Action Of Drugs Research Articles

A review on current scenarios of pharmaceutical and herbal medicine and future prospects

Plants are intentionally or unwittingly making a difference the living creatures since the starting of civilization. In spite of the fact that unused and modern maladies are getting found day by day, creator had given us with most of the remedy in the frame of restorative plants. Herbal medicate Industry is experiencing a major alter with regard to household and global necessities. Nutraceuticals is the quickest developing home-grown components due to increment in day to day way of life concern among worldwide populace. A number of logical examinations have highlighted the significance and the commitment of numerous plant families i.e. Asteraceae, Liliaceae, Apocynaceae, Solanaceae, Caesalpinaceae, Rutaceae, Piperaceae, Sapotaceae used as therapeutic plants. Therapeutic plants play a crucial part for the advancement of unused drugs. The bioactive extract ought to be standardized on the premise of dynamic compound. The bioactive extricate ought to undergo safety considers. Nearly, 70% advanced solutions in India are determined from characteristic items. Medicinal plants play a central part not as it were as conventional medications but too as exchange commodities, assembly the demand of far-off markets. India has a exceptionally little share (1.6%) of this evergrowing worldwide advertise. To compete with the developing advertise, there is direness to quickly utilize and deductively approve more medicinally valuable plantsIn 1991 WHO created rules for the appraisal of herbal pharmaceutical. Recommendations for home grown pharmaceutical standardization are out lined. The situation and recognition of home-grown medication are examined. The publicís conviction that home grown and normal items are more secure than manufactured solutions can as it were be discovered by forcing administrative benchmarks on these items that ought to be made utilizing these Great Hones. Home grown drugs are fundamental components of conventional pharmaceutical in several nations counting China and India. India has a well-established system of medication known as Ayurveda. Need of the Department of Biotechnology, Government of India and the Indian Chamber of Agricultural Inquire about, request that the beat 20 restorative plants in India be imported and traded from India vis-à-vis world request. Logical approval of phar- macological action of age-old drugs utilized in Ayurveda strengthens confidence in the traditional framework, in which plants are chosen as it were on the premise of encounter. Need of the Department of Biotechnology, Government of India and the Indian Board of Agricultural Inquire about, request that the beat 20 restorative plants in India be imported and traded from India vis-à-vis world request. Logical approval of pharmacological action of age-old drugs utilized in Ayurveda fortifies confidence in the traditional framework, in which plants are chosen as it were on the premise of encounter.

Investigating the molecular mechanism of Mori Cortex against osteosarcoma by bioinformatics analysis and in vitro experimental.

To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation. Gene expression data from normal and OS tissues were obtained from the GEO database and underwent differential analysis. Active Mori Cortex components and target genes were extracted from the Traditional Chinese Medicine System Pharmacology database. By intersecting these targets with differentially expressed genes in OS, we identified potential drug action targets. Using the STRING database, a protein-protein interaction network was constructed. Subsequent analyses of these intersected genes, including Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were performed using R software to elucidate biological processes, molecular functions, and cellular components, resulting in the simulation of signaling pathways. Molecular docking assessed the binding capacity of small molecules to signaling pathway targets. In vitro validations were conducted on U-2 OS cells. The CCK8 assay was used to determine drug-induced cytotoxicity in OS cells, and Western Blotting was employed to validate the expression of AKT, extracellular signal-regulated kinases (ERK), Survivin, and Cyclin D1 proteins. Through differential gene expression analysis between normal and OS tissues, we identified 12,364 differentially expressed genes. From the TCSMP database, 39 active components and 185 therapeutic targets related to OS were derived. The protein-protein interaction network indicated that AKT1, IL-6, JUN, VEGFA, and CASP3 might be central targets of Mori Cortex for OS. Molecular docking revealed that the active compound Morusin in Mori Cortex exhibits strong binding affinity to AKT and ERK. The CCK8 assay showed that Morusin significantly inhibits the viability of U-2 OS cells. Western Blot demonstrated a reduction in the p-AKT/AKT ratio, the p-ERK/ERK ratio, Survivin, and Cyclin D1. Mori Cortex may exert its therapeutic effects on OS through multiple cellular signaling pathways. Morusin, the active component of Mori Cortex, can inhibit cell cycle regulation and promote cell death in OS cells by targeting AKT/ERK pathway.

