Larkin University

Tripathi M., Gharti L., Bansal A., Kaurav H., Sheth S.

Background: The neuroprotective efficacy of glibenclamide (GLIB) has been demonstrated in multiple rodent models of ischemia, hemorrhagic stroke, traumatic brain damage, spinal cord injury, and metastatic brain tumors. Due to its poor solubility, GLIB has low oral bioavailability, limiting its transportation to the brain via the oral route. Objectives: Here, we attempted to develop and optimize an intranasal mucoadhesive in situ gel of GLIB-loaded bilosomes using a 32 Box–Behnken design for brain drug delivery. Methods: To facilitate a longer residence time of the administered dose within the nasal cavity, the prepared bilosomes were loaded into a mucoadhesive in situ gel providing resistance to rapid mucociliary clearance. The amounts of sodium deoxycholate, the cholesterol/Span 40 mixture, and the molar ratio between the mixture’s components were chosen as independent variables, while the entrapment efficiency and in vitro drug release were selected as dependent variables. Results and conclusions: The optimal formulation was analyzed for particle size and entrapment efficiency, which were found to be 270.6 nm and 68.39%, respectively. In vitro drug release from optimal formulation after 12 h was 87.29 ± 1.98% as compared to 52.01 ± 2.04% of plain in situ gel of drug. An in vivo brain drug delivery study performed on Swiss albino mice showed that the brain concentration of drug through intranasal administration from mucoadhesive in situ gel of GLIB-bilosomes after 12 h was 2.12 ± 0.16 µg/mL as compared to 0.68 ± 0.04 µg/mL from plain in situ gel of drug. Conclusively, the developed bilosomal formulation offers a favorable intranasal substitute with enhanced therapeutic drug delivery to the brain.

Benneh C.K., Abotsi W.K., Mante P.K., Biney R.P., Fetse J.P., Abeka M.K., Adongo D.W., Woode E.

Major depressive disorder is one of the most common and burdensome psychiatric disorders worldwide. This study evaluated the anxiolytic- and antidepressant-like activity of three semi-synthetic derivatives of xylopic acid (XA) to identify the most promising derivative based on mechanism(s) of action, in vivo pharmacokinetics and in vitro cytotoxicity. The anxiolytic potential and the involvement of GABAergic mechanisms were assessed in the elevated plus-maze and open field tests in mice. The antidepressant-like effects were also investigated in the tail suspension test (TST) and forced swim test (FST). Possible mechanism(s) of antidepressant-effect was assessed by selective depletion of monoamines, using either reserpine, alpha-methyl-para-tyrosine or para-chlorophenylalanine (pCPA) prior to repeating the TST and FST. A single oral (100 mg kg−1) and intravenous bolus dose (100 mg kg−1) of XA or deacetylated XA (dXA) was administered separately to mice and the plasma concentration of each compound subjected to non-compartmental analyses. The potential cytotoxic effect of XA and dXA was also assessed with the MTT assay using HepG2 and Caco-2 cells. XA and all the derivatives (10–100 mg kg−1) reduced anxiety- and depression-related behaviours. The anxiolytic-like effect of dXA was attenuated by pentylenetetrazole while its antidepressant-like properties were reversed in reserpine and pCPA pre-treated mice. In comparison to XA, dXA had lower oral clearance, longer half-life, shorter time to reach peak plasma concentration and was less toxic to hepG2 cells. All the semi-synthetic derivatives of XA exert varying degrees of anxiolytic- and antidepressant-like effects in mice. The anxiolytic- and antidepressant-like effects of dXA and XA are mediated, at least partly, through GABAergic and serotoninergic systems, respectively. In comparison with XA, dXA has a much lower clearance, longer half-life, shorter time to reach peak plasma concentration and was less toxic to HepG2 cells.

Basak D., Mostofa A., Madala H.R., Srivenugopal K.S.

