanthins, biogenic poisons such as aconitines, aflatoxins, amanitins and nicotine, and pesticides. LC–MS interface types, mass spectral detection modes, sample preparation procedures and chromatographic systems applied in the reviewed papers are discussed. Basic information about the biosample assayed, work-up, LC column, mobile phase, interface type, mass spectral detection mode, and validation data of each procedure is summarized in tables. Examples of typical LC–MS applications are presented.     

Analytical methodologies for metallomics studies of antitumor Pt-containing drugs

Pt-containing drugs are nowadays essential components in cancer chemotherapy. However, drug resistance and side effects limit the efficiency of the treatments. In order to improve the response to Pt-based drugs, different administration strategies or new Pt-compounds have been developed with little success. The reason for this failure could be that the mechanism of action of these drugs is not completely understood. In this way, metallomics studies may contribute to clarify the interactions of Pt-containing drugs within the organism. This review is mainly focused on the role of Analytical Chemistry on the study of the interactions between Pt-based drugs and biomolecules. A summary of the analytical techniques and the most common sample treatment procedures currently used in metallomics studies of these drugs is presented. Both are of paramount importance to study these complex samples preserving the drug-biomolecule interaction. Separation and detection techniques must be carefully selected in order to achieve the intended goals. The use of multidimensional hyphenated techniques is usually necessary for a better understanding of the Pt-based drugs interactions in the organism. An overview of Pt-drugs biological interactions is presented, considering the different sample matrices and the drugs course through the organism. Samples analysed in the included studies are blood, urine, cell cytosol, DNA as well as the drugs themselves and their derivatives. However, most of these works are based on in vitro experiments or incubations of standards, leading in some cases to contradictory results depending on the experimental conditions used. Though in vivo experiments represent a great challenge due to the high complexity and the low concentrations of the Pt-adducts in real samples, these studies must be undertaken to get a deeper understanding of the real interactions concerning Pt-containing drugs.     

Recent developments of enantioseparation techniques for adrenergic drugs using liquid chromatography and capillary electrophoresis: a review

This review provides the achievements of enantioseparation of adrenergic drugs and application of these methods in clinical and pharmaceutical analysis. The adrenergic agonist and antagonist drugs are analyzed in the direct and indirect modes by liquid chromatography (LC) and capillary electrophoresis (CE). Other chromatographic enantioseparation methods including super- and sub-critical fluid chromatography (SFC), and capillary electrochromatography (CEC) are presented likewise to analyse the cited compounds. The different separation processes for these drugs are briefly discussed and some applications are presented.     

The control of growth of mouse mastocytoma Cells by N6,O2′-dibutyryladenosine cyclic 3′,5′-monophosphate

Summary Addition of N⁶,O^2′-Dibutyryladenosine cyclic 3′,5′ monophosphate (DB cyclic AMP) plus theophylline or transfer to medium containing 0.2% serum slowed the growth of cultured mouse mastocytoma cells and eventually arrested their growth in G1 phase. Examination of the properties of cells arrested by either procedure suggested that the drugs arrested cells in G1 phase 1.5–2 h after the point of low serum arrest. Cycloheximide prevented the recovery of cell growth after low serum or drug-induced arrest demonstrating that protein synthesis was necessary to pass either growth restriction point. Cordycepin also prevented drug-arrested cells from progressing into cycle indicating a requirement for RNA synthesis to overcome the drug-induced growth arrest. Evidence is also presented that DB cyclic AMP prevented the cells receiving a pulse of calcium necessary to proceed past the DB cyclic AMP-sensitive growth restriction point. It is suggested that high cyclic AMP levels prevent mastocytoma cells from receiving a surge of calcium in G1 phase that is necessary if the cells are to proceed to S phase and eventually divide.     

The mathematical modelling of adjuvant chemotherapy scheduling: Incorporating the effects of protocol rest phases and pharmacokinetics

In this paper the modelling objective is to determine the drug alternation time which minimises the formation of resistant tumour cells when delivering two non-cross resistant chemotherapeutics given such drugs cannot be delivered simultaneously and constraints due to pharmacokinetics and protocol rest phases. We initially consider cell cycle phase non-specific models, as investigated by Goldie and Coldman. By extending previous work, these models are generalised to consider chemotherapeutic S-phase specificity. We find with the cell cycle phase non-specific models that once the alternation time of the drugs is reduced below a critical threshold, a substantial improvement in protocol outcome is predicted. Extensive improvements are also observed for the S-phase specific investigation if the drugs can be alternated extremely rapidly. However, this is typically impossible due to pharmacokinetic constraints. Under such circumstances, the most appropriate choice of the alternation time can depend sensitively on the median and variance of the tumour cell cycle time in a complicated manner. For schedulings motivated by Capecitabine protocols, we find that switching the drugs only once, or at most twice, between rest phases gives the most reliable alternation time. The main and novel conclusion of this paper is the modelling prediction that one must be much more specific in the choice of the protocol alternation time if attempting to observe the improvements promised by Goldie and Coldman’s alternation hypothesis for the rest phases, pharmacokinetics and delivery mechanisms typically encountered in cell cycle phase specific chemotherapy protocols.     

Apoptosis in anititumor strategies: Modulation of cell cycle or differentiation

There is a strong evidence that administration of antitumor drugs triggers apoptotic death of target cells. A characteristic feature of appotosis is active participation of the affected cell in its demise. Attempts have been made, therefore, to potentiate the cytotoxicity of a variety of agents by modulating the propensity of cells to respond by apoptosis. Several strategies to enhance apoptosis that involve modulation of the cell cycle or differentiation are discussed. Loss of control of the G₁ checkpoint in tumor cells allows one to design treatments that arrest normal cells at the checkpoint and attempt to selectively kill tumor cells with S phase specific drugs. The possibility of a restoration of the apoptosis triggering function of the tumor suppressor gene p53 when the G₁ checkpoint function is abolished is expected to increase tumor cells' sensitivity to S phase poisons. Because induction of apoptosis by many antitumor drugs is cell cycle phase specific, drug combinations that preferentially trigger apoptosis at different phases of the cycle, or recruitment of cells to the sensitive phase, offer another antitumor strategy. There is also evidence that apoptosis is potentiated when cell differentiation is triggered follwing DNA damage. This observation suggests that strategies which combine DNA damaging and differentiating drugs, under conditions where the latter are administered following DNA damage caused by the former, may be successful.