Breaking down barriers: The potential of smarter CAR-engineered NK cells against solid tumors.

Natural killer (NK) cells are considered to be the foremost fighters of our innate immune system against foreign invaders and thus tend to promptly latch onto the virus-infected and tumor/cancerous cells, killing them through phagocytosis. At present, the application of genetically engineered Chimeric antigen receptor (CAR) receptors ensures a guaranteed optimistic response with NK cells and would not allow the affected cells to dodge or escape unchecked. Hence the specificity and uniqueness of CAR-NK cells over CAR-T therapy make them a better immunotherapeutic choice to reduce the load of trafficking of numerous tumor cells near the healthy cell populations in a more intact way than offered by CAR-T immunotherapy. Our review mainly focuses on the preclinical, clinical, and recent advances in clinical research trials and further strategies to achieve an augmented and efficient cure against solid tumors.

The Complex Interplay between the Gut Microbiome and Osteoarthritis: A Systematic Review on Potential Correlations and Therapeutic Approaches.

The objective of this review is to systematically analyze the potential correlation between gut microbiota and osteoarthritis (OA) as well as to evaluate the feasibility of microbiota-targeted therapies for treating OA. Studies conducted from October 2013 to October 2023 were identified via a search on electronic databases such as PubMed, Web of Science, and Scopus, following established PRISMA statement standards. Two reviewers independently screened, assessed, and extracted relevant data, and then they graded the studies using the ROBINS I tool for non-randomized interventions studies and SYRCLE's risk-of-bias tool for animal studies. A search through 370 studies yielded 38 studies (24 preclinical and 14 clinical) that were included. In vivo research has predominantly concentrated on modifying the gut microbiota microenvironment, using dietary supplements, probiotics, and prebiotics to modify the OA status. Lactobacilli are the most thoroughly examined with Lactobacillus acidophilus found to effectively reduce cartilage damage, inflammatory factors, and pain. Additionally, Lactobacillus M5 inhibits the development of OA by preventing high-fat diet (HFD)-induced obesity and protecting cartilage from damage. Although there are limited clinical studies, certain compositions of intestinal microbiota may be associated with onset and progression of OA, while others are linked to pain reduction in OA patients. Based on preclinical studies, there is evidence to suggest that the gut microbiota could play a significant role in the development and progression of OA. However, due to the scarcity of clinical studies, the exact mechanism linking the gut microbiota and OA remains unclear. Further research is necessary to evaluate specific gut microbiota compositions, potential pathogens, and their corresponding signaling pathways that contribute to the onset and progression of OA. This will help to validate the potential of targeting gut microbiota for treating OA patients.

Anticancer potential of garlic and its bioactive constituents: A systematic and comprehensive review.

Vegetables of the Allium genus, such as garlic (Allium sativum L.), onions, shallots, leaks, and chives, have been used for many years for food consumption and for medicinal purposes. Historical medical texts have indicated the therapeutic applications of garlic as an antitumor, laxative, diuretic, antibacterial and antifungal agent. Specifically, garlic's antitumor abilities have been traced back 3500 years as a chemotherapeutic agent used in Egypt. Other beneficial effects of garlic consumption include lowering blood pressure, blood cholesterol, sugar and lipids. The processing and aging of garlic result in the production of non-toxic organosulfur by-products. These sulfur-containing compounds, such as allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, alliin, S-allylcysteine, and S-allylmercaptocysteine, impact various stages of carcinogenesis. The anticancer mechanisms of action of these garlic-derived phytochemicals include altering mitochondrial permeability, inhibiting angiogenesis, enhancing antioxidative and proapoptotic properties, and regulating cell proliferation. All these effects of garlic's sulfur-compounds have been demonstrated in various human cancers. The intent of this literature research is to explore the potential of garlic-derived products and bioactive organosulfur compounds as cancer chemopreventive and chemotherapeutic agents. This investigation employs criteria for systematic review and critically analyzes published in vitro, in vivo and clinical studies. Concerns and limitations that have arisen in past studies regarding standards of measurement, bioavailability, and method of delivery are addressed. Overall, it is hoped that through this systematic and comprehensive review, future researchers can be acquainted with the updated data assembled on anticancer properties of garlic and its phytoconstituents.

Regulatory changes in China on xenotransplantation and related products.

