Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales.

The nucleic acid topoisomerases (TOP) are an evolutionary conserved mechanism to solve topological problems within DNA and RNA that have been historically well-established as a chemotherapeutic target. During investigation of trends within clinical trials, we have identified a very high number of clinical trials involving TOP inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 233 unique molecules with TOP-inhibiting activity. In this review, we provide an overview of the clinical drug development highlighting advances in current clinical uses and discussing novel drugs and indications under development. A wide range of bacterial infections, along with solid and hematologic neoplasms, represent the bulk of clinically approved indications. Negative ADR profile and drug resistance among the antibacterial TOP inhibitors and anthracycline-mediated cardiotoxicity in the antineoplastic TOP inhibitors are major points of concern, subject to continuous research efforts. Ongoing development continues to focus on bacterial infections and cancer; however, there is a degree of diversification in terms of novel drug classes and previously uncovered indications, such as glioblastoma multiforme or Clostridium difficile infections. Preclinical studies show potential in viral, protozoal, parasitic and fungal infections as well and suggest the emergence of a novel target, TOP IIIß. We predict further growth and diversification of the field thanks to the large number of experimental TOP inhibitors emerging.

Advances in development of biomarkers for brain damage and ischemia.

Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes.

Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov.

Major depressive disorder (MDD), commonly known as depression, affects over 300 million people worldwide as of 2018 and presents a wide range of clinical symptoms. The international clinical trials registry platform (ICTRP) introduced by WHO includes aggregated data from ClinicalTrials.gov and 17 other national registers, making it the largest clinical trial platform. Here we analysed data in ICTRP with the aim of providing comprehensive insights into clinical trials on depression. Applying a novel hidden duplicate identification method, 10,606 depression trials were identified in ICTRP, with ANZCTR being the largest non- ClinicalTrials.gov database at 1031 trials, followed by IRCT with 576 trials, ISRCTN with 501 trials, CHiCTR with 489 trials, and EUCTR with 351 trials. The top four most studied drugs, ketamine, sertraline, duloxetine, and fluoxetine, were consistent in both groups, but ClinicalTrials.gov had more trials for each drug compared to the non-ClinicalTrials.gov group. Out of 9229 interventional trials, 663 unique agents were identified, including approved drugs (74.5%), investigational drugs (23.2%), withdrawn drugs (1.8%), nutraceuticals (0.3%), and illicit substances (0.2%). Both ClinicalTrials.gov and non-ClinicalTrials.gov databases revealed that the largest categories were antidepressive agents (1172 in ClinicalTrials.gov and 659 in non-ClinicalTrials.gov) and nutrients, amino acids, and chemical elements (250 in ClinicalTrials.gov and 659 in non-ClinicalTrials.gov), indicating a focus on alternative treatments involving dietary supplements and nutrients. Additionally, 26 investigational antidepressive agents targeting 16 different drug targets were identified, with buprenorphine (opioid agonist), saredutant (NK2 antagonist), and seltorexant (OX2 antagonist) being the most frequently studied. This analysis addresses 40 approved drugs for depression treatment including new drug classes like GABA modulators and NMDA antagonists that are offering new prospects for treating MDD, including drug-resistant depression and postpartum depression subtypes.

Pharmacokinetics, tissue distribution, bioavailability and excretion of the anti-virulence drug Fluorothiazinon in rats and rabbits.

Growing antimicrobial resistance has accelerated the development of anti-virulence drugs to suppress bacterial toxicity without affecting cell viability. Fluorothiazinon (FT), an anti-virulence, type three secretion system and flagella motility inhibitor which has shown promise to suppress drug-resistant pathogens having the potential to enhance the efficacy of commonly prescribed antibiotics when used in combination. In this study we characterized the pharmacokinetics, tissue distribution, bioavailability and excretion of FT in rats and rabbits. FT presented a dose-proportional linear increase in the blood of rats. Tissue distribution profiling confirmed that FT distributes to all organs being substantially higher than in the blood of rats. The bioavailability of FT was higher when administered with starch than with water implying FT should be ideally dosed with food. FT was primarily excreted in the feces in rats and rabbits while negligible amounts are recovered from the urine.

The international clinical trials registry platform (ICTRP): data integrity and the trends in clinical trials, diseases, and drugs.

