Zidovudine

The Discovery of Zidovudine

            Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication typically used to treat HIV infection in adults and children +4 weeks old and to prevent mother-to-child transmission of HIV¹. ZDV was first described by Jerome P. Horowitz at the Barbara Ann Karmanos Cancer Institute as a part of an NIH funded anticancer program². Unfortunately, the compound showed no anticancer activity when tested on leukemic mice³. ZDV was then shelved. It was not until May 20, 1983, when researchers at the Institut Pasteur identified the retrovirus now known as HIV, that ZDV was revisited as a possible therapeutic⁴. This led research efforts to focus on a key enzyme, reverse transcriptase, as a target. A paper was published in October 1985 that demonstrated ZDV; (1) produced nearly no toxicity even at high doses to mice and dogs, (2) essentially completely inhibited viral replication without effecting T-cell immune reactivity, and (3) could be absorbed through oral administration⁵. On March 20, 1987, ZDV was FDA approved for use against HIV and AIDS. Only a short period of time had passed between demonstrated efficacy and FDA approval.

The mechanism of action is rather elegant and simple. ZDV belongs to the nucleoside analog reverse-transcriptase inhibitor (NARTI) class of reverse-transcriptase inhibitors and works because it is an analogue of the endogenous thymidine nucleoside. ZDV, in its inactive form, enters the cell and must be successively phosphorylated by cellular kinase enzymes, eventually yielding Zidovudine-triphosphate (ZDV-TP). ZDV-TP can then be incorporated into the growing DNA strand by the virus’ reverse-transcriptase enzyme. It has been shown that “… a relationship between the observed inhibitory effects of both AZT and nevirapine and the length of target template makes it unlikely that these drugs have any direct effect on [reverse transcriptase] through mechanisms other than direct inhibition of viral DNA chain elongation⁶.” This chain termination occurs because the deoxynucleotide that follows ZDV cannot form the 5’à3’ phosphodiester bond thus halting DNA elongation. While the safety of inhibiting DNA elongation is certainly a cause for concern, ZDV has been shown to inhibit HIV replication between 50-500 nM whereas inhibition of human fibroblasts and lymphocytes occurs at concentrations > 1 mM⁷. Furthermore, it has been theorized that cellular repair enzymes present in human cells are able to remove ZDV from the growing DNA strand. HIV has no such mechanism, which helps explain the noted low toxicity for human cells and high toxicity for the virus⁸. However, there are some adverse effects including flu-like symptoms, kidney and liver problems, and lipodystrophy⁹.

Regarding this assignment, it was somewhat surprising to discover that the newer generation of HIV medication, Nevirapine, is less effective than Zidovudine. This is because Nevirapine binds at the polymerase active site which can easily mutate to prevent binding. This is the case with HIV-2, against which Nevirapine is ineffective¹⁰. Resistance to ZDV can occur, though can be overcome when used in conjunction with foscarnet¹¹. Future development for ZDV may be limited. ZDV has been used for over three decades and long-term use is associated with resistance, though the mechanism of directly interrupting DNA elongation may continue to be utilized within HIV research.

While the science behind how the drug works is certainly interesting, a large portion of the drug’s history concerns both its commercial aspects and intellectual property. Shortly after the Institut Pasteur identified reverse transcriptase, the NCI and NIH quickly began research for compounds that were efficacious against HIV/AIDS. In 1984, Burroughs-Wellcome (BW) worked in conjunction with these government agencies in an attempt to find a treatment. During this time, Janet Rideout, the lead researcher for BW sent eleven compounds to the NCI for testing, one of which was AZT¹². NCI in vitro trials found AZT to be effective against HIV reverse transcriptase¹³. Following successful clinical trials, the FDA approved AZT in March 1987¹⁴ and BW filed for a patent in February 1988¹⁵. A legal battle ensued between BW and both Barr Laboratories and Novopharm. Barr Laboratories and Novopharm argued, unsuccessfully, that their respective work deserved to be recognized in the patent¹⁶. BW’s (later GSK) patent expired in 2005 and the FDA approved three generic versions¹⁷.

Since the expiration of the patent, ViiV Healthcare has taken over the proprietary name, Retrovir and dozens of companies have begun producing the generic version of AZT¹⁸. Considering AZT was one the first retrovirals drugs, it is also one of the most studied. There is a plethora of both pre-clinical and clinical trials from which data can be derived. Generally, it is a well-tolerated and efficacious therapeutic drug, especially when used in combination with various other retrovirals. Each manufacturer has their own Material Safety Data Sheet (MSDS) but the commonalities are that AZT is stable, non-reactive, non-flammable, and non-hazardous. However, the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) indicate that AZT may have the following characteristics; germ cell mutagenicity, carcinogenicity, reproductive toxicity (effects on or via lactation), and specific target organ toxicity¹⁹.

