Psychedelics for the Treatment of PTSD

 

    Post-Traumatic Stress Disorder (PTSD) is a disorder that affects millions of people that have witnessed/experienced traumatic events, the effects of which alter the futures of those affected. There are no defining parameters that identify people who will experience PTSD symptoms, however, certain factors such as length, intensity, and reaction to the trauma all play a role, it is thought that 1 in 10 men and 2 in 10 women that experience traumatic events will experience PTSD symptoms.¹

   The behaviors that accompany PTSD are thought to be incurred from stress induced structural changes in the amygdala, hippocampus, and the prefrontal cortex, as well as neurochemical changes (cortisol and norepinephrine) altering the long term circuitry that is involved in the stress response (Figure 1 and 2.).³ Each of these areas can be seen to play a role in the symptoms that accompany PTSD. The amygdala becomes hyperactive and amplifies both the flight or fight response and feelings of anxiety/fear. The hippocampus becomes underactive/down regulated showing decreases in hippocampal volume along with deficits in memory. The prefrontal cortex acts on logical thinking and also becomes down regulated, impairing executive cognitive function.²

                                     Figure 1. Effects of stress on the cortisol/norepinephrine neurochemical response.

                                               Figure 2. Overview of regulation in the main areas affected by PTSD.

    To date, the current treatment plans are time intensive and geared more towards cognitive reframing and mitigation of symptoms.¹ Trauma-focused therapy is the most common approach used for treating PTSD and commonly lasts 3-4 months.¹  Antidepressants continue to be the first line of defense against PTSD. Both SSRI (selective serotonin reuptake inhibitor) and SNRI (serotonin-norepinephrine reuptake inhibitor) have shown to be effective in treating PTSD symptoms because of their ability to increase neurogenesis within the hippocampus. However, the common themes in literature suggests that this approach is modest at best and new therapies must be introduced. The unique world of psychedelics has shown promise in the area of treating not only PTSD but also anxiety, depression, even addiction disorders. The Multidisciplinary Association for Psychedelic Studies (MAPS) has entered into phase 3 clinical trials for the use of 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) in the treatment of PTSD.

     The usage of MDMA as a treatment differs from other psychedelics as it acts as an enactogen rather than a hallucinogen. This enhancement in feelings of openness highlights the difference between the psychoactivity between the two, and this is precisely the lens that allows the patient to process and eventually accept traumatic memories.⁴ The first controlled study was completed in 2010 and showed significant results in psychoactive assisted therapy using MDMA. The study used 20 patients with treatment-resistant PTSD, with patients either receiving a placebo or MDMA at the regular treatment intervals (Figure 3.) At follow up appointments of 2 and 12 months, 83% of participants in the experimental group no longer met the criteria to be diagnosed with PTSD.⁴

Figure 3. Treatment outline.

    MDMA exerts its effect as a release of serotonin, noradrenaline and even dopamine. As an activator of the 5-HT system that enhances activity at the 5-HT1a and 5-HT1b; MDMA reduces the fear response elicited by the amygdala.^4,5 In addition to dampening of the fear response, MDMA aids in the release of oxytocin, yielding a feeling of bonding and closeness which facilitates the effect of psychotherapy and causes a decrease in the overall stress response.⁴

     While the advent of this research still lies ahead of us, the initial breach has shown promising results. Even though we may feel like we are viewing an event horizon, there is a promise of better days ahead and in all cases it can’t come quite soon enough. Yet, as the light starts to edge its way over the horizon,quickly approaching we can forget how fast progress moves.  MDMA is currently in Phase 3 clinical trials and may potentially be approved by the FDA in 2021.

Joseph Devine, Master’s Medical Sciences Student, University of Kentucky 

 References

 1.  Https://www.ptsd.va.gov/publications/print/understandingptsd_booklet.pdf. (n.d.). Retrieved November 17, 2020, from https://www.ptsd.va.gov/

2.  Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2012). A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology, 27(1), 40-52. doi:10.1177/0269881112464827

3.  Bremner, J. D., MD. (2006). Traumatic stress: Effects on the brain. Dialogues Clinical Neuroscience, 8(4), 445-461.

4.  Sessa, B., Higbed, L., & Nutt, D. (2019). A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Frontiers in Psychiatry, 10. doi:10.3389/fpsyt.2019.00138

5.  Sessa, B. (2011). Could MDMA be useful in the treatment of post-traumatic stress disorder? Progress in Neurology and Psychology, 15(6).