BACKGROUND: Given the persistence and the worldwide shortage of organs from both the deceased and living donors for clinical transplantation, pig organs or tissues hold immense promises for the patients on the waiting list, and xenotransplantation is deemed as one of the solutions to the organ shortage crisis. Indeed, the emerging gene editing technologies, such as CRISPR/Cas9, have led to tremendous progress in the generation of genetically modified pigs to overcome many barriers associated. METHOD: We presented a description of the xenotransplantation regulations in China and the related products. RESULT: Several groups in China have successfully generated transgenic pigs with the elimination of immune rejection or coagulation-related genes, and both pre-clinical and clinical studies have been reported. However, the pre-clinical evaluation and clinical application of porcine xenotransplantation raises ethical and regulatory considerations. Herein, in this review, we will summarize and discuss the progress in xenotransplantation in China and xenotransplantation-related products from the regulatory perspective. CONCLUSION: There has been remarkable progress in both the genetically modified pigs and pre-clinical studies in China, and China will be the first country to successfully fulfill the xenotransplantation from pig organ to human in the near future.

Chronic pelvic pain syndrome: Highlighting medicinal plants toward biomolecules discovery for upcoming drugs formulation.

Chronic pelvic pain syndrome (CPPS) can be triggered by a various types of gynecological, gastrointestinal, urological, and musculoskeletal disorders. Recently, the role of the central nervous system has proven to be an integral part on the development of any chronic pain syndrome, including CPPS. However, owing to the complex and heterogeneous etiology and pathophysiology of CPPS, the establishment of effective therapeutic interventions remains challenging for both physicians and patients. Nonetheless, recent studies have pointed that medicinal plants and their secondary metabolites can be effectively used in CPPS therapy, besides contributing to restore the patients' quality of life and potentiate the conventional CPPS management. In this sense, this review aims to provide a careful overview on the biomedical data for the use of medicinal plants use and their secondary metabolites on CPPS management.

Cell penetration: scope and limitations by the application of cell-penetrating peptides.

The penetration of polar or badly soluble compounds through a cell membrane into live cells requires mechanical support or chemical helpers. Cell-penetrating peptides (CPPs) are very promising chemical helpers. Because of their low cytotoxicity and final degradation to amino acids, they are particularly favored in in vivo studies and for clinical applications. Clearly, the future of CPP research is bright; however, the required optimization studies for each drug require considerable individualized attention. Thus, CPPs are not the philosopher's stone. As of today, a large number of such transporter peptides with very different sequences have been identified. These have different uptake mechanisms and can transport different cargos. Intracellular concentrations of cargos can reach a low micromole range and are able to influence intracellular reactions. Internalized ribonucleic acids such as small interfering RNA (siRNA) and mimics of RNA such as peptide nucleic acids, morpholino nucleic acids, and triesters of oligonucleotides can influence transcription and translation. Despite the highly efficient internalization of antibodies, enzymes, and other protein factors, as well as siRNA and RNA mimics, the uptake and stabile insertion of DNA into the genome of the host cells remain substantially challenging. This review describes a wide array of differing CPPs, cargos, cell lines, and tissues. The application of CPPs is compared with electroporation, magnetofection, lipofection, viral vectors, dendrimers, and nanoparticles, including commercially available products. The limitations of CPPs include low cell and tissue selectivity of the first generation and the necessity for formation of fusion proteins, conjugates, or noncovalent complexes to different cargos and of cargo release from intracellular vesicles. Furthermore, the noncovalent complexes require a strong molar excess of CPPs, and extensive experimentation is required to determine the most optimal CPP for any given cargo and cell type. Yet to predict which CPP is optimal for any given target remains a complex question. More recently, there have been promising developments: the enhancement of cell specificity using activatable CPPs, specific transport into cell organelles by insertion of corresponding localization sequences, and the transport of drugs through blood-brain barriers, through the conjunctiva of eyes, skin, and into nerve cells. Proteins, siRNA, and mimics of oligonucleotides can be efficiently transported into cells and have been tested for treatment of certain diseases. The recent state of the art in CPP research is discussed together with the overall scope, limitations, and some recommendations for future research directions.

Latest advances on new promising molecular-based therapeutic approaches for Huntington's disease.

Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments, and neuropsychiatric symptoms. It is caused by excessive cytosine-adenine-guanine (CAG) trinucleotide repeats within the huntingtin gene (HTT). Presently, therapeutic interventions capable of altering the trajectory of HD are lacking, while medications for abnormal movement and psychiatric symptoms are limited. Numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. In this review, we update the latest advances on new promising molecular-based therapeutic strategies for this disorder, including DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. We mainly focus on the ongoing clinical trials and the latest pre-clinical studies to explore the progress of emerging potential HD therapeutics.

Current knowledge of bone-derived factor osteocalcin: its role in the management and treatment of diabetes mellitus, osteoporosis, osteopetrosis and inflammatory joint diseases.

Osteocalcin (OC) is the most abundant non-collagenous and osteoblast-secreted protein in bone. It consists of two forms such as carboxylated OC (cOC) and undercarboxylated OC (ucOC). While cOC promotes bone mineralization and increases bone strength, ucOC is regarded an endocrinologically active form that may have several functions in multiple end organs and tissues. Total OC (tOC) includes both of these forms (cOC and ucOC) and is considered a marker of bone turnover in clinical settings. Most of the data on OC is limited to preclinical studies and therefore may not accurately reflect the situation in clinical conditions. For the stated reason, the aim of this review was not only to summarize current knowledge of all forms of OC and characterize its role in diabetes mellitus, osteoporosis, osteopetrosis, inflammatory joint diseases, but also to provide new interpretations of its involvement in the management and treatment of aforementioned diseases. In this context, special emphasis was placed on available clinical trials. Significantly lower levels of tOC and ucOC could be associated with the risk of type 2 diabetes mellitus. On the contrary, tOC level does not seem to be a good indicator of high bone turnover status in postmenopausal osteoporosis, osteoarthritis and rheumatoid arthritis. The associations between several pharmacological drugs used to treat all disorders mentioned above and OC levels have also been provided. From this perspective, OC may serve as a medium through which certain medications can influence glucose metabolism, body weight, adiponectin secretion, and synovial inflammation.

Emerging roles of bacteriophage-based therapeutics in combating antibiotic resistance.

Amid the growing challenge of antibiotic resistance on a global scale, there has been a notable resurgence in bacteriophage-based treatments, signaling a shift in our approach to managing infections. Bacteriophages (BPs), bacterial predators of nature, present a promising alternative for tackling infections caused by antibiotic-resistant pathogens. This review delves into the intricate relationship between bacteriophages and resistant bacteria, exploring various treatment strategies. Drawing upon both preclinical and clinical studies, the review highlights the effectiveness of bacteriophage therapy, particularly when integrated synergistically with conventional antibiotics. It discusses various treatment approaches for systemic and localized infections, demonstrating the adaptability of bacteriophage therapy across different clinical scenarios. Furthermore, the formulation and delivery of bacteriophages shed light on the various methods used to encapsulate and administer them effectively. It also acknowledges the challenge of bacterial resistance to bacteriophages and the ongoing efforts to overcome this hurdle. In addition, this review highlights the importance of the bacteriophage sensitivity profile (phagogram), which helps tailor treatment regimens to individual patients and specific pathogens. By surpassing the limitations of traditional antibiotics, bacteriophage-based therapies offer a personalized and potent solution against antibiotic resistance, promising to reshape the future of infectious disease management.

An overview of retinal light damage models for preclinical studies on age-related macular degeneration: identifying molecular hallmarks and therapeutic targets.

Age-related macular degeneration (AMD) is a complex, multifactorial disease leading to progressive and irreversible retinal degeneration, whose pathogenesis has not been fully elucidated yet. Due to the complexity and to the multiple features of the disease, many efforts have been made to develop animal models which faithfully reproduce the overall AMD hallmarks or that are able to mimic the different AMD stages. In this context, light damage (LD) rodent models of AMD represent a suitable and reliable approach to mimic the different AMD forms (dry, wet and geographic atrophy) while maintaining the time-dependent progression of the disease. In this review, we comprehensively reported how the LD paradigms reproduce the main features of human AMD. We discuss the capability of these models to broaden the knowledge in AMD research, with a focus on the mechanisms and the molecular hallmarks underlying the pathogenesis of the disease. We also critically revise the remaining challenges and future directions for the use of LD models.

An Update on Potential Antidepressants Derived from Marine Natural Products.

