The Unusual Discovery of Commonly Prescribed Medications: Part 4

The process of drug discovery and testing can be a long, slow, and painful road. It’s estimated that for approximately every 10,000-15,000 new compounds identified, only 5 will be considered safe for testing in human volunteers and 1 will be approved by the FDA.¹ Additionally, the journey from preclinical studies to FDA approval can take 10-15 years and range in cost from $800 million to $1.4 billion.

There are many factors that contribute to the process of drug discovery. One particular phenomenon that has been described in the literature involves serendipity, or chance discovery (i.e. finding one thing while looking for another). According to 1 analysis, serendipitous events were identified in the discovery of nearly 6% of all drugs in use today.²

This article will describe the unusual discovery of 5 commonly prescribed medications, some of which were through serendipitous events. Part 3 previously covered 5 medications.

16. Glatiramer acetate (Copaxone, Teva)³

Glatiramer acetate is an immunomodulator medication used to treat multiple sclerosis (MS). The compound was discovered serendipitously in the late 1960s to early 1970s during research at the Weizman Institute in Israel. Researchers were investigating synthetic polymers of amino acids to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of demyelinating brain inflammation. Instead of inducing EAE, glatiramer acetate demonstrated a protective effect against EAE and reduced the prevalence and severity of histological lesions.

It was ultimately approved in 1996 for relapsing-remitting MS after studies had demonstrated its safety and efficacy in this population. In 2015, the FDA approved the first generic version of glatiramer acetate (Glatopa, Novartis).

17. Lofexidine hydrochloride (Lucemyra, US WorldMeds)⁴

Lofexidine is a structural analog of clonidine that works as a centrally acting α2-adrenergic receptor agonist. It was initially approved in Germany to treat hypertension, but was subsequently withdrawn from the market due to a lack of clinical efficacy (likely due to its high receptor affinity). In October 1992, lofexidine was approved in the UK to treat opioid withdrawal symptoms. Due to its greater selectivity for the α2-receptor than clonidine, it’s believed to be associated with fewer adverse events.

In May 2018, the FDA approved lofexidine for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. With its approval, lofexidine became the first nonopioid treatment approved for management of opioid withdrawal symptoms in adults.

18. Sotalol hydrochloride^5,6

Sotalol hydrochloride, is an antiarrhythmic drug with Class II (beta-adrenergic blocking) and Class III (potassium channel blocking) properties. It was first synthesized in 1960 by Mead-Johnson Pharmaceutical and unlike many initial beta-adrenergic blocking compounds, sotalol had no local anesthetic activity. Additionally, due to its hydrophilic nature, it lacked central nervous system side effects.

Sotalol was originally thought to be a useful agent for lowering blood pressure and reducing symptoms of angina. Starting in the late 1970s, sotalol was commonly used outside of the United States for its beta-blocking effects, accounting for nearly 1 million prescriptions in 1983 within the United Kingdom, France, Germany, and Sweden. In the 1980s, sotalol generated new interested as an antiarrhythmic agent. Following a large scale study publication in 1986, sotalol’s antiarrhythmic properties were distinguished from those reported for other beta-blockers and it would be formally approved in the United States in 1992.

19. Dimethyl fumarate (Tecfidera, Biogen)^7,8

The first medical use of fumaric acid was described in the literature in 1959 by Walter Schweckendiek, a German chemist. At the time, some had theorized that psoriasis might be caused by a metabolic imbalance involving the citrate cycle. Schweckendiek, who had psoriasis himself, began taking fumaric acid in a self-experiment and discovered clinical benefit. Initially, the fumaric acid was used as a topical formulation and in the early 1990s, an oral formulation was brought to the market in Germany for psoriasis.

In Germany, 2 psoriasis patients who also suffered from MS improved in both diseases. This prompted further research and Biogen ultimately began developing dimethyl fumate, a derivative of fumaric acid, for the treatment of MS. In May 2013, dimethyl fumarate became the third oral therapy FDA approved for relapsing multiple sclerosis.

While the exact mechanism of action of dimethyl fumarate is not fully understood, the compound appears to exhibit immunomodulatory effects by inhibiting release of pro-inflammatory cytokines, which is valuable in treating both psoriasis and MS).

20. Theophylline⁹

Theophylline was first extracted from tea leaves in 1888 by the German biologist Albert Kossel. In the early 1900s, a new and cheaper method of synthesizing theophylline was developed and it found medical use as a diuretic, as early as 1902. In the 1920s and 30s, the favorable effect of theophylline had been highlighted in treating bronchospasm and asthma; however, it wasn’t until the 1970s after further testing and development of sustained release preparations that theophylline started gaining more mainstream medical acceptance.

Although not currently a first line agent, theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

References

• About Drug Development Process. PPD. Available at: http://www.ppdi.com/About/About-Drug-Discovery-and-Development. Accessed January 20, 2019.
• Hargrave-Thomas E, Yu B, Reynisson J. Serendipity in anticancer drug discovery. World J Clin Oncol 2012; 3(1): 1-6.
• Weinstock-Guttman B, Nair KV, Glajch JL, et al. Two decades of glatiramer acetate: From initial discovery to the current development of generics. J Neurol Sci. 2017 May 15;376:255-259. doi: 10.1016/j.jns.2017.03.030.
• Gish EC, Miller JL, Honey BL, Johnson PN. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother. 2010 Feb;44(2):343-51. doi: 10.1345/aph.1M347. Epub 2009 Dec 29.
• Hara, Takuji. Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development. 2003. Edward Elgar Publishing. p. 47.
• Anderson JL, Askins JC, Gilbert EM, et al Multicenter trial of sotalol for suppression of frequent, complex ventricular arrhythmias: a double-blind, randomized, placebo-controlled evaluation of two doses. J Am Coll Cardiol. 1986 Oct;8(4):752-62.
• Lowe D. Tecfidera’s Price. Science Translational Medicine. April 2, 2013. Available at: https://blogs.sciencemag.org/pipeline/archives/2013/04/02/tecfideras_price?r3f_98
• Martinez, Ana, Carmen Gil. Comprehensive medicinal chemistry. Amsterdam, the Netherlands Oxford, United Kingdom: Elsevier, 2017. p. 58.
• Wettengel R. Theophylline--past present and future. Arzneimittelforschung. 1998 May;48(5A):535-9.