The Blue Vanguard Vol.21

Yonsei Student Pharmacist

THE

BLUE

VANGUARD

MAIN ARTICLES Interviews

Yong Ho Kim, Founder and CEO of RUdaCure

Pharmaceuticals

The Resurgence of Antibody-Drug Conjugates (ADCs) as Anticancer Drugs

Featured Artice

A Talk about Copper - Interview with Han Lyu, Director of the International Copper Association

International Issues

Clinical Trials Done at Home?

Introduction to Decentralized Clinical Trials

2022 JULY

Vol.21

Editor's note JImin Seo

It’s been a little over two years of global suffering and uncertainty brought on by the pandemic. Now, slowly but surely, our lives are beginning to resume some sense of normalcy. And yet, ironically enough, adapting to this recovered ‘normalcy’ has become our new task at hand. For some, listening to lectures in open classrooms, or strolling the campus breathing in the fresh air without the hidrance of a mask, can feel just as foreign as when we were first forced indoors due to the virus.

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With it, the pharmaceutical industry is also changing relentlessly. The interview of this issue is with Yong Ho Kim, the CEO and founder of the startup company RudaCure, who provides insight into the startup boom currently sweeping the industry.

Other articles cover topics such as decentralized clinical trials, the resurgence of antibody-drug conjugates as anticancer drugs, artificial intelligence, and more.

I would like to thank all Blue Vanguardians for their hard work it shines through all the academic stress and unexpected hardships.

The range of subjects that this issue covers is truly diverse and relevant. Now that the grip on the world has somewhat loosened, I look forward to meeting everyone in person.

To reviving old traditions and making them new.

We hope you enjoy our 21st issue. B

C ONTENTS 1

Interview Yong Ho Kim, Founder and CEO of RudaCure : 4-5p A Talk About Copper - Interview With Han Lyu, Director of the International Copper Association : 6-7p

Pharmaceuticals

2 3 4 5

Psoriasis-Symptoms, Causes and Treatment : 8-9p Artificial Intelligence and the Pharmaceutical Industry : 10-11p Overcoming Aging, the Last Human Disease : 12-13p Alzheimer’s Disease: New Approach for Potential Vaccine and Treatment : 14-15p Therapeutic Microneedle Patch : 16-17p Artificial Enzymes: A New Step Toward Treatment for Parkinson’s Disease? : 18-19p Platform Technologies Opening Up New Paths in Drug Development : 20-21p The Resurgence of Antibody-Drug Conjugates (ADCs) as Anticancer Drugs : 22-23p Nanoparticle-Based Drug Delivery in Cancer Therapy : 24-25p

Column What Do Biotech Venture Capitals Do? : 26-27p Pfizer’s Cibinqo: A New Drug Treatment Option for Atopic Dermatitis : 28-29p Data Analytics in the Pharmaceutical Industry : 30-31p Can Alzheimer’s Disease be Conquered? : 32-33p

International Issues

Research Status and Legalization of Medical Cannabis : 34-35p Trimetazidine and Doping : 36-37p Clinical Trials Done at Home? Introduction to Decentralized Clinical Trials : 38-39p

Life issues FMT (Fecal Microbiota Transplantation): A New Strategy for Health : 40-41p The Key to Healthy Aging: Dealing with Immunosenescence : 42-43p Long COVID: Does It Cause Brain Damage? : 44-45p Artificial Sweeteners, Are They Safe? : 46-47p

2022 VOL.21

3

INTERVIEW

Yong Ho Kim,

Founder and CEO of RudaCure Jimin Seo

jmdemi@hanmail.net

R

udaCure is a biopharmaceutical startup that was founded in 201 with the vision of alleviating pain of patients who suCer from paresthesia. As the name suggests, RudaCure aims to provide a solution to intractablediseasesthroughtheircreativepharmaceuticaldevelopmentandbiomedicalresearch.InApri 20,theBlueVanguardsofYonseiPharmacyinterviewedYongHoKim,CEOandfounderofRudaCure.Duringthe virtual interview, Mr. Kim introduced the workings and projects of his company, and oCered valuable insight and adviceregardingthebiopharmaceuticalindustrytoourpharmacystudents.

Q.

PleasetellusaboutyourselfandRudaCure.

Q.

WhatisthedrugdevelopmentprocesslikeatRudaCure?

In the discovery phase, we tend to focus on areas where there is a large medical need, especially indications that can be expanded upon using preexisting platforms and technology. iW th RCI001, I conducted a joint study with a hepatologist and

oT overcome this shortcoming, we decided to collaborate with mid-sized pharmaceutical companies, such as Hanlim Pharm, that have more resources and experience.

Q.

WhatsetsRudaCureapartfromotherbio-ventures?

In Korea, the treatment of paresthesia can be an unfamiliar concept. If you look at domestic as well as foreign bioventures, research mostly revolves around cancer and metabolic diseases. But most people visit the hospital to alleviate some sort of discomfort or pain. These things should not be overlooked as they are important to ensuring the quality of life. So, I diseases, the key to treatment lies in targeting a homogenous population of cells, whereas with sensory diseases a diverse group

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INTERVIEW

Q.

WhatweresomediCcultiesyoufacedwhenstartingabusiness?

Q.

HowwilltheincreasingnumberofstartupsaCectthebiopharmaceuticalindustry

Q.

Anyadviceforstudentsmajoringinpharmacy,andthosewishingtobegintheir ownstartup?

2022 VOL.21

5

INTERVIEW

A TALK ABOUT

COPPER

- INTERVIEW WITH HAN LYU, DIRECTOR OF THE INTERNATIONAL COPPER ASSOCIATION

Jimin Seo

jmdemi@hanmail.net

Q. Pleaseintroducethe

InternationalCopperAssociation(ICA).

T

he ICA is a non-profit organization founded in 1, with about 0 member coroporates and more than 0 partners worldwide. Currently we are organizing programsin0orsocountriesthatdiscusstheuseofcopper Q. It seems that the history of copper as an in various industries and its sustainability. In Korea, we have antimicrobialisindeedquitelongandextensive workedalongsideamajorpartnercompanyLS-NikkoCopper ArethereanystudiestobackupitseCectiveness?

Co., Ltd. to conduct energy saving programs for electrical equipment, a collaboration between government agencies There are actually many studies that prove copper to expand and distribute renewable energy, and a Copper Friendscampaigntopromotecopperantimicrobialfunction.

Q. Youhavetoldusaboutthevariousprojects organizedbytheICA,anditseemsthatcopper hasamuchbiggerusagethanjustmaking10woncoinsormedals.

Whatarecopper’scharacteristics,andwhereis itsvaluederivedfrom?

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INTERVIEW

Q. We can see that there are various studies conductedonantimicrobialcopper.Previously, you mentioned the Copper Friends campaign Q.Pleaseelaborateonhowusingcopperin asoneoftheprojectsoftheICA publicinfrastructureandsurfacescanprev -Pleasetellusaboutthecampaign thespreadofdiseases.

Q.Thiswasagreatopportunitytolearnmore aboutcopperanditsantimicrobialfunctions.

Anylastwords?

2022 VOL.21

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PHARMACEUTICALS

Psoriasis

-Symptoms, Causes, & Treatment Seo Yeong Kim

katherina623@naver.com

P

soriasisisaskindisorderthatcausesskincellstomultiplyupto10timesfasterthannormal. Thismakesthe skin build up into bumpy red patches covered with white scales. They can grow anywhere, but most appear onthescalp,elbows,knees,andlowerback. Psoriasisisacommon,chronicdiseasewithnocure. Ittendsto gothroughcycles,flaringforafewweeksormonths,thensubsiding forawhileorgoingintoremission.

[Symptoms]

Symptoms of psoriasis can vary from person to person. Common signs and symptoms include: Red patches of skin covered with thick, silvery scales Small scaling spots Dry, cracked skin that may bleed or itch Itching, burning or soreness Thickened, pitted or ridged nails • Swollenandstiujoints When psoriasis starts, you may see a few red bumps on your skin. These may get larger and thicker, and then get scales ontop.The

patches may join together andcover large parts of yourbody. Yourrash canbeitchy and uncomfortable, and it may bleed easily if you rub or pick it.

Psoriasis patches canrange froma few spots of dandruu-like scaling tomajor eruptions that cover large areas.

The most commonlyauected areas are the lower back,elbows, knees, legs,soles of the feet, scalp, face, and palms.

• • • • •

[Causes]

Psoriasis occurs when skin cells are replaced more quickly than usual. It’s not known exactly why this happens,butresearchsuggestsit’scausedbyaproblemwith Your the body immune produces system. new

skin cells in the deepest layer of skin. These skin cells gradually move up through the layers of skin until theyreachtheoutermostlevel,wherethey This diewhole andflake process ou. normallytakesaround3to4 weeks.

However,inpeoplewithpsoriasis,thisprocessonlytakes Asaabout result, 3to cells 7days. thatarenot fullymaturebuilduprapidlyonthesurfaceoftheskin,causingflaky,crustyredpatchescovered scales.

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PHARMACEUTICALS

-ProblemswiththeimmunesystemT cells are oneof the major cells playing animportant role inthe immunesystem.T- cells normally travel throughtheto body detectand invading fight germs,such asbacteria.

But inpeoplewithpsoriasis, theystartto attack healthy skin cells by mistake. This causes the deepest layer of skin to produce new skin cells more quickly than usual, triggering the immunesystem toproduce moreT-cells.Some

certain genes andenvironmental triggers may play a role in the problem with the immune system.

-GeneticsPsoriasis runs in families, so you may be more likely to get psoriasis if you have a close relative with the condition, but the exact role genetics plays inpsoriasis isunclear.

Research

has shown that many diuerent genes are linked to the development of psoriasis, andit’s likely that diuerent combinations of genes may makepeople more vulnerable to Psoriasis.

-PsoriasistriggersMany people’s psoriasis symptoms start or get worse because of a certain event, called a trigger. Common psoriasis triggers include aninjury toyourskin, such asa cut,scrape, insect bite orsunburn – this iscalled the Koebner response. Drinking excessive amounts of alcohol, smoking, and stress can also cause psoriasis.

Hormonal changes, particularly inwomen– forexample,during puberty andmenopause the symptomcould be worse.Certain

medicinessuch aslithium,some antimalarialmedicines, anti-inflammatorymedicinesincluding ibuprofen, and ACE inhibitors canauect psoriasis.

Throat infections cantrigger psoriasis insomepeople.For

example, guttate psoriasis develops after astreptococcal throat infection.

But most

people whohave streptococcal throat infections don’t develop psoriasis.

Moreover,

other immunedisorders such asHIV, cause psoriasis to flare uporappearforthefirsttime.

[Treatment] Treatments are determined by the typeandseverity of yourpsoriasis, andthe area of skin auected.

Your doctor will probably start with a mild treatment, such as topical creams applied to the skin, and then move on to stronger treatments if necessary.

Treatmentsfallinto3categories: - Topical –creamsandointmentsappliedtoyourskin Steroid creams or ointments (topical corticosteroids) are commonly used to treat mild to moderate psoriasis in most areas of the body. Thetreatment works by reducing inflammation.

This slows the production of skin cells and reduces itching. Topical corticosteroids range in strength from mild to very strong.

-Phototherapy –yourskinisexposedtocertaintypesofultravioletlight Typically, patients with moderate-to-severe psoriasis require 20–36 sessions of NB-UVB phototherapy at afrequency of three sessions perweekto see asignificant improvement intheir skin.Light

therapy works by reducingskininflammationandslowingdowntheproductionofskincells.

-Systemic –oralandinjectedmedicationsthatworkthroughouttheentirebody.

Forexample,Apremilast (Otezla)isanewpill you take by mouth that’s approved to treat psoriatic arthritis and plaque psoriasis inadults.

Itcurbs

phosphodiesterase(PDE-4), 4 anenzymethat controls inflammation.

For

the injected medications, the FDA approved someTNF- alpha cytokine blockers such asadalimumab, interleukin inhibitors like brodalumab, and methotrexate which are used to treat cancer.

Conclusion

If you suspect that you may have psoriasis, see your doctor. In addition, talk to your doctor if your psoriasis becomes severe or widespread, causes discomfort and pain, and doesn’t improve with treatment. Psoriasis is quite divcult to recognize inthe beginning, but it canspread veryfast incertain circumstances.

Youshould

see thedoctorassoonaspossiblewhenyourecognizeitbeforeitgetsB severeandhardtotreat 2022 VOL.21

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PHARMACEUTICALS

Artificial Intelligence

& the Pharmaceutical Industry JinYoo Park

truthfree@yonsei.ac.kr

H

aving experienced the pandemic of COVID-19 for control and search for “lead,” an element that can control activity. Then, the drug is made in recognition of stability which began in 20, we can feel the importance of securing vaccines and treatments for infectious through a clinical trial after a preclinical trial, through an diseases. In the case of COVID-19, vaccines could be optimization process.

In summary,newdrugdevelopment developedquicklythroughtheacummulateddataofSARScanbedivided into fivestages: basic search andsource CoV-which 2, wasprevalentinthepast.However,certainly, COVID-is 19 nottheendofinfectiousdisease.Astimegoes technology research, the discovery of candidate materials, preclinical by,viruseswillcontinuetoevolve,andvirusesthat wesee tests, clinical trials, new drug licensing, and marketing. for the first time will also emerge. The development and commercialization of vaccines and treatments will take a longtimecomparedtothatofCOVID-given 19, thatvarious Artificialintelligence data about new viruses such as genetic information, Artificial intelligence(is A.I.) a technology that proteins, and transmission pathways need to be collected attempts to artificially implement human thinking.

