EFFECT OF TRANQUILIZERS ON REGIONAL DISTRIBUTION OF ASCORBIC ACID IN THE RAT BRAIN

—Studies were made of the effects of fluphenazine, chlorpromazine and triflupromazine on tissue concentration, liver synthesis of ascorbic acid and its distribution in different areas of the brain. All the three drugs were found to increase liver concentration and synthesis of the vitamin at 24 hr after administration of a single oral dose of the vitamin, but only fluphenazine was found to increase its concentration in the adrenals and brain; the increase in the latter case was found to vary in different regions of the brain, the olfactory lobes, hypothalamus and residual brain showing maximum increases, andthe basal ganglia, visual cortex and remaining dorsal cortex showing minimum increases. The effects were found to be reversed 72 hr after drug treatment.     

胆酸钠和依地酸二钠复合用药的溶石效果研究

目的:探讨胆酸钠和依地酸二钠不同摩尔比、胆汁中不同药物浓度、溶解时间与胆管结石溶石效果之间的关系。方法:设计在一个月内胆汁中药物浓度为0.1%的、摩尔比分别为0:1、8:1、4:1、2:1、1:1、1:2、1:4、1:8和1:0的九个等级的胆酸钠和依地酸二钠的溶石实验,摩尔比为1:1的这两种溶石药物在胆汁中药物浓度为0、0.1%、0.2%、0.4%、0.8%、1.6%和3.2%的溶石实验,和摩尔比1:1的溶石药物在胆汁中浓度为0.1%的经过0、1、2、4、8、16、32和64d的溶石实验;评估这三个实验的各自溶石质量是否相等(P<0.05有显著性统计意义)。结果:胆汁中药物浓度、溶石时间相同时,单药依地酸二钠溶石效果比胆酸钠强,复合药物比单药效果好,越靠近摩尔比为1:1时的溶石能力越强,在摩尔比为1:1时溶石能力最强;在相同时间、摩尔比为1:1的复合药物中,药物浓度越大,溶石能力越强;在有充足溶石药物的条件下,相同摩尔比、相同药物浓度,溶解的时间越长,溶石能力越强(P<0.05,有显著性统计意义)。结论:胆酸钠和依地酸二钠摩尔比为1:1时,复合药物具有最大的溶石效果;在有充足溶石药物的条件下,药物浓度越大,溶解的时间越长,溶石能力越强     

Single-cell partition analysis—A direct fluorescence technique for examining ligand-macromolecule interactions

Single-cell partition analysis is described as a novel technique for examining ligand-macromolecule interactions. This procedure is a combination of the classical fluorescence titration technique and phase-partition techniques and allows three separate methods for calculating and comparing both free and bound drug concentrations. The value of this technique is demonstrated by the comparison of the binding properties of the potent antitumor antibiotic adriamycin and ethidium bromide to nucleic acids. Binding isotherms of both drugs were obtained at low r (concentration of bound drug per base pair) values, showing strikingly different results, thus allowing insight to be gained into the cooperative binding of these drugs to DNA.     

Water-soluble platinum phthalocyanines as potential antitumor agents

Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance. These drugs have been the guide for the research, in last years, of novel platinum and ruthenium based compounds, able to overcome these limitations. In this work, ruthenium and platinum based phthalocyanines were synthesized through conventional techniques and their antiproliferative and/or cytotoxic actions were tested. Normal mammary gland (MCF10A) and several models of mammarian carcinoma at different degrees of invasiveness (BT474, MCF-7 and MDA-MB-231) were used. Cells were treated with different concentrations (5–100 μM) of the above reported compounds, to evaluate toxic concentration and to underline possible dose–response effects. The study included growth curves made by trypan blue exclusion test and scratch assay to study cellular motility and its possible negative modulation by phthalocyanine. Moreover, we investigated cell cycle and apoptosis through flow cytometry and AMNIS Image Stream cytometer. Among all the tested drugs, tetrasulfonated phthalocyanine of platinum resulted to be the molecule with the best cytostatic action on neoplastic cell lines at the concentration of 30 μM. Interestingly, platinum tetrasulfophtalocyanine, at low doses, had no antiproliferative effects on normal cells. Therefore, such platinum complex, appears to be a promising drug for mammarian carcinoma treatment.     