Background: O6-Methylguanine-DNA methyltransferase (MGMT) is a unique antimutagenic DNA repair protein that plays a crucial role in conferring resistance to various alkylating agents in brain tumor therapy. In this study, we exploited the susceptibility of the active site Cys145 of MGMT for thiolation and nitrosylation, both of which inactivate the enzyme. Methods: We designed a redox perturbing glutathione mimetic, a platinated homoglutathione disulfide (hGTX) by adding small amounts of cisplatin (1000:10) and used a nitric oxide-donor spermine NONOate. N6022, a potent inhibitor of S-nitrosoglutathione reductase was used to extend the retention of nitrosylated MGMT in tumor cell culture and subcutaneous xenografts. Results: Both hGTX and spermine NONOate inhibited MGMT activity in HT29, SF188, T98G, and other brain tumor cells. There was a robust increase in the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle arrest, cytotoxicity, and the levels of apoptotic markers when either of the agents was used with alkylating agents. In the nude mice bearing T98G and HT29-luc2 xenografts, combinations of hGTX and spermine NONOate with alkylating agents produced a marked reduction in MGMT protein and tumor growth delay and regressions. N6022 treatment increased the presence of nitrosylated MGMT for a longer time, thereby extending the DNA-repair deficient state both in cell culture and preclinical settings. Conclusions: Our findings highlight the options for redox-driven therapeutic strategies for MGMT and suggest that oxidative and/or nitrosative inactivation of DNA repair in combination with alkylating agents could be exploited.

Valerio-Pascua F., Baires F., Sekhon A.K., Tesch M.L., Pineda E.J., Rizvi S.A., Singh J., Cortes-Bandy D.A., Madril A.C., Radwanski J., Lewis A.S., Sierra-Hoffman M., Stevens M.L., Rahaghi F.F.

The World Health Organization (WHO) declared the end of the COVID-19 (SARS-CoV-2) global public health emergency on May 5, 2023, but its long-term consequences have still been haunting the global population. Post-acute sequelae of COVID-19 (PASC) and long-term COVID-19 are serious concerns and present with various symptoms. Intranasal chlorpheniramine (iCPM) has been shown to decrease the viral burden of SARS-COV-2. iCPM uses decreased COVID-19 disease progression and severity in Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACROSS)-I & III randomized control trials (RCT). This prospective survey study included 259 participants in ACROSS I and III RCTs. We compared the effect of iCPM versus placebo on the reduction of PASC symptoms. A PASC questionnaire containing 17 questions regarding the most common PASC symptoms was used in this study. T-test and Pearson chi-square statistics were performed according to continuous and categorical data using STATA 17.0 Basic Edition software. The iCPM cohort had a lower proportion of patients with fatigue or tiredness vs. placebo (0 Vs 17, 21, p < 0.001). iCPM cohort had a lower proportion of patients with difficulty concentrating or mental confusion (0 vs. 22, 27, p < 0.001). iCPM cohort had also a lower number of patients with difficulty in the ability to perform daily activities or work vs. placebo (1 Vs 38, 48, p < 0.001). A smaller number of patients in the iCPM cohort sought medical attention for PACS symptoms compared to placebo (0 vs. 48, 68, p < 0.001). The use of intranasal chlorpheniramine shows promise in preventing COVID-19 progression to the often-debilitating post-COVID-19 syndrome PASC. The association between iCPM use and a lower prevalence of PASC symptoms is strong. Further studies are needed to establish the role of ICPM in preventing PASC.

Boylan P.M., Santibañez M., Thomas J., Weeda E., Noel Z.R., Caballero J.

AbstractCannabinoids have emerged as a potential treatment for obstructive sleep apnea (OSA). This systematic review aimed to summarize the efficacy and safety of cannabinoids to treat OSA. Databases including Ovid MEDLINE, EMBASE, Scopus, PsycINFO, and International Pharmaceutical Abstracts were searched; experimental and observational studies were eligible for inclusion. One‐hundred seventy unique records were screened, and nine studies included: five full‐text studies and four published abstracts. The five full‐text studies were judged for quality appraisal: two studies deemed at low risk for bias, one study deemed to have some concerns for bias, and two studies deemed to have high risk for bias. Seven of nine total studies were experimental designs and evaluated dronabinol, and the other two studies were observational designs evaluating cannabis. The range of cannabinoid therapy duration spanned from 1 to 6 weeks, and the median duration was 3 weeks. Eight of nine total studies reported statistically significant, positive OSA outcomes due to cannabinoid therapy including reductions in the apnea hypopnea index and improvements in patient‐reported daytime sleepiness scales. Between 70% and 80% of study participants reported neuropsychiatric and gastrointestinal adverse events attributable to cannabinoids. The American Academy of Sleep Medicine does not recommend using cannabinoids to treat OSA due to a lack of long‐term safety and efficacy data. This systematic review found similar limitations, with the median cannabinoid treatment duration being only 3 weeks. Adequately powered experimental trials over longer time frames are necessary to more completely assess the long‐term efficacy and safety of cannabinoids in the treatment of OSA and its effects on common comorbid conditions, such as obesity and cardiovascular disease.

