Another Opioid?

According to US World News, Kentucky ranks in the top five of states with the highest rates of opioid overdose deaths.¹ In 2017 alone, 1,565 people in the state of Kentucky died from drug overdoses.¹ Overdose deaths from heroin are declining, but drugs like fentanyl are taking their place.¹ As of Friday, November 2^nd, the FDA approved a new opioid painkiller known as Dsuvia. Dsuvia is a synthetic form of sufentanil that is 10 times more potent than fentanyl and about 1,000 times more potent than morphine.²

 

 

Figure 1: Rate of Opioid-Related Overdose Deaths in Kentucky vs. U.S. 1999-2016.³

Sufentanil is an opioid analgesic and can be administered intravenously, orally, or via epidermal route.⁴ Sufentanil acts by selectively binding to Mu opioid receptors distributed in the brain, spinal cord and other tissues throughout the body.⁴ Opioids achieve the relief of painful symptoms by decreasing cAMP levels and neurotransmitter release, allowing for membrane hyperpolarization.⁴ When the drug binds to the opiate receptor, GTP is exchanged for GDP to inhibit the release of nociceptive neurotransmitters such as GABA, acetylcholine and noradrenaline.⁴

 

Sufentanil also has a high bioavailability rate of 52% just from a single sublingual tablet.⁴ Bioavailability rate is defined as the degree and rate to which an administered drug is absorbed by the body. The main sites of metabolism in the body include the liver and small intestine.⁴ * Dsuvia is available as 3 millimeter wide tablets to be administered sub-lingual by healthcare providers in a hospital setting, or surgical center.⁵ The sublingual dose is intended to work by managing acute to severe pain in adults. The company AcelRx projects $1.1 billion in annual sales of Dsuvia and projects its availability in hospitals by early 2019.⁵

 

FDA Commissioner Scott Gottlieb justified their decision to approve Dsuvia by saying, “The FDA is taking new steps to actively confront the opioid epidemic, while also paying careful attention to the needs of patients and physicians managing pain.”⁶ The Wall Street Journal published an article agreeing with the FDA by arguing that Dsuvia is an ideal option for wounded soldiers on the battlefield.² This is because soldiers lack access to intravenous injections or drip and a quick dissolving pill sub lingual is much easier to administer.²

 

However, many physicians and researchers also disagree with the FDA’s decision to allow another opioid on the streets. Dr. Raeford Brown Jr, a professor of anesthesiology and pediatrics at the University of Kentucky, stated “There is no good reason at this point in the US to put another opioid on the streets.”² In another article, Dr. Brown stated, “I have strong feelings about the opioid crisis, as someone who lives in the Commonwealth of Kentucky, where we continue to have people die.”⁵ Rather than overprescribing these dangerous and addictive medications, physicians should evaluate the efficacy and necessity of opioids. Without the concern of each patient’s overall health and well-being, physicians are facilitating the opioid crisis.   

 

References:

1. Kentucky Drug Overdose Deaths Jump 11.5 Percent in 2017. US & World Report News. https://www.usnews.com/news/best-states/kentucky/articles/2018-07-25/kentucky-drug-overdose-deaths-jump-115-percent-in-2017. Published July 25, 2018. Accessed November 11, 2018.

 

2. Satel S. The FDA Was Wise to Approve a New Opioid. The Wall Street Journal. https://www.aei.org/publication/the-fda-was-wise-to-approve-a-new-opioid/. Published November 8, 2018. Accessed November 11, 2018.

 

3. Kentucky Opioid Summary. National Institute on Drug Abuse. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-summaries-by-state/kentucky-opioid-summary. Published 2016. Accessed November 11, 2018.

 

4.  Sufentanil. DrugBank. https://www.drugbank.ca/drugs/DB00708. Published 2018. Accessed November 11, 2018.

 

5.  Harper J. Despite Warnings, FDA Approves Potent New Opioid Painkiller. National Public Radio. https://www.npr.org/sections/health-shots/2018/11/02/663395669/despite-warnings-fda-approves-potent-new-opioid-painkiller. Published November 2, 2018. Accessed November 11, 2018.