Porous bioactive glass scaffolds for local drug delivery in osteomyelitis: development and in vitro characterization

A new bioactive glass-based scaffold was developed for local delivery of drugs in case of osteomyelitis. Bioactive glass having a new composition was prepared and converted into porous scaffold. The bioactivity of the resulting scaffold was examined by in vitro acellular method. The scaffolds were loaded with two different drugs, an antibacterial or antifungal drug. The effects of the size of the scaffold, drug concentration, and dissolution medium on drug release were studied. The scaffolds were further coated with a degradable natural polymer, chitosan, to further control the drug release. Both the glass and scaffold were bioactive. The scaffolds released both the drugs for 6 weeks, in vitro. The results indicated that the bigger the size and the higher the drug concentration, the better was the release profile. The scaffolds appeared to be suitable for local delivery of the drugs in cases of osteomyelitis.     

Swelling/Floating Capability and Drug Release Characterizations of Gastroretentive Drug Delivery System Based on a Combination of Hydroxyethyl Cellulose and Sodium Carboxymethyl Cellulose

The aim of this study was to characterize the swelling and floating behaviors of gastroretentive drug delivery system (GRDDS) composed of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) and to optimize HEC/NaCMC GRDDS to incorporate three model drugs with different solubilities (metformin, ciprofloxacin, and esomeprazole). Various ratios of NaCMC to HEC were formulated, and their swelling and floating behaviors were characterized. Influences of media containing various NaCl concentrations on the swelling and floating behaviors and drug solubility were also characterized. Finally, release profiles of the three model drugs from GRDDS formulation (F1-4) and formulation (F1-1) were examined. Results demonstrated when the GRDDS tablets were tested in simulated gastric solution, the degree of swelling at 6 h was decreased for each formulation that contained NaCMC in comparison to those in de-ionized water (DIW). Of note, floating duration was enhanced when in simulated gastric solution compared to DIW. Further, the hydration of tablets was found to be retarded as the NaCl concentration in the medium increased resulting in smaller gel layers and swelling sizes. Dissolution profiles of the three model drugs in media containing various concentrations of NaCl showed that the addition of NaCl to the media affected the solubility of the drugs, and also their gelling behaviors, resulting in different mechanisms for controlling a drug’s release. The release mechanism of the freely water-soluble drug, metformin, was mainly diffusion-controlled, while those of the water-soluble drug, ciprofloxacin, and the slightly water-soluble drug, esomeprazole, were mainly anomalous diffusion. Overall results showed that the developed GRDDS composed of HEC 250HHX and NaCMC of 450 cps possessed proper swelling extents and desired floating periods with sustained-release characteristics.     

Hair analysis for abused and therapeutic drugs

This review focuses on basic aspects and recent studies of hair analysis for abused and therapeutic drugs and is discussed with 164 references. Firstly, biology of hair and sampling of hair specimens have been commented for the sake of correct interpretation of the results from hair analysis. Then the usual washing methods of hair samples and the extraction methods for drugs in hair have been shown and commented on. Analytical methods for each drug have been discussed by the grouping of three analytical methods, namely immunoassay, HPLC–CE and GC–MS. The outcomes of hair analysis studies have been reviewed by dividing into six groups; morphine and related, cocaine and related, amphetamines, cannabinoids, the other abused drugs and therapeutic drugs. In addition, reports on stability of drugs in the living hair and studies on drug incorporation into hair and dose–hair concentration relationships have been reviewed. Applications of hair analysis to the estimation of drug history, discrimination between OTC drug use and illegal drug use, drug testing for acute poisoning, gestational drug exposure and drug compliance have also been reviewed. Finally, the promising prospects of hair analysis have been described.     

