A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants.

AIDS (Acquired immunodeficiency syndrome) is one of the chronic and potentially life-threatening epidemics across the world. Hitherto, the non-existence of definitive drugs that could completely cure the Human immunodeficiency virus (HIV) implies an urgent necessity for the discovery of novel anti-HIV agents. Since integration is the most crucial stage in retroviral replication, hindering it can inhibit overall viral transmission. The 5 FDA-approved integrase inhibitors were computationally investigated, especially owing to the rising multiple mutations against their susceptibility. This comparative study will open new possibilities to guide the rational design of novel lead compounds for antiretroviral therapies (ARTs), more specifically the structure-based design of novel Integrase strand transfer inhibitors (INSTIs) that may possess a better resistance profile than present drugs. Further, we have discussed potent anti-HIV natural compounds and their interactions as an alternative approach, recommending the urgent need to tap into the rich vein of indigenous knowledge for reverse pharmacology. Moreover, herein, we discuss existing evidence that might change in the near future.

Evaluation of safety, pharmacokinetics, and pharmacodynamics of apixaban in pediatric subjects at risk of venous or arterial thrombotic disorder.

Apixaban is an oral small-molecule, direct factor Xa (FXa) inhibitor approved in adults for treatment of deep vein thrombosis and pulmonary embolism, and for reducing risk of venous thromboembolism recurrence after initial anticoagulant therapy. This phase I study (NCT01707394) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of apixaban in pediatric subjects (<18 years), enrolled by age group, at risk of venous or arterial thrombotic disorder. A single apixaban dose, targeting adult steady-state exposure with apixaban 2.5 mg, was administered using two pediatric formulations: 0.1 mg sprinkle capsule (age <28 days); 0.4 mg/ml solution (age 28 days to <18 years; dose range, 1.08-2.19 mg/m2 ). End points included safety, PKs, and anti-FXa activity. For PKs/PDs, four to six blood samples were collected ≤26 h postdosing. A population PK model was developed with data from adults and pediatric subjects. Apparent oral clearance (CL/F) included fixed maturation function based on published data. From January 2013 to June 2019, 49 pediatric subjects received apixaban. Most adverse events were mild/moderate, and the most common was pyrexia (n = 4/15). Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in subjects aged 12 to <18 years. Maturation affected CL/F most notably in subjects aged <9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations, with no apparent age-related differences. Pediatric subjects tolerated single apixaban doses well. Study data and population PK model supported phase II/III pediatric trial dose selection.

Comparison of two antifibrotic treatments for lung fibrosis in post-COVID-19 syndrome: A randomized, prospective study.

BACKGROUND: Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment with nintedanib and pirfenidone in patients with COVID-19-related fibrosis. METHODS: Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks. RESULTS: After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting. CONCLUSION: In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.

[Pharmacotherapy: New drugs and vaccines in 2022]. / Pharmacothérapie - Nouveaux médicaments et vaccins disponibles en 2022.

A selection of drugs and vaccines newly available in Switzerland is reviewed. Shingrix: recombinant shingles vaccine recommended for all patients ≥65 years and some immunosuppressed patients. Nirmaltrevir/ritonavir: oral treatment of SARS-CoV-2 with a high potential of drug-drug interactions. Tixagevimab/cilgavimab: antibody combination for pre-exposure prophylaxis of SARS-CoV-2 in subjects without vaccine response or contraindication to vaccine. Cabotegravir/rilpivirine: 1st long-acting injectable treatment for HIV. Imvanex: monkeypox vaccine for subjects most at risk. Tezepelumab: first-in-class treatment for severe asthma. Eptinezumab: another anti-CGRP antibody for the prevention of migraine. Ponesimod: multiple sclerosis treatment with the advantage of a shorter half-life than fingolimod or ozanimod.

