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

Gabapentin: The Everything Drug

According to the National Institute of Drug Abuse, there are more than 115 people dying from opioid overdoses every day in the United States.¹ However, opioids are not the only drugs contributing to the staggering amount of overdose deaths. One drug in particular whose usage has been on the rise is gabapentin. In 2017, gabapentin was implicated in more than one-third of overdose deaths in Kentucky.² Gabapentin was first approved by the FDA in January, 1994 as an antiepileptic medication.³ Since then, its usage has skyrocketed. In 2015, there were over 43 million prescriptions written for gabapentin, and it is currently the seventh-most prescribed medication in the United States.⁴

Figure 1: Gabapentin prescription rates (in millions) between the years of 2004 and 2015.⁴

           

            The rise in gabapentin prescriptions is mainly due to the drug company Pfizer promoting their brand-name gabapentin (Neurontin) to physicians for a plethora of off-label uses. Due to this mass-marketing, gabapentin is now prescribed not only for epilepsy, but for anxiety, trigeminal neuralgia, restless legs syndrome, diabetic neuropathy, migraines, insomnia, bipolar disorder, and many other conditions.⁵ Some analysts have stated that “up to 90 percent of Neurontin prescriptions were for off-label uses.”⁶

            Pfizer’s mass-marketing campaign to physicians was so voracious that a felony case was settled against them in 2004.⁶ According to the San Francisco Chronicle, Pfizer “agreed to plead guilty to two felonies and pay $430 million in penalties to settle charges that it fraudulently promoted the drug Neurontin for a string of unapproved uses.”⁶ Ironically, the FDA approved Neurontin to be sold as generic gabapentin in the same year, making it more readily available and more affordable. Coupled with the rise in prescriptions, gabapentin’s potential for abuse has caused it to be added to the DEA’s list of controlled substances in Kentucky, Ohio, and West Virginia in 2017.³

             Gabapentin’s potential for abuse lies mainly in its mechanism of action. Although its molecular structure closely resembles the neurotransmitter GABA, it does not directly act on GABA receptors.⁷ Its proposed mechanism is that it mainly binds to voltage-gated calcium channels on glutamatergic neurons.⁷ By closing the voltage-gated calcium channels, less glutamate is released from presynaptic neurons, therefore lowering the excitation level of the postsynaptic neurons. This contributes to gabapentin’s perceived analgesic or anxiolytic/sedative effects.

            Although gabapentin has shown some efficacy in treating conditions like epilepsy, its off-label usage is unlike any other medication on the market today. Even after debunking many of its off-label uses and being placed on the DEA’s controlled substances list in 3 states, gabapentin prescriptions are still being given out at an alarming rate. Gabapentin’s contribution to drug overdoses should not be overlooked, especially with the opioid epidemic the U.S. is currently experiencing. Instead of being a first-line course of action, both physicians and patients should question the efficacy of gabapentin before beginning treatment.

 

References:

1. National Institute on Drug Abuse. (2018, March 06). Opioid Overdose Crisis. Retrieved from https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis

2. Gabapentin Abuse. (n.d.). Retrieved from https://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2018/05/10/abuse-of-opioid-alternative-gabapentin-is-on-the-rise

3. Honarmand, A., Safavi, M., & Zare, M. (2011). Gabapentin: An update of its pharmacological properties and therapeutic use in epilepsy. Journal of Research in Medical Sciences, 16(8), 1062-1069.

4. (n.d.). Retrieved from https://www.addictionpro.com/article/prescription-drug-abuse/states-eye-adding-gabapentin-controlled-substance-list

5. Fukada, C., Kohler, J., Boon, H., Austin, Z., & Krahn, M. (2012). Prescribing gabapentin off label: Perspectives from psychiatry, pain and neurology specialists. Canadian Pharmacists Journal, 145(6), 280-284.

6. Tansey, B. (2012, January 28). Huge penalty in drug fraud / Pfizer settles felony case in Neurontin off-label promotion. Retrieved from https://www.sfgate.com/business/article/Huge-penalty-in-drug-fraud-Pfizer-settles-2759293.php

7. Taylor, C. P. (1997). Mechanisms of action of gabapentin. Revue Neurologique, 153(1), 39-45.

 

By Hart Foley, Master of Medical Sciences Student, University of Kentucky

Selective Serotonin Reuptake Inhibitors



        In the 1970s, the discovery that serotonin played a significant role in mood disorders initiated efforts to develop Selective Serotonin Reuptake Inhibitors (SSRIs). Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants (TCA) had been used to treat major depressive disorder since the late 1950s. Both of these classes of drugs were developed serendipitously; MOAs were discovered originally for treatment of tuberculosis and TCAs were initially intended for patients suffering from schizophrenia. MAO enzymes break down amines such as neurotransmitters, and their inhibition results in the increase of neurotransmitter concentrations in the presynaptic terminal. TCAs contain a core of three benzene rings and inhibit both neurotransmitter transporter and receptor functions. Although these medications were mildly effective, they had a narrow therapeutic index and long list of serious side effects.¹

           

 

Figure 1. Mechanism of Action of Selective Serotonin Reuptake Inhibitors⁷

 

In the clinic, SSRIs proved to be much more tolerable than MAO inhibitors and TCAs for patients based on their specificity for serotonin receptors.² They bind only serotonin transporters and increase the amount of serotonin in the synapse. Over time, the serotonin receptor 5HT1A is downregulated and even more serotonin is released. This mechanism explains why these medications take a few weeks to show full effect.³ SSRIs were initially thought to be free of side effects and could be used by children and elderly populations.

 

            However, as clinical use increased, the side effects of SSRIs became more apparent. It is possible that the dosages used in early clinical trials were relatively low and at levels that did not exert observable side effects. It is also possible that side effects were not reported as they relied on self-report measures which often lack accuracy. The most significant adverse side effects of SSRIs are serotonin syndrome, sexual dysfunction, and weight gain, but appetite and sleep may be affected. Serotonin syndrome can result from overdose and presents with muscle spasms, increased heart rate, and possible psychosis. If a patient abruptly stops taking SSRIs, discontinuation syndrome may ensue. This is similar to withdrawal, so patients should be weaned off these medications.² A 2005 study showed patients who tapered their SSRI medications exhibited half the symptoms of discontinuation syndrome than those who stopped taking them abruptly. Tapering schedules were developed by patients, general practitioners, and psychiatrists, with periods varying from two weeks to four months.⁴

 

            The controversy on the efficacy of SSRIs prevails. Irving Kirsch is a psychologist and a researcher of the Placebo Studies Program at Harvard Medical School. In a 60 Minutes special, Kirsch argued that the placebo effect, not the actual chemical substance of antidepressants, accounted for patients’ improvement By performing a meta-analysis, he concluded that SSRIs were only effective with severe levels of depression. However, Dr. Michael Thase of the University of Pennsylvania School of Medicine disagreed, saying that by focusing on research, Kirsch was overlooking the success of SSRIs seen in clinic. Although the efficacy Thase observes is low, more success is seen in the mildly and moderately depressed than what is shown in the research.⁵ A newer meta-analysis conducted by Hieronymus et al. compared paroxetine and citalopram (information was requested for fluoxetine and sertraline but was not received) and refuted this placebo effect. More research is needed to provide conclusive evidence on SSRI efficacy, but this study was able to provide support for the pharmacodynamic effects of these drugs.⁶

 

1. Hillhouse, T. M., & Porter, J. H. (2015). A brief history on the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1). http://doi.org/10.1037/a0038550
2. Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability. The Primary Care Companion to the Journal of Clinical Psychiatry, 3(1), 22-27. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181155/#i1523-5998-003-01-0022-b11
3. Guzman, F. (n.d.). Mechanism of Action of SSRIs. Retrieved from https://psychopharmacologyinstitute.com/antidepressants/ssris/mechanism-action-ssris/
4. van Geffen, E. C. G., Hugtenberg, J. G., Heerdink, E. R., van Hulten, R. P., & Egberts, A. C. G. (2005). Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. European Journal of Clinical Pharmacology, 61, 303-307. https://doi.org/10.1007/s00228-005-0921-x
5. Stahl, L. (Interviewer), Kirsch, I. & Thase, M. (Interviewees). (2012, February 19). Treating Depression: Is there a Placebo Effect? [Interview Transcript]. Retrieved from https://www.cbsnews.com/news/treating-depression-is-there-a-placebo-effect/
6. Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017). Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry. https://doi.org/10.1038/mp.2017.147
7. Lattimore, K. A. , Donn, S., Kaciroti, N., Kemper, A. R., Neal, C. R., & Vázquez, D. (2005). Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis. Journal of Perinatology, 25, 595-604. doi:10.1038/sj.jp.7211352.

 

By Catie White, Master of Medical Sciences Student, University of Kentucky

 

Weakening the Immune System: How Immunosuppressants Help Save Lives

The immune system is designed to aid in protection against potential infection and disease from invasion of foreign bodies. One example of how this defense mechanism becomes problematic, however, is when the ‘foreign’ tissue is a necessity for one’s survival – as in the case of organ transplantation.

