Internet Resources Related to Drug Action and Human Response: A Review

It has been demonstrated that numerous proteins interact with drugs or their metabolites. Knowledge of these proteins is necessary to understand the mechanisms of drug action and human response. Progress in modern genetics, molecular biology, biochemistry and pharmacology is generating a comprehensive mechanistic understanding of drug-target interaction on the molecular level. This is valuable for researchers and pharmaceutical companies in their efforts to improve the efficacy of existing drugs and to discover new ones. Most recently, the integration of a systems biology approach into drug discovery processes calls for more holistic knowledge and easily accessible resources of the proteins that are important in drug action and human response. We have reviewed many publicly accessible internet resources of these proteins, according to their roles in drug action and human response, such as therapeutic effect, adverse reaction, absorption, distribution, metabolism and excretion.     

Variability in Response to Drugs

Variability in the response to drugs is due to three principal components—the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.     

Preclinical testing of new drugs for tuberculosis: current challenges

The continuing global epidemic of tuberculosis, the increasing rate of multidrug resistant (MDR) tuberculosis and the more recent emergence of extensively drug resistant (XDR) tuberculosis are great causes for concern. A major international effort is currently underway to optimize current drug therapies and to discover new drugs that are active against these organisms. This effort has created a pipeline of new candidate drugs at various stages of preclinical and early clinical evaluations. Major challenges still exist, however, varying from the standardization and application of current animal models and their application to drug discovery and characterization to the fact that our knowledge about the basic biology of the MDR and XDR strains of Mycobacterium tuberculosis is minimal at best.     

Chemotherapeutic Drugs Interfere with Gene Delivery Mediated by Chitosan-Graft-Poly(ethylenimine)

Combined chemo-gene therapy is one of the treatment modalities that have attracted extensive research interests; however, there is little information regarding the influence of drug application on gene transfer. This study bridges this gap by examining how chemotherapeutic drugs (teniposide, cis-diamminedichloroplatinum(II) and temozolomide) interfere with polyplex formation and transfection of chitosan-graft-poly(ethylenimine). Our results indicate that the degree of drug interference varies with the mechanism of drug action, with the transgene expression being severely suppressed when the plasmid is co-delivered with cis-diamminedichloroplatinum(II) or teniposide but not temozolomide. In addition, the interference with transfection by drugs varies with different gene/drug co-formulations. This is the first study to evidence that, though combined chemo-gene therapy has therapeutic potential, some chemotherapeutic drugs may reduce the treatment efficiency of gene therapy.     

The use of 3-D cultures for high-throughput screening: the multicellular spheroid model

Over the past few years, establishment and adaptation of cell-based assays for drug development and testing has become an important topic in high-throughput screening (HTS). Most new assays are designed to rapidly detect specific cellular effects reflecting action at various targets. However, although more complex than cell-free biochemical test systems, HTS assays using monolayer or suspension cultures still reflect a highly artificial cellular environment and may thus have limited predictive value for the clinical efficacy of a compound. Today's strategies for drug discovery and development, be they hypothesis free or mechanism based, require facile, HTS-amenable test systems that mimic the human tissue environment with increasing accuracy in order to optimize preclinical and preanimal selection of the most active molecules from a large pool of potential effectors, for example, against solid tumors. Indeed, it is recognized that 3-dimensional cell culture systems better reflect the in vivo behavior of most cell types. However, these 3-D test systems have not yet been incorporated into mainstream drug development operations. This article addresses the relevance and potential of 3-D in vitro systems for drug development, with a focus on screening for novel antitumor drugs. Examples of 3-D cell models used in cancer research are given, and the advantages and limitations of these systems of intermediate complexity are discussed in comparison with both 2-D culture and in vivo models. The most commonly used 3-D cell culture systems, multicellular spheroids, are emphasized due to their advantages and potential for rapid development as HTS systems. Thus, multicellular tumor spheroids are an ideal basis for the next step in creating HTS assays, which are predictive of in vivo antitumor efficacy.     

