Mefenamic acid prodrugs and codrugs - two decades of development
Journal name: World Journal of Pharmaceutical Research
Original article title: Mefenamic acid prodrugs and codrugs - two decades of development
The WJPR includes peer-reviewed publications such as scientific research papers, reports, review articles, company news, thesis reports and case studies in areas of Biology, Pharmaceutical industries and Chemical technology while incorporating ancient fields of knowledge such combining Ayurveda with scientific data.
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Alaa Abu-Jaish, Gennaro Mecca, Salma Jumaa, Ameen Thawabteh, Rafik Karaman
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Full text available for: Mefenamic acid prodrugs and codrugs - two decades of development
Source type: An International Peer Reviewed Journal for Pharmaceutical and Medical and Scientific Research
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Summary of article contents:
Introduction
Prodrugs are pharmacologically inactive compounds that are converted into active drugs through metabolic processes in the body. They offer several advantages, including increased solubility, improved stability, enhanced bioavailability, and reduced side effects. The concept of prodrugs dates back to the mid-20th century and has been applied extensively over the past two decades, particularly for drugs with poor bioavailability. This mini-review focuses on the development of prodrugs and codrugs for mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID), which is commonly associated with gastrointestinal (GI) intolerance.
Prodrug Design and Mechanisms
The design of a prodrug typically involves attaching a promoiety or modifying the structure of the active drug to enhance its properties. Prodrugs can be classified into carrier-linked prodrugs and bioprecursors. Carrier-linked prodrugs contain a covalent bond between the drug and the promoiety, which must be cleaved upon administration to release the active drug. These can be further divided into bipartite, tripartite, and mutual prodrugs. In contrast, bioprecursors are inactive compounds that convert to pharmacologically active drugs via metabolic processes. The utilization of prodrugs has been shown to significantly address pharmacokinetic challenges, allowing approximately 10% of marketed drugs to be classified as prodrugs.
Mefenamic Acid and Its Challenges
Mefenamic acid, an NSAID, has analgesic and anti-inflammatory properties but poses significant risks for GI complications, including ulceration and bleeding. Such side effects severely limit its clinical utility. The review highlights various chemical modifications made to mefenamic acid to produce prodrugs that mitigate these adverse effects. Studies have shown that ester and amide prodrugs of mefenamic acid can overcome GI toxicity while retaining efficacy. The ability to mask the unpleasant taste, which is particularly challenging for pediatric and geriatric patients, has also been successfully addressed through prodrug synthesis.
Role of Codrugs
In addition to prodrugs, the development of codrugs—compounds that combine two pharmacologically active drugs into a single entity—has been explored to enhance therapeutic effects and improve patient compliance. The codrug approach holds potential for synergistic effects, especially in controlling pain associated with conditions like heavy menstrual bleeding, which is prevalent among women using contraceptive methods such as intrauterine devices (IUDs). By connecting mefenamic acid to other active pharmaceuticals via linker systems, researchers aim to enhance bioavailability and minimize adverse reactions without compromising therapeutic efficacy.
Conclusion
The research surrounding mefenamic acid prodrugs and codrugs emphasizes the innovation in drug design aimed at reducing the gastrointestinal side effects commonly associated with NSAIDs. Future efforts will focus on developing prodrugs that do not require enzymatic activation, thus providing more consistent therapeutic outcomes by relying on intramolecular reactions. Continual advancements in synthetic chemistry and a deeper understanding of organic reaction mechanisms present exciting opportunities for the creation of effective and safer therapeutic agents, further improving patient health outcomes and drug compliance.
FAQ section (important questions/answers):
What are prodrugs and their significance in drug development?
Prodrugs are inactive molecules that convert to active drugs through metabolic processes. They enhance drug properties like solubility and bioavailability, reducing side effects and improving therapeutic efficiency.
How do mefenamic acid prodrugs improve gastrointestinal tolerance?
Mefenamic acid prodrugs are designed to reduce gastrointestinal intolerance by masking the bitter taste and harmful effects associated with the parent drug, potentially leading to better patient compliance.
What distinguishes carrier-linked prodrugs from bioprecursors?
Carrier-linked prodrugs involve covalently attaching a drug to a linker that can be cleaved to release the active drug. Bioprecursors, however, have no linker and rely on metabolism to produce active entities.
What are common strategies to create NSAID prodrugs?
Strategies to create NSAID prodrugs include ester and amide modifications, utilizing anhydride linkages, mutual prodrugs, and conjugating with amino acids to enhance stability and reduce side effects.
What challenges do prodrugs face in enzyme catalysis?
Prodrugs relying on enzyme activation can face variability in effectiveness due to genetic differences, age-related changes, or interactions with other drugs, potentially leading to inconsistent clinical outcomes.
What are the future directions in prodrug design?
Future prodrug design aims to utilize intramolecular reactions, reducing reliance on enzymes, and enhancing drug release control through improved understanding of organic reaction mechanisms to optimize therapeutic effects.