Cannabinoid Modulation of Monoamine Levels in Mouse Brain: Unveiling Neurochemical Dynamics through an Innovative High-performance Liquid Chromatography-Fluorescence Detection Bioanalysis

AbstractHomeostasis of monoaminergic pathways is compromised in aging and neurodegenerative/neurological diseases such as Alzheimer’s disease and depression. On the other hand, their modulation has also been linked to the mechanism of action of several drugs. Therefore, monitoring the levels of noradrenaline (NA), adrenaline (AD), dopamine (DA), and serotonin (5-HT), as well as those of tryptophan (TRYP), the precursor of 5-HT, and DA metabolites, namely 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), is fundamental for assessing disease severity and progression. This work aimed to develop and validate the first High-Performance Liquid Chromatography (HPLC) coupled with fluorescence detector (FLD) method that simultaneously and accurately quantifies NA, AD, DA, DOPAC, HVA, 5-HT and TRYP in mouse brain and prefrontal cortex (PFC) matrices. Previous sample preparation by protein precipitation was required to extract the compounds. Calibration curves were plotted using the background subtraction approach to reduce the interference of the endogenous analytes. Intra and inter-day accuracy and precision were within the ranges defined by ICH (The International Council for Harmonisation) guideline for bioanalytical method validation. Following validation, the impact of cannabidiol (CBD), cannabigerol (CBG), and cannabidivarin (CBDV) was explored in mice brains post-administration, revealing significant alterations in specific neurotransmitter levels upon cannabinoid exposure and shedding light on the complex modulation of neurochemical dynamics by cannabinoids. This research highlights the fit-for-purpose of the HPLC-FLD method and provides insights into potential mechanisms underlying phytocannabinoid actions in the central nervous system (CNS).

Kinetically Inert Platinum (II) Complexes for Improving Anticancer Therapy: Recent Developments and Road Ahead.

The search for better chemotherapeutic drugs to alleviate the deficiencies of existing platinum (Pt) drugs has picked up the pace in the millennium. There has been a disparate effort to design better and safer Pt drugs to deal with the problems of deactivation, Pt resistance and toxic side effects of clinical Pt drugs. In this review, we have discussed the potential of kinetically inert Pt complexes as an emerging class of next-generation Pt drugs. The introduction gives an overview about the development, use, mechanism of action and side-effects of clinical Pt drugs as well as the various approaches to improve some of their pharmacological properties. We then describe the impact of kinetic lability on the pharmacology of functional Pt drugs including deactivation, antitumor efficacy, toxicity and resistance. Following a brief overview of numerous pharmacological advantages that a non-functional kinetically inert Pt complex can offer; we discussed structurally different classes of kinetically inert Pt (II) complexes highlighting their unique pharmacological features.

Model of Chronic Itch in Aged Mice: Beneficial Effects of Drugs Affecting Descending Modulatory Systems.

Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69-80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.

In Vivo Bioluminescence Imaging Reveals Differences in Leishmania infantum Parasite Killing Kinetics by Antileishmanial Reference Drugs.

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life (t1/2) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t1/2 of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t1/2 of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

Total-body imaging of mu-opioid receptors with [11C]carfentanil in non-human primates.

Mu-opioid receptors (MORs) are widely expressed in the central nervous system (CNS), peripheral organs, and immune system. This study measured the whole body distribution of MORs in rhesus macaques using the MOR selective radioligand [11C]carfentanil ([11C]CFN) on the PennPET Explorer. Both baseline and blocking studies were conducted using either naloxone or GSK1521498 to measure the effect of the antagonists on MOR binding in both CNS and peripheral organs. The PennPET Explorer was used for MOR total-body PET imaging in four rhesus macaques using [11C]CFN under baseline, naloxone pretreatment, and naloxone or GSK1521498 displacement conditions. Logan distribution volume ratio (DVR) was calculated by using a reference model to quantitate brain regions, and the standard uptake value ratios (SUVRs) were calculated for peripheral organs. The percent receptor occupancy (%RO) was calculated to establish the blocking effect of 0.14mg/kg naloxone or GSK1521498. The %RO in MOR-abundant brain regions was 75-90% for naloxone and 72-84% for GSK1521498 in blocking studies. A higher than 90% of %RO were observed in cervical spinal cord for both naloxone and GSK1521498. It took approximately 4-6min for naloxone or GSK1521498 to distribute to CNS and displace [11C]CFN from the MOR. A smaller effect was observed in heart wall in the naloxone and GSK1521498 blocking studies. [11C]CFN total-body PET scans could be a useful approach for studying mechanism of action of MOR drugs used in the treatment of acute and chronic opioid use disorder and their effect on the biodistribution of synthetic opioids such as CFN. GSK1521498 could be a potential naloxone alternative to reverse opioid overdose.