References

1.     “Zidovudine Dosage, Side Effects.” National Institutes of Health, U.S. Department of Health and Human Services, 23 Feb. 2018, aidsinfo.nih.gov/drugs/4/zidovudine/0/patient.

2.     Horwitz, Jerome P. et al. “Nucleosides. V. The Monomesylates of l-(2'-Deoxy-β-D-Lyxofuranosyl)Thymine.” Journal of Organic Chemistry, vol. 29, no. 7, 1964, pp. 2076–2078.

3.     Special to the New York Times. “A FAILURE LED TO DRUG AGAINST AIDS.” The New York Times, The New York Times, 20 Sept. 1986, nytimes.com/1986/09/20/us/a-failure-led-to-drug-against-aids.html?sec=health.

4.     Barré-Sinoussi, F. et al. “Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS).” Science (Washington), vol. 220, no. 4599, 1983, pp. 868–870.

5.     Mitsuya, H. et al. “3'-Azido-3'-Deoxythymidine (BW A509U): An Antiviral Agent That Inhibits the Infectivity and Cytopathic Effect of Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus in Vitro.” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 20, 1985, pp. 7096–7100.

6.     Quan, Y. et al. “Reverse Transcriptase Inhibitors Can Selectively Block the Synthesis of Differently Sized Viral DNA Transcripts in Cells Acutely Infected with Human Immunodeficiency Virus Type 1.” The Journal of Virology, vol. 73, no. 8, 1999, pp. 6700–6707.

7.     Furman, P. et al. “Phosphorylation of 3'-Azido-3'-Deoxythymidine and Selective Interaction of the 5'-Triphosphate with Human Immunodeficiency Virus Reverse Transcriptase.” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 21, 1986, pp. 8333–8337.

8.     Ostertag, W. et al. “Induction of Endogenous Virus and of Thymidine Kinase by Bromodeoxyuridine in Cell Cultures Transformed by Friend Virus.” Proceedings of the National Academy of Sciences of the United States of America, vol. 71, no. 12, 1974, pp. 4980–4985.

9.     “HIV Medicines and Side Effects Understanding HIV/AIDS.” National Institutes of Health, U.S. Department of Health and Human Services, 29 Aug. 2018, aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/22/63/hiv-medicines-and-side-effects.

10.  Ren, J. et al. “Structure of HIV-2 Reverse Transcriptase at 2.35-Å Resolution and the Mechanism of Resistance to Non-Nucleoside Inhibitors.” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 22, 2002, pp. 14410–14415.

11.  Sneader, Walter. Drug Discovery: A History. Wiley, 2006.

12.  Tachedjian, G. et al. “Zidovudine Resistance Is Suppressed by Mutations Conferring Resistance of Human Immunodeficiency Virus Type 1 to Foscarnet.” The Journal of Virology, vol. 70, no. 10, 1996, pp. 7171–7181.

13.  Mitsuya, H et al. “3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro” Proceedings of the National Academy of Sciences of the United States of America vol. 82,20 (1985): 7096-100.

14.  Brook, Itzhak. “Approval of Zidovudine (AZT) for Acquired Immunodeficiency Syndrome.” JAMA, American Medical Association, 18 Sept. 1987, jamanetwork.com/journals/jama/article-abstract/368218.

15.  Cochrane, James MT. “Zidovudine's Patent History.” The Lancet, vol. 356, no. 9241, 2000, pp. 1611–1612., doi:10.1016/s0140-6736(05)74463-9.

16.  “Burroughs Wellcome Co. v. Barr Laboratories, Inc., 828 F. Supp. 1208 (E.D.N.C. 1993).” Justia Law, law.justia.com/cases/federal/district-courts/FSupp/828/1208/2352375/.

17.  Office of the Commissioner. “HIV/AIDS History of Approvals - HIV/AIDS Historical Time Line 2000 - 2010.” U S Food and Drug Administration Home Page, Office of the Commissioner, www.fda.gov/ForPatients/Illness/HIVAIDS/History/ucm151081.htm.

18.  Approved Drug Products with Therapeutic Equivalence Evaluations, FDA, 2018.

19.  “Zidovudine.” National Center for Biotechnology Information. PubChem Compound Database, U.S. National Library of Medicine, pubchem.ncbi.nlm.nih.gov/compound/zidovudine#section=GHS-Classification&fullscreen=true.