Une sélection de nouveaux médicaments et vaccins disponibles en Suisse est passée en revue. Shingrix : vaccin recombinant du zona recommandé chez les ≥ 65 ans et certains immunosupprimés. Nirmaltrevir/ritonavir : traitement oral du SARS-CoV-2 à haut potentiel d'interactions. Tixagévimab/cilgavimab : anticorps pour la prophylaxie préexposition du SARS-CoV-2 chez des sujets sans réponse vaccinale ou avec contre-indication au vaccin. Cabotégravir/rilpivirine : premier injectable à longue durée d'action contre le VIH. Imvanex : vaccin contre la variole du singe destiné aux sujets les plus à risque. Tézépélumab : premier traitement de sa classe pour l'asthme grave. Eptinézumab : un anticorps anti-CGRP de plus pour la prévention des migraines. Ponésimod : pour traiter la sclérose en plaques, avec l'avantage d'une plus courte demi-vie que le fingolimod ou l'ozanimod.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Brief Report: Impact of COVID-19 on Cabotegravir Plus Rilpivirine Long-Acting Dosing Across 6 Ongoing Global Phase IIb and III Clinical Trials.

BACKGROUND: Cabotegravir + rilpivirine long-acting (LA) is a novel antiretroviral therapy (ART) administered intramuscularly monthly or every 2 months by a health care provider. The COVID-19 pandemic presents a potential challenge to patients' ability to attend scheduled clinic visits for dosing administration. SETTING: This analysis evaluated implementation fidelity across 6 phase IIb/III/IIIb cabotegravir + rilpivirine LA clinical trials in 16 countries during the COVID-19 pandemic. METHODS: COVID-19-impacted visits were defined as modified dosing visits for which oral therapy was provided to participants unable to attend the clinic or injection visits that were rescheduled. Data from December 1, 2019, to March 1, 2021, were aggregated and analyzed using descriptive statistics. RESULTS: Of 2127 participants in cabotegravir + rilpivirine LA trials, 1997 (94%) had LA dosing visits proceed as planned during the COVID-19 pandemic. Of 130 (6%) participants with injection visits affected by COVID-19, most were from North America (57%) and Europe (26%). Most participants with COVID-19-impacted visits used oral therapy with cabotegravir + rilpivirine (75%) or alternative oral standard-of-care ART (21%) to maintain continuous ART. The most common reasons for missed visits were clinic closure/staffing constraints (48%) and COVID-19-related travel restrictions (23%). Most (98%) participants who used oral ART maintained virologic suppression; 2 participants had viral load between 50 and 100 copies/mL. CONCLUSION: During the COVID-19 pandemic, most trial participants maintained their LA dosing schedules. Flexibility of the LA dosing regimen, with the ability to switch to oral therapy, facilitated continuous ART provision and implementation fidelity.

A Computational Insight on the Inhibitory Potential of 8-Hydroxydihydrosanguinarine (8-HDS), a Pyridone Containing Analog of Sanguinarine, against SARS CoV2.

The unprecedented global pandemic of COVID-19 has created a daunting scenario urging an immediate generation of therapeutic strategy. Interventions to curb the spread of viral infection primarily include setting targets against the virus. Here in this study we target S protein to obstruct the viral attachment and entry and also the M pro to prevent the viral replication. For this purpose, the interaction of S protein and M pro with phytocompounds, sanguinarine and eugenol, and their derivatives were studied using computational tools. Docking studies gave evidence that 8-hydroxydihydrosanguinarine (8-HDS), a derivative of sanguinarine, showed maximum binding affinity with both the targets. The binding energies of the ligand with S protein and M pro scored to be ΔGb -9.4 Kcal/mol and ΔGb -10.3 Kcal/mol, respectively. MD simulation studies depict that the phytocompound could effectively cause structural perturbations in the targets which would affect their functions. 8-Hydroxydihydrosanguinarine distorts the α-helix in the secondary structure of M pro and RBD site of S protein. Protein-protein interaction study in presence of 8-hydroxydihydrosanguinarine also corroborate the above findings which indicate that this polyphenol interferes in the coupling of S protein and ACE2. The alterations in protonation of M pro suggest that the protein structure undergoes significant structural changes at neutral pH. ADME property of 8-hydroxydihydrosanguinarine indicates this could be a potential drug. This makes the phyto-alkaloid a possible therapeutic molecule for anti COVID-19 drug design.