HANSynergy: Heterogeneous Graph Attention Network for Drug Synergy Prediction.

Drug synergy therapy is a promising strategy for cancer treatment. However, the extensive variety of available drugs and the time-intensive process of determining effective drug combinations through clinical trials pose significant challenges. It requires a reliable method for the rapid and precise selection of drug synergies. In response, various computational strategies have been developed for predicting drug synergies, yet the exploitation of heterogeneous biological network features remains underexplored. In this study, we construct a heterogeneous graph that encompasses diverse biological entities and interactions, utilizing rich data sets from sources, such as DrugCombDB, PubChem, UniProt, and cancer cell line encyclopedia (CCLE). We initialize node feature representations and introduce a novel virtual node to enhance drug representation. Our proposed method, the heterogeneous graph attention network for drug-drug synergy prediction (HANSynergy), has been experimentally validated to demonstrate that the heterogeneous graph attention network can extract key node features, efficiently harness the diversity of information, and further enhance network functionality through the incorporation of a multihead attention mechanism. In the comparative experiment, the highest accuracy (Acc) and area under the curve (AUC) are 0.877 and 0.947, respectively, in DrugCombDB_early data set, demonstrating the superiority of HANSynergy over the competing methods. Moreover, protein-protein interactions are important in understanding the mechanism of action of drugs. The heterogeneous attention mechanism facilitates protein-protein interaction analysis. By analyzing the changes of attention weight before and after heterogeneous network training, we investigated proteins that may be associated with drug combinations. Additionally, case studies align our findings with existing research, underscoring the potential of HANSynergy in drug synergy prediction. This advancement not only contributes to the burgeoning field of drug synergy prediction but also holds the potential to provide valuable insights and uncover new drug synergies for combating cancer.

Evaluation of indole-based organometallics as transfer hydrogenation catalysts with anticancer activity

Half-sandwich complexes containing transition metals offer a wide range of applications owing to their interactions with a variety of targets/molecules that are not accessible for some organic scaffolds. The use of such complexes is therefore a way to provide new mechanisms of drug action. Here, we report a series of neutral metal complexes of the type [(arene)M(O-cyclohexyl-1H-indole-2-carbothiolate)Cl] that have the ability to reduce the coenzyme NAD+ at physiological conditions in the presence of sodium formate as an hydride donor. The influence of the metal ion (Ru, Os, Rh, Ir) is studied to establish some structure-activity relationships. The [(η6-p-cym)Ru(O-cyclohexyl-1H-indole-2-carbothioate)Cl] is the most active catalyst of this family of complexes with a turnover frequency (TOF) of 14.79 h-1 for the transfer hydrogenation reaction of NAD+ to give 1,4-NADH in the presence of formate. Further in vitro studies were carried out to determine a relationship between catalytic activity and potency as an anticancer drug, with the rhodium complex promisingly showing 7x more selectivity towards cancer cells (A2780) than normal cells (PNT2). Preliminary in vivo studies demonstrated the importance of co-treatment with formate to enhance activity. This work gives insights into the mechanism of action of this family of indole-based organometallic complexes.

Enhanced efficacy of brucine dissolving-microneedles as a targeted delivery system in rheumatoid arthritis treatment: a comprehensive pharmacokinetic-pharmacodynamic analysis.

Our previous studies have shown the therapeutic efficacy of brucine dissolving-microneedles (Bru-DMNs) in treating rheumatoid arthritis (RA). Bru delivered via the DMNs can bypass some of the issues related to oral and systemic delivery, including extensive enzymatic activity, liver metabolism and in the case of systemic delivery via hypodermic needles, pain resulting from injections and needle stick injury. However, the underlying mechanism of Bru-DMNs against RA has not been investigated in depth at the pharmacokinetic-pharmacodynamic (PK-PD) level. In this study, a microdialysis-based method combined with ultra-performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous and continuous sampling and quantitative analysis of blood and joint cavities in fully awake RA rats. The acquired data were analyzed by the PK-PD analysis method. Bru delivered via microneedles showed enhanced distribution and prolonged retention in the joint cavity compared to its administration in blood. The correlation between the effect of Bru and its concentration at the action site was indirect. In this study, we explored the mechanism of Bru-DMNs against RA and established a visualization method to express the PK-PD relationship of Bru-DMNs against RA. This study provides insights into the mechanism of action of drugs with potential side effects administered transdermally for RA treatment.