Tamsulosin: Background and Commercialization

Discovery, Development, and Commercialization of Carbidopa Levodopa

Discovery, Development, and Commercialization of Carbidopa Levodopa

Carbidopa levodopa is a combination of two different medicines: carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an aromatic amino acid.[1] Levodopa occurs naturally in plants, such as fava beans. However, a semi-synthetic form of levodopa is used in medicine.[2] Similarly, semi-synthetic methods are also used in the preparation of carbidopa.[3] The combinatory product carbidopa levodopa is taken by mouth 3 to 4 times daily, with its primary function being to manage the symptoms of Parkinson's disease, a chronic and progressive movement disorder. 

Parkinson's disease is thought to be caused by a deficiency of dopamine in the brain. However, because dopamine cannot cross the blood-brain barrier, the administration of dopamine is ineffective in the treatment of Parkinson's disease.[1] Consequently, levodopa helps to control movement by converting into dopamine in the brain. Levodopa is converted to dopamine via aromatic L-amino acid decarboxylase both peripherally and in the central nervous system after levodopa has crossed the blood-brain barrier. Levodopa is generally combined with carbidopa, an inhibitor of aromatic amino acid decarboxylase that cannot cross the blood-brain barrier.[4] Carbidopa thus prevents the breakdown of levodopa in the bloodstream so that more levodopa can enter the brain. 

Carbidopa can also reduce some of levodopa's side effects. While the activation of central dopamine receptors improves symptoms of Parkinson’s disease, the activation of peripheral dopamine receptors causes side effects, such as nausea and vomiting.[5] Thus, levodopa is usually combined with carbidopa to prevent the peripheral conversion of levodopa and decrease the chance of negative side effects.[6][7]

Common side effects in patients taking carbidopa levodopa include nausea, vomiting, loss of appetite, trouble sleeping, weight loss, hallucinations, dyskinesias, and depression.[1] In addition, some products may interact with the medication; these include antipsychotic drugs (such as chlorpromazine, haloperidol, thioridazine) and certain drugs used to treat high blood pressure (such as methyldopa). Furthermore, taking certain monoamine oxidase (MAO) inhibitors with carbidopa levodopa may cause a serious and potentially fatal drug interaction.[8] Alternative medications include dopamine agonists, like pramipexole, which may be used in the early stages of Parkinson’s disease. These drugs have many of the same side effects; however, such dopamine agonists do not require modification from brain enzymes to stimulate dopamine receptors, as levodopa does.[9] Nevertheless, carbidopa levodopa is still largely considered the most effective medication in the treatment of Parkinson’s disease.

            In 1960, Austrian biochemist Oleh Hornykiewicz was the first to suggest that Parkinson’s disease is associated with, or caused by, a reduction in the levels of dopamine in the brain. Since dopamine cannot enter the brain, he attempted to treat twenty patients with a racemic mixture of dihydroxyphenylalanine (DOPA), which could enter the brain and be converted to dopamine via the action of aromatic L-amino acid decarboxylase. His results were positive, as were those in another trial run by André Barbeau in Montreal. In the late 1960s, Curt Porter at Merck discovered that levodopa was the active stereoisomer of racemic DOPA, which enabled the dose to be effectively reduced to half. In 1962, Victor Lotti at Merck synthesized and patented carbidopa, and in 1971, Lotti showed that the use of the L-form of carbidopa further reduced the necessary dosage of levodopa. The combination of L-carbidopa and levodopa was marketed under the brand name of Sinemet, which was approved by the Food and Drug Administration in 1975.[10]

In addition to Sinemet, carbidopa levodopa is marketed today by over 26 other brand names, including Parkimet, Pardopa, Syndopa, Neocare, Rytary, and Duopa.[11] Among these brand names, there are many different dosage options. Sinemet was and is offered in tablet form only. Sinemet CR is offered as an extended release tablet, and Parcopa is offered as a disintegrating tablet. Among the newer advancements in Parkinson’s Disease treatment with carbidopa levodopa are Rytary, an extended release capsule, and Duopa, an extended release enteral suspension administered intrajejunally.[12] Rytary and Duopa are the most recently approved of these brand names, both approved by the FDA in 2015. Duopa, however, was approved as an orphan drug for the treatment of motor fluctuations in people with advanced Parkinson’s Disease. Duopa’s status as an orphan drug means it was given seven years of market exclusivity as is standard of approved orphan drugs.[13] It is marketed by Abbvie, a global, research-based, publicly traded biopharmaceutical company formed in 2013. In 2017, Abbvie generated 28.22 billion USD in revenue.[14]

