Compounds, Drugs and Mathematical Image Processing

Innovative Partnerships for Drug Discovery against Neglected Diseases

Biochemical markers of bone turnover are used increasingly during the clinical development of drugs for the treatment of metabolic bone diseases such as Paget's disease, osteoporosis and cancer that has metastasised to the bone. However, assessing the optimal value of these markers is often complicated, and such an assessment is an obvious prerequisite for rational use of the markers and, consequently, potential improvement of clinical drug development. Biochemical markers of bone turnover are substances in the blood or urine that are produced or released during bone remodelling. They provide semiquantitative information on bone remodelling, and are often the most adequate tool to describe the pharmacodynamics of the drug. Their use has increased considerably because of dose-effect relationships that have been seen with certain drugs, but also because they have proven relationships with clinical outcomes in several metabolic bone diseases. However, there is a lack of information on the kinetics of these markers, and the immunoassays that are frequently used in their monitoring often measure a mixture of fragments rather than a single molecular entity. For drug development it should also be realised that different markers, but also different assays for the same marker, may provide different results, considerably limiting the ability to compare results. In postmenopausal osteoporosis, relationships have been shown between several biochemical markers of bone turnover, and either fracture risk and/or the antifracture efficacy of drugs. Such relationships can be used for the development of drugs with similar mechanisms of action, but also for the development of these drugs for closely related indications, such as corticosteroid-induced osteoporosis. In both of these instances, data on effects on biochemical markers of bone turnover are usually employed in combination with information about effects on bone mineral density. However, the relationships of these parameters with clinical outcomes may be remarkably different for drugs with alternative mechanisms of action, challenging the use of the markers for the development of new drugs for the treatment of patients with osteoporosis. At present, the pharmacological treatment of cancer that has metastasised to the bone is limited to several bisphosphonates. Recent studies have shown relationships between the normalisation of levels of biochemical markers of bone turnover and clinical outcomes, and prospective studies investigating the application of such relationships are ongoing. The markers may play an important role in the optimisation of registered bisphosphonate treatments. However, their role in the development of new drugs is still limited to dose selection, and potential relationships with clinical outcomes remain to be investigated in instances of new mechanisms of action. Biochemical markers of bone turnover are a valuable asset for drug development, but their rational use is determined by a number of variables. Correctly manipulating these may improve clinical development of drugs for the treatment of patients with metabolic bone diseases such as osteoporosis and cancer metastatic to the bone.

Chapter 2 - From Bench to Bedside: Natural Products and Analogs for the Treatment of Neglected Tropical Diseases (NTDs)

Potential of sulfur-selenium isosteric replacement as a strategy for the development of new anti-chagasic drugs

The influenza virus represents a permanent global health threat because it circulates not only within but also between numerous host populations, thereby frequently causing unexpected outbreaks in animals and humans with a generally unpredictable course of disease and epidemiology. Conventional influenza therapy is directed against the viral neuraminidase protein, which promotes virus release from infected cells, and the viral ion channel M2, which facilitates viral uncoating. However, these drugs, albeit effective, have a major drawback: their targets are of a highly variable sequence. As a consequence, the virus can readily acquire resistance by mutating the drug targets. Indeed, most seasonal A/H1N1 viruses and the 2009 H1N1 virus are resistant to M2 inhibitors, and a significant proportion of the seasonal A/H1N1 viruses are resistant to the neuraminidase inhibitor oseltamivir. Development of new effective drugs for treatment of disease during the regular influenza seasons and the possible influenza pandemic represents an important goal. The results presented here point out natural products as a promising source of low toxic and widely accessible drug candidates for treatment of the influenza disease. Natural products combined with new therapeutic targets and drug repurposing techniques, which accelerate development of new drugs, serve as an important platform for development of new influenza therapeutics.

