Drug Repurposing for Parasitic Diseases.pptx

Drug Repurposing for Parasitic: Drug repurposing, or drug repositioning, involves identifying new therapeutic uses for existing drugs. This approach leverages the known safety profiles, established manufacturing processes, and previously conducted clinical trials of existing drugs, thereby significantly reducing the time and cost associated with bringing new treatments to market.

1. Drug Repurposing for Parasitic Diseases Therapy Review Article By: Prof. Dr. Ibrahim Abouelasaad

2. Introduction In response to these challenges, drug repurposing has emerged as a promising strategy for the treatment of parasitic diseases. Drug repurposing, or drug repositioning, involves identifying new therapeutic uses for existing drugs. This approach leverages the known safety profiles, established manufacturing processes, and previously conducted clinical trials of existing drugs, thereby significantly reducing the time and cost associated with bringing new treatments to market. Parasitic diseases continue to pose significant public health challenges worldwide, particularly in developing countries. These diseases are responsible for considerable morbidity and mortality, impacting millions of lives and straining healthcare systems. De novo drug design ( traditional drug development) for parasitic infections faces numerous hu r dles, such as high costs, lengthy timelines, and the emergence of drug-resistant parasites.

3. In this topic, we will explore the principles and benefits of drug repurposing, examine case studies of successful repurposing efforts, and discuss the potential challenges and future directions in this field. By the end, you will have a comprehensive understanding of how drug repurposing can revolutionize the treatment landscape for parasitic infections and improve global health outcomes. Introduction By exploring the potential of repurposed drugs, researchers aim to provide effective and timely solutions to combat parasitic infections, improving patient outcomes and alleviating the global burden of these diseases. Additionally, advances in artificial intelligence (AI) and machine learning are enhancing the drug repurposing process by efficiently analyzing vast datasets to identify promising drug candidates , their therapeutic targets, and predict their efficacy against parasitic pathogens.

4. Comparison of Traditional Drug Development and Drug Repurposing: Aspect Drug Development De Novo Drug Repurposing Timeframe Long (10-15 years) Short (2-5 years) Cost High (billions of dollars) Low to moderate (millions of dollars) Risk High (many compounds fail in trials) Lower (existing safety data available) Regulatory Approval Requires extensive preclinical and clinical trials Streamlined due to existing safety and efficacy data Innovation High potential for new and innovative treatments Limited to existing drugs but new applications Success Rate Low (high failure rate) Higher (existing drugs with known profiles) Examples New antibiotics discovered through screening natural products, chemical synthesis, and advanced technologies like genomics and bioinformatics. Chloroquine and Hydroxychloroquine: Repurposed used for management of autoimmune diseases such as rheumatoid arthritis

5. Steps Involved in Drug Repurposing The idea of drug repurposing reuses old drugs for the treatment of emerging diseases. Using the drug repurposing method there are only five different stages (identify hits, target validation, clinical research, FDA approval, and public use) instead of six in the conventional method. It excludes the discovery and development stages in the conventional method, speeding up the process of bringing the potential drug into public use. It reduces the long-term (~15 years) drug development process into a short period (~4- 5 years). In silico approaches

6. Identify Hits ( Screening for Potential drug Candidates) : Duration: Approximately 12-24 months. This step involves screening existing drugs to identify potential candidates that may be effective for a new therapeutic use. Target Validation : Duration: Approximately 12 months. Once potential drug candidates are identified, this step involves validating the target to ensure that the drug interacts with the intended biological target effectively. Here is a detailed explanation of each step: In silico approaches The term ‘ in silico’   refers to computational models used to investigate pharmacological hypotheses. In silico  approaches are used to explore how novel therapeutics interact with certain molecules in the body, biological tissues, and pathogens. The results of this approach are the selection of the candidate drug (I) and identification of potential therapeutic targets (II). This approach significantly reduces the costs associated with early-stage drug development by minimizing the need for physical materials and lab space. Moreover, it speeds up the research process by allowing for rapid hypothesis testing and data analysis.

