Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study.

The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.

Application of physiologically based pharmacokinetic modeling of novel drugs approved by the U.S. food and drug administration.

Physiologically based pharmacokinetic (PBPK) models which can leverage preclinical data to predict the pharmacokinetic properties of drugs rapidly became an essential tool to improve the efficiency and quality of novel drug development. In this review, by searching the Application Review Files in Drugs@FDA, we analyzed the current application of PBPK models in novel drugs approved by the U.S. Food and Drug Administration (FDA) in the past five years. According to the results, 243 novel drugs were approved by the FDA from 2019 to 2023. During this period, 74 Application Review Files of novel drugs approved by the FDA that used PBPK models. PBPK models were used in various areas, including drug-drug interactions (DDI), organ impairment (OI) patients, pediatrics, drug-gene interaction (DGI), disease impact, and food effects. DDI was the most widely used area of PBPK models for novel drugs, accounting for 74.2 % of the total. Software platforms with graphical user interfaces (GUI) have reduced the difficulty of PBPK modeling, and Simcyp was the most popular software platform among applicants, with a usage rate of 80.5 %. Despite its challenges, PBPK has demonstrated its potential in novel drug development, and a growing number of successful cases provide experience learned for researchers in the industry.

Clinical development and marketing application review times for novel orphan-designated drugs.

Development of an orphan-designated drug has been more challenging and financially less attractive than that of other drugs due to low prevalence of the condition, poorly defined biomarkers and lack of experience of healthcare providers in diagnosing and treating the condition. Guidance and incentives in some countries support the sponsors in developing orphan-designated drugs despite the challenges. Expedited regulatory programs as offered by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) support the development of drugs, provide shorter marketing application review times or provide preliminary approval. In this study, we analyze marketing application review times in the US and in the European Union (EU) and clinical development times for novel, i.e., containing new molecular entity, orphan-designated drugs that were approved in the US between 1 June 2020 and 31 May 2023, and their correlation with expedited regulatory programs. Seventy-three marketing applications for novel orphan-designated drugs were approved by the FDA, and 39 also received a positive opinion from the EMA. The marketing application review time by the FDA for the 73 novel orphan-designated drugs approved in the US was 244 days (n = 73, median), and the marketing application review time by the EMA for the 39 drugs that were also approved in the EU was 353 days (n = 39, median). The typical clinical development time for a novel orphan-designated drug was 7.2 years (n = 72).

Genus Echinophora-Biological Activity, Chemical Composition, and Future Perspectives.

Species belonging to the genus Echinophora (Apiaceae) have been used by humanity since ancient times as flavoring agents, preservatives, and medicines for the treatment of a broad spectrum of conditions, including respiratory, digestive and kidney disorders, fungi infections, wounds, and gastric ulcers. Phytochemical studies on this botanical genus mainly investigate the essential oil composition and reveal the species as a rich source of volatile compounds, including monoterpenes and phenylpropanoids. Among the non-volatile secondary metabolites, flavonoids, coumarins, phenolic acids, phytosterols, and polyacetylenes have been identified. Pharmacological studies revealed Echinophora extracts and essential oils exhibit different biological properties, including antibacterial, antifungal, anticancer, insecticidal, anti-inflammatory, and hepatoprotective activities. However, compared to other genera, the biological activity and chemical diversity of this genus are not well studied. In future decades, it is highly likely that the small genus Echinophora will play an important role in drug discovery and drug development.

Current Perspectives in Giant Cell Arteritis: Can We Better Connect Pathogenesis and Treatment?

Giant cell arteritis (GCA) is a large-vessel vasculitis affecting elderly patients and targeting the aorta and its main branches, leading to cranial and extracranial manifestations. The mechanism behind the ischemia is a granulomatous-type inflammation with potentially critical lesions, including visual loss involving the ophthalmic artery. Despite significant progress in unraveling the pathophysiology of this disease, treatment options still rely on glucocorticoids (GCs) to overcome active vascular lesions and disease flares. However, uncertainty still revolves around the optimal dose and tapering rhythm. Few corticosteroid-sparing agents have proven useful in GCA, namely, methotrexate and tocilizumab, benefiting cumulative GC dose and relapse-free intervals. The future looks promising with regard to using other agents like abatacept and Janus-kinase inhibitors or blocking the granulocyte-macrophage colony-stimulating factor receptor.

Stroke genetics and how it Informs novel drug discovery.