6.  Goldschmidt D. Amid Deepening Addiction Crisis, FDA Approves Powerful New Opioid. CNN. http://www.wdrb.com/story/39412586/amid-deepening-addiction-crisis-fda-approves-powerful-new-opioid. Published November 3, 2018. Accessed November 11, 2018.

 

 

Katie Flynn, A Master’s in Medical Sciences Student, University of Kentucky

 

Atezolizumab Gives Hope to Triple-Negative Breast Cancer Patients

 

According to the Centers for Disease Control and Prevention, more than 1.5 million people are diagnosed with cancer each year and nearly 600,000 die of the disease.¹ This makes cancer the second most leading cause of death in the U.S. By the year 2020, the number of new diagnoses is expected to increase to almost 2 million per year.¹ Breast cancer is the most common cancer in women, excluding skin cancer. Nearly 250,000 new cases are diagnosed each year. Of these new cases, about 10- 20 % are triple-negative breast cancers. ² Triple-negative breast cancers (TNBCs), as the name suggests, lack receptors for estrogen, progesterone, and HER2.

Figure 1: Rates are per 100,000 people and age-adjusted to the 2000 US standard population.¹

          

          Since hormones and HER2 are not involved in supporting cancer growth, individuals with triple-negative breast cancers fail to respond to hormonal therapies or HER2 targeted therapies. In addition, triple-negative breast cancers tend to more aggressive and more likely to recur than other forms of cancer. Once the disease becomes metastatic, the median survival is around 12 to 15 months.²  The first line of treatment for TNBCs is chemotherapy, but many patients develop resistance to chemotherapy within a few months of treatment.³ Fortunately, researchers in Munich, Germany have found a new therapeutic target, PD-L1 receptor, against TNBC.

 

            PD-L1 or programmed cell death protein 1 receptor is a receptor on the surface of T-cells which inhibits T-cell-mediated immune response when it binds to its respective ligand, programmed death ligand 1 (PD-L1).⁴ Current evidence suggests that cancer cells evade antigen-specific T-cell immunologic response by activation of PD-1/PD-L1 signaling. By blocking or inhibiting PD-1/PD-L1 signals, cancer becomes subjected to T-cell mediation immune response.^4,5 Atezolizumab, is a monoclonal antibody against the PD-L1 receptor, was used by the researchers in Munich in their clinical trials with patients with metastatic triple-negative breast cancer.  

Figure 2: Mechanism of action of PD-1 and PD-L1 inhibitors. ⁵

 In a phase II trial, 902 patients with TNBC, without prior treatment, were randomized into 2 groups: standard chemotherapy (nab-paclitaxel) plus atezolizumab or standard chemotherapy plus placebo. The two main objectives were to measure if the drug combination could slow cancer growth (progression-free survival) and prolong life (overall survival) in all patients and in a subset of patients expressing PD-L1.⁶

 

Dr. Schmid and colleagues found that combination therapy (chemo plus atezolizumab) reduced the risk of disease worsening or death by 20% in all patients and 38% in the subgroup expressing PD-L1.⁶ The median progression-free survival was 7.2 months with the combination compared to 5.5 months with chemotherapy alone.⁶ In the PD-L1 positive group, the median progression-free survival was 7.5 months with the combination versus 5.0 months with just chemotherapy.⁶ In patients with PD-L1 positive tumors, the median overall survival was 25.0 months with the combination compared to 15.5 months with standard chemotherapy alone. In all patients, survival was 21.3 months with the combination versus 17.6 months with just chemotherapy.⁶

These results suggest the Atezolizumab is the first targeted treatment to improve survival up to 10 months in TNBC patients expressing PD-L1. Dr. Schmid believes the outcomes can be further improved by selecting for a better chemotherapy backbone for the combination therapy. Many clinical trials are still ongoing, investigating the effectiveness of PD-L1 antibodies in head, neck, and lung cancers. Other studies are looking at CTLA-4 as potential checkpoint target in myeloma and other forms of cancers. Bi-specific antibodies and cancer vaccines are currently in development as well.⁵ Our fight against cancer appears more hopeful than ever before thanks in large part to recent advances in cancer biology and immunotherapy. 

