Diverse Class Of Drugs Research Articles

TRLS-04. EARLY INSIGHTS FROM PNOC027: PERSONALIZED TREATMENT APPROACHES BASED ON REAL-TIME DRUG SCREENING AND GENOMIC TESTING IN PEDIATRIC AND ADOLESCENT PATIENTS WITH RECURRENT MEDULLOBLASTOMA

Abstract BACKGROUND PNOC027, a clinical trial conducted by the Pediatric Neuro-Oncology Consortium (PNOC), explores a precision medicine strategy with up to four FDA-approved agents integrating real-time drug screening with whole exome DNA and RNA sequencing to guide personalized treatment approaches for children and young adults with relapsed medulloblastoma. METHODS Freshly isolated tumor cells from patients undergo high-throughput drug screening, evaluating responses to 232 clinically available compounds over 72 hours. In vitro drug responses are integrated with tumor genomic and transcriptomic data to predict drug combinations for each patient. Drugs are prioritized based on blood-brain barrier permeability, patient age, prior treatments, and other co-morbidities. Correlative studies include the collection of blood to assess circulating tumor DNA (ctDNA) before surgery and during treatment. Health-related quality of life (HRQOL) assessments will also be collected during therapy. RESULTS To date, nine patients have been enrolled. Eight of these have successfully completed real time drug screening with a median turnaround of 7 days from sample receipt. One patient was excluded due to ineligible (non-medulloblastoma) pathology after enrollment. Seven of these had whole exome sequencing, and six had RNA sequencing. Tumor board recommendations were rendered within 21 business days from the date of surgery. Among the diverse drug classes evaluated, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anthracyclines, DNA crosslinkers, and kinase inhibitors showed the most robust in vitro responses. Six patients received the recommended regimens, experiencing tolerable (grade 1/2) toxicities. Two patients succumbed to disease prior to therapy initiation, three exhibited disease progression while on therapy, and three remain on therapy. CONCLUSION PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection in clinically relevant timeframes and with potential for disease response.

Herbs as Skeletal Muscle Relaxant: An Updated Review

When compared to modern drugs, herbal medicines are usually accepted by doctors and patients for having greater therapeutic efficacy and fewer adverse effects.A diverse class of drugs known as skeletal muscle relaxants is frequently used to treat two distinct underlying disorders: spasticity resulting from upper motor neuron syndromes and muscular pain or spasms resulting from peripheral musculoskeletal problems. Skeletal muscle (SM) controls insulin sensitivity, glucose uptake, and blood glucose homeostasis, all of which are essential for energy and glucose metabolism. A progressive and widespread loss of skeletal muscle mass and strength that results in physical handicap, a low quality of life, and perhaps death is known as sarcopenia. Herbs are a valuable tool for illness prevention. These all have dysregulated skeletal muscle and sarcopenia. These medicinal herbs are being used over recent years. In this Review article we will keep an eye on an updated review on herbs as skeletal muscle relaxant. We will discuss about musculoskeletal disorders, phytochemicals role in disorders. Herbs like aloe barbedensis, curcuma longa, zingiber officinale,citrus aurantium,chamaemelum nobile,hibiscus rosa sinensis etc. will be studied for their role in skeletal muscle relaxation. Keywords: Skeletal muscle relaxant, sarcopenia, herbal medicines, herbs, skeletal muscles, myopathy

Tegoprazan as a New Remedy for Gastrointestinal Diseases in Comparison with its Therapeutic Predecessors: A Mini-Review.

Potassium-competitive acid blockers (P-CABs), such as tegoprazan, are a new and diverse class of drugs that can completely block the potassium-binding site of gastric H+/K+ ATPase, potentially overcoming the limitations of proton-pump inhibitors (PPIs). A number of studies have compared the effectiveness as well as the safety profile of tegoprazan to PPIs and other P-CABs for the treatment of gastrointestinal diseases. The current review study evaluates the published works of literature related to clinical pharmacology and clinical trials of tegoprazan for the treatment of diseases related to the gastrointestinal tract. The findings of this study revealed that tegoprazan is safe and well-tolerated and can be used to treat a group of gastrointestinal diseases, including gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), and H. pylori infection.

Recent Developments and Applications of Biocatalytic and Chemoenzymatic Synthesis for the Generation of Diverse Classes of Drugs.

