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

 References:

1.    Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA Cancer J Clin, 69(1), 7-34. doi:10.3322/caac.21551

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

3.    Hidalgo, M. (2010). Pancreatic cancer. N Engl J Med, 362(17), 1605-1617. doi:10.1056/NEJMra0901557

4.    Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., . . . Iacobuzio-Donahue, C. A. (2010). Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467(7319), 1114-1117. doi:10.1038/nature09515

5.    Yu, J., Blackford, A. L., Dal Molin, M., Wolfgang, C. L., & Goggins, M. (2015). Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages. Gut, 64(11), 1783-1789. doi:10.1136/gutjnl-2014-308653

6.    Bekkali, N. L. H., & Oppong, K. W. (2017). Pancreatic ductal adenocarcinoma epidemiology and risk assessment: Could we prevent? Possibility for an early diagnosis. Endoscopic ultrasound, 6(Suppl 3), S58-S61.

doi:10.4103/eus.eus_60_17

7.    Sohn, T. A., Yeo, C. J., Cameron, J. L., Koniaris, L., Kaushal, S., Abrams, R. A., . . . Lillemoe, K. D. (2000).

Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg, 4(6), 567-579. doi:10.1016/s1091-255x(00)80105-5

8.    Dauer, P., Nomura, A., Saluja, A., & Banerjee, S. (2017). Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 17(1), 7-12. doi:10.1016/j.pan.2016.12.010

9.    Oberstein, P. E., & Olive, K. P. (2013). Pancreatic cancer: why is it so hard to treat? Therapeutic advances in gastroenterology, 6(4), 321-337. doi:10.1177/1756283X13478680

10.  Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., . . . Ducreux, M. (2011).

FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New England Journal of Medicine, 364(19), 1817-1825. doi:10.1056/NEJMoa1011923

11.  Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., . . . Renschler, M. F. (2013).

Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine, 369(18), 1691-1703. doi:10.1056/NEJMoa1304369

12.  Ellenrieder, V., König, A., & Seufferlein, T. (2016). Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma. Digestion, 94(1), 44-49. doi:10.1159/000447739

13.  Delalande, A., Kotopoulis, S., Rovers, T., Pichon, C., & Postema, M. (2011). Sonoporation at a low mechanical index. Bubble Science, Engineering & Technology, 3(1), 3-12. doi:10.1179/1758897911Y.0000000001

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

15.  Erchinger, F., Dimcevski, G., Engjom, T., & Gilja, O. (2011). Transabdominal ultrasonography of the pancreas: basic and new aspects. Imaging in Medicine, 3, 411-422. 

16.  Kotopoulis, S., Delalande, A., Popa, M., Mamaeva, V., Dimcevski, G., Gilja, O. H., . . . McCormack, E. (2014). Sonoporation-Enhanced Chemotherapy Significantly Reduces Primary Tumour Burden in an Orthotopic Pancreatic Cancer Xenograft. Molecular Imaging and Biology, 16(1), 53-62. doi:10.1007/s11307-0130672-5

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

 

High Blood Pressure in the US: A Pharmacological and Cultural Problem

 

Extracted from source 3: Holland, K. (2020, June 17). High Blood Pressure: Causes, Symptoms, Medication, Diet, and More. Retrieved October 03, 2020, from https://www.healthline.com/health/high-blood-pressure-hypertension 

     It is no surprise that high blood pressure remains a growing problem in the United States. In 2018, alone half a million deaths were attributed to complications associated with hypertension (1). The current leading cause of death for the United States is heart disease with hypertension contributing greatly to the fatalities (2). With a rise in the overall number of hypertension cases in the US, the amount of prescribed blood pressure medication has also been on the rise. Currently, the American Heart Association guidelines define hypertension as a blood pressure at or above 130/80 mmHg with stage 2 hypertension being above 140/90 mmHg (1). The current treatment for diagnosed high blood pressure is usually a high blood pressure medication (4). Common hypertension medications include diuretics, beta blockers, ACE inhibitors, alpha blockers, calcium channel blockers, and central agonists. Medication options are prescribed by the physician based on their potential to alleviate the symptoms that the patient presents as well as incur the side effects. Most treatment options are coupled with medication as well as changes in lifestyle to help alleviate symptoms of high blood pressure. Unfortunately, it appears that most patients are reluctant to major lifestyle changes but instead prefer to rely on the use of medications. 