References: 

1. National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP). (2017, November 13). Retrieved November 2, 2018, from https://www.cdc.gov/chronicdisease/resources/publications/aag/dcpc.htm
2. What Is Triple-Negative Breast Cancer? (n.d.). Retrieved November 2, 2018, from https://www.breastcancer.org/symptoms/diagnosis/trip_neg/behavior
3. Study may explain why some triple-negative breast cancers are resistant to chemotherapy. Retrieved November 4, 2018, from https://www.mdanderson.org/newsroom/2018/04/study-may-explain-why-some-triple-negative-breast-cancers-are-resistant-to-chemotherapy.html
4. Immune checkpoint inhibitors to treat cancer. (n.d.). Retrieved November 2, 2018, from https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html
5. Gong, J., Chehrazi-Raffle, A., Reddi, S., & Salgia, R. (2018). Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. Journal for ImmunoTherapy of Cancer,6(1). doi:10.1186/s40425-018-0316-z
6. Schmid, P. (2018). ESMO 2018 presidential symposium—IMpassion130: Atezolizumab nab-paclitaxel in triple-negative breast cancer. ESMO Open,3(6). doi:10.1136/esmoopen-2018-000453
   
   

   By Satyanarayana Alluri, Master of Medical Sciences Student, University of Kentucky
   

 

 

A pill for concussions?

Former prestigious collegiate athlete to New England Patriots tight end star, Aaron Hernandez was found hanged in his prison cell on April 19, 2017.¹ He was sentenced to life in prison without parole after being found guilty of first-degree murder of his associate, Odin Lloyd.¹ There are many unanswered questions that still remain. Why did he do it? What led Hernandez to so quickly spiral out of control? The Boston Globe’s Spotlight team recently released a podcast, Gladiator: Aaron Hernandez & Football Inc.² They use Aaron Hernandez’s story to create awareness of the crisis facing football: Concussions.²

Figure 1: Dr. Ann McKee, director of the CTE Center at Boston University presented this image, comparing Aaron’s brain with a normal, 27-year old’s. She stated that this was the worst case of CTE seen in someone at Hernandez’s age.⁴

  

If you are a football fan, you should not be unaccustomed to the topic of football concussions. I am a huge fan myself and am very much familiar with the matter. However, it was not until I started listening to this podcast a week and half ago to where it got me thinking. One question I had was how much of Aaron’s brain damage played a role in his violent behavior? A posthumous examination of Aaron’s brain had shown that he had a severe form of the degenerative brain disease, Chronic Traumatic Encephalopathy (CTE).³ His brain was heavily damaged to an extent that resembled that of a player in their 60’s.³

Aaron Hernandez is not the only football player to have CTE. This degenerative brain disease is most commonly found in athletes, military veterans, and individuals with a history of recurring trauma to the brain.⁵ The major contributor to this disease is a protein known as, Tau.  Tau forms clumps (Figure 2) which gradually spread throughout the brain, ultimately killing brain cells.⁵ My second question that arose was “if this is not a newly introduced disease, are there studies being conducted to produce a drug that will treat this horrible ailment”?

Figure 2: Dr. McKee shows  Tau proteins surrounding blood vessels in the superior frontal cortex of Hernandez’s brain.⁴