Role of racemization in optically active drugs development

U.S. Food and Drug Administration issues certain guidelines for marketing of optically active drugs as some enantiomers racemize into human body, leading to the generation of other antipodes, which may be toxic or ballast to the human beings. Moreover, racemization reduces the administrated dosage concentration as optically active enantiomer converted into its inactive counter part. Therefore, the study of racemization of such type of drugs is an important and urgent need of today. This article describes in vitro and in vivo racemization of optically active drugs. The racemization process of various optically active drugs has been discussed considering the effect of different variables i.e. pH, temperature, concentration of the drug, ionic concentration, etc. Attempts have also been made to discuss the mechanisms of racemization. Besides, efforts have been made to suggest the safe dosages of such type of drugs too.     

Modification of proportion sensitivity testing method for ethionamide

Standardized methodology for drug susceptibility testing of second line drugs is vital for treatment of multi/extensively drug resistant tuberculosis. Discrepancy between laboratory methods and clinical interpretation is well established for bacteriostatic drugs such as ethionamide. Optimization of the standard proportion sensitivity testing (PST) method for ethionamide was under taken in 235 Mycobacterium tuberculosis isolates from new and previously treated pulmonary tuberculosis patients. An additional higher concentration of 57 μg/ml was evaluated against at the standard 40 μg/ml concentration in PST method. Performance parameters and agreement between the two drug concentrations was higher indicating the efficiency of PST method at its present format at 40 μg/ml and additional higher concentration of 57 μg/ml as an alternative when required.     

Influence of kinetics of drug binding on EGFR signaling: a comparative study of three EGFR signaling pathway models

We used three models of the epidermal growth factor receptor (EGFR) signaling pathway mimicking three different cell lines to study the effects of kinetics of drug binding on influencing molecular signaling in the pathways. With no incubation of drugs before the external cue epidermal growth factor (EGF) was applied, we found that fast kinetics of binding to protein kinases was advantageous in suppressing the production of the Extracellular signal-regulated kinase (ERK) that triggers cell proliferation, with some exceptions. Incubation of a drug with a protein kinase target for an hour before a pathway was initiated with an external cue made kinetics less significant, so did high concentration of drugs. In addition, we found that applying a drug to a protein kinase mostly affected downstream signaling although upstream events were also affected in a few cases. In examining whether applying two drugs to two protein kinase targets in the pathways could produce synergistic effects, we found positive, negative, or no effects, depending on the protein kinases targeted and the pathway model considered.     

斑马鱼胚胎和肿瘤细胞评价细胞毒药物活性比较研究*

目的:比较斑马鱼胚胎和肿瘤细胞作为药物筛选模型的优缺点.方法:采用MTT法检测顺铂、紫杉醇、阿霉素、5-氟尿嘧啶四种药物对HL-60和Hela细胞的增殖影响;同时,观察药物对斑马鱼胚胎发育的影响.结果:阿霉素、顺铂及紫杉醇作用于HL-60及Hela细胞的IC50均显著高于作用于斑马鱼胚胎的LD50;而5-FU作用于肿瘤细胞和斑马鱼胚胎的结果与其它药物相反;四种抗肿瘤药物对斑马鱼胚胎的生长发育均有致畸作用.结论:斑马鱼胚胎作为细胞毒类药物筛选模型,对于抗微管类药物较为敏感,但对于抗代谢药敏感性较肿瘤细胞差.     

Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness.

OBJECTIVE: To assess the impact of the colour of a drug''s formulation on its perceived effect and its effectiveness and to examine whether antidepressant drugs available in the Netherlands are different in colour from hypnotic, sedative, and anxiolytic drugs. DESIGN: Systematic review of 12 published studies. Six studies examined the perceived action of different coloured drugs and six the influence of the colour of a drug on its effectiveness. The colours of samples of 49 drugs affecting the central nervous system were assessed using a colour atlas. MAIN OUTCOME MEASURES: Perceived stimulant action versus perceived depressant action of colour of drugs; the trials that assessed the effect of drugs in different colours were done in patients with different diseases and had different outcome measures. RESULTS: The studies on perceived action of coloured drugs showed that red, yellow, and orange are associated with a stimulant effect, while blue and green are related to a tranquillising effect. The trials that assessed the impact of the colour of drugs on their effectiveness showed inconsistent differences between colours. The quality of the methods of these trials was variable. Hypnotic, sedative, and anxiolytic drugs were more likely than antidepressants to be green, blue, or purple. CONCLUSIONS: Colours affect the perceived action of a drug and seem to influence the effectiveness of a drug. Moreover, a relation exists between the colouring of drugs that affect the central nervous system and the indications for which they are used. Research contributing to a better understanding of the effect of the colour of drugs is warranted.     

