Diazepam

Introduction

Diazepam is a drug belonging to the family of compounds known as benzodiazepines. These drugs are primarily used in the treatment of anxiety, alcohol withdrawal and sleep disorders. Originally released in 1963, diazepam (in addition to other benzodiazepines) was a revolutionary compound for its targeted symptoms and that was reflected in the fact that it was the most sold drug between the years of 1968 to 1982 in the US [1]. The compounds origins are traced back to synthetic sources, however, multiple studies have shown it to possibly be a natural product found in humans and plants [2].

Although diazepam was not the first benzodiazepine discovered, the initial synthesis of this class of compounds is fascinating and equally important as the discovery of diazepam itself. Benzodiazepines were discovered almost by complete accident by the pharmacist Leo Sternbach. Originally, Sternbach developed the compounds for the purpose of researching synthetic dyes in the 1930s. Two decades later, Sternbach revisited the benzodiazepine compounds (which he originally believed to be heptoxdiazines) in “the hope of finding compounds with psychopharmacological activity” [3]. He chose to stabilize one of these compounds and placed it on a shelf in the laboratory. Sometime later this compound was found while the lab was being cleaned and was shown to exhibit similar properties of the leading anxiolytic compound at the time. In 1960, this compound was released as chlordiazepoxide (Librium). This benzodiazepine was quickly improved upon and in 1963 diazepam was released under the name Valium by Hoffmann-La Roche [3].

Target

Diazepam targets the γ-aminobutyric type A (GABA_A) receptor. When it binds to the GABA_A receptor, it acts a positive allosteric modulator. This means that instead of affecting the function of the protein that it binds to, it rather “increases neuronal chloride-ion influx upon Gaba binding… thus enhancing CNS depression response” [1]. This increased CNS depression response is what triggers the calming effect of diazepam. Once in the body, a large portion of the initial dosage is circulated and allowed to bind to GABA_A receptors making it a bioavailable compound – typically in the range of 93-100% [1]. Wide therapeutic indexes are also an important property of diazepam as the previous generation of anxiolytic drugs, primarily meprobamate, was narrow in its treatment.

Diazepam has been proven to create adverse respiratory affects when administered intravenously as well as when rectal diazepam is given in the case of a seizure [4]. It has also been associated with self-aggressive behavior and impairment of motor functions at higher doses. Despite this, adverse effects “are most often a consequence of interaction with another drug (such as opiates or alcohol)” [1]. Diazepam has historically been linked to abuse and dependence and as a result is often linked do addiction.

Commercialization

When diazepam was originally produced and sold as Valium by Hoffmann La Roche, it was manufactured in the form of a tablet that came in three dosage sizes: 2, 5, and 10 mg. Roche was granted a process patent in the US in 1963 and Valium quickly became a top seller [5]. As stated earlier Valium dominated the drug market in the years following its release, going 14 years straight as the top selling drug in the US. As Valium reached its peak usage in 1975, Hoffmann La Roche had a 70% hold on the benzodiazepine market [5]. In 1984 (the year before the patent for Valium expired), Roche reported over $270 million in sales from Valium which is about $650 million in 2018 after adjusting for inflation [6].

Following the expiration of Hoffmann La Roche’s patent in 1985 there was a large influx of generic brands that were all trying to seize part of the diazepam market. By 1987 there were already 15 generic brands of diazepam and as of 2014 there were over 500 formulations [5][1]. Generic brands that began producing diazepam include Bar Pharmaceuticals, Teva Pharmaceutical Industries, Mylan, Roxane Laboratories, DuraMed, and many others [7]. Not only was production of diazepam expanded, so were the methods of delivery. Diazepam is now also delivered in the form of intravenous and intramuscular injectables, oral solutions, and a rectal gel. The FDA currently lists only one form of diazepam in a rectal gel: Diastat® [7].

The Company & Controversy

Hoffmann La Roche continues to sell Valium tablets, and in 2017 the company reported bringing in over CHF 41.2 million from pharmaceutical sales, or about $41.1 million [8]. Hoffmann La Roche is a Swiss company that is involved mainly in pharmaceuticals and diagnostics. While they have had much success, the company has had a couple of legal issues in the past 50 years. Most notably, the company as twice been accused and found to be fixing the price of vitamins – once in 1973 and again in 1999 [9].

The first offense in 1973 was brought to the European Economic Community’s (EEC) attention by an executive in Hoffman La Roche. Stanley Adams let the EEC know about the company’s price-fixing of vitamins, however, he was ultimately convicted of espionage by the Swiss government when the EEC failed to keep Adams’ name anonymous [9].

The company was again involved in price-fixing vitamins throughout the 1990s, although this time it was a lot more significant. Hoffmann La Roche was found to be conspiring with multiple other drug companies in a cartel that became known as “Vitamins Inc” to fix the price of vitamins for companies all around the world [10]. In the US the companies involved were ordered to pay over $1 billion dollars in fines and charges as a result, a record fine [10][11]. Hoffmann La Roche, the largest of the companies involved, paid $500 million in charges [11].

  

References

1.     Calcaterra, Nicholas E., and James C. Barrow. “Classics in Chemical Neuroscience: Diazepam (Valium).” ACS Chemical Neuroscience 5.4 (2014): 253–260. PMC. Web. 25 Sept. 2018.

2.     Fischer, Dr. Margarete. “Occurrence of ‘Natural’ Benzodiazepines.” Life Science, vol. 48, no. 3, 1991, pp. 209–215.

3.     Ban, Thomas MD. “The Role of Serendipity in Drug Discovery.” Dialogues in Clinical Neuroscience, vol. 8, no. 3, Sept. 2006, pp. 335–344.

4.     Aronson, Dr. Jeffrey. “Diazepam.” Meyler's Side Effects of Drugs, 16th ed., Elsevier B.V., 2016, pp. 930–937.

5.     Colburn, Don. “Valium In The Marketplace.” The Washington Post, 17 Feb. 1987.

6.     “Valium Patent Expires.” United Press International, 28 Feb. 1985.

7.     U.S. Food and Drug Administration. FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. (Accessed November 4, 2018). 

8.     Roche. Financial Information Tool. Sales Pharmaceuticals. Available at: https://www.roche.com/investors/rofis.htm. (Accessed November 4, 2018).

9.     Mathiason, Nick. “Blowing The Final Whistle.” The Guardian, 25 Nov. 2001.

10.  Barboza, David. “Tearing Down The Facade of 'Vitamins Inc.'.” The New York Times, 10 Oct. 1999.

11.  Marshall, Robert, et al. “Cartel Price Announcements: The Vitamins Industry.” International Journal of Industrial Organization, vol. 26, 13 July 2007, pp. 762–802.