Third-generation Drug Research Articles

Eu-MOF-based highly sensitive and selective luminescence probe for trace, in situ and visual detection of flunitrazepam

Flunitrazepam, as an emerging new psychoactive substance classified as a third-generation drug that is more harmful and camouflaged, is gradually proliferating globally. Maliciously used as a criminal tool in homicide and rape cases, it has already caused serious harm to public safety and social stability. Owing to its special molecular structure, low concentration level and rapid metabolic process in the human body, accurate detection of flunitrazepam remains a major challenge, especially for real sample and on-site detection. In this paper, a lanthanide MOF (Eu-MOF) based on bi-ligand was constructed as a luminescence probe and used for the first time to detect trace amounts of flunitrazepam. The ’antenna effect’ promotes strong luminescence of Eu-MOF, while the lower LUMO orbital energy level of flunitrazepam allows it to accept electrons from the electron donor leading to quenching of Eu-MOF luminescence. The probe has a high sensitivity and can detect flunitrazepam in the range of 0–800 μM with a detection limit as low as 73 nM. Moreover, flunitrazepam was detected in urine from real samples as well as in a variety of beverages to further validate its accuracy and practicality. The reported Eu-MOF represents one of the pioneering luminescence probes for the detection of flunitrazepam, which offers great promise for the on-site or on-line analysis of flunitrazepam.

Evolution, mechanism of action, and clinical applications of three generations of Antihistamines

Introduction. This review investigates the evolution, mechanisms of action, and clinical applications of three generations of antihistamines. Materials and methods: To identify relevant studies, an extensive search was performed across multiple databases, including PubMed, MEDLINE, Web of Science, and Scopus, using a strategic combination of keywords and MeSH terms. The selection process yielded relevant scientific literature sources published between 1985 and 2023. Results and discussion: the study demonstrated that the initial step in the creation and development of antihistamines involved analysing the mechanisms of anaphylaxis and allergy. This analysis led to the discovery of histamine as a mediator of allergic reactions and subsequently to the synthesis of substances with antihistamine effects, resulting in the gradual discovery of three generations of antihistamines. These drugs are designed to block H1-histamine receptors to eliminate allergic manifestations. Due to their non-selective antihistamine activity, first-generation drugs have many side effects, primarily sedation, in addition to their intended therapeutic effects. Second- and third-generation drugs are selective for peripheral H1 receptors and have significantly fewer side effects. The third generation of drugs, as active metabolites of the second generation, demonstrate the highest efficacy and safety profile. First-generation medicines are used for emergency care in acute allergic reactions and to reduce local allergy manifestations, whereas second and third generations are used to treat symptoms of seasonal and chronic allergic rhinitis. Conclusions: The significance of the study lies in the potential application of its results in the clinical practice of allergists.

Possibility analysis of antiepileptic drugs import substitution in the Russian Federation

Relevance. Epilepsy is a common chronic disease of the nervous system that can be treated rationally, ensuring the possibility of remission in most patients. The availability of antiepileptic drugs (AEDs) for patients with epilepsy is an important characteristic for achieving a long and quality life. Domestic AED production in the Russian Federation guarantees accessible medicinal assistance.Objective. Assessment of the AED import substitution level in the Russian Federation.Methods. The assessment is based on an analysis of the State Register of Medicines (SRM), the list of vital and essential drugs (VED) for 2023, and the clinical recommendations of the Ministry of Health of the Russian Federation “Epilepsy and status epilepticus in adults and children”.Results. Currently, the SRM registers 27 international non-proprietary names of AEDs, 101 trade names, mainly in the form of oral dosage forms, and 1,355 nomenclature items. All AEDs are prescription drugs. Generally, 70.6% of AED manufacturers are domestic. In 2020, the share of manufacturers from the Russian Federation increased by 20%. However, only 14.2% of the substances are directly produced in the Russian Federation. A high 100% level of import substitution is available only for firstgeneration antiepileptic drugs, and for third-generation drugs it remains at 43%. Import substitution of antiepileptic drug substances stays significantly low — 75% — 47.5% — 14% for antiepileptic drugs of I — II — III generations, respectively.Conclusion. The level of import substitution of modern AEDs for generations II–III should be increased to improve the efficiency and safety of epilepsy therapy.