    With the increasing percent of the population succumbing to high blood pressure and the associated cardiovascular diseases, it is important to spread awareness of treatment options as well as advocate for lifestyle changes. Unfortunately, the issue of high blood pressure is very complicated and ingrained within layers of socioeconomic and health predispositions. While blood pressure medications have been shown to significantly reduce the risk of cardiovascular disease, taking these medications in concert with a healthy lifestyle and diet are also important. 

Image extracted from source 1: Facts About Hypertension. (2020, September 08). Retrieved October 03,  2020, from https://www.cdc.gov/bloodpressure/facts.htm 

    It is also important to acknowledge that cases of hypertension have increased with change in diagnostic guidelines as well as the increased availability of healthcare services in less affluent areas. Most high blood pressure cases in the United States have appeared to be in the southern regions with 32 – 38% of adults 20 years and older being diagnosed with hypertension (1). Young adults in the US have been shown to have increased sodium and potassium in their diets that have helped to contribute to increased levels of high blood pressure (7).  In other countries, it has be shown that governmental regulations to lower salt concentrations by 30% has led to a reduction of 10 mmHg in the average population (8). Other ways to help lower high blood pressure without the use of medication include regular exercise, healthier diet, limiting caffeine and alcohol use, cutting out smoking, and reducing daily stress(9). Ultimately the use of medications to lower hypertension is effective, but it is important to improve daily lifestyle habits in order to continually improve blood pressure. The use of medication is not intended to be used to maintain the diet and lifestyle that had led to the initial hypertension.  

Image extracted from source 11:  Socioeconomic Environment. (n.d.). Retrieved October 03, 2020, from https://www.healthandenvironment.org/environmental-health/environmental-risks/socioeconomic-environment 

    Ideally, the goal would be to overall lower the number of hypertension cases in the United States, however it is important to acknowledge the many barriers that limit this success. Unfortunately, studies have shown that socioeconomic status is directly tied to increased risk of developing cardiovascular disease (10). Lower income areas have less access to both healthy foods as well as workout facilities that are prominent in much more affluent areas. This perpetuates the cycle of increased blood pressure as lower income families are not only constantly under immense stress financially, but also faced with the fact that heavily processed foods are more readily available and cheaper than fresh produce. Not only are they disadvantaged with the limited resources available, but also, they are less likely to seek medical care unless necessary due to fear of healthcare costs.  

    While it is encouraging that there has been more attention focused on the prevalent problem of increased blood pressure in the United States, it is important to understand this problem is not easily fixed by just prescribing hypertension medication. These medications do help to decrease blood pressure in patients that have already presented hypertension symptoms, however it is equally crucial to focus on preventative measures. There must be efforts in culturally changing lifestyles and diet by making healthier food options readily available as well as providing opportunities to improve the overall health of those that would not have the opportunity otherwise. The problem has been identified and medications have been used to mitigate outcomes, but the focus must turn to preventing the problem in the first place.  

