Analysis and prediction of drug–drug interaction by minimum redundancy maximum relevance and incremental feature selection

Drug–drug interaction (DDI) defines a situation in which one drug affects the activity of another when both are administered together. DDI is a common cause of adverse drug reactions and sometimes also leads to improved therapeutic effects. Therefore, it is of great interest to discover novel DDIs according to their molecular properties and mechanisms in a robust and rigorous way. This paper attempts to predict effective DDIs using the following properties: (1) chemical interaction between drugs; (2) protein interactions between the targets of drugs; and (3) target enrichment of KEGG pathways. The data consisted of 7323 pairs of DDIs collected from the DrugBank and 36,615 pairs of drugs constructed by randomly combining two drugs. Each drug pair was represented by 465 features derived from the aforementioned three categories of properties. The random forest algorithm was adopted to train the prediction model. Some feature selection techniques, including minimum redundancy maximum relevance and incremental feature selection, were used to extract key features as the optimal input for the prediction model. The extracted key features may help to gain insights into the mechanisms of DDIs and provide some guidelines for the relevant clinical medication developments, and the prediction model can give new clues for identification of novel DDIs.     

Albumin–drug interaction and its clinical implication

Background

Human serum albumin acts as a reservoir and transport protein for endogenous (e.g. fatty acids or bilirubin) and exogenous compounds (e.g. drugs or nutrients) in the blood. The binding of a drug to albumin is a major determinant of its pharmacokinetic and pharmacodynamic profile.

Scope of review

The present review discusses recent findings regarding the nature of drug binding sites, drug-albumin binding in certain diseased states or in the presence of coadministered drugs, and the potential of utilizing albumin–drug interactions in clinical applications.

Major conclusions

Drug–albumin interactions appear to predominantly occur at one or two specific binding sites. The nature of these drug binding sites has been fundamentally investigated as to location, size, charge, hydrophobicity or changes that can occur under conditions such as the content of the endogenous substances in question. Such findings can be useful tools for the analysis of drug–drug interactions or protein binding in diseased states. A change in protein binding is not always a problem in terms of drug therapy, but it can be used to enhance the efficacy of therapeutic agents or to enhance the accumulation of radiopharmaceuticals to targets for diagnostic purposes. Furthermore, several extracorporeal dialysis procedures using albumin-containing dialysates have proven to be an effective tool for removing endogenous toxins or overdosed drugs from patients.

General significance

Recent findings related to albumin–drug interactions as described in this review are useful for providing safer and efficient therapies and diagnoses in clinical settings. This article is part of a Special Issue entitled Serum Albumin.     

Molecular mechanism of an adverse drug–drug interaction of allopurinol and furosemide in gout treatment

Gout patients receiving a combination of allopurinol and furosemide require higher allopurinol doses to achieve the target serum urate (SU) of <6 mg/dl (Stamp et al., 2012) [1]. Our study aimed to identify the molecular basis for this observation. We used a fluorimetric assay to determine the impact of furosemide and oxypurinol (the active metabolite of allopurinol) on xanthine oxidase (XO) activity. Immunoblot analysis quantified expression of XO and AMP-kinase (AMPK) in drug-treated human liver (HepG2) and primary kidney (HRCE) cells. In silico analysis identified miR-448 as a potential XO-regulator, whose expression level in HepG2 cells was examined by qPCR.     

Injection drug use and HIV/AIDS transmission in China

After nearly three decades of being virtually drug free, use of heroin and other illicit drugs has re-emerged in China as a major public health problem. One result is that drug abuse, particularly heroin injection, has come to play a predominant role in fueling China＇s AIDS epidemic. The first outbreak of HIV among China＇s IDUs was reported in the border area of Yunnan province between China and Myanmar where drug trafficking is heavy. Since then drug-related HIV has spread to all 31 provinces, autonomous regions and municipalities. This paper provides an overview to HIV/AIDS transmission through injection drug use in China. It begins with a brief history of the illicit drug trade in China, followed by a discussion of the emergence of drug related AIDS, and a profile of drug users and their sexual partners who have contracted the virus or who are vulnerable to infection. It ends by summarizing three national strategies being used by China to address both drug use and AIDS as major health threats.     

Determination and pharmacokinetics of a furosemide–amiloride drug combination

The study presents an accurate and precise HPLC assay for the determination of furosemide and amiloride in human specimens. Both drugs were extracted from human plasma with ethyl acetate; furosemide was extracted at pH 1 and amiloride at pH 12. While chromatographic separation conditions, i.e., column, mobile phase and flow-rate were the same for both investigated drugs, furosemide was detected using a UV absorbance detector, whereas amiloride, because of its very low therapeutic range, was detected with a spectrofluorimetric detector. The linearity of the furosemide and amiloride assays were confirmed over the range of 30–3000 ng/ml and 0.5–30 ng/ml, respectively. These concentrations correspond well with the therapeutic ranges of both drugs. The extraction recoveries, depending on concentration, exceed 80% for furosemide and 74% for amiloride. The reported methods were applied to pharmacokinetic investigations of the two compounds taken in form of a drug combination.     