Amlodipine-Induced Gingival Enlargement – A Case Report

One of the etiological factors for Gingival Enlargement is administration of certain drugs like calcium channel blockers, anticonvulsants, and immunosuppressant. The drug that is been commonly used for the management of portal hypertension is calcium channel blockers. Among the various drugs in calcium channel blockers, the occurrence of drug-induced gingival enlargement is high with the use of nifedipine drug whereas the occurrence of gingival enlargement due to the usage of amlodipine drug is a very rare phenomenon. Amlodipine is a third-generation drug belonging to dihydropyridine calcium channel blocker that has been used for its longer duration of action. Treatment for drug-induced gingival enlargement includes referral of patients to their physician for possible drug substitution or alteration in dosage of drug, periodontal therapy that includes oral prophylaxis followed by gingivectomy or gingivoplasty, and maintenance care. In this study, we report a case of gingival enlargement in a 44-year-old female patient taking amlodipine drug for a period of six months and nonsurgical and surgical management of amlodipine-induced gingival enlargement in the patient.

Insight into systematic development of ALK (anaplastic lymphoma kinase) inhibitors towards NSCLC treatment

Among cancer-related disorders, lung carcinoma is one of the leading causes of mortality. Anaplastic lymphoma kinase (ALK) belongs to tyrosine kinase receptor family and exhibits similar characteristics to insulin type receptors. The treatment of advanced non-small cell lung cancer (NSCLC) associates with ALK gene rearrangement has significantly improved since the approval of Crizotinib in 2011 as the first generation ALK inhibitor. In continuation, the second-generation drugs like ceritinib, alectinib, and brigatinib were developed to address and counteract resistance that was associated with the first-generation agents. However, resistance can develop over time, necessitating ongoing research to enhance their effectiveness. Therefore, the third-generation drug lorlatinib, which has demonstrated broad-spectrum potency against the majority of known resistance mutations and better lipophilicity, has been developed. According to current reports, the USFDA has approved five ALK-TKIs crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib for ALK-associated lung cancer. Currently, several clinical trials are underway in search of better ALK inhibitors. Trials such as TPX-0131 and NVL-655 are considered fourth-generation ALK inhibitors for the treatment of patients with advanced ALK-positive or metastatic NSCLC. This review aims to provide specifics information on research works involving various ALK tyrosine kinase inhibitors, clinical studies, and the development of ALK TKIs. Additionally, we suggest potential future strategies involving sequential therapy and combination techniques for managing non-small cell carcinoma.

Перспективы применения иммуномодулирующих препаратов и модуляторов цереблон Е3-лигазы в лечении множественной миеломы

In recent decades, the progress in multiple myeloma (MM) treatment has been linked to a clearer insight into the biology of this disease and practical application of new pharmaceutical classes, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (MABs). Modern IMiDs (lenalidomide and pomalidomide) are thalidomide derivatives which despite the similarity of chemical structure show only a relative cross-resistance. Lenalidomide is a second-generation immunomodulator with high anti-tumor activity and a favorable safety profile. In 2006, the use of lenalidomide combined with dexamethasone (Rd regimen) was approved by FDA (USA) for the treatment of relapsed/refractory MM, and 9 years later, in 2015, for newly diagnosed MM. During 2015–2019, the treatment of relapsed MM applied the newly developed regimens involving Rd combined with bortezomib (VRd), carfilzomib (KRd), ixazomib (IRd), elotuzumab (ERd), and daratumumab (DRd), the so-called triplets. Pomalidomide is a third-generation drug used in lenalidomide-refractory patients. For patients with relapsed/refractory MM who received at least two therapy lines with lenalidomide and bortezomib, regimens with 3 drugs were introduced which include pomalidomide and dexamethasone combined with elotuzumab (EPd), isatuximab (Isa-Pd), and daratumumab (DPd). In 2010, the molecular target of IMiD action was discovered, that is protein cereblon (CRBN), a component of CRBN E3 ligase enzyme complex. The insight into this mechanism provided the basis for developing a new family of thalidomide derivatives which are now called CRBN E3 ligase modulators (CELMoDs). In phase I/II trials, two drugs belonging to this group (iberdomide and mezigdomide) showed promising activity in MM refractory to three classes of antitumor drugs (IMiDs, PIs, and anti-CD38 MABs). The present review is focused on prospective studies of IMiDs and CELMoDs at different stages of MM treatment.

