Association of genetic polymorphisms in glucocorticoid pathway with dexamethasone treatment in COVID-19 patients

Background/Objectives: Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19 caused by SARS-CoV- 2 as they attenuate the immune response with their antiinflammatory properties. Genetic polymorphisms of glucocorticoid receptor, metabolizing enzymes or transporters may affect treatment response to dexamethasone. The aim of this study was to evaluate the association of polymorphisms in glucocorticoid pathway with disease severity and duration of dexamethasone treatment in COVID-19 patients. Method(s): Our study included 107 hospitalized COVID-19 patients treated with dexamethasone. We isolated DNA from peripheral blood and genotyped all samples for polymorphisms in NR3C1 (rs6198, rs33388), CYP3A4 (rs35599367), CYP3A5 (rs776746), GSTP1 (rs1695, rs1138272), GSTM1/GSTT1 deletions and ABCB1 (1045642, rs1128503, rs2032582 Fisher's and Mann- Whitney tests were used in statistical analysis. Result(s): The median (min-max) age of the included patients was 62 (26-85) years, 69.2 % were male and 30.8 % female and they had moderate (1.9 %), severe (83 %) or critical (15.1 %) disease. NR3C1 rs6198 polymorphism was associated with more severe disease in additive genetic model (P = 0.022). NR3C1 rs6198, ABCB1 rs1045642 and ABCB1 rs1128503 polymorphisms were associated with a shorter duration of dexamethasone treatment in additive (P = 0.048, P = 0.047 and P = 0.024, respectively) and dominant genetic models (P = 0.015, P = 0.048 and P = 0.020, respectively), while carriers of the polymorphic CYP3A4 rs35599367 allele required longer treatment with dexamethasone (P = 0.033). Other polymorphisms were not associated with disease severity or dexamethasone treatment duration. Conclusion(s): Genetic variability of glucocorticoid pathway genes was associated with the duration of dexamethasone treatment of COVID-19 patients.

No Dose Adjustments for Cyp3a4 Substrates When Coadministered with Bemnifosbuvir

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug in development for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor [competitive and time-dependent inhibition (TDI)] and inducer of CYP3A4, prompting evaluation of the clinical relevance of these results in a Ph 1 drug-drug interaction (DDI) study in healthy participants using midazolam (MDZ), a sensitive CYP3A4 substrate as an index drug. Method(s): Two groups of 12 healthy participants were enrolled and received a single dose of 2mg MDZ alone on Day 1. Between Days 3 and 7 inclusive, all participants received oral BEM 550mg twice daily (BID). On day 3 and day 7, Group A received a single dose of 2mg MDZ simultaneously with BEM;Group B on these two days received 2mg MDZ 2h after BEM. Serial plasma samples were obtained and measured for MDZ and 1-OH-MDZ levels. Result(s): A single dose (simultaneous or staggered) of BEM slightly increased the plasma exposure of MDZ (14%-26%). Staggered BEM had less impact (8%-17%) on 1-OH-MDZ than simultaneous dosing (22%-31%). Inhibitory effect of BEM was more pronounced with repeat dosing, consistent with in vitro data showing TDI on CYP3A4. After repeat dosing, simultaneously administered BEM increased plasma MDZ exposure by 83%-98%, without affecting the exposure of 1-OH-MDZ. With repeat dosing, staggered BEM showed less effect on both MDZ and 1-OH-MDZ. There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): BEM is a weak inhibitor (ratio between 1.25 and 2) of CYP3A4. No dose adjustment is needed for drugs that are substrates of CYP3A4 when co-administered with BEM.

The Concept of Repurposing in COVID-19 Infection

The strategy of drug repurposing has been proved successful in response to the current corona-virus pandemic, with remdesivir becoming the first drug of choice, an antiviral drug approved for the treatment of COVID-19. In parallel to this, several drugs, such as antimalarial, corticosteroids, and antibi-otics, like azithromycin, are used to treat the severe condition of hospitalized COVID-19 patients, while clinical testing of additional therapeutic drugs, including vaccines, is going on. It is reasonably expected that this review article will deliver optimized and specific curative tools that will increase the attentive-ness of health systems to the probable outlook of epidemics in the future. This review focuses on the ap-plication of repurposed drugs by studying their structure, pharmacokinetic study, different mechanisms of action, and Covid-19 guidelines, which can potentially influence SARS-CoV-2. For most of the drugs, direct clinical evidence regarding their effectiveness in the treatment of COVID-19 is missing. Future clinical trial studies may conclude that one of these can be more potential to inhibit the progression of COVID-19.Copyright © 2022 Bentham Science Publishers.