Glossary definitions and references:
Scientific and Ayurvedic Glossary list for “Mefenamic acid prodrugs and codrugs - two decades of development”. This list explains important keywords that occur in this article and links it to the glossary for a better understanding of that concept in the context of Ayurveda and other topics.
1) Drug:
A drug is a substance used to diagnose, cure, treat, or prevent diseases. In the context of the text, drugs referred to include non-steroidal anti-inflammatory drugs (NSAIDs) like mefenamic acid, which are used for pain relief and reducing inflammation. Prodrugs and codrugs are designed to enhance the effectiveness and reduce side effects of these drugs.
2) Activity:
In pharmacology, the term 'activity' refers to the effectiveness of a drug in producing a desired therapeutic effect, such as pain relief or anti-inflammatory action. In the studies discussed, the activity of various prodrugs and codrugs is measured in terms of their pharmacological effects compared to the parent drugs, like mefenamic acid.
3) Study (Studying):
The study in the context of the text refers to the systematic investigation of prodrugs and codrugs to evaluate their pharmacological properties, stability, and effects on gastrointestinal side effects. This includes examining formulations, drug interactions, and the overall safety profile in preclinical and clinical scenarios.
4) Pharmacological:
Pharmacological pertains to the science of drugs and their effects on biological systems. In the article, pharmacological studies focus on the activity of NSAIDs, their mechanisms, and the therapeutic effects of synthesized prodrugs and codrugs in treating inflammation, pain, and other conditions.
5) Pain:
Pain is a sensory and emotional experience typically associated with tissue damage or injury. The text describes the use of NSAIDs like mefenamic acid, which are used to alleviate pain, particularly in conditions like menstrual cramps. Reducing pain and discomfort is a primary goal of developing these pharmaceutical agents.
6) Bleeding:
Bleeding refers to the loss of blood due to injury or medical conditions. In the context of NSAIDs, gastrointestinal bleeding is a serious side effect associated with their use. The discussion includes how prodrugs aim to mitigate these adverse effects, improving patient safety and compliance.
7) Ulcer:
An ulcer is a sore that develops on the lining of the gastrointestinal tract, often as a side effect of NSAIDs. The text emphasizes the importance of developing prodrugs that reduce the incidence of ulcers while maintaining the therapeutic effectiveness of the parent drug to enhance patient outcomes.
8) Toxicity:
Toxicity refers to the degree to which a substance can harm humans or animals. The text addresses the gastrointestinal toxicity of NSAIDs, specifically mefenamic acid, highlighting the need to develop prodrugs with lower toxicity profiles to improve safety and efficacy in clinical use.
9) Disease:
A disease is a pathological condition of a bodily part, an infection, or a system resulting from various factors. The article discusses NSAIDs in the context of diseases characterized by pain and inflammation, reiterating the need for effective treatments that do not exacerbate side effects.
10) Science (Scientific):
Science is the systematic study of the structure and behavior of the physical and natural world through observation and experimentation. The text encompasses the scientific exploration of drug development, particularly the synthesis and evaluation of prodrugs and codrugs, which relies on rigorous scientific methodologies.
11) Bitter:
Bitter describes a sharp, pungent taste often associated with certain drugs, including NSAIDs like mefenamic acid. The text mentions the challenge of masking the bitter taste in oral formulations to enhance patient compliance, especially in pediatric and geriatric populations where taste sensitivity may be heightened.
12) Edema (Oedema):
Oedema is another term for edema, often used interchangeably and specifically denotes swelling resulting from fluid retention. The significance in the context of the text is related to the therapeutic applications of NSAIDs in combating inflammation-related oedema, thereby highlighting their anti-inflammatory properties.
13) Table:
A table in scientific literature is a systematic arrangement of data, often used to summarize results. In this context, the table refers to hydrolysis rates of synthesized prodrugs at different pHs, serving as a critical aspect of understanding drug stability and release profiles during studies.
14) Blood:
Blood is the fluid that circulates in the body's cardiovascular system, delivering oxygen and nutrients while removing waste products. The article mentions drug metabolism occurring in the blood, affecting the action and efficacy of prodrugs and their active forms once converted within the circulatory system.
15) Miṇi (Mini):
Mini typically refers to something of small size or extent. Here, it refers to a review, which is a concise summary of developments over the past two decades concerning prodrugs and codrugs, focusing on mefenamic acid’s synthesis and pharmacological evaluations.
16) Life:
Life refers to the condition distinguishing animals and plants from inorganic matter, including the ability to grow, reproduce, and respond to stimuli. In a medical context, improving quality of life through effective, safe pain relief and treatment of inflammatory conditions is a primary goal of drug development.
17) Antibiotic (Antibacterial):
Antibacterial refers to substances that inhibit bacterial growth or kill bacteria. Although the focus is on NSAIDs, the text acknowledges the importance of drug formulations with antibacterial properties, particularly in the context of improving overall therapeutic profiles of certain NSAIDs by reducing side effects.
18) Medium:
Medium generally refers to a surrounding environment or substance in which processes occur. In pharmacological studies, various mediums are used to evaluate drug stability and activity, such as buffer solutions at different pH levels, providing insights into how drugs behave in the human body.