Biocatalytic and chemoenzymatic biosynthesis are powerful methods of organic chemistry that use enzymes to execute selective reactions and allow the efficient production of organic compounds. The advantages of these approaches include high selectivity, mild reaction conditions, and the ability to work with complex substrates. The utilization of chemoenzymatic techniques for the synthesis of complicated compounds has lately increased dramatically in the area of organic chemistry. Biocatalytic technologies and modern synthetic methods are utilized synergistically in a multi-step approach to a target molecule under this paradigm. Chemoenzymatic techniques are promising for simplifying access to essential bioactive compounds because of the remarkable regio- and stereoselectivity of enzymatic transformations and the reaction diversity of modern organic chemistry. Enzyme kits may include ready-to-use, reproducible biocatalysts. Its use opens up new avenues for the synthesis of active therapeutic compounds and aids in drug development by synthesizing active components to construct scaffolds in a targeted and preparative manner. This study summarizes current breakthroughs as well as notable instances of biocatalytic and chemoenzymatic synthesis. To assist organic chemists in the use of enzymes for synthetic applications, it also provides some basic guidelines for selecting the most appropriate enzyme for a targeted reaction while keeping aspects like cofactor requirement, solvent tolerance, use of whole cell or isolated enzymes, and commercial availability in mind.

On the Application of Microfluidic-Based Technologies in Forensics: A Review.

Microfluidic technology is a powerful tool to enable the rapid, accurate, and on-site analysis of forensically relevant evidence on a crime scene. This review paper provides a summary on the application of this technology in various forensic investigation fields spanning from forensic serology and human identification to discriminating and analyzing diverse classes of drugs and explosives. Each aspect is further explained by providing a short summary on general forensic workflow and investigations for body fluid identification as well as through the analysis of drugs and explosives. Microfluidic technology, including fabrication methodologies, materials, and working modules, are touched upon. Finally, the current shortcomings on the implementation of the microfluidic technology in the forensic field are discussed along with the future perspectives.

Diverse Drug Classes Partition into Human Sweat: Implications for Both Sweat Fundamentals and for Therapeutic Drug Monitoring.

Therapeutic drug monitoring to optimize drug therapy typically relies on the inconvenience of repeated plasma sampling. Sweat is a potential alternative biofluid convenient for sampling. However, limited information exists regarding the range of drugs excreted in sweat and their correlation with plasma concentrations. This study evaluated drugs in sweat and plasma of an ambulatory clinical cohort. Pilocarpine-induced sweat was collected from ambulatory participants at a single instance using an absorbent nylon mesh, followed by concurrent blood sampling for ratio and correlation analyses. In a model drug study, the pharmacokinetics of acetaminophen in sweat and plasma were compared. Of the 14 drugs and 2 metabolites monitored in the clinical study, all compounds were present in sweat and plasma; however, the sweat-to-plasma ratio varied substantially across the drugs. Opioids and methocarbamol demonstrated the highest concentrations in sweat, sometimes exceeding plasma concentrations. Selected antidepressants and muscle relaxants were also detected in sweat at a 2-10-fold dilution to the plasma. Others, such as gabapentin and pregabalin, were highly diluted (>30-fold) in sweat compared with plasma. Together, these data suggest that molecular attributes, specifically hydrophobicity (logP) and charge state at physiologic pH (7.4), enable reasonable prediction of sweat-to-plasma drug correlation. These findings demonstrated that sweat could be used as an alternative biofluid for therapeutic drug monitoring. The findings also suggest that although it has been broadly accepted that small hydrophobic molecules most likely have a strong plasma correlation, there is a small window of hydrophobicity and charge state that permits sweat partitioning.

