Drug repurposing represents a highly strategic and impactful approach in the pharmaceutical industry and medical therapy. , drug repurposing offers significant advantages over traditional drug development, including reduced costs, shorter timelines.

1. Drug repurposing for
Treatment of Parasitic
Infections
Prof. Dr. Ibrahim Abouelasaad
MD Lecture
Main Parasitology
Elective Course

2. Introduction
• The process of drug discovery involves many stages but can be
categorized into three stages: lead identification followed by preclinical
testing in animals and then clinical trials in humans.
• Treating parasitic infections poses significant challenges due to
development of drug resistance, high costs of treatment, and the complex
life cycles of parasites. Additionally, treatments can have severe side
effects, which may prevent compliance with treatment. Addressing these
issues necessitates a multi-faceted approach that includes advancements
in drug development.
• In order to avoid such long-term process of conventional drug
discovery, reverse engineering process is gaining importance. Another
alternative in drug development strategy is exploration of drug that have
already been approved for treatment of other diseases and/or whose
targets have already been discovered.

3. Drug repurposing, also known as drug repositioning, is the process of
identifying new therapeutic indications for existing drugs that are outside
the scope of the original medical indication. Drug repurposing in the
treatment of parasitic infections refers to the innovative process of using
existing drugs, which may have been initially developed for other diseases
or conditions, to treat parasitic infections.
This strategy uses what we already know about drugs and their safety to
quickly introduce new treatments for parasitic diseases, including those
that are often overlooked or are newly emerging. It offers a promising
way for enhancing the therapeutic reservoir against parasitic diseases
with potentially lower investment and shorter time frames.
Introduction

4. Advantages of
drug repurposing
in treatment of
parasitic
infections
1) Time Efficiency: Developing a new drug from scratch can take
over a decade. Repurposed drugs can reach patients much
faster because they have already passed many hurdles.
2) Cost Reduction: The process of bringing a new drug to
market is extremely costly. Repurposing existing drugs can
reduce these costs substantially as the early phases of drug
development (discovery and initial testing) are bypassed.
3) Established Safety Profiles: Drugs that are candidates for
repurposing have already been tested in humans, so their
safety profiles are well-understood.
4) Available Efficacy Data: There is already data available
regarding the drug's efficacy, which can provide initial
insights into how it might work against parasitic infections.
Drug repurposing in the treatment of parasitic infections
offers several significant advantages:

5. 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.
4) Accessibility: Repurposed drugs are often already produced at scale, which means
that manufacturing processes and distribution channels are established, potentially
making these treatments more accessible to patients, especially in resource-limited
settings.
5) Potential for Addressing Drug Resistance: With the rise of resistance to current
antiparasitic drugs, repurposing offers a quicker way to provide alternative
treatment options.
6) Combination Therapies: Repurposed drugs can be combined with existing
treatments to enhance efficacy or to reduce the risk of developing resistance.
Advantages of drug repurposing

6. Challenges of Drug Repurposing in
Treatment of Parasitic Infections
1) 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.
2) 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.
3) Intellectual Property Constraints: Patents and exclusivity rights can
restrict the repurposing of drugs.
4) 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.

7. 5) Clinical Trial Recruitment: Recruiting patients for clinical trials can be
difficult.
6) Market Competition: A repurposed drug might need to compete with
established treatments, making it difficult to penetrate the market without
clear advantages.
7) 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.
8) 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. Collaboration between stakeholders, including governments, NGOs,
and the pharmaceutical industry, can help to overcome these obstacles.
Challenges of Drug Repurposing in Treatment of Parasitic Infections

8. Each step is crucial for ensuring the safety, efficacy, and viability of repurposed drugs in
treating parasitic infections.
Steps of Drug Repurposing
for Treating Parasitic
Infections
The process of drug repurposing for use as antiparasitic
involves several key steps:
﹃ In silico approaches
﹃ In Vitro Evaluation:
﹃ In Vivo Evaluation:
﹃ Clinical Trials:
﹃ Registration
﹃ Production and Distribution:
﹃ Post-Marketing Surveillance (PMS):