Targeting EGFR allosteric site with marine-natural products of Clathria Sp.: A computational approach

The EGFR-C797S resistance mutation to third-generation drugs has been overcome by fourth-generation inhibitors, allosteric inhibitors, namely EAI045 and has reached phase 3 clinical trials, so the Allosteric Site is currently an attractive target for development. In this study, researchers are interested in knowing the activity of metabolite compounds from marine natural ingredients Clathria Sp. against the Allosteric Site of EGFR computationally. The methods used include molecular docking using Autodock4 software and Molecular Dynamics simulation performed using GROMACS software. The research began with the preparation of metabolite samples from Clathria Sp. through the KnapSack database site and the preparation of EGFR receptors that have been complexed with allosteric inhibitors, namely proteins with PDB code 5D41. Each compound was docked to the Allosteric Site of the natural ligand and then molecular dynamics simulations were performed on the compound with the best docking energy compared to the natural ligand. From the docking results, the Clathrin_A compound showed the lowest binding energy compared to other metabolites, and the value was close to the natural ligand. Then from the molecular dynamics results, the clathrin_A compound shows good stability and resembles the natural ligand, which is analyzed through RMSD, RMSF, SASA, Rg, and PCA, and shows the binding free energy from MMPBSA analysis which is close to the natural ligand. It can be concluded, Clathrin_A compound has potential as an allosteric inhibitor.

Machine Learning Model Training and Practice: A Study on Constructing a Novel Drug Detection System

Drugs, AIDS and terrorism are the three major public hazards in the world. Drug abuse seriously endangers social security and human life and health. The World Drug Report 2023 shows that the continued record supply of illicit drugs and increasingly flexible trafficking networks are exacerbating the global crisis and posing challenges for health services and law enforcement responses. The number of people injecting drugs worldwide in 2021 is estimated to be 13.2 million, 18% higher than previous estimates. At present, the world drug control situation is very serious, and it is necessary to increase the means to solve the drug problem and curb the spread of drugs, and efficient and accurate drug detection technology plays a very important role in drug control work. NPS, also known as "planning drugs" or "laboratory drugs", is a drug analogue obtained by the chemical structure modification of controlled drugs by criminals in order to evade the crackdown. It has similar or stronger excitatory, hallucinogenic, narcotic and other effects with controlled drugs, and has become a third-generation drug popular in the world after traditional drugs and synthetic drugs. Therefore, through the drug detection technology based on artificial intelligence machine learning technology, the current development of AI as a "drug detector" and the future space are analyzed.

First-line treatment option for patients with ALK-positive metastatic NSCLC

Non-small cell lung cancer (NSCLC) that occupies a leading place in the pattern of cancer incidence and mortality is a highly heterogeneous group of diseases. The presence of a wide spectrum of NSCLC driver mutations has led to a fundamentally different understanding of the treatment strategy for this cohort of patients and a significant improvement in long-term oncological outcomes, even in the metastatic process. Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene loci on chromosome 2 are found in approximately 3–5% of patients with metastatic NSCLC (mNSCLC) and in most cases are associated not only with a number of specific clinical features, but also with high sensitivity to targeted therapy with tyrosine kinase inhibitors (TKI). Crizotinib was the first approved ALK inhibitor, but although most patients achieved response within the first two years after start of the treatment, disease progression occurred often due to intracranial injury. The development of second-(ceritinib, alectinib), brigatinib and third-generation (lorlatinib) drugs has led to a statistically significant improvement in progression-free survival (PFS) rates, as well as control over intracranial manifestations of the disease and a change in the initial treatment strategy for these patients. In addition, new-generations of TKIs were developed to solve the problem of acquired resistance, as well as to achieve the best outcomes in the presence of such unfavourable factors as the presence of a TP53 mutation and/or ALK inhibitor low-sensitive translocation variants of the intracellular kinase domain of EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) protein. Thus, advances in the therapeutic options for ALK-positive mNSCLC has completely changed the course of the disease, resulting in a significant increase in overall survival (OS) rates not only with the sequential use of different generation TKIs, but also with the choice of the most effective first-line option. In this article, we present an analysis of data on the efficacy and toxicity of lorlatinib, a third-generation TKI, in the first-line treatment for ALK+ mNSCLC.