A Review of Deep Learning-Based Approaches for Detection and Diagnosis of Diverse Classes of Drugs

A Review of Deep Learning-Based Approaches for Detection and Diagnosis of Diverse Classes of Drugs

Abstract 2275: Preclinical testing of therapeutic biologics using patient-derived 3D spheroids

Abstract Biological therapies for the treatment of cancer are utilized for the same ultimate purpose as chemically derived cancer drugs, to induce tumor cell death. However, the differing mechanisms of action often make the evaluation of biologic drug efficacy more complex, requiring the support and/or recapitulation of functional immune components. Biologics also have different limitations that can govern their efficacy such as their large size potentially impeding sufficient penetration to target sites and in the case of live biotherapeutic products, the need to maintain sustained function, or persistence, by resisting immunosuppression by the tumor microenvironment. Preclinical testing of biologics is often confined to cell lines which lack an immune system and mouse models which are expensive, time consuming, and poor proxies for the human immune system. To address these issues, we have developed ex vivo 3D spheroid platforms to measure the efficacy of three types of biologics: antibody-drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cells. Primary cells from cancer patients or from patient-derived xenografts were evaluated for the expression of the biologic target molecule then cultured to form 3D spheroids. Spheroid models were validated for the evaluation of antibody-based therapies by determining sufficient diffusion of antibodies to target sites. For ADC testing, cell death was measured in a plate-based read-out following treatment with the ADC trastuzumab deruxtecan, and the cytotoxic efficacy of the ADC was compared to trastuzumab alone or free exatecan. Differences in killing kinetics and the maximum efficacy of the ADC were determined compared to the other tested agents. HER2 inhibition was evaluated through changes in constitutive downstream signaling. Two biologics with the same molecular target, a bispecific antibody targeting carcinoembryonic antigen (CEA) on tumor cells and CD3 on T-cells, as well as a CAR T-cell product targeting CEA were also evaluated. Following treatment with the bispecific, tumor cell viability was detected using flow cytometry and changes in T-cell activation were measured via cytokine secretion using primary colorectal cancer models. Importantly, bispecific antibody efficacy was dependent upon the presence of T-cells. Finally, CAR T-cell mediated tumor cell killing was detected using a fluorescent image-based approach. Collectively, this work establishes a model for testing multiple classes of drugs in a 3D ex vivo model that can be used to advance preclinical drug development and evaluate mechanisms of action of diverse drug classes in a physiologically relevant model. Citation Format: Katy A. Lassahn, Ashley K. Elrod, Aaron L. Carlson, Natalie A. Dance, Melissa Millard, Michael J. Wick, Teresa M. DesRochers, Kathryn M. Appleton. Preclinical testing of therapeutic biologics using patient-derived 3D spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2275.

Insights on prospective role of Gallic acid as a Bioavailability Enhancer

The poor bioavailability of various drugs is the utmost obstacle in oral drug delivery. The use of natural bioenhancer as supplements with the primary therapeutic agent has gained wider acceptance and has been emerged as a potential method to increase the bioavailability of various drugs. Gallic acid is one of the chief phenolic natural compounds extensively distributed in plants and fruit. Despite its broad spectrum pharmacological effects, gallic acid significantly augments the bioavailability of diverse classes of drugs at low doses by impeding liver metabolism and altering gastrointestinal permeability. In this context, this review aims to summarise the promising bioavailability enhancing activity of gallic acid on different therapeutic agents. Furthermore, current evidence confirms that the intervention with gallic acid leads to enhance the bioavailability of various drugs; however, extensive research is need of the hour so that it could be utilized in drug formulations in the future for clinical use.

Phenothiazines and their Evolving Roles in Clinical Practice: A Narrative Review.

Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice.

Histone deacetylase inhibitor use as a radiosensitizer in solid organ malignancies: a systematic review protocol.

The objective of this review is to evaluate the efficacy and adverse effects of histone deacetylase inhibitors (HDACi) in combination with radiotherapy for the treatment of solid organ malignancies. Histone deacetylase inhibitors are a diverse class of drugs that have shown promise as novel anti-cancer therapeutics via epigenetic modification and radiosensitization of neoplastic cells. The aim of HDACi in combination with radiotherapy is to reduce radiation dosage requirements, improve radiotherapy efficacy, and reduce treatment side effects. This review will consider studies utilizing HDACi in conjunction with radiotherapy in adult patients with solid organ malignancy. Sources to be included in this review include experimental and quasi-experimental study designs, analytical studies, and descriptive observational studies. A systematic review of effectiveness will be conducted in accordance with JBI methodology. A detailed search will be conducted via MEDLINE (Ovid), Embase (Ovid), and Scopus. A search of the Cochrane Central Register of Controlled Trials, the International Clinical Trials Registry Platform, and ClinicalTrials.gov will also be performed for relevant trials. Inclusion and exclusion criteria will be utilized to select studies, and papers selected for retrieval will be assessed for methodological validity using the JBI critical appraisal instruments. Evidence will be extracted from eligible studies and summarized using quantitative methods, where possible, including meta-analysis and assessment of heterogeneity. Where statistical pooling is not possible, the findings will be presented in diagrammatic or tabular form accompanied by a narrative summary. PROSPERO CRD42021293005.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Abstract SP116: B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas

Abstract Triple Negative Breast Cancer (TNBC) makes up 10-15% of breast cancers, disproportionally affects African Americans, and if considered its own disease type, would rank as the #5 cause of cancer deaths in women in the USA each year. Among the most promising new therapeutic approaches for TNBC is immunotherapy using Immune Checkpoint Inhibitors (ICI). Many ICI trials for TNBC patients are underway with early results showing response rates to single agent ICI in the range of 10-20% in the metastatic setting. Thus, there is a good sign of efficacy, but the majority of TNBC patients still fail to respond, even despite the recent improvements made by combination regimens of ICI and chemotherapy. These findings illustrate a clear need for 1) improved biomarker(s) to identify the subset TNBC patients who will respond to current ICI-based regimens, and 2) improvements in ICI regimens that may include additional immune modulating therapeutics, and/or combinations with specific mechanistically chosen chemotherapeutics. Improving response rates of breast cancer patients to immune checkpoint inhibitors requires an understanding of mechanism of action of ICI, and robust in vivo models to further evaluate mechanisms and to empirically test new regimens in the preclinical setting first. In our prior work, we identified and credentialed mouse models with genomic and transcriptomic similarities to human TNBC, and in a subtype aware manner. In completing these studies, we found that the majority of TNBC mouse models reflect those human tumors with low tumor mutation burden (TMB), and these models had low immune infiltrates. In our efforts to model human TNBCs with elevated tumor mutation burdens we “mutagenized” our low TMB models into the range of high TMB human TNBC. We found that these mouse models with high tumor mutation burden had increased tumor infiltrating lymphocytes and were now responsive to anti-PD1 and anti-CTLA4 immune checkpoint inhibitors. Specifically, we discovered that in ICI sensitive mouse models, CD4+ T follicular helper cells and B cells coactivate one another and both are necessary for the full effects of the anti-tumor response to immune checkpoint therapy. We further used additional genetically engineered mouse models to discover a requirement for active antibody production as being needed for an effective anti-tumor response to immune checkpoint therapy. The direct and active involvement of B cells in response to ICI has recently been shown to also occur in melanoma patients. This suggests a broader role for B cells as being a key component of a coordinated anti-tumor immune response. In addition, we captured these mechanistic features within a small gene expression signature that we further demonstrated predicted response to ICI treatment in melanoma patients, to trastuzumab in HER2+ breast cancer patients, and to neoadjuvant chemotherapy in TNBC patients. To translate this knowledge to therapeutic advances, we are now using our mouse models to test if immunomodulators of B cells can improve T cell focused immunotherapies, some of which are showing promising results. In summary, the adaptive immune system is a critical component of response to multiple and diverse classes of drugs in breast cancer, including chemotherapy, HER2 targeting therapy, and ICI. Further studies aimed at boosting these responses could have a significant impact for many TNBC patients, and non-TNBC patients, as well. Citation Format: C Perou. B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP116.

The Role of Non-Coding RNAs as Prognostic Factor, Predictor of Drug Response or Resistance and Pharmacological Targets, in the Cutaneous Squamous Cell Carcinoma.

Simple SummaryCutaneous Squamous Cell Carcinoma is poorly understood at a molecular level, however emerging evidence have highlighted that non-coding RNAs play a key role in the oncogenesis and tumor progression. Herein we focused on the translational potential of non-coding RNAs, such as miRNAs, circular RNAs and lncRNAs, by reporting cutting edge findings showing that they can be considered as potential predictors of response to diverse class of drugs, including chemotherapeutics and immune checkpoints inhibitors and as reliable prognosticators. Additionally, by reporting the molecular mechanisms of drug sensitivity and resistance in which non-coding RNAs are involved, we highlighted their potential role as druggable targets and suggested new therapeutic options for CSCC patients.Cutaneous squamous cell carcinoma (CSCC) is the most common keratinocyte-derived skin cancer in the Caucasian population. Exposure to UV radiations (UVRs) represents the main risk carcinogenesis, causing a considerable accumulation of DNA damage in epidermal keratinocytes with an uncontrolled hyperproliferation and tumor development. The limited and rarely durable response of CSCC to the current therapeutic options has led researchers to look for new therapeutic strategies. Recently, the multi-omics approaches have contributed to the identification and prediction of the key role of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), circularRNAs (circRNAs) and long non-coding RNAs (lncRNAs) in the regulation of several cellular processes in different tumor types, including CSCC. ncRNAs can modulate transcriptional and post-transcriptional events by interacting either with each other or with DNA and proteins, such as transcription factors and RNA-binding proteins. In this review, the implication of ncRNAs in tumorigenesis and their potential role as diagnostic biomarkers and therapeutic targets in human CSCC are reported.

High-throughput screening of clinically approved drugs that prime nonviral gene delivery to human Mesenchymal stem cells

BackgroundHuman mesenchymal stem cells (hMSCs) are intensely researched for applications in cell therapeutics due to their unique properties, however, intrinsic therapeutic properties of hMSCs could be enhanced by genetic modification. Viral transduction is efficient, but suffers from safety issues. Conversely, nonviral gene delivery, while safer compared to viral, suffers from inefficiency and cytotoxicity, especially in hMSCs. To address the shortcomings of nonviral gene delivery to hMSCs, our lab has previously demonstrated that pharmacological ‘priming’ of hMSCs with the glucocorticoid dexamethasone can significantly increase transfection in hMSCs by modulating transfection-induced cytotoxicity. This work seeks to establish a library of transfection priming compounds for hMSCs by screening 707 FDA-approved drugs, belonging to diverse drug classes, from the NIH Clinical Collection at four concentrations for their ability to modulate nonviral gene delivery to adipose-derived hMSCs from two human donors.ResultsMicroscope images of cells transfected with a fluorescent transgene were analyzed in order to identify compounds that significantly affected hMSC transfection without significant toxicity. Compound classes that increased transfection across both donors included glucocorticoids, antibiotics, and antihypertensives. Notably, clobetasol propionate, a glucocorticoid, increased transgene production 18-fold over unprimed transfection. Furthermore, compound classes that decreased transfection across both donors included flavonoids, antibiotics, and antihypertensives, with the flavonoid epigallocatechin gallate decreasing transgene production − 41-fold compared to unprimed transfection.ConclusionsOur screen of the NCC is the first high-throughput and drug-repurposing approach to identify nonviral gene delivery priming compounds in two donors of hMSCs. Priming compounds and classes identified in this screen suggest that modulation of proliferation, mitochondrial function, and apoptosis is vital for enhancing nonviral gene delivery to hMSCs.

Solvent Effect at Ibuprofen Adsorption Using Zinc Oxide Plate Rod-Like from Gelatine

The ubiquitous occurrence of several pharmaceuticals in sewage effluents has led to the considerable deterioration of some life forms and the quality of the receiving water bodies. Ibuprofen is a nonsteroid anti-inflammatory drug, represents a diverse class of drugs andthe most commonly used analgesics for the management of pain and/or inflammation associated with rheumatoid arthritis and osteoarthritis, muscle stiffness and pain, dental pain, migraine, and headache. The present work investigated the effect of different solvents on ibuprofen dissolution during the adsorption of Ibuprofen on to zinc oxide plate rod-like from its hexane, methanol, ethanol solutions, and water as co-solvents. The zinc oxide plate rod-like was synthesized using block copolymer and gelatine as a template and zinc sulphate as zinc precursor was then characterized by X-ray diffraction, scanning electron microscopy, and FTIR to analyse the structure and morphology. The impact of various solvents on the percentage removal (%) of Ibuprofen was determined by batch adsorption experiments. The data obtained were subjected to isotherm and kinetic analysis to describe the distribution of ibuprofen between the liquid and solid phases in the batch studies. The results obtained best fitted the Langmuir isotherm model with an adsorption capacity close to 110mg/g at room temperature with an initial concentration of 100 ppm. To sum up, for large-scale removal, ibuprofen treatment for aquatic, zinc oxide plate rod-like maybe an adsorbent in future.

