Chapter One - The hybrid antimalarial approach: A roadmap: 2024

Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

PurposeThe purpose of this paper is to examine the pharmaceutical supply chain for artemisinin‐based combination therapies (ACT) in Ghana.Design/methodology/approachThis study employed an inductive approach in examining the dynamics of the pharmaceutical supply chain. The study also used analytical hierarchical process in identifying factors that are detrimental to the ACT supply chain.FindingsThe study revealed that there are basically two main supply channels through which ACT enters the Ghanaian pharmaceutical system – private and public. The ACT network depicts a strong evidence of actor interdependence and long‐term relationships. However, the key supply chain enabler – the use of information technology – was found to be lacking, leading to delays and disruptions in the supply chain system. Disruption was found to be the main detrimental factor to the supply chain although delay was found to be occurring more frequently. Price increases indicated a low effect on the supply network at the pharmacy level, but the general price of the highly subsidised effective ACT (Coartem) remains very high.Research limitations/implicationsOwing to constraints in accessibility, it was challenging to contact all the actors in the network individually, especially the consumer. Drugs considered in the study were the WHO approved ACT, even though efforts were made to compile available anti‐malarial drugs on the market.Practical implicationsThis study has provided insights into the supply chain for ACT. The findings of the study are relevant in improving the supply chain system.Originality/valueThe paper brings to the fore the need for a proper pharmaceutical supply chain management in the health sector with regards to one of the world's most infectious and deadly diseases – malaria.

Approaches of formulation bridging in support of orally administered drug product development

Artemisinin-based combination therapies (ACTs): Best hope for malaria treatment but inaccessible to the needy!

Filamentous fungi are a rich source of bioactive compounds, which make them a promising resource for the discovery of new drugs. Objective: The objective of this study was to systematically review research data on bioactive compounds of filamentous fungi with biological activity. Theoretical Frame: This study used, as a theoretical basis, the literature published in the Medline, Web of Science and Science Direct databases in the period from 2012 to 2021, with the main citations: Main Items for Reporting Systematic Reviews and Meta-analyses (PRISMA) and Meta-Analysis of Statistics Assessment and Review Instrument (MASTARI). Method: A systematic electronic search was conducted in the Medline (PubMed), Web of Science (WoS) and Science Direct databases, using the descriptors “Filamentous fungi” AND “Bioactive compounds”, in order to identify articles related to the selected topic. The articles were selected by three independent reviewers among those published in English in the last 10 years. Results and Conclusions: The search resulted in 151 articles, of which 8 met the inclusion criteria and were eligible for bias risk assessment using six quality criteria. Filamentous fungi are a large and promising source of bioactive compounds due to various biological activities such as strong inhibition of phosphodiesterase 4B, cytotoxicity against cancer cells, and antimicrobial, immunosuppressive, antibacterial, antifungal, antiviral and anti-inflammatory activities. In view of the results, further efforts are hoped to discover new drugs from filamentous fungi. Currently, several studies are being developed with different strains of filamentous fungi collected in different environments, such as forests, sea, icy regions and soil. Aspergillus and Penicillium are among the most studied genera. These fungi produce several bioactive compounds, some already reported and others recently discovered. In vitro and in silico studies are being used to test the different biological activities provided by bioactive compounds; therefore, the results of these researches are very promising for the discovery of new drugs. Additionally, further studies are needed to test these activities in in vivo models. The results obtained are of great relevance for medicine and the pharmaceutical industry, as they bring an update of the main bioactive compounds and their biological activities from biodiversity, which can be used in the development of new drugs capable of fighting different diseases. Still, they can help the academic and scientific community about what has been studied and what remains to be researched. In the future, other species and strains of fungi can be studied, aiming to discover new bioactive compounds with biological activity; for this, fungi can be collected from different environments, such as forests, sea and soil microbiota, or isolated from plants, extreme and remote environments. In this way, it would be possible to make better use of the world's biodiversity, use molecular-based approaches and tools and produce resources capable of improving the quality of human life. Implications of the research: This study is highly relevant for the purposes of the Programa de Pós-Graduação em Saúde e Desenvolvimento Socioambiental da Universidade de Pernambuco, Campus Garanhuns, as well as for the entire academic, scientific and pharmaceutical community interested in discovering new bioactive compounds with biological activity. Originality and value: The study sought to present to the academic, scientific and pharmaceutical community what is currently being researched on bioactive compounds of filamentous fungi with biological activity, providing current information and main researchers, indicating what remains to be investigated and collaborating for the environmental and social management of the sector of health.

Introduction Malaria, the most devastating parasitic disease, is currently treated with artemisinin-based combination therapies (ACTs). Unfortunately, some ACTs are unable to rapidly clear Plasmodium falciparum parasites from the blood stream and are failing to cure malaria patients; a problem, so far, largely confined to Southeast Asia. There is a fear of resistant Plasmodium falciparum emerging in other parts of the world including Sub-Saharan Africa. Strategies for alternative treatments, ideally non-artemisinin based, are needed. Areas covered This narrative review gives an overview of approved antimalarials and of some compounds in advanced drug development that could be used when an ACT is failing. The selection was based on a literature search in PubMed and WHO notes for malaria treatment. Expert opinion The ACT drug class can still cure malaria in malaria endemic regions. However, the appropriate ACT drug should be chosen considering the background resistance of the partner drug of the local parasite population. Artesunate-pyronaridine, the ‘newest’ recommended ACT, and atovaquone-proguanil are, so far, effective, and safe treatments for uncomplicated falciparum malaria. Therefore, all available ACTs should be safeguarded from parasite resistance and the development of new antimalarial drug classes needs to be accelerated.