By James Warinner, A Master of Medical Science Student at the University of Kentucky 

 References

1. Facts About Hypertension. (2020, September 08). Retrieved October 03, 2020, from https://www.cdc.gov/bloodpressure/facts.htm
2. FastStats - Leading Causes of Death. (2020, February 06). Retrieved October 03, 2020, from https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
3. Holland, K. (2020, June 17). High Blood Pressure: Causes, Symptoms, Medication, Diet, and More. Retrieved October 03, 2020, from
https://www.healthline.com/health/high-blood-pressure-hypertension
4. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. (2003). McLean, VA: International Medical Pub.
5. Types of Blood Pressure Medications. (n.d.). Retrieved October 03, 2020, from https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/types-of-blood-pressure-medications
6. Shah, S. J., & Stafford, R. S. (2017). Current Trends of Hypertension Treatment in the United States. American Journal of Hypertension, 30(10), 1008-1014.
doi:10.1093/ajh/hpx085
7. Chmielewski, J., & Carmody, J. B. (2017). Dietary sodium, dietary potassium, and systolic blood pressure in US adolescents. The Journal of Clinical Hypertension, 19(9),
904- 909. doi:10.1111/jch.13014
8. Barrera, L. (2018). High Blood Pressure prevention and control: From evidence to action. Colombia Médica, 49(2), 137-138. doi:10.25100/cm.v49i2.3940
9. 10 drug-free ways to control high blood pressure. (2019, January 09). Retrieved October 03, 2020, from https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/high-blood-pressure/art-20046974
10. Conen, D., Glynn, R. J., Ridker, P. M., Buring, J. E., & Albert, M. A. (2009). Socioeconomic status, blood pressure progression, and incident hypertension in a prospective cohort of female health professionals. European Heart Journal, 30(11), 1378-1384. doi:10.1093/eurheartj/ehp072
11. Socioeconomic Environment. (n.d.). Retrieved October 03, 2020, from
https://www.healthandenvironment.org/environmental-health/environmental-
risks/socioeconomic-environment

One Pill Fits All: The 3D Printing of Drugs

 

Image from: https://www.the-scientist.com/news-opinion/on-the-road-to-3-d-printed-organs-67187

 The other day I sat with my grandmother, watching her set up her pillbox. There were morning and night pills, once-daily pills, twice-daily pills, big pills and small pills. I sat there thinking, “I can hardly go a week without losing my wallet or keys; there is no way I could ever be so organized as to keep straight this medication regimen”. I thought there must be a better answer for this, and thankfully, scientists over the last 40 years have been working diligently on a solution: 3D printing of drugs. First patented in the 1986 by Charles Hull⁵, this technology is the precipice at which the future of personalized medicine lies; it could truly be the next major revolution in treating patients who are vulnerable to drug toxicity or failure to follow recommended therapies. With 3D drug printing, the possibility exists that instead of 16 pills per day, my grandmother could take one pill, with exactly the right concentration of each active pharmaceutical ingredient (API) personalized to her needs.

Additive manufacturing, or 3D printing, has been a rapidly expanding field in which innovation has driven this technology to applications in practically every industry which currently exists. The market for 3D printing is valued at $13.68 billion dollars for 2020, and is predicted to grow up to a worth in excess of $35B¹² as aggressive research and development takes place over the next several decades. There are several techniques with which an object can be created; each involves a layer-by-layer manufacturing process in which the object is first designed from a computer, and then the blueprint is transmitted to the printing equipment (for additional information into how 3D printing works, I suggest this video). This technique has been used already in the medical field for decades; there are people walking around with 3D printed limbs, rib cages, and jaws. Much like these devices are custom made for individuals, the pharmacotherapy of the 55% of American people who take a prescription medicine can be customized in the same way. Indeed, with Americans taking more prescription drugs than ever, it is no shock that 1.3 million people have ended up in the emergency room to be treated for adverse events related to their medications⁷. This serves as a crucial reminder that we must work to reduce inadvertent drug overdoses and toxic interactions, and increase patient compliance and overall prognosis through their polypharmacy regimens.  All of these  can potentially be accomplished by 3D printing medicines.

Figure 1: Dose flexibility scheme shown for different patient populations, where each pill has precisely the amount of API needed. 

3D drug printing has several key advantages over traditionally mass-produced pills^3,8,9:

1)     Provides dose flexibility, with tailored release profiles and pharmacokinetics

2)     Reduces waste in terms of mass-manufacturing and transport of conventional drugs

3)     Provides opportunity for mass production in remote locations (i.e. disaster zones, outer space, etc.)

The dose flexibility is the most commonly toted benefit, and for good reason.  Being able to change not only the identity of the API as well as their shape can alter the way drugs are released and transported around the body, enhancing both pharmacokinetics and pharmacodynamics of the medicine. 

Figure 2: Printlets showcasing the variety of shapes that can be created. Pills which are less dense will increase the speed of absorption. Also, compliance of pediatric patients may increased by utilizing more interesting shapes and incorporating various flavors. From:  https://www.ondrugdelivery.com/personalising-drug-products-using-3d-printing/

    It is well known that  drug therapy is complicated for certain populations. For example, older people generally have several comorbidities, which may have disease-related decreases in organ functioning. Pharmacogenomics studies have revealed that many of us have different levels of expression for metabolic enzymes which has implications for drugs toxicity.  As an example, we have discussed, warfarin in our 422G course, which is metabolized by a CYP2C9 enzyme. This particular enzyme has common genetic frequencies across patients with different ages and ethnicities⁶.  Thus,  for a patient with abnormal CYP2C9 expression, critically dangerous levels of warfarin can be avoided by taking a 3D printed drug. Children also have a documented need for customized medications.  According to the European Medicines Agency, many products are simply not produced in doses or formulations which meet the safety standards for pediatrics¹¹. Because drugs can be designed with precise spatial control and geometries, fewer excipients and APIs are needed as well¹. This could substantially bring down medication costs for drugs, especially those of rare diseases such as spinal muscular atrophy, where one annual course of treatment can run about $2 million². When one thinks about the logistical benefits of 3D printing, it is easy to see the carbon footprints of mass-scale drug production begin to slowly dissipate. Fuel and energy consumption, as well as the necessary resources to maintain those drugs which are temperature sensitive, would drop to more sustainable levels⁸, and bring cost savings in the billions according to FDA Commissioner Scott Gottlieb⁷. Lastly, 3D printing requires few resources in terms of space and operation of the equipment. This would provide critical medications at the point of care for patients in areas which aren’t reliably accessible can drastically improve outcomes of patients who otherwise may have gone untreated³.

       As we continue to navigate the technologies being developed at break-neck speeds, we must also keep in mind the ethical and regulatory considerations necessary to harness the power of these technologies and ensure they are applied in a safe manner to the global population. The first truly 3D printed drug was brought to market in 2016 by Aprecia⁴, a major milestone in the industry of pharmaceuticals. However,  there are still many hurdles we must cross before 3D drug printing reaches its full pharmacologic potential. Currently, the FDA has not been able to fully translate the regulatory pathways used for conventional drug manufacture to that of 3D printing of drugs, a process known as good manufacturing practices.  These practices state that all parts of the additive manufacturing printer must be able to be easily cleaned, and the printer must be validated to fabricate the pills between acceptable parameter ranges. Quality control of the products remains a big concern as the safe level of reproducibility of certain products has not been achieved. New challenges surrounding personal data security, counterfeit production, and as previously stated, translating the good manufacturing practice protocols from traditional drug production to 3D printed medications, will continue to slow the progress of bringing this technology to mass scale^9,12,13. Currently, none of the various techniques used to 3D print medications are fool-proof; some printers fabricate pills which are too friable, and others use heat or lasers which may degrade the API¹². Until these regulatory needs are met, unfortunately, we are stuck with our imperfect prescribing system. However, the good news is that the FDA and the federal government are continuing to allocate funds to develop the clarity and architecture needed to one day bring 3D drug printing to the masses awaiting its life-saving benefits.

