Pharmacology today and in ancient natural medicine

This essay illustrates the discovery of a few drugs from the hundreds used today. Some emerged from laboratory studies while others progressed from traditional ancient remedies to modern pharmaceuticals.  From these many therapeutics, seven are described: artemisinin, a modern treatment for malaria; quinine, another malarial treatment; digitalis, for congestive heart disease; statins, for high cholesterol and cardiovascular disease; taxanes, for cancer treatment; checkpoint inhibitors also for the treatment of cancer; and aspirin (acetylsalicylic acid), a non-steroidal anti-inflammatory, which, by reducing inflammation, helps with headache and may have some benefits for cardiovascular disease and even for cancer. The standard text for serious students of pharmacology is Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition.

While modern science deciphers molecular compounds and the underlying physiology precisely designing treatments, ancient practices have offered insights into holistic healing by using nature’s bounty and the biochemical diversity of structures that have developed through billions of years of botanical evolution. Tree bark, herbs, and roots used for centuries often have served as the foundation and inspiration for breakthroughs leading to modern drugs.

Histories

Artemisinin.  Malaria is a disease that causes alternating and debilitating episodes of fever and chills. It is caused by a parasite injected by mosquitoes into the blood stream, where it multiplies and then may be transmitted by mosquitoes to others. Foreign antigens on the parasitic plasmodium, which is not a bacterium or a virus, triggers the body to mount a defense, which includes fever, chills, and headache.

Early treatment with artemisinin drugs started over a thousand years ago in China, using wormwood extracts. Extracts taken under cool conditions in aqueous solution were placed into a tea for medicinal consumption, a procedure that Youyou Tu later adapted for her modern-day extraction procedures. She won the Nobel Prize in 2015 for leading the scientific team that analyzed and modified artemisinin extraction for its successful use as an anti-malarial drug.

Derived from sweet wormwood, artemisinin exemplifies how traditional Chinese medicine has shaped modern antimalarial therapies.

Quinine. Quinine, extracted from the bark of cinchona trees and long used in indigenous practices, highlights again nature’s role in combating this primarily tropical disease.

The cinchona tree, found in northwest South America, was likely discovered by native people to alleviate the symptoms of malaria. The active ingredient in the bark of this tree is a plant alkaloid, quinine, which has other medicinal effects in addition to its treatment for malaria. Quinine was first chemically isolated by the French chemists, Pierre-Joseph Pelletier and Joseph-Bienaime in 1829, and its molecular formula determined in 1854 by Adolph Strecker; its chemical structure suggested in 1908 by P. Rabe. Quinine is used today in conjunction with artemisinin to treat and to prevent malaria.

Digitalis. The transformative journey of this drug treatment also draws from ancient practices and a botanical origin. Digitalis, derived from the foxglove plant, is a life-prolonging drug for congestive heart failure. Its effects were recognized long before it was integrated into modern pharmacological disease management.

Relatively recently, the action of digitalis was revealed. It influences cardiovascular physiology by an indirect route: All cells have in their surface membrane an “ion pump” that removes sodium and replenishes the cell with potassium, ( see https://ronaldabercrombie.blog/2024/04/10/on-biology-and-cellular-neuroscience/). Digitalis inhibits the activity of this sodium/potassium ion pump, and heart cells are especially sensitive to digitalis. Consequently, the intracellular sodium in heart cells rises, which would seem to be an unwanted result. However, the rise in intracellular sodium brings about a rise in intracellular calcium through a co-transport-mediated exchange – termed sodium/calcium exchange. Thus, the intracellular calcium rises because of the elevated intracellular sodium, which is removed by Na/Ca exchange. The heart muscle strength of contraction is enhanced by the increase of intracellular calcium

In summary, congestive heart failure, which results from insufficient heart muscle contraction, is remedied by digitalis: Higher calcium enhances the heart muscle’s contraction. The name digitalis comes from the foxglove plant, whose Latin name is digitalis purpurea.

Statins.  For this drug, a large pharmaceutical company is largely responsible. In 1978, a team led by Alfred Alberts at Merck Research Laboratories discovered a natural product in the fermentation broth made from a mold fungus found in the soil. This product showed good HMGR (HMG-CoA reductase) inhibition and was named mevinolin. This later became known as lovastatin.

HMGR inhibition results in the reduction of the body’s cholesterol levels as HMGR is crucial for its endogenous biosynthesis: statins lower serum cholesterol by inhibiting cholesterol production.  Lower cholesterol reduces plaque formation and obstruction of arteries.

Taxanes. Monroe Wall, Mansukh Wani and colleagues at the Natural Products Laboratory of the Research Triangle Institute in North Carolina discovered and elucidated the structure of Taxol which is used for the treatment of cancer. It kills cancer cells via a mechanism of action that had not previously been imagined… that is by interfering with the cell’s cytoskeleton, which is essential for cell division. Their work led to the eventual development and marketing of drugs that have been approved by the Food and Drug Administration for treatment of ovarian, breast, lung and colon cancer, and Kaposi’s sarcoma, a cancer associated with HIV.