Razdan S., Parekh S., Watts E., Munoz J., Parmar J., Khanfar N.M., Woodhouse C., Razdan S.

Fetse J., Olawode E.O., Deb S.

Cytochrome P450 enzymes (CYPs) represent a diverse family of heme-thiolate proteins involved in the metabolism of a wide range of endogenous compounds and xenobiotics. In recent years, proteomics and metabolomics have been used to obtain a comprehensive insight into the role of CYPs in health and disease aspects. The objective of the present work is to better understand the status of proteomics and metabolomics in CYP research in optimizing therapeutics and patient safety from a personalized medicine approach. The literature used in this narrative review was procured by electronic search of PubMed, Medline, Embase, and Google Scholar databases. The following keywords were used in combination to identify related literature: “proteomics,” “metabolomics,” “cytochrome P450,” “drug metabolism,” “disease conditions,” “proteome,” “liquid chromatography-mass spectrometry,” “integration,” “metabolites,” “pathological conditions.” We reviewed studies that utilized proteomics and metabolomics approaches to explore the multifaceted roles of CYPs in identifying disease markers and determining the contribution of CYP enzymes in developing treatment strategies. The applications of various cutting-edge analytical techniques, including liquid chromatography-mass spectrometry, nuclear magnetic resonance, and bioinformatics analyses in CYP proteomics and metabolomics studies, have been highlighted. The identification of CYP enzymes through metabolomics and/or proteomics in various disease conditions provides key information in the diagnostic and therapeutic landscape. Leveraging both proteomics and metabolomics presents a powerful approach for an exhaustive exploration of the multifaceted roles played by CYP enzymes in personalized medicine. Proteomics and metabolomics have enabled researchers to unravel the complex connection between CYP enzymes and metabolic markers associated with specific diseases. As technology and methodologies evolve, an integrated approach promises to further elucidate the role of CYPs in human health and disease, potentially ushering in a new era of personalized medicine.

Lakhman S., Murzello A., Gueits P.G.

As we journey through life, our mental well-beingMental well-being becomes increasingly linked with our physical health, especially as we age. The connection between physical activityPhysical activity and diet is pivotal for shaping our mental healthMental health and longevity. Exercise is essential for mental vitality in ageingAgeing, not just for physical fitness but also for cognitive functionCognitive functions and emotional balance. Activities like walking, swimming, or yoga release endorphins, boosting mood, and promoting neuroplasticityNeuroplasticity, which enhances cognitive resilience against ageingAgeing. Every movement, from a stroll to tai chi, nurtures a resilient mind. Dietary choices also profoundly impact mental healthMental health as we age. A diet rich in antioxidants, omega-3 fatty acids, and plant-based nutrients nourishes both body and mind, protecting against oxidative stressStress and inflammation linked to cognitive declineCognitive decline and mood disordersMood disorders. Emphasizing a Mediterranean-style diet, with fruits, vegetables, whole grains, and lean proteins, enhances cognitive vitality and emotional well-being in later years. The synergy between physical activityPhysical activity and diet offers a powerful prescription for mental healthMental health and longevity in ageingAgeing. By embracing an active lifestyle and mindful eating, we can cultivate a resilient mind, enriching our lives with vitality and purpose.

Atre P., Rizvi S.A.

Bilayer liposome structure with encapsulated hydrophilic drug in the aqueous core.

Johnson B., Alho H., Addolorato G., Lesch O.M., Chick J., Liu L., Schuyler V.

BackgroundAlcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50–60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects.MethodsThis was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V–categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53Johnson B., Diclimente C., Ait-Daoud N., Stokes S. Brief behavioral compliance enhancement treatment (BBCET) manual. Handbook of clinical alcoholism treatment Baltimore Lippincott Williams & Wilkins. 2003a; In: Johnson, B.A., Ruiz, P., and Galanter, M. (Editors):282–301.Google Scholar]) was administered every two weeks to enhance medication compliance and clinic attendance.ResultsThere was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03–11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's.ConclusionsIn this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

Umumararungu T., Nyandwi J.B., Katandula J., Twizeyimana E., Claude Tomani J., Gahamanyi N., Ishimwe N., Olawode E.O., Habarurema G., Mpenda M., Uyisenga J.P., Saeed S.I.

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

Addolorato G., Alho H., Bresciani M․ De Andrade P., Lesch O.M., Liu L., Johnson B.