Analysis of control impact on the HIV reproductive cycle in a cross infection epidemic model

AbstractDespite the great advances in HIV treatment, there are still several processes in the dynamics of the infection that are not yet fully understood. Some evidences show that when the therapy HAART is suspended, infection resumes, suggesting the existence of virus reservoirs; these have been identified in the lungs, brain and guts. In this paper, following the compartmental approach, a recently proposed model is addressed, considering in particular the brain as virus reservoir and distinguishing the cells depending on whether they are inside or outside the brain, both infected and non infected. Controls mimicking the drug action are introduced and the model is analysed in terms of equilibrium points and stability, also determining the reproduction number. Numerical results are used to put in evidence the main dynamics characteristics.

Efficacy and safety of levosalbutamol in patients with mild to moderate asthma compared with racemic salbutamol: results of a crossover placebo-controlled study

Aim. Effectiveness and safety of levosalbutamol metered dose inhaler (MDI) in comparison with placebo and salbutamol. Materials and methods. In this multicenter, randomized, placebo-controlled, 3-period crossover study, all asthma patients (n=91) received levosalbutamol (90 mcg), salbutamol (180 mcg), and placebo using standard MDI. Pulmonary function testing – forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) – was performed 45 and 15 minutes before and 5, 10, 15, 30, 60, 90, 120, 180, 240, 300 and 360 minutes after dosing. The primary efficacy endpoint was the baseline-corrected area under FEV1 curve from 0 to 6 hours (AUC(0–6h)). Secondary endpoints were the baseline adjusted FEV1 and FVC peak values, as well as the onset of drug action. Results. The FEV1 AUC0–6 hours analysis confirmed similar bronchodilatory levosalbutamol and salbutamol effect (p=0.595), significantly improved compared with placebo (p0.001). The peak values of FEV1 and FVC after levosalbutamol or salbutamol dosing were similar (p=0.643) and significantly higher compared with placebo group (p0.001). The active therapy effect was observed 5 minutes after dosing and throughout the entire observation period up to 6 hours, however, there was some tendency towards a longer duration of action of levosalbutamol compared to salbutamol. Levosalbutamol was well tolerated by patients; after levosalbutamol dosing twiсе fewer adverse reactions were observed compared to salbutamol. Conclusion. Levosalbutamol at a 90-mcg dose showed efficacy similar to that of salbutamol at a dose of 180 mcg, assosiated with a good safety profile.

Effects induced by η6-p-cymene ruthenium(II) complexes on Langmuir monolayers mimicking cancer and healthy cell membranes do not correlate with their toxicity

The mechanism of chemotherapeutic action of Ru-based drugs involves plasma membrane disruption and valuable insights into this process may be gained using cell membrane models. The interactions of a series of cytotoxic η6-p-cymene ruthenium(II) complexes, [Ru(η6-p-cymene)P(3,5-C(CH3)3-C6H3)3Cl2] (1), [Ru(η6-p-cymene)P(3,5-CH3-C6H3)3Cl2] (2), [Ru(η6-p-cymene)P(4-CH3O-3,5-CH3-C6H2)3Cl2] (3), and [Ru(η6-p-cymene)P(4-CH3O-C6H4)3Cl2] (4), were examined using Langmuir monolayers as simplified healthy and cancerous outer leaflet plasma membrane models. The cancerous membrane (CM1 and CM2) models contained either 40 % 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 30 % cholesterol (Chol), 20 % 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and 10 % 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (DPPS). Meanwhile, the healthy membrane (HM1 and HM2) models were composed of 60 % DPPC or DOPC, 30 % Chol and 10 % DPPE. The complexes affected surface pressure isotherms and decreased compressional moduli of cancerous and healthy membrane models, interacting with the monolayers headgroup and tails according to data from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). However, the effects did not correlate with the toxicity of the complexes to cancerous and healthy cells. Multidimensional projection technique showed that the complex (1) induced significant changes in the CM1 and HM1 monolayers, though it had the lowest cytotoxicity against cancer cells and is not toxic to healthy cells. Moreover, the most toxic complexes (2) and (4) were those that least affected CM2 and HM2 monolayers. The findings here support that the ruthenium complexes interact with lipids and cholesterol in cell membrane models, and their cytotoxic activities involve a multifaceted mode of action beyond membrane disruption.