Pharmacological and Host Considerations Surrounding Dose Selection and Duration of Therapy with Echinocandins

Caspofungin, micafungin and anidulafungin are antifungal drugs with excellent safety profiles. Dosing regimens and treatment durations must be appropriate for optimal patient outcomes. Overall, factors that affect dosing of all three drugs are similar. Drug-specific properties, including in vitro concentration-dependent antifungal activity, activity against fungal biofilms, and pharmacokinetic and pharmacodynamic parameters influence dose selection and duration of therapy. Dosing strategies that provide “unbound” plasma drug concentrations exceeding the minimum inhibitory concentration (or minimum effective concentration) of the fungus are essential. Patient weight, age and illness severity are also important considerations for adequate exposure to drug: individuals >66 kg, pediatric patients and the critically-ill clear drug at higher rates although drug product information guidelines do not recommend for these populations to receive doses higher than those currently used. Clinical studies of treatment of, and prophylaxis against, Candida and Aspergillus infection indicate that currently recommended dosing regimens are adequate in most instances.     

A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes

Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can ‘repair’ the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K⁺ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the ‘composition’ of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.     

A Systematic In Silico Search for Target Similarity Identifies Several Approved Drugs with Potential Activity against the Plasmodium falciparum Apicoplast

Most of the drugs in use against Plasmodium falciparum share similar modes of action and, consequently, there is a need to identify alternative potential drug targets. Here, we focus on the apicoplast, a malarial plastid-like organelle of algal source which evolved through secondary endosymbiosis. We undertake a systematic in silico target-based identification approach for detecting drugs already approved for clinical use in humans that may be able to interfere with the P. falciparum apicoplast. The P. falciparum genome database GeneDB was used to compile a list of ≈600 proteins containing apicoplast signal peptides. Each of these proteins was treated as a potential drug target and its predicted sequence was used to interrogate three different freely available databases (Therapeutic Target Database, DrugBank and STITCH3.1) that provide synoptic data on drugs and their primary or putative drug targets. We were able to identify several drugs that are expected to interact with forty-seven (47) peptides predicted to be involved in the biology of the P. falciparum apicoplast. Fifteen (15) of these putative targets are predicted to have affinity to drugs that are already approved for clinical use but have never been evaluated against malaria parasites. We suggest that some of these drugs should be experimentally tested and/or serve as leads for engineering new antimalarials.     

新型缓释片剂辅料甲壳胺的研究 Ⅰ:甲壳胺性质对药物溶出的影响

本文以非甾体抗炎药吲哚美辛为模型药物制备了骨架型缓释片剂,以体外溶出为检验指标,考察了甲壳胺的脱乙酰度、表观粘度及用量对药物释放的影响,并确定了甲壳胺的脱乙酰度及粘度范围。实验结果表明,缓释作用随脱乙酰度升高而降低;随用量增多而增强;粘度对药物释放的影响随脱乙酰度不同而不同。脱乙酰度为85％的甲壳胺,其缓释作用随表观粘度的增大而增大;脱乙酰度为75％的甲壳胺缓释作用随粘度升高而降低。     

Competitive binding of fluoroquinolone antibiotics and some other drugs to human serum albumin: a luminescence spectroscopic study