经皮给药纳米载体及靶向系统治疗类风湿关节炎研究进展

类风湿关节炎(RA)是全世界难治性自身免疫疾病,其治疗药物虽不断发展,但病灶药物浓度达不到有效水平导致药物疗效不理想或存在各种毒副反应,因此,基于新技术、新方法研究开发针对RA的安全、高效新型制剂是必要的.研究表明,纳米技术的运用可提高药物生物利用度,经皮给药可改善口服和注射带来的毒副作用.对近年来基于经皮给药系统治疗...     

Quantitative analysis on the characteristics of targets with FDA approved drugs

Accumulated knowledge of genomic information, systems biology, and disease mechanisms provide an unprecedented opportunity to elucidate the genetic basis of diseases, and to discover new and novel therapeutic targets from the wealth of genomic data. With hundreds to a few thousand potential targets available in the human genome alone, target selection and validation has become a critical component of drug discovery process. The explorations on quantitative characteristics of the currently explored targets (those without any marketed drug) and successful targets (targeted by at least one marketed drug) could help discern simple rules for selecting a putative successful target. Here we use integrative in silico (computational) approaches to quantitatively analyze the characteristics of 133 targets with FDA approved drugs and 3120 human disease genes (therapeutic targets) not targeted by FDA approved drugs. This is the first attempt to comparatively analyze targets with FDA approved drugs and targets with no FDA approved drug or no drugs available for them. Our results show that proteins with 5 or fewer number of homologs outside their own family, proteins with single-exon gene architecture and proteins interacting with more than 3 partners are more likely to be targetable. These quantitative characteristics could serve as criteria to search for promising targetable disease genes.     

Nanotechnology based drug delivery system(s) for the management of tuberculosis

The era of nanotechnology has allowed new research strategies to flourish in the field of drug delivery. Nanoparticle-based drug delivery systems are suitable for targeting chronic intracellular infections such as tuberculosis. Polymeric nanoparticles employing poly lactide-co-glycolide have shown promise as far as intermittent chemotherapy in experimental tuberculosis is concerned. It has distinct advantages over the more traditional drug carriers, i.e. liposomes and microparticles. Although the experience with natural carriers, e.g. solid lipid nanoparticles and alginate nanoparticles is in its infancy, future research may rely heavily on these carrier systems. Given the options for oral as well as parenteral therapy, the very nature of the disease and its complex treatment urges one to emphasize on the oral route for controlled drug delivery. Pending the discovery of more potent antitubercular drugs, nanotechnology-based intermittent chemotherapy provides a novel and sound platform for an onslaught against tuberculosis.     

Discovering the targets of drugs via computational systems biology

Computational systems biology is empowering the study of drug action. Studies on biological effects of chemical compounds have increased in scale and accessibility, allowing integration with other large-scale experimental data types. Here, we review computational approaches for elucidating the mechanisms of both intended and undesirable effects of drugs, with the collective potential to change the nature of drug discovery and pharmacological therapy.     

Recent updates on drug resistance in Mycobacterium tuberculosis

Tuberculosis (TB) along with acquired immune deficiency syndrome and malaria rank among the top three fatal infectious diseases which pose threat to global public health, especially in middle and low income countries. TB caused by Mycobacterium tuberculosis (Mtb) is an airborne infectious disease and one-third of the world's population gets infected with TB leading to nearly 1·6 million deaths annually. TB drugs are administered in different combinations of four first-line drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) which form the core of treatment regimens in the initial treatment phase of 6–9 months. Several reasons account for the failure of TB therapy such as (i) late diagnosis, (ii) lack of timely and proper administration of effective drugs, (iii) lower availability of less toxic, inexpensive and effective drugs, (iv) long treatment duration, (v) nonadherence to drug regimen and (vi) evolution of drug-resistant TB strains. Drug-resistant TB poses a significant challenge to TB therapy and control programs. In the background of worldwide emergence of 558 000 new TB cases with resistance to rifampicin in the year 2017 and of them, 82% becoming multidrug-resistant TB (MDR-TB), it is essential to continuously update the knowledge on the mechanisms and molecular basis for evolution of Mtb drug resistance. This narrative and traditional review summarizes the progress on the anti-tubercular agents, their mode of action and drug resistance mechanisms in Mtb. The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti-TB agents in pipeline and international recommendations to manage MDR-TB. It is based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.     