Pharmacogenetic and liquid biopsy: The new tools of precision medicine in cancer

The main difficulty in the treatment of cancer lies in the already known mechanism of resistance to conventional chemotherapy. It is mainly due to the expression of the multidrug transport systems known as ABC transporters, both in neoplastic cells and in excretory organs that reduce the chemotherapeutic concentration. The cancer cell proliferation by activation of growth factor receptors induces their intrinsic tyrosine kinase activity, and their intracellular signaling pathways involved in such activation. Tumor proliferation can respond to the direct action of growth factors on their respective receptors, or due to somatic mutations in different steps of their signaling pathway, in an independent manner of growth factor stimulus. Pharmacogenetics studies have been performed to identify these drivers’ mutations and their detection enables targeted inhibitory therapies against their abnormal proteins. The design of new molecules capable of inhibiting these signals has opened a new line of treatment for each type of tumor, thereby enabling tumor growth control and giving rise to the precision medicine approach. It is possible that mutations of sensitive and resistant to these targeted therapies coexist in the same tumor, from the start of therapy or as a consequence of the first-line treatment. The mutations in circulating DNA in body fluids, which are detected and quantified by droplet digital polymerase chain reaction-assisted liquid biopsy, are the ideal biomarkers for the evaluation of pharmacological response, which is crucial for facilitating the change of therapeutic strategy involving second- or third-generation drugs. The quantification of these mutations can be used to assess minimal residual disease in the therapeutic follow-up of each case.

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022.

Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

Safety and Efficacy of Zavegepant in Treating Migraine: A Systematic Review.

Drugs that act on the calcitonin gene-related peptide (CGRP) pathway herald the dawn of a new era in the management of migraine headaches. The blockade of CGRP alleviates neural inflammation and has been associated with reduced pain sensitization. Zavegepant is a third-generation drug and is the first intranasal CGRP antagonist to be developed. This systematic review aims to assess the safety, efficacy, pharmacokinetics, and tolerability of Zavegepant as an abortive treatment for migraine.Studies that assessed the safety, tolerability, and efficacy of Zavegepant for migraine were identified through a systematic literature review of PubMed, Clinicaltrials.gov, and Cochrane databases in April 2023. Our systematic review yielded a total of six studies that fit our inclusion criteria. Of these, data from only two randomized control trials (RCTs) was homogenous; hence, forest plots of results pooled from the included studies were not reported. The included studies showed that Zavegepant is an efficacious and well-tolerated abortive treatment modality for episodic migraine in adult patients. Zavegepant showed safety and efficacy in migraine treatment according to various parameters throughout the six included studies. These parameters include adverse events, pharmacokinetic properties, CGRP inhibition, effect on blood pressure/electrocardiogram, pain freedom, and freedom from most bothersome symptoms.

Mechanism of Anti-seizure Medications and Emerging Trends in Epilepsy Treatment

Review Mechanism of Anti-seizure Medications and Emerging Trends in Epilepsy Treatment Zubin Singh Rana 1, Reena Suman 1, Shobi Veleri 2, and Pradeep Punnakkal 1, * 1 Department of Biophysics, Postgraduate Institute of Medical Education and Research Chandigarh, 160012, India 2 Drug Safety Division, ICMR-National Institute of Nutrition, Hyderabad, 500007, India. * Correspondence: p.pradeep@pgimer.edu.in Received: 28 November 2022 Accepted: 24 January 2023 Abstract: About one percent of the world’s population is affected by epilepsy. Epilepsy-induced psychiatric co-morbidity and mortality impose a huge burden on patients, their families, and society. Anti-seizure medications (ASMs) are drugs used to control seizures in patients with epilepsy. Epilepsy constitutes a spectrum of disorders, with various underlying causes. Hence, finding the right drug to control seizures with minimal side effects is a difficult task for clinicians. Besides controlling seizures, many ASMs have off-target effects that result in unwanted side effects. Compared to first and second-generation drugs, third-generation drugs have shown better tolerance. Even though the target of many ASMs is known, their mechanism of action is not well understood. The main mechanism behind epilepsy is defined as an imbalance in the excitatory-to-inhibitory ratio in neurotransmission. So, the key target of ASMs is the ion channels controlling the intrinsic property of neurons like sodium channels, potassium channels, and calcium channels, the excitatory synaptic transmission via glutamate receptors, and the inhibitory synaptic transmission by GABA receptors. Here we review the role of ion channels in epilepsy, and how the ASMs act on them for seizure control.

A retrospective comparative fractal and radiomorphometric analysis of the effect of 3 generations of anti-epileptic drugs on the mandible

The present study investigated the possible impacts of anti-epileptic drugs (AEDs) on trabecular and cortical bone in the mandible. Fractal dimension (FD) and the radiomorphometric parameters of mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) were assessed on 497 dental panoramic radiographs (DPRs) of patients in the case group and controls. AEDs were compared according to 3 generations, duration of use, and patient age and sex. FD of the angle and body of the mandible and MCW were significantly lower in the case group than in the control group (P < .001). FD values in the ramus and angle were lower in first-generation and third-generation AEDs than in second-generation drugs (P ≤ .011). FD in the mandibular body was lower in first-generation and second-generation AED users than in third-generation drugs (P=.017). Drug use for at least 1 year resulted in significantly lower values for all FDs and MCW values and more class 3 MCI assessments than short-duration use, but PMI was higher with more than 1 year of AED use (P ≤ .020). Age and sex had no significant effects. AEDs caused significant changes in bone compared with controls in some FD values, MCW, and MCI. The effect of drug generation is pronounced in trabecular bone. Anti-epileptic drug use for more than 1 year had a greater effect than short-term use.