Introduction: Clinical trials are the gold standard for testing new therapies. Databases like ClinicalTrials.gov provide access to trial information, mainly covering the US and Europe. In 2006, WHO introduced the global ICTRP, aggregating data from ClinicalTrials.gov and 17 other national registers, making it the largest clinical trial platform by June 2019. This study conducts a comprehensive global analysis of the ICTRP database and provides framework for large-scale data analysis, data preparation, curation, and filtering. Materials and methods: The trends in 689,793 records from the ICTRP database (covering trials registered from 1990 to 2020) were analyzed. Records were adjusted for duplicates and mapping of agents to drug classes was performed. Several databases, including DrugBank, MESH, and the NIH Drug Information Portal were used to investigate trends in agent classes. Results: Our novel approach unveiled that 0.5% of the trials we identified were hidden duplicates, primarily originating from the EUCTR database, which accounted for 82.9% of these duplicates. However, the overall number of hidden duplicates within the ICTRP seems to be decreasing. In total, 689 793 trials (478 345 interventional) were registered in the ICTRP between 1990 and 2020, surpassing the count of trials in ClinicalTrials.gov (362 500 trials by the end of 2020). We identified 4 865 unique agents in trials with DrugBank, whereas 2 633 agents were identified with NIH Drug Information Portal data. After the ClinicalTrials.gov, EUCTR had the most trials in the ICTRP, followed by CTRI, IRCT, CHiCTR, and ISRCTN. CHiCTR displayed a significant surge in trial registration around 2015, while CTRI experienced rapid growth starting in 2016. Conclusion: This study highlights both the strengths and weaknesses of using the ICTRP as a data source for analyzing trends in clinical trials, and emphasizes the value of utilizing multiple registries for a comprehensive analysis.

The Epigenetics of Migraine.

Migraine is a complex neurological disorder and a major cause of disability. A wide range of different drug classes such as triptans, antidepressants, anticonvulsants, analgesics, and beta-blockers are used in acute and preventive migraine therapy. Despite a considerable progress in the development of novel and targeted therapeutic interventions during recent years, e.g., drugs that inhibit the calcitonin gene-related peptide (CGRP) pathway, therapy success rates are still unsatisfactory. The diversity of drug classes used in migraine therapy partly reflects the limited perception of migraine pathophysiology. Genetics seems to explain only to a minor extent the susceptibility and pathophysiological aspects of migraine. While the role of genetics in migraine has been extensively studied in the past, the interest in studying the role of gene regulatory mechanisms in migraine pathophysiology is recently evolving. A better understanding of the causes and consequences of migraine-associated epigenetic changes could help to better understand migraine risk, pathogenesis, development, course, diagnosis, and prognosis. Additionally, it could be a promising avenue to discover new therapeutic targets for migraine treatment and monitoring. In this review, we summarize the state of the art regarding epigenetic findings in relation to migraine pathogenesis and potential therapeutic targets, with a focus on DNA methylation, histone acetylation, and microRNA-dependent regulation. Several genes and their methylation patterns such as CALCA (migraine symptoms and age of migraine onset), RAMP1, NPTX2, and SH2D5 (migraine chronification) and microRNA molecules such as miR-34a-5p and miR-382-5p (treatment response) seem especially worthy of further study regarding their role in migraine pathogenesis, course, and therapy. Additionally, changes in genes including COMT, GIT2, ZNF234, and SOCS1 have been linked to migraine progression to medication overuse headache (MOH), and several microRNA molecules such as let-7a-5p, let-7b-5p, let-7f-5p, miR-155, miR-126, let-7g, hsa-miR-34a-5p, hsa-miR-375, miR-181a, let-7b, miR-22, and miR-155-5p have been implicated with migraine pathophysiology. Epigenetic changes could be a potential tool for a better understanding of migraine pathophysiology and the identification of new therapeutic possibilities. However, further studies with larger sample sizes are needed to verify these early findings and to be able to establish epigenetic targets as disease predictors or therapeutic targets.

Nanoparticles in Clinical Trials: Analysis of Clinical Trials, FDA Approvals and Use for COVID-19 Vaccines.

Nanoparticles are heterologous small composites that are usually between 1 and 100 nanometers in size. They are applied in many areas of medicine with one of them being drug delivery. Nanoparticles have a number of advantages as drug carriers which include reduced toxic effects, increased bioavailability, and their ability to be modified for specific tissues or cells. Due to the exciting development of nanotechnology concomitant with advances in biotechnology and medicine, the number of clinical trials devoted to nanoparticles for drug delivery is growing rapidly. Some nanoparticles, lipid-based types, in particular, played a crucial role in the developing and manufacturing of the two COVID-19 vaccines-Pfizer and Moderna-that are now being widely used. In this analysis, we provide a quantitative survey of clinical trials using nanoparticles during the period from 2002 to 2021 as well as the recent FDA-approved drugs (since 2016). A total of 486 clinical trials were identified using the clinicaltrials.gov database. The prevailing types of nanoparticles were liposomes (44%) and protein-based formulations (26%) during this period. The most commonly investigated content of the nanoparticles were paclitaxel (23%), metals (11%), doxorubicin (9%), bupivacaine and various vaccines (both were 8%). Among the FDA-approved nanoparticle drugs, polymeric (29%), liposomal (22%) and lipid-based (21%) drugs were the most common. In this analysis, we also discuss the differential development of the diverse groups of nanoparticles and their content, as well as the underlying factors behind the trends.

Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules.

The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.

Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999-2021. A total of 695 interventional trials were manually assessed from clinicaltrial.gov with the search term « ADHD¼, and trial data has been used for analysis. A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants (e.g., methylphenidate hydrochloride, lisdexamfetamine dimesylate, amphetamine sulfate, mixed amphetamine salts, a combination of dexmethylphenidate hydrochloride and serdexmethylphenidate chloride), selective noradrenaline reuptake inhibitors (atomoxetine, viloxazine), and alpha2 adrenergic receptor agonists (guanfacine hydrochloride, clonidine hydrochloride). Several studies investigated antidepressants (e.g., bupropion hydrochloride, vortioxetine), and atypical antipsychotics (e.g., quetiapine, aripiprazole) but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.

Stem Cells in Clinical Trials on Neurological Disorders: Trends in Stem Cells Origins, Indications, and Status of the Clinical Trials.

Neurological diseases can significantly reduce the quality and duration of life. Stem cells provide a promising solution, not only due to their regenerative features but also for a variety of other functions, including reducing inflammation and promoting angiogenesis. Although only hematopoietic cells have been approved by the FDA so far, the number of trials continues to expand. We analyzed 492 clinical trials and illustrate the trends in stem cells origins, indications, and phase and status of the clinical trials. The most common neurological disorders treated with stem cells were injuries of brain, spinal cord, and peripheral nerves (14%), stroke (13%), multiple sclerosis (12%), and brain tumors (11%). Mesenchymal stem cells dominated (83%) although the choice of stem cells was highly dependent on the neurological disorder. Of the 492 trials, only two trials have reached phase 4, with most of all other trials being in phases 1 or 2, or transitioning between them (83%). Based on a comparison of the obtained results with similar works and further analysis of the literature, we discuss some of the challenges and future directions of stem cell therapies in the treatment of neurological diseases.

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review.

BACKGROUND: This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment. METHODS: A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021. RESULTS: Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication-gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/CYP2C9; (2) celecoxib/CYP2C9; (3) piroxicam/CYP2C8, CYP2C9; (4) diclofenac/CYP2C9, UGT2B7, CYP2C8, ABCC2; (5) meloxicam/CYP2C9; (6) aspirin/CYP2C9, SLCO1B1, and CHST2; (7) amitriptyline/CYP2D6 and CYP2C19; (8) imipramine/CYP2C19; (9) nortriptyline/CYP2C19, CYP2D6, ABCB1; and (10) escitalopram/HTR2C, CYP2C19, and CYP1A2. CONCLUSIONS: Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the CYP2C9 poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management.

Genetic and Clinical Factors Associated with Olokizumab Treatment in Russian Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease and its treatment is an urgent problem of rheumatology. Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-6 and is one of the few promising drugs for RA therapy. One-hundred-and-twenty-five DNA samples from Russian patients with RA, treated with olokizumab, were genotyped with an NGS panel containing 60 single nucleotide polymorphisms (SNPs) and the whole coding sequences of IL6, IL6R, TNFRSF1A, CTLA4, IL10, IL23R, and PADI4; and by RT-PCR for HLA-DRB1 and HLA-B. Associations of polymorphic variants with olokizumab efficacy according to the scores ACR20, ACR50, and DAS28-CRP were determined. We analyzed the obtained data by using logistic regression, ROC curves, and multivariate ANOVA. A high predictive value of the response to olokizumab therapy at 24 weeks was found for the combination of HLA-DRB1*04 and HLA-B*27 alleles with SNPs located in non-HLA genes (IL1B, IL17A, PADI4, DHODH, GLCCI1, IL23R, and TNFAIP3), and clinical characteristics (age, RA duration, and intensity) according to ACR20. Thus, the comprehensive assessment of polymorphic variants of HLA and non-HLA genes considering population characteristics in combination with clinical parameters allows for the elaboration of an RA prognostic panel.

Advances in the development of new biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.

Cancer Vaccine in Cold Tumors: Clinical Landscape, Challenges, and Opportunities.