9. Steps of drugs
repurposing for use
as antiparasitic
In recent years in silico models have become increasingly popular. The term ‘in silico’ refers to computational
models that investigate pharmacological hypotheses. The number of research projects that have begun to rely
on these methods is rapidly growing. Often, they are being used to explore how novel therapeutics interact
with certain molecules in the body, biological tissues, and pathogens.
The result of this approach is identification of potential therapeutic targets and selection of the candidate
drug.
By following these steps, repurposed drugs can be systematically evaluated and
introduced as new treatments for parasitic infections, offering potentially quicker and
more cost-effective solutions than developing new drugs from scratch. Here's a
breakdown of these steps:
a) Cost-Effective: Significantly reduces the costs associated with early-stage drug development by minimizing
the need for physical materials and lab space.
b) Time-Efficient: Speeds up the research process by allowing for rapid hypothesis testing and data analysis.
c) Reduction in Animal Testing: Provides an alternative to some forms of animal testing, aligning with ethical
standards and regulatory preferences towards reducing animal use in pharmaceutical research.
1. In silico approaches:
Benefits of In Silico Methods

10. In silico methods continue to evolve with advancements in computational power and
algorithms, increasingly becoming an indispensable part of modern drug development and
biomedical research.
In silico approaches:

11. 2. In Vitro Evaluation:
• Testing Against Parasites: Conduct laboratory tests of the candidate drugs against cultures of the parasites or infected
cells to assess their efficacy.
• Mechanism of Action Studies: Investigate how the drugs affect the parasites at the cellular and molecular levels.
Steps of drug repurposing for use as antiparasitic
3. In Vivo Evaluation:
• Animal Models: Test the drugs in animal models of parasitic infection to evaluate efficacy, dosage, and toxicity.
• Pharmacokinetics and Pharmacodynamics Studies: Assess how the drug is processed in the body and how it affects the
parasite within a living organism.
4.Clinical Trials:
•Phase I Trials: Conduct trials primarily to test the safety of the drug in a small group of healthy volunteers or patients, if
the drug is already known to be safe, these may be skipped.
•Phase II Trials: Evaluate the efficacy and safety of the drug in a larger group of patients with the parasitic infection.
•Phase III Trials: Further assess the efficacy and monitor adverse reactions in diverse populations and compare with
existing treatments.
5. Registration:
• Regulatory Approval: Obtain approval from relevant health authorities, such as the FDA or EMA, for the new indication
based on the evidence of the drug’s safety and efficacy.

12. 6. Post-Marketing Surveillance (PMS):
• As PMS allows assessing the effectiveness of the drug in a larger and more diverse population
over a longer period than was possible during clinical trials. So, PMS of repurposed drugs can
provide the opportunity to:
a) Monitoring Safety: Identifying, quantifying, and understanding the side effects and adverse reactions
that were not apparent during the pre-marketing phase.
b) Evaluating Long-term Efficacy: Assessing the effectiveness of the drug in a larger and more diverse
population over a longer period.
c) Detecting Rare Adverse Events: PMS enables the detection of these events as it involves a larger, more
varied group of people over a more extended period.
d) Observing Drug Interactions: identifying potential harmful interactions and for providing guidelines on
drug combinations.
e) Adjusting Drug Usage Guidelines: may include adjusting dosages, treatment durations to maximize
efficacy and minimize risks.
7. Production and Distribution:
• Scale up manufacturing and distribute the drug for the new
indication.

13. Comparison between the Steps of drugs repurposing and de novo drug
development

14. Role of Artificial Intelligence
(AI) in Drug Repurposing for
Parasitic Infections
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.

15. 1. Research and Discovery: AI analyzes vast biomedical datasets to identify potential new
uses for existing drugs. This includes evaluating chemical properties, biological activities,
and patient data to predict which drugs may be effective against unaddressed diseases.
2. 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.
3. 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.
Role of Artificial Intelligence (AI) in Drug Repurposing for Parasitic Infections

16. 4. 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.
5. 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.
6. Post-Market Surveillance: After a drug is on the market, AI monitors patient health outcomes
and drug performance in real-world scenarios, quickly identifying any adverse effects or areas
for further improvement.
Role of Artificial Intelligence (AI) in Drug Repurposing for Parasitic Infections

17. Case Studies in Drug
Repurposing as
Antiparasitic
• Antimalarial from Anticancer Drugs.
• Antiprotozoal from Antifungals Drugs.
• Antiparasitic from antibiotics Drugs.
• Other Notable Examples.
• Serendipitously discovered repurposed drugs as antiparasitic.