Neuroprotective and nootropic drug noopept rescues α-synuclein amyloid cytotoxicity

Parkinson's disease is a common neurodegenerative disorder characterized by α-synuclein (α-Syn)-containing Lewy body formation and selective loss of dopaminergic neurons in the substantia nigra. We have demonstrated the modulating effect of noopept, a novel proline-containing dipeptide drug with nootropic and neuroprotective properties, on α-Syn oligomerization and fibrillation by using thioflavin T fluorescence, far-UV CD, and atomic force microscopy techniques. Noopept does not bind to a sterically specific site in the α-Syn molecule as revealed by heteronuclear two-dimensional NMR analysis, but due to hydrophobic interactions with toxic amyloid oligomers, it prompts their rapid sequestration into larger fibrillar amyloid aggregates. Consequently, this process rescues the cytotoxic effect of amyloid oligomers on neuroblastoma SH-SY5Y cells as demonstrated by using cell viability assays and fluorescent staining of apoptotic and necrotic cells and by assessing the level of intracellular oxidative stress. The mitigating effect of noopept against amyloid oligomeric cytotoxicity may offer additional benefits to the already well-established therapeutic functions of this new pharmaceutical.     

Cortical thickness abnormalities in cocaine addiction--a reflection of both drug use and a pre-existing disposition to drug abuse?

The structural effects of cocaine on neural systems mediating cognition and motivation are not well known. By comparing the thickness of neocortical and paralimbic brain regions between cocaine-dependent and matched control subjects, we found that four of 18 a priori regions involved with executive regulation of reward and attention were significantly thinner in addicts. Correlations were significant between thinner prefrontal cortex and reduced keypresses during judgment and decision making of relative preference in addicts, suggesting one basis for restricted behavioral repertoires in drug dependence. Reduced effortful attention performance in addicts also correlated with thinner paralimbic cortices. Some thickness differences in addicts were correlated with cocaine use independent of nicotine and alcohol, but addicts also showed diminished thickness heterogeneity and altered hemispheric thickness asymmetry. These observations suggest that brain structure abnormalities in addicts are related in part to drug use and in part to predisposition toward addiction.     

Signaled drug delivery and transport across the blood–brain barrier

We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood–brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson’s disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US.     

Aptamers—basic research, drug development, and clinical applications

Since its discovery in the early 1990s, aptamer technology has progressed tremendously. Automated selection procedures now allow rapid identification of DNA and RNA sequences that can target a broad range of extra- and intracellular proteins with nanomolar affinities and high specificities. The unique binding properties of nucleic acids, which are amenable to various modifications, make aptamers perfectly suitable for different areas of biotechnology. Moreover, the approval of an aptamer for vascular endothelial growth factor by the US Food and Drug Administration highlights the potential of aptamers for therapeutic applications. This review summarizes recent developments and demonstrates that aptamers are valuable tools for diagnostics, purification processes, target validation, drug discovery, and even therapeutic approaches.     

Can medical genetics and evolutionary biology inspire drug target identification?

New strategies for target identification are urgently needed to tackle the current productivity challenges in drug discovery. By examining successful human drug targets, it can be seen that approximately 50% are associated with genetic disorders. Further analysis shows that these successfully targeted genes share some common evolutionary features, which strongly suggests that evolutionary information can help identify drug targets with the greatest potential for therapeutic development.     

The role of α-satellite DNA and heterochromatin polymorphism in leukemia patients and illicit drug addicts

Heterochromatin is considered to play a role in protecting the genome against mutagens. Changes in the quantity and proportion of different types of satellite DNA could increase genetic susceptibility in individuals with heterochromatic variations; they cause chromosome instability and predispose patients to malignancies. We evaluated the heterochromatin associated with chromosomes in 50 leukemia patients, 93 drug addicts and 93 healthy controls from Tehran, Iran. Barium hydroxide saline Giemsa staining was used to examine heterochromatin polymorphism of chromosomes 1, 9 and 16 in lymphocyte cultures. There were significant differences in this polymorphism in lymphocytes from drug addicts and leukemia patients compared to healthy controls. These polymorphisms could serve as markers for the detection and characterization of chromosome damage in leukemia patients and drug addicts.     

Papain-like lysosomal cysteine proteases and their inhibitors: drug discovery targets?

Papain-like lysosomal cysteine proteases are processive and digestive enzymes that are expressed in organisms from bacteria to humans. Increasing knowledge about the physiological and pathological roles of cysteine proteases is bringing them into the focus of drug discovery research. These proteases have rather short active-site clefts, comprising three well defined substrate-binding subsites (S2, S1 and S1') and additional broad binding areas (S4, S3, S2' and S3'). The geometry of the active site distinguishes cysteine proteases from other protease classes, such as serine and aspartic proteases, which have six and eight substrate-binding sites respectively. Exopeptidases (cathepsins B, C, H and X), in contrast with endopeptidases (such as cathepsins L, S, V and F), possess structural features that facilitate the binding of N- and C-terminal groups of substrates into the active-site cleft. Other than a clear preference for free chain termini in the case of exopeptidases, the substrate-binding sites exhibit no strict specificities. Instead, their subsite preferences arise more from the specific exclusion of substrate types. This presents a challenge for the design of inhibitors to target a specific cathepsin: only the cumulative effect of an assembly of inhibitor fragments will bring the desired result.     

BioBanking - The Holy Grail of novel drug and diagnostic developments?

The ever increasing social cost that society pays for illness and disease are currently steadily increasing in many countries in the world today. These changes in society becomes a major financial burden that activates politicians and health care organizations in order to find new solutions. Biobanks are becoming the new powerful modality within the field of modern Life Science, that is expected to be important in the proactive awareness of patient health status. Biobanks are also expected to promote the developments of targeted treatments with personalized indicator assays, for effective use of Personalized Medicine treatments in the near future.     

Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions

Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC₅₀) was 1.1 ± 0.3 and 4.6 ± 0.3 μM for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with K_i of 1.6 and 2.0 μM, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4 ± 2.1 μM and 0.06 ± 0.01 min^–1 for K_I and k_inact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.     

Targeted therapeutics and nanodevices for vascular drug delivery: quo vadis?

This issue of the journal is dedicated to targeted delivery of therapeutics in the vasculature, an approach that holds promise to optimize treatment of diverse pathological conditions ranging from ischemia and tumor growth to metabolic and genetic diseases. From the standpoint of drug delivery, circulation system represents the natural route to the targets, whereas its components (blood and vascular cells) represent targets, carriers or barriers for drug delivery. Diverse nanodevices and targeted therapeutic agents that are designed and tested in animal and early clinical studies to achieve optimal and precise spatiotemporal control of the pharmacokinetics, destination, metabolism and effect of pharmacological agents will be discussed in this introductory essay and subsequent critical reviews in this series.     

Potassium ion channels and human disease: phenotypes to drug targets?

A significant difficulty faced by the pharmaceutical industry is the initial identification and selection of macromolecular targets upon which de novo drug discovery programs can be initiated. A drug target should have several characteristics: known biological function; robust assay systems for in vitro characterization and high-throughput screening; and be specifically modified by and accessible to small molecular weight compounds in vivo. Ion channels have many of these attributes and can be viewed as suitable targets for small molecule drugs. Potassium (K⁺) ion channels form a large and diverse gene family responsible for critical functions in numerous cell types, tissues and organs. Recent discoveries, facilitated by genomics technologies combined with advanced biophysical characterization methods, have identified novel K⁺ channels that are involved in important physiologic processes, or mutated in human inherited disease. These findings, coupled with a rapidly growing body of information regarding modulatory channel subunits and high resolution channel structures, are providing the critical information necessary for validation of K⁺ channels as drug targets.     

Effect of potassium chloride and cationic drug on swelling,erosion and release from κ-carrageenan matrices

The basic objective of this work was to study the effect of model cationic drug metformin HCl on swelling and erosion and, in turn, the release of KCl and drug itself, from the κ-carrageenan matrices. Water uptake by the matrix up to 2 hours was found to increase with KCl concentration from the plain matrix. Erosion was not affected by concentration of KCl. Incorporation of drug favors water uptake, but in presence of KCl it was found to be reduced. Drugcontaining matrices have shown higher release of KCl as compared with plain batches. Drug release was retarded as KCl concentration increased up to 5%, above which the reduced cohesivity of the matrix caused increase in drug release.     

Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes?

Evidence is reviewed which suggests a linkage may exist between certain forms of de novo or acquired drug resistance and metastasis. This includes finding that expression of certain dominantly acting mutant oncogenes or tumor suppressor genes, e.g. genes which normally act to “drive” tumor progression and metastasis, can also affect the expression of drug resistance. Moreover, this can be accompanied by altered expression of certain cellular genes thought to be involved in expression of drug resistance. A direct linkage between acquired drug resistance and metastasis would suggest that tumor sublines selected for drug resistance should manifest more aggressive malignant properties than their drug-sensitive counterparts. While this does not appear to be true for drug resistant sublines selected in vitro, indeed such cell lines frequently manifest diminished in vivo tumorigenic and/or metastatic competence, there is some evidence to support such a correlation exists for tumor cell lines that are selected in vivo for drug resistance. Attention is also drawn to the fact that new linkages between metastasis and drug resistance may be uncovered by analyzing the ability of tumor subpopulations to acquire drug resistance after one or several previous exposures to chemotherapeutic drugs, as opposed to examining intrinsic drug resistance only. Furthermore, ability to detect induced or acquired drug resistance in vitro may be strongly influenced by the types of assay used to detect and monitor drug resistanc. In particular, three-dimensional cell culture systems may reveal acquired or induced “multicellular” drug resistance in situations where conventional two-dimensional culture systems may therefore reveal as yet undiscovered associations between the phenotypes of metastasis and drug resistance.