7. Clinical Studies: Duration: Approximately 12-24 months. This step involves conducting clinical trials to test the safety and efficacy of the repurposed drug in humans on using for the new indication. FDA Approval: Duration: Approximately 12-18 months. After successful clinical trials, the drug must be submitted for approval to the FDA (Food and Drug Administration) or other regulatory bodies, which involves a thorough review process. Market or Public Use: Once approved, the drug can be marketed and made available for public use. Safety Monitoring, Post-Marketing Surveillance (PMS):: Continuous monitoring of the drug's safety and effectiveness in the general population after it has been marketed.

8. Advantages of Drug Repurposing in the Treatment of Parasitic Infections Reduced Development Time : Since repurposed drugs have already undergone extensive testing for other uses, the time required to bring them to market for new indications is significantly shorter. Lower Costs : Repurposing existing drugs can be more cost-effective as many stages of drug development, such as safety and toxicity testing, have already been completed. Known Safety Profiles : Repurposed drugs have established safety profiles from their previous uses, reducing the risk of unforeseen adverse effects during new applications. Immediate Availability : Repurposed drugs are often readily available and can be rapidly deployed to treat parasitic infections, which is crucial in managing outbreaks and endemic diseases.

9. Overcoming Drug Resistance: Repurposing can provide new treatment options for parasitic diseases that have developed resistance to current therapies. Broad Spectrum Activity: Some repurposed drugs may have broad-spectrum activity, potentially treating multiple parasitic infections or other co-infections. Regulatory Benefits: Regulatory pathways for repurposed drugs can be more straightforward compared to new drug approvals, facilitating quicker access to patients. Utilization of Existing Infrastructure: Manufacturing, distribution, and clinical infrastructure already in place for the original use of the drug can be leveraged for its new application. Overall, drug repurposing presents an opportunity to provide effective treatments against parasitic infections in a way that is cost-effective, safer, and faster than the traditional drug development from scratch.

10. Regulatory Hurdles : Even if a drug is already approved for one condition, obtaining approval for a new indication requires a new set of clinical trials and regulatory review, which can be time-consuming and costly. Dosage and Formulation Issues: The effective dose for the original condition may not be appropriate for treating parasitic infections. Additionally, the formulation might need alteration to target the parasite effectively. Intellectual Property Constraints: Patents and exclusivity rights can restrict the repurposing of drugs. Pharmacokinetic and Pharmacodynamic Variability : Drugs may behave differently in the body when targeting parasites versus their original targets, leading to troubles with absorption, distribution, metabolism, and excretion. Challenges of Drug Repurposing in Treatment of Parasitic Infections

11. Clinical Trial Recruitment: Recruiting patients for clinical trials can be difficult. Market Competition : A repurposed drug might need to compete with established treatments, making it difficult to penetrate the market without clear advantages. Resistance Surveillance: There's a need for ongoing surveillance for drug resistance, which can be resource-intensive, to ensure the continued efficacy of repurposed drugs. Biological Complexity: Parasites often have complex life cycles and can exhibit unique survival mechanisms that make it challenging for repurposed drugs to be effective across different stages or species. These challenges necessitate careful consideration and strategic planning to ensure that drug repurposing efforts are both successful and sustainable in the long term. Challenges of Drug Repurposing in Treatment of Parasitic Infections

12. Case Studies in Drug Repurposing as Antiparasitics Antiparasitic from anticancer drugs . Antiprotozoals from Antifungal Drugs. Antiparasitic from antibiotics Drugs. Additional Significant Cases .

13. Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Miltefosine Anti-cancer (breast cancer) Anti-leishmanial Leishmaniasis Disrupts parasite membrane integrity and induces apoptosis Eflornithine Anti-cancer (ornithine decarboxylase inhibitor) Anti- trypanosomal African Trypanosomiasis (Sleeping Sickness) Inhibits ornithine decarboxylase, preventing polyamine synthesis and cell proliferation Methotrexate Anti-cancer (various cancers) Anti-parasitic Toxoplasmosis Malaria Inhibits dihydrofolate reductase, interfering with folate metabolism and DNA synthesis in the parasite Tamoxifen Anti-cancer (breast cancer) Anti-parasitic Schistosomiasis Malaria Induces oxidative stress and apoptosis in schistosome parasites Imatinib Anti-cancer (chronic myeloid leukemia) Anti-parasitic Chagas Disease Malaria Inhibits tyrosine kinase, interfering with parasite cell signaling and growth Artesunate Anti-cancer (under investigation) Anti-malarial Malaria Generates reactive oxygen species that damage parasite proteins and DNA Antiparasitics repurposed from anticancer drugs

14. Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Amphotericin B Antifungal Anti-protozoal visceral and cutaneous Leishmaniasis Binds to ergosterol in parasite membranes, creating pores and causing cell death Pentamidine Antifungal Anti-protozoal African Trypanosomiasis, Leishmaniasis Binds to parasite DNA and interferes with replication and transcription Ketoconazole Antifungal Anti-protozoal Leishmaniasis Inhibits ergosterol synthesis, disrupting parasite cell membrane integrity Fluconazole Antifungal Anti-protozoal Cryptococcosis, Microsporidiosis Inhibits ergosterol synthesis, leading to membrane disruption and parasite death Itraconazole Antifungal Anti-protozoal Chagas Disease, Leishmaniasis Inhibits ergosterol synthesis, affecting membrane permeability and function Antiprotozoals repurposed from Antifungal Drugs

15. Antiparasitics repurposed from antibiotic Drugs Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Metronidazole Antibiotic (bacterial infections) Anti-protozoal Amoebiasis, Giardiasis, Trichomoniasis Causes DNA strand breakage and inhibits nucleic acid synthesis in anaerobic parasites Doxycycline Antibiotic (bacterial infections) Anti-parasitic Malaria prophylaxis, Filariasis Inhibits protein synthesis in Wolbachia bacteria, endosymbionts of filarial worms Clindamycin Antibiotic (bacterial infections) Anti-malarial falciparum malaria, toxoplasmosis, and babesiosis. Inhibits protein synthesis by binding to the 50S ribosomal subunit of the parasite Paromomycin Antibiotic (bacterial infections) Anti-protozoal Amoebiasis, Leishmaniasis Inhibits protein synthesis by binding to the 30S ribosomal subunit of the parasite Trimethoprim-Sulfamethoxazole Antibiotic (bacterial infections) Anti-protozoal Toxoplasmosis Inhibits folate synthesis pathway in parasites Azithromycin Antibiotic (bacterial infections) Anti-malarial Malaria Inhibits protein synthesis by binding to the 50S ribosomal subunit of the parasite

16. Antiparasitics repurposed from antibiotic Drugs Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Tetracycline Antibiotic (bacterial infections) Anti-malarial Malaria Inhibits protein synthesis by binding to the 30S ribosomal subunit of the parasite Rifampicin Antibiotic (tuberculosis) Anti-protozoal Cryptosporidiosis, Leishmaniasis Inhibits DNA-dependent RNA polymerase, disrupting RNA synthesis in the parasite Erythromycin Antibiotic (bacterial infections) Anti-malarial Malaria Inhibits protein synthesis by binding to the 50S ribosomal subunit of the parasite Spiramycin Antibiotic (bacterial infections) Anti-protozoal Toxoplasmosis Inhibits protein synthesis by binding to the 50S ribosomal subunit of the parasite Neomycin Antibiotic (bacterial infections) Anti-protozoal Amoebiasis Inhibits protein synthesis by binding to the 30S ribosomal subunit of the parasite Sulfadiazine Antibiotic (bacterial infections) Anti-protozoal Toxoplasmosis Inhibits folic acid synthesis by competing with para-aminobenzoic acid (PABA) Nitazoxanide Antibiotic (bacterial and viral infections) Anti-protozoal Cryptosporidiosis, Giardiasis Inhibits pyruvate oxidoreductase (PFOR) enzyme-dependent electron transfer

17. Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Atovaquone Anti-pneumocystis pneumonia Anti-malarial Malaria Inhibits mitochondrial electron transport, disrupting ATP production in the parasite Rosiglitazone Anti-diabetic (type 2 diabetes) Anti-parasitic Chagas Disease Modulates host cell metabolism and immune response, reducing parasite replication Allopurinol Anti-gout Anti-leishmanial Leishmaniasis Inhibits purine metabolism, leading to reduced DNA and RNA synthesis in the parasite Chlorpromazine Antipsychotic (schizophrenia) Anti-protozoal Trypanosomiasis Inhibits energy metabolism and disrupts cell membrane integrity in the parasite Auranofin Anti-rheumatic Anti-parasitic Amebiasis Inhibits thioredoxin reductase, leading to oxidative stress and parasite death Disulfiram Anti-alcoholism Anti-parasitic Giardiasis, Malaria Inhibits aldehyde dehydrogenase and disrupts redox balance in parasites Additional Significant Cases

18. Drug Original Indication Repurposed Indication Parasitic Disease Treated Mechanism of Action as Antiparasitic Auranofin Anti-rheumatic Anti-parasitic Amebiasis Inhibits thioredoxin reductase, leading to oxidative stress and parasite death Disulfiram Anti-alcoholism Anti-parasitic Giardiasis, Malaria Inhibits aldehyde dehydrogenase and disrupts redox balance in parasites Dapsone Antibiotic (leprosy) Anti-protozoal Malaria, Pneumocystis pneumonia Inhibits dihydropteroate synthase, disrupting folate synthesis in parasites Deferoxamine Iron chelator (thalassemia) Anti-protozoal Malaria, Leishmaniasis Binds free iron, depriving parasites of essential nutrients Zidovudine (AZT) Anti-retroviral (HIV/AIDS) Anti-leishmanial Leishmaniasis Inhibits reverse transcriptase and DNA polymerase, affecting DNA synthesis in parasites Deferoxamine Iron chelator (thalassemia) Anti-protozoal Malaria, Leishmaniasis Binds free iron, depriving parasites of essential nutrients Dapsone Antibiotic (leprosy) Anti-protozoal Malaria, Pneumocystis pneumonia Inhibits dihydropteroate synthase, disrupting folate synthesis in parasites Additional Significant Cases

19. Artificial Intelligence (Ai) plays a transformative role across the entire spectrum of drug repurposing, specifically for parasitic diseases. AI significantly enhances the efficiency, effectiveness, and personalization of the drug repurposing process from initial research through to marketing and post-market analysis, promising quicker delivery of effective treatments to patients who need them. "Role of Artificial Intelligence (AI) in Drug Repurposing for the Treatment of Parasitic Infections"

20. Research and Discovery ( In silico  approaches ): AI analyzes vast biomedical datasets to identify potential new uses for existing drugs. The results of this approach is the selection of the candidate drug and identification of potential therapeutic targets. This approach significantly reduces the costs associated with early-stage drug development by minimizing the need for physical materials and lab space. Moreover, it speeds up the research process by allowing for rapid hypothesis testing and data analysis. Role of Artificial Intelligence (A i ) in Drug Repurposing for Parasitic Infections

21. Development and Testing: In the development phase, AI models simulate drug interactions at a molecular level to predict efficacy and side effects, reducing the need for early-stage clinical trials. It accelerates the design and optimization of drug formulations and dosing regimens. Clinical Trials: AI optimizes the design of clinical trials by identifying the most suitable patient demographics and predicting outcomes using historical data. This helps in reducing trial durations and improving success rates by targeting the right patient groups. Regulatory Approval: AI tools can streamline the preparation of documentation for regulatory review, ensuring accuracy and compliance with regulatory standards. It can also predict potential regulatory concerns by analyzing data from similar previously approved drugs. Marketing and Sales: In the marketing phase, AI analyzes market data to identify potential target markets, predict market demand, and optimize pricing strategies. It also personalizes marketing materials and strategies to healthcare providers and patients based on demographics and health profiles. Post-Market Surveillance: After a drug is on the market, AI monitors patient health outcomes and drug performance. Role of Artificial Intelligence (AI) in Drug Repurposing for Parasitic Infections

22. Conclusion Drug repurposing represents a highly strategic and impactful approach in the pharmaceutical industry, particularly for addressing the unmet needs of treating parasitic infections. By utilizing existing medications, drug repurposing offers significant advantages over traditional drug development, including reduced costs, shorter timelines, and an improved probability of success due to the established safety profiles of these drugs. This approach not only accelerates the introduction of treatments but also effectively combats issues like insufficiency of treatment options for neglected parasitic diseases and emerging parasites. Also, this approach opens up possibilities for addressing drug resistance—a growing concern in many parasitic infections. Moreover, repurposing can broaden the spectrum of treatment options, enhance global health security, and improve health outcomes for populations burdened by these diseases.