18. • Cancer drugs are designed to target specific pathways that are often crucial for cell proliferation
and survival. Some of these pathways are also essential for the survival and replication of malaria
parasites. This crossover can happen because the malaria parasite, Plasmodium spp., shares some
biological pathways with human cells, particularly those related to rapid cell division and
metabolism.
• For example, hydroxyurea, a drug used in cancer therapy, has been studied for its potential
antimalarial properties due to its inhibitory effect on DNA replication. Another example includes
antifolates used in chemotherapy, such as methotrexate.
Antimalarials from Anticancer Drugs
The concept of deriving antimalarial drugs from anticancer agents is an intriguing area of drug
repurposing. This approach not only has the potential to introduce new antimalarial medications
more quickly and cheaply than developing new drugs from start, but also offers hope for treating
drug-resistant strains of malaria.

19. • Repurposing antifungal agents as antiprotozoal drugs is based on the similarities between fungal
cells and protozoan parasites, which allow drugs targeting one to be effective against the other in
some cases. Both fungi and protozoa are eukaryotic, meaning they share certain cellular structures
and metabolic pathways.
• For example, amphotericin B, a potent antifungal medication, is also used to treat visceral and
cutaneous leishmaniasis. Its mechanism of binding to ergosterol, a component of fungal cell
membranes, is similarly effective against the cell membranes of certain protozoa, which also contain
ergosterol or similar sterols. Other drugs, like the azole class of antifungals, including fluconazole
and itraconazole, have been used to treat protozoal infections like Chagas disease and
leishmaniasis, because they inhibit the synthesis of ergosterol, essential for cell membrane integrity
in these pathogens.
Antiprotozoals from Antifungals
This strategy offers a shortcut to new treatments for protozoal infections, saving time and resources while
potentially providing immediate relief in areas where protozoal infections are endemic and present
significant health burdens.

20. • Doxycycline: This tetracycline antibiotic is used against the bacteria-like endosymbiont
Wolbachia within filarial nematodes. Eliminating Wolbachia with doxycycline can lead to the
death of the worms, making doxycycline an effective treatment for diseases like onchocerciasis
(river blindness) and lymphatic filariasis.
• Azithromycin: Known as a macrolide antibiotic, azithromycin has been shown to have
antimalarial properties and is used in combination therapies for malaria. It is thought to interfere
with the parasite's protein synthesis, similar to its antibacterial action.
• Clindamycin: A macrolide antibiotic that targets bacterial ribosomes, Clindamycin used as an
antiprotozoal agent, is always combined with other therapies for the treatment of falciparum
malaria, toxoplasmosis, and babesiosis..
Antiparasitic from Antibiotics
Repurposing antibiotics as antiparasitic agents exploits their action on bacterial-like targets
within parasites or targets shared between bacteria and parasites.
Here are some examples:

21. • Rifampicin: While primarily an antibiotic for tuberculosis, rifampicin has shown activity against
certain protozoa by inhibiting RNA polymerase. This has led to research for repurposing of
rifampicin, particularly as part of combination therapies of malaria to prevent the development
of resistance.
• Metronidazole and Tinidazole: These are antibiotics effective against anaerobic bacteria and
protozoans like Trichomonas vaginalis. They are also the treatment of choice for Giardia lamblia
and Entamoeba histolytica infections.
Antiparasitic from Antibiotics
• Co-trimoxazole (Trimethoprim/Sulfamethoxazole): This antibiotic combination also exhibits
effectiveness against some protozoal infections due to its inhibition of folate synthesis. It's been used
for toxoplasmosis, especially in immunocompromised patients.
• Spiramycin is a macrolide antibiotic that's often used in the treatment of bacterial infections. In
terms of antiparasitic use, spiramycin is notable for its role in the management of toxoplasmosis,
particularly in pregnant women. The drug doesn't necessarily kill the parasite outright but is believed
to control the active multiplication of the tachyzoites, thereby preventing the establishment of a fetal
infection when administered to pregnant women with toxoplasmosis.

22. Other Notable Examples
o Antidepressants: Certain antidepressants, such as sertraline and trazodone, have been found to
have antiparasitic activity. They're being investigated for their potential to treat protozoal
infections due to their ability to interfere with the uptake of polyamines or disrupt parasite-
specific ion channels.
o Statins: Originally used to lower cholesterol, statins have been reported to have antiparasitic
effects as well, potentially due to their immunomodulatory and anti-inflammatory properties.
o Diabetes Medications: Drugs like metformin have shown promise against malarial parasites,
hinting at possible repurposing for antiparasitic treatments. Other example, the anti-
inflammatory properties of Pioglitazone are explored to treat myocarditis in Chagas disease.
o Anticancer Agents: Some drugs developed for cancer, such as miltefosine (kinase inhibitors) are
being explored for their anti-protozoal activity., have been successfully repurposed for parasitic
diseases like leishmaniasis.

