Reverse Pharmacology: Need of the Time

Drug development is no more a by chance discovery now. It is an arduous, time-taking, and costly process. There are two established processes of drug discovery and development: conventional approach and reverse pharmacology (RP) approach. The term RP, an alternative path for drug discovery, began to gain recognition in the early 2000s, although the concept was not new. It was rather quite in vogue and practiced since late 19th century. Pain relieving and fever reducing properties of willow bark were well known since antiquity. In early the 19th century the physiologically active substance, salicylic acid, was isolated from the bark by several chemists. Felix Hoffmann in 1897, by acetylating salicylic acid, produced a new medicine popularly known as aspirin. They used the backward process to identify the active phytochemical in willow bark, understand its mechanism of action, and synthesized aspirin.[1] Similarly, quinine, an antimalarial drug, was also developed from cinchona bark. This process, in fact, was RP though it was named so after nearly 100 years of being in practice. Reserpine, an alkaloid found in Rauwolfia serpentina (Indian snakeroot), was a major discovery made using the RP approach. In 1931, Indian chemists Sen and Bose demonstrated the antihypertensive and tranquillizing effects of the plant.[2]

Knowledge of traditional medicine and documented clinical observations lead to the discovery and development of new drugs to treat metabolic and noncommunicable diseases. The “global burden” of these diseases is significant and a major public health concern. Thus, the RP approach is the need of the time.

The history of RP in India goes back to Sir Ram Nath Chopra and Gananath Sen who laid the foundation for drug discovery and development of ayurvedic drugs in India using the RP approach. Dr. Ashok D.B. Vaidya, a distinguished scientist from Drexel University College of Medicine, Philadelphia, along with his brother, conceived a pioneering and promising concept of RP. The term RP was popularized by Dr. Bhushan Patwardhan and other researchers who aimed to integrate the knowledge of traditional medicine with the modern drug discovery process.

The government of India has amended the Drugs and Cosmetics Act to include a category of “Phytopharmaceuticals” to be developed from medicinal plants by using the RP approach.[3] Recognizing the importance of RP, Indian Council of Medical Research (ICMR) has established an advanced center for RP at Swami Prakashananda Ayurveda Research Centre, Mumbai, where the research focus is on diabetes, musculoskeletal health, malaria, cancer, and neuronal plasticity.[4]

Several pharma industries in collaboration with academia are eagerly pursuing drug discovery and development from medicinal plants using this reverse approach. ICMR, Council of Scientific & Industrial Research (CSIR), and pharma industries have developed and standardized many drugs such as Gugulipid, a cholesterol lowering drug from Commiphora mukul taking leads from experiential database of traditional medicine and ayurveda.[5] A memory enhancer was derived and developed from Bacopa monnieri by Central Drug Research Institute (CDRI), Lucknow.[6]

RP is an approach to drug discovery and development that begins with the knowledge of traditional medicine and documented clinical observations where traditional medicine has shown tangible results. In the RP approach, drug candidates are first identified based on experiential evidence, and then validated in clinical trials. It works backward “clinic to laboratory” to identify the active compounds in the medicinal plants and understand their mechanism of action such as pharmacodynamics, pharmacokinetics, and drug-receptor sites of these phytochemicals. This contrasts with the conventional route of drug discovery and development process, which typically begins with a hypothesis about drug target, cellular/molecular structures, drug-receptor sites, a protein, etc., and then searches for compounds that can modulate the target. Thus, identified target-specific compound progresses through laboratory and clinical testing, “laboratory to clinic” to validate its therapeutic efficacy. This process of drug discovery and development is a time-consuming prolonged process; it may take 15 to 20 years or even more, involving huge investment of funds. Above all a greater risk is involved to human participants while carrying out clinical trials. On the other hand, the RP process is less time-consuming, economical, and relatively safer for human participants.

Many of the plant-derived drugs and other phytocompounds prescribed in lower decimal dilutions/potencies are an integral part of many homoeopathic prescriptions either for the management of an acute episode or for certain chronic conditions as an adjunct regimen. These are potential drug candidates whose target, mechanism of action, standardization, and evaluation of their safe dose and dosage regimen fall within the scope of RP in homoeopathy. The rising dengue (DEN) and chikungunya (CHIK) burden in the tropics, due to vector borne arboviruses, is of great public health concern. Our experiential data show that Eupatorium perfoliatum has astonishing results in ‘DEN-CHIK like symptoms’. In this backdrop Eupatorium perf. becomes a good drug candidate for study using reverse pharmacology process. Although there is a good therapeutic experiential database of these drugs and despite having been in use since long, adverse effects (AE) and severe adverse effects (SAE) of these drugs especially on the liver and kidney have not been fully studied by undertaking exploratory studies.

RP has a promising future; collaboration between academia and homoeopathic pharma industries can validate the pharmacological effects and study the AE/SAE of homoeopathic drugs mostly used in lower decimal dilutions whose therapeutic effects have been established experientially culminating in a paradigm shift in drug development in homoeopathy.

Echinacea has been used as an antitoxic, antibacterial, antifungal, antiviral, for centuries. Echinacea extracts have been traditionally used to treat infections and wounds. Its ability to stimulate monocytes and natural killer cells, which are the first line of defense in the body against infections, supports its immunomodulatory activity. It has an antioxidant and preservative action too.[7] Taking a lead from RP, a study on “Chemical profiling, in silico pharmacokinetics analysis and molecular docking study of phytocompounds of homeopathy medicine Echinacea angustifolia Q against suppurative bacterial proteins” is included in this issue. It concludes that Echinacea angustifolia Q has an action against most of the suppurative bacteria such as Salmonella enterica, Proteus mirabilis, and Staphylococcus aureus.

As we welcome a new year, the editorial board of Homoeopathic Links extends warmest wishes to our readers, contributors, and reviewers around the world. Each year brings new challenges and advancements, and we are honored to be part of a community that continually pushes the boundaries of medical knowledge and practice.

Happy New Year!

Publication History

Article published online:
04 December 2024

• References

• 1 Science History Institute. Felix Hoffmann. Accessed September 10, 2024 at: https://www.sciencehistory.org
• 2 Sen G, Bose K. Rauwolfia serpentina, a new Indian drug for insanity and high blood pressure. Indian Med World 1931; 2: 194
• 3 Patwardhan B, Vidya A, Chorghade M. Ayurveda, and natural products drug discovery. Curr Sci 2004; 86: 789-799
• 4 Kushwaha V, Agrawal P, Sukla V, Khan NF. Reverse pharmacology: an overview. World J Pharm Res 2022; 11 (16) 344-352
• 5 Central Drug Research Institute. Gugulipid. Accessed October 22, 2024 at: https://cdri.res.in/Gugulipid.aspx
• 6 Central Drug Research Institute. Memory enhancer (standardised brahmi). Accessed October 22, 2024 at: https://cdri.res.in/memorydrug.aspx
• 7 Sharifi-Rad M, Mnayer D, Morais-Braga MFB. et al. Echinacea plants as antioxidant and antibacterial agents: from traditional medicine to biotechnological applications. Phytother Res 2018; 32 (09) 1653-1663