In 1963, crude extracts of the bark of the Pacific yew tree, Taxus brevifolia, demonstrated a broad anti-cancer activity in preclinical tumor models. In 1971, Wall and coworkers identified and purified paclitaxel as the active constituent of the bark extract. Paclitaxel’s early development was delayed, however, by the limited supply of its primary source, the Pacific Yew; difficulties inherent in large-scale isolation and extraction from a natural product, and its poor aqueous solubility. Interest was maintained during this time, however, by the characterization of its novel mechanism of action on the microtubules of the cell’s cytoskeleton, despite an inadequate supply at the time. Later, taxanes were derived from more abundant resources, which led to the semi-synthesis of 10-deacetylbaccatin III, an inactive taxane precursor, which is found in the needles of more abundant yew species. Needles could be harvested without destroying the tree. The supply of paclitaxel and subsequent synthesis of taxol is no longer limiting for the production of this effective drug.

Keytruda, Opdivo, and Yervoy. When our body reacts to a foreign substance with inflammation, the resulting discomfort informs us that we have an infection. Occasionally, this inflammatory reaction can be harmful or even fatal. Immune checkpoints like CTLA-4, PD1, and PDL1 help regulate and mitigate a too-aggressive immune response. This check on the immune system prevents damaging overreactions.

In 1996, James Allison presented the first in vivo evidence demonstrating the efficacy of checkpoint inhibitors as possible anti-cancer therapy. His research indicated that anti-CTLA-4 antibodies were capable of eradicating carcinomas and fibro-sarcomas in mice. This breakthrough paved the way for these therapies to be utilized in human treatments and ultimately earned him, along with Tasuku Honjo, the Nobel Prize in Physiology or Medicine in 2018.

Checkpoint inhibitors mitigate the body’s mechanisms against overreaction to foreign substances, including cancer. T-cells, which are part of the immune system, originate from bone marrow stem cells and mature in the thymus. They play a crucial role in identifying and responding to foreign substances and pathogens. The development of T-cell targeted immunomodulators of immune checkpoints such as CTLA-4, PD1, or PDL1 has been a significant advancement in cancer treatment over the past decade.

The first checkpoint inhibitor approved by the FDA was ipilimumab in 2011 for treatment of advanced melanoma.

The CTLA-4 gene had been discovered in 1987 and the PD-1 gene in 1992. These genes produce proteins that are negative regulators of T cell immune function, suppressing the immune response, thus preventing autoimmune diseases and potentially reducing the ability of these immune cells to destroy cancer cells. Checkpoint inhibitors take the breaks off the immune system’s response, allowing it to attack the cancer more vigorously.

Programmed cell death (PD) is a natural process in which cells systematically disassemble. Proteins PD-L1 (programmed cell death protein 1) and PD-L2 are present on blood cells, non-blood cells, and tumor cells. When these proteins bind to the PD-1 receptors on T cells, this inhibits T cell activity and diminish the immune response. This is a checkpoint activity which is eliminated by checkpoint inhibitors.

Keytruda received FDA approval on September 4, 2014. In 2017, the FDA expanded use of Keytruda (pembrolizumab) to include any metastatic or nonremovable solid tumor with certain specific molecular characteristics. Additionally, the U.S. Food and Drug Administration has approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of adult patients with inoperable or metastatic liver cancer.

Aspirin. Information for this essay was taken largely from the Journal of Cardiovascular and Thoracic Research: Historical perspective of aspirin: A journey from discovery to clinical practice Ancient and modern history by Aysa Rezabakhsh , Ata Mahmoodpoor, and Hassan Soleimanpour.

Acetylsalicylic acid (Aspirin) is a synthetic derivative of salicylic acid, which had been used as a pharmaceutical for centuries. The Sumerians first recorded its use from willow bark. Even earlier, around 4000 BC, Assyrians and Egyptians recognized the pain-relieving and fever-reducing effects of willow leaves. By ~1300 BC, willow extracts were used to treat colic, gout, and earache. In 1824, two Italian pharmacists, Bartolomeo Rigatelli and Francesco Fontana, extracted the bioactive components from willow bark; Raffaele Piria isolated salicylic acid in 1838.

In 1853, Frédéric Gerhardt first synthesized aspirin by chemically combining acetyl chloride with a salt of salicylic acid, sodium salicylate. In 1874, Friedrich von Heyden produced a synthetic form of salicylic acid in Germany. The mass production of salicylates was extended by Friedrich Bayer and William Weskott, who applied knowledge derived from manufacturing yarn dyes to the production of this pharmaceutical agent. In 1897, Felix Hoffmann, a German chemist, was the second to modify the chemical structure of salicylic acid by acetylating it. Eventually, aspirin was patented in the U.S. (1900), and the original powdered form of aspirin became available as a stamped tablet in 1904.

Aspirin is therapeutic for headaches, coronary thrombosis, angina pectoris, and vascular diseases. It works by inhibiting cyclooxygenase enzymes involved in prostaglandin synthesis from arachidonic acid.

For a more detailed description of aspirin, go to an article by Daniel Goldberg, a senior principal scientist in the medicinal chemistry department at Boehringer-Ingelheim Pharmaceuticals in Ridgefield, Connecticut, excerpted from Molecules That Matter, a compilation of essays published by the Frances Young Tang Teaching Museum and Art Gallery at Skidmore College and by the Chemical Heritage Foundation (now the Science History Institute).