With longer lifespans and heightened stress levels, the risk of neurological diseases has surged. Neurodegenerative and psychiatric conditions pose significant challenges, demanding effective therapies. Yet, drug development in this field has been disorderly, and hypothesis-driven programs have shown disappointing results. Insufficient understanding of disease mechanisms, intricate genetic and environmental factors, and oversimplified diagnostics play a role. As we explore modern treatments for central nervous system disorders, we'll delve into how Serendipity played a vital role in discovering drugs that successfully treat these abnormalities.
Ephedrine
Ephedra (ma-huang) is a Chinese shrub that was known for at least 5000 years. Emperor of China, Shen Nung, around 2700 BC, listed 365 herbs of their bitterness when the main factions were strong, medium and light. Ma-huang, whose literal translation meaning "cannabis yellow", was placed in the middle group. In China, it has been used for hundreds of years as a circulatory stimulant, diaphoretic, antipyretic, and cough sedative. Its active ingredient was isolated nearly 4,000 years later and it was named ephedrine.
As a central nervous system stimulant, ephedrine is used to treat various problems related to breathing, nasal congestion, low blood pressure, or myasthenia gravis. Ephedrine is also used to treat narcolepsy, menstrual cramps, or urinary control problems.
In 1985, Nagayoshi Nagai first synthesized and characterized the pure alkaloid ephedrine. The German chemical company, E Merck, also obtained a pure ephedrine compound in 1886. It then fell into oblivion until in 1917 its pharmacology was examined again by two Japanese researchers, who showed that it had sympathomimetic effects like its chemical relative, adrenaline.
Ephedrine was almost unknown to the western world till early 1920s. The prime factor for this ignorance was that the original articles of the Nagai (and Merck) were published either in Japanese or German. Knowledge of these languages was limited. More than 30 years later, Chen and Schmidt resynthesized ephedrine in 1923 and proved that it acted like adrenaline before discovering that these facts were already known. However, their paper, published in 1924, had a very important impact because it was written in English.
Ephedrine became extremely popular and effective as an asthma treatment, mainly because, unlike epinephrine (the standard treatment until then), it could be taken orally. Ephedrine for the treatment of asthma reached its heights in the late 1950s, since then its therapeutic use has gradually and inevitably declined. From mainstream medicine, ephedrine has slipped into the shadows of street drugs and dietary supplements. Products associated with ephedra and ephedrine are now banned in many countries because they are a key source of the production of the addictive drug methamphetamine (crystal meth).
Lidocaine
Lidocaine, a classic local anasthetic, was discovered in systematic studies by the Institute of Chemistry at Stockholm University. Hans v. Euler, studying how genes and enzymes were chemically linked in indole-chlorophyll-deficient mutants of barley, isolated gramme.
Erdtman, an organic chemist in Stockholm, knew the importance of chemical analysis. While researching the structure of gramine, he tasted one of the precursors of gramine i.e. isogramine. The numbness he later felt immediately became a hot topic, attracting attention from scholars and others. Edrtman began searching for a derivative for clinical use. Later, he and Löfgren synthesized other aminoamides, but none of them could compete with the existing ester-type local anesthetics, para-aminobenzoic acid derivatives, e.g. procaine. Löfgren and Lundqvist later continued these studies and discovered the compound lidocaine. Lidocaine represented such a significant improvement over procaine in clinical tests conducted by T. Gordh that it was adopted for clinical use.
Although lidocaine has a wide range of local anesthetic properties, it can also cause toxic irritation and damage when used in spinal anesthesia.
A Bound on History of Anesthesia on MedBound by Shuchitha Krishnamurthy (@shuchitha)
Marinol
Dronabinol, which is marketed by the trade name Marinol, is a cannabinoid, a man-made form of cannabis (herbal form of cannabis is Marijuana), used to treat loss of appetite in HIV patients and severe nausea and vomiting caused by chemotherapy in cancer treatment. Dronabinol (Marinol) is given to the patients only when other medicines fail to control severe nausea and vomiting. It was discovered accidently while studying the effects of marijuana.
Delta-9-tetrahydrocannabinol (THC) is the vital ingredient in cannabis or marijuana. The FDA approved THC for the treatment of vomiting in 1985. Since then, a synthetic THC, dronabinol (Marinol), has become available. It is formulated in sesame oil and is available as a gelatin capsule. After administration, dronabinol, also known as delta-9-THC, targets the central nervous system (CNS) and binds to the cannabinoid receptors (CBR) located there.
The most common adverse effects of Marinol are linked with the central nervous system (CNS): anxiety, confusion, depersonalization, dizziness, euphoria, dysphoria, drowsiness and abnormal thinking.
Follow the Author on MedBound: Dhanashree Thombare (@Thombare_dmt94)
References:
1. O’Neill, T. (2015, January 8). 8 drugs that exist in nature. The Week. https://theweek.com/articles/464010/8-drugs-that-exist-nature
2. Gaddum, J.H. (1954) ‘Discoveries in therapeutics’, Journal of Pharmacy and Pharmacology, 6(1), pp. 497–512. doi:10.1111/j.2042-7158.1954.tb10979.x.
3. Holmdahl, M. H. (1998). Xylocain (Lidocaine, Lignocaine), its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiologica Scandinavica, 42, 8–12. https://doi.org/10.1111/j.1399-6576.1998.tb04979.x
4. Yu, S., Wang, B., Zhang, J., & Fang, K. (2019, December 30). The development of local anesthetics and their applications beyond anesthesia. International Journal of Clinical and Experimental Medicine. Retrieved May 29, 2023, from https://e-century.us/files/ijcem/12/12/ijcem0100790.pdf
5. Dronabinol Uses, Side Effects & Warnings. (n.d.). Drugs.com. https://www.drugs.com/mtm/dronabinol.html