 For more information on this topic, I suggest this Ted talk by Daniel Kraft, who describes the process of biomanufacturing pharmaceuticals, and its application to personalized medicine. https://www.youtube.com/watch?v=-RkhAP0_ms4

By Amy L. Rice, Post-Baccalaureate student at the University of Kentucky 

 References

1.     1.Awad, A., Trenfield, S. J., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). Reshaping drug development using 3D printing. Drug Discovery Today, 23(8), 1547-1555. doi:https://doi.org/10.1016/j.drudis.2018.05.025

2.    2.  Chase, L. (2020, August 25). 10 Most Expensive Drugs in the U.S., Period - GoodRx. Retrieved September 22, 2020, from https://www.goodrx.com/blog/most-expensive-drugs-period/

3.   3.  Fan, D., Li, Y., Wang, X., Zhu, T., Wang, Q., Cai, H., . . . Liu, Z. (2020, January 28). Progressive 3D Printing Technology and Its Application in Medical Materials. Retrieved September 19, 2020, from https://www.frontiersin.org/articles/10.3389/fphar.2020.00122/full

4.   4.  FDA approves first ever 3D printed drug product: Spritam. (2017, June 08). Retrieved September 19, 2020, from https://www.europeanpharmaceuticalreview.com/news/33832/fda-approves-first-ever-3d-printed-drug-product-spritam/

5.   5. Hull, C. W., Modrek, B., Parker, B., Freed, R. S., Almquist, T., Spence, S. T., Albert, D. J., Smalley, D. R., Harlow, R. A., Stinebaugh, P., Tarnoff, H. L., Nguyen, H. D., Lewis, C. W., Vorgitch, T. J., Remba, D. Z., & Vinson, W. B. (1986). U.S. Patent No. US5137662A. Washington, DC: U.S. Patent and Trademark Office.

6.    6. Koukouritaki, S. B., Manro, J. R., Marsh, S. A., Stevens, J. C., Rettie, A. E., McCarver, D. G., & Hines, R. N. (2004). Developmental Expression of Human Hepatic CYP2C9 and CYP2C19. The Journal of Pharmacology and Experimental Therapeutics, 308(3), 956-974. doi:10.1124/jpet.103.060137

7.   7.   Lynch, M. (2019, February 01). Next step in personalized medicine enabled by 3D printing. Retrieved September 22, 2020, from https://www.outsourcing-pharma.com/Article/2019/02/01/Personalized-medicine-enabled-by-3D-printing

8.   8. Preidt, R. (2017, August 03). Americans Taking More Prescription Drugs Than Ever. Retrieved September 22, 2020, from https://www.webmd.com/drug-medication/news/20170803/americans-taking-more-prescription-drugs-than-ever-survey

9.   9. Prasad, L. K., & Smyth, H. (2016). 3D Printing technologies for drug delivery: A review. Drug Development and Industrial Pharmacy, 42(7), 1019-1031. doi:10.3109/03639045.2015.1120743

10 10.  Sandler, N., & Preis, M. (2016). Printed Drug Delivery Systems for Improved Patient Treatment. Trends in Pharmacological Sciences, 37(12), 1070-1080. doi:https://doi.org/10.1016/j.tips.2016.10.002

1111. Scordo, M. G., Aklillu, E., & Ingelman-Sundberg, M. (2001). Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. British Journal of Clinical Pharmacology, 52(4), 447-450. doi:10.1046/j.0306-5251.2001.01460.x

1212. Trenfield, S. J., Awad, A., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). 3D Printing Pharmaceuticals: Drug Development to Front-line Care. Trends in Pharmacological Sciences, 39(5), 440-451. doi:10.1016/j.tips.2018.02.006

1313. Zhu, X., Li, H., Huang, L., Zhang, M., Fang, W., & Cui, L. (2020). 3D printing promotes the development of drugs. Biomedicine and Pharmacology, 131. doi:https://doi.org/10.1016/j.biopha.2020.110644

1414. 3D Printing Market Size & Share: Industry Trends Report, 2027. (2020, February). Retrieved September 22, 2020, from https://www.grandviewresearch.com/industry-analysis/3d-printing-industry-analysis