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.

Pancreatitis Secondary to Paxlovid-Induced Tacrolimus Toxicity

Introduction: Pancreatitis is a very common gastrointestinal disease that results in hospital admission. Early detection and treatment leads to better outcomes. This is the first reported case of pancreatitis secondary to elevated tacrolimus in a patient with prior renal transplantation after receiving Paxlovid for a COVID-19 infection. Case Description/Methods: A 57-year-old male with past medical history of 4 renal transplants secondary to posterior urethral valves who presented to the emergency room with acute onset epigastric pain for 24 hours. He was on tacrolimus 5 mg every 48 hours monotherapy for his immunosuppression. 10 days prior to his presentation he had developed chills and anxiety. He tested positive for COVID-19 at that time on a home rapid test. His symptoms had not significantly improved and given his immunosuppressed state he was given Paxlovid (Nirmatrelvir/ritonavir). He took 2 days of Paxlovid, however after his second day of treatment he developed severe epigastric pain requiring him to go to the emergency room. On admission his labs were notable for a lipase of 150 U/L (ULN 63 U/L). He underwent a CT scan was notable for an enlarged pancreatic head and neck with peripancreatic fat stranding (Figure). He also had a right upper quadrant ultrasound without any cholelithiasis and only trace sludge noted. His creatinine was noted to be 1.81 mg/dl which was above his baseline of 1.2 mg/dl. His tacrolimus trough level resulted at a level 45.6 ng/ml and later peaked at 82.2 ng/ml. His liver enzymes were normal. He was treated as acute pancreatitis with hydration and his tacrolimus was held with overall clinical improvement. Discussion(s): Tacrolimus is one of the most common medications used in solid organ transplantation. It is a calcineurin inhibitor that inhibits both T-lymphocyte signal transduction and IL-2 transcription. It is metabolized by the protein CYP3A and levels are monitored closely. Paxlovid is currently prescribed as an antiviral therapy for COVID-19 infection. The ritonavir compound in Paxlovid is potent inhibitor of CYP3A. Currently the guidelines do not recommend Paxlvoid as a therapeutic in patients taking tacrolimus as there is concern about increased drug levels. There have been several case reports of pancreatitis in setting of tacrolimus. This case report helps to demonstrate the need for close monitoring of therapeutics levels, especially in medications with high risk of drug to drug interaction to help prevent serious side effects such as tacrolimus induced pancreatitis.

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.

Controversies around COVID-19 Vaccines and Antidepressants: Scope and Perspective in Malaysia.

BACKGROUND: Individuals with severe mental illness are prone to severe COVID-19 infection with increased morbidity and mortality. Psychiatric patients are often concerned about the potential interactions between the newly approved COVID-19 vaccines in Malaysia and psychotropic drugs like antidepressants. To date, such data are unavailable. OBJECTIVES: This review aims to clear the polemics of COVID-19 vaccine-antidepressants interaction in these 3 aspects: (1) cytokines and cytochrome P450 pathway, (2) blood-brain barrier (BBB) involvement and (3) and its interaction with polyethylene glycol (PEG), the potential allergenic culprit following COVID-19 vaccination. METHODS: A systemic scoping approach was employed to search for peer-reviewed journal articles across four healthcare and scientific databases (PubMed, MEDLINE, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL)). RESULTS: Antidepressants metabolism often involve the CYP450 enzymes. Vaccine-antidepressants interactions are probable, likely to be triggered by interactions of CYP450 enzymes and inflammatory cytokines, resulting in diminished drug metabolism and chemical detoxification. Aside, PEG, the excipient in mRNA-based COVID-19 vaccines and antidepressants, has been reported as the anaphylaxis causative allergen. However, whether it leads to a synergistic, potentiation or antagonistic effects when used in combination, remains to be elucidated. CONCLUSION: Psychotropic medications, including antidepressants, showed potentially relevant safety risk for COVID-19 patients. These vulnerable patient group must be prioritized for early access to safe and efficacious COVID-19 vaccines, as vaccination remains the most important public health intervention to tackle the ongoing COVID-19 pandemic.

Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml. Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL. DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.Copyright © 2023

Effect of polycyclic aromatic hydrocarbons on skin pigmentation

Despite COVID-19 lockdowns, gradual restarting of the global economy has rapidly increased air quality index (AQI) values. With over 99 % of the world population living in areas exceeding air quality guidelines, air pollution is more so a threat to our health. Within particulate matter, a major air pollutant, lies polycyclic aromatic hydrocarbons (PAH). While recent studies explore the link between air pollution and pigmentation disorders, the molecular mechanisms responsible for this alteration remain largely unknown. To challenge our hypothesis that exposure to PAH leads to an increase in abnormal pigmentation, we have utilized in vitro and in vivo assays. In vitro, novel 2D and 3D co-culture assays were developed to analyze pigment production, transfer and total melanin content in human keratinocytes and melanocytes. Following that, bulk RNA-sequencing was also carried out on isolated melanocytes post co-culture to possibly elucidate the mechanism behind this phenomenon. In vivo, a mouse model bearing epidermal melanin was generated to investigate the effect of PAH exposure. Notably, our initial studies have indicated a significant increase in melanin production, transfer and total melanin content when exposed to PAH. From our transcriptome analysis, we have also pinpointed to several genes which have been differentially expressed, most significant being CYP1A1. This prompted us to look further into the AhR signaling pathway. Interestingly, we did not see an increase in classic melanogenesis genes, but instead genes which are usually associated with senescence-associated secretory phenotype (SASP). This hints to a possible alternative pathway leading to an eventual increase in melanin production. We believe that our findings highlight potential approaches for novel therapeutics the treatment of skin pigmentation disorders triggered by air pollution.Copyright © 2023

Transcriptome in Human Mycoses

Mycoses are infectious diseases caused by fungi, which incidence has increased in recent decades due to the increasing number of immunocompromised patients and improved diagnostic tests. As eukaryotes, fungi share many similarities with human cells, making it difficult to design drugs without side effects. Commercially available drugs act on a limited number of targets and have been reported fungal resistance to commonly used antifungal drugs. Therefore, elucidating the pathogenesis of fungal infections, the fungal strategies to overcome the hostile environment of the host, and the action of antifungal drugs is essential for developing new therapeutic approaches and diagnostic tests. Large-scale transcriptional analyses using microarrays and RNA sequencing (RNA-seq), combined with improvements in molecular biology techniques, have improved the study of fungal pathogenicity. Such techniques have provided insights into the infective process by identifying molecular strategies used by the host and pathogen during the course of human mycoses. This chapter will explore the latest discoveries regarding the transcriptome of major human fungal pathogens. Further we will highlight genes essential for host–pathogen interactions, immune response, invasion, infection, antifungal drug response, and resistance. Finally, we will discuss their importance to the discovery of new molecular targets for antifungal drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

In Silico Analysis of Bioactive Compounds from Sea Urchin (Echinometra mathaei) against SARS-COV-2

SARS-CoV-2 is a kind of coronavirus that produces Covid-19 illness, which is still a public health concern in Indonesia. Meanwhile, an effective drug has not yet been found and although vaccination has been carried out, in several regions and neighboring countries there is still an increase in Covid-19 cases. This study aimed to obtain bioactive compounds from sea urchins (Echinometra mathaei) that have greater antiviral potential and lower toxicity than remdesivir. This research was started by predicting druglikeness with SwissADME, followed ADMET predicition with pkCSM online, and docking of molecule using the Molegro Virtual Docker (MVD) 5.5 software against the main protease (Mpro) target (PDB ID: 6W63). The results showed that six compounds from sea urchins (Echinometra mathaei) had antiviral activity, where the bioactive compound from sea urchins (Echinometra mathaei) with the highest affinity was shown by Spinochrome C a smaller rerank score compared with Remdesivir and native ligand (X77). So that Spinochrome C compounds are candidates as SARS-CoV-2 inhibitors potential developed drug.Copyright Published by Oriental Scientific Publishing Company © 2023.

Impact of Inflammation on Voriconazole Exposure in Critically ill Patients Affected by Probable COVID-19-Associated Pulmonary Aspergillosis.