6.  Devine, W. (2019). Crowd’s at 23rd. New York, NY: www.billydevine.com..

Postpartum Depression: Brexanolone the next best thing?

 Illustration by Erin McPhee (Tansey, 2016)

“I refused to take prescribed medication because I believed the best cure for depression was hard work, faithful prayer, and persistence. Not taking antidepressants turned out to be a really good bad decision. My search for natural healing led me to a huge Ah-ha revelation that my own toxic thoughts were making me sick. Learning how to retrain my brain has changed my life!

 

Today I faithfully pray, work hard, AND take [MEDICATION]. Every day. I wouldn’t trade my journey through postpartum depression because it taught me awesome life tools like practicing gratitude, yoga, nutrition, and prioritizing self-care and relationships. I’ve learned to let go of perfectionism and enjoy the richness of ordinary life.

                                                                                                                                                                 —Maleah W.”

 *Adaption from Danielle Radden’s Real Stories of Postpartum Mood Disorders: Motherhood beyond the smiling images.

             Just like Maleah’s story, many women are suffering from postpartum depression but are reluctant to share their symptoms with their physician or want to take medications to help with their depression. Postpartum depression affects up to 15% of women and can have long lasting effects on mother-infant interactions (Perfetti et al., 2004). Yet in the media, the portrayal of motherhood is one of perfect health, glowing skin, happiness and lacking mental illness. In reality, society's picture of motherhood is not always the true picture for every case, oftentimes leaving women suffering in a silent battle against this vicious illness. Postpartum mood disorders range from postpartum blues, postpartum depression, and postpartum psychosis (Perfetti et. al, 2004). The symptoms typically include anxiety, fatigue, anger, sadness, irritability, with more extreme cases presenting with suicidal ideation, hallucinations, paranoia, infanticide (Perfetti et. al, 2004). Postpartum depression can start as early as 1 day postpartum and last up to 1 year, with most mothers experiencing symptoms within the first three months postpartum. Without treatment, 30-70% of women will experience depression for a year or longer (Perfetti et. al, 2004).

            Treatment remains an imperative part of fighting this illness because of the impact chronic depression of the mother has on the infant. Children born to women with chronic depression typically have greater developmental delays in language, cognition, and emotion (Yonkers et. al 2009; Perfetti et al, 2004). Often children of depressive women have behavioral difficulties in school as well. This raises two questions. First, what are treatment options? Secondly, which are the best options for combating PPD?

            Fortunately, there are therapies that can be used for treatment of postpartum depression that have proven to be successful at combating and preventing severe depressive moods.  Currently, the most common tools are psychotropic medications (Perfetti et. al, 2014). Recently, the FDA approved the drug in this class, called Brexanolone, specifically to be used for treatment of postpartum depression (NIH, 2019). Brexanolone is an analog of the endogenous human hormone allopregnanolone, specifically developed and designed through a series of basic and translational neuroscience studies (NIH, 2019).

Figure 1. Comparison of Normal brain signaling compared to patients with PPD and treatment with Brexanolone.

The journey to Brexanolone began in 1980’s when NIMH Intramural Research Program (IRP) researchers discovered that metabolites of the hormones progesterone and deoxycorticosterone bound to and acted upon receptors for gamma-aminobutyric acid (GABA) (NIH, 2019). When these steroids act on GABA, they amplify GABA-activated chloride ion currents and impact the excitability of neurons (Figure 1). Researchers funded by NIMH and researchers of NIMH IRP continued their research by clarifying how the metabolites fluctuate during times of stress in rats, the estrous cycle in rats and the menstrual cycle in humans.  Concentrations of allopregnanolone, a metabolite from steroid hormones, was shown to increase during pregnancy then drops after birth (NIH, 2019). This shift in hormone changes is believed to lead to the development of depression and anxiety. This information resulted in a biopharmaceutical company developing the injectable drug brexanolone.

So how successful is brexanolone? In Kanes et al. (2017) a small proof of concept study on brexanolone, the drug was well tolerated in all patients with severe PPD. The study participants were assessed for depression using the Hamilton Rating Scale for Depression (HAMD and Edinburgh Postnatal Depression Scale (EPDS) and for anxiety using the Generalized Anxiety Disorder 7-item scale (GAD-7). Overall, the mean HAMD, EPDS, GAD-7 and Patient Health Questionnaire (PHQ-9) scores were decreased after infusion initiation and remained low through the end of infusion (60 hours post infusion) and at the last time point assessed (84 hours post infusion) (see Figure 2.).