The currently diagnosis of CTE can only be done only after death, by performing a brain tissue analysis.⁵ As of right now, the only recommended treatment  for a concussion is to solely rest.⁶ However, Dr. Jacob VanLandingham, a neuroscientist at Florida State University has developed a drug known as, PRV-002 to hopefully change this.⁶ This drug is synthetic neurosteroid.⁷ He has invented this medication to be taken nasally within the initial minutes of head trauma an individual endures.⁶ Once PRV-002 has been absorbed into the brain, it is hypothesized to elicit three separate positive responses at a cellular level: a decline in the amount of inflammation, swelling, and stress.⁶ Due to PRV-002’s lipophilic characteristic, it can easily cross the blood-brain barrier to quickly remove the swelling, oxidative stress, and inflammation in the brain.⁷ When tested in rats, use of the drug resulted in evidence of improvement in short-term memory and motor performance, as well as a decrease in depression and anxiety.⁶ The suggested timeline of treatment is administer PRV-002 twice a day for 14 days in order to minimalize the post-concussion symptoms that will usually develop, such as dizziness, short-term memory loss, chronic headaches, and sleep disorders.⁶ The drug should decrease post-traumatic stress disorder and post-concussion symptoms, but Dr. VanLandingham states that in time, there is a possibility that this drug could also reduce chronic traumatic encephalopathy as well.⁶

The biopharmaceutical company, Prevacus plans to begin a Phase I clinical trial to investigate use of PRV-002 for treating concussions/mild traumatic brain injuries.⁷ An article published in May 2018, released that the upcoming Phase 1b study formed a new partnership between Prevacus’s new drug and BrainScope, a medical-neurotechnology company based in Bethsda, Maryland.⁸ The company will use its BrainScope One device in this study in order to provide assessments of the brain’s function.⁸ These assessments include EEG measures, cognitive performance tests, and standard, digitized concussion tests.⁸ This device is vital because it is accompanied with a Brain Function Index which will permit the scientists to accurately gauge the functional injury element of the brain after an injury has occurred.⁸  

Although PRV-002 is still in the works, it seems promising compared to the only current treatment of just resting. Even former NFL football star, Brett Favre seems confident about the drug’s potential. He has invested about half a million dollars and has raised a further $800,000 for Prevacus’s PRV-002.⁶ If the drug proves to be both, safe and effective in these upcoming Clinical trials, Prevacus is optimistic in releasing the drug to be on the market in about three to four years.⁶  
      

    References

 

1.  CNN Library. Aaron Hernandez Fast Facts. CNN. https://www.cnn.com/2014/03/09/us/aaron-hernandez-fast-facts/index.html. Published September 22, 2017. Accessed October 27, 2018.

 2.  Lewy M, Lopez H, Lavender G. Gladiator: Aaron Hernandez and Football Inc. The Boston Globe. October 2018. https://itunes.apple.com/us/podcast/gladiator-aaron-hernandez-and-football-inc/id1437935588?mt=2. Accessed October 16, 2018.

 

3. Belson K. Aaron Hernandez Had Severe C.T.E. When He Died at Age 27. The New York Times. https://www.nytimes.com/2017/09/21/sports/aaron-hernandez-cte-brain.html. Published September 21, 2017. Accessed October 27, 2018.

 

4.  Press A. New images show Aaron Hernandez suffered from extreme case of CTE. The Guardian. https://www.theguardian.com/sport/2017/nov/09/aaron-hernandez-cte-brain-damage-photos. Published November 9, 2017. Accessed October 27, 2018.

 

5.  Concussion Legacy Foundation. What is CTE? CTE Resources. https://concussionfoundation.org/CTE-resources/what-is-CTE. Published October 23, 2018. Accessed October 27, 2018.

 

6.  Fleming K. Can this concussion drug save football? New York Post. https://nypost.com/2018/01/08/can-a-drug-save-football/. Published January 9, 2018. Accessed October 27, 2018.

 

7.  Drug Development Technology. Prevacus to initiate Phase I trial of PRV-002 to treat concussion. Drug Development Technology. https://www.drugdevelopment-technology.com/news/newsprevacus-to-initiate-phase-i-trial-of-prv-002-to-treat-concussion-5737385/. Published February 12, 2017. Accessed October 27, 2018.

 

8.  Romero T. PREVACUS, BRAINSCOPE TEAM UP TO STUDY CONCUSSIONS. Sports Medicine Feature. https://ryortho.com/breaking/prevacus-brainscope-team-up-to-study-concussions/. Published May 25, 2018. Accessed October 27, 2018


By Beverly Balasuriya, Master of Medical Sciences Student, University of Kentucky