Follicular lymphoma is essentially a disease of the elderly, and the aging of the population in developed countries will increase patient numbers in coming years. Significant achievements have been made for treatment, but better understanding of the disease and major progress in biology now facilitate the development of many new drugs, which may have improved toxicity profiles making them appropriate for treatment of older adults. However, the increasing number of treatment possibilities, can also increase the toxicity risks, and unexpected toxicities specific to older adults may be encountered. Consequently, specific studies of older patients should be considered, using appropriate evaluation tools such as comprehensive geriatric assessment. This review will described the development of these new drugs, in the context of the treatment of older-adults with follicular lymphoma.

world population (Bieber et al, 2023). Among these the inflammatory diseases like rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, Crohn's disease, ulcerative colitis, psoriasis, and myasthenia gravis are prominent ones. The ever-increasing number of senior citizens (age >60 years) across the globe and the advent of newer and better diagnostic tools for immune-mediated diseases has produced an increase in the incidence of inflammatory diseases. While the general population grew from one billion in the year 1800 to eight billion at present, and it is estimated that by 2030 one in six people in world will be aged sixty or older (Bolkan et al., 2023;Pereira et al., 2023). In addition to this, studies suggest that there is an increased risk of developing immune-mediated diseases to the individuals who got SARS-CoV-2 infections (Kim et al, 2024). Despite the great advances in the treatment of these medical conditions in recent past, many patients suffer with serious conditions of the disease for a long time. This situation demands constant research, to identify new drugs, with more specific targets and fewer side effects to treat inflammatory diseases (Wang et al, 2015).In Brazil, despite the guarantee of free access to medicines through the Unified Health System for all citizens as a constitutional right, immune-mediated diseases represent a significant challenge. This is due to its complexity and the lack of adequate resources for early diagnosis and effective treatment. For example, one of the main obstacles to the accurate diagnosis of rheumatological diseases in Brazil is the shortage of specialized professionals. Recent data indicates that 53.3% of the all the rheumatologists in the country live in the capitals of state in the southeast region; 16.8% live in the very populous northeast region, while only 4.1% of medical professionals reside in the north region. This data represents the heterogeneity in the territorial distribution of professionals in Brazil, a developing country. Furthermore, the lack of adequate medical training for those who work in primary care can lead to diagnostic errors or delays in referral to specialists, which ends up worsening the health condition, with irreversible damage to patients (Scheffer et al, 2023;BRAZIL, 2021). The same kind of situation is prevalent in almost all the developing or underdeveloped countries where most of the advance medical facilities are concentrated to affluent and populous cities and rural areas are devoid of such facilities. Despite the existence of specific clinical protocols for treatment, there is a great difficulty in the diagnosis for immune disease due to complex definition of diagnostic criteria, leading to severe impact on the quality of life of affected individuals (Dal Lin et al, 2023). In this scenario, the discovery of new molecules capable of treating diseases mediated by the immune system remains fundamental.Identification of new natural products, synthetic molecules, drug repurposing, in silico molecular modelling studies associated with chemical synthesis represent important strategies for the development of new drugs (Wainwright et al, 2022;Spitschak et al, 2022). The global demand for new drugs and the associated scientific challenges were motivations for this special edition, with the aim to bring together scientific research works that addressed the development of new immunomodulatory drugs. As a result, we have very interesting articles, coming from different research aspects, which lead us to believe that they will be very useful in discovering new treatments for inflammatory diseases in near future.The study "A real-world disproportionality analysis of mepolizumab based on the FDA adverse event reporting system" investigated adverse events associated with mepolizumab in the treatment of severe asthma with an eosinophilic phenotype. Reports of expected adverse events were identified, but also unexpected ones, such as coughing, malaise and chest discomfort, recommending continued attention to safety in long-term use and in paediatrics. In conclusion, the field of anti-inflammatory drug development for immune mediated diseases is evolving rapidly and breath-taking research, supported by innovative techniques is giving transformative breakthroughs and cutting-edge solutions.However, despite the current research diversity with this edition and optimism for the future, inflammatory diseases are known for their complexity and will remain an intriguing challenge for researchers for future studies too.

Ligand based pharmacophore model development for the identification of novel antiepileptic compound

Extremophilic microorganisms from a wide variety of extreme natural environments have been researched, and many biotechnological applications have been carried out, due to their capacity to produce biomolecules resistant to extreme conditions, such as fibrinolytic proteases. The search for new fibrinolytic enzymes is important in the development of new therapies against cardiovascular diseases. This article aimed to evaluate the patents filed about protease with fibrinolytic activity produced by extremophilic microorganisms whose use is aimed at the development of new drugs for the treatment of cardiovascular diseases. The prospecting was carried out using data on deposits and patent concessions made available on the technological bases: European Patent Office (EPO), United States Patent and Trademark Office (USPTO), World Intellectual Property Organization (WIPO), Instituto Nacional de Propriedade Industrial - Brazil (INPI), The LENS and Patent Inspiration. The International Patent Classification and subclasses and groups for each document were also evaluated. Although 382 patents were selected using terms related to extreme environments, such as "thermophile" and "acidophiles", few were related to clinical use and were mainly performed using Bacillus subtilis and Streptomyces megasporus strains. A highlight of nattokinase was produced by Bacillus subtilis GDN and actinokinase by Streptomyces megasporus SD5. The low number of patents on enzymes with this profile (extreme environments) revealed a little-explored field, promising in the development of new microbial thrombolytic drugs, such as fibrinolytic enzymes with less adverse effects.

Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.

Aim. In order to determine the role of the biopharmaceutical classification system in the development of new drugs, the concept of bioavailability and bioequivalence has been investigated. Methods and results. Theoretically analysis of application of BCS in pharmaceutical development of solid dosage forms and systems analysis of research, relating to BCS has been studied. Article shows the analysis of the scientific researches of BSС and original sources application in the scientific bases of world level of SciTech development, a comparative analysis of freeing and absorption operating substances’ models, introduction of generic pharmaceutical preparations based on EMA, FDA, USP, WHO regulator documents. Conclusion. Biopharmaceutical classification system is a powerful factor in the development of new and effective generic drugs.

BackgroundPlasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.ResultsThe two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.ConclusionsThese derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

Lack of development of new antimicrobial drugs: a potential serious threat to public health

Pharmaceutical innovation is a fundamental process that involves the development, research and introduction of new drugs and therapies onto the market. This includes the discovery of new molecules, improvements in drug delivery technologies, enhancement of existing formulations and the search for new treatments for various diseases. One of the current challenges in this field is antimicrobial resistance, especially in relation to multi-resistant bacteria. To meet these challenges, innovation in the discovery and development of new drugs is essential. This is crucial for the development of new antibiotics and therapies capable of effectively combating multidrug-resistant bacteria. In addition, strategies to prevent and control antimicrobial resistance are key to ensuring the continued effectiveness of drugs over time. An important approach to gathering up -to-date information and developing better therapeutic options against multidrug-resistant bacteria is to search for the latest literature. In this context, a study was carried out to compile the most recent pharmaceutical innovations used to combat these infections by multidrug- resistant bacteria. The methodology used was a literature review of academic databases, with specific exclusion criteria to e nsure the relevance of the selected studies. This literature review covered several innovative techniques, such as computational modeling, technologies using nanocomposites, gold and silver nanoparticles, natural extracts, among others. These techniques represent promising approaches for the development of new antimicrobial treatments that can be effective against multidrug- resistant bacteria, complementing or replacing conventional treatments.

The 1962 Amendments to the Food, Drug, and Cosmetic Act have substantially increased the accountability of manufacturers of new drugs, both by raising standards for clinical testing as well as requiring, for the first time, a demonstration of proof of efficacy. Critics of the new regulatory system of the Food and Drug Administration (FDA) which imposes the requirements, have called for the repeal of the new standards on the grounds that they are stringent to the point of being counterproductive, reflect an unwarranted and excessive concern over drug safety, and have jeopardized the position of the U.S. in the worldwide development of new drugs. The author defends the regulatory system against these criticisms by demonstrating the importance of the scientific standards it has deemed essential for evaluating and approving new drug applications. Evidence of tragedy caused by inefficacious and unsafe drugs used in other countries but not in the U.S. supports FDA concern over safety and efficacy, and indicates that through its caution, the U.S. has doubtlessly been spared similar tragedy. Finally, worldwide trends in new drug development are investigated and it is shown that many factors are involved in the variation in the number and variety of drugs introduced in the marketplace of any given country which have nothing to do with its regulatory policies. It is concluded that FDA's regulatory system serves to assure the safety and efficacy of all drugs introduced into this country, while at the same time, continues to support and encourage the development of significant new drugs.