                Organ transplants, especially kidney transplantations, impact many lives each year. According to the Kidney Alliance of Kentucky, “there are over 750 people in Kentucky waiting for a life saving kidney transplant.”¹ The University of Kentucky Transplant Center set a record for the most transplants performed by any Kentucky medical center in a single year with 208 total transplants in 2017 – of those, 101 were kidney transplants, 43 were heart transplants, 41 were liver transplants, and 23 were lung transplants². The basis for transplant ‘success’ is the ability to use drugs that suppress the immune system (called immunosuppressants) in a manner in which the immune system does not recognize and/or target the foreign organ to allow for successful donated organ function.

                Immunosuppressants are a highly specialized class of drugs that are essential in the organ transplant process. They not only function as a hinderance to organ rejection but are also used to treat graft versus host disease and reduce damage to tissues in autoimmune and other inflammatory diseases³. There are several classes of immunosuppressants in this particular drug family, including corticosteroids, calcineurin inhibitors, mTOR (mammalian target of rapamycin) inhibitors, IMDH (inosine monophosphate dehydrogenase) inhibitors, biologics, and monoclonal antibodies⁴.

Some examples of the most common classes of immunosuppressants involved in organ transplantation are calcineurin inhibitors and IMDH inhibitors. Calcineurin acts to catalyze reactions associated with T cell activation in the immune response; inhibitors of calcineurin bind to immunophilin proteins to block its effect and prevent NFAT (nuclear factor of activated T-cells) activation⁴. The result is a reduction in production of cytokine IL-2 and proliferating T cells⁶. In contrast, IMDH inhibitors perform by blocking the inosine monophosphate dehydrogenase pathway, an important enzyme involved in cell interactions and DNA replication⁴. This results in a reduction of infiltrating immune cells during potential transplant rejection⁷. Prograf (tacrolimus) and Mycophenolate mofetil (MMF) are two commonly prescribed combination immunosuppressant drugs to prevent organ rejection for transplant patients; they fall under the calcineurin inhibitor and IMDH inhibitor classes respectively⁸. There are several other immunosuppressant drugs being used in similar clinical settings that fall under different subcategories according to other pathways used to target the immune system.

 

Immunosuppressive Drugs. (n.d.). Retrieved from https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs

Like any drug, there are side effects/precautions when taking immunosuppressants. By weakening the immune system, patients are more susceptible to infection and illness while taking immunosuppressants. Those taking these types of drugs may also be subject to delayed wound healing for similar reasons. Doctors often prescribe antibiotics in addition to these medications to help prevent such problems and advise patients to limit their interactions/possibilities of introducing bacteria into their compromised environment³. These risks can be especially troublesome because transplant recipients must often take these drugs for the rest of their lives to ensure the viability and protection of the donated organ.

                While the immune system is normally a beneficial protective mechanism, it can be detrimental to the successful integration of a transplanted organ. It is quite interesting to explore the mechanisms that scientists, chemists, pharmacologists, and other teams have utilized to suppress this system in order to help save the lives of many people through organ transplantation.

References:

1. How To Help: Be a Living Kidney Donor. (n.d.). Retrieved from https://www.khaky.org/how-to-help/living-kidney-donor.html

2. UK Transplant Center Sets New State Record for Total Transplants in 2017. (2018, January 08). Retrieved from https://uknow.uky.edu/uk-healthcare/uk-transplant-center-sets-new-state-record-total-transplants-2017

3. Immunosuppressants in Organ Transplantation. (2014, March 13). Retrieved from https://www.myvmc.com/treatments/immunosuppressants-in-organ-transplantation/

4. Immunosuppressants. (n.d.). Retrieved from https://www.amboss.com/us/knowledge/Immunosuppressants

5. Immunosuppressive Drugs. (n.d.). Retrieved from https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs

6. P. (2006, August 01). Immunosuppressants - mechanisms of action and monitoring | Australian Prescriber. Retrieved from https://www.nps.org.au/australian-prescriber/articles/immunosuppressants-mechanisms-of-action-and-monitoring

7. Blaheta, R. A., Leckel, K., Wittig, B., Zenker, D., Oppermann, E., Harder, S., . . . Markus, B. H. (1998, December). Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10342739

8. Giorgi, A., & Gregory, P. (2016, December 7). About Immunosuppressant Drugs. Retrieved from https://www.healthline.com/health/immunosuppressant-drugs#drug-list

By Caitlin Seward, Master of Medical Sciences Student, University of Kentucky