23. Enhance Collaboration : Strengthen partnerships among academia, industry, and government bodies to share resources, data, and expertise, which are crucial for successful drug repurposing. Invest in AI and Machine Learning : Allocate resources to support AI-driven initiatives in drug repurposing. These technologies can revolutionize the identification of new therapeutic uses for existing drugs by analyzing vast datasets more efficiently. Increase Funding : Encourage increased investment from both public and private sectors, especially for repurposing drugs to treat neglected and tropical diseases, which often suffer from a lack of funding. Public Awareness and Education: Promote awareness about the benefits and successes of drug repurposing through public health campaigns and educational programs, ensuring that healthcare providers and patients understand the potential and safety of repurposed drugs. Recommendations By adopting these recommendations, stakeholders can maximize the impact of drug repurposing, turning existing drugs into new solutions for challenging parasitic infections and thereby enhancing global health outcomes efficiently.

24. References Books: "Drug Repurposing: Approaches and Applications" by Farid A. Badria . This book provides comprehensive insights into the methodologies and case studies related to drug repurposing. "Antiparasitic and Antibacterial Drug Discovery: From Molecular Targets to Drug Candidates" by Paul M. Selzer. This book covers various aspects of drug discovery for parasitic diseases, including repurposing strategies. Review Articles: Ashburn, T.T., & Thor, K.B. (2004). Drug repositioning: identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery, 3(8), 673-683. Pushpakom , S., Iorio , F., Eyers, P.A., Escott, K.J., Hopper, S., Wells, A., ... & Pirmohamed , M. (2019). Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41-58. Talevi , A., & Bellera , C.L. (2020). Challenges and opportunities with drug repurposing: finding strategies to find alternative treatments for parasitic infections. Drug Discovery Today, 25(6), 1056-1062. Research Articles: Barrows, N.J., Campos, R.K., Powell, S.T., Prasanth, K.R., Schott-Lerner, G., Soto-Acosta, R., ... & Garcia-Blanco, M.A. (2016). A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host & Microbe, 20(2), 259-270. Denny, P.J., & Steel, P.G. (2015). Antimalarial drugs: old drugs and new ones. Parasitology, 141(1), 58-71. Harris, R.N., Hill, C.L., & Noor, Z. (2017). Drug repurposing: identifying alternative treatments for parasitic infections. Parasitology Today, 33(12), 1003-1012.

25. References Websites and Databases: RepurposeDB : A comprehensive database of drug repurposing studies and clinical trials. Available at: RepurposeDB NIH National Center for Advancing Translational Sciences (NCATS) - Drug Repurposing: Information and resources on drug repurposing initiatives. Available at: NCATS Drug Repurposing World Health Organization (WHO): Information on parasitic diseases and treatment guidelines. Available at: WHO Parasitic Diseases Conference Papers: Presentations and papers from recent conferences on drug discovery and parasitology can provide up-to-date information and case studies. Check proceedings from conferences like the International Conference on Drug Repurposing and Development or the World Congress on Parasitology and Infectious Diseases. Organizations and Research Institutes: Drugs for Neglected Diseases initiative ( DNDi ): A not-for-profit research and development organization that works to deliver new treatments for neglected diseases, including parasitic infections. Available at: DNDi Bill & Melinda Gates Foundation: They fund numerous projects related to drug development for parasitic diseases. Available at: Gates Foundation Global Health.

26. Thank you Prof. Dr. Ibrahim Abouelasaad https://www.slideshare.net/slideshow/drug-repurposing-for-parasitic-diseases-pptx/270136445