Figure 2. Changes in mean total scores of assessments: HAMD, EPDS, GAD-7, PHQ-9 from baseline to last time point assessed ( Kanes et al.,2017).

Following the results reported by Kanes et al. (2017), larger studies were performed as phase III clinical trials which reported very promising results (Dacarette-Galeano & Diao, 2019). In March 2019, Brexanolone was approved through a risk evaluation and mitigation strategy known as the (REMS) program and is now available only to patients at certain certified health facilities with active monitoring by health care providers (Dacarette-Galeano & Diao, 2019). So dear reader, I’m sure you are asking why is such a huge requirement and precaution undertaken with a drug that has been proven to be successful? Brexanlone, though very effective, produced adverse events in a couple of the women in the larger studies, which included suicidal ideation, intentional overdose attempt and altered states of consciousness (Dacarette-Galeano & Diao, 2019). Therefore despite the enthusiasm surrounding the novel drug, there are still concerns about Brexanolone’s accessibility, contingent approval only with a REMS program, and cost-- which comes to around $34,000 for patients not including hospitalization cost (Dacarette Galeano & Diao, 2019).

 

By Toacca Taylor, Master of Medical Science candidate, University of Kentucky

 References

Tansey, Claire (2017). Recognizing the signs of postpartum depression. Retrieved November, 2020, from https://www.todaysparent.com/family/womens-health/recognizing-the-signs-of-postpartum-depression/

 

Radden, D. (2020). Real Stories of Postpartum that Mamas should know about - Mindful Mamas: Self-Care and Mindfulness for Moms. Retrieved November, 2020, from https://www.mindfulmamasclub.com/bloghub/real-stories-of-postpartum-mood-disorders danielle-radden

 

Perfetti, J., Clark, R., & Fillmore, C. M. (2004). Postpartum depression: identification, screening, and treatment. WMJ-MADISON-, 103, 56-63.

 

NIH, NIMH. (2019). Bench-to-bedside: NIMH research leads to brexanolone, first-ever drug specifically for postpartum depression [Press release]. Retrieved November, 2020, from

https://www.nih.gov/news-events/news-releases/bench-bedside-nimh-research-leads-br exanolone-first-ever-drug-specifically-postpartum-depression

 

Yonkers, K. A., Wisner, K. L., Stewart, D. E., Oberlander, T. F., Dell, D. L., Stotland, N.,

& Lockwood, C. (2009). The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General hospital psychiatry, 31(5), 403-413.

 

Kanes, S. J., Colquhoun, H., Doherty, J., Raines, S., Hoffmann, E., Rubinow, D. R., & Meltzer-Brody, S. (2017). Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Human Psychopharmacology: Clinical and Experimental, 32(2), e2576.

 

Dacarett-Galeano, D. J., & Diao, X. Y. (2019). Brexanolone: A Novel Therapeutic in the Treatment of Postpartum Depression. American Journal of Psychiatry Residents' Journal, 15(2), 2-4.

Tuberculosis - A disease old as ancient civilizations still wreaking havoc

 

TB granuloma.
https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

    Usually, when you are about to join new job or enroll in a school/university, you are told go through a mandatory health check-up to make sure you have been vaccinated. You may even get a Tuberculosis (TB) skin test. If you were born in the United States, the TB skin test will most likely not result in any reaction. For me, however, I develop a giant, itchy red bump within two days where the nurse had inserted a small fluid known as tuberculin underneath my skin. Looking at my medical history, I have had the BCG vaccine and had been treated for latent TB. The next step for me is to get a chest x-ray which have been normal so far. Although tuberculosis cases in the United States are low, about 2.7 cases per 100,000 persons, nearly 80% of the active TB cases are due to reactivation of latent TB¹. These cases can become incredibly serious, if the person with reactivated TB had already been treated with TB previously¹. Screening for drug resistance becomes an immediate priority. 