The role of pharmacogenetics in treating central nervous system disorders

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients' quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a "trial and error" fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient's genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.     

抗体偶联药物的技术现状和展望

抗体偶联药物（antibody drug conjugate,ADC）通常由抗体通过链接体与毒素小分子偶联而成,同时具备抗体的高靶向性和小分子药物的高活性,使之作为一种新兴的靶向治疗手段,在肿瘤治疗领域展现出了优秀的疗效和潜力,成为药物研发领域的新热点。目前全球已有14款ADC药物获批上市,处于临床研究阶段的ADC候选药物分子超过140个。为了进一步提高ADC药物的安全性和有效性,近年来涌现出了各种新颖的技术。本文对ADC药物分子的关键元素,包括抗体、链接体、毒素小分子以及偶联技术等方面的最新研究进展进行总结,并讨论其优缺点。期望这些讨论能够帮助增加对ADC药物研究和开发更加系统的理解,为研发出更加高效和安全的ADC药物带来一些思考。     

Validation of Molecular and Genomic Biomarkers of Retinal Drug Efficacy: Use of Ocular Fluid Sampling to Evaluate VEGF

The use of tissue- and cell-based methods in developing drugs for retinal diseases is inefficient. Consequently, many aspects of ocular drug therapy for retinal diseases are poorly understood. Biomarkers as prognostic indicators of change are needed to optimize the use of drugs. VEGF is considered an important target of drug therapy and VEGF levels in tissue are indicative of solid tumor growth. However, since many aspects of VEGF as a biomarker of ocular disease have not been validated, it has been difficult to ascertain without invasive procedures whether VEGF in the eye is a biomarker of response to drug therapy. Using published papers, registered clinical trials, and proteomic databases we assessed the earlier evidence for VEGF as an exploratory biomarker of proliferative and vasculopathic disease of the retina and asked whether the molecule has been rigorously validated in clinical trials. The emerging use of aqueous humor sampling has made it possible to explore biomarkers in oculo, and determine whether they are predictive of drug efficacy. We present data supporting the use of aqueous humor to validate drug-signaling pathways and biomarkers in the eye. In addition, we recommend convening a collaborative congress to help standardize the identification, validation, and use of biomarkers in retinal disease.     

Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action

Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.     

Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release

Tumor specific drug delivery has become increasingly interesting in cancer therapy, as the use of chemotherapeutics is often limited due to severe side effects. Conventional drug delivery systems have shown low efficiency and a continuous search for more advanced drug delivery principles is therefore of great importance. In the first part of this review, we present current strategies in the drug delivery field, focusing on site-specific triggered drug release from liposomes in cancerous tissue. Currently marketed drug delivery systems lack the ability to actively release the carried drug and rely on passive diffusion or slow non-specific degradation of the liposomal carrier. To obtain elevated tumor-to-normal tissue drug ratios, it is important to develop drug delivery strategies where the liposomal carriers are actively degraded specifically in the tumor tissue. Many promising strategies have emerged ranging from externally triggered light- and thermosensitive liposomes to receptor targeted, pH- and enzymatically triggered liposomes relying on an endogenous trigger mechanism in the cancerous tissue. However, even though several of these strategies were introduced three decades ago, none of them have yet led to marketed drugs and are still far from achieving this goal. The most advanced and prospective technologies are probably the prodrug strategies where non-toxic drugs are carried and activated specifically in the malignant tissue by overexpressed enzymes. In the second part of this paper, we review our own work, exploiting secretory phospholipase A2 as a site-specific trigger and prodrug activator in cancer therapy. We present novel prodrug lipids together with biophysical investigations of liposome systems, constituted by these new lipids and demonstrate their degradability by secretory phospholipase A2. We furthermore give examples of the biological performance of the enzymatically degradable liposomes as advanced drug delivery systems.     

Measuring drug-related receptor occupancy with positron emission tomography

Several techniques can be used to measure indirectly the effect of drugs (e.g., EEG, fMRI) in healthy volunteers and in patients. Although each technique has its merits, a direct link between drug efficacy and site of action in vivo usually cannot be established. In addition, when the specific mode of action of a drug has been determined from preclinical studies, it is often not known whether the administered dose is optimal for humans. Both industry and academia are becoming more and more interested in determining the dose-related occupancy of specific targets caused by administration of drugs under test. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available. Although SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited. This review focuses on PET methodology for conducting drug occupancy studies in humans.     

Multicomponent phytotherapeutic approach gaining momentum: Is the “one drug to fit all” model breaking down?

Natural product based drugs constitute a substantial proportion of the pharmaceutical market particularly in the therapeutic areas of infectious diseases and oncology. The primary focus of any drug development program so far has been to design selective ligands (drugs) that act on single selective disease targets to obtain highly efficacious and safe drugs with minimal side effects. Although this approach has been successful for many diseases, yet there is a significant decline in the number of new drug candidates being introduced into clinical practice over the past few decades. This serious innovation deficit that the pharmaceutical industries are facing is due primarily to the post-marketing failures of blockbuster drugs. Many analysts believe that the current capital-intensive model-“the one drug to fit all” approach will be unsustainable in future and that a new “less investment, more drugs” model is necessary for further scientific growth. It is now well established that many diseases are multi-factorial in nature and that cellular pathways operate more like webs than highways. There are often multiple ways or alternate routes that may be switched on in response to the inhibition of a specific target. This gives rise to the resistant cells or resistant organisms under the specific pressure of a targeted agent, resulting in drug resistance and clinical failure of the drug. Drugs designed to act against individual molecular targets cannot usually combat multifactorial diseases like cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory diseases. Combination drugs that affect multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance. This multicomponent therapy forms the basis of phytotherapy or phytomedicine where the holistic therapeutic effect arises as a result of complex positive (synergistic) or negative (antagonistic) interactions between different components of a cocktail. In this approach, multicomponent therapy is considered to be advantageous for multifactorial diseases, instead of a “magic bullet” the metaphor of a “herbal shotgun” might better explain the state of affairs. The different interactions between various components might involve the protection of an active substance from decomposition by enzymes, modification of transport across membranes of cells or organelles, evasion of multidrug resistance mechanisms among others.     

Computational methods and applications for quantitative systems pharmacology

Background: Quantitative systems pharmacology (QSP) is an emerging discipline that integrates diverse data to quantitatively explore the interactions between drugs and multi-scale systems including small compounds, nucleic acids, proteins, pathways, cells, organs and disease processes. Results: Various computational methods such as ADME/T evaluation, molecular modeling, logical modeling, network modeling, pathway analysis, multi-scale systems pharmacology platforms and virtual patient for QSP have been developed. We reviewed the major progresses and broad applications in medical guidance, drug discovery and exploration of pharmacodynamic material basis and mechanism of traditional Chinese medicine. Conclusion: QSP has significant achievements in recent years and is a promising approach for quantitative evaluation of drug efficacy and systematic exploration of mechanisms of action of drugs.     

Transport proteins of the ABC systems superfamily and their role in drug action and resistance in nematodes

The completion of a number of nematode genomes has provided significant information on ABC systems in these organisms. Nematodes have more ABC systems genes and greater diversity than do mammalian species. Class 1 and class 2 ABC systems, more commonly known as ABC transporters, are present. As in other organisms, nematode ABC systems are characterized by a highly conserved ATP-binding domain (ABC_2) and a less conserved transmembrane domain (ABC_TM1/TM1F). Studies of drug resistance in nematodes have suggested that ABC transporters are part of the resistance mechanism. Evidence in support of this has been obtained from genetic studies where an association between anthelmintic selection and ABC transporters was shown by comparisons between unselected and drug selected, or resistant, populations of parasitic nematodes. In drug resistant populations, genetic polymorphism and diversity, genotype patterns, and linkage disequilibrium were disrupted. Multidrug resistance (MDR) reversing agents that inhibit ABC function improve efficacy in sensitive nematode populations and restore sensitivity in resistant populations. Similar to the situation in clinical oncology, overexpression of ABC systems occurs in drug resistant and sensitive populations following drug exposure, particularly those in the P-glycoprotein (PGP) subfamily. Deletion or disruption of ABC genes, particularly PGP and the multidrug resistance associated protein (MRP), increases sensitivity to some drugs, particularly ivermectin. These studies provide evidence that ABC transporters play a role in drug action and resistance in nematodes.