Using Real World Evidence (Rwe) to Assess Drug-Drug Interaction (Ddi) between Paxlovid and the Top 100 Prescribed Drugs in the Us

BACKGROUND: Paxlovid (nirmatrelvir/ritonavir) has received a US Emergency Use Authorization for patients >=12 years with mild-to- moderate COVID-19 at high-risk of progression to severe disease. DDI studies conducted with Paxlovid implicate the PK enhancer ritonavir as the main perpetrator of DDIs. Ritonavir is a potent inhibitor of CYP3A4, CYP2D6, and P-gp. The Paxlovid Fact Sheet1 identifies contraindicated drugs and those with a potentially important interaction. METHOD(S): A retrospective analysis was conducted using RWE from the Optum Clinformatics Data Mart. Patients were identified based on CDC criteria for high-risk COVID-19 and confirmed continuous insurance enrollment from Jan 1 to Dec 31, 2019 with >=1 prescription claim. Excluding non-drug claims (e.g., vaccines), the top 100 drugs were selected and ranked based on total patient counts. DDI potential with Paxlovid was evaluated using US Prescribing and DailyMed Information or relevant literature for each drug. RESULT(S): Of the top 100, 70 drugs are not expected to have a DDI with Paxlovid. These drugs are eliminated unchanged in urine, cleared by enzymes other than CYP3A4 or CYP2D6, are not P-gp substrates, or are cleared by multiple pathways. The remaining 30 drugs expected to have a DDI are represented in the Paxlovid Fact Sheet. The top four drug classes expected to interact with Paxlovid include corticosteroids, narcotic analgesics, anticoagulants, and statins. One drug, simvastatin, is contraindicated. The mechanism of interaction with Paxlovid, or lack thereof, will be presented in detail for each drug. CONCLUSION(S): Paxlovid DDI management is important to ensure the right patients receive this antiviral. This analysis provides an understanding of Paxlovid interactions with the top 100 drugs likely to be used in high-risk COVID-19 patients and serves as an additional DDI management resource.

Alternative Management of Cushing's Syndrome During Covid-19 Pandemic

Cushing's syndrome results from prolonged exposure to glucocorticoids. Surgery is often the first-line treatment for this condition, regardless of etiology. However, the COVID-19 pandemic caused a decrease in surgical procedures due to the risk of infection transmission. There are still emergency cases of Cushing's syndrome that are admitted to the hospital and require urgent management. The current treatment should be focused on medical management and endovascular embolization in selective cases. Embolization can be performed in facilities where there aretrained personnel with experience in adrenal embolization. Surgery, which traditionally is a first-line therapy, can increase the risk of infection, therefore, it should be avoided. The current review provides a brief description of the possible options for the management of adrenal Cushing's syndrome during the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

Paxlovid ( Nirmatrelvir/Ritonavir ) and Cyclosporin in a Kidney Transplant Patient with Covid-19 Infection

Introduction: COVID-19 infection causes high morbidity,mortality and burden to the healthcare system.Solid organ transplant patients with COVID-19 have been reported to have between 13-30% rate of mortality.Over the past 2 years,treatment of COVID-19 has evolved with new drugs being introduce such as Molnupiravir which reported to reduce death and hospitalization up to 50%.Recently a new novel drug Paxlovid (Nirmatrelvir/Ritonavir) develop by Pfizer has shed much hope in terms of managing COVID-19 patient especially in those with solid organ transplant.However,there is not much data in using Paxlovid for kidney transplant with COVID-19.Paxlovid is known to have drug-drug interaction with medication that is highly dependent on CYP3A4 which is a member of Cytochrome P450 enzyme for clearance.It is advice to withhold certain calcineurin inhibitor drugs if on Paxlovid.However,there was no mention on withholding cyclosporin which is one of the drugs in in kidney transplant patient.We've reported the first case in literature of a kidney transplant patient on cyclosporin diagnose with COVID 19 on Paxlovid. Method(s): Our patient is a End Stage Renal Disease on regular hemodialysis for a year.He subsequently had a living related renal transplant.He was vaccinated and boosted with SARS-CoV-2 Vaccine from Pfizer BioNTech.Baseline creatinine level was 126 umol/L.Immunosuppressants are Cyclosporin 50mg BD,Prednisolone 7.5mg OD and Azathioprine 50mg OD.Baseline cyclosporin trough level was 113ng/ml.He was well until SARS-CoV-2 Rapid Test Kit was positive on day four of illness.Serum Creatinine level was 137 umol/L.His estimated Glomerular Filtration Rate was 53 ml/min/1.73m2.Chest Radiograph shows ground glass opacity on both lower zone.Patient was treated for COVID-19 Pneumonia Category 3A.In view eGFR was 53 ml/min/1.73m2,Paxlovid was started at adjusted dose (Nirmatrelvir 150mg/Ritonavir 100mg BD).Patient had four doses of Paxlovid before we were able to send cyclosporin level on day three of his admission due to logistic problem.Cyclosporin trough level was 737 ng/ml and we withheld his cyclosporin.Paxlovid was continued and there was improvement in terms of his symptoms.Serial chest radiographs showed improvement as in Figure 1.We were able to monitor his cyclosporin trough level and serum creatinine on daily basis as shown in Figure 2 and Figure 3 respectively.He completed five days of Paxlovid.On day seven of admission,cyclosporin was restarted back at 25mg BD. [Formula presented] [Formula presented] [Formula presented] Results: He was discharged well with cyclosporin dose being adjusted back to his old dose.We followed him up as outpatient and monitor his cyclosporin level which was stable and continued on his old immunosuppressant regime. Conclusion(s): This case highlights the potential treatment with Paxlovid in patients with kidney transplant on cyclosporin diagnosed to have COVID-19 infection.Drug-drug interaction between cyclosporin and Paxlovid needs to be taken into account.Moving forward in the endemic era,there will be increase usage of Paxlovid that can help to reduce severity,hospital admission and mortality in solid organ transplant with COVID-19 infection.Close monitoring of cyclosporin level,proper mitigation strategy,adjustment of immunosuppressants and safe prescription of Paxlovid will be beneficial for kidney transplant patient infected with COVID-19.This can help in reducing morbidity and mortality in our kidney transplant patients. No conflict of interestCopyright © 2023

The Effect of Carriage of CYP3A5*3 and CYP3A4*22 Polymorphic Variants on the Safety of Remdesivir Therapy in Patients with COVID-19.

The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods. The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results. Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion. An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.Copyright © Team of Authors, 2022.

The Effect of Carriage of CYP3A5*3 and CYP3A4*22 Polymorphic Variants on the Safety of Remdesivir Therapy in Patients with COVID-19

The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods. The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results. Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion. An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.

Phenytoin to Expedite Sirolimus & Tacrolimus Elimination: A Case Report

Purpose: Sirolimus (SIR), a mammalian target of rapamycin inhibitor (mTORi), may be used with or without a calcineurin inhibitor after heart transplant (HT). The antiproliferative properties & 72-hour half-life (T1/2) that make SIR desirable to provide uniform drug exposure & attenuate cardiac allograft vasculopathy add complications when surgical needs or toxicities arise.1,2 SIR-related wound healing impairment necessitates cessation before invasive procedures, yet managing long-acting SIR in these settings is complex due a large volume of distribution & vulnerability to interactions with CYP3A4 inhibitors, prolonging T1/2.2 Phenytoin (PHY), a potent inducer of CYP3A4, has been used to speed tacrolimus (FK) clearance.3 Interaction between PHY & SIR is reported.4 Strategic use of PHY to clear SIR is not described. Method(s): Case review leveraging PHY-inducing effects to expedite SIR & FK elimination while awaiting urgent thoracotomy for mucormycosis. Result(s): The patient developed invasive pulmonary mucormycosis 3 years post-HT. Supratherapeutic levels on admission were SIR 20 ng/mL & FK 15 ng/mL with mycophenolate 500 mg twice daily & prednisone 5 mg twice daily. Treatment was initiated with CYP3A4-inhibiting isavuconazonium sulfate (ISU) & amphotericin B irrigation. Infected lung segment resection was delayed for wound healing risks of SIR. To hasten SIR elimination via CYP3A4 induction, fosPHY load then PHY 100 mg orally thrice daily was initiated on day 5. To maintain infection treatment while inducing metabolism, ISU was converted to systemic amphotericin B. Figure 1 describes SIR, FK, ISU & PHY courses. The calculated T1/2 was shorted from 440 hours on ISU days 3-5 to 32 hours days 7-10 (allowing time for induction). On day 14 thoracotomy & left upper lobectomy were successfully performed with FK & SIR unquantifiable. Conclusion(s): This case illustrates effective induction SIR & FK metabolism using PHY. In the era of CYP 3A4-inhibiting nirmatrelvir-ritonavir availability for COVID-19, strategies to address inadvertent calcineurin inhibitor or mTORi toxicity are paramount. Employing this approach when needing to clear drugs quickly may be beneficial.

A CASE OF COVID-19-ASSOCIATED PULMONARY ASPERGILLOSIS

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: COVID-19 patients requiring admission to an ICU have a higher risk of invasive pulmonary aspergillosis (IPA) with a reported incidence of 19.6%-33.3%. CASE PRESENTATION: A 63-year-old male presented with progressively worsening dyspnea for one week. He has a past medical history of atrial fibrillation, hypertension, and obesity. He was tested positive for COVID about two weeks prior. He did receive a single dose of Moderna vaccine. Initial chest x-ray(CXR) showed diffuse ground-glass opacities. He was initiated on Remdesivir and decadron, and later received a dose of tocilizumab. He was intubated on hospital day 3 for worsened hypoxemia. Repeat CXR suggested some improvement but a new left lower lobe airspace haziness. He also had new-onset leukocytosis with elevated procalcitonin level. He was started on cefepime for concern of superimposed hospital-acquired pneumonia. A second dose of tocilizumab was administered. No clinical improvement was seen, and additional workups were obtained. Serial CXRs revealed increasing diffuse airspace opacities concerning for ARDS. Tracheal aspirate culture grew coagulase-negative staphylococcus and Aspergillosis Fumigatus. Cefepime was changed to vancomycin, and voriconazole and caspofungin were added. Unfortunately, the patient's respiratory status worsened with increasing ventilation requirement. He also developed septic shock and acute renal failure requiring CVVH. He became even more hypotensive after CVVH initiation, and multiple vasopressors were required to maintain his hemodynamics. Unfortunately, he continued to deteriorate and he also developed profound respiratory acidosis. He died shortly afterwards after family decided to withdraw care. DISCUSSION: In this case, in addition to superimposed bacterial pneumonia, pulmonary aspergillosis likely also contributed to his clinical deterioration. The mechanism by which fungal infections develop in COVID-19 infection is not well-understood. Severe COVID-related immune dysregulation, ARDS, and high-dose steroids use are potential culprits for the increased risk of IPA. Tocilizumab, an IL-6 receptor monoclonal antibody used in patients with severe COVID-19 infection, may also predispose the patient to IPA according to post-marketing data. The mortality rate from current case reports is as high as 64.7%. Diagnosis and treatment in such a scenario remain a challenge. Sputum culture, serum Beta-galactomannan, Beta-D glucan, and aspergillosis PCR have low sensitivity. Tissue biopsy and CT scan in critically ill patients are often not feasible. Voriconazole is usually considered the first-line treatment in IPA. CYP3A4-mediated drug interactions between azoles and antiviral agents require further investigation. CONCLUSIONS: Clinicians should be aware that severe COVID-19 patients are at higher risk of IPA. The prognosis is poor. Early detection and treatment in clinically deteriorated patients are warranted. Reference #1: Borman, A.M., Palmer, M.D., Fraser, M., Patterson, Z., Mann, C., Oliver, D., Linton, C.J., Gough, M., Brown, P., Dzietczyk, A. and Hedley, M., 2020. COVID-19-associated invasive aspergillosis: data from the UK National Mycology Reference Laboratory. Journal of clinical microbiology, 59(1), pp.e02136-20. Reference #2: Lai CC, Yu WL. COVID-19 associated with pulmonary aspergillosis: A literature review. J Microbiol Immunol Infect. 2021;54(1):46-53. doi:10.1016/j.jmii.2020.09.004 Reference #3: Thompson Iii GR, Cornely OA, Pappas PG, et al. Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa242. Published 2020 Jun 19. doi:10.1093/ofid/ofaa242 DISCLOSURES: No relevant relationships by Jason Chang No relevant relationships by Jason Chang No relevant relationships by kaiqing Lin No relevant relationships by Guangchen Zou

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme.

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

Hydroxychloroquine is metabolized by CYP2D6, CYP3A4 and CYP2C8, and inhibits CYP2D6, while its metabolites also inhibit CYP3A4 in vitro

Introduction: Hydroxychloroquine is used for the treatment of malaria, rheumatoid arthritis and lupus erythematosus. In 2020, hydroxychloroquine was also repurposed for the treatment of COVID-19. Although current evidence does not encourage the use of hydroxychloroquine to treat COVID-19, its therapeutic and prophylactic use against COVID-19 is still investigated in clinical trials. Despite being in clinical use for more than 60 years, its clinical pharmacology is not well understood. Hydroxychloroquine is metabolized into three active metabolites, but the key metabolizing enzymes have not been unambiguously identified. Moreover, little is known about the inhibitory effects of hydroxychloroquine on cytochrome P450 (CYP) enzymes. Objectives: This study aimed to investigate the CYP metabolic and inhibitory profile of hydroxychloroquine and its three metabolites in vitro. Methods: Hydroxychloroquine metabolism was studied in human liver microsomes (HLM) and recombinant CYP enzymes using substrate depletion and CYP-selective inhibitors. The inhibitory effects of hydroxychloroquine and its metabolites on nine CYP enzymes were also determined in HLM, using automated probe substrate cocktail assays. Results: Based on screening experiments, CYP3A4, CYP2D6 and CYP2C8 were the key enzymes involved in hydroxychloroquine metabolism in vitro. Although the intrinsic clearance (CLint) value of hydroxychloroquine depletion by recombinant CYP2D6 (0.87 μl/min/pmol) was more than 10-fold higher than that by CYP3A4 (0.075 μl/min/pmol), scaling of the recombinant data to HLM level resulted in similar CLint values for CYP2D6 and CYP3A4 (11 and 14 μl/min/mg) because of the much greater abundancy of CYP3A4 than that of CYP2D6. The scaled HLM CLint of CYP2C8 was 5.7 μl/min/mg. Data in HLM with CYPselective inhibitors also suggested relatively equal roles for CYP2D6 and CYP3A4 in hydroxychloroquine metabolism, and a smaller contribution for CYP2C8. In CYP inhibition experiments, hydroxychloroquine and its three metabolites were direct CYP2D6 inhibitors (50% inhibitory concentration IC50 18-135 μM), while all metabolites were CYP3A timedependent inhibitors (IC50 12-117 μM, IC50 shift 2.2-3.4-fold). CYP2D6 inhibition explains the reported clinical drug-drug interaction between hydroxychloroquine and the CYP2D6 substrate metoprolol. The present data, together with the inhibitors' estimated intracellular hepatocyte concentrations, were successfully used in a static model to predict the fold increase in metoprolol AUC (predicted: 2.3- 2.8-fold, observed: 1.65-fold). Conclusion: The present study unambiguously demonstrates that hydroxychloroquine is metabolized mainly by CYP2D6, CYP3A4 and CYP2C8 in vitro. Moreover, hydroxychloroquine and its three metabolites are CYP2D6 reversible inhibitors, and hydroxychloroquine metabolites are CYP3A time-dependent inhibitors. The current data can be used in static and physiologically-based pharmacokinetic models to predict hydroxychloroquine drug-drug interaction potential, as shown with the successful prediction of hydroxychloroquine - metoprolol drug-drug interaction. (Table Presented).

Opioid and neuroHIV Comorbidity - Current and Future Perspectives.

With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and µ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

Immunization and Drug Metabolizing Enzymes: Focus on Hepatic Cytochrome P450 3A.

OBJECTIVE: Infectious disease emergencies like the 2013-2016 Ebola epidemic and the 2009 influenza and current SARS-CoV-2 pandemics illustrate that vaccines are now given to diverse populations with preexisting pathologies requiring pharmacological management. Many natural biomolecules (steroid hormones, fatty acids, vitamins) and ~60% of prescribed medications are processed by hepatic cytochrome P450 (CYP) 3A4. The objective of this work was to determine the impact of infection and vaccines on drug metabolism. METHODS: The impact of an adenovirus-based vaccine expressing Ebola glycoprotein (AdEBO) and H1N1 and H3N2 influenza viruses on hepatic CYP 3A4 and associated nuclear receptors was evaluated in human hepatocytes (HC-04 cells) and in mice. RESULTS: CYP3A activity was suppressed by 55% in mice 24 h after administration of mouse-adapted H1N1, while ˂10% activity remained in HC-04 cells after infection with H1N1 and H3N2 due to global suppression of cellular translation capacity, indicated by reduction (70%, H1N1, 56%, H3N2) of phosphorylated eukaryotic translation initiation factor 4e (eIF4E). AdEBO suppressed CYP3A activity in vivo (44%) and in vitro (26%) 24 hours after infection. CONCLUSION: As the clinical evaluation of vaccines for SARS-CoV-2 and other global pathogens rise, studies to evaluate the impact of new vaccines and emerging pathogens on CYP3A4 and other metabolic enzymes are warranted to avoid therapeutic failures that could further compromise the public health during infectious disease emergencies.