(1) Background: To explore the impact of the degree of inflammation on voriconazole exposure in critically ill patients affected by COVID-associated pulmonary aspergillosis (CAPA); (2) Methods: Critically ill patients receiving TDM-guided voriconazole for the management of proven or probable CAPA between January 2021 and December 2022 were included. The concentration/dose ratio (C/D) was used as a surrogate marker of voriconazole total clearance. A receiving operating characteristic (ROC) curve analysis was performed by using C-reactive protein (CRP) or procalcitonin (PCT) values as the test variable and voriconazole C/D ratio > 0.375 (equivalent to a trough concentration [Cmin] value of 3 mg/L normalized to the maintenance dose of 8 mg/kg/day) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated; (3) Results: Overall, 50 patients were included. The median average voriconazole Cmin was 2.47 (1.75-3.33) mg/L. The median (IQR) voriconazole concentration/dose ratio (C/D) was 0.29 (0.14-0.46). A CRP value > 11.46 mg/dL was associated with the achievement of voriconazole Cmin > 3 mg/L, with an AUC of 0.667 (95% CI 0.593-0.735; p < 0.001). A PCT value > 0.3 ng/mL was associated with the attainment of voriconazole Cmin > 3 mg/L (AUC 0.651; 95% CI 0.572-0.725; p = 0.0015). (4) Conclusions: Our findings suggest that in critically ill patients with CAPA, CRP and PCT values above the identified thresholds may cause the downregulation of voriconazole metabolism and favor voriconazole overexposure, leading to potentially toxic concentrations.

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.

Drug Interactions of Psychiatric and COVID-19 Medications

Introduction:Coronavirus disease 2019 (COVID-19) has become a pandemic with 1771514 cases identified in the world and 70029 cases in Iran until April 12, 2020. The co-prescription of psychotropics with COVID-19 medication is not uncommon. Healthcare providers should be familiar with many Potential Drug-Drug Interactions (DDIs) between COVID-19 therapeutic agents and psychotropic drugs based on cytochrome P450 metabolism. This review comprehensively summarizes the current literature on DDIs between antiretroviral drugs and chloroquine/hydroxychloroquine, and psychotropics, including antidepressants, antipsychotics, mood stabilizers, and anxiolytics.Methods:Medical databases, including Google Scholar, PubMed, Web of Science, and Scopus were searched to identify studies in English with keywords related to psychiatric disorders, medications used in the treatment of psychiatric disorders and COVID-19 medications.Results:There is a great potential for DDIs between psychiatric and COVID-19 medications ranging from interactions that are not clinically apparent (minor) to those that produce life-threatening adverse drug reactions, or loss of treatment efficacy. The majority of interactions are pharmacokinetic interactions via the cytochrome P450 enzyme system.Conclusion:DDIs are a major concern in the comorbidity of psychiatric disorders and COVID-19 infection resulting in the alteration of expected therapeutic outcomes. The risk of toxicity or lack of efficacy may occur due to a higher or lower plasma concentration of medications. However, psychiatric medication can be safely used in combination with COVID-19 pharmacotherapy with either a wise selection of medication with the least possibility of interaction or careful patient monitoring and management.

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.

Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml . Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/ mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.

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.

Safety and efficacy of apremilast in adults hospitalized with COVID-19

Introduction: Apremilast, a nonbiologic oral phosphodiesterase 4 (PDE4) inhibitor, was evaluated as a treatment for the hyperinflammatory response in patients (pts) hospitalized with severe COVID-19. Aims and Objectives: To assess the safety and effectiveness of apremilast plus standard of care (SoC) in pts hospitalized with severe COVID-19. Method(s): COMMUNITY (EudraCT 2020-002594-10) was a phase 3, double-blind, randomized, multinational, platform trial in adult pts hospitalized with COVID-19. Pts received apremilast 30 mg BID (APR) or placebo (PBO) for 14 days or until hospital discharge, whichever occurred first. Supportive care (per study center practices) was allowed except for CYP3A inducers and concurrent PDE4 antagonists. Result(s): From November 24, 2020 to June 4, 2021, 384 pts were enrolled (APR+SoC: n=194;PBO+SoC: n=190);enrollment halted early due to futility. Mean age was 56.5 years;59% were men. Most pts had a COVID-19 clinical severity score of 4 (48%) or 3 (29%) (range: 1-8, 1=death). Median (95% CI) time to confirmed clinical recovery through Day 29 (primary endpoint) was 14 (11-15) days for both groups (P=0.8779). All-cause mortality incidence rates through Day 29 (key secondary endpoint) were 18% (APR+SoC) and 17% (PBO+SoC) (P=0.9665). Treatmentemergent adverse event (TEAE) rates were similar between APR+SoC (54%;n=189) and PBO+SoC (55%;n=187) groups. TEAEs Common Terminology Criteria AE grade >=3 occurred in 25% of APR+SoC pts and 30% of PBO+SoC pts. Serious TEAE rates were 27% (APR+SoC) and 30% (PBO+SoC). Conclusion(s): Although APR+SoC did not improve survival in pts hospitalized with severe COVID-19, APR was well tolerated with a safety profile consistent with the established safety profile.

Live to die another day: novel insights may explain the pathophysiology behind smoker's paradox in SARS-CoV-2 infection.

The severe acute respiratory coronavirus 2 (SARS-CoV-2) infection demonstrates a highly variable and unpredictable course. Several reports have claimed a smoker's paradox in coronavirus disease 2019 (COVID-19), in line with previous suggestions that smoking is associated with better survival after acute myocardial infarction and appears protective in preeclampsia. Several plausible physiological explanations exist accounting for the paradoxical observation of smoking engendering protection against SARS-CoV-2 infection. In this review, we delineate novel mechanisms whereby smoking habits and smokers' genetic polymorphism status affecting various nitric oxide (NO) pathways (endothelial NO synthase, cytochrome P450 (CYP450), erythropoietin receptor (EPOR); ß-common receptor (ßcR)), along with tobacco smoke modulation of microRNA-155 and aryl-hydrocarbon receptor (AHR) effects, may be important determinators of SARS-CoV-2 infection and COVID-19 course. While transient NO bioavailability increase and beneficial immunoregulatory modulations through the above-mentioned pathways using exogenous, endogenous, genetic and/or therapeutic modalities may have direct and specific, viricidal SARS-CoV-2 effects, employing tobacco smoke inhalation to achieve protection equals self-harm. Tobacco smoking remains the leading cause of death, illness, and impoverishment.

In vitro metabolic characterization of the SARS-CoV-2 papain-like protease inhibitors GRL0617 and HY-17542.

The SARS-CoV-2 pandemic requires a new therapeutic target for viral infection, and papain-like protease (Plpro) has been suggested as a druggable target. This in-vitro study was conducted to examine the drug metabolism of the GRL0617 and HY-17542, Plpro inhibitors. Metabolism of these inhibitors was studied to predict the pharmacokinetics in human liver microsomes. The hepatic cytochrome P450 (CYP) isoforms responsible for their metabolism were identified using recombinant enzymes. The drug-drug interaction potential mediated by cytochrome P450 inhibition was estimated. In human liver microsomes, the Plpro inhibitors had phase I and phase I + II metabolism with half-lives of 26.35 and 29.53 min, respectively. Hydroxylation (M1) and desaturation (-H2, M3) of the para-amino toluene side chain were the predominant reactions mediated with CYP3A4 and CYP3A5. CYP2D6 is responsible for the hydroxylation of the naphthalene side ring. GRL0617 inhibits major drug-metabolizing enzymes, including CYP2C9 and CYP3A4. HY-17542 is structural analog of GRL0617 and it is metabolized to GRL0617 through non-cytochrome P450 reactions in human liver microsomes without NADPH. Like GRL0617 and HY-17542 undergoes additional hepatic metabolism. The in-vitro hepatic metabolism of the Plpro inhibitors featured short half-lives; preclinical metabolism studies are needed to determine therapeutic doses for these inhibitors.

COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics.

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2nd, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12,000,000,000 vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amidst an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 (CYP) activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. Significance Statement Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver CYP metabolism of small molecules, enhanced innate immune system metabolism of complex molecules and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety and effectiveness and fetal neurodevelopment.