    To understand the growing concern of drug-resistant Mycobacterium tuberculosis bacteria, we must understand TB history and how it infects people. Tuberculosis has been around since antiquity. Mycobacterial DNA has been found in ancient Egyptian mummied remains dating back to the Middle Kingdom, 2050 B.C².  During the 17^th and 18^th century, many scientists have documented various pathological signs of tuberculosis. It was not until 1882 when Robert Koch figured out that the cause of tuberculosis was a mycobacterium³. M. tuberculosis spreads when an infected person coughs, sneezes, spits or speaks. Most people infected with TB do not have any signs or symptoms of the disease until the disease is activated. These people have latent TB and about 10% of persons with latent TB later have active TB if untreated⁴. Interestingly, persons who have latent TB are not contagious; only persons with active TB are⁴. When the bacteria is activated and grows in the lungs, it’s known as pulmonary TB⁴. Extrapulmonary TB affects tissues such as the lymphatics (tuberculosis lymphadenitis), bones (skeletal tuberculosis), various tuberculosis of the abdomen, or CNS tuberculosis which causes meningitis⁵. However, let us just focus on pulmonary tuberculosis, which is the most common.

Robert Koch
.https://www.thefamouspeople.com/profiles/robert-koch-6563.php

    When tuberculosis bacterium is inhaled, the bacteria migrates to the alveolar sacs. Here pulmonary macrophages endocytose the bacterium. The bacteria reside in the phagosome and replicate and evade macrophage digestion⁶. The infected macrophage attracts other cells of the immune system such as more macrophages, T cells and B cells⁶. Macrophages fuse around the infected macrophage and T cells form a barrier around the macrophages⁶. Fibroblasts and collagen that surround the T cells and form a granuloma⁶. The on-going infection is a constant battle between tissue destruction and healing causing an increasing amounts of scar tissue⁶. In the chest x-ray, granulomas are the primary characteristic of a TB infection⁶. TB can become dormant during the granuloma stage and can be reactivated if the immune system is weakened when challenged by other events such as an infection by another pathogen like HIV ⁶. Therefore, it is essential that persons with latent TB are treated to reduce any chance of activating the infection⁷. Persons wIsoniazid is a pro-drug that is activated by the catalase-peroxidase enzyme found in M. tuberculosis⁸. Once activated, isoniazid becomes isonicotinic acyl-NADH which inhibits the synthesis of mycolic acids in the mycobacterial cell wall⁸. Rifampin, also known as rifampicin, inhibits bacterial RNA polymerase ⁹. Isoniazid and rifampin are two of the most potent drugs used to treat active and latent TB. From 2018 to 2019, there have been a 10% increase of multi-drug resistant (MDR) TB, where both rifampin and isoniazid no longer have an effect⁴. Only 57% of MDR TB patients have been successfully treated globally⁴. MDR TB is diagnosed by detecting growth rate of the bacteria in a sputum sample treated with the rifampin or isoniazid¹⁰. This is then followed by a series of PCR tests to check for drug resistant genotypic markers¹⁰. Persons with MDR TB are treated with a second line of TB medications which are much more toxic.  Other agents used are expensive injectable agents such as amikacin/kanamycin, fluoroquinolone as well as other compounds that might have some activity against the infection like cycloserine¹⁰. The side effects vary from nephrotoxicity to drug induced hepatitis depending on the treatment plan¹⁰. Although rare, extensively drug resistant (XDR) TB exists as well where the person is not only resistant to the first line of drugs but also resistant to at least one of the second line of drugs¹⁰. Scientists are now focusing on generating better antibiotic drugs that better target mycobacteria for patients with MDR TB¹⁰.

https://www.who.int/news/item/30-10-2017-who-report-signals-urgent-need-for-greater-political-commitment-to-end-tuberculosis

     For the first time in few decades, two new TB drugs have shown to have positive outcomes for persons with MDR-TB as compared to those treated with the usual regime¹⁰. Delamanid belongs to a class of nitroimidazoles and was developed by Otsuka Pharmaceutical Development and Commercialization, in Osaka, Japan¹¹. The mechanism of action is similar to isoniazid. It inhibits mycolic acid synthesis¹¹. The side effects are dizziness and QT prolongation, which means the heart takes a longer time to repolarize¹¹. Bedaquiline belongs to the diarylquinoline group and was developed by Janssen Pharmaceuticals in Titusville, NJ¹¹. The drug inhibits mycobacterial ATP synthase and has a long half-life¹¹. More studies need to be conducted regarding bedaquiline’s side effects and toxicity as well as possible resistance¹¹. With two new drugs on the market, there is potential that MDR-TB can be treated and hopefully eradicated in countries where TB is endemic.

By Bhavani Gudlavalleti, A Master’s of Medical Sciences Student at the University of Kentucky

Literature Cited

1.       Schwartz, N. G., Price, S. F., Pratt, R. H., & Langer, A. J. (2020, March 19). Tuberculosis - United States, 2019. Retrieved October 23, 2020, from https://www.cdc.gov/mmwr/volumes/69/wr/mm6911a3.htm

2.     Zink, A. R., Sola, C., Reischl, U., Grabner, W., Rastogi, N., Wolf, H., & Nerlich, A. G. (2003). Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. Journal of clinical microbiology, 41(1), 359–367. https://doi.org/10.1128/jcm.41.1.359-367.2003

3.     Iseman, M. (2013, February 01). Tuberculosis: History. Retrieved October 23, 2020, from https://www.nationaljewish.org/conditions/tuberculosis-tb/history

4.     WHO. (2020, October 14). Tuberculosis (TB). Retrieved October 23, 2020, from https://www.who.int/news-room/fact-sheets/detail/tuberculosis

5.     Golden, M. P., & Vikram, H. R. (2005). Extrapulmonary tuberculosis: an overview. American family physician, 72(9), 1761–1768.

6.     Desai, Rishi. [Medscape]. (2018, Jan. 9). Tuberculosis | Clinical Presentation. [Video]. YouTube. https://www.youtube.com/watch?v=0qFiflLL21U

7.     CDC. (2020, February 13). Treatment Regimens for Latent TB Infection. Retrieved October 23, 2020, from https://www.cdc.gov/tb/topic/treatment/ltbi.htm

8.     Timmins, G. S., & Deretic, V. (2006). Mechanisms of action of isoniazid. Molecular microbiology, 62(5), 1220–1227. https://doi.org/10.1111/j.1365-2958.2006.05467.x

9.     Wehrli W. (1983). Rifampin: mechanisms of action and resistance. Reviews of infectious diseases, 5 Suppl 3, S407–S411. https://doi.org/10.1093/clinids/5.supplement_3.s407

10.  Millard, James, Ugarte-Gil, Cesar, and Moore, David A J. "Multidrug Resistant Tuberculosis." BMJ : British Medical Journal 350.Feb26 10 (2015): H882. Web.

11.  Migliori, G. B., Pontali, E., Sotgiu, G., Centis, R., D'Ambrosio, L., Tiberi, S., Tadolini, M., & Esposito, S. (2017). Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review. International journal of molecular sciences, 18(2), 341. https://doi.org/10.3390/ijms18020341ith latent TB are treated with either rifampin for three to four months or isoniazid for six to nine months⁷. The dosage and drug concentrations vary based on age and body mass. These same drugs are used for persons with active TB⁷.

Parkinson’s Disease: A New Avenue for Drug Development

     Neurodegenerative Diseases affect millions of people worldwide and your chances only go up as you age. Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease behind Alzheimer’s affecting ~10 million worldwide. PD is mainly a movement disorder causing tremors in the extremities. As the disease progresses tremors worsen along with the development of a stooped posture, shuffling gait, gastrointestinal issues, and many cases progress into dementia¹. Simply put, these effects are caused by the accumulation of Lewy bodies (aggregates mainly composing of the protein α-synuclein) in dopamine producing neurons (dopaminergic neurons). These Lewy bodies affect the neuron’s ability to produce dopamine along with negatively affecting other cellular functions. There are no current cures for PD, but there are a host of treatments to offset symptoms. One of the most successful of these treatments is dopamine injections which help compensate for the dysfunction of the affected neurons².

https://www.labiotech.eu/medical/axovant-parkinsons-disease-gene/

    Research and drug development for PD has focused mainly on the main culprit of the disease, dopaminergic neurons.  However, there are many other cell types in the brain which all interact with each other. Astrocytes have recently become of interest as drug targets for neurodegenerative disease. Astrocytes perform many roles in the brain and work directly with neurons to keep them healthy and functional. They provide metabolic and structural support, are involved in the blood brain barrier, contribute to neuroinflammation, and take up and degrade extracellular debris including α-synuclein. In fact, reactive astrocytes are a key factor in PD development³. To study the interaction of astrocytes and dopaminergic neurons Domenico et al. employed a co-culture system using induced pluripotent stem cells (iPSC). These stem cells are made by taking an adult cell and transfecting them with four specific genes. These genes help the cells revert to a stem cell state wherein they can become any type of cell, a state similar to that of early embryos. The resultant stem cells were then induced to become either dopaminergic neurons or astrocytes. The use of iPSC allows us to create cells which will have the disease of any patient. 

(Domenico et al. 2019)

    This co-culture system allows us to study the interactions between astrocytes and dopaminergic neurons with and without PD. Using this system, we have been able to detect astrocyte involvement in the progression of PD. Most notably is their role in the accumulation of Lewy bodies. When healthy astrocytes and healthy neurons are co-cultured there is no evident accumulation of Lewy bodies. To see if astrocytes with PD could drive disease a co-culture was done with PD astrocytes and healthy neurons. In this experiment not only were Lewy bodies detected but the survival of dopaminergic neurons was decreased. This suggests that dysfunctional astrocytes contribute to the development of PD. A final co-culture was set up using PD neurons and healthy astrocytes to see if astrocytes were able to offset the dysfunction of diseased neurons. This resulted in a significantly lower accumulation of Lewy bodies and increased survival of neurons⁴.

     At the time of writing this blog there are only a few studies that have been published studying astrocyte interactions with dopaminergic neurons in PD. There is evidence that astrocytes actively exchange α-synuclein, the main component of Lewy bodies, with dopaminergic neurons and degrade it. PD astrocytes have varying degrees of impairment in autophagy and lysosomal function meaning that they are not as able to destroy and discard unwanted or dysfunctional proteins and cellular components⁵. Astrocytes have also been shown to be mitochondrial donors to neurons in another model of PD. Dysfunctional mitochondria are often implicated in PD and the donation of healthy mitochondria to dopaminergic neurons significantly offset PD related phenotypes in dopaminergic neurons⁶.

    The evidence of astrocyte involvement in PD opens the doors to new research into drug development. We may design drugs to target astrocytes to slow or stall the progression of not only PD but other neurodegenerative diseases. The co-culture system using iPSC also allows us a more compete picture for study neurodegenerative diseases.

By Meagan Medley, a Master of Medical Science Student at the University of Kentucky

  References

 1.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

2.  Chaudhuri, K. R., & Schapira, A. H. (2009). Non-motor symptoms of Parkinson's disease: Dopaminergic pathophysiology and treatment. The Lancet Neurology, 8(5), 464-474. doi:10.1016/s1474-4422(09)70068-7

3.   Booth, H. D., Hirst, W. D., & Wade-Martins, R. (2017). The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends in Neurosciences, 40(6), 358-370. doi:10.1016/j.tins.2017.04.001

4.   Domenico, A. D., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J. P., Richaud-Patin, Y., . . . Consiglio, A. (2019). Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease. Stem Cell Reports, 12(2), 213-229. doi:10.1016/j.stemcr.2018.12.011

5.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

6. Cheng, X., Biswas, S., Li, J. et al. (2020) Human iPSCs derived astrocytes rescue rotenone-induced mitochondrial dysfunction and dopaminergic neurodegeneration in vitro by donating functional mitochondria. Transl Neurodegener 9, 13. https://doi.org/10.1186/s40035-020-00190-6

 

Use of Sonoporation to Increase Pancreatic Cancer Treatment Efficacy Without Additional Toxicity

 

                Figure 1 Changes in overall survival across multiple cancers between 1971 and 2011.        

Credit: Cancer UK; from (2) Cancer Research UK. (2019, July 19). Cancer survival for common cancers. Retrieved October 14, 2020, from https://www.cancerresearchuk.org/health-professional/cancerstatistics/survival/common-cancers-compared.

    Pancreatic Ductal Adenocarcinoma (PDAC) is currently one of the most difficult to treat types of cancer, with an overall five-year survival rate of only 9%, and an increase in death rates between 2012 and 2016 (1). There has been very little progress in PDAC treatment efficacy despite decades of research. This in in contrast to many other cancer types which have seen significant improvements in available treatment options, as seen in figure 1 (2). This sets PDAC apart as an area of particular importance for developing effective treatment strategies to try to overcome many of these difficulties. 

    PDAC is a disease that develops from non-malignant precursor lesions that progress slowly, often taking years to adapt a metastatic phenotype and developing into an advanced stage invasive cancer(3,4). At this point, disease progression becomes much more rapid, contributing to the poor survival rates (5). This pattern of progression is perhaps the largest hurdle that clinicians need to overcome, as during this long period of growth and development most patients experience no symptoms at all, making early detection or treatment next to impossible (6). Because of this, when most patients are finally diagnosed the disease is already at an advanced stage, with less than 20% of PDAC diagnoses shown to be surgically resectable due to tissue invasion or metastasis (7). This puts an emphasis on the need for non-surgical treatment options, but these treatments have many of their own problems.

    PDAC is characterized by a highly desmoplastic and fibrotic microenvironment surrounding the tumor core, packed with immune cells and cancer-associated fibroblasts that produce large amounts of extracellular matrix factors (8). This microenvironment serves to isolate the tumor core, which is the reason why most patients are asymptomatic. However, it also serves as very effective barrier for chemotherapy treatments (9), and because most drugs have difficulties reaching the tumor core they are developed to act on, even the most promising drugs will inevitably prove ineffective. Currently, the most effective chemotherapeutic agent is FOLFIRINOX, which is a combination of oxaliplatin, irinotecan, fleurouracil, and leucovorin that has been shown to increase overall survival by 11.1 months (10). However, this efficacy comes with a price of high toxicity, with serious side effects including severe fatigue, sensory neuropathy, anemia, thrombocytopenia, and diarrhea. Because of the toxicity of FOLFIRINOX, many patients are not able to receive this treatment due to poor health. As a way of providing some treatment to patients who cannot withstand the toxicity of FOLFIRINOX, gemcitabine along with albumin-bound paclitaxel (nab-paclitaxel) can be administered to increase overall survival by 8.5 months with a much better safety profile (11, 12). However, these patients have to settle for suboptimal therapy, so there is certainly a need to find a way to increase the efficacy of chemotherapy in these patients without increasing toxicity.  

Figure 2 Visualization of microbubble forces in sonoporation. 

From (14) Fan, Z., Kumon, R. E., & Deng, C. X. (2014). Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery. Therapeutic delivery, 5(4), 467-486.

doi:10.4155/tde.14.10

    To address this issue, studies are being performed using sonoporation in conjugation with less toxic PDAC treatments including gemcitabine and paclitaxel to try and elicit a more effective response. Sonoporation involves the use of microbubbles that, along with ultrasound stimulation, can result in temporary formations of small pores in the nearby cells (13). These pores are created by the forces generated by the microbubbles as they are manipulated by the ultrasound waves (14). The different types of forces can be seen illustrated in figure 2. The idea behind using this technique is that creating these pores will facilitate drug entry into cells, both increasing efficacy and reducing the required dose.

Additionally, sonoporation can be localized to very specific areas depending on ultrasound administration, and the process is very safe, as microbubbles have been used for many years as a contrast agent in ultrasound imaging (15).

Figure 3 Overall survival increases seen in patients treated with gemcitabine + sonoporation. 

From (17) Dimcevski, G., Kotopoulis, S., Bjånes, T., Hoem, D., Schjøtt, J., Gjertsen, B. T., . . . Gilja, O. H. (2016). A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. Journal of Controlled Release, 243, 172-181.

doi:https://doi.org/10.1016/j.jconrel.2016.10.007

    Initial tests of this technique applied in orthotopic xenograft mouse models of PDAC demonstrated a significant decrease in tumor volume compared to normal gemcitabine treatment alone, as well as an increased survival rate in the mice treated with sonoporation (16). These results were very promising, and prompted a shift to human clinical trials to understand if sonoporation could result in more effective treatments without toxicity. Testing sonoporation + gemcitabine chemotherapy in patients with inoperable pancreatic cancer proved quite successful. Median survival of patients was increased from 8.9 months to 17.6 months, and patients were able to undergo more cycles of chemotherapy. Many patients also experienced an overall decrease in tumor volume (17). These results are very promising, and demonstrate the potential utility of sonoporation in conjunction with chemotherapy as a means of increasing treatment efficacy without putting the patient at a higher risk of toxicity. However, much work remains to be done to determine the ideal conditions to ensure the greatest efficacy increase while maintaining a safe profile. 

By Zeke Rozmus, A Master of Medical Science Student at the University of Kentucky

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doi:https://doi.org/10.1016/j.jconrel.2016.10.007