Audit of drug–drug interactions and adverse drug reactions due to polypharmacy in older cancer patients: First report from India

In elderly people, the body's metabolic processes are not optimal and pharmacokinetics and pharmacodynamic profile of drugs are compromised or reduced. Under these conditions, the concomitant use of diverse classes of drugs can potentially increase the risk of adverse reactions and drug interactions. This will consequentially affect the already debilitated organ system. As far as the authors are aware, there are no studies addressing the drug-drug interactions and adverse drug reactions due to polypharmacy in older patients with cancer and therefore, we conducted this study. This was an observational chart-based study and was carried out in a tertiary care cancer hospital. The data concerning prescription of all prescribed medications were noted down from the medication chart of the patient in the wards. The most common drug-to-drug interaction that could have happened was due to the combination of theophylline with budesonide (26.10%). Adverse drug reactions were noted during the course of time, the most common being nausea and vomiting (71.9%). As the geriatric population is increasing, the need to address medical problems among aged patients with cancer is the need of the hour. The adverse drug reactions and drug interactions that have occurred were lesser when compared to published observations.

Screening of over 100 drugs in horse urine using automated on-line solid-phase extraction coupled to liquid chromatography-high resolution mass spectrometry for doping control

A fast method for the direct analysis of enzyme-hydrolysed horse urine using an automated on-line solid-phase extraction (SPE) coupled to a liquid-chromatography/high resolution mass spectrometer was developed. Over 100 drugs of diverse drug classes could be simultaneously detected in horse urine at sub to low parts per billion levels. Urine sample was first hydrolysed by β-glucuronidase to release conjugated drugs, followed by centrifugal filtration. The filtrate (1mL) was directly injected into an on-line SPE system consisting of a pre-column filter and a SPE cartridge column for the separation of analytes from matrix components. Through valves-switching, the interfering matrix components were flushed to waste, and the analytes were eluted to a C18 analytical column for refocusing and chromatographic separation. Detections were achieved by full-scan HRMS in alternating positive and negative electrospray ionisation modes within a turn-around time of 16min, inclusive of on-line sample clean-up and post-run mobile phase equilibration. No significant matrix interference was observed at the expected retention times of the targeted masses. Over 90% of the drugs studied gave estimated limits of detection (LoDs) at or below 5ng/mL, with some LoDs reaching down to 0.05ng/mL. Data-dependent acquisition (DDA) was included to provide additional product-ion scan data to substantiate the presence of detected analytes. The resulting product-ion spectra can be searched against an in-house MS/MS library for identity verification. The applicability of the method has been demonstrated by the detection of drugs in doping control samples.

Computational Analysis of Physicochemical Factors Driving CYP2D6 Ligand Interaction.

The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic outcomes for many drug molecules while others are either only slightly affected or not affected altogether. This study seeks to understand, atomistic resolution, the structural and physicochemical factors influencing CYP2D6 metabolic discrimination. Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the conformational dynamics of CYP2D6 following which the most populated structures were employed for ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates. Using atomistic treatment at the molecular mechanics level and multiple CYP2D6 conformations for docking, two primary ligand binding subsites (subsites A and B) were identified within an otherwise extensive ligand recognition site. The studied drug molecules were found to display distinct preference for either of the two subsites. Correlation and center-of-mass distribution analysis showed subsite binding preference to depend significantly on CYP2D6 conformation, as well as molecular properties such as molecular size and number of hydrogen bond donor present in the drug molecule. CYP2D6 binding subsite A was found to be relatively selective for small molecular weight with higher polarity compared with subsite B which tends to favor larger molecular weight and relatively hydrophobic molecules such as tamoxifen and imipramine. Our simulations further suggest that the ability of the CYP2D6 binding site residues to sample different conformations may partly account for its ability to metabolize diverse drug classes.

Cyclooxygenase in Cancer Prevention and Treatments for Actinic Keratosis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a chemically diverse class of drugs that target the cyclooxygenase (COX) pathway and have anti-inflammatory, analgesic, and antipyretic properties. Elevated expression of COX-2 has been associated with tumor progression in skin cancer through multiple mechanisms. We present evidence for a chemoprotective effect of NSAIDs and discuss potential mechanisms of action of COX-2 in cancer. We also discuss the challenges associated with the treatment of actinic keratosis and the factors that should be taken into consideration when selecting a treatment regimen. A range of treatments are reviewed, with an emphasis on combination therapies.