Acharya Priyavrata Sharma: A life that personified the term “Apta” in the modern era

Abstract Acharya Priyavrata Sharma, who enlightened the wisdom of Ayurveda in the twentieth century, is known for shaping the postgraduate specialty of “Dravyaguna” in Ayurveda’s curriculum. His noted literary works have enriched contemporary Ayurveda literature. He published over 500 articles and 50 books and guided many scholars of Ayurveda through his visionary academic skills. He stressed the need to follow the principles of Ayurveda in research while advocating modern techniques to understand the therapeutic action of different drugs. His disciplined, passionate, and devoted life encourages us to walk the path of dedication, hard work, and diligence for the cause of Ayurveda.

Bioinformatic Analysis of Ping-Wei-San Decoction for Pulmonary Malignancy Based on UPLC-QE-Orbitrap-MS Detection

Background The traditional Chinese medicine prescription Ping-Wei-San decoction (PWS) has been used historically in East Asian countries. This study aimed to investigate the ingredients of the decoction and explore its potential role in the adjuvant treatment of pulmonary malignancies. Objectives The primary objective was to analyze the ingredients of PWS and understand its potential in the treatment of pulmonary malignancy. Methods Medical records of 143 394 patients using PWS over a decade were collected from the Affiliated Hospital of Qingdao University. UPLC-QE-Orbitrap-MS detected 13 chemical components, including 12 known components. Lung adenocarcinoma data were obtained from the TCGA-LUAD dataset, and differential genes were screened using R studio. The EVENN website and the STRING database were used to identify drug action and disease targets. Setting The study was conducted at the Affiliated Hospital of Qingdao University. Participants The study included 3147 patients with “pulmonary malignancies.” Intervention PWS was used as an adjuvant treatment. Results Network analysis revealed 10 core targets (CCNA2, CHEK1, TOP2A, CDK1, CCNB1, CCNB2, AURKA, AURKB, KIF11, and MELK) for the treatment of lung adenocarcinoma and associated pathways. Conclusion PWS may offer multifunctional efficacy in the treatment of pulmonary malignancies based on constituent analysis. Further research and clinical trials are needed to explore its potential.

ScRank infers drug-responsive cell types from untreated scRNA-seq data using a target-perturbed gene regulatory network.

Cells respond divergently to drugs due to the heterogeneity among cell populations. Thus, it is crucial to identify drug-responsive cell populations in order to accurately elucidate the mechanism of drug action, which is still a great challenge. Here, we address this problem with scRank, which employs a target-perturbed gene regulatory network to rank drug-responsive cell populations via in silico drug perturbations using untreated single-cell transcriptomic data. We benchmark scRank on simulated and real datasets, which shows the superior performance of scRank over existing methods. When applied to medulloblastoma and major depressive disorder datasets, scRank identifies drug-responsive cell types that are consistent with the literature. Moreover, scRank accurately uncovers the macrophage subpopulation responsive to tanshinone IIA and its potential targets in myocardial infarction, with experimental validation. In conclusion, scRank enables the inference of drug-responsive cell types using untreated single-cell data, thus providing insights into the cellular-level impacts of therapeutic interventions.

Development of supramolecular anticoagulants with on-demand reversibility.

Drugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drug's action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors (Ki = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified.

Nanotechnology for Pain Management.