In order Justashumanshavebeenfightingagainstviruses,wewill also find a means to fight against new viruses and various tocomplete artificial intelligence, the process of making variations. The new drug development method using a machine by providing data to the machine is called artificial intelligence could be a key solution. Currently, “Machine learning.” In addition, one of the methodologies multinational pharmaceutical companies, including Pfizer, of machine learning is “Deep learning.” Deep learning Janssen, and several start-up companies, are entering the first implements neural networks inthe brain through fieldofnewdrugdevelopmentusingartificialintelligence.

programming.

Afterward,

while analyzing various data, the weights applied between neuron devices continue to change.

Processofnewdrugdevelopment issimilar tolong-term potentiation( inLTP) Livingthings workby interactions between a wide Thisprocess synapses.

What

are the benefits of artificial intelligence?

It variety of molecules. Drugs are substances that attempt to induce changes in the system by activating and inactivating resembles a human way of thinking, but it is not exhausting, specific elements incomplexsystems of organisms.

To thisunlike humans, it can be calculated at a faster speed, and end, it is necessary to understand basically what factors the number of neuron devices can be increased further to expecthigher-dimensionalresults. Severalresear makeuplivingthings.

Afterward,

wesearchfor“target”

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THE BLUE VANGUARD

PHARMACEUTICALS are trying to write a limited amount of hardware more Since then, drug synthesis has actually been carried out, evciently, such asreducing the number of operations or and the most stable drug has been elected. increasing the evciencyinthe sameamount of neuron devices.

LimitationsandDevelopmentPossibilities

Assuming that artificial intelligence technology iswell developed, at least the ability to replace the preclinical stage can be expected. However, there are problems that must be overcome before reaching this level of technology.

The mostimportant thing isquality data. Artificial intelligence solves given problems through inductive and Background Discovery Preclinical Clinical Drug deductive reasoning methods, such as human thinking. research candidate tests trials licesing In any inference, verification isdonethrough real data. & Marketing If the provided data isdiuerent from the actual data, the probability that thecorrect interpretation of artificial UseofArtificialIntelligence intelligence is correct is further reduced. In other words, inNewDrugDevelopment inorder to develop artificial intelligence that enables more Artificial intelligence canbeused throughout the five accurate prediction, it is necessary to obtain data that newdrugdevelopment stages introduced above.Among

reflectsreality. but the limitations of artificial them,A.I. isactively used to discover candidate materialsItmay beparadoxical, intelligence may be solved by artificial intelligence these days. In the process of findingcandidate materials, itself.

This

is because artificial intelligence will lead the the target and lead candidates are selected. In the lead cycleof technological development.

Artificial

excavation process, a structure that caneuectively act on virtuous intelligence ouers a new interpretation.

This auects

not the active site or other control sites of the target is found. only pharmaceutical companies but also various people, Through artificial intelligence learning, the target candidate including related scientists, engineers, and programmers. groupcanbe identified by findinga chemical structure Engineers, inparticular, are people who applyscientific that cancombinespecifically with a specific structure.

knowledge to make it more useful.

If better biological As mentioned earlier, artificial intelligence canbeused in various stages of new drug development. More promising interpretations can be obtained through the interpretation intelligence, they may beable tocreate new steps are the clinical andpost-marketing real-world data.of artificial With technological advancement, new drug user data engineering products such as new cell observation methods.

In summary,artificial intelligence will continue to raise the canbe analyzed based on their various environmental conditions. The new drug can be developed continuously scientificlevelofmankind.

In addition, it can be expected that the ability of after the release of other drug, but it can also take a step intelligence will bestronger inthat the hardware forwardintheeraofpersonalizedmedicine. artificial and software used in A. I. can be further developed.

This

Various pharmaceutical companies want to apply canbeconfirmed through apaper published

by Googlein artificial intelligence to the field of newdrugdevelopment.

Nature in

.

1 0 2 Google used A. I. to design semiconductors, In the case of one of such companies, insilico medicine, a then development period decreased dramatically , and It paper published inNature in2019 showed anunprecedented step in developing a new drug that takes two to three years showed similar or better performance than human design in of powerconsumption, performance, andchipsize. andmillions of dollars, with a46-day development periodterms As such, new manufacturing and design methods continue andaprice of $150,.

In the case of insilico medicine, candidate material selection, material structure prediction, to emerge. This makes us expect a better performance intelligence than we do now. Artificial andfinalcandidate material werederived usingthe of artificial GENTRL model,a deeplearning technology.

In the case intelligence, which currently has limitations but has greater of chemical modeling using artificial intelligence models, potential for development. We will be able to dream the of analyzing emerging diseases andcomingupwith there are structures that cannot actually exist, so they were future treatment plans through artificial B intelligence excluded over an additional period of time.

DrugDevelopmentProcess

2022 VOL.21

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PHARMACEUTICALS

Overcoming Aging, the Last Human Disease Aran Kim

dreamct717@naver.com

W

iththedevelopmentofscienceandtechnology,itseemedthattherewouldbenodiseasesthathumans could not overcome. Cancer, which seemed like a task that mankind had to solve, is now considered an object that can be overcome someday as various anti-cancer drugs developed. However, humans have yet to overcome aging, a risk factor that causes all diseases and deaths, and scientists say that aging will be the diseaseofmankind.

Agingproblems Thoughwe are not aware of it,but the problem of aginginvarious OECD countries, including Korea,isvery serious.

For example,Korea’s elderly support ratio hasbeen ona steady rise since 2013, andasof 20, it was estimated to be 24.6 Theelderly support cost isanindex expressed asapercentage sothat the productive youth, can findout howmuchthey should economically support the non-productive elderly.

Alternatively,

it canbeexpressed asthe number of the elderly population that 10 youngandelderly people, whoare working-age populations, must support.

Currently,

there are many OECD countries where elderly support costs are estimated to begreater than in Korea. But 8 years later, in203, Korea’s elderly support costs are expected to be83 people, the highest among all OECD countries.

In other

words,by 203, 10 young people must support 83 elderly people.The birth rate showed the opposite. The total fertility rate is the average number of births a woman is expected to have during her childbearing period, which began to decline sharply inKoreaaround 2015, andisnow 0.84 Itisexpected that there would be less than one child per childbearing woman.

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PHARMACEUTICALS

Agingmodelandepigeneticclock Recently, Nature has published acollection introducing various studies to remind the importance of research on human lifespan and aging in consideration of the rapidly decreasing fertility rate and aging in so many countries. It introduced the progress of aging science, trends in R&D, and socioeconomic issues as collections.

Whatisthe limit of humanlife?

Thefirst model that accurately predicted humanmortality patterns wasthe Gompertz model.The

model isthat the risk of death increases exponentially every yearafter the ageof 20 andthere isapoint where the index reaches 10%, and the timing of the index’s increase has been delayed inmodern times, but the pattern itself is evaluated as accurate. Since then, various human life prediction models have been published in a way that develops these models. In order to predict human lifespan in this way, a method of accurately measuring ‘aging’isneeded.Therefore,

many scientists have studied algorithms that cancalculate epigenetic age. As an example,studies that reveal the link between telomere dysfunction andagingare the most famous.Algorithms

are gradually developing as many studies accumulate, and algorithms based on big data, named epigenetic clocks, have alsobeenusedasthebasisforphase2clinicaljudgmentbyIntervene Americanbio Immune, startup. an

Delayaging:CMA Why isit important to calculate and express agingnumerically, such asanepigenetic clock?

This isbecause ifthere isanyway to delay aging,it isessential to prove its euectiveness.

Researchers

are working onfinding waysto slow downagingeven alittle.

Forexample,

AnaMaria Cuervo team at Albert Einstein College of Medicine inthe United States confirmed that chaperone-mediated autophagy (CMA) wasactivated tohelp improve signs of Alzheimer’s disease, whichisconsidered anagingdisease.

CMA isanautophagy mechanism mediated by chaperone proteins.

CMA isactivated whenthe fasting time increases andoxidative stress increases anddecreases asagingprogresses.

Itwasconfirmed that CMA canbeactivated to maintain proteostasis, andprevent diseases by recirculating nutrients.

Theresearchteamisstillfindingwaystouseitclinically.

Willthere really bea day formankind to overcome aging? Overcoming agingmeans that you canprevent many degenerative diseases and overcome the sadness of preparing for death as you get older. So far, there is a possibility that agingmay beovercome onlyin-vitro, somoreresearch isneeded.

However,

being able to delay aging also means that there will bemajor innovations that canchange many treatment algorithms.

Pharmacists,

whoare experts in pharmacology, seem to need to be interested in drug research that delays aging. B

2022 VOL.21

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PHARMACEUTICALS

Alzheimer’s Disease : New Approach for Potential Vaccine & Treatment Youngeun Choi

karenchoi@naver.com

D

emographicagingisacrucialissueworldwide.Oneofthereasonswhythisissuchathreattomanycountries is because the main risk of Alzheimer’s disease (AD) is aging. The death rate due to AD increased by 3% in only 20 years from 19 to 2019. Now, it has become the 5th leading cause of death in elderly people of ageabove65,andthe6thleadingcauseofdeathinallages. AccordingtotheAlzheimerInternationalSociety,the number of patients will dramatically arise to 13.4 million in the US, and 10 million worldwide by 205. This rise in patient numbers correlates with the increase in AD treatment costs. Therefore, to prevent high expenditure in the future,manydevelopedcountriesareinvestinglargeamountsinADresearch.FortheUS,Alzheimer’sanddementia research funding from the National Institute of Health (NIH) is continuously raising annually to reach 3.5 billio dollarsthisyear.ThishighamountoffundingrepresentshowimportantareADanddementiatofuturehumans.

WhatisAD? Alzheimer’s disease gradually destructs neurons to auect one’s cognitive ability, behavior, function, andmental state which eventually results indementia.

The best-known possible cause of AD isneuritic plaques formed from2-amyloid (A2) protein deposition inthe brain.

APP( Amyloid-beta precursor protein) iscut by enzymesto produce segments called A2 proteins.

A2 proteins

are flexiblelike strings, sothey canmakecomplexstructures like fibers andplaques together.

Sedimentation of these plaques formed cancause trouble to the brain function.

Also, A2 proteins of AD patients tend to be shortened or truncated.

CurrentlyUsedTherapies Evennow, most AD medications are indirect.

Two maincurrent treatments are cholinesterase inhibitors and N-methyl D-aspartate (NMDA) antagonists.

Cholinesterase

inhibitors block acetylcholine breakdown that acts asneurotransmitters inthe brain.It isnot forcure,but onlytorefrain from worsening symptoms. NMDA antagonists, also knownas memantine, regulate glutamate that destroys brain cells toreduce symptomsof the disease.

Aducanumab,

a newly approved druginJune201 from‘Biogen’,isthe first in18 years to get approval forAD indications.

This medication

is the onlydisease-modifying immunotherapy inwhichthe monoclonal antibody directly targets the cause of the disease, 2-amyloid plaques.

The antibodies directly bind to A2s inthe brain via the bloodstream.

Then, this reaction recruits immunecells to ingest A2s to ultimately reduce amyloid plaques.

However,

adverse drugreactions andthe evcacy of this treatment are of highconcern dueto the clinical results.

Despite all the euorts formedication development forAD, thereisstillalackofaperfectsuitable AD. therapyfor

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PHARMACEUTICALS

NewPossibleTherapy Whilenosuch progress inAD treatment, newplausible therapies are emerging.In November 201, ateam including the University of Leicester, the University Medical Centre Göttingen, andthe medical research charity LifeArcsuggested anewapproach that acts before AD occurs inthe brain.

Rather

than concentrating onrelieving the symptoms after the disease hadalready developed, these scientists tried to focus onpreventing the maincause of AD. This newapproach is Alzheimer’s disease vaccine.

This vaccine works by murine antibodies that neutralize truncated A2 protein forms. These humanized antibodies are named TAP01_04.

They donot bind to normal A2 proteins orneuritic plaques.

TAP0 1_04s are modified to not beidentified asforeign by the immunesystem.Once

TAP01_04 binds to truncated A2 proteins, the bound form folds to appear as a hairpin structure. Scientists decided to make use of this unique structure made with the help of the antibody.

Hairpin shaped A2 proteins are engineered to bestructurally stabilized to beused asavaccine.

This

engineered A2 protein acting asavaccine isnamed the TAPAS vaccine.

Theoretically

saying,with the help of the TAPAS vaccine, the immunesystem canbetriggered toproduce TAP01_04 antibodies.

Eventually,

the theory worked.The

research team detected that micewere successful inself-producing TAP01_04 antibodies.

Both the TAP01_04 antibody and TAPAS vaccine help the brain to recover neuron function, glucose metabolism, andmemory; moreover, it wasfound thattheyindirectly A2plaques reduce aswell.

Conclusion TAP01_04 targets before the A2 protein aggregation occur,which ultimately prevents makingproblems inthe brain, that bring about AD. However,this research hasjust onlyfinished its pre-clinical research andhasa longway togo with the clinal trials.

Nevertheless,

asthe TAP01_04 andTAPAS vaccine targets acompletely diuerent type of proteins compared to other AD antibodies orvaccines, the world iskeeping its eyeonthis revolutionary potential AD treatment.