Duopa’s approval was based on a Phase 3, 12-week, double-blind, double-placebo, active control, parallel group trial (N=71) that compared the efficacy and safety of Duopa to oral, immediate release carbidopa levodopa tablets, such as Sinemet, in advanced Parkinson's disease patients. The study showed that Duopa significantly reduced daily mean “off” time (periods when the medication is not working and symptoms are not controlled) at 12 weeks by four hours, thus resulting in an average of about 2 fewer hours of “off” time when compared to the IR tablets. Furthermore, dyskinesia, a troubling adverse effect of most carbidopa levodopa medications, was not observed as a side effect of Duopa.[14] The most common adverse events included those commonly observed for carbidopa levodopa medication, as well as complication of device insertion, incision site erythema, and post procedural discharge.

In the United States, carbidopa levodopa is available by prescription only. It is not subject to the Controlled Substances Act of 1970, and it falls into pregnancy category C. In animal studies, pregnant animals were given carbidopa levodopa, and some of the babies were born with problems. However, no adequate and well-controlled studies have been done in humans, thus carbidopa levodopa may be used while pregnant if the potential benefits outweigh the potential risks to the fetus.[17]

The generic of carbidopa levodopa is marketed by over 9 different companies. There were 2,918,441 prescriptions for carbidopa levodopa per year as of 2015, and the Parkinson’s Disease treatment market was worth 4.24 billion USD in 2017.[15][16] The Parkinson’s disease therapeutic drugs market is divided by drug class, segmented into carbidopa levodopa, dopamine receptor agonists, and MAO inhibitors, among others. By drug class, carbidopa levodopa dominated this market in 2017. The treatment market is projected to increase to 5.69 billion USD by 2022, at a compound annual growth rate of 6.1%.[15]

Bibliography

1.     “Carbidopa and Levodopa,” Drugs.com. www.drugs.com/pro/carbidopa-and-levodopa.html (Accessed Sept. 20, 2018).

2.     “Levodopa,” tapi. www.tapi.com/products/levodopa/ (Accessed Sept. 20, 2018).

3.     “Carbidopa,” tapi. www.tapi.com/products/carbidopa/ (Accessed Sept. 20, 2018).

4.     “Carbidopa And Levodopa,” PubChem. pubchem.ncbi.nlm.nih.gov/compound/104778#section=Top (Accessed Sept. 20, 2018).

5.     Aminoff, MJ. “Pharmacologic management of Parkinsonism & other movement disorders,” Basic & Clinical Pharmacology 2004, 447.

6.     “levodopa-carbidopa,” MedicineNet.com. www.medicinenet.com/levodopa-carbidopa/article.htm#what_is_levodopa-carbidopa,_and_how_does_it_work_(mechanism_of_action)? (Accessed Sept. 21, 2018).

7.     “carbidopa/levodopa - Drug Summary,” PDR Search. www.pdr.net/drug-summary/Sinemet-CR-carbidopa-levodopa-389 (Accessed Sept. 21, 2018).

8.     “Carbidopa-Levodopa,” WebMD. www.webmd.com/drugs/2/drug-3394-41/carbidopa-levodopa-oral/carbidopa-levodopa-oral/details (Accessed Sept. 22, 2018).

9.     “Dopamine Agonist Drugs List, Side Effects & Natural Supplements,” NOOTRIMENT. nootriment.com/dopamine-agonist/ (Accessed Sept. 22, 2018).

10.  Scriabine, Alexander. "Discovery and Development of Major Drugs Currently in Use," Pharmaceutical Innovation: Revolutionizing Human Health 1999, 222.

11.   “Carbidopa-Levodopa - Price List of 26 Brands,” Medindia, 2 Feb. 2017. www.medindia.net/drug-price/carbidopa-levodopa.htm (Accessed Nov. 2, 2018).

12.  “carbidopa/levodopa (Rx),” Medscape. reference.medscape.com/drug/sinemet-rytary-carbidopa-levodopa-343043 (Accessed Nov. 4, 2018).

13.  Radke, James. “FDA Approves Duopa (carbidopa and levodopa) as an Orphan Drug for Advanced Parkinson's Disease,” Rare Disease Report. www.raredr.com/news/fda-approves-duopa-advanced-parkinsons (Accessed Nov. 4, 2018).