INTRODUCTION: Stroke is one of the main causes of death and disability worldwide. Nevertheless, despite the global burden of this disease, our understanding is limited and there is still a lack of highly efficient etiopathology-based treatment. It is partly due to the complexity and heterogenicity of the disease. It is estimated that around one-third of ischemic stroke is heritable, emphasizing the importance of genetic factors identification and targeting for therapeutic purposes. AREAS COVERED: In this review, the authors provide an overview of the current knowledge of stroke genetics and its value in diagnostics, personalized treatment, and prognostication. EXPERT OPINION: As the scale of genetic testing increases and the cost decreases, integration of genetic data into clinical practice is inevitable, enabling assessing individual risk, providing personalized prognostic models and identifying new therapeutic targets and biomarkers. Although expanding stroke genetics data provides different diagnostics and treatment perspectives, there are some limitations and challenges to face. One of them is the threat of health disparities as non-European populations are underrepresented in genetic datasets. Finally, a deeper understanding of underlying mechanisms of potential targets is still lacking, delaying the application of novel therapies into routine clinical practice.

Promising therapies for the treatment of myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune condition targeting the neuromuscular junction, which manifests with neuromuscular symptoms of varying severity and significant morbidity. The mainstay of treatment in MG is mitigation of the immune cascade with steroids and non-steroidal immunosuppressive therapies. The therapeutic strategies in MG are transitioning from broad and indiscriminate immunosuppression to novel agents targeting key steps in MG pathogenesis, including T cell activation, B cell proliferation, complement activation, maintenance of pathogenic antibody production, and proinflammatory cytokine production. AREAS COVERED: In this review, an overview of the pathogenesis of MG and traditional MG therapies is presented, followed by a discussion of the novel MG drugs that have been evaluated in phase 3 clinical trials with an emphasis on those which have received regulatory approval. EXPERT OPINION: Novel MG therapeutics belonging to the classes of complement inhibitors, neonatal Fc receptor (FcRn) inhibitors and B cell depletors, as well as the other emerging MG drugs in the pipeline constitute promising treatment strategies with potentially better efficacy and safety compared to the conventional MG treatments. However, further long-term research is needed in order to optimize the implementation of these new treatment options for the appropriate patient populations.

Exploration of Antileishmanial Compounds Derived from Natural Sources.

AIMS: Leishmaniasis is a deadly tropical disease that is neglected in many countries. World Health Organization, along with a few other countries, has been working together to protect against these parasites. Many novel drugs from the past few years have been discovered and subjected against leishmaniasis, which have been effective but they are quite expensive for lower-class people. Some drugs showed no effect on the patients, and the longer use of these medicines has made resistance against these deadly parasites. Researchers have been working for better medication by using natural products from medicinal plants (oils, secondary metabolites, plant extracts) and other alternatives to find active compounds as an alternative to the current synthetic drugs. MATERIALS AND METHODS: To find more potential natural products to treat Leishmania spp, a study has been conducted and reported many plant metabolites and other natural alternatives from plants and their extracts. Selected research papers with few term words such as natural products, plant metabolites, Leishmaniasis, in vivo, in vitro, and treatment against leishmaniasis; in the Google Scholar, PubMed, and Science Direct databases with selected research papers published between 2015 and 2021 have been chosen for further analysis has been included in this report which has examined either in vivo or in vitro analysis. RESULTS: This paper reported more than 20 novel natural compounds in 20 research papers that have been identified which report a leishmanicidal activity and shows an action against promastigote, axenic, and intracellular amastigote forms. CONCLUSION: Medicinal plants, along with a few plant parts and extracts, have been reported as a possible novel anti-leishmanial medication. These medicinal plants are considered nontoxic to Host cells. Leishmaniasis treatments will draw on the isolated compounds as a source further and these compounds compete with those already offered in clinics.

Efflux-mediated Multidrug Resistance in Critical Gram-negative Bacteria and Natural Efflux Pump Inhibitors.

Multidrug Resistance mechanisms in microorganisms confer the slackness of the existing drugs, leading to added difficulty in treating infections. As a consequence, efficient novel drugs and innovative therapies to treat MDR infections are necessarily required. One of the primary contributors to the emergence of multidrug resistance in gram-negative bacteria has been identified as the efflux pumps. These transporter efflux pumps reduce the intracellular concentration of antibiotics and aid bacterial survival in suboptimal low antibiotic concentration environments that may cause treatment failure. The reversal of this resistance via inhibition of the efflux mechanism is a promising method for increasing the effectiveness of antibiotics against multidrug-resistant pathogens. Such EPI, in combination with antibiotics, can make it easier to reintroduce traditional antibiotics into clinical practice. This review mostly examines efflux-mediated multidrug resistance in critical gram-negative bacterial pathogens and EPI of plant origin that have been reported over previous decades.

Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus.

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

Quantifying Clinical Trial Diversity in Pivotal Registration Trials of FDA Novel Drug Approvals.

BACKGROUND: Health care inequity includes the lack of adequate representation of various populations in clinical trials. Government, academic and industry organizations have highlighted these issues and committed to actions to improve. In order to assess the current status and future success of these initiatives a quantitative objective measure to assess the state of clinical trial diversity is needed. METHODS: FDA review documents for all novel drug approvals from January 2022 through March 2023 were assessed using a scorecard that considers diversity across different demographic subgroups including age (≥ 65 years old), sex (female), race (Black and Asian) and ethnicity (Hispanic/Latino). The scorecard assigns each drug a letter grade, between A and F, for each subgroup (and overall) based on (1) the percent of each sub-population included in the trials and grades relative to the percent of the US population per the 2020 Census, (2) the number of participants from each subpopulation that received the novel new drug in the trials, (3) the incidence or prevalence of the disease/condition in each of the sub-populations. RESULTS: The FDA approved 49 novel new drugs for 50 indications (one drug was simultaneously approved for two indications). There was good representation of elderly and females with only two drugs receiving a D grade in either of these sub-populations. In contrast, Black (5 F grades) and Hispanic (4 F grades) representation was often inadequate. There were 10 drugs (20.0%) where there were no Black participants receiving the novel new drug and 16 (32.0%) approvals where there were 1-9 Black participants receiving the novel drug. In the Hispanic/Latino population there were 4 (8.0%) approvals with no Hispanic participants receiving the novel drug and 15 (30.0%) approvals where there were 1-9 Hispanic participants receiving the drug. CONCLUSIONS: This scorecard provides an objective quantitative approach to assess the current state of diversity in clinical trials supporting new drug approvals. Substantial improvement in racial and ethnic representation is needed. Meaningful change will require actions and cooperation among all stakeholders to address this multifaceted issue and will take commitment, perseverance, and appropriate incentives.

Tracing down the updates on Ebola virus surges: An update on anti-ebola therapeutic strategies.

Ebola virus (EBOV) related health complications have presented a great threat to the healthcare system in the endemic regions. The outbreaks of 2013-2016 and 2018-2020 brought along a huge healthcare burden for the afected communities. Knowing the seriousness of the matter, a series of research experiments have been actively carried out to devise efective therapeutics, drugs, and vaccination protocols against the Ebola virus disease (EVD) in the past decade. The purpose of this piece of literature is to shed light on vaccination protocols being clinically evaluated for EVD. A methodological approach has been adopted to gather relevant data from the latest publications. The compiled data include the molecular mechanistic insights into Ebola infection and a brief overview of diferent vaccination strategies: inactivated and DNA vaccines, virus-like particles and replicons, reverse genetic and recombinant approaches, entry, ion, and gene expression inhibitors, and some repurposed drugs. This data will help the scientific community to get a comprehensive overview of therapeutic interventions against Ebola that could be related to modifying EBOV vaccines and designing other antiviral vaccinations. Having said that, further work in modern therapeutic design is pertinent to tackle and lessen the healthcare burden expected from such outbreaks in the future.

Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases.

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.

A novel mitochondria-targeting compound exerts therapeutic effects against melanoma by inducing mitochondria-mediated apoptosis and autophagy in vitro and in vivo.

Melanoma is the most invasive skin cancer, with a high mortality rate. However, existing therapeutic drugs have side effects, low reactivity, and lead to drug resistance. As the power source in cells, mitochondria play an important role in the survival of cancer cells and are an important target for tumor therapy. This study aimed to develop a new anti-melanoma compound that targets mitochondria, evaluate its effect on the proliferation and metastasis of melanoma cells, and explore its mechanism of action. The novel mitochondria-targeting compound, SCZ0148, was synthesized by modifying the structure of cyanine. Then, A375 and B16 cells were incubated with different concentrations of SCZ0148, and different doses of SCZ0148 were administered to A375 and B16 xenograft zebrafish. The results showed that SCZ0148 targeted mitochondria, had dose- and time-dependent effects on the proliferation of melanoma cell lines, and had no obvious side effects on normal cells. In addition, SCZ0148 induced melanoma cell apoptosis through the reactive oxygen species-mediated mitochondrial pathway of apoptosis and promoted autophagy. SCZ0148 significantly inhibited the migration of melanoma cells via a matrix metalloprotein 9-mediated pathway. Similarly, SCZ0148 inhibited melanoma cell proliferation in a concentration-dependent manner in vivo. In summary, SCZ0148 may be a novel anti-melanoma compound that targets mitochondria.