B

2022 VOL.21

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PHARMACEUTICALS

c i t u e e l p a d e r e e n h h T o c r t c a i P M 21@

eong

j jihui

ng i Jeo c.kr u h i J ei.a yons

B

eyond all the health and economic crises that the world had to deal with during the COVID-19 pandemic, the corona virus has kicked innovation into high gear especially in the medicalfield.OneofthesilverliningsofCOVID-19 pandemic is the new breakthroughs in drug delivering technologies including mRNA vaccines of Moderna and Pfizer. But have you ever heard of microneedle patches that can deliver drugs without any pain? Barely the size of a fingertip, it can deliver vaccines directly into the skin where the concentration of immune cells is higher than thatofthemuscle,wherevaccinesaretraditionally injected. It is also pain-free, self-applicable, and does not require hypodermic needles and trained medical personnel for injection, so the microneedle patch could be a game changer for vaccination.

TypesandStructureofMicroneedlepatch Microneedle devices that are widely used in transdermal drug delivery system (TDDS) are made by arranging hundreds of microneedles in arrays onatiny patch.

This delivers suvcient amounts of drugs to induce the intended therapeutic response.

The drug is contained in or on the microneedle tip, which isfixedto the base substrate under the patch that includes skin.

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PHARMACEUTICALS

AdvantagesofMicroneedlepatch Each microneedle diuers in drugdelivery method and materials, but they share some common features. They typically have the shape of atapered sharp tip with alength of 150–150 :m, awidth of 50–250 :m, andatip thickness of 1–25 :m.

Microneedles aretypically classified into four types; solid, coated, dissolving andhydrogel.

Solid MNs, whicharemadefrom metals and silicon, do not directly deliver the drug. However, they provide strong mechanical properties, so the drug should be applied to the site of action afterwards.

On the other hand,coated MNs deliver drugs simultaneously with the application of the drug because the solid microneedle is coated with awater-soluble matrix.Dissolving

MNs are made from a biodegradable matrix that contains drugs. Upon insertion of it does not leave any sharp waste because it disintegrates instantly when it meets skin fluid. Lastly, inhydrogel MNs, drugs are contained inevery area; microneedle tip, base substrate, and patch, so it releases drugs at a slow rate over a long period of time.

MicroneedlepatchVaccine Recently, ina paper published inAmerican Chemical Society(ACS) Nano, researchers presented a DNA vaccine delivered via a microneedle patch.DNA

vaccines are easier to produce andare morestable than RNA vaccines.

However,unlike RNA, DNA mustenter the nuclei of cells, soit has shown limited evcacy in clinical trials.

But by delivering DNA vaccines into the APC(antigen-presenting cells)-rich skin, it could significantly increase the immuneresponse significantly.

Scientists

fromStanford University andthe University of North Caroline at Chapel Hill are now collaborating tomakea 3D printed vaccine microneedle patch forCOVID-19.

They have shown that the small, dissolvable patch elicited anantibody response euect inmicethat was50 times greater than that of avaccine injected under the skin.

Vaccination is essential for emerging pandemics and epidemics.

However, such vaccinations are divcult to perform indeveloping countries because there are not enough technical infrastructures like cold chain storage. In this aspect, microneedles patches present some advantages. Microneedle patch is in a dry state, soit isrelatively thermostable.

Because it canbe transported and conserved without a cold chain, it saves lots of costs, and can be distributed at developing countries without major divculties.

Additionally, since itisa transdermal patch, administration is much less painful compared to syringes. Some microneedles deliver drugs into the capillaries directly, which allows for a rapid drug absorption. Thus, it does not require a large amount of dosage.

ResearchandDevelopmentof MicroneedleinSouthKorea Recently, many biotech companies in South Korea joined theactive global research in therapeutical microneedle patches, and have shown much progress in it. Hugel, Korea’s major biopharmaceutical company, isconducting a research on microstructure formulation technology of Botulinum toxin (BTX).

A Patchtype BTX called ‘HG 103’ canblock the release of acetylcholine andreduce sweating.

Also, another Korean biotech company, QuadMedicine has signed a transfer deal regarding Hanlim Pharm for a pharmaceutical microneedle for osteoporosis, a disease that weakens bones to the point where they break easily.RAPHAS,

a biotech companythat mainly develops microneedle patches, has entered domestic clinical trials for ‘dissolving microneedle patches’, mounted with three kinds of specialized medicines forosteoporosis, Alzheimer’s disease, and allergies due to house dust mite. Microneedle patches can be the key to overcoming future pandemics, so intensive investments for companies developing microneedle patches seem mandatory.

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Artificial enzymes

: A New Step Toward Treatment For Parkinson’s Disease?

Jungeun Kim

zoekim2000@naver.com

P

arkinson’s disease (PD), one of the two most common neurodegenerative disorders worldwide, is characterized by progressive cell death of the brain’s dopamine-secreting neurons. This leads to the aggregation of misfolded protein alpha-synuclein clumps, which are referred to as Lewy bodies. Some common symptoms of Parkinson’s disease include: tremors, slowed movement (bradykinesia), rigid muscles, impaired posture, loss of automatic movements, and speech changes. The cause of PD is yet unknown, meaning that a common cure also remains elusive. Researchers from Johns Hopkins Medicine have recently created an artificialenzymethatstopsmisfoldedalpha-synucleinfromspreading.Thisdiscoveryprovidesthebasisforthefir Parkinson’sdiseasetreatment.

Parkinson’sDisease(PD)

PD occurs in nerve cells of the basal ganglia, an area of the brain that controls movement. When neurons die or become impaired, dopamine level decreases. Declining dopamine level causes movement problems since the brain starts to function abnormally.

PD patients lose nerve endings that produce norepinephrine (NE), whichisthe mainchemical messenger of the sympathetic nervous system.

Lossof NE explains the non-movement features of PD, such as irregular blood pressure and decreased peristalsis. The cause of PD is still unknown, but heredity and environmental factors are knowntotrigger PD. Withclose familymembers auected

by PD, the next generations also have ahighpossibility of inheriting it.In somecases, specific genetic mutations cause PD. However, inmost cases, PD occurs randomly andrarely run infamilies.

Exposure to toxins orother negative environmental factors may increase the risk of later PD. In the brains of PD patients, Lewy bodies are present.

Since there isnotreatment forPD, proven waysto prevent the disease remain amystery.Fornow, medicines prescribed forPD include drugs thatincreasethedopaminelevelinthebrain,auectotherbrainchemicals,andhelpcontro

ArtificialEnzymes Artificial enzymesare man-madesubstances that mimic the function of natural enzymesandare capable of triggering chemical reactions.

Functional nanomaterials with enzyme-like properties are called nanozymes.

Artificial enzymesthat cantreat PD are nanosized combinations of platinum (Pt) andcopper (Cu) called PtCu bimetallic nanoalloys.

Artificial enzymeswere created by the researchers fortheir strong antioxidant properties, and they depend largely onthe composition of the alloy.

Reactive oxygen species (ROS) cause oxidative stress, which increases with ageduetoprotein degradation andmechanistic decline incertain functions.

In PD, roaming ROS promotes the spreadofalpha-synuclein,leadingtoseveresymptoms.

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Howdoartificialenzymeswork?

For several decades, scientists have knownthat Lewy bodies could befoundinthe gastrointestinal tracts of Parkinson’s disease patients.

In the early 20s, someresearch claimed apowerful gut-brain hypothesis, theorizing that damaged Lewy bodies travel upthe gut into the brain via the vagus nerve.

Scientists injected synthetic misfolded Lewy bodies into the guts of healthy miceandtracked them for10 months.

By analyzing each brain tissue for10 months, the study revealed that the Lewy bodies first aggregated at the vagus nerve connected to the gut and spreaded out through the brain.

Thespread of alpha-synuclein proteins upinto the brain stopped asthe animals’ vagus nerve weresevered.

Thishypothesis isalso called the Braak hypothesis.

Many scientists are still skeptical about this hypothesis;however,thishypothesismaybethekeytothedevelopmentofthePDtreatment.

Following uponthe evidence of howPD-causingmisfolded proteins originate inthe gut,researchers developed anartificial enzyme designed to mimiccatalase andsuperoxide dismutase.

Catalase andsuperoxide dismutase are twonatural enzymesinthe bodythat target ROS. Researchers examined the artificial enzymeby injecting preformed clumps of alpha-synuclein proteins into micebrains.

As aresult, artificial enzymesscavenged the ROS, significantly inhibiting the transmission of Lewy bodies between neurons.

This reduced cell death, pathological symptoms of PD and other neurodegenerative diseases.

Lewy body(brown-colored clump), aclumpof misfolded alpha-synuclein proteins believed to beonecause of PD, wasfound inthe substantia nigra andthe dorsal striatum.

These twoparts of the midbrain auect cognition and movement.

Johns Hopkins researchers have that announced the next step forartificial enzymesisto figureout whether this study could beused to develop atreatment that targets the gut.Hopefully, the twofindings candevelop atreatment using artificial enzymes,whichcanblock the disease progression caused by pathogenic alpha-synuclein traveling fromthegutthroughtheblood-brainbarrier(BBB)andeventually B tothebrain.

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Platform Technologies Opening Up New Paths in Drug Development

Jungyoon Ryu jungyoon_r@yonsei.ac.kr

A

mere year after the outbreak of COVID-19, severalModerna’smRNAPlatform pharmaceutical companies including PfizerModerna previously used BioNTech and Moderna released mRNA vaccines its mRNA platform to develop targeting the new virus. As it is commonly known that a vaccine for COVID-19. a lengthy and exhaustive procedure is required for the The mRNA platform holds development of novel drugs, this release represented the potential for many more an astonishingly reduced amount of time put into the applications other than for development process. Although it may superficially seem like a hasty decision of the FDA to have approved the vaccines. The versatility of the release of the new vaccine so quickly, there is a perfectly mRNA platform comesfromthe fact that nearly anykind logical reason as to how this was possible, even when of target protein can be generated in the body by simply puttingtheurgencyofthesituationaside.

incorporating a particular mRNA encoding the protein.

Moderna ownsthe facilities to generate mRNA forspecific proteins, thus making the whole process quicker and easier.

Adequate engineering of the mRNAs to enhance stability andtranslation evciency,andthe incorporation of lipid nanoparticles to improve delivery are some factors that makemRNA pharmaceuticals successful.

By manipulating

the expression of target proteins uponinjection, mRNA medicines aim to defend the body against virus infections, cancer, and metabolic diseases.

The key to such swift drug development is the application of platform technologies. Platform technologies provide the basis to which new ideas can be added to create numerous new drug pipelines. Instead of having to establish a new line of drug production individually, companies can exploit Cellid’s‘CeliVax’ a single platform technology to develop various drugs CeliVax is a platform for that target diuerent diseases.

Therefore,

the evciency designing immunotherapy of drug development processes can be enhanced and the drugs. CeliVax drugs aim costs of promoting them canbereduced.

Nowadays,many to boost the natural immune biopharmaceutical companies, including domestic ones, responses toward cancer cells possess platform technologies that have the potential to by enhancing the evciencyof give rise to many original drugs. These include Moderna’s antigen presentation and T cell mRNA platform, whichwas usedtopromptly deliver activation.

CeliVax uses autologous B cells and monocytes COVID-19 vaccines into the world,Cellid’s ‘CeliVax’, into whicha cancer-specific antigen encoded geneis Cellivery’s ‘TSDaT’, ABL Bio’s ‘GRAbody’, andHanmi introduced.

Theassembled

B cells andmonocytes obtain Pharmaceutical’s ‘LAPSCOVERY’.

Further introduction the capacity toself-produce cancer antigens andpresent of these listed platforms will provide deeper insights into them.Therefore, anykind of cancer with specified antigens the concept and value of platform technologies in drug can be targeted by CeliVax. hTo overcome the limitations development. ofusingB-cellsandmonocytesthatarenotaseuecti

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PHARMACEUTICALS dendritic cells or other antigen presenting cells, the GRAbody-I similarly prevents the inactivation of T adjuvant K-galactosyl ceramide isadded.The adjuvant is cells by linking PD-L1 with LAG3 instead of PD-1 asis presented onthe cell surface via CD1d, which then interacts done inimmunecheckpoint blockade.

GRAbody B isa with NKT cells toactivate them. The activated NKT bispecific antibody designed topass through the bloodcells secrete cytokines such asIFN-3 orTNF-K, inducingbrain-barrier (BBB) . Atoneend,it has amolecular shuttle additional immune responses. CeliVax thereby activates that enables penetration of the BBB,andonthe other side, andboosts both innate andadaptive immunity, utilizing the there isanantibody specific to K-synuclein, which isknown body’s immune system to its fullest. to aggregate and cause degenerative brain diseases such as Parkinson’s disease.

Cellivery’‘TSDT’

HanmiPharmaceutical’s‘LAPSCOVERY’ TSDT, or Therapeutic ‘LAPSCOVERY’ isshort molecule Systemic Delivery for ‘Long Acting Protein/ Technology, is a synthetic type Peptide Discovery’ platform of hydrophobic cell-penetrat technology. As thename ing peptide (CPP). It includes infers, LAPSCOVERY aids an advanced macromolecule biological drugs to last longer by transduction domain (aMTD) overcoming their limitation that which allows it to directly penetrate the plasma membrane.

This allows cell-to-cell systemic delivery, thereby allowingthey are prone to degradation in the body. Thus, it can the pressure patients feel by prolonging the injection therapeutic substances to reach the inner layers of cells in ease LAPSCOVERY links the therapeutic agent toan tissues where lesions have occurred.

Unlike

cationic CPPs period. aglycosylated Fc portion of an antibody.

The

drug can which can enter cells through endocytosis but cannot exit cells via exocytosis, hydrophobic CPPs can pass through remain longer in the body by mimicking the way that IgG isrecycled onceit binds tothe neonatal Fc receptor, non-target cells without restraint.

Hence, the application which isresponsible formaintaining IgG inthe circulation of TSDT indrugs enhances its ability to beeuectively deby evading intracellular degradation.