14.  “AbbVie Announces U.S. FDA Approval Of DUOPA™ (carbidopa and levodopa) Enteral Suspension For The Treatment Of Motor Fluctuations In Patients With Advanced Parkinson's Disease,” BioSpace. www.biospace.com/article/releases/abbvie-announces-u-s-fda-approval-of-duopa-carbidopa-and-levodopa-enteral-suspension-for-the-treatment-of-motor-fluctuations-in-patients-with-adva627762/ (Accessed Nov. 4, 2018).

15.  “Carbidopa; Levodopa: Drug Usage Statistics, United States, 2006 – 2016,” ClinCalc.com, 19 July 2018. clincalc.com/DrugStats/Drugs/CarbidopaLevodopa (Accessed Nov. 2, 2018).

16.  “Parkinson's Disease Treatment Market worth 5.69 Billion USD by 2022,” MarketsandMarkets. www.marketsandmarkets.com/PressReleases/parkinson-disease-treatment.asp (Accessed Nov. 2, 2018).

17.  “Medications for Parkinson's Disease,” Drugs.com. www.drugs.com/condition/parkinson-s-disease.html (Accessed Nov. 2, 2018).

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.

Promethazine Development and Commercialization

Promethazine


Developed in 1946 when a team of scientists from French pharmaceutical company Rhône-Poulenc combined phenothiazine and a diamine side chain of diphenhydramine in order to create the synthetic compound promethazine2.  Paul Charpentier, lead scientist, is credited with the discovery of promethazine, as well as helping to immerse Rhône-Poulenc into the company we now know as Sanofi3. Merely seeking to find a better antihistamine than diphenhydramine, Charpentier and his team synthesized a compound with a wide range benefits.

Promethazine is a first-generation H1 receptor antagonist, antihistamine, and antiemetic medication with strong sedative effects that has been sold under the name brands of Phenergan and Phenadoz. Since its introduction, promethazine has been used for prevention and treatment of nausea and vomiting caused by narcotic therapy, migraine episodes, morning sickness, and cancer chemotherapy4. Also, promethazine is used to treat allergic symptoms such as itching, runny nose, sneezing, itchy or watery eyes, hives, and itchy skin rashes, as well as to prevent motion sickness4. Another benefit from promethazine, one which I have seen first-hand in the UK Medical Center OR Pharmacy, is that it can be used as a pre-/post-operative surgical analgesic and hypnotic.

The phenothiazine derivative has a multi-target mechanism of action that includes: blocking postsynaptic mesolimbic dopaminergic receptors in the brain, strongly blocking alpha-adrenergic effects which in turn depresses the release of hypothalamic and hypophyseal hormones, competing with histamine for the H1 receptor, and lastly a muscarinic-blocking effect that may be responsible for antiemetic activity4. The result of these mechanisms induce bronchoconstriction, vasodilation, and spasmodic contractions of GI smooth muscle5.

The adverse drug event profile of promethazine includes: dizziness, sleepiness, dry mouth, N&V, altered cardiac conduction causing life threatening arrhythmias, CNS depression, photosensitivity, temperature regulation impairment, as well as a US boxed warning for serious tissue injury related to promethazine injections3. Anti-cholinergic effects such as constipation, blurred vision, urinary region, and xerostomia are also a main concern as patients with decreased GI motility, urinary retention problems, GI or urinary obstructions, or visual problems will all have to be closely monitored3.

Important pharmacokinetic information regarding promethazine includes its hepatic metabolism by hydroxylation using CYP2D6 and N-demethylation via CYP2B6. Promethazine is 93% protein bound, which helps generate an effect duration of 4-6 hours and a half life of 16-19 hours4,6. Absorption of oral promethazine is rapid and approximately 88%, but with a large first pass effect its systemic bioavailability is limited and approximately 25%, leaving substantial room for improvement (5). Oral and intramuscular promethazine has an onset of action of approximately 20 minutes, whereas IV promethazine has an onset of approximately 5 minutes6.

Being closely related to ondansetron as an antiemetic medication, promethazine has the upside of being available as a rectal suppository, whereas ondansetron has the advantage of being available as a sublingual tablet or oral film. Ondansetron has risks associated with Serotonin syndrome that promethazine doesn’t, but promethazine has breathing impairment risk factors that make it contraindicated for children under the age of two2. Promethazine also requires patients to increase their intake of dietary riboflavin, whereas ondansetron lacks this requirement5.

One of the most detrimental aspects of promethazine is the unfortunate fact that it causes heavy sedation in many patients. This of course is brought on by promethazine’s mechanism of action that correlates with most first generation antihistamines. However, ondansetron has greatly improved upon the typically undesired sedative effect that comes with promethazine by changing the mechanism of action to a serotonin 5-HT3 receptor antagonist2. Therefore, decreasing the antiemetics role in sedation by changing the medication’s target allows ondansetron to be a better option for patients that have the need to stay awake for daily activities.

