Medicine and Health Sciences Commons^™

Incidence Of Cancer, Depression, And Economic Burden Of Prescription Nsaids Among Older Adults With Osteoarthritis: Statistical And Machine Learning Approaches, Nazneen Fatima Mohammed Umer Shaikh

Graduate Theses, Dissertations, and Problem Reports (ETD)

Understanding the role of chronic inflammation among older adults is critical because of its implications on chronic inflammatory conditions as well as its interaction with anti-inflammatory medications. Osteoarthritis (OA) is a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity, and increasing evidence demonstrates a key role of chronic inflammation in its pathogenesis. Approximately 30 million adults in the United States have OA, and it is reported that a large proportion (43%) of them are older than 65 years. OA is typically treated using non-steroidal anti-inflammatory drugs (NSAIDs) for minimizing pain and reducing inflammation. NSAIDs have consistently shown clinically …

Formulation Development Of Drug Loaded Cyclodextrin-Based Nanoparticles For Ocular Delivery, Hay Man Saung Hnin Soe

Chulalongkorn University Theses and Dissertations (Chula ETD)

The development of topical eye drops for treatment of glaucoma and fungal keratitis is still challenging. Due to low aqueous solubility of drugs and the presence of ocular barriers, it is difficult to achieve effective therapeutic drug levels in targeted ocular tissues. In this present study, cyclodextrin (CD)-based nanoparticles (NPs) and synthetic CD-polymers were introduced to overcome these drawbacks and evaluated for their safety and efficacy. γ-Cyclodextrin (γCD) was able to increase the solubility of intraocular pressure lowering drugs, i.e., irbesartan (IRB) and candesartan cilexetil (CAC). The addition of Soluplus® significantly enhanced the complexation efficiencies of IRB/γCD and CAC/γCD complexes. …

Development Of An Extraction Method Of Mucuna Pruriens Seeds For A Chemically And Physically Stable Extract, Chayarit Vilairat

Chulalongkorn University Theses and Dissertations (Chula ETD)

Levodopa (L-DOPA) is a drug for the treatment of Parkinson's disease (PD). Currently, it derives from chemical synthesis and plants, especially Mucuna Pruriens (MP) seeds. The results of clinical studies found using the L-DOPA-containing MP for the treatment of PD could reduce side effects more than the synthetic one but patients must take MP powder in high amounts per a single dose which may cause inconvenience. Therefore, using the extract can help in the reduction of the dose. Unfortunately, the water extract from the MP seeds can be easily degraded physically and chemically; especially the physical appearance e.g., darkening color, …

Anti-Adipogenic Activity Of 4,5,4'-Trihydroxy-3,3'-Dimethoxybibenzyl From Dendrobium Ellipsophyllum In 3t3-L1 Preadipocytes, Hnin Ei Ei Khine

Chulalongkorn University Theses and Dissertations (Chula ETD)

Obesity and its global prevalence have become a threat to human health due to not only the abnormal lipid accumulation in the body as a result of aberrant expression levels in adipocyte differentiation and lipogenesis but also the underdeveloped pharmacotherapy. Recently, the bioactive compounds from the natural products have gained a lot of attention due to undertaking prophylactic and therapeutic effects on obesity. Here, we probed how 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB) extracted from an Thai orchid (Dendrobium ellipsophyllum) could exert its roles on the differentiation and function of murine (3T3-L1) and human (PCS-210-010) preadipocytes and offer some implications to modulate obesity. Cytotoxic …

Clinical Skills Development In The Virtual Learning Environment: Adapting To A New World, Erini S. Serag-Bolos, Liza Barbarello Andrews, Jennifer Beall, Kelly A. Lempicki, Aimon C. Miranda, Carol Motycka, Chelsea Phillips Renfro, Brittany L. Riley, Chasity M. Shelton, Deepti Vyas, Kimberly Won

Pharmacy Faculty Books and Book Chapters

The rapid transition to distance learning in response to the unexpected SARS-CoV-2/COVID-19 pandemic led to disruption of clinical skills development, which are typically conducted face-to-face. Consequently, faculty adapted their courses, using a multitude of active learning modalities, to meet student learning objectives in the didactic and experiential settings. Strategies and considerations to implement innovative delivery methods and address potential challenges are elucidated. Furthermore, integration of a layered learning approach may allow for more broad perspectives and allow additional interactions and feedback, which is especially necessary in the virtual environment.