Co‐administration of several drugs in multidrug therapy may alter the binding of each to human serum albumin (HSA) and hence their pharmacological activity. Thirty‐two frequently prescribed drug combinations, consisting of four fluoroquinolone antibiotics and eight competing drugs, have been studied using fluorescence and circular dichroism spectroscopic techniques. Competitive binding studies on the drug combinations are not available in the literature. In most cases, the presence of competing drug decreased the binding affinity of fluoroquinolone, resulting in an increase in the concentration of free pharmacologically active drug. The competitive binding mechanism involved could be interpreted in terms of the site specificity of the binding and competing drugs. For levofloxacin, the change in the binding affinity was small because in the presence of site II‐specific competing drugs, levofloxacin mainly occupied site I. A competitive interference mechanism was operative for sparfloxacin, whereas competitive interference as well as site‐to‐site displacement of competing drugs was observed in the case of ciprofloxacin hydrochloride. For enrofloxacin, a different behavior was observed for different combinations; site‐to‐site displacement and conformational changes as well as independent binding has been observed for various drug combinations. Circular dichroism spectral studies showed that competitive binding did not cause any major structural changes in the HSA molecule. Copyright © 2013 John Wiley & Sons, Ltd.     

Modeling the Dynamics of Heterogeneity of Solid Tumors in Response to Chemotherapy

In this paper, we extend the model of the dynamics of drug resistance in a solid tumor that was introduced by Lorz et al. (Bull Math Biol 77:1–22, 2015). Similarly to the original, radially symmetric model, the quantities we follow depend on a phenotype variable that corresponds to the level of drug resistance. The original model is modified in three ways: (i) We consider a more general growth term that takes into account the sensitivity of resistance level to high drug dosage. (ii) We add a diffusion term in space for the cancer cells and adjust all diffusion terms (for the nutrients and for the drugs) so that the permeability of the resource and drug is limited by the cell concentration. (iii) We add a mutation term with a mutation kernel that corresponds to mutations that occur regularly or rarely. We study the dynamics of the emerging resistance of the cancer cells under continuous infusion and on–off infusion of cytotoxic and cytostatic drugs. While the original Lorz model has an asymptotic profile in which the cancer cells are either fully resistant or fully sensitive, our model allows the emergence of partial resistance levels. We show that increased drug concentrations are correlated with delayed relapse. However, when the cancer relapses, more resistant traits are selected. We further show that an on–off drug infusion also selects for more resistant traits when compared with a continuous drug infusion of identical total drug concentrations. Under certain conditions, our model predicts the emergence of a heterogeneous tumor in which cancer cells of different resistance levels coexist in different areas in space.     

Combination therapies for combating antimicrobial resistance

New drug development strategies are needed to combat antimicrobial resistance. The object of this perspective is to highlight one such strategy: treating infections with sets of drugs rather than individual drugs. We will highlight three categories of combination therapy: those that inhibit targets in different pathways; those that inhibit distinct nodes in the same pathway; and those that inhibit the very same target in different ways. We will then consider examples of naturally occurring combination therapies produced by micro-organisms, and conclude by discussing key opportunities and challenges for making more widespread use of drug combinations.     

Electron crystallography reveals plasticity within the drug binding site of the small multidrug transporter EmrE

EmrE is a Small Multidrug Resistance transporter (SMR) family member that mediates counter transport of protons and hydrophobic cationic drugs such as tetraphenylphosphonium (TPP⁺), ethidium, propidium and dequalinium. It is thought that the selectivity of the drug binding site in EmrE is defined by two negatively charged glutamate residues within a hydrophobic pocket formed from six of the α-helices, three from each monomer of the asymmetric EmrE homodimer. It is not apparent how such a binding pocket accommodates drugs of various sizes and shapes or whether the conformational changes that occur upon drug binding are identical for drugs of diverse chemical nature. Here, using electron cryomicroscopy of EmrE two-dimensional crystals we have determined projection structures of EmrE bound to three structurally different planar drugs, ethidium, propidium and dequalinium. Using image analysis and rigorous comparisons between these density maps and the density maps of the ligand-free and TPP⁺-bound forms of EmrE, we identify regions within the transporter that adapt differentially depending on the type of ligand bound. We show that all three planar drugs bind at the same pocket within the protein as TPP⁺. Furthermore, our analysis indicates that, while retaining the overall fold of the protein, binding of the planar drugs is accompanied by small rearrangements of the transmembrane domains that are different to those that occur when TPP⁺ binds. The regions in the EmrE dimer that are remodelled surround the drug binding site and include transmembrane domains from both monomers.