First approved on May 5th, 1958 Promethazine HCl and many of its generics have been produced by quite a few companies, including Akorn Pharmaceuticals, and supplied by an abundant amount of wholesalers, including McKesson. McKesson is a major pharmaceutical wholesaler with a total revenue of over $208 billion, up 5% from last year. McKesson CEO, John Hammergren, has helped the company build an operating income of $672 million, but has lost a net income of 138 million (144%) compared to last year.

Preclinical toxicology of promethazine studies showed possible overdose symptoms such as mild CNS and cardiovascular depression, profound hypotension, respiratory depression, and unconsciousness. One efficacy study that compared promethazine to ondansetron found that the percentage of relief of nausea and vomiting at 3 hours were 67% and 71% respectively5.

Overall there have been five patents for promethazine hydrochloride. Patients differ by what type of dosage form the company supplies: Able supplies a rectal suppository, Kvk Tech supplies an oral tablet, Amneal Pharms supplies an oral syrup, Sandoz supplied an oral tablet (patent was approved in 1982), and Teva supplied an oral tablet (patent was approved in 1985).

Promethazine was recently in a phase 3 parallel group clinical trial (Identifier #NCT01827293) with lorazepam in order to compare the efficacy of IV promethazine with lorazepam on peripheral vertigo in emergency department settings.8 Primary outcomes were to observe changes in vertigo intensity, whereas secondary outcomes sought out to determine safety and adverse event occurrences. Specific exclusion criteria were laid out, including emetic medication use within the past 24 hours and known allergy to either of the medications.

In 2015, there was an urgent drug recall for promethazine DM syrup  by MooreMedical. The recall expressed concern about possible polypropylene particles contaminating the dispensed product. They instructed customers to review complete details of affected products, quarantine and discontinue the product, and contact the MooreMedical regulatory affairs department if they were affected by the product.



References

(1) C. Cantisani, S. Ricci, T. Grieco, et al., “Topical Promethazine Side Effects: Our Experience and Review of the Literature,” BioMed Research International, vol. 2013, Article ID 151509, 9 pages, 2013. https://doi.org/10.1155/2013/151509.

(2) IODINE, “Compare Zofran vs Phenergan.” IODINE API, accessed Sept. 21st  from https://www.iodine.com/compare/zofran-vs-phenergan

(3) Laguna Treatment Hospital, “What is Promethazine, And How Can It Be Abused?” American Addiction Centers. Retrieved Sept. 20th, 2018 from https://lagunatreatment.com/promethazine-abuse/

(4) Lexicomp, “Promethazine (Lexi-Drugs).” Wolters Kluwer. Retrieved Sept. 20th, 2018 from https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7563#fbnlist

(5) Moser, JD., “No more than necessary: safety and efficacy of low-dose promethazine.” Ann Pharmacotherapy. Jan 2006, 40(1):45-8. ePub 2005 Dec 13.

(6) National Center for Biotechnology Information. PubChem Compound Database; CID=4927, https://pubchem.ncbi.nlm.nih.gov/compound/4927 (accessed Sept. 21, 2018).

(7) Peters RJ Jr, Kelder SH, Markham CM,: “Beliefs and social norms about codeine and promethazine hydrochloride cough syrup (CPHCS) onset and perceived addiction among urban Houstonian adolescents: an addiction trend in the city of lean.” J Drug Educ. 2003;33(4):415-25. [PubMed:15237866]

(8) Shadi, Asadollahi, “Promethazine vs. Lorazepam for Treatment of Vertigo.” ClinicalTrials.gov, Shahid Beheshti University of Medical Sciences, June 2013, https://clinicaltrials.gov/ct2/show/study/NCT01827293


Bibliography

C. Cantisani, S. Ricci, T. Grieco, et al., “Topical Promethazine Side Effects: Our Experience and Review of
 the Literature,” BioMed Research International, vol. 2013, Article ID 151509, 9 pages, 2013
. https://doi.org/10.1155/2013/151509.

IODINE, “Compare Zofran vs Phenergan.” IODINE API, accessed Sept. 21st  from
 https://www.iodine.com/compare/zofran-vs-phenergan

Laguna Treatment Hospital, “What is Promethazine, And How Can It Be Abused?” American Addiction
 Centers. Retrieved Sept. 20th, 2018 from https://lagunatreatment.com/promethazine-abuse/

Lexicomp, “Promethazine (Lexi-Drugs).” Wolters Kluwer. Retrieved Sept. 20th, 2018 from
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7563#fbnlist

National Center for Biotechnology Information. PubChem Compound Database; CID=4927,
 https://pubchem.ncbi.nlm.nih.gov/compound/4927 (accessed Sept. 21, 2018).