19) Death:
Death refers to the cessation of all biological functions sustaining a living organism. The article underscores the potential fatal consequences of NSAID-related gastrointestinal complications, stressing the urgency of developing safer prodrug alternatives to mitigate risks associated with traditional NSAIDs.
20) Pur:
Poor indicates a lack of quality or deficiency. In the literature, it describes situations such as poor bioavailability of traditional drugs and challenges in achieving therapeutic efficacy, motivating research into new formulations that optimize drug delivery and patient outcomes, particularly in NSAIDs.
21) Rheumatoid arthritis:
Rheumatoid arthritis is a chronic inflammatory disorder affecting joints, leading to painful swelling and potential joint deformities. NSAIDs are commonly prescribed to alleviate pain and inflammation in patients with rheumatoid arthritis, and thus, the literature discusses optimizing these treatments through prodrugs and codrugs.
22) Human body:
The human body refers to the physical structure of a human being, encompassing various systems and biological mechanisms. Understanding how drugs affect the human body is critical for pharmacological research, particularly for optimizing drug development and reducing adverse effects in drug therapies.
23) Inflammation:
Inflammation is the body's response to injury or infection, characterized by redness, swelling, heat, and pain. NSAIDs like mefenamic acid target inflammation as part of their therapeutic action, and the text explores how prodrugs can enhance efficacy while minimizing adverse gastrointestinal effects.
24) Company:
A company refers to a commercial business. In the context of the article, it mentions the historical use of prodrugs by pharmaceutical companies like Parke-Davis, indicating the long-standing industry interest in optimizing drug formulations to improve therapeutic properties and patient safety.
25) Family:
Family in the biological context refers to a group of related organisms or drugs. In pharmacology, mefenamic acid and other NSAIDs belong to a family of compounds that share similar pharmacodynamic and chemical properties, which influences their development and application in treating pain and inflammation.
26) Nature:
Nature encompasses the inherent qualities or characteristics of something. In the context of pharmaceuticals, the nature of drug interactions, their stability, metabolism, and effects on the human body is vital in informing future drug development and therapeutic strategies, particularly regarding safety and efficacy.
27) Reason:
Reason implies a cause or justification for an action. In drug development, the reason for creating prodrugs or codrugs often involves the aim to reduce adverse effects, such as gastrointestinal toxicity, while enhancing overall efficacy, thereby improving patient compliance and safety standards in treatments.
28) Water:
Water is a solvent essential for life and plays a crucial role in biological processes. In drug formulation, the solubility of drugs in water affects their bioavailability and therapeutic potential; therefore, the article discusses strategies to enhance water solubility in drug design, particularly for NSAIDs.
29) Field:
Field refers to a branch of study or domain of knowledge. In this mini review, the field pertains to pharmaceutical sciences, emphasizing advancements in drug formulation with a focus on improving prodrug and codrug designs, aiming for better therapeutic outcomes and reduced side effects.
30) Fever:
Fever is a temporary increase in body temperature often due to infection or illness. While the text primarily addresses the anti-inflammatory properties of NSAIDs, the historical context acknowledges their original use for reducing fever symptoms, showcasing the diverse therapeutic applications of these drugs.
31) Sah:
Shah refers to an author mentioned in the text, possibly indicating a group of researchers contributing to the study of NSAIDs and their modifications. Collaborations in research help advance knowledge and lead to innovations in drug formulations and therapeutic strategies.
32) Wall:
Wall often denotes confinement or enclosure. In the medical field, it may refer to anatomical structures, like cell walls in tissues. The text relates to gastrointestinal walls when discussing NSAIDs' adverse effects, particularly ulceration, reflecting the importance of protective measures in treatment development.
33) Line:
Line refers to a series, sequence, or a boundary. In the pharmacological context, it can relate to drug classes or dosing protocols. The article examines the line of development for prodrugs and codrugs aiming to refine therapeutic options within established treatment boundaries.
34) Hand:
Hand refers to the limb of a human. Although not directly related to the main subject, mentioning 'hand' may point to manual dexterity in performing drug experiments or may metaphorically signify human involvement in drug trials and patient care related to NSAID use.
Other Science Concepts:
Discover the significance of concepts within the article: ‘Mefenamic acid prodrugs and codrugs - two decades of development’. Further sources in the context of Science might help you critically compare this page with similair documents:
Therapeutic effect, Pain relief, Anti-inflammatory activity, Pharmacological evaluation, Analgesic activity, Gastrointestinal side effects, Ulcer index, Non steroidal anti inflammatory drug, Bioavailability enhancement, Pharmacokinetic properties, Tail-flick method, Therapeutic efficiency, Analgesic and Anti-inflammatory Activity, Eddy's hot plate method, Mefenamic Acid, In vivo evaluation, Pharmaceutical science, Kinetic Studies, Chemical modification, Dichloromethane, Controlled manner, Genetic polymorphism, Prodrug approach, Gastrointestinal adverse effects, Anti-ulcerogenic effect, Gastrointestinal intolerance, Parent drug, Caco-2 cell monolayers.