23. • Antiepileptics: Valproic acid, an antiepileptic, has been researched for its histone deacetylase
inhibitory activity, which could be effective against parasites by altering gene expression.
• Antirheumatics: Drugs like hydroxychloroquine, used for rheumatoid arthritis, have also been used
as antimalarials. Auranofin, another rheumatoid arthritis drug, has shown potential against
protozoal parasites due to its ability to inhibit certain enzymes.
• Blood Pressure Medications: Some antihypertensive drugs have mechanisms that may be toxic to
parasites. For example, calcium channel blockers have been proposed as treatments for malaria.
Other Notable Examples

24. Coincidental discovered repurposed drugs as antiparasitic treatments
Several drugs have been repurposed as antiparasitic treatments after their efficacy against
parasites was discovered by chance. Here are some notable examples:
 Ivermectin: Originally developed for veterinary use to treat parasitic infections in animals,
ivermectin's potential against human parasites was discovered by chance. It is now widely
used to treat onchocerciasis (river blindness) and lymphatic filariasis in humans. Its
discovery for human use earned the developers the Nobel Prize in Physiology or Medicine in
2015.
 Amphotericin B: This antifungal drug was initially used to treat fungal infections, but its
effectiveness against the protozoan parasites that cause visceral leishmaniasis was
discovered incidentally. It has since become a key drug for treating this severe form of
leishmaniasis, especially in cases resistant to first-line treatments.

25.  Hydroxychloroquine: Originally used as an antimalarial drug, hydroxychloroquine was later
found to be effective in treating autoimmune diseases such as rheumatoid arthritis and lupus.
The drug's anti-inflammatory properties were recognized after its antimalarial use, highlighting
a different mechanism of action that proved beneficial for autoimmune conditions.
 Praziquantel: While praziquantel was specifically developed for treating schistosomiasis, its use
was later extended to treat other parasitic worm infections, including those caused by cestodes
(tapeworms). Its broadening use was partly accidental as it showed efficacy against a wider
range of parasites than initially anticipated.
 Doxycycline: While it is a broad-spectrum antibiotic primarily used against bacterial infections,
doxycycline was found to have effects against malaria and was incorporated into antimalarial
treatment regimens as a prophylactic agent. This application emerged from observations of
reduced malaria incidences in populations taking doxycycline for other infections.
 Atovaquone: Known for its use in treating Pneumocystis pneumonia in AIDS patients,
atovaquone was later found to be effective against malaria when used in combination with
proguanil. The antimalarial property was recognized following the observation of its broad-
spectrum activity against various protozoans.
Coincidental discovered repurposed drugs as antiparasitic treatments

26.  Azithromycin: Originally developed as an antibiotic for bacterial infections, azithromycin was
later found to have antimalarial properties during routine screenings. This discovery was
unexpected and led to its use in combination therapies for malaria, particularly in areas with drug
resistance to older antimalarials.
 Mebendazole: Initially developed for treating intestinal worm infections, mebendazole’s
potential to inhibit cancer cell growth was discovered through its mechanism of action, which
involves disrupting microtubule dynamics. This was an unexpected finding that has led to clinical
trials testing its efficacy in treating tumor growth.
 Metronidazole: Originally developed for treating Trichomonas vaginalis, a protozoan infection,
metronidazole's broader antiprotozoal activity was recognized post-launch, leading to its use in
treating giardiasis and amoebiasis. Its efficacy against these diseases was discovered during
routine clinical use and further laboratory tests.
These examples underscore how unexpected drug properties can lead to significant shifts in treatment
strategies, providing additional benefits beyond their original indications. Such serendipitous discoveries
highlight the importance of ongoing surveillance and research, even after a drug has been marketed, as new
uses can emerge that broaden the impact of existing therapies.
Coincidental discovered repurposed drugs as antiparasitic treatments

27. 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 drug resistance and the insufficiency of treatment options for neglected
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.

28. 1. Enhance Collaboration: Strengthen partnerships among academia, industry, and government
bodies to share resources, data, and expertise, which are crucial for successful drug repurposing.
2. 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.
3. 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.
4. 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.

29. Prof. Dr. Ibrahim Abouelasaad