Ogbru, Omudhome. “Promethazine.” MedicineNet. Accessed Sept 21st, 2018 from
 https://www.medicinenet.com/promethazine/article.htm

Page, C.B.: QJM: An International Journal of Medicine, Volume 102, Issue 2, 1 February 2009, Pages 123
–131, https://doi.org/10.1093/qjmed/hcn153

Peters RJ Jr, Kelder SH, Markham CM,: “Beliefs and social norms about codeine and promethazine
 hydrochloride cough syrup (CPHCS) onset and perceived addiction among urban Houstonian
 adolescents: an addiction trend in the city of lean.” J Drug Educ. 2003;33(4):415-25.
 [PubMed:15237866]

Amoxicillin

Amoxicillin: From Discovery to Commercialization

Discovery

     In 1928, Alexander Fleming discovered that penicillin, a substance being produced by the mold, Penicillin notatum, appeared to inhibit bacterial growth. [1] Likely unbeknownst to Fleming at the time, this discovery would revolutionize the treatment of infectious diseases caused by bacteria. Later, the use of penicillin as a therapeutic agent, while certainly a landmark event which lead to subsequent clinical breakthroughs, was not without its deficits. Most notably, penicillin has a limited spectrum of bacteria against which it is able to exert its effect, as was observed by its inactivity against gram-negative pathogens such as Escherichia coli and Klebsiella pneumoniae. [2] As such, researchers looked for ways to improve the structure of penicillin such that the impact of its disadvantages might be mitigated. Through chemical modification of the structure of penicillin, specifically, addition of an amino group to its side chain, the aminopenicillins were created. 

     Aminopenicillins have the same mechanism of action as their parent compound, which is inhibition of bacterial cell wall synthesis via binding to penicillin-binding proteins (PBPs). [3] The first aminopenicillin was ampicillin; a drug which was later further modified via addition of a hydroxyl group. Hydroxylation of ampicillin yielded amoxicillin, a compound with greater polarity, and therefore, greater oral absorption. [4] The synthetic modification described allows aminopenicillins to exert effect against some gram-negative bacteria by allowing them to pass through the outer layer of the pathogen. [5] With extended spectrum of activity, amoxicillin is an effective therapeutic agent against ailments caused by these bacteria, such as in treatment of lower respiratory tract infection and infections of the ear, nose, and throat. [6]

     

     It is important to draw contrast to the nature of the discovery/synthesis of amoxicillin and its predecessor. Penicillin is considered a natural product, as it is naturally occurring in nature; in contrast, amoxicillin is considered to be semi-synthetic, as it is synthesized via modification of a natural product (penicillin). [7] While the improvements in its design lessen amoxicillin’s adverse effect profile relative to other related compounds, patients may still experience hypersensitivity, diarrhea, confusion, and abdominal pain. [6]

Commercialization

     Amoxicillin arrived on the market for the first time in 1974 as the branded product Amoxil^®. The patent for the product is held by GlaxoSmithKline (GSK), a company which resulted from the consolidation of SmithKline Beecham and Glaxo Wellcome in 1995. [8] In 2010, GSK transferred ownership of its penicillin manufacturing plant in Bristol, Tennessee, as well as the rights for its Amoxil^®and Augmentin^® (amoxicillin and clavulanic acid) brands in the United States (U.S.) to Dr. Reddy’s. GSK retained the existing rights to these brands outside the U.S. [9] The transfer to Dr. Reddy’s was one that seemed logical as Dr. Reddy’s already had authorized generic products on the market in tablet form (1978) and powder for oral suspension (1999).  [10] Dr. Reddy’s is an Indian multinational company with its headquarters in Hyderabad, Telangana, India. According to a report to its investors, as of June 2018, the company had experienced revenues of $2,181M in 2018 with earnings before interest, taxes, depreciation, and amortization (EBITDA) of $370M. [11]

     Amoxicillin is now available in capsule, tablet, chewable tablet, and powder for suspension and is available from eight generic manufacturers (Table 1). [12] The drug is approved for a variety of conditions, including infections of the ear, nose, throat due to Streptococcusspp., H. pylori, and infections of the lower respiratory tract due to Streptococcusspp., Staphylococcus spp., or H.influenzae, among other conditions. Drug resistance due to beta-lactamase production by some of these pathogens limits the drug’s use in certain conditions. [13] 