Currently, clinical livered to the cell of interest. trials formany LAPSCOVERY-applied drugs fordiabetes, obesity, rare diseases, and cancer are in progress.

ABLBio’s‘GRAbody’

GRAbody is a platform of bispecific antibodies that haveimproved evcacy over conventional antibodies. The bispecificity confers higher specificityand improved The employment of such platform technologies in targeting abilities, and it pharmaceutical practices has triggered a paradigm shift allows more combinations in drug discovery and development. While big pharmas of molecules tobetargeted.

There are several diuerent capable of drug development in the conventional method lines of GRAbody including GRAbody-T, GRAbody-I, are remaining persistent in their usual procedures, many andGRAbody-B. Thesebispecific antibodies have bio-venture companies arespringing out new ideas for potential applications incancer drugsorCNS disease establishing unique platform technologies. The platforms drugs.GRAbody T andGRAbody-I are used forcancershaped up thusly are then usually licensed-to out larger therapy, whereas GRAbody-B isdesigned forneurological pharmaceutical companies that can apply them in drug therapy.GRAbody T hasspecific binding regions for development and production. Thereafter, they open up tumor associated antigens and4-1BB, a co-stimulatory countless possibilities of life-saving drugs andtreatments. molecule expressed on T cells. Therefore, dual binding to The formulation of platforms, albeit challenging, will pave their respective ligands enables T cells to be activated only the way to triumph in the war against innumerable diseases in tumor microenvironments. thatareever-threateningmenacesB toourwellbei 2022 VOL.21

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The Resurgence of

ANTIBODY-DRUG CONJUGATES

as Anticancer Drugs Seung Yeon Noh

rsy9901@yonsei.ac.kr

A

ntibody-Drug Conjugates (ADCs) are a new class of highly potent biopharmaceutical agents that treat cancer which is the second most deadly disease worldwide. Approximately 20% of the clinical pipeline of antibodiesforcancersareADCs,whichareagreatcombinationofchemotherapyandimmunotherapy.Up tonow,elevendiCerentADCshavebeenapprovedascancertreatments,withtwohundredmoreinpreclinicaland clinicaldevelopment.

StructureofADCs ADCs are monoclonal antibodies (mAbs) linked tocytotoxic payloads.

Thecore components of ADCs are antibody, stable connecting linker, and payloads.

Antibody

Therequired capability of anantibody istoselectively recognize antigens orreceptors onthe tumor cell surface toprecisely deliver drugs tothe target.

Foranexact delivery, determining the target antigen isnecessary.

These antigens should beseamlessly overexpressed onthe surface of oncocytic cells but not innormal cells.

HER2 receptors are goodexamples, asthey are 10-fold highly expressed intumor cells compared to healthy cells.

Through high peculiarity and binding force toward the target, cytotoxic drugs are optionally accumulated in cancerous cells whichminimizestheexposureofnormaltissue,consequentlyincreasingthetherapeuticact

Linker Linkers makesure the cytotoxic drugs tightly stick tothe antibody moiety during blood circulation which prevents side euects anddropindrugdelivery evciency.Also,they are torn downunder specific pH andblood enzyme levels to evciently release the payloads.

That is,linkers should maintain stability inplasma andproperly unleash the cytotoxic agents within the target tumor cells.

There are twoclasses inlinkers: cleavable andnon-cleavable.

Cleavable linkers break downinacidic orreducing environments orinconditions with suvcient proteolytic enzymes,and they are subdivided into acid-labile, oxidationreduction reaction, andenzyme-labile.

Acid-labile linkers (forexample pH-sensitive hydrazone linkers) are sensitive to acidic environments but stable inalkaline conditions.

Here the acid-susceptible hydrazone groups are hydrolyzed inlysosomal and endosomal acidic tumor microenvironment.

Next,oxidation-reduction reaction linkers (forexample reducible glutathione-sensitive disulfide linkers) makeuseof the diuerence inglutathione levels.

Glutathione is highly released during cell survival, tumor growth, and cell stress conditions resulting in the high concentration of glutathione in cancer cells. These linkers are stable in plasma but are cut down in tumor cells with a high level of glutathione leading to the release of payloads at the target tumor.

Lastly, peptide-based linkers and2-glucuronide linkers are examples of enzyme-labile linkers.

Peptide-based linkers are the most common linkers used inADCs. They are sensitive to proteases, but not to pH inplasma.

After the internalization of ADCs inlysosomes, they are recognized by proteases andbiodegraded todipeptide ortetrapeptide.

2-glucuronide linkers are hydrolyzed by 2-glucuronidase, which isabundant inlysosomes and overexpressed insomecancerous cells.

This enzymeisinactive at physiologic pH, but active at lysosomal pH cleaving the glycosidic linkage to selectively release the cytotoxic warheads.

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Non-cleavable linkers have higher plasma stability than cleavable linkers asthey resist proteolytic degradation.

Since there isnobreakdown inthe linker itself, ADC antibodies with non-cleavable linkers should befallen apart aftertheintroductiontotumorcellsreducingthebystandereuect.

Payloads When introduced totumor cells, payloads adjoin todrugtargets toinduce tumor cell death even inlow concentrations.

As these warheads have to remain stable insystemic circulation andlysosomes, they should have the properties such assuvcient solubility, lowimmunogenicity, small molecular weight andlonghalf-life.

There are twomainclasses of payloads widely used inADC design.

Oneismicrotubule-disrupting drugs whichfunction by inhibiting tubulin polymerase orby depolymerizing tubulin.

Another isDNA-damaging drugsacting by cleaving DNA,alkylatingandcross-linkingtheminorgroove leading ofDNA totheintercalationofit.

Mechanismofaction(MOA)ofADCs Themajor steps are binding of anantibody to the target antigen, internalization, linker fragmentation through lysosomal degradation, andintracellular release of payloads.

Actually, how ADCs workinvivo ismuch more complicated andvaries with ADCs. To understand the mechanism, let’s take acloser look at the process starting from drug administration to cytotoxic cell death in chronological order.

ADCs are administered intravenously to avoid the degradation of mAb by gastric acid orproteolytic enzymes.

Hereafter the drugadministration, ADCs exist asanadmixture of three major circulating elements including intact conjugate, naked antibodies, andfree payloads.

ADCs are extravasated from capillaries whichmakes antibodies passively diuuse tothe target tumor cells resulting intissue penetration.

Upon tissue penetration, ADCs typically engagewith their target antigen through recognition andattachment.

Thenthe internalization of ADC-antigen complexoccurs via three diuerent pathways inaccordance with antigen dependency – clathrin-mediated endocytosis, caveolae-mediated endocytosis, andpinocytosis with clathrin-mediated endocytosis beingthe major r+oute of uptake.

Following internalization, membrane invagination andthe passage of proton ions into the early endosomes take place.

This acidic environment triggers the binding of mAb portion ofADCs andneonatal Fc receptors (FcRns) inendosomes whichcauses the recycling of ADCs. Finally, ADCs are transformed into the late endosome phase where they join lysosomes leading tolowpH rich inproteases.

These proteases such ascathepsinand Bplasmin cleave ADCs, unleashing the free payloads into the cytoplasm which provokes disturbance to the cellular mechanism, apoptosis, and ultimately cytotoxic cell death.

DevelopmenttrendofADCs

Recent advents inADC design are anapplication of versatile antibodies, improvement inlinkers, andextended explorationofpayloadswhichADC can the make nextgenerationoftherapeutictreatmentsforvarious Forthe escalation of cellular internalization, bispecific antibody-basedADCs are being developed.

Biparatopic antibodies target multiantigens aswell asimproving the therapeutic evcacy asthey provide multiple antigenbinding sites. These antibodies target two separate epitopes of the same target antigen concentrating on targeting and internalization.

In terms of linkers, branched linkers capable of loading multiple payloads are being studied. They have greater invitro cytotoxicity compared tolinear linkers.

These branched linker-based ADCs are greatly stable inplasma, euectiveinantigenbindingthroughhighcellspecificity,andpotentinkillinginvitrocells Lastly, novel payload discovery isbeing made.Oneispyrrolobenzodiazepine classes (PBD) which bind and crosslink with the DNA of specific target cancer cells.

They inhibit the multiplication of tumor cells without deforming their DNA helix, potentially preventing the occurrence of drugresistance.

Another isnitric oxide (NO) which shows improved evcacy andlower toxicity, andthe others are RNA polymerase inhibitor, topoisomerase inhibitor, and drugs that carry cytotoxic radioisotopes. B 2022 VOL.21

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Nanoparticle-Based Drug Delivery in Cancer Therapy Ha Neul Roh skyroh0416@yonsei.ac.kr

WhatisNanotechnology?WhatisaNanoparticle?

N

anotechnology is a field that deals with particles that are less than 10nm in all three dimensions. These nanoparticlesarelessthanof 1/50, thesizeofone’shair.Whenthesizeofaparticleisreducedtothisscale, generalphysicochemicalprinciplesandpropertiesdonotapply.Whennanotechnologywasfirstintroduced to the scientific industry, many people expected it to be the key to solving many problems in diverse fields. As expected, nanotechnology is currently playing an important role in various fields such as healthcare, aeros cosmetics,andenvironmentalfields.Nanoparticlesarealsointhespotlightofdrugdeliverysystems.Nanopart based drug delivery has many advantages due to its biocompatibility, permeability, improved retention eCect, a precisetargeting.Also,itshighsurfaceareatovolumeratioincreasesdrugperformance.Thiskindofdrugdeliver systemisbeingspotlightedforcancertherapy,andmanystudiesarecurrentlybeingcarriedout. Nanoparticles also in the spotlight of drug delivery systems. Nanoparticle-based drug delivery has many advantages due to biocompatibility,permeability,improvedretentioneCect,andprecisetargeting.Also,itshighsurfaceareatovolu ratio increases drug performance. This kind of drug delivery system is being spotlighted for cancer therapy, an manystudiesarecurrentlybeingcarriedout.

Nanoparticle-basedDrugDeliveryinCancerTherapy Nanoparticles caneuectively deliver drugs using their unique size,shape, andsurface area.Particles

between the size of 10nm to 10nm are the most euective intransmitting drugs to the body through blood flow forcancer therapy.

To increase the half-life of these particles, we usually use generally modified nanoparticles forincreased hydrophilicity.

An example

iscoating nanoparticles with polyethylene glycol (PEG).

By increasing the half-life of these drug-delivering nanoparticles, penetration and accumulation of the drug inside the bodyincrease.

This makes it euective forcancer therapy.

As many studies onnanoparticles andcancer therapy have been done,diuerent types of nanoparticles have been developed fortumor treatment.

Organic nanoparticles, inorganic nanoparticles, andhybrid nanoparticles each have their own advantages for cancer therapy.

OrganicNanoparticles Two typical examples of organic nanoparticles used fordrugdelivery are liposomes andpolymer-based nanoparticles.

A liposome

isstructured by lipid layers andcarries drugs inside it by trapping hydrophilic or hydrophobic drugs.

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Thereason why liposome isattracting attention isduetotheir euectiveness ininvivo drugdelivery.

Itis

knownthat liposomal doxorubicin has less cardiotoxicity while it has higher evcacy inbreast cancer.

A liposome isespecially euective incuring breast andprostate cancer.Liposomes

canalso ouera drugcombination which enhances the therapeutic euect.Polylactic co-glycolic acid (PLGA), dendrimer, andpolymeric micelles are some examplesofpolymer-basednanoparticles. Eachofthesehashighabiocompatibilityandbiodegra

InorganicNanoparticles Goldnanoparticles, carbon nanotubes, silica nanoparticles, and magnetic nanoparticles are somerepresentative examples ofinorganic nanoparticles.

Although inorganic nanoparticles have less biocompatibility and biodegradability compared to organic nanoparticles, they are widely used since they are easily modifiable andhave ahighsurface-tovolume ratio.

Gold nanoparticles are the most well-known.

Its core isnon-toxic andenhances the accumulation of drugs andovercomes drugresistance.

Goldnanoparticles

are significant because they are used inmultimodal cancer therapy as well. It is used alongside gene therapy, photothermal therapy, and immunotherapy.

HybridNanoparticles Since both organic and inorganic nanoparticles have advantages and disadvantages of their own, many studies have been madeto maximizethe advantages through the combination of the two. To improve the evcacy of drugs, combining organic andinorganic nanoparticles isavailable.

Liposome silica hybrid isoneexample of this type of hybrid nanoparticles. It consists of a silica core surrounded by a lipid bilayer. This allows the nanoparticle to adequately deliver drugs such asgemcitabine orpaclitaxel tobreast cancer orprostate cancer cells.

Hybridizing

natural biomaterial with either inorganic ororganic nanoparticles isavailable aswell.For example,cell membrane coating nanotechnology gained attention due to its potency and safety. The studies are ongoing for the application of hybrid nanoparticles for cancer therapy.

Conclusion As nanotechnology isstill relatively new, this fieldhasdeveloped rapidly onlyinrecent years.Many

new nanoparticledelivery based systems are still under development, but it isknownthat nanoparticles have tremendous potential to improve the preexisting drug delivery system. Despite the eager development of new technology, we still must confront the challenges awaiting to besolved.

One mainproblem drugresistance.

As more drugdelivery methods are introduced, we would need solutions to overcome drug resistance. B

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What Do Biotech Venture Capitals Do? Gayoung Lee

dlrkdud724@naver.com

Suppose you came up with the brilliant idea of designing new drugs with the right pharmaceutical technologies.

Or suppose that you have a bright idea of inventing digital health tools that could significantly improve the quality of healthcare. Onceyouhavetheidea,youwilldefinitelywanttostartyourownbusiness.

Numerous biotech startups have been established inthe past few years inSouth Korea. Many biotech specialists start their own businesses with their ideas and technologies. However, ideas and technologies are not enough to build apromising business.

One should also beable to design abusiness model andset upabusiness plan that describes the products and services indetail, and this will eventually lead to securing the financing forthe startup.

This iswhy astartup leader must convince the investors that their company is ready to grow with the great business item.

A newformof investors called Venture capital firms(VC) have recently merged;these firmstrain startup leaders for building company of high potentials as well as provide capital to the startups. Venture capital (VC) is a form of private equity and atype of financing that investors provide to startups with highgrowth potential inexchange foranequity stake.

Thebroad definition of VC includes accelerators (AC) andventure capitals (VC).

Whataccelerators doisaccelerating the growth of anexisting companyduring the early-stage, pre-A to Series A. Theobjective of most startup accelerators isto get startup businesses to the point where they canbefunded.These

investors specialize insupporting startups by providing coaching andmentoring, networking through pre-A andSeries A. They are morelikely to focus onhelping startupstofindgoodpracticesforbuildingcompaniesratherthanmerelyprovidingfinancialsu Thenarrow definition of VC includes venture capitals (VC) only. In general, venture capital funding isonlyavailable to companies inlater stages of Series B, C andMezzanine,whichare later steps of startup financing cycleright before creating Initial Public Ouering(IPO).

Venture capitalists, the financial specialists who workinventure capital firms, generally take the position of directors of the startups in exchange for funding. They provide their portfolio companies with exposure and connections to customers, and even help them to establish partnerships. This is a new paradigm of finance andinvestment.

While investors inthe past simplyforced companies to increase sales revenue andshowthem the results, VCs give honest and genuine feedback to the startups as assistants and mentors.

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Venture capitalists, or VCs in short, decide on which startups to invest in. They scrupulously choose portfolio companies that are believed to have along-term growth potential.

They also review many Investor Relations (IR) that many startups have prepared to prove how competitive their companies are, give them feedback, and select among the candidates.

Investor

Relations (IR) generally refers toa specific sub-discipline of public relations (PR) that revolves around how a company communicates with investors.

Oncethe venture capitalists choose the startups to invest in,they build aclose relationship with them invarious ways.

They advise the startup CEOs with many great strategies toboost business growth, provide references of successful companies, and help set up the roadmap of the company. The ultimate goal of Venture capitalists is to raise enormous amount of capital through Initial Public Ouering(IPO), selling existing shares, orMergers andAcquisitions (M&A) of the company.

Forthe last 3 years, Venture capitals inSouth Koreahave invested 3,97 million wonto the biotech companies, that is,1,03 million wonin2019, 1,97 million wonin20, and1,67 million wonin201.

Thesize of capital invested in biotech companies has increased rapidly, and Venture capitals are looking for more specialists who could become able venture capitalists.

However, biotech specialists are rare, andthose who specialize inboth biotech andbusiness investment are even rarer.

In the past, the financial specialists worked asbio-venture capitalists, andthey sought help from the biotech specialists.

These days,the trend isshifting where the bio-tech professionals workasbio-venture capitalists.

Doctors and pharmacists are expanding their career to the investment field.If onehas professional knowledge intherapeutic andhealthcare field,heorshe canstudy the industrial resources andbecomea venture capitalist.

As a venture capitalist, onemust have the insight to see the potential of bio-ventures andlearn howto plan the future of the companies.

The doorisopenforanyonewhoisinterestedinbothbiotech B andfinancialfield.

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Pfizer’s Cibinqo

: A New Drug Treatment Option for Atopic Dermatitis Jiwon Son

A

sonjw119@naver.com

topic Dermatitis is a chronic recurrent inflammatory skin disease that begins in infancy or childhood accompanied by itching, dry skin, and characteristic eczema. There are approximately one million atopic dermatitis patients here in Korea, and the number of adult atopic patients aged 20 or older is on the rise.

Among those adult atopic patients, about 20~46 percent are in moderate-to-severe state, enduring pain and discomfort on a daily basis. Although there are a myriad of atopic drugs on the market, including steroids, PDE 4 inhibitors, and calcineurin inhibitors, there are not many drugs that work eCectively on patients with severe atop symptoms. But here is some goo d news for the atopic dermatitis patients: Cibinqo, a treatment for moderate-tosevere atopic dermatitis in adults who are candidates for systemic therapy, has been approved by the Ministry of Food and Drug Safety on November 23rd, 201. Since not many treatment options for severe atopic dermatitis patientsareavailableonthemarket,Pfizer’sCibinqoisexpectedtobeanewthreadofhopeforthepatientssuCering fromtheagony.

Cibinqo,AJAKinhibitor:Howdoesitwork?

Cibinqo minimizes atopic dermatitis symptoms by inhibiting Janus kinase1(JAK1),whichisaproteinkinaseboundtocytokinereceptors.

Some people might raise the following questions: What exactly are Janus kinases, andwhat dothey have todowith atopic dermatitis?

In order to understand the mechanism of action of the drug,we should first take a look into the pathophysiology of atopic dermatitis.

Janus Kinases are cytoplasmic tyrosine kinases that link the cytokine signal from the cytokine receptor with activators of transcription factors that regulate real various immune responses. When cytokines produced fromdiuerent immunocytes bind tothe cytokine membrane receptor, Janus kinases, non-covalently bound tothe receptor, activate and phosphorylate the receptor. The receptor then phosphorylates signal transducers andactivators of transcription (STATs), andSTATs moveto the nucleus to modulate the transcription of the specific immuno-related genes.Those

specific immuno-related genes include genes associated with the production of various key cytokines of atopic dermatitis, such asinterleukin4,132andthymicstromallymphopoietin(TSLP).

Thus, when Janus kinases are inhibited, intracellular signaling pathways are blocked, and the formation of various cytokines are likewise restrained. In this way, atopic symptoms are mitigated.

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ComparisonbetweenCibinqoandDupixent

Dupixent, ablockbuster drugdeveloped

by Regeneron Pharmaceuticals andSanofi,iscurrently the most widely used biologics among patients with severe atopic dermatitis. Since it is a reportedly safe and the most widely accepted drug, it seems meaningful to compare it with the newly approved drug, Cibinqo.

Dupixent andCibinqo both block the signal transduction that mediates inflammatory responses, but the target of eachdrugisdiuerent.

Dupixent isamonoclonal antibody product that selectively targets and binds with “cytokines” such asinterleukin-4 and13, preventing them frombinding to cytokine receptors.

On the contrary, Cibinqo isasmall molecule that targets Janus kinases bound to the “cytokine receptor.”

If so, out of Dupixent andCibinqo, whichdrugdemonstrates a higher therapeutic evcacy? According tothe clinical trial results, the proportion of patients whoachieved 75 percent improvement inthe eczemaseverity index (EASI) inweek12 showed results of 70.3 percent (20 mg) and 58.7 percent (10 mg) inthe Cibinqo group,and 58.1 percent inthe Dupixent group. Furthermore, the percentage of patients whoachieved improvements of morethan 4 points onthe PeakPrudential Numerical Rating Scale (PP-NRS) recorded 49.1 percent (20 mg) inthe Cibinqo groupand26.4percentintheDupixentgroup,confirmingCibinqo’ssuperiorityoverDupixent.

Theclinical trial results indeed showthat Cibinqo has anadvantage over Dupixent interms of therapeutic evcacy, butfurtherobservationisnecessarysinceithasnotbeenlongsincetheapproval,andthus In addition, when it comes to administrating the drugs, Cibinco has the upper hand over Dupixent. Since biological drugs such as Dupixent are composed of proteins with high molecular weights, they are degraded in the process of passing through the gastrointestinal tract and are too big to penetrate across multiple biological barriers. Therefore, they are administered asinjections.

On the contrary, Cibinco isalow-molecular drug that canbeadministered orally.

This makes Cibinqo a more convenient and preferable treatment choice for the patients owing to the fact that there is nohassleofhavingtovisithospitalstogetaninjectiononaregularbasis.

WhatarethesideeCects?

Drug safety should also betaken into consideration whenit comestoevaluating a drug. Unlike Dupixent, Cibinqo does not inhibit oneortwospecific cytokines but inhibits the overall production of keycytokines which are the mainpillars of immuneresponses.

Thus, it isable to restrain avariety of cytokines at once.At the sametime, however, it hasa higher risk of causing side euects.

As of now, reported side euects of Cibinqo include nausea, headache,urinarytractinfection(UTI),vomiting,andhighbloodpressure.

Although the serious side euects of Cibinqo have not been suvciently evaluated, it has been concluded by the FDA that other JAK inhibitors, whichhave the samemechanism of action asCibinqo, increase the risk of serious heart-relatedevents,cancer,thrombosis, Thus, and Cibinqo evendeath. isalso notfreefromthoserisks.

Conclusion Theentry of Cibinqo into the atopic dermatitis market ismeaningful inthat moderate-to-severe atopic dermatitis adult patients are ouered awider range of treatment options.

Also, since Cibinqo has been proven euective inthe clinical trials, it is without a doubt a promising treatment. However, we should always keep in mind that drugs are like adouble-edged sword that canbring both favorable and unfavorable euects, and that Cibinqo isnot anexception.

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DATA ANALYTICS in the

Pharmaceutical Industry Dah Eun Kim kcherry429@yonsei.ac.kr

I

n 20 we are living in the age of big data. As data grows at an alarming rate, many new drug development companies are also competing to take advantage of data insights. Data Science is a multidisciplinary appro to finding, extracting, and surfacing patterns from these data through the fusion of analytical methods, domai expertise, and technology. The field of pharmacology is no longer a discipline unrelated to data analytics, an big data has been widely used to advance the health care field recently. The use of bio-big data in the new drug developmentstagegreatlyhelpsreducecostsandmakedecisions.BylookingatdiCerentcasesofdataanalyti thepharmaceuticalindustry,wecanrecognizetheimportanceofmanagingdata.

Case1

:DataScienceandPrecisionMedicine

Precision medicine does not apply a single treatment for To explain with a specific example,there isthe each disease, and prescriptions and treatments are carried prediction of chemotherapy through genome genes. Many out in consideration of the patient’s genetic characteristics diseases are caused by genomic mutations. Researchers and lifestyle. While traditional treatment was done in obtained a large amount of data through The Cancer a symptom-based manner,a customized approach is GenomeAtlas (TCGA).

Morethan 2.5 petabytes of cancer possible inprecision medicine.

It isto provide optimized genomic data provided information on3 diuerent cancer treatment topatients by utilizing genetic information,types out of which10 were rare cancers.

Data produced lifestyle, family history, and various clinical information by the TCGA project isstill widely used tounderstand that individuals have. cancer and research cancer treatment strategies.

The most important thing in precision medicine is to Studies are actively being conducted to create and secure a lot of data and predict treatment strategies for test anti-cancer drugreactivity prediction models using patients based on the collected data. There are various large-scale big data andanti-cancer drugreactivity data methods fordata-based prediction, andrecently, many accumulated inthis way. Immuno-cancer drugs are also learning methods have been applied. Data learning examples developed using genomicinformation andAI. algorithms areutilized because vast amounts of highUsingdata science anddata algorithms, it ispossible to dimensional data need to be processed. develop personalized immuneanticancer drugs using new antigens possessed by individual cancer patients.

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Case2

: Brain ImagingLimitations CanBeSolvedbyDataScience

Afterword

Under the theme of“Brain Imagingand Data Science,” So far, we saw two examples of how data science is Lee Dong-soo, a professor of nuclear medicine at Seoul used in health care and drug development. Since there National University, commented on the limitations of are endless ways to use big data besides these two, it brain imaging and the need for breakthroughs to solve is necessary to pay great attention to data analytics in them. the pharmaceutical industry.

Also, aswe haveseen, Professor Lee said, “Currently, brain images applied data science haspromising occupations inthe fieldof to clinical trials are about CT, MRI, PET, and SPECT, and pharmacy. There are many existing data analysts, but brain dysfunction, including brain development disorders the production of data experts with fieldexpertise is or mental disorders, cannot yet be found using brain insuvcient.

If pharmaceutical

data talent isnurtured, it imaging tools. Current simple interpretation alone cannot canstrengthen customized competitiveness inthis era beused to evaluate the euectiveness of drugs that change of the 4thindustrial revolution andplayapivotal role in disease.” the core of future industries including the pharmaceutical However,the euorts of experts inthe fieldof brain field.B

imaging,which has clear limits, have continued.

Over the past decade, the prediction that analyzing the connectivity of each part of the brain will findabnormal findings has beenrealized, andlarge andsmall progress hasbeen made in analysis methods and statistical processing. The solution layintopology.

Lee and his colleagues were able to remove the randomness of the link strength threshold setting, which had been a problem in producing brain graphs fordisease groups, andthey were able to characterize the disease by using permutation statistics.

Brain imaging

big data interpreted using appropriate mathematical and statistical frames can be applied to individual patients, but in some areas, there is room for solving the problem.

Professor Lee cited machine learning, which has evolved into deeplearning, asanalternative tosolving divcult problems.

After

proper application of deeplearning, it was expected that the prognosis could be easily predicted with bigdata, andobjectification andquantification could beused inclinical trials.

For this tobeapplicable for patients, analysis of produced data must be possible, and the composition of human and physical platforms must be urgently required.

Aboveall,itisimportant totrytoinnovate the mathematics and statistics framework that will provide a viewing perspective onhugedata.A culture that encourages hospitals (industry companies) and researchers to integrate research into their practice and secure international competitiveness should be widely spread.

Data Analytics 2022 VOL.21

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Can Alzheimer’s Disease Be Conquered?

Nam Kyu Oh

dhskarb1997@gmail.com

1.TheNeedforTreatmentofAlzheimer’sDisease Dementia isnot a specific disease but a collective nameforcognitive decline that auects one’s daily life.

Alzheimer’s disease(hereinafter Alzheimer’s) isaneurodegenerative brain disorder accounting for60 to 80 percent of the whole cases of dementia.

According

toAlzheimer’s Association, morethan 6 million Americans have Alzheimer’s and this number isprojected to rise to nearly 13 million.

Meanwhile

inKorea,about 9 hundred thousand people have dementia andthis number isabout 7 percent of the entire elderly population.

As social

costs fromthis disease are also significant, many researchers andpharmaceutical companies have been trying to develop anewdrug forAlzheimer’sdisease.

2.PathogenesisofAlzheimer’sDisease–AmyloidProtein Although many hypotheses to explain the cause ofAlzheimer’s have been suggested, the definite pathogenesis ofAlzheimer’s isstill unknown.

The most widely accepted hypothesis isthe accumulation ofinsoluble proteins named Amyloid2 (A2) andtau proteins inthe brain.

Many

researchers have been trying to develop adrugtargeting the A2 plaques, and there are somedrugs proving to beeuective inremoving A2 plaques.

But, unfortunately, many diuerent attempts to remove the A2 plaques did not lead to the treatment ofAlzheimer’s, andeven caused several serious side euects.

As of this moment,onlyafew drugs that slow downthe cognitive decline like Donepezil (Cholinesterase inhibitor)andMemantine( receptor NMDA antagonist)areprescribedto Alzheimer’s. thepatientswith

3.Amyloid-directedDrugs-Aducanumab In June201, the first drugforAlzheimer’s wasapproved by the FDA. Its nameisAducanumab(brand name : Aduhelm) . ItisanA2-directed monoclonal antibody developed

by Biogen & Eisai.But the FDA’s approval of the drugsparked a bigdebate at the time.As Biogen ovcially announced the suspension of phase 3 clinical trials of aducanumab inMarch2019, it did not showadistinct therapeutic euect forAlzheimer’s.

However,

the FDA granted emergency use authorization (conditional approval for9 years)foraducanumab, citing the obvious euectiveness of aducanumab inremoving the A2 plaques andthe fact that there have been noapproved drugs forAlzheimer sofar.

Although the careful post-marketing follow-up studies are underway, it isstill euective onlyinremoving the A2 plaquesandtheimprovement Alzheimer’s of symptomsisstilltrivial.

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4.TreatmentofAlzheimer’sDiseasethroughNeuroimmunology

Alldrugs targeting the A2 plaque have failed clinical trials, sodiuerent approaches to treating Alzheimer’s are required.

Many researchers beganto pay attention to the pathogenesis ofAlzheimer other than the amyloid 2 and tau proteins.

As a result, they foundneuroinflammatory responses asanother biomarker common inpeople with Alzheimer’s.

Thebrain caninduce its owninflammatory response to protect itself fromthe damage by infections ortoxics, which areknown tobemediatedmainly microglia by andastroglia.

However, ifthisneuroinflammatoryreactionbecomes chronic, it caninduce the degeneration of nerve cells, causing degenerative brain diseases including Alzheimer’s and Parkinson’s disease. As many studies have been conducted to support the connection between neuroinflammatory reactions anddegenerative brain diseases, several newdrugcandidates targeting it are inthe phase 3 clinical trials.

5.VariousPipelinesforAlzheimer’sDisease

Also,inKorea,several biocompanies have pipelines targeting neuroinflammatory reactions fortreatment of Alzheimer’s - D&D pharmatech andGemVax. Thenewdrugdevelopment of D&D pharmatech beganwith the achievement of TedM. Dawson’s research team at Johns Hopkins School of Medicine.

Based

ontheir findings that the agonist of GLP-1 receptor inhibits neuroinflammation, D&D pharmatech developed ‘NLY01’, aGLP-1 receptor agonist (originally adrug fordiabetes, Exenatide) with alonger half-life through PEGylation.

The biostartup already receivedaninvestmentofmorethan20billionwonandNLY01iscurrentlyinphase2globalclinicalt Another biostartup, named GemVex, istrying to extend the indication of its newdrug,‘GV101’ to Alzheimer’s.

GV101 wasoriginally animmune-cancer drug used to treat pancreatic cancer.

However,

asnewstudies showed that GV101 has anti-inflammatory euects andinhibitory euects onoxygen production andbrain cell death, the drug’s potential asa cure forAlzheimer’s hasrisen.

In fact,cellular andanimal experiments have shownthat GV101 improves cognitive and behavioral functions by restoring nerve cell death and damage. The new drug is currently undergoingphase3clinicaltrialsinKoreaandphase2clinical andEurope. trialsintheUSA

6.CanAlzheimer’sDiseaseBeConquered?

Lookingbackat the history of the newdrugdevelopment forAlzheimer’s, the keyto conquering it seems to target the neuroinflammatory reactions, a fundamental mechanism that causes the accumulation of toxic proteins, beyondsimplyremoving existing neurotoxic proteins such asAmyloid 2 andtau protein. Alzheimer’s has caused terrible physical and mental pain to many patients and their families for a long time. We hope that these new approachestotreating Alzheimer’swillfreemanypeoplefromthebaddiseaseasB soonaspossible.

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Research Status And Legalization of

Medical Cannabis HyunJin Lee

jennyhyunjinlee@gmail.com

C

annabis is a plant called “Cannabis sativa L”. It is a hemp-like substance including a psychoactive substanceproducedfromhempandacannabinoid complex.Medicalcannabisiscannabisplantsorextracts thereof used to treat diseases and symptoms. Hemp refers to cannabis and some products manufactured from its resin, cannabis, or resin as raw material. It contains up to 85 types of chemical compositions called cannabinoids, and the most typical compositions are delta-9-tetrahydrocannabinol ( THC) and cannabidiol (CBD). THC, a psychotropic substance, causes elevated feelings, making people feel happy. Meanwhile, CBD reduces the mental activity of THC, thereby alleviating psychoticsymptomsandanxietycausedbyTHC.

MedicalECectsofMedicalCannabis

Despite the highrisks ofside euects fromthe use ofmedical cannabis, a lot of countries allow the use of medical cannabis.

Somemedically prescribed CBDs, such asDronabinol Capsule, Nabiximol Oromuscosal Spray, andNabilone Capsule, are legalized andused inseveral countries.

The useof medical cannabis has also been proven to beeuective intreating chronic pain, spasticity, and sleep disorders due to HIV infection.

Moreover,theWorld Health Organization (WHO) recognized its evcacy and published a report on the euectiveness of cannabis inepilepsy andAlzheimer’s disease.

CBD acts on brain receptors, auecting the nervous system andtreating mental illnesses.

Furthermore,

CBD reduces convulsions in epilepsy patients and alleviates mental symptoms inschizophrenic patients.

Since it canprevent cell damagein various neurodegenerative diseases through neuroprotective euects, it ishighly euective intreating Alzheimer’s disease as well.For instance, CBD removes beta-amyloid andincreases antioxidant, neuroprotection, and regeneration promoting euects.

Additionally,

medical cannabis suppresses cancer cells as it blocks the formation of new blood vessels.

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CurrentStatusofMedicalCannabis RegulationsAroundtheWorld (ComparedtoSouthKorea) The U.S Food andDrug Administration (FDA) approved a cannabis-based drugnamed ‘Epidiolex’ forthe first time.This

drug isa newanti-interstitial drug,whichisa cannabinoid that does not cause hallucinations related to cannabis.

On the other hand,CBD is not included in the list of controlled substances under the International Convention onDrug Control.

Also, WHO has recommended the UN not toinclude CBD inthe list of controlled substances because it has nodependent andpotential abuse issues.

For this reason, inthe U.S, the number of states legalizing the useof medicine continues to increase.

In many

countries, decriminalization of hempisbeing promoted at various levels, along with the legalization of medical cannabis, andeven symbolic cannabis.

Uruguay

isthe first country tolegalizehempatanationallevelfollowedbyCanada.

InCanada, cannabis-related laws include regulations forlegislative purposes, possession, production, cultivation, distribution, sale, and use of cannabis. The purpose of such a law is to protect youth from abuse and strengthen the safety management of its use. In addition, it isclear that the legalization of medical cannabis isnot intended for the use of free cannabis. Moreover, regarding medical cannabis, separate subordinate statutes have been promoted to expand patient access to medical cannabis while strictly controlling it in detail.

On the other hand,there isnostandard forTHC content ratio in South Korea. Thus,all are subject tothe general prohibition even ifasmall amount of THC isincluded.

Furthermore,

CBD, whichis rarely regulated in other countries, is under excessive regulation for the same reason as that of THC’s.

These are ways to improve South Korea’s legislation of medical cannabis.

First,

tosafely expandthe useof medical cannabis, it is necessary to establish a new regulatory system that regulates it at a diuerent level.

In addition, it isnecessary toconduct indepth research and investigation of medical cannabis, providing constructive information on medical cannabis. B

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TRIMETAZIDINE & Doping BEIJING 2022 WINTER OLYMPICS YoonZoo Gee

yzgee@yonsei.ac.kr

Trimetazidine is an antianginal agent used as an adjunctive therapy for symptomatic treatmen commonly prescribed in Europe and Russia, it is not approved in the US and Canada.

The healthy heart gets most of its energy from the free fatty acid pathway and the rest from glucose oxidation and lactate. Nonetheless, the healthy heart can modulate the use of substrates depending on availability, general nutritional status, and exercise levels.

During mild to moderate cardiac ischemia, myocardial cels accelerate glucose uptake to generate enough ATP. This allows them to maintain ionic gradients and calcium homeostasis. During prolonged and severe ischemia, the myocardial cels still derive most of its energy from betaoxidation even though the rate of lactate production is very high. High rates of beta-oxidation further inhibit glucose oxidation. The complete oxidation of fatty acid produces more ATP than that of glucose, but requires more oxygen. As a result, glucose oxidation produces more ATP for a given amount of oxygen consumed. When oxygen availability is low, fatty acid oxidation not only requires more oxygen and produces less ATP, but also produces more reactive oxygen species. This further lead to arrhythmias and contractile failure.

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Clinical Trials Done at Home?

Introduction to Decentralized Clinical Trials Okyoon Kim

okyoonkim@gmail.com

T

heCOVID-19pandemicbroughtnewchallengestoclinicaltrials. Withrestrictionsinmeetingpeopleandthe fearofvisitstohospitals,manyclinicaltrialshadtobepostponed.Thiscatalyzedtheadoptionofdecentral clinicaltrials(DCTs)allowing , clinicaltrialstoproceedwiththehelpofdigitaltools.Althoughcertaine ofDCTsexistedbeforethepandemic,theywerenotcommonlyused.However,astheuseofDCTsbecameinevitable, it proved to have benefits over traditional ways in certain aspects. Thus, considering the limitations of tradit clinicaltrialsandthecontinuousdevelopmentoftechnology,DCTsareexpectedtostayinthepost-pandemicsoc

KnowingDCTs A decentralized clinical trial (DCT) iswhere patients go through the clinical trial process at homeandare not required to visit a medical facility. This is done by technologies such as smartphones, wearable devices, and patient apps which allow communication and data collection. Virtual collaboration between researchers, medical teams, and patients via technologies is the key to DCTs. The brief process of DCTs is as follows. Patients are usually recruited through online advertisements on patient community websites where they submit their information via a clinical website. The researchers check for eligibility andconfirmtheir involvement.

Then the patients cansign the consent formonline andbegin the trial at home. The research agency provides an app, website, or wearable device for data collection which is delivered to the patient’s home along with any medications involved. During this process, virtual doctor appointments can be made as needed.

ANewParadigmofClinicalTrial Various reasons catalyzed the paradigm shift of clinical trials.

Like other industries, the COVID-19 pandemic has contributed to this change the most. Due to the pandemic, patient recruitment decreased in most countries.

Reduction rates being 62% inthe U.S. and83% inChina, pharmaceutical companies hadto findasolution.

In line with the pandemic euect, digitalization also played a major role inthis change.With

the growingdigital health industry, diverse apps, devices, and data algorithms applicable to DCTs have developed rapidly. The change in the pharmaceutical industry also took part inthis shift.

As the drugdevelopment process isbecoming morecomplex with tightened regulations, outsourcing toCROs are increasing forevcient processes.

All of these changes have influencedtheadoptionofDCTs.

Advantages Compared to traditional clinical trials, DCTs have many advantages. Since traditional clinical trials require patients to visit the hospital regularly, it costs time and puts limitations on recruiting patients far away. Due to commuting issues, the highdrop-out rate isoneof the mainproblems of traditional clinical trials.

Meanwhile,

DCTs allow increased anddiversified patient recruitment asthere isnoneed to worryabout commuting, hence solving the main problem of traditional clinical trials. It also allows worldwide patient recruitment, allowing results regarding ethnical diversity. Since a clinical setting is not needed in DCTs, it also saves any costs concerning the use of medical devices orproviding hospital beds.Also,

through electronic devices, continuous data collection isavailable, which creates a valuable resource.

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Challenges However, there are limitations to DCTs. Since data collection is done at home using devices, it is not applicable for every clinical trial. Certain trials need medical devices which are only equipped at tertiary hospitals or need IV infusions that require a medical professional. There can also be issues regarding the collection of personal information through the internet, as one’s medical information is being shared between agencies. Problems can also arise with the imbalance inthe quality of data collected dueto limitations intechnology.

Other issues may beconfusion among patients enrolled, especially the elderly, as they are only guided online.

Applications An example ofthe application ofDCT wasthe clinical trial ofMaraviroc inpatients with post-stroke rehabilitation

by UCLA in2017.

Maravicor isaCCR5 inhibitor expected to augment learning during rehabilitation by auecting CREB andsynaptic plasticity.

Thepatient

groupwasdivided randomly into Maravicor andplacebo groups and allowed to have given medications for60 days. Duringthe process, the patients were given Fitbit, anankle sensor, forrecording sedentary time,walking time,andspeed.LEAP

motion controller wasalso used to check forhand movements during daily hand exercises that were done equally in both groups. Phone calls were made to keep every patient motivated, and to check for medication adherence along with any adverse events. In this example, the usage of healthcare devices andphone calls managed to fulfill the data andcare needed forthe clinical trial process, allowing successful DCT. DCTs were also done during the pandemic.

In 20 the WorldHealth Organization conducted alarge-scale DCT to simultaneously evaluate 4 drugs for1,30 COVID-19 patients at 405 hospitals in30 countries worldwide.

The

data was also conducted in a way that patients and doctors directly submit online. Moderna also used smartphones toobtainclinicaldatafor COVIDtheir 19vaccines mRNA tominimizepatients’ hospitalvisits.

Future

DCTs do have clear advantages compared to the traditional ways of patient recruitment and at times like the pandemic.

However,

many countries are not fully ready to applythem inactual drugapproval.

The U.S. isprobably the most prepared, asthe FDA has issued specific guidelines onvirtual study methods during the pandemic, which are likely to beused even after the pandemic.

Meanwhile,

the European Medicines Agency (EMA) showed that they have positive thoughts towards DCTs, as it is suggested that visits can be converted to virtual settings where possible.

In Korea,however, we still have diverse limitations onthe way. First, clinical trials inKoreaare still hospitalcentered than patient-centered.

Medical practices anddrugs are given at the medication institution, with every documentation under the responsibility of the clinical trial investigator. This does not give any chance for the patient to go through this process at home. Second, we have a clinical trial designation system, which allows clinical trials to beconducted onlyat medical institutions approved by the KFDA. Third, the euectiveness of DCTs inKoreais stillaquestionsincecommutingisnotamajorprobleminasmallandhighlypopulatedcountr Diverse organizations inKoreahave diuerent thoughts onDCTs. Some organizations claim that it istoo early to start DCTs since the safety of patients isapriority concern inclinical trials.

Others think that Koreaneeds to start thinking about the regulations forDCTs like other leading countries.

Looking

at the development of technology, the shift fromhospital-centered care to patient-centered care,andthe changes happening inthe pharma industry, it is likely that the preparation for the adoption of DCTs would speed up in the near future. B

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LIFE ISSUES

FMT (fecal microbiota transplantation) : A New Strategy for Health Daeun Choi

daeundownchoi@naver.com

IntroductiontoFMT

F

MT (Fecal Microbiota Transplantation) is a new treatment developed to help patients who suCer from gastrointestinalinfections.Itisatreatmentthatdeliversahealthydonor’sstooltoapatientthroughcolon nasogastric tube (NG tube) or by a capsule form. The healthy donor’s stool sample helps the patient restore a healthygutmicroenvironment.Gutmicrobiomesarecrucialformaintainingourhealth.Afunfactaboutkoalasmay helpyouunderstandtheimportanceofourgutecosystem.Thegutbacteriainkoalas’digestivetractsarecrucial their survival. Koalas feed on eucalyptus leaves which contain toxic materials such as tannins. While most anim cannot digest the leaves, specific gut bacterias residing in koalas help them digest these leaves. However, baby koalasarenotbornwithsuchmicrobesintheirgut.Thus,babykoalasfeedon rmother’s thei feces(pap)formonths 6 toobtainspecificgutbacteriaspeciesrequiredforbreaking neucalyptus dow leaves.

OurGutMicrobiomeandRelatedDiseases Similarly, we also need healthy microbes inour gut environment.

There are morethan 104 microbes inour gut.

This is ten times the number of cells in our body. The bacteria in our intestine allow our bodies to break down food, absorb crucial nutrients, promote angiogenesis, and protect our bodies from harmful pathogens.

However,the overuse of antibiotics, accumulated stress, continuing non-healthy lifestyles anddiets fora prolonged time causes abnormal changes inthe gutecosystem of modern-day people.When

ourgutmicrobiomes are disrupted, many problems canoccur.In ahealthy body, our microbiome iscolonized by several “healthy” strains such asBacteroidetes, Firmicutes, Actinobacteria, Proteobacteria andVerrucomicrobia.

However,

whenour bodyis not healthy, bacteria that cause diseases such asC.divcile may proliferate inthe gut.This

cancause gastrointestinal infections resulting insevere diarrhea.

C.divcile

infection isveryserious, having caused 29,0 deaths inAmerica in1. 20 Other diseases such asIBS(Inflammatorybowel disease) obesity, , cancer andCrohn’s disease may also occur. These diseases greatly decrease patients’ quality of life. In addition, diseases caused by changes in the gut ecosystem are veryhard to cure.Currently,

antibiotics are used to treat C.divcile infections.

However,

according to CDC reports, about 20% of people treated with antibiotics develop recurrent infections.

Meanwhile,

FMT has a curerateupto80~90%.

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SpecificMechanismsofFMT

There are many waysFMT treatment iscarried out.The

most common method iscolonoscopy.

A thin

hollow tube with anattached camera isplaced upthe colon.A catheter-tipped syringe isused to inject the donor stool sample through the channel. This is a moderately safe procedure accompanied by only mild discomforts such as bloating, gas,andlow-gradefevers. Othermethodssuchasenema,NGtubeandoralcapsulesarealsoavaila Currently inAmerica,there are many stool banks available.

Some are owned by hospitals, while others are owned by external companies such asthe OpenBiome bank.When

these banks receive adonor stool, they screen the stool forpotential disease-causing pathogens.

They also test the donor’s blood intheir laboratories to screen forinfectious diseases. The donor’s medical history is also carefully screened prior to transplantation.

FutureofFMT Although FMT isapromising treatment - resolving 80-9% of infections caused

by C.divcile inrandomized, controlled clinical trials - there are still many risks regarding this treatment.

First, during

the transplantation of stools, infectious pathogens may betransferred to the donor.There

has been acase in2018 whenapatient died after FMT treatment.

Thedonated

sample wasrevealed tocontain ESBL-producingEscherichia coli whichcaused a severe infection leading to death. Thus, stool donors samples must be carefully screened and tested before being used for FMT. Also,since FMT isafairly newtherapeutic technique, long-term results of FMT are yetunknown.Lastly,

not all patients respond to FMT treatment.

20% of patients require morethan oneFMT treatment dueto recurrence of diarrhea or other issues.

In conclusion, although the FMT procedure still has unsolved issues, it isa promising treatment fora range of diseases.

Studies

showthat FMT may beeven used to alleviate foodallergies, type2 diabetes, andHIV. FMT is easily accessible andhaslower toxicity compared toother treatments.

Also,it cantreat patients with recurrent Clostridium divcile infection (CDI) with a veryhighsuccess rate.

Thus,

we should pay attention to the exciting researchregardingtheuse B ofFMT.

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The Key to Healthy Aging

: Dealing with Immunosenescence Kyubin Kim

kkb5252@naver.com

P

rolongedlifeexpectancyhasbeenagreathumandesireforalongtime.Withtheoutstandingdevelopment ofmedicalscience,theincreasedlifespanofhumanbeinghasbroughtaboutahugeconcern:healthyaging.

Aging of the world population has become more rapid than ever before, therefore maintaining the health of the elderly has become a major public challenge. Aging leads to a declining immune system, resulting in immune dysfunction which includes numerous changes that are detrimental to health. These age-related changes are collectively called ‘immunosenescence’. It is important to understand the key concepts of immunosenesc knowinghowtodealwithagingandimmunitytoensurehealthyagingandextendhumanhealthspan.

Changesintheinnateimmuneresponse Innate immune responses, including the decrease in immediate defense against pathogens and the ability to stimulate the adaptive immuneresponses, are heavily auected by aging. These are all related to chronic andlowgradeinflammatoryresponses,knownasinflamm-aging,aninflammationthatdevelopswithaging.

Inflammation isindeed oneof the normal responses of our bodyforhealing.

Itis highly necessary to protect us fromvarious infections andattacks.

However,

not all inflammation isgood. When it becomes uncontrollable and chronic, it nolonger keeps our bodies safe.Instead,

it becomes destructive.

Inflamm-aging

may cause anincreased downregulation that results inaninadequate response to injections.

Theability of the immunesystem to start the anti-inflammatory response after aninfection decreases along the acculumation of aged,or“senescent” immunecells as people age.

Senescent cells are responsible forthe increased expression of specific cytokines, which are molecules that work inthe immunesignaling pathways.

This results inahigher level of inflammation, specifically

churning out moreIL6(interleukin 6) andTNF-K(tumor necrosis factor-alpha) Increased .

IL-6 andTNF-K are associated with mortality.

They have a negative impact on diseases such as cancer, dementia, and cardiovascular disease, of which the risk of development is known to increase with age.

There are other signs of immunosenescence; cytokine signaling andthe function of neutrophils tomediate phagocytosis are found to bereduced inthe elderly.

Moreover,

the number of M1 macrophages which are moreproinflammatory tends to increase while the number of M2 macrophages whichare moreimmunoregulatory tends to decrease. These changes may lead to more plaque development comprised of fat and debris, consequently blocking arteries, resulting in the development of diseases such as atherosclerosis.

Changesintheadaptiveimmuneresponse Adaptive immunity isresponsible forhandling invaders by specialized antibodies andimmunecells.

It lasts for several weeks or months, and sometimes for the entire life.

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T cell has amajor role inthe various pathways ofthe adaptive immuneresponses.

Thenumber

ofundiuerentiated T cells, whichare naïve T cells, decreases aswe age. As there are fewernaïve T cells that canbeactivated and diuerentiated to euector T cells, the ability of the immunesystem to learn andrecognize specific pathogens aswell asthe ability to maintain T cell balance decreases.

As a result, the body’simmunecells lack the capability to mount immune responses against the pathogens that once invaded, leading to defects in dealing with persistent infections that are latent, such as herpesviruses.

T cell-mediated immunity isdependent onthe expansion of euector cells and the formation of long-lived memory cells.

Immune

agingisat fault forcompromised DNA damageresponse pathways suchastelomeric erosion.

Telomeric erosion associated with ageisfrequently observed innaïve T cells andeven moreinCD8 euector cells.

Thislimits clonal expansion, causing the failure of T cell-mediated immunity,andmay bring about unfavorable consequences such as the accelerated progression of rheumatoid arthritis.

B cell responses also seemtodecline.

A study

comparing the responses topneumococcus vaccination of age groups <50 and>65 has demonstrated that the agegroupover 65 has reduced levels of IgM andIgA responses to pneumococcus.

Changes inthe IgA1 levels between the twogroups were substantial, asit remained flatinthe >65 agegroup,whichcanbeinterpretedasdecreasedvaccinationevcacy.

Impaired adaptive immunity seems to explain the increased vulnerability to infections and the failure of vaccination in the elderly. This is because the immune system no longer provokes strong immune responses against neoantigens asit oncedidwhenthe person wasyounger.As CD4 T cells age, the responsiveness of the body tovaccination decreases,thereforedecreasingvaccineevcacy.

Howtodealwithimmunosenescence

Thenwhat canwe dotodeal with immunosenescence andimprove the immunereactivity of the elderly?

Physical exercise ishighly recommended, asit has a profound euect onimmunity.Exercising

canslow andeven reverse someprocesses of immunosenescence.

A study has shown that physical exercise done by 10 males 18 to 61 years old wasinversely proportional to the number of senescent T cells after ageadjusted.

Another study found that among61 elderly menaged65 to 85 years, those whohadmoreintense training lifestyle hadhigher antibody responses to the influenza vaccine than those who didnot.This

suggests that immunosenescence isconsiderably influencedbydeficientphysicalactivity,highlightingthefactthatphysicalexerciseisessent Notonlyexercising, but also adopting a well-nutritioned diet andmaintaining a moderate weight may help to slow downthe agingof the immunesystem.About

30% of IL-6, the pro-inflammatory cytokine, originates from adiposetissues.

Thismeans

weightgainorobesitymaycontributetochronicinflammation.

Immunecellsneedtogracefullyage Compared tothe 18th century, humanlife expectancy morethan doubled thanks tothe advancements in healthcare and sanitation. People desire to live longer and thus understanding immunosenescence would be the key to it. Cellular changes occur while people age, so our goal would be to identify them even more precisely.

Systematic information on infections in the elderly needs to be collected from all over the world while developing redesigned and tailored vaccines forthe senescent immunecells would hopefully increase vaccine evcacy. There are still lots of work to do to deal with aging immunosenescence, and hopefully in the future, we can expect an increased lifespanandhealthylongBliving.

2022 VOL.21

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LIFE ISSUES

Long COVID :

Does It Cause Brain Damage?

YouYoung Cho youyoung0129@naver.com

T

hecoronaviruspandemichasattractedattentionduetoitsvariousaftereCects.Examplesincludeextremef problemsregardingmemoryandconcentration,diCcultysleeping,depressionandanxiety,andevenlossofsm and taste. For some people, these symptoms lasted for weeks or months even after the initial infection. This phenomenoncausedanewterm,“longCOVID”toappear.Asforthebrainfoginparticular,questionshavebeenraised as to whether it damages the brain, and actual studies have been conducted. If COVID-19 is a respiratory disease, why doesitcausebraindamage?Howisthatpossible?

BrainFog Brain fog isnot amedical orscientific term; it isterm used by individuals to describe howthey feel whenthey feel sluggish, fuzzy, andnot clear.

We often suuer fromsuch symptoms whenwe are sick with other diseases.

Forexample,

it isdivcult forusto concentrate onstudying orcarry out complicated tasks whenwe are tired fromaheadache oracold.

However,thereexistsaclearresearchresultonbraindamagecausedbyCOVID-19.

BrainScansoftheUKBiobank Study onthe connection of the coronavirus to brain damage started fromthe brain scan data of UK Biobank.

Biobank

is a human resource bank that collects and stores human blood and cells and provides them when requested by research institutes.

United Kingdom

Biobank hadboth pre-COVID andpost-COVID data of 785 individuals.

Thus, this study wasable to overcome someof the major limitations of most brain-related studies of COVID-19 to date, which relied on analysis and interpretation of data collected at a single time point.

UK BioBank provided pre-pandemic brain scans of 785 individuals.

About three years later, inMay 201, the samepopulation of participants returned fornewbrain scans.From

the total cohort, 401 individuals were infected with COVID-19betweenscansandtheremainingservedascontrols.

BrainShrinkage-CorticalGrayMatterLoss Withthe Biobank data, astudy has been conducted at the University of Oxfordby ateam led by professor Gweanaelle Douaud. They looked at brain magnetic resonance imaging (MRI) scans and test results of brain function. They then compared this to the same data collected three years later, when about half of those participants had experienced mild COVID infections.

Comparing

the brain volume before andafter individuals were exposed to SARS-CoV-2, this study documents significant cortical graymatter loss, equivalent to nearly 10 years of aging. Some people have suggested that itislike Alzheimer’s.

LinkageBetweenLossofOlfactionandBrainShrinkage

Although it isclear that SARS-CoV-2 candamagethe brain, howthis damageoccurs without directly infecting nerve cells remains a mystery. Multiple factors may contribute. It may in fact be secondary to infection occurring in other sites around the body, including the olfactory epithelium.

Considering

how close the nose isto the brain, this Oxford UniversityStudyconsideredwhetherlosingthesenseofsmellmaybelinkedtootherneurolog

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LIFE ISSUES

Figure1: Marked regions show the parts of the brain that shrank.

Figure2: Schematic view of the human olfactory system.

Douaudfound reduced graymatter inseveral regions associated with olfaction.

Individuals

exposed to COVID-19 experienced the most significant neural damage to the primary olfactory cortex, orpiriform cortex.

This structure receives input directly fromolfactory receptors that pass through the olfactory bulb,makingit the first neural target forprocessing and perceiving odors. Reduced cortical thickness was also observed in a connected region called the orbitofrontal cortex.

As illustrated inFigure 2, the orbitofrontal cortex (OFC) receives input fromthe primary olfactory cortex and iscommonly referred to as the secondary olfactory cortex.

Researchers speculate that the loss of volume to brain regions associated with olfaction may be partially attributed to widespread damageto the olfactory epithelium that disrupts neural pathways andimpairs function.

As with many other neural systems, pathways that are not being used over a long period of time cease to exist, which neuroscientists often call “use it or lose it” that causes brain tissues to shrink.

The study also found additional abnormalities in regions that are not associated with the sense of smell. There was a decrease in volume of some regions of the limbic system, involving structures important for producing behavioral and emotional responses.

The largest diuerences, ranging from0.2% to 2% reductions, were seen inthe left parahippocampal gyrus and the entorhinal cortex. These regions play an important role in the hippocampal memory system, so gray matter loss could signify future memory impairments.

More likely, however, these and other changes in brain structure may be a consequence of a robust immune response occurringallaroundthebrain,albeitthemechanismsunderlyinginflammation-inducedbrainda

TheNeedforaThirdBrainScan

Theassociation between cortical damageandsymptoms isnot yetknown. Evenindividuals with mild symptoms of COVID-19 displayed noticeable changes andcortical damageseems to occur regardless of disease severity, age, orsex.

Theeuect of vaccination status has not yet been investigated.

Itmay be years before the long-term consequences of these structural diuerences are fully understood.

There may begenetic links orconfusing factors like characteristics of the samplepopulationofbrainscansubjectsthemselves.

The brain is made up of nerve cells and is an organ that does not regenerate easily. Therefore, a third brain scan and carefulfollow-upresearcharerequiredtoclearlyunderstandthisphenomenon.

Moreover, although the loss of smell isoften oneof the first symptoms of COVID-19 preceding any respiratory complications, the hypothesis that the SARS-CoV-2 damages the brain whenit infects cells inthe olfactory epithelium remains heavily debated.

Researchers

doseemconfident that the virus does not directly infect brain cells.

If the nose is awindowtothebrain,itmaybetimetodevelopnewvaccinesthataimtocloseitoufrom B theSARS-Co 2022 VOL.21

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LIFE ISSUES

Artificial Sweeteners, Are They Safe?

Donghyeon Kim kdhbbr@naver.com

Introduction

A

rtificial sweeteners, simply put, are substitutes for sugar. They are sweet as sugar; but have significantly l calories than sugar. Accordingly, artificial sweeteners can be eCectively used not only for people on diet bu for obese or diabetic patients because they do not increase body fat while satisfying their appetite. This tak advantageofthefactthatartificialsweetenershavediCerentdegreesofsweetnesspersameweightcomparedtosug Detailedanalysiswillproceedinthetextbelow. Asaresult,byusingthesecharacteristics,wesucceededinmakin ‘sweetanddeliciousfoodthatdoesnotgainweight’desiredbymodernpeoplewhoaresensitivetoweightmanagement.

Typicalexamplesofsuchfoodarezero-caloriesoftdrinkslikezerocolaandzerosprite.Carbonateddrinksaresweet,b there are disadvantages in that they may lead to weight gain and are bad for health. Zero calorie sodas overcame this problem, and many companies such as Coca Cola, Lotte have entered the zero soda market, and the demand is still growing.ChilsungCiderZero,launchedbyLotteChilsungBeverageinearlysold 201, million 10 canswithinmonths 9 of its launch, and Coca-Cola Zero’s sales increased by 65% year-on-year. Furthermore Dong-A Otsuka’s zero-calorie ‘NarandCider’salesalsoincreasedby10%comparedtothepreviousyear.Asthedemandandconsumptionincreases, people began to have doubts: Are artificial sweeteners truly good for weight control and safe to use? Therefore, in th article,Iwouldliketoanalyzetheprinciplesandsafety lsweeteners. ofartificia

PrinciplesandSafetyofArtificialSweeteners Compare sugar andcalories indetail.

For comparison, take Aspartame, oneof the mostwidelyused artificial sweeteners infoodsuch asdiet coke,candy,gum, andsnacks.

Sugar

has 3.90kcal pergram, andaspartame has 6kcalper gram. Compared to calories perweight, aspartame seems to behigher.

However,

since aspartame has 20 times higher sweetness than sugar, it canproduce asimilar amount of sweetness even ifused inamuchsmaller amount.

Among

the foodthat use artificial sweeteners, the most commonfoodare drinks that emphasize zerocalories, such ascoke zeroand zerocider.

Artificial

sweeteners inzero-calorie drinks canbeclassified into three maincategories.

Thefirst

isaspartame, the second is trisodium citrate, and the third is acesulfame potassium. Starting with aspartame, the daily intake of aspartame is50mg perkg of weight, calculated

to be3.5g perdayforadults weighing 70kg.

In the case of regular coke, ifthere isabout 50g of sugar isina50mL bottle, the previous text saysthat aspartame isabout 20 times sweeter per weight than sugar, soit iscalculated that even ifonly0.25g of sugar isinacanof coke zero,it tastes the same. In other words, 3.5g seems like asmall amount, but it isactually about 6-7L of coke zero,soit isdivcult to drink onlycoke zero and exceed the recommended daily intake of aspartame. In other words, you have to drink a lot to get into some problems.

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LIFE ISSUES

Aspartame isa substance that isdivcult to digest, soexcessive intake cancause abdominal pain anddiarrhea.

In addition, aspartame is very easily discharged after being absorbed into the small intestine, so there is no need to worry about the accumulation inthe body. Notonlyaspartame, but also trisodium citrate andacesulfam potassium donot cause major problems unless consumed inaveryexcessive amount.

FAO

(United Nations Foodand Agriculture Organization), WHO (WorldHealth Organization) and , JECFA also confirmed that they are veryeasyto discharge andare verystable in humanbodywithin 24 hours.

However,

since trisodium citrate isasodium compound,people with highblood pressure should be careful when taking it.

Misunderstandingofartificialsweeteners

People are suspicious about sweet but calorie-free drinks.

There

are controversies regarding artificial sweetners since even ifthey are calorie-free, sweet tastes may stimulate the brain to raise blood sugar orlowcalories may increase the desire to satisfy the diuerence fromthe sweetness to the calories the brain expects through other food. However, this has not been confirmed through research andisjust aspeculation fromsomepeople.Looking

at “TheTruth andFiction of Aspartame” published

by Steven Novella, aneurologist at Yale University inthe United States, said that taking aspartame has not auected the brain normadeit crave formoresweets.

In other words,ingestion of aspartame does not auect the body’s metabolism or nervous system.

It can be assumed that the reason for the suspicion mentioned previously is the phenomenon that body fat does not decrease even though drinking zerosoda instead of regular soda.However,

this canbeseen not because artificial sweeteners actually appear to behighincalories orincrease appetite, but rather to drink zero soda to reduce calorie intake, sotheytendtothinkitisokaytoeatotherfoodsmoreasmuchasthediuerencemadebyazerosod

Conclusion Many people inmodern society consume artificial sweeteners through foodordrinks andartificial sweeteners are preferred as they are sweet but do not make them gain weight. However, many people are also curious about their safety.

They are worried about whether artificial sweeteners will increase their appetite orblood sugar, andside euects andare hesitant to use them.However,

the most common side euects of aspartame isabdominal pain ordiarrhea, whichonly appears inafew people whendrunk asmuchas6-7L, andsodium citrate should betaken exceptionally carefully onlyfor hypertensive patients.

Of course,

excessive intake may have side euects, but except forsomecases, I canconfidently say that it issafe forthe people to take artificial sweeteners.

I hope you take advantages of artificial sweeteners according to your purpose. B

l a i c i f i t s r r A tene e e Sw 2022 VOL.21

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THE BLUE VANGUARD

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THE BLUE

VANGUARD

MEMBERS

JOURNALIST

- Editor in Chief : Jimin Seo

- Vice Editor in Chief : Jungeun Kim - Copy Manager : Ji Won Son Aran Kim Daeun Choi Dah Eun Kim Dong Hyeon Kim Gayoung Lee Ha Neul Roh Hyunjin Lee Jihui Jeong

Jinyoo Park Jungyoon Ryu Kyubin Kim Namkyu Oh Ok Yoon Kim Seung Yeon Noh

Seo Yeong Kim Yoon Zoo Gee Youngeun Choi You Young Cho

DESIGNERS

Design Manager : Ji Won Kim Hwan Lee Jinyoo Park Ji In Shin Ji Won Yang

Seo Kyung Kim Tae Ho Kim Yeong Seo Park

2022 VOL.21

49

Farewell Yoon Zoo Gee

It was a real pleasure writing articles for the Blue Vanguard these past two years. Although it was challenging from time to time, I was always so proud of the final product we all put together. The fact that we did everything from writing to designing articles is truly amazing. I have no doubt that the Blue Vanguard will continue to publish great articles even when we leave. Hope you all have a wonderful summer break! You deserve it!

Being apart of the Blue Vanguard have been a meaningful time. Not only was I given the chance to practice writing, but also encounter diverse topics that helped me broaden my knowledge and perspective. It also enabled me to feel a sense of belonging during the COVID-19 times. Thank you everyone! :) Ok Yoon Kim I can’t believe we are already graduating from Blue Vanguard! It was such a meaningful experience to be part of this amazing crew. I was so fortunate to have the opportunity to study, write, and share various interesting pharmaceutical topics with everyone, thanks to Blue Vanguard. Thank you.

Hope you enjoy our last journal!

Young Eun Choi

It was nice to meet you all. It’s a shame we couldn’t meet up often in person, but feel free to contact me anytime! I’m always open. See you guys!

Dong Hyeon Kim I had a lot of fun and I was happy while doing Blue Vanguard activities.

Now I’m leaving Blue Vanguard, but I won’t forget all the articles that were published. Thank you for everything!

Aran Kim

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THE BLUE VANGUARD

It was challenging for me to write articles in English, but I really enjoyed expressing my ideas overall. It was also not easy writing articles during the semester, but I was so proud of myself when I finished writing and editing them. I hope all current and future members also enjoy writing and designing articles during their time as Blue Vanguardians. Good-bye!

Ga Young Lee I started working at Blue Vanguard because I wanted to interact with my classmates and seniors after entering a pharmacy school in a time of Corona.

I didn't know much about design, but I learned a lot while working as a design manager for two years while learning from my seniors. It's a pity that we didn't have many opportunities to interact with our seniors and juniors due to the current Corona virus. I really enjoyed!

Ji Hyun Kim

It was an unforgettable memory. It was a thankful memory.

I’ve always been grateful for the last two years.

Dae Hyun Kim

Hello, I’m Yang Heedo, graduating from Blue Vanguard. I could learn a lot from Blue Vanguard. Thank you to my colleagues who worked with me. I hope you have fun in Blue Vanguard!

Hee Do Yang

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