Background:The increasing prevalence of alcohol use disorder (AUD) and the parallel surge in alcohol-associated liver disease (ALD) emphasize the urgent need for comprehensive alcohol management strategies.Low-dose ondansetron (AD04, a 5-HT3 antagonist) was shown recently to be a promising treatment for AUD with a specific genotypic profile (5-marker).The liver safety of AD04 has never been evaluated in subjects with AUD.The aim of the present study was to assess the liver safety profile of AD04 compared with placebo in subjects with AUD.Methods: Liver biochemical parameters were assessed in subjects with AUD with a 5-marker genetic profile who participated in a Phase 3 randomized controlled trial and received either twice-daily, low-dose AD04 (ondansetron 0.33 mg twice daily) or matching placebo, combined with brief psychosocial counseling.ALT, AST, GGT, Serum Bilirubin, MCV, and Prothrombin were evaluated at weeks 0, 12, and 24.Adverse cardiac events, general well-being, and study completion were also assessed.Results: Low-dose AD04 did not significantly change biochemical markers of liver injury, such as ALT, AST, and Serum Bilirubin.While patients with AUD displayed elevated GGT levels, typically associated with increased alcohol consumption, this parameter remained unaffected by low-dose AD04.Notably, no significant adverse effects were observed due to oral low-dose AD04 treatment.Conclusions: Low-dose AD04 has the potential to be a safe treatment option for subjects with AUD and ALD, indicating the need for an RCT for this specific cohort.Such a trial would pave the way for the design of a precision treatment for combined AUD with ALD.

Bustos G., Sanchez-Gonzalez M.A., Grogan T., Bonansea-Frances A., Wright C., Lichtenberger F., Rizvi S.A., Kaplan A.

Allergic rhinitis (AR), a condition characterized by sensitivity to allergens leading to poor quality of life, including disrupted sleep, reduced vitality, lowered mood, changes in blood pressure limited frustration tolerance, impaired focus, decreased performance in academic and professional settings, and millions of missed work and school days every year. Approximately 20–40% of individuals in the United States are affected by AR, which carries notable clinical and financial burdens. Interestingly, there is a strong link between AR and asthma to the extent that countries with a high prevalence of rhinitis have asthma rates ranging from 10% to 25%. Research has indicated that Allergen Immunotherapy (AIT) is associated with improved AR symptoms, a potential to resolve the AR over time, a decreased likelihood of asthma exacerbations and incidence of pneumonia in individuals with concurrent asthma, which are advantages that persist for years even after the cessation of treatment. Although patients presenting with allergies are first seen and treated in the primary care setting, gaps in training and the lack of available guidance for primary care practitioners have significantly impacted the quality of care for these patients with persistent AR symptoms, resulting in inefficient use of healthcare resources. To complicate matters, there is an insufficiency of allergists and immunologists, impacting the capacity to provide next-level care to the number of AR patients who could benefit from AIT. Hence, there is a critical need to equip primary care providers with educational experiences on essential concepts related to immune responses in allergies and asthma, recognizing the significance of the common airway in treating these entities and familiarization with the scientific evidence supporting various options for AIT. The development and implementation of medical education and algorithms designed to assess diverse patients’ symptoms, pharmacotherapy approaches, and situations where AIT can be initiated or sustained are warranted. The present commentary proposes a workflow model of the critical steps for managing and treating mild to moderate respiratory allergies via AIT in primary care settings. In addition, the initial development of medical education programs to minimize the burden on allergy-specialized care while, importantly, actively improving patient outcomes will be discussed.

Nohria R., Nielsen N., Sabnis G.

Podcasts are a popular way to learn and engage at the convenience of the listener. Education is incorporating podcasts to supplement and reinforce students learning inside and outside the classroom. The authors created a podcast covering the Top 200 commonly prescribed medications. This was to help students recall and reinforce medication knowledge they typically must learn on their own. Student performance on post-tests improved (p = 0.0011) compared to pre-tests with an effect size r of 0.39 (0.37, 0.32, and 0.42 for P1, P2 and P3 respectively). Students reported the content was easy to follow, and they enjoyed learning from other students. The total number of plays for the podcast as of 19 July 2023 were 882. Each episode had a range of one to 89 number of plays. The podcast was well received by students, and drug knowledge increased. While the podcasts were shorter in time, they still provided the foundational information for a first-year pharmacy student to know. Overall, podcasts provide another way to help students retain and reinforce material learned inside and outside the classroom.

Mazumder R., Ichudaule, Ghosh A., Deb S., Ghosh R.

Chalcone is a simple naturally occurring α,β-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.