Phosphodiesterase 5 inhibitors: preclinical and early-phase breakthroughs for impotence treatments.

INTRODUCTION: Erectile dysfunction (ED) is a condition that affects millions of men worldwide and is characterized by the inability to achieve or maintain an erection for satisfactory sexual performance. There are numerous treatment options for ED, including medications, mechanical assist devices, and surgical management; however, first-line treatment is usually a phosphodiesterase 5 (PDE5) inhibitor. There is a growing interest in developing novel, efficacious PDE5 inhibitors that provide better quality, safety, and tolerability profiles with less adverse effects. Our review of udenafil, mirodenafil, youkenafil, lodenafil, and SLx-2101 analyzes the safety, efficacy, and pharmacokinetic properties of these new ED drugs. AREAS COVERED: Clinical trials demonstrated improved scores in questionnaires, such as the International Index of Erectile Function and Sexual Encounter Profile, for udenafil, mirodenafil, and lodenafil, while youkenafil and SLx-2101 revealed enhanced safety and tolerability in early pharmacokinetic studies. EXPERT OPINION: It is our opinion that more robust clinical trials are required before these medications can be made available in the United States. Additionally, the field of urology may benefit from pursuing other avenues of pharmacotherapy, such as injections, tablets with a different mechanism of action, or stem cell therapy, to restore the integrity of the endothelium within the penis.

Arsinothricin Inhibits Plasmodium falciparum Proliferation in Blood and Blocks Parasite Transmission to Mosquitoes.

Malaria, caused by Plasmodium protozoal parasites, remains a leading cause of morbidity and mortality. The Plasmodium parasite has a complex life cycle, with asexual and sexual forms in humans and Anopheles mosquitoes. Most antimalarials target only the symptomatic asexual blood stage. However, to ensure malaria eradication, new drugs with efficacy at multiple stages of the life cycle are necessary. We previously demonstrated that arsinothricin (AST), a newly discovered organoarsenical natural product, is a potent broad-spectrum antibiotic that inhibits the growth of various prokaryotic pathogens. Here, we report that AST is an effective multi-stage antimalarial. AST is a nonproteinogenic amino acid analog of glutamate that inhibits prokaryotic glutamine synthetase (GS). Phylogenetic analysis shows that Plasmodium GS, which is expressed throughout all stages of the parasite life cycle, is more closely related to prokaryotic GS than eukaryotic GS. AST potently inhibits Plasmodium GS, while it is less effective on human GS. Notably, AST effectively inhibits both Plasmodium erythrocytic proliferation and parasite transmission to mosquitoes. In contrast, AST is relatively nontoxic to a number of human cell lines, suggesting that AST is selective against malaria pathogens, with little negative effect on the human host. We propose that AST is a promising lead compound for developing a new class of multi-stage antimalarials.

Designing New Magic Bullets to Penetrate the Mycobacterial Shield: An Arduous Quest for Promising Therapeutic Candidates.

Mycobacterium spp. intimidated mankind since time immemorial. The triumph over this organism was anticipated with the introduction of potent antimicrobials in the mid-20th century. However, the emergence of drug resistance in mycobacteria, Mycobacterium tuberculosis, in particular, caused great concern for the treatment. With the enemy growing stronger, there is an immediate need to equip the therapeutic arsenal with novel and potent chemotherapeutic agents. The task seems intricating as our understanding of the dynamic nature of the mycobacteria requires intense experimentation and research. Targeting the mycobacterial cell envelope appears promising, but its versatility allows it to escape the lethal effect of the molecules acting on it. The unique ability of hiding (inactivity during latency) also assists the bacterium to survive in a drug-rich environment. The drug delivery systems also require upgradation to allow better bioavailability and tolerance in patients. Although the resistance to the novel drugs is inevitable, our commitment to the research in this area will ensure the discovery of effective weapons against this formidable opponent.