Approach to Evaluating QT Prolongation of Quetiapine Fumarate in Late Stage of Clinical Development Using Concentration-QTc Modeling and Simulation in Japanese Patients With Bipolar Disorder

Introduction Despite advances in the medical management of ulcerative colitis (UC), a subgroup of patients does not respond to currently available therapies. A number of novel drugs are in late stages of clinical development or have recently received regulatory approval for UC. Areas covered This review focuses on three drug classes that have recently been approved or are awaiting approval for UC: antibodies against interleukin (IL)-23, sphingosine-1-phosphate receptor (S1PR) modulators, and selective inhibitors of Janus kinases (JAK). We provide an overview of their mechanism of action and summarize available evidence for their efficacy and safety. Finally, we discuss expected future challenges in UC management. Expert opinion The evaluated drugs have demonstrated efficacy with an acceptable safety profile. IL-23 antagonists appear to be safest with very few (serious) adverse events, while the use of S1PR modulators or JAK inhibitors has been associated with infectious and cardiovascular/thromboembolic events, albeit in low numbers. Although advances in drug development are promising, there is an urgent need for (validated) biomarkers to guide rational treatment selection. The scarcity of head-to-head trials also complicates comparisons between available drugs. Breaking the therapeutic ceiling of efficacy in UC will require marked advances in management extending well beyond drug development.

Introduction: Development of new antiretroviral drugs which are highly potent, tolerable over the long term and with a high genetic barrier to resistance is essential for the treatment of a chronic viral disease that requires life-long therapy with near-perfect medication adherence. Integrase inhibitors (INI) are a new class of antiretroviral drugs that block the action of HIV integrase, which catalyses several key steps in the virus life cycle which are essential for insertion of the viral genome into the DNA of host cell.Areas covered: Dolutegravir (DTG), a second-generation INI currently in the late stage of clinical development, is an effective orally available drug with a long half-life that does not need to be pharmacologically enhanced, is effective as a once daily drug in the absence of INI resistance mutations and twice daily in presence of INI resistance mutations.Expert Opinion: DTG, as other drugs in the INI class, appears safe and well tolerated. Results from ongoing large Phase III studies will bring more generalizable and robust information on the long-term effects of DTG.

Resistance to many antimalaria drugs developed on the Cambodia-Thailand border long before developing elsewhere. Because antimalaria resistance is now a global problem, artemisinin-based combination therapies (ACTs) are the first-line therapies in most malaria-endemic countries. However, recent clinical and molecular studies suggest the emergence of ACT-resistant Plasmodium falciparum infections in the Cambodia-Thailand border area, where standard ACT is artesunate and mefloquine. These ACT failures might be caused by high-level mefloquine resistance because mefloquine was used for monotherapy long before the introduction of ACT. This observation raises 2 questions. First, how can existing P. falciparum-resistant strains be controlled? Second, how can the evolution of new ACT- resistant strains be avoided elsewhere, e.g., in Africa? Enforcement of rational drug use and improved diagnostic capacity are among the measures needed to avoid and contain ACT resistance.

Malaria is a disease caused by parasitic protozoa of the genus Plasmodium. Despite significant advances in understanding the disease and the parasite biology, malaria still remains one of the leading causes of morbidity and mortality, particularly in malaria-endemic regions of the world. The main factor hampering malaria control is the high degree of resistance developed by Plasmodium species against several classes of drugs. Artemisinin-based Combination Therapy (ACT) is the most rapidly acting antimalarial treatment effective against multi-drug resistant strains, and is, at present, the only group of antimalarial drugs to which resistance by Plasmodium falciparum has not developed yet in the field, even though the isolation of artemisinin-resistant strains is raising concern. As a result, discovering and developing novel antimalarial agents is one of the greatest challenges facing malaria control today. This review covers patent literature from 2007 to date regarding small molecules or natural compounds targeting the asexual forms of the parasite. Recent patents filed and issued for ameliorating conventional antimalarial treatment methods by non-conventional dosage forms are also reviewed.

As chloroquine and sulfadoxine-pyrimethamine (SP) are replaced by more effective artemisinin-based combination therapies (ACTs), strategies for monitoring (and, if possible, deterring) drug-resistant malaria must be updated and optimized. In vitro methods for measuring resistance will be critical for confirming and characterizing resistance to ACTs. Molecular markers are useful for tracking the emergence and dissemination of resistance and guiding treatment policy where resistance is low or moderate. Genomic approaches may help identify molecular markers for resistance to artemisinins and their partner drugs. Studies of reported ACT treatment failure should include assessing factors other than resistance that affect efficacy, including pharmacokinetics. Longitudinal clinical trials are particularly useful for comparing the benefits and risks of repeated treatment in high transmission settings. The malaria research and control community should not fail to exploit this opportunity to apply the lessons of the last 50 years to extend the useful therapeutic lives of ACTs.

Antibody–drug conjugates (ADCs) represent a promising class of drugs with a wider therapeutic index (TI) than conventional chemotherapeutic agents due to their efficient and specific drug delivery. ADC payload is attached to antibody by chemical linkage. Two classes of cytotoxins – DNA damaging agents and microtubule inhibitors – have been validated as ADC payloads in clinical trials and four ADCs, MYLOTARG®, ADCETRIS®, KADCYLA®, and BESPONSA®, have been approved so far. There are many different ADCs in clinical development stage. Novel linker-payload technologies are evaluated and a new class of payload DNA topoisomerase I inhibitor is emerging. This review will focus on introduction of the four approved ADC drugs and promising novel ADCs with DNA topoisomerase I inhibitors, Sacituzumab Govitecan and [fam-] Trastuzumab Deruxtecan, in late stages of clinical development.

Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.

Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores.