Pharmacology Research & Perspectives

ObjectiveThe primary objective of this study was to explore fentanyl and fentanyl derivative distribution patterns from 2010 and 2019 across the United States (US). This study builds upon previous literature that has analyzed the trends in opioid distribution and assesses changes in opioid prescription preferences. MethodsThe amount of fentanyl base distributed in the US from 2010-2019 was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS). Fentanyl derivatives (sufentanil, alfentanil, remifentanil) were also analyzed using ARCOS from 2010-2017, the most recent date reported. Census data from the American Community Survey was used to correct for population. Prescriptions, units, and reimbursement of fentanyl and fentanyl citrate formulations for 2010 and 2019 were obtained from Medicaid and prescriber specialty in Medicare Part D. ResultsTotal grams of fentanyl distributed in the US from 2010 to 2019 decreased by 63%. Correspondingly, there was a 65% decrease in the milligrams per person distributed when correcting for population. From a regional perspective, Ohio had the greatest decrease (-79.3%) while Mississippi saw the smallest (-44.5%). Medicaid reimbursement in 2019 was $165 million for over eight hundred-thousand prescriptions with the majority to generic (99.7%) and injectable (77.6%) formulations. Interventional pain management and anesthesia were over-represented, and hematology/oncology under-represented for fentanyl in Medicare. ConclusionThe production and distribution of fentanyl-based substances has decreased, although not uniformly, in the US over the last decade. Additionally, the most prescribed formulations of fentanyl have transitioned away from transdermal, potentially in an effort to regulate its availability. Although impactful, the overdose deaths attributed to synthetic opioid deaths continue to increase highlighting the need for public health interventions beyond the pharmaceutical and medical communities.

PurposeThe purpose of our study was to investigate dronabinol prescribing in Medicare from 2014 to 2019 by provider specialty and state. MethodsData was collected and analyzed from the Centers for Medicare & Medicaid Services databases from 2014 to 2019. The mean number of prescriptions for each area of practice, each individual year, and for 2014 to 2019 overall for the 50 United States and District of Columbia was determined. The prescriptions were separated by state and the state totals were determined. Individual states with dronabinol prescriptions [&ge;]1.96 standard deviations (SD) from the mean were identified as significant. ResultsThe total number of dronabinol prescriptions decreased 9.1% from 2014 to 2019. Dronabinol prescriptions were more concentrated in the eastern United States in 2019 than compared to 2014 [Tennessee (107.2), Kentucky (94.2), and West Virginia (87.6) (>1.96 SD)]. The largest portion of dronabinol prescriptions originated from primary care (1,736) compared to specialty areas of practice (1,233). Internal medicine (789.5), family medicine (608.8), hematology-oncology (343.3), nurse practitioners (337.3), and infectious disease (271.0) had the highest average number of dronabinol prescriptions per year (p<0.05). The areas of practice with the highest ratio of percent dronabinol prescriptions to percent Medicare utilization were infectious disease (15.8), hematology-oncology (12.2), and medical oncology (12.1). ConclusionDronabinol usage declined among Medicare patients and became more concentrated in the eastern United States. Most prescriptions originated from primary care, although after accounting for Medicare patient utilization, the highest ratios originated from infectious disease, hematology-oncology, and medical oncology.

ObjectiveTo evaluate the changing pattern of the distribution of Schedule II and III opioids, stimulants, and barbiturates by advanced practice providers (APP; i.e., physician assistants and nurse practitioners) in the United States (US). DesignRetrospective study. SampleAdvanced practice providers from every US state (and DC) that directly dispense Schedule II/III drugs to patients. ProceduresControlled substances distributed by APP was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Orders System (DEAs ARCOS) for opioids (e.g., hydrocodone, fentanyl, buprenorphine), barbiturates (pentobarbital, butalbital), and stimulants (amphetamine, methylphenidate, lisdexamfetamine) from 2006-2023. Opioids were converted to their morphine milligram equivalents (MME), stimulants converted to daily doses, and barbiturates to kilograms. Opioid use by state in three selected years (2013, 2020, 2023) was further analyzed. ResultsThe total weight of controlled substances as distributed exhibited both overall and drug-specific changes since 2006. Buprenorphine accounted for only a modest amount (0.6%) in 2013 but the preponderance (94.6%) of opioids distributed by MME in 2023 nationally. Examination of the opioid MME per state and corrected for population revealed the states with the highest reported use for 2013 (Nevada), 2020 (North Dakota), and 2023 (Maine). There has been an overall modest decline in stimulant (-97.9%) and barbiturate (-64.1%) since 2010. Conclusions and Clinical RelevanceThe use of Schedule II/III drugs as distributed to APP has fluctuated yet overall increased in the past decades. Opioids by total MME have had rather small changes throughout the years, except for buprenorphine. APP direct distribution has transitioned from treating pain to Opioid Use Disorder. Future research should discover the causes underlying the yearly and state level disparities for opioid, stimulant, and barbiturate use.

BackgroundOpioid overdoses in the US have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018-2021 as well as Medicare in 2019. MethodsThe Medicaid State Drug Utilization Data File was utilized to extract information on number of prescriptions and amount prescribed of naloxone at a national and state level. States with naloxone prescription rates differing from the mean by [&ge;] 1.96 standard deviations were considered statistically significant. The Medicare Provider Utilization and Payment was also utilized to analyze prescription data from 2019. ResultsThe number of generic naloxone prescriptions per 100,000 Medicaid enrollees decreased 5.15% whereas brand naloxone prescriptions increased 245.00% from 2018-2021. There was a 33.14-fold difference in prescriptions between the highest (New Mexico = 1809.55) and lowest (South Dakota = 54.61) states in 2019. Medicare saw a 30.32-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100,000 enrollees. ConclusionsThis pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018-2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19.

BackgroundOpioid-related overdoses are a major concern in the United States (US) stemming from the high rates of Opioid Use Disorder (OUD). The rates of US overdoses continue to exceed one-hundred thousand per year. Methadone, a medication used as a treatment for OUD, is effective in reducing cravings and withdrawal symptoms which improves the quality of life for OUD. This study analyzed the distribution of methadone to Opioid Treatment Programs (OTP) across the US including the District of Columbia and Puerto Rico. MethodsThe weight of methadone (in grams) was gathered from the Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS) database and population data from the US Census Bureau. The number of OTPs per state from the ARCOS Database was obtained. GraphPad Prism Version10.2.3 was used to make figures and perform data analysis. A paired t-test compared distribution in 2019 to 2023. Datawrapper was used to create heat maps. ResultsAnalyzing the population-adjusted percent change by state from 2019 to 2023 showed 32 states had a positive percent change (61.5%), 19 states had a negative one (36.5%), and one state had no change (1.9%). The percent change between 2019 and 2023 (+6.2%) was statistically significant (p=0.047). When looking at the number of OTPs (population-adjusted), there was a twenty-fold state-level difference in 2023. DiscussionAlthough there was a modest increase overall, there were pronounced state-level differences in methadone distribution across the nation. An emphasis on establishing policies to make a positive change widespread over the nation is crucial. New policies are urgently needed to increase the availability of OUD treatments more widely by initiating more OTPs and a more treatment retention focused program to reverse the escalation in overdose deaths.

ObjectiveTo compare the 2017 National Academies of Sciences, Engineering, and Medicine (NAS) report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 to 2024 and to determine if there exist gaps in evidence-based decision making. MethodsThe 2017 NAS report assessed therapeutic evidence for over twenty medical conditions treated with MC. We identified the QCs of 38 states (including Washington, D.C.) where MC was legal in 2024. We also identified the QCs that these states used in 2017. QCs were then categorized based on NAS-established level of evidence: substantial/conclusive evidence of effectiveness, moderate evidence of effectiveness, limited evidence of effectiveness, limited evidence of ineffectiveness, and no/insufficient evidence to support or refute effectiveness. This study was completed between January 31, 2023 through May 20, 2024. ResultsMost states listed at least one QC with substantial evidence--80.0% of states in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states QC lists met the standard of substantial evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (chronic pain) was categorized by the NAS as having substantial evidence for effectiveness. However, seven (ALS, Alzheimers disease, epilepsy, glaucoma, Huntingtons disease, Parkinsons disease, spastic spinal cord damage) were rated as either ineffective or insufficient evidence. ConclusionMost QCs lack evidence for use based on the 2017 NAS report. Many states recommend QCs with little evidence, such as amyotrophic lateral sclerosis (ALS), or even those for which MC is ineffective, like depression. There have been insufficient updates to QCs since the NAS report. These findings highlight a disparity between state-level MC recommendations and the evidence to support them.

BackgroundHealth care inequity includes the lack of adequate representation of various populations in clinical trials. Government, academic and industry organizations have highlighted these issues and committed to actions to improve. In order to assess the current status and future success of these initiatives a quantitative objective measure to assess the state of clinical trial diversity is needed. MethodsFDA review documents for all novel drug approvals from January 2022 through February 16, 2023 were assessed using a scorecard that considers diversity across different demographic subgroups including age (>65 yo), sex (female), race (Black and Asian) and ethnicity (Hispanic/Latino). The scorecard assigns each drug a letter grade, between A and F, for each subgroup (and overall) based on 1) the percent of each sub-population included in the trials and grades relative to the percent of the US population, 2) the number of participants from each subpopulation that received the novel new drug in the trials, 3) the incidence or prevalence of the disease/condition in each of the sub-populations. ResultsThe FDA approved 43 novel new drugs for 44 indications (one drug was simultaneously approved for two indications). The three drugs with A Grades reflecting the best diversity in their registration trials were tapinarof (Vtama from Dermavant), daprodustat (Jesduvroq from GlaxoSmithKline) and eflapegrastim (Rolvedon from Spectrum Pharmaceuticals.) There was good representation of elderly and females with only two drugs receiving a D grade in either of these sub-populations. In contrast, Black and Hispanic representation was often inadequate with 4 drugs receiving F grades. There were 9 drugs (20%) where there were no Black participants receiving the novel new drug and an additional 14 approvals where there were <10 Black participants receiving the novel drug. The median number of Black participants receiving the investigational drug was 9. In the Hispanic/Latino population there were 2 approvals with no Hispanic participants receiving the novel drug and 14 approvals where there were < 10 Hispanic participants receiving the drug. The median number of Hispanic participants receiving the novel drug was 12.5. ConclusionsThis newly developed scorecard provides an objective quantitative approach to assess the current state of diversity in clinical trials supporting new drug approvals. Substantial improvement in racial and ethnic representation is needed. Meaningful change will require actions and cooperation amongst all stakeholders to address this multifaceted issue and will take commitment, perseverance, and appropriate incentives.

PurposeWe investigated if the use of peripheral nerve blockade (PNB) was associated with a lower incidence of prescription opioid fill within 30 days post-surgery and persistent postoperative opioid use (PPOU) in patients undergoing foot and ankle surgery. MethodsWe identified adults who had undergone foot or ankle surgery between 2012 and 2018 and did or did not receive PNB in an Optums de-identified Integrated Claims-Clinical dataset (n=12,643). Pharmacy data was used to track opioid prescription fill date and supply. PPOU was defined as >90 days of continuous opioid use. Entropy balancing was used to control differences in the distribution of covariates. Log-binomial models in unweighted and weighted data estimated crude and adjusted relative risk (RR) with 95% confidence intervals (CI) for the outcomes. ResultsOne-third of the sample filled an opioid within 30 days of surgery, and among these patients, 57.3% continued use for > 90 days. Performance of PNB was associated with an increased risk for filling opioid prescriptions within 30 days post-surgery before (RR=1.40; 95%CI:1.32-1.49) and after (RR=1.31; 95%CI:1.22-1.41; p<0.0001) controlling for confounding. However, the group that received a PNB showed significantly lower risk of PPOU before (0.91; 95%CI:0.85-0.98; p=0.016) and after controlling for confounding (RR=0.92; 95%CI:0.85-0.99; p=0.029). ConclusionPerformance of PNB for patients undergoing foot and ankle surgery was associated with a 31% increased risk of any opioid prescription fill within 30 days after surgery. However, among the patients that initially filled their prescriptions, patients that received PNB had a significantly (8%) lower risk for PPOU.

Due to the uncertainty of the health effects medical marijuana poses, states differ in their medical marijuana laws (MML). Long-term effects of marijuana are found to be like attention-deficit-hyperactive disorder (ADHD). With amphetamines being prescribed to treat ADHD symptoms we hypothesized that amphetamine prescriptions would increase in states implementing MML. The number of amphetamine prescriptions filled quarterly for each state from 2006 to 2021 were calculated. States with MML and dispensaries opened before 2020 were examined and states with no MML laws were the control. Prism was utilized to visualize the data and conduct four t-tests between the pre and post of MML+ versus MML-states. Three MML+ states were excluded due to limited post-MML data. Among the remaining states, 31 were MML+ and 17 were MML-. No significant differences were found in amphetamine prescribing (p > 0.30). Medical marijuana legalization did not have a statistically significant impact on amphetamine prescribing in Medicaid patients during the analyzed period. Contrary to the hypothesis, the results revealed a non-significant decrease in prescriptions in MML+ states. Further research with recreational cannabis laws or with electronic health records is warranted.

In this paper, we investigate what conditions need to be in place to make progress in combating a disease using a case-control design: we compare cases (diseases with a successful therapy) to controls (diseases without a successful therapy). We find five conditions ("hurdles") must typically be cleared for success: (A) understanding of biological drivers, (B) ability to modulate biology, (C) availability of translational models, (D1) ability to identify patients, and (D2) ability to measure clinical response. This framework is similar to ones deployed to evaluate individual drug candidates but is employed here to make inferences about entire diseases. It can be used to identify diseases most ready for progress, where efforts should be focused to make progress in diseases that are currently intractable, and where the industry could benefit from development of tools to address the hurdle that is most commonly the last to be cleared across diseases--namely, (C) translational models.

BackgroundZ-drugs are nonbenzodiazepine hypnotics used for sleep initiation and maintenance that have been shown to increase the risk of fall-related injuries in patients aged 65 and older. The American Geriatrics Society Beers criteria classifies them as a high-risk medication and strongly recommends avoiding prescribing z-drugs to the elderly due to adverse effects. The objective of this study was to determine the prevalence of Z-drug prescribing among Medicare patients. MethodsZ-drug prescription data was extracted from the Centers for Medicare and Medicaid Services State Drug Utilization Data (CMS SDUD) for 2018. For all 50 states, the number of prescriptions per 100 Medicare enrollees and days-supply per prescription was determined. The percentage of total prescriptions prescribed by each specialty and the average number of prescriptions prescribed by providers within each specialty was also determined. ResultsZolpidem was the most prescribed z-drug, making up 95.0% of all z-drug prescriptions. Prescriptions per 100 enrollees were significantly elevated in Utah (28.2) and Arkansas (26.7) and significantly lower in Hawaii (9.3) relative to the national average (17.5). The specialties family medicine (32.1%), internal medicine (31.4%), and psychiatry (11.7%) made up the largest percentages of total prescriptions. The number of prescriptions per provider was significantly elevated for psychiatry relative to other specialties. ConclusionsContrary to the Beers criteria, z-drugs are being prescribed to Medicare enrollees over age 65 at high rates. While sleep disturbances in the elderly should not be ignored, alternative therapies must be considered to avoid the serious adverse effects of z-drugs. Key PointsMore than one-half million Medicare patients received z-drug prescriptions in 2018 that were inconsistent with the Beers criteria. Z-drug prescriptions per 100,000 Medicare patients were significantly elevated in Utah and Arkansas. Family Medicine had the highest number of prescriptions out of all medical specialties. Psychiatry had a significantly higher number of prescriptions per provider compared to all other specialties.

Approximately 77,000 children 16 years or less suffered burn injuries in the United States in 2018. Treatment, reconstruction, and rehabilitation are painful experiences. For some, the experience triggers post-traumatic stress disorder (PTSD) and/or a chronic pain syndrome. Given the role pain plays as a major secondary disease, it must be addressed to achieve optimal healing. Regional anesthesia has been used extensively to manage postoperative pain and reduce the need for opioids following other surgical procedures in children. Nevertheless, regional anesthesia has not yet been widely used in pediatric burn care. We present a demonstration project utilizing regional anesthesia in 15 pediatric burn patients over an eight-month period. Our results indicate that the use of regional anesthesia reliably reduces perioperative pain and opioid requirements in the immediate peri-operative period. In this cohort, 93% of patients scored a 0/10 on a FLACC scale for pain by post-anesthesia care unit (PACU) discharge, with an average PACU stay of 70 minutes. Thirty-three percent of patients received no opioids, and the average opioid dose was only 0.06mg/kg morphine equivalents. We conclude that regional anesthesia can be used to improve patient comfort and decrease opioid requirement.

ObjectivesCharacterize oxycodones distribution in the US by state and its adverse effect profile from 2000-2021. DesignObservational SettingMore than 80,000 Americans died of an opioid overdose in 2021 as the United States (US) continues to struggle with an opioid crisis. Prescription opioids play a substantial role, introducing patients to opioids and providing a supply of drugs that can be redirected to those seeking to misuse them. MethodsThe Drug Enforcement Administration annual summary reports from the Automation of Reports and Consolidated Orders System (ARCOS) provided weights of oxycodone distributed per state by business type (pharmacies, hospitals, and practitioners). Weights were converted to Morphine Milligram Equivalents (MME) per capita and normalized for population. ResultsThere was a sharp 280.13% increase in total MME/person of oxycodone from 2000-2010, followed by a slower 54.34% decrease from 2010-2021. Florida (2007-11), Delaware (2003-20), and Tennessee (2012-21) displayed consistent and substantial elevations in combined MME/person compared to other states. In the peak year (2010), there was a 15-fold difference between the highest and lowest states. MME/person from only pharmacies, which constituted >94% of the total, showed similar results. Hospitals in Alaska (2000-01, 2008, 2010-21), Colorado (2008-21), and DC (2000-11) distributed substantially more MME/person over many years compared to other states. Florida stood out in practitioner-distributed oxycodone, with an elevation of almost 15-fold the average state from 2006-2010. The percentage of consumer reports in the FDA Adverse Drugs Events Reporting System (FAERS) increased from 6.3% (2001) to 95% (2021). Adverse effects distribution remained constant by age and sex, with higher average proportions in males (55%) and the 18-65 age group (79%). ConclusionsOxycodone distribution across the US showed marked differences between states and business types over time. Investigation of opioid policies in states of interest may provide insight for future actions to mitigate opioid misuse. Strengths and limitations of this studyO_LIARCOS is publicly accessible, comprehensive, and includes institutions that are unavailable in other commonly used databases (i.e. IQVIA). C_LIO_LIDiversion of oxycodone or whether the prescribed amounts were utilized cannot be determined from ARCOS data. C_LIO_LIFAERS data includes duplicates, incomplete results, and non-verifiable data which cannot be used to suggest causation between oxycodone and adverse events. C_LIO_LIThese complementary results from two databases may not generalize to other countries with more restrictive oxycodone policies. C_LI

BackgroundSome payors and clinicians require alcohol abstinence for direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection. ObjectiveTo evaluate whether alcohol use at DAA treatment initiation was associated with decreased odds of sustained virologic response (SVR). DesignObservational cohort study using electronic health records. SettingUS Department of Veterans Affairs (VA), the largest integrated national healthcare system that provides unrestricted access to HCV treatment. PatientsAll patients born between 1945 and 1965 who were dispensed DAA therapy between 1 January 2014 and 30 June 2018. MeasurementsWe used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SVR associated with alcohol category. SVR was defined as undetectable HCV RNA [&ge;]12 weeks after completion of DAA therapy. Alcohol category was determined using information on alcohol use disorder diagnoses and Alcohol Use Disorders Identification Test - C (AUDIT-C) at DAA initiation. ResultsAmong 69,229 patients who initiated DAA therapy (mean age 63 years; 97% men; 50% non-Hispanic White; 41% non-Hispanic Black; 85% HCV genotype 1), 65,355 (94.4%) of patients achieved SVR. After multivariable adjustment, we found no difference in SVR across alcohol use categories (lowest OR 0.92, 95% CI 0.82-1.04). There was no evidence of interaction by stage of hepatic fibrosis measured by FIB-4 (p-interaction=0.3001). LimitationsPredominately male population. ConclusionAlcohol use was not associated with lower odds of SVR, suggesting that DAA therapy should not be withheld due to alcohol use. Restricting access to DAA therapy based on alcohol use creates an unnecessary barrier to patients and challenges HCV elimination goals. Funding sourceNational Institute on Alcohol Abuse and Alcoholism