Phytochemical Constituents Of Aquilaria Malaccensis Leaf Extract And Their Anti-Inflammatory Activity Against Lps/Ifn-Γ-Stimulated Raw 264.7 Cell Line, Eman Ramadan, Manar A. Eissa, Yumi Z. H-Y Hashim, Dina M. El-Kersh

Pharmacy

This study aims to identify the major phytochemical constituents in Aquilaria malaccensis (Thymelaeaceae) ethanolic leaf extract (ALEX-M) and elucidate their ability to suppress nitric oxide (NO) production from a murine macrophage-like cell line (RAW 264.7) stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Dichloromethane (DCM) and ethyl acetate (EtOAc) fractions of ALEX-M were subjected to column chromatography. Eight known compounds were isolated for the first time from this species. Compounds were identified using spectroscopic techniques (IR, UV, HRESIMS, and 1D and 2D NMR). Anti-inflammatory activity of both extract and isolated compounds were investigated in vitro. The fractions offered the isolation of …

Neuroprotective Effect Of Liraglutide In An Experimental Mouse Model Of Multiple Sclerosis: Role Of Ampk/Sirt1 Signaling And Nlrp3 Infammasome, Marwa Safar

Pharmacy

The heterogeneous nature of multiple sclerosis (MS) and the unavailability of treatments addressing its intricate network and reversing the disease state is yet an area that needs to be elucidated. Liraglutide, a glucagon-like peptide-1 analogue, recently exhibited intriguing potential neuroprotective effects. The currents study investigated its potential effect against mouse model of MS and the possible underlying mechanisms. Demyelination was induced in C57Bl/6 mice by cuprizone (400 mg/kg/day p.o.) for 5 weeks. Animals received either liraglutide (25 nmol/kg/day i.p.) or dorsomorphin, an AMPK inhibitor, (2.5 mg/ Kg i.p.) 30 min before the liraglutide dose, for 4 weeks (starting from the …

Research News, Publications, 2022, Volume 2, Soumyajit Majumdar

Publications (2015-)

Publications that appeared during the period of April 1 through June 30, 2022.

Research News, Publications, 2022, Volume 1, Soumyajit Majumdar

Publications (2015-)

Publications that appeared during the period of January 1 through March 31, 2022.

Research News, Publications, 2022, Volume 3, Soumyajit Majumdar

Publications (2015-)

Publications that appeared during the period of July 1 through September 30, 2022

Research News, Grants, 2022, Volume 2, Soumyajit Majumdar

Grants (2015-)

Grants and contracts awarded during April - June 2022.

Research News, Grants, 2022, Volume 3, Soumyajit Majumdar

Grants (2015-)

Grants and contracts awarded during July - September 2022

Will Covid-19 Be Eradicated?, Matthew Kieke

Williams Honors College, Honors Research Projects

In this paper I want to define the meaning of “eradication”, explain the history of various diseases that have been eradicated, and compare and contrast them to covid-19, to answer the question of “Will covid-19 be eradicated”?

Melatonin As An Antimicrobial Adjuvant And Anti-Inflammatory For The Management Of Recurrent Clostridioides Difficile Infection, S. Scott Sutton, Joseph Magagnoli Ph.D., Ms, Tammy H. Cummings, James W. Hardin

Faculty Publications

Clostridioides difficile (C. difficile) infection (CDI) is strongly associated with inflammation and has the potential to cause recurrent infections. Pre-clinical data suggest that melatonin has beneficial effects in the gastrointestinal tract due to its anti-inflammatory and antibacterial properties. This analysis examines the association between melatonin and the risk of recurrent CDI. Methods: A retrospective cohort study was conducted among patients with an inpatient diagnosis of CDI along with a positive C. difficile polymerase chain reaction (PCR) or enzyme immunoassay (EIA) test result. Patients were followed until the first study end point (death) or the first instance of recurrent …

Prenatal Exposure To Methamphetamine Causes Vascular Dysfunction In Adult Male Offspring, Hasitha Chavva, Adam M. Belcher, Daniel A. Brazeau, Boyd Rorabaugh

Pharmaceutical Science and Research

Methamphetamine use during pregnancy can have negative consequences on the offspring. However, most studies investigating the impact of prenatal exposure to methamphetamine have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine on the adult cardiovascular system. This study investigated the impact of chronic fetal exposure to methamphetamine on vascular function in adult offspring. Pregnant female rats received daily saline or methamphetamine (5 mg/kg) injections starting on gestational day 1 and continuing until the pups were born. Vascular function was assessed in 5 month old offspring. Prenatal methamphetamine significantly decreased both the efficacy …

Clinically Relevant Drug Interactions With Monoamine Oxidase Inhibitors., Amber N. Edinoff, Connor R. Swinford, Amira S. Odisho, Caroline R. Burroughs, Cain W. Stark, Walid A. Raslan, Elyse M. Cornett, Adam M. Kaye, Alan David Kaye

School of Pharmacy Faculty Articles

Monoamine oxidase inhibitors (MAOI) are a class of drugs that were originally developed for the treatment of depression but have since been expanded to be used in management of affective and neurological disorders, as well as stroke and aging-related neurocognitive changes. Ranging from irreversible to reversible and selective to non-selective, these drugs target the monoamine oxidase (MAO) enzyme and prevent the oxidative deamination of various monoamines and catecholamines such as serotonin and dopamine, respectively. Tyramine is a potent releaser of norepinephrine (NE) and is found in high concentrations in foods such as aged cheeses and meats. Under normal conditions, NE …

Examining Ayahuasca Constituents At 5-Ht2a Receptors In Search Of Antidepressant Action, Jeremy D. Rolquin

Theses and Dissertations

Recently, it has been reported that ligands of the 5-HT_2A receptor can have drastic and fast-acting efficacy towards a number of different mental health disorders, such as depression and anxiety. A mixture of Amazonian plants calledayahuasca contains multiple compounds which have been shown to interact with the serotonergic system, and the 5-HT_2Areceptor in particular.

The structurally similar compounds (DMT, harmine, harmaline, and tetrahydroharmine) found in ayahuasca were examined for differences in their physiochemical properties that might contribute to their binding affinity for the 5-HT_2Areceptor. 3D Molecular modeling and docking studies of these compounds were …

Maternal Diet In Pregnancy And Child’S Respiratory Outcomes: An Individual Participant Data Meta-Analysis Of 18 000 Children, Sara M. Mensink-Bout, Evelien R. Van Meel, Johan C. De Jongste, Isabekka Annesi-Maesano, Adrien M. Aubert, Johnathan Y. Bernard, Lin-Wei Chen, Cryus Cooper, Sarah R. Crozier, Wojciech Hanke, Nicholas C. Harvey, James R. Hébert Scd, Barbara Heude, Joanna Jerzynska, Cecily C. Kelleher, John Mehegan, Fionnuala M. Mcauliffe, Catherine M. Phillips, Kinga Polanska, Carolina L. Relton, Nitin Shivappa Mbbs, Mph, Ph.D., Matthew Suderman, Vincent Wv Jaddoe, Liesbeth Duijts

Faculty Publications

Rationale Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health.

Methods We performed an individual participant meta-analysis among 18 326 mother–child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using …

ประสิทธิศักย์และความปลอดภัยของแคลเซียมที่สกัดจากกระดูกปลาในอาสาสมัครภาวะกระดูกบาง, ขวัญวิวัฒน์ ศรีวิฑูรย์

Chulalongkorn University Theses and Dissertations (Chula ETD)

โรคกระดูกพรุนเป็นปัญหาทางสาธารณสุขทั่วโลกส่งผลต่ออัตราการตายและคุณภาพชีวิตที่แย่ลง ผู้ป่วยควรได้รับการชะลอการเกิดโรคกระดูกพรุนตั้งแต่ตรวจพบภาวะกระดูกบางด้วยการบริโภคแคลเซียมให้เพียงพอ แคลเซียมที่สกัดจากกระดูกปลาเป็นเกลือแคลเซียมจากแหล่งธรรมชาติแต่การศึกษาในมนุษย์ยังมีจำกัด การศึกษานี้จึงมีวัตถุประสงค์เพื่อศึกษาประสิทธิศักย์และความปลอดภัยของแคลเซียมที่สกัดจากกระดูกปลาในอาสาสมัครภาวะกระดูกบาง การศึกษาเป็นรูปแบบเชิงทดลองไปข้างหน้าแบบสุ่มมีกลุ่มควบคุมไม่ปกปิดอาสาสมัครและผู้วิจัย อาสาสมัครตามเกณฑ์การคัดเลือก 48 คนถูกแบ่งกลุ่มให้ได้รับแคลเซียมที่สกัดจากกระดูกปลาหรือแคลเซียมคาร์บอเนตในอัตราส่วนที่เท่ากัน ผลลัพธ์หลักคือการเปลี่ยนแปลงความหนาแน่นของกระดูกบริเวณกระดูกสันหลังและกระดูกสะโพกในเดือนที่ 6 ผลลัพธ์รองได้แก่ ค่าทางชีวเคมีของการหมุนเวียนกระดูก การทดสอบสมรรถภาพร่างกาย ความเจ็บปวดทั่วร่างกาย ค่าทางห้องปฏิบัติการต่าง ๆ ในเดือนที่ 3 และ 6 และอาการไม่พึงประสงค์ในเดือนที่ 6 กำหนดระดับนัยสำคัญ 0.05 ผลการศึกษาพบว่า ข้อมูลพื้นฐานของอาสาสมัครทั้งสองกลุ่มไม่แตกต่างกัน หลังรับประทานผลิตภัณฑ์แคลเซียมเป็นระยะเวลา 6 เดือน ค่าความแตกต่างของความหนาแน่นของกระดูกบริเวณกระดูกสันหลังส่วนเอวและกระดูกคอสะโพกของอาสาสมัครทั้งสองกลุ่มไม่แตกต่างกันอย่างมีนัยสำคัญทางสถิติ (0.009±0.034 vs 0.007±0.023 กรัมต่อตารางเซนติเมตร; 95% CI -0.015, 0.019; P-value 0.835 และ-0.002±0.025 vs 0.006±0.017 กรัมต่อตารางเซนติเมตร; 95% CI -0.021, 0.004; P-value 0.181 ตามลำดับ) ค่าชีวเคมีของการหมุนเวียนกระดูกและความเจ็บปวดทั่วร่างกายที่ 3 เดือนและ 6 เดือนลดลงจากก่อนรับประทาน และอาสาสมัครมีสมรรถภาพทางกายดีขึ้นในทั้งสองกลุ่มแต่ไม่แตกต่างกันอย่างมีนัยสำคัญทางสถิติ อาสาสมัครที่ได้รับแคลเซียมที่สกัดจากกระดูกปลาพบความถี่อาการข้างเคียงน้อยกว่ากลุ่มแคลเซียมคาร์บอเนต ดังนั้นจึงสรุปได้ว่าแคลเซียมที่สกัดจากกระดูกปลามีประสิทธิศักย์ในการชะลอการเสื่อมของมวลกระดูกได้ไม่แตกต่างจากแคลเซียมคาร์บอเนต และมีความปลอดภัย

Effect Of Vernonia Cinerea Lozenges As A Smoking Cessation Aid In Patients With Non-Communicable Diseases, Krittin Bunditanukul

Chulalongkorn University Theses and Dissertations (Chula ETD)

Background: This study aims to investigate the effect of Vernonia Cinerea (VC) lozenges on smoking cessation when compared with a placebo. Methods: This study is designed as a randomized, paralleled, double-blinded, controlled trial. Ninety-three patients who are the age 18 years or over at five hospitals and two community pharmacies were randomized to receive VC lozenges (n=45) or placebo (n=48) for 12 weeks. The primary outcome in this study is the continuous abstinence rate (CARs) at 4 and 12 weeks after the quit date. Results: There was no statistically significant difference in CARs rates at week 4 in the study …

Compounds With Anti-Neuroinflammatory Activity From Aerides Falcata, Bachtiar Rivai

Chulalongkorn University Theses and Dissertations (Chula ETD)

In this study, a plant from the Orchidaceae family, Aerides falcata, was investigated for its chemical constituents and anti-neuroinflammatory activity. A total of ten compounds were isolated and characterized. The isolated compounds included a new compound which was named aerifalcatin and nine known compounds: n-eicosyl-trans-ferulate, denthyrsinin, 2,4-dimethoxy-3,7-dihydroxyphenanthrene, 2,7-dihydroxy-3,4,6-trimethoxyphenanthrene, 3,7-dihydroxy-2,4,6-trimethoxyphenanthrene, agrostonin, syringaresinol, trans-n-feruloyltyramine, and trans-n-coumaroyltyramine. All the isolated compounds were evaluated for their anti-neuroinflammatory activity, except for trans-n-coumaroyltyramine, which was excluded due to its insufficient amount. In vitro testing was conducted on LPS-induced BV2 microglia cells to evaluate their potential anti-neuroinflammatory activity using NO inhibition model. Minocycline, a neuroinflammatory modulator, was …

Putative Mechanisms Underlying The Antidepressant Actions Of Ketamine: A Review And Study Proposal, Tristan Reece

CMC Senior Theses

Major Depressive Disorder (MDD) is a highly debilitating and common psychiatric disorder that affects over 250 million people globally; it is among the most financially and emotionally burdensome illnesses in the world. Currently approved antidepressants are suboptimal in their efficacy and latency of therapeutic action. In contrast, single administrations of sub-anesthetic ketamine have been shown to rapidly alleviate depressive symptoms within hours, even in treatment-resistant patients. Ketamine is believed to exert these effects by increasing glutamatemediated neurotransmission and promoting rapid neurotrophic factor release, restoring the integrity of neural circuits that are compromised in depression. However, uncertainty surrounding its specific antidepressant …

Incorporating Glutamic Acid-Valine-Citrulline Linker In Trifunctional Molecules Targeting Psma Ensures Enhanced Stability, Safety, And Efficacy In Mouse Model Of Prostate Cancer, Toufiq Ul Amin

University of the Pacific Theses and Dissertations

This project describes the development of a new antitumor therapeutic platform that combines the benefits of small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are popular cathepsin B cleavable ADC linkers. Due to its instability in mouse serum, translating efficacy data from mouse to human is more difficult. It has been reported that replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) improves ADC stability in mouse serum. The effect of the EVCit linker on the stability of SMDCs has not been reported so far. In a xenograft mouse model of prostate cancer, we found that …

Dna Methylation Pattern Of Cpg Site In The Promoter Region Of Calca-Alpha Gene As A Putative Epigenetic Biomarker In Neonatal Sepsis- A Prospective Observational Study In South India, Rudra Rupesh Reddy Narsapurapu, Deepti Thandaveshwara, Anshu Kumar Yadav, Akila Prashant

Digital Journal of Clinical Medicine

Background: Recently, several studies have been reported on epigenetic modifications of DNA as a predisposing factor for several diseases among neonates and adults. Here we aimed to study the changes in the DNA methylation pattern in the promoter region of the CALCA gene among the neonates suspected to have sepsis in a tertiary care hospital.

Methodology: All the neonates suspected to have sepsis based on the inclusion criteria during the study period were included in the study as cases. Normal healthy neonates were included in the study as controls. Positive cases were isolated from suspected cases based on …

Factors Causing Commercial Leaders In U.S. Multinational Pharmaceutical Businesses To Change Companies, Robert J. Britting Jr

Walden Dissertations and Doctoral Studies

Employee turnover in U.S. multinational pharmaceutical companies remains high, even though U.S. multinational pharmaceutical companies offer competitive salaries and benefits compared to other large industries. A recent survey found that 67% of 2,400 pharmaceutical leaders would be looking for a new job within 12 months and that general employee turnover costs organizations 70% to 300% of each employee's salary. The purpose of this case study was to explore the factors that cause commercial leaders from mid- to large-size U.S. pharmaceutical companies to seek employment outside of their organization. Lewin’s three-stage model of unfreezing, moving, and refreezing, along with the psychology …

Investigation Of Cdk8 Inhibitor Q-12 Effects On Cdk8 And Cdk8 Substrates In Triple Negative Breast Cancer Cell Line Mda-Mb-468, Shengxi Li

University of the Pacific Theses and Dissertations

Cyclin-dependent kinases (CDKs) and cyclins (Cyclins) are the core molecules in the regulation mechanism of the entire cell cycle. Cell cycle dysregulation is a common feature of human cancers, and inhibitors of cyclin-dependent kinases (CDKs) play a crucial role in cell cycle control and are one of the most promising areas of cancer therapy. We aspired to use our cyclin-dependent kinase 8 (CDK8) inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer (TNBC) and colorectal cancer cell lines …

Optimization Of The Structure Of Ttr Ligands For Half-Life Extension (Tlhe), Guanming Jiang

University of the Pacific Theses and Dissertations

Many potential therapeutic agents face challenges for their clinical development due to short circulation half-life. As a result, prolonging the half-life of therapeutic drugs in circulation while preserving their hydrophilicity and small size will be a key step toward more effective and safe pharmacological molecules. Our lab developed a new approach for enhancing the safety and efficacy of therapeutic agents. By endowing therapeutic agents with a hydrophilic small molecule (a derivative of the clinical candidate, AG10) which reversibly binds to the serum protein transthyretin (TTR), the half-life of the therapeutic agent should be extended by binding to the TTR in …

Expression Of Mouse Full-Length Aryl Hydrocarbon Receptor And Human Aryl Hydrocarbon Receptor Ligand Binding Domain In Pichia Pastoris, Yiyuan Wang

University of the Pacific Theses and Dissertations

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates biological responses to planar aromatic hydrocarbon. AHR activates gene transcription by binding to its corresponding enhancer with its partner-aryl hydrocarbon receptor nuclear translocator (ARNT). In addition, this receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. AHR exists widely in body tissues and affects bioactivation of carcinogenic compounds, T cell differentiation, fatty acid synthesis, cell proliferation, hematopoietic stem cell differentiation, respiratory reactivity, and insulin sensitivity. Although the precise mechanism illustrating the endogenous AHR function remains unclear, there has been intense interest in exploring AHR as a …

Optimizing The Human Aryl Hydrocarbon Receptor (Hahr) Expression In Pichia Pastoris, Junyu Qian

University of the Pacific Theses and Dissertations

The aryl hydrocarbon receptor (AHR) is a transcription factor which heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) to regulate downstream gene transcription. For the purpose of studying the crystal structure of human aryl hydrocarbon receptor (hAHR), it is essential to obtain abundant amount of pure recombinant protein.Basing on the benefits of using P. pastoris system to produce recombinant protein, including appropriate folding, secretion of interest proteins to the external environment of the cell, and easier purification process of protein due to the its limited production of endogenous secretory proteins [1], our lab chose P. pastoris yeast as the …

Peripherally Restricted Delivery System Provides Insights On The Role Of Cns In Precipitating Opioid-Induced Constipation, Dengpan Liang

University of the Pacific Theses and Dissertations

A serious opioid crisis is affecting public health and economics, eroding people’s quality of life. 80% of patients who receive opioids suffer from adverse effects such as Opioid-induced constipation (OIC). However, there is no efficient medicine for these adverse effects. Notably, mainstream theory supports that analgesia effects are mainly controlled by CNS while OIC is predominately controlled by peripheral. In addition, the sites of action of opioid was based on the assumption that mu-opioid receptor antagonists (PAMORAs), did not cross the blood-brain barrier (BBB). Unfortunately, the BBB crossing of PAMORAs mislead the understanding of the role of the central nervous …