Introduction: In the context of the current opioid crisis, non-pharmacologic approaches to pain management have been considered important alternatives to the use of opioids or analgesics. Advancements in nano and quantum technology have led to the development of several nanotransporters, including nanoparticles, micelles, quantum dots, liposomes, nanofibers, and nano-scaffolds. These modes of nanotransporters have led to the development of new drug formulations. In pain medicine, new liposome formulations led to the development of DepoFoam™ introduced by Pacira Pharmaceutical, Inc. (Parsippany, NJ, USA). This formulation is the base of DepoDur™, which comprises a combination of liposomes and extended-release morphine, and Exparel™, which comprises a combination of liposomes and extended-release bupivacaine. In 2021, Heron Therapeutics (San Diego, CA, USA) created Zynrelef™, a mixture of bupivacaine and meloxicam. Advancements in nanotechnology have led to the development of devices/patches containing millions of nanocapacitors. Data suggest that these nanotechnology-based devices/patches reduce acute and chronic pain. Methods: Google and PubMed searches were conducted to identify studies, case reports, and reviews of medical nanotechnology applications with a special focus on acute and chronic pain. This search was based on the use of keywords like nanotechnology, nano and quantum technology, nanoparticles, micelles, quantum dots, liposomes, nanofibers, nano-scaffolds, acute and chronic pain, and analgesics. This review focuses on the role of nanotechnology in acute and chronic pain. Results: (1) Nanotechnology-based transporters. DepoDur™, administered epidurally in 15, 20, or 25 mg single doses, has been demonstrated to produce significant analgesia lasting up to 48 h. Exparel™ is infiltrated at the surgical site at the recommended dose of 106 mg for bunionectomy, 266 mg for hemorrhoidectomy, 133 mg for shoulder surgery, and 266 mg for total knee arthroplasty (TKA). Exparel™ is also approved for peripheral nerve blocks, including interscalene, sciatic at the popliteal fossa, and adductor canal blocks. The injection of Exparel™ is usually preceded by an injection of plain bupivacaine to initiate analgesia before bupivacaine is released in enough quantity from the depofoarm to be pharmacodynamically effective. Finally, Zynrelef™ is applied at the surgical site during closure. It was initially approved for open inguinal hernia, abdominal surgery requiring a small-to-medium incision, foot surgery, and TKA. (2) Nanotechnology-based devices/patches. Two studies support the use of nanocapacitor-based devices/patches for the management of acute and chronic pain. A randomized study conducted on patients undergoing unilateral primary total knee (TKA) and total hip arthroplasty (THA) provided insight into the potential value of nanocapacitor-based technology for the control of postoperative acute pain. The results were based on 2 studies, one observational and one randomized. The observational study was conducted in 128 patients experiencing chronic pain for at least one year. This study suggested that compared to baseline, the application of a nanocapacitor-based Kailo™ pain relief patch on the pain site for 30 days led to a time-dependent decrease in pain and analgesic use and an increase in well-being. The randomized study compared the effects of standard of care treatment to those of the same standard of care approach plus the use of two nanocapacitor-based device/patches (NeuroCuple™ device) placed in the recovery room and kept in place for three days. The study demonstrated that the use of the two NeuroCuple™ devices was associated with a 41% reduction in pain at rest and a 52% decrease in the number of opioid refills requested by patients over the first 30 days after discharge from the hospital. Discussion: For the management of pain, the use of nano-based technology has led to the development of nano transporters, especially focus on the use of liposome and nanocapacitors. The use of liposome led to the development of DepoDur™, bupivacaine Exparel™ and a mixture of bupivacaine and meloxicam (Zynrelef™) and more recently lidocaine liposome formulation. In these cases, the technology is used to prolong the duration of action of drugs included in the preparation. Another indication of nanotechnology is the development of nanocapacitor device or patches. Although, data obtained with the use of nanocapacitors are still limited, evidence suggests that the use of nanocapacitors devices/patches may be interesting for the treatment of both acute and chronic pain, since the studies conducted with the NeuroCuple™ device and the based Kailo™ pain relief patch were not placebo-controlled, it is clear that additional placebo studies are required to confirm these preliminary results. Therefore, the development of a placebo devices/patches is necessary. Conclusions: Increasing evidence supports the concept that nanotechnology may represent a valuable tool as a drug transporter including liposomes and as a nanocapacitor-based device/patch to reduce or even eliminate the use of opioids in surgical patients. However, more studies are required to confirm this concept, especially with the use of nanotechnology incorporated in devices/patches.

PBAC: A pathway-based attention convolution neural network for predicting clinical drug treatment responses.

Precise and personalized drug application is crucial in the clinical treatment of complex diseases. Although neural networks offer a new approach to improving drug strategies, their internal structure is difficult to interpret. Here, we propose PBAC (Pathway-Based Attention Convolution neural network), which integrates a deep learning framework and attention mechanism to address the complex biological pathway information, thereby provide a biology function-based robust drug responsiveness prediction model. PBAC has four layers: gene-pathway layer, attention layer, convolution layer and fully connected layer. PBAC improves the performance of predicting drug responsiveness by focusing on important pathways, helping us understand the mechanism of drug action in diseases. We validated the PBAC model using data from four chemotherapy drugs (Bortezomib, Cisplatin, Docetaxel and Paclitaxel) and 11 immunotherapy datasets. In the majority of datasets, PBAC exhibits superior performance compared to traditional machine learning methods and other research approaches (area under curve = 0.81, the area under the precision-recall curve = 0.73). Using PBAC attention layer output, we identified some pathways as potential core cancer regulators, providing good interpretability for drug treatment prediction. In summary, we presented PBAC, a powerful tool to predict drug responsiveness based on the biology pathway information and explore the potential cancer-driving pathways.

Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I.

G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.