Preventing Teratogenicity in Women with Epilepsy

Over the last 50 years there has been a significant increase in our understanding of the issues faced by women with epilepsy, in both planning and undertaking pregnancy. The risks of teratogenicity associated with antiseizure medications have emerged slowly. The major pregnancy registers have substantially contributed to our knowledge about teratogenic risk associated with the commonly used antiseizure medications. However, there are substantial gaps in our knowledge about the potential risks associated with many third-generation drugs. The remit of the pregnancy registers and the wider research focus has moved beyond anatomical major congenital malformations. Increasingly neurodevelopmental and behavioral abnormalities have been investigated after in utero exposure to antiseizure medications. Public health approaches can help reduce the risk of teratogenicity. However, neurologists still have a vital role in reducing the risk of teratogenicity at an individual level for women attending their clinic. They also have responsibility to ensure that women with epilepsy are aware of the rationale for the different available options.

Cardiovascular management of patients with chronic myeloid leukemia treated with BCR-ABL tyrosine kinase inhibitors: it is time for a shared management

Chronic myeloid leukemia is a rare myeloproliferative disease, characterized by a chromosomal translocation detected in 95% of cases, defined as "Philadelphia chromosome", encoding for the BCR-ABL fusion protein with continuous activation of the tyrosine kinase domain. Over the last 20 years, treatment has been revolutionized by the use of BCR-ABL tyrosine kinase inhibitors (TKI). Imatinib is the first TKI approved with a good cardiovascular safety profile, while some second-generation (nilotinib and dasatinib) and third-generation (ponatinib) drugs, developed to overcame drug resistance, can be associated with cardiovascular adverse events. The major adverse effect of dasatinib is pulmonary hypertension, reversible after treatment discontinuation. Conversely, nilotinib or ponatinib assumption is associated with a higher incidence of ischemic events, including coronary artery disease, cerebral stroke and peripheral arterial disease. Therefore, the management of patients receiving TKI therapy should include an integrated multidisciplinary evaluation and follow-up, involving highly specialized figures such as a cardiologist, hematologist and/or oncologist and the application of dedicated pathways, in order to prevent the onset or manage cardiovascular complications associated with these drugs.

Clinical response of carboplatin-based chemotherapy and its association to genetic polymorphism in lung cancer patients from North India - A clinical pharmacogenomics study.

Lung cancer mostly diagnosed at advanced inoperable stages; thereby, the chemo-, radiation-, targeted or immune-therapy alone or in combination remains the treatment of choice. In chemotherapy, platinum-based compounds such as cisplatin and carboplatin and third-generation drugs such as docetaxel, paclitaxel, gemcitabine, and vinorelbine are widely used. The beneficial therapeutic outcome of the chemotherapy alone or in combination with radiation (chemoradiation) and/or development of drug resistance depends on the inter-individual genetic differences. Hence, this study was carried out to find gene biomarker that could be useful in the diagnosis of the disease and to predict the outcome of chemo/chemoradiation therapy in ethnic North Indian population. In this clinical study, lung cancer (n = 52) patients from North Indian population were recruited. All the patients were treated with carboplatin target area under curve-5 in combination with third-generation drugs (gemcitabine 1.2 mg/m2; paclitaxel 175 mg/m2; and etopside 100 mg/m2) and radiation therapy. The genomic DNA was isolated from the blood sample and performed polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. We found hazard ratio to be significantly higher for XPDLys751Gln (hazard ratio [HR] =2.11, 95% confidence interval [CI]: 0.98-4.53, P = 0.056) and IL1 β511C/T (HR = 9.9, 95% CI: 2.55-38.40, P = 0.001). GSTT1 null (HR = 0.39, 95%CI: 0.18-0.84, P = 0.017) genotype has better response to chemotherapy. Generalized multidimensional reduction model suggested that IL1RN (cross-validation consistency [CVC] =10/10, P = 0.054) and XRCC1399Gln, GSTM1 (CVC = 10/10, P = 0.001) as best predicted model in lung cancer patients to the treatment response. Genetic polymorphisms and single nucleotide polymorphisms in DNA repair gene (XRCC1, XPD) and drug-metabolizing gene (GSTM1 and GSTT1) could serve as genetic biomarkers in lung cancer patients treated with the above indicated chemotherapy. Based on genotype and chemotherapy treatments, the toxicity effects can be minimized, this will help in the development of personalized medicine in future with better efficacy.