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION. MethodsSixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessed ex vivo and in vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval. ResultsBoth NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9{+/-}21.7%) than celecoxib (35.7{+/-}25.2%; p<0.05). Similarly, naproxen treatment inhibited PGI2 formation in vivo (48.0{+/-}24.9%) to a greater degree than celecoxib (26.7{+/-}24.6%; p<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95% CI: 0.8, 2.8); p<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p<0.05). ConclusionsCelecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent. ClinicalTrials.gov identifier: NCT02502006 (https://clinicaltrials.gov/study/NCT02502006) Clinical PerspectiveO_LINaproxen 250 mg twice a day inhibited COX-2 activity to a greater degree than celecoxib 100 mg twice a day. C_LIO_LIThe degree of COX-2 inhibition was associated with the increase in systolic blood pressure with NSAID treatment relative to placebo. C_LIO_LIDose and its pharmacological potency achieved in vivo should be considered when evaluating the relative cardiovascular safety of COX-2-selective vs. non-selective NSAIDs. C_LI

BackgroundCompounded versions of tirzepatide are widely available in the U.S. in the form of fixed-dose combinations of tirzepatide and various analogs of vitamin B12. These combinations are mass marketed in the U.S. and other countries as comparable to FDA-approved tirzepatide products even though they undergo no evaluation of their potency or impurity profiles. Research Design and MethodsSamples of compounded tirzepatide combined with B12 obtained from various sources in the U.S. market were tested using various analytical methods. Samples were assessed for unacceptable levels of peptide-related impurities. ResultsOur testing identified a widespread and previously unidentified impurity in compounded tirzepatide-B12 products resulting from a chemical reaction between tirzepatide and certain analogs of B12. ConclusionDespite the presence of this impurity, these products continue to be mass marketed as "personalized" treatments. Our findings underscore the importance of testing and FDA approval before new drugs are marketed and highlights potential risks for patients associated with untested combinations. A novel impurity, present at substantial levels in compounded tirzepatide/B12 products, highlights risks inherent in marketing complex therapies outside the drug-approval framework. Although clinical effects of this impurity are unknown, the identification of a widespread impurity adds to the existing quality concerns presented by compounded tirzepatide.

Ovarian cancer currently ranks as the fourth most common cancer. This cancer is metastatic in nature and making it more challenging to manage. Prostate cancer is the one of the major causes of disease and death among men. Approximately 1.6 million men are diagnosed with prostate cancer. Rucaparib, a poly-ADP ribose polymerase inhibitor has been approved by United States Food and Drug Administration for management of ovarian cancer and prostate cancer. Rucaparib was approved by US Food and Drug Administration in the year 2016 for the treatment of ovarian cancer and 2020 for the treatment of prostate cancer. To assess the potential association between rucaparib and the identified signals, a disproportionality analysis of spontaneous reports is being conducted. Reports were taken from FAERS data base and retrospective case/non case study was conducted. Reporting Odds ratio (ROR), Relative Reporting Ratio (RRR), Chi Squared Value ({chi}2) and Proportional Reporting Ratio (PRR) and Drug Event (DE) were used to perform disproportionality analysis. 144 signals were considered as positive adverse drug reactions using the criteria {chi}2 >4, PRR >2, ROR >2 and DE [&ge;] 3. Through disproportionality analysis of the FAERS data, signal was identified between the signals-increased prostate specific antigen, decreased serum magnesium levels, decreased glomerular filtration rates, blood iron decreased and vitamin d decreased and rucaparib. The current investigation indicated that rucaparib may increase the incidence of the identified signals.