INTRODUCTION: Depression is one of the most frequently occurring psychiatric disorders worldwide, affecting 121 million worldwide. World Health Organization (WHO) estimates that it is the leading cause of disability and the fourth leading contributor to the "global burden of diseases". OBJECTIVE: Investigating and developing a drug with a novel benefit-risk profile is critical. Marine sources have been explored for their benefits as an alternative therapy for depression treatment. Numerous studies have shown that natural compounds containing peptides, alkaloids, polyphenols, diterpenes, glycosides, vitamins, and minerals from marine sources can potentially treat a wide range of disorders, including depression. Such phytoconstituents are known to reduce oxidative stress and neuroinflammation, regulate the synthesis or function of neurotransmitters such as glutamate and acetylcholinesterase, and aid in enhancing serotonin levels and nerve development. METHODS: In this review study, a literature search was conducted using terms often used, including animal models of depression and their precise phases, marine sources, algae, sponges, and indole alkaloids. Additionally, databases were examined, including Scopus, Wiley, Elsevier, Google Scholar, and Web of Science. The Snowball technique was used to identify several articles about depression but correlated to marine sources in addition to database searches. RESULTS: Current antidepressant medications have several negative side effects on the human body, including dry mouth, cardiovascular interference, gastrointestinal symptoms, genitourinary symptoms, hepatotoxicity, convulsions, and obesity. As a result, researchers can identify a wide range of potential targets for medications derived from marine sources. A combination of marinederived drugs and available treatments can be estimated to minimize the negative effects. So that these resources can be used as efficiently as possible, and various marine-derived substances can be studied for therapeutic efficacy. CONCLUSION: This review focuses on the preclinical and clinical findings of marine-derived compounds with antidepressant properties that alter behavioural parameters and biochemical abnormalities, as well as their mechanism of action and in-vivo potential.

Honey Bee Products: Preclinical and Clinical Studies of Their Anti-inflammatory and Immunomodulatory Properties.

Inflammation is a defense process triggered when the body faces assaults from pathogens, toxic substances, microbial infections, or when tissue is damaged. Immune and inflammatory disorders are common pathogenic pathways that lead to the progress of various chronic diseases, such as cancer and diabetes. The overproduction of cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, is an essential parameter in the clinical diagnosis of auto-inflammatory diseases. In this review, the effects of bee products have on inflammatory and autoimmune diseases are discussed with respect to the current literature. The databases of Google Scholar, PubMed, Science Direct, Sci-Finder and clinical trials were screened using different combinations of the following terms: "immunomodulatory", "anti-inflammatory", "bee products", "honey", "propolis", "royal jelly", "bee venom", "bee pollen", "bee bread", "preclinical trials", "clinical trials", and "safety". Honey bee products, including propolis, royal jelly, honey, bee venom, and bee pollen, or their bioactive chemical constituents like polyphenols, demonstrate interesting therapeutic potential in the regulation of inflammatory mediator production as per the increase of TNF-α, IL-1ß, IL-6, Il-2, and Il-7, and the decrease of reactive oxygen species (ROS) production. Additionally, improvement in the immune response via activation of B and T lymphocyte cells, both in in vitro, in vivo and in clinical studies was reported. Thus, the biological properties of bee products as anti-inflammatory, immune protective, antioxidant, anti-apoptotic, and antimicrobial agents have prompted further clinical investigation.

A Healthy Gut for a Healthy Brain: Preclinical, Clinical and Regulatory Aspects.

A large body of research has shown the presence of a complex pathway of communications between the gut and the brain. It is now recognized that, through this pathway, the microbiota can influence brain homeostasis and plasticity under normal and pathological conditions. This review aims at providing an overview of preclinical and clinical pieces of evidence supporting the possible role of gut-brain axis modulation in physiological aging, in a neurodevelopmental disorder, the autism spectrum disorders and in a substance abuse disorder, the alcohol addiction. Since the normalization of gut flora can prevent changes in the behavior, we postulate that the gutbrain axis might represent a possible target for pharmacological and dietary strategies aimed at improving not only intestinal but also mental health. The present review also reports some regulatory considerations regarding the use of probiotics, illustrating the most debated issues about the possibility of considering probiotics not only as a food supplement but also as a "full" medicinal product.