The idea of cancer immunotherapy is to stimulate the immune system to fight tumors without destroying normal cells. One of the anticancer therapy methods, among many, is based on the use of cancer vaccines that contain tumor antigens in order to induce immune responses against tumors. However, clinical trials have shown that the use of such vaccines as monotherapy is ineffective in many cases since they do not cause a strong immune response. Particular tumors are resistant to immunotherapy due to the absence or insufficient infiltration of tumors with CD8+ T cells, and hence, they are called cold or non-inflamed tumors. Cold tumors are characterized by a lack of CD8+ T cell infiltration, the presence of anti-inflammatory myeloid cells, tumor-associated M2 macrophages, and regulatory T cells. It is very important to determine the stage of the antitumor response that does not work properly in order to use the right strategy. Applying other therapeutic methods alongside cancer vaccines can be more rational for cold tumors, which do not provoke the immune system strongly. Herein, we indicate some combinational therapies that have been used or are in progress for cold tumor treatment alongside vaccines.

Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies.

Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.

Pharmacological treatment of migraine: Drug classes, mechanisms of action, clinical trials and new treatments.

Migraine is the sixth most prevalent disease globally, a major cause of disability, and it imposes an enormous personal and socio-economic burden. Migraine treatment is often limited by insufficient therapy response, leading to the need for individually adjusted treatment. In this review, we analyse historical and current pharmaceutical development approaches in acute and chronic migraine based on a comprehensive and systematic analysis of Food and Drug Administration (FDA)-approved drugs and those under investigation. The development of migraine therapeutics has significantly intensified during the last 3 years, as shown by our analysis of the trends of drug development between 1970 and 2020. The spectrum of drug targets has expanded considerably, which has been accompanied by an increase in the number of specialised clinical trials. This review highlights the mechanistic implications of FDA-approved and currently investigated drugs and discusses current and future therapeutic options based on identified drug classes of interest.

Biological Mechanisms of Atypical and Melancholic Major Depressive Disorder.

BACKGROUND: This review summarizes recent findings in molecular biology and neuroimaging and their applicability to the classification and identification of depression. We discuss whether there is reliable evidence that could become a basis for biomarkers or subtyping that may enhance our understanding of the biological foundations of depression and may be useful for clinical practice with respect to diagnosis and prognosis as well as the selection of treatments. OBJECTIVE: The purpose of this investigation is to present molecular mechanisms that contribute to different origins of depressions that could prove useful in the daily psychiatric clinic-based practices. METHODS: The authors have analyzed and summarized electronic publications available in PubMed, Science Direct, Google Scholar, and Scopus. RESULTS: The introduction of molecular diagnostic methods into medical practice is a promising method to improve the accuracy of the diagnosis of depression in clinical settings. The literature analysis revealed structural changes in some areas of the brain, its neuroplasticity, as well as changes at the molecular, epigenetic, and genetic levels. However, there are no current reliable biomarkers for differential diagnosis of the types and subtypes of depression. CONCLUSION: Major depressive disorder is a biologically and genetically heterogeneous disorder. Given its complexity, subtyping is worthwhile to identify biological bases of conditions. The literature review provides ample findings that reveal possible underlying biological mechanisms associated with atypical and melancholic depression. Additional focused research should be continued with respect to the molecular and genetic biology of different types of depression. There already are promising findings, but additional research to define biologically based depressive subtypes is needed and worthwhile.

Therapy response prediction in major depressive disorder: current and novel genomic markers influencing pharmacokinetics and pharmacodynamics.

Major depressive disorder is connected with high rates of functional disability and mortality. About a third of the patients are at risk of therapy failure. Several pharmacogenetic markers especially located in CYP450 genes such as CYP2D6 or CYP2C19 are of relevance for therapy outcome prediction in major depressive disorder but a further optimization of predictive tools is warranted. The article summarizes the current knowledge on pharmacogenetic variants, therapy effects and side effects of important antidepressive therapeutics, and sheds light on new methodological approaches for therapy response estimation based on genetic markers with relevance for pharmacokinetics, pharmacodynamics and disease pathology identified in genome-wide association study analyses, highlighting polygenic risk score analysis as a tool for further optimization of individualized therapy outcome prediction.

Recent developments of HDAC inhibitors: Emerging indications and novel molecules.

The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.

High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis.

BACKGROUND: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression. METHODS: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October [Formula: see text], 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random-effects empirical Bayes model. RESULTS: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of [Formula: see text] points (CI [[Formula: see text]], [Formula: see text]) in the BDI scale, of [Formula: see text] points (CI [[Formula: see text]], [Formula: see text]) in the BDI-II scale and of [Formula: see text] points (CI [[Formula: see text]], [Formula: see text]) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of [Formula: see text] (CI [[Formula: see text]], [Formula: see text]) points in the HIT6 scale, [Formula: see text] (CI [[Formula: see text]], [Formula: see text]) in the MIDAS scale, [Formula: see text] (CI [[Formula: see text]], [Formula: see text]) points in the VAS scale and of [Formula: see text] (CI [[Formula: see text]], [Formula: see text]) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores. CONCLUSION: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.