Most recently, an extended release version of the therapeutic was approved for treatment of tonsillitis and/or pharyngitis in patients 12 years and older. The approval was based upon a phase 3, double-blind, double-dummy, randomized, parallel-group study involving more than 600 pediatric and adult patients. In the study, once daily amoxicillin 775 mg was found to be non-inferior to penicillin VK 250 mg four times daily for the treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes. The extended release tablet is the only once daily formulation of amoxicillin and is branded as Moxatag^®, the license for which is held in the U.S. by Vernalis Therapeutics. [14] 

Despite growing concerns of resistance, the drug continues to experience success, especially within the pediatric population. As was proven by the recent approval of a once daily regimen, while amoxicillin's prime may have passed with regard to its patent status, the drug still has a lot to contribute to modern medicine. Nearly a century later, Alexander Fleming’s discovery continues to greatly impact the market for infectious diseases treatment across the globe. 

Table 1. Available dosage forms of amoxicillin
Dosage form	Strength(s)	Manufacturer(s)	Brand Available	Generic Available	Price [6]
Capsule	250 mg	Dr. Reddy’s, AM Antibiotics, Dava Pharms Inc, Teva, Sandoz, Hikma, Aurobindo	Y	Y	$0.13-$0.25 per cap
	500 mg				$0.19-$5.88 per caps
Tablet, chewable	125 mg	Teva	N	Y	$0.34 per tab
	250 mg				$0.67 per tab
Powder for reconstitution (suspension)	125 mg / 5 mL	Dr. Reddy’s, Dava Pharms Inc, Teva, Sandoz, Hikma, Aurobindo, Wockhardt Bio AG	Y	Y	$0.04 per mL
	200 mg/ 5 mL				$0.09 per mL
	250 mg / 5 mL				$0.06 per mL
	400 mg / 5 mL				$0.10 per mL
Tablet, extended release	775 mg	Vernalis Therapeutics	Y	N	$18.90 per tab
Tablet	500 mg	Teva, Sandoz, Hikma, Aurobindo	N	Y	$0.50 per tab
	875 mg				$0.87 per tab

References

1. American Chemical Society International Historic Chemical Landmarks. Discovery and Development of Penicillin. http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html(accessed September 22, 2018).  
2. Kok-Fai K, Schneper K, Mathee K. Beta-lactam Antibiotics: From Antibiosis to Resistance and Bacteriology. APMIS: acta pathologica, microbiologica, et immunologica Scandinavica. 118.1 (2010): 1-36. 
3. National Institutes of Health. Aminopenicillins: Third generation penicillins. https://livertox.nih.gov/Aminopenicillins.htm(accessed September 23, 2018). 
4. Sjovall J, Alvan G, Akerlund JE, Svenson JO, Painstaud G, Nord CE, Angelin B. Dose-dependent absorption of amoxicillin in patients with an ileostomy. Eur J Clin Pharmacol. (1992) 43:277-281.
 5. Hauser A. Antibiotic Basics for Clinicians: The ABCs of Choosing The Right Antibacterial Agent, 2^ndEdition. (2007): 23-36. Lippincott Williams & Wilkins: Philadelphia, PA. 
6. Amoxcillin: Drug Information. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. www.uptodate.com/contents/amoxicillin-drug-information. (Accessed September 23, 2018). 
7. Bardal SK, Waechter JE, Martin DS. Applied Pharmacology. (2011): 233-291. Elsevier: Amsterdam, Netherlands.
8. GlaxoSmithKline. “Creating the GSK of Today: 1950 – 1999.” Available at: https://www.gsk.com/en-gb/about-us/our-history/creating-the-gsk-of-today-1950-1999/. (Accessed November 2, 2018).
9. GlaxoSmithKline. Press Release: “GlaxoSmithKline and Dr. Reddy’s agree to the sale of US Penicillin Facility and Products.” (2010). (Accessed November 2, 2018).
10. U.S. Food and Drug Administration. “FDA Listing of Authorized Generics, as of September 27, 2018. (Accessed October 29, 2018). 
11. Dr. Reddy’s Laboratories Limited. Investor Presentation. (2018). Available at: http://www.drreddys.com/media/639830/dr-reddys-investor-presentation-june-2018.pdf. (Accessed November 1, 2018). 
12. 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 October 27, 2018). 
 13. Amoxicillin [package insert]. Bridgewater, NJ: Dr. Reddy’s Laboratories; 1999. 
14. Moxatag [package insert]. Berwyn, PA: Vernalis Therapeutics, Inc.; 2016.