Determination of Oxaliplatin by a UHPLC-MS/MS Method: Application to Pharmacokinetics and Tongue Tissue Distribution Studies in Rats

Oxaliplatin (OXP), a third-generation platinum-based chemotherapy drug, was often indirectly analyzed via total platinum by an ICP-MS because it was difficult to directly quantify using an LC-MS/MS method, due to its instability, bad column separability and severe MS signal inhibition. Here, we developed and validated a specific, sensitive and reproducible LC-MS/MS method for the quantification of OXP itself in rat plasma and tongue tissue on a SCIEX 4000 QTRAP® MS/MS system equipped with a Phenomenex Lux 5u Cellulose-1 column (250 × 4.6 mm, 5 μm). This method was validated at the lower limit of detection (LOD) and the lower limit of quantitation (LLOQ) of 5 ng/mL and 10 ng/mL, with linearity of 10–5000 ng/mL (r2 > 0.99) and 10–2500 ng/mL (r2 > 0.99), in rat plasma and tongue homogenates, respectively. The intra- and inter-day precision (CV%) and accuracy (RE%) were within 15% for LLOQ, low-, medium- and high-quality control samples. The mean extraction recoveries were around 50% and 80% for plasma and tongue homogenates, respectively. This assay was successfully applied to pharmacokinetics study following intravenous administration of OXP, as well as tongue tissue distribution after 1 h and 4 h of a novel oral mucosal patch application.

AI-Based Drug Discovery of TKIs Targeting L858R/T790M/C797S-Mutant EGFR in Non-small Cell Lung Cancer.

Lung cancer has a high mortality rate, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Patients have been observed to acquire resistance against various anticancer agents used for NSCLC due to L858R (or Exon del19)/T790M/C797S-EGFR mutations. Therefore, next-generation drugs are being developed to overcome this problem of acquired resistance. The goal of this study was to use artificial intelligence (AI) to discover drug candidates that can overcome acquired resistance and reduce the limitations of the current drug discovery process, such as high costs and long durations of drug design and production. To generate ligands using AI, we collected data related to tyrosine kinase inhibitors (TKIs) from accessible libraries and used LSTM (Long short term memory) based transfer learning (TL) model. Through the simplified molecular-input line-entry system (SMILES) datasets of the generated ligands, we obtained drug-like ligands via parameter-filtering, cyclic skeleton (CSK) analysis, and virtual screening utilizing deep-learning method. Based on the results of this study, we are developing prospective EGFR TKIs for NSCLC that have overcome the limitations of existing third-generation drugs.

S-1 and Capecitabine for the Treatment of Colorectal Cancer: A Meta-Analysis

Colorectal cancers common tumors that develop in the large intestines. The incidence of colorectal cancer is second only to gastric and esophageal cancers. Both S-1 and capecitabine are the third-generation fluorouracil-based chemotherapeutic drugs. We hope to summarize the therapeutic effects of tecotae and capecitabine in patients with colorectal cancer through this Meta-analysis. We performed a meta-analysis of the findings in the current literature. We performed a systematic review of outcomes associated with S-1 and capecitabine used to treat advanced colorectal cancer based on findings from both English and Chinese publications listed in PubMed, Embase, CNKI, Wanfang, EBSCO, Web of Science and the Cochrane Library. End-points included ORR, DCR, OS, and PFS; adverse events (grades 1–2 and 3–4) were also evaluated. Statistical analysis was performed using RevMan 5.3. A total of 12 studies were eventually included, involving a total of 3,375 patients. Of this group, 1,683 and 1,692 patients underwent treatment with S-1 or capecitabine, respectively. There were no greatly differences with respect to ORR, DCR, or OS; however, PFS was bettered in the group of S-1 compared to those treated with capecitabine. The incidence of leukopenia, diarrhea and anorexia were all higher among those in S-1 group compared to the capecitabine group, but a higher incidence of hand-foot syndrome was linked with use of capecitabine. Use of S-1 for the treatment of colorectal cancer may result in superior outcomes when compared to use of capecitabine.