Novel therapeutics for the treatment of hypertension and its associated complications: peptide- and nonpeptide-based strategies.

The renin-angiotensin-aldosterone system (RAAS) is responsible for maintaining blood pressure and vascular tone. Modulation of the RAAS, therefore, interferes with essential cellular processes and leads to high blood pressure, oxidative stress, inflammation, fibrosis, and hypertrophy. Consequently, these conditions cause fatal cardiovascular and renal complications. Thus, the primary purpose of hypertension treatment is to diminish or inhibit overactivated RAAS. Currently available RAAS inhibitors have proven effective in reducing blood pressure; however, beyond hypertension, they have failed to treat end-target organ injury. In addition, RAAS inhibitors have some intolerable adverse effects, such as hyperkalemia and hypotension. These gaps in the available treatment for hypertension require further investigation of the development of safe and effective therapies. Current research is focused on the combination of existing and novel treatments that neutralize the angiotensin II type I (AT1) receptor-mediated action of the angiotensin II peptide. Preclinical studies of peptide- and nonpeptide-based therapeutic agents demonstrate their conspicuous impact on the treatment of cardiovascular diseases in animal models. In this review, we will discuss novel therapeutic agents being developed as RAAS inhibitors that show prominent effects in both preclinical and clinical studies. In addition, we will also highlight the need for improvement in the efficacy of existing drugs in the absence of new prominent antihypertensive drugs.

Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development.

Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

Lithium - Pharmacological and Toxicological Aspects: The Current State of the Art.

Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in the pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3ß) which is included in the regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc. Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well as clinical studies in order to a precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning the pharmacological and toxicological effects of lithium.

The Safety, Efficacy and Therapeutic Potential of Histone Deacetylase Inhibitors with Special Reference to Panobinostat in Gastrointestinal Tumors: A Review of Preclinical and Clinical Studies.

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

Paclitaxel: What has been done and the challenges remain ahead.

In recent years, the nanotechnology has offered researchers the opportunity to solve the problems caused by the vehicle of the standard and first formulation of paclitaxel (Taxol®), while maximizing the proven antineoplastic activity of the drug against many solid tumors. Hence, different types of nanocarriers have been employed to improve the efficacy, safety, physicochemical properties and pharmacokinetic/pharmacodynamic profile of this drug. To date, paclitaxel is the unique drug that is marketed in three different nanoplatforms for its parenteral delivery: polymeric nanoparticles (Abraxane®), liposomes (Lipusu®), and polymeric micelles (Genexol®, Nanoxel® and Paclical®). Indeed, a fourth nanocarrier might be available soon, because phase III studies of Opaxio™, a polymeric-conjugated, are near completion. Furthermore, other several nanoformulations are currently in various stages of clinical trials. Therefore, it is only through the critical analysis of clinical evidence from these studies that we can get a more concrete idea of what has been achieved with pharmaceutical nanotechnology so far. This review attempts to summarize current information available regarding the clinical status and the physicochemical characteristic of different nanocarriers for paclitaxel delivery in cancer therapy. We present an overview of the preclinical and clinical data of these systems including their pharmacokinetics, dose and administration, adverse events and clinical efficacy.

Investigational drugs for treating major depressive disorder.

INTRODUCTION: Treatment of patients suffering from major depression could be highly challenging for psychiatrists. Intractability as well as relapse is commonly seen among these patients, leading to functional impairment and poor quality of life. The present review discusses some of the novel investigational drugs that are under pre-clinical or clinical phases in the treatment of major depression. Areas covered: Molecules belonging to different classes such as triple reuptake inhibitors, opioid receptors, ionotropic and metabotropic glutamate receptors, and neurotrophin in the treatment of major depression are covered in this article. Expert opinion: Although the historical discovery of earlier antidepressant molecules (iproniazid and imipramine) is through serendipitous discovery, the present research focuses on discovering novel molecules based on our current pathophysiological knowledge of the disease condition. The fast-acting antidepressant property of N-methyl-d-aspartate (NMDA) receptor molecules, including ketamine is an exciting area of research. Other drug molecules such as amitifadine (triple reuptake inhibitor), ALKS-5461 (kappa receptor antagonist and mu opioidergic receptor agonist), rapastinel (NMDA glutamatergic receptor modulator) are under Phase-III clinical trials and could be approved in the near future for the treatment of major depression.