There are currently relatively few small-molecule antiviral drugs that are either approved or emergency approved for use against SARS-CoV-2. One of these is remdesivir, which was originally repurposed from its use against Ebola and functions by causing early RNA chain termination. We used this as justification to evaluate three molecules we had previously identified computationally with antiviral activity against Ebola and Marburg. Out of these we previously identified pyronaridine, which inhibited the SARS-CoV-2 replication in A549-ACE2 cells. Herein, the in vivo efficacy of pyronaridine has now been assessed in a K18-hACE transgenic mouse model of COVID-19. Pyronaridine treatment demonstrated a statistically significant reduction of viral load in the lungs of SARS CoV-2 infected mice. Furthermore, the pyronaridine treated group reduced lung pathology, which was also associated with significant reduction in the levels of pro-inflammatory cytokines/chemokine and cell infiltration. Notably, pyronaridine inhibited the viral PLpro activity in vitro (IC50 of 1.8 {micro}M) without any effect on Mpro, indicating a possible molecular mechanism involved in its ability to inhibit SARS-CoV-2 replication. Interestingly, pyronaridine also selectively inhibits the host kinase CAMK1 (IC50 of 2.4 {micro}M). We have also generated several pyronaridine analogs to assist in understanding the structure activity relationship for PLpro inhibition. Our results indicate that pyronaridine is a potential therapeutic candidate for COVID-19. One sentence summaryThere is currently intense interest in discovering small molecules with direct antiviral activity against the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Pyronaridine, an antiviral drug with in vitro activity against Ebola, Marburg and SARS-CoV-2 has now statistically significantly reduced the viral load in mice along with IL-6, TNF-, and IFN-{beta} ultimately demonstrating a protective effect against lung damage by infection to provide a new potential treatment for testing clinically.

The simple two-state conformational selection model of G-protein coupled receptor (GPCR) activation suggests that, by binding to a high affinity site, an agonist will shift receptor equilibrium in favor of active state (R*) conformations that recruit heterotrimeric G proteins over inactive state (R) conformations. Agonist binding to the -opioid receptor is highly sensitive to Na+ ions which stabilize an inactive receptor state. Higher efficacy opioid agonists, such as DAMGO and fentanyl, are sensitive to Na+ compared to lower efficacy ligands at the -opioid receptor. However, the binding of the highly potent oripavine agonists etorphine and dihydroetorphine are less sensitive to Na+ than expected such that the prevailing models fail to explain their pharmacology. To explain this discrepancy, experiments were performed to evaluate the binding properties and G protein activation of the highly potent agonists carfentanil, BU72, etorphine, etonitazene and similarly potent opioid peptidomimetics in comparison to the standard agonists DAMGO, fentanyl, and morphine in the presence or absence of Na+ or K+ ions. Several of the superagonists retained high affinity and potency in both ionic conditions, whereas DAMGO, fentanyl and morphine displayed enhanced binding and signaling in K+, compared to Na+ ions. These functional parameters were used to determine an intrinsic efficacy value, determined as [Formula]. Comparison of affinity shifts with intrinsic efficacy afforded a negative correlation in which superagonists with the highest intrinsic efficacy are least sensitive to Na+. These data suggest that select -opioid receptor superagonists have high affinity for the Na+ bound receptor states (R) and shift these species into active receptor conformations (R*) that efficiently couple to G proteins. Significance StatementThe simple theory of conformational selection suggests the binding affinities of high efficacy -opioid receptor ligands, such as fentanyl and DAMGO, are more sensitive to Na+ and guanine nucleotide which stabilize inactive receptor states than lower efficacy agonists and antagonists. Here, we show that ligands with high intrinsic efficacy (superagonists) are much less sensitive to Na+ and guanine nucleotide. This work demonstrates that highly potent ligands can engage a low affinity Na+-bound receptor state that may then convert to a receptor species that efficiently couples to G protein - i.e. a conformational induction.