Dolutegravir Plus Lamivudine Dual-Drug Regimen in Treatment-Naive HIV-1-Infected Patients With High-Level Viral Load: Preliminary Data From the Real World.

BACKGROUND: Some inpatients with HIV-RNA ≥500,000 copies/mL in China need to use 2-drug regimen for some reasons, although limited data are available for dolutegravir plus lamivudine (3TC) in those patients with ultra-high viral loads. METHODS: We conducted a single-center retrospective-prospective study in China and enrolled 42 ART-naive HIV-infected inpatients who use a once-daily 2-drug regimen because of various reasons (drug interaction, renal impairment, age, and other related comorbidities).They were divided into 2 groups, low viral load group (baseline viral load <500,000 copies/mL, n = 20) and high viral load group (baseline viral load ≥500,000 copies/mL, n = 22). All patients were followed up for 48 weeks. RESULTS: The median of baseline viral load was 5.74 log10 copies/mL and CD4+ T-cell count was 59 cells/µL. At week 48, there was no significant difference (P = 0.598) in proportions of participants with HIV-1 RNA <50 copies/mL [90%, 95% confidence interval (CI) (75.6% to 104.4%) in low viral load groups vs 95.5%, 95% CI (86.0% to 104.9%) in high viral load groups]. No differences were found in mean increase of CD4+ T-cell count from baseline between 2 groups (218 ± 122 vs 265 ± 127 cells/µL, P = 0.245). There is no grade 3 or higher treatment-related adverse events and none discontinued treatment because of adverse events. CONCLUSIONS: The results of our study in real world support dolutegravir + 3TC dual regimen as a promising therapy option for treatment-naive HIV-infected patient with baseline viral load ≥500,000 copies/mL.

Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2.

Pirfenidone (PFD) is a non-peptide synthetic chemical that inhibits the production of transforming growth factor-beta 1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), Interleukin 1 beta (IL-1ß), and collagen 1 (COL1A1), all of which have been linked to the prevention or removal of excessive scar tissue deposition in many organs. PFD has been demonstrated to decrease apoptosis, downregulate angiotensin-converting enzyme (ACE) receptor expression, reduce inflammation through many routes, and alleviate oxidative stress in pneumocytes and other cells while protecting them from COVID-19 invasion and cytokine storm. Based on the mechanism of action of PFD and the known pathophysiology of COVID-19, it was recommended to treat COVID-19 patients. The use of PFD as a treatment for a range of disorders is currently being studied, with an emphasis on outcomes related to reduced inflammation and fibrogenesis. As a result, rather than exploring the molecule's chemical characteristics, this review focuses on innovative PFD efficacy data. Briefly, herein we tried to investigate, discuss, and illustrate the possible mechanisms of actions for PFD to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2 candidate.

Perspectives of people living with HIV-1 on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings: results from the CUSTOMIZE hybrid III implementation-effectiveness study.

INTRODUCTION: The CUSTOMIZE hybrid III implementation-effectiveness study evaluated implementation of once-monthly long-acting (LA) cabotegravir + rilpivirine in diverse US healthcare settings. Here, we report patient participant perspectives after 12 months in CUSTOMIZE. METHODS: CUSTOMIZE was a phase IIIb, 12-month study conducted from July 2019 to October 2020 at eight diverse US HIV clinics that enrolled virologically suppressed people living with HIV-1 (PLHIV) on a stable oral regimen to receive monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. Participants were administered quantitative surveys before injections at months 1 (baseline), 4 and 12. A randomly selected subset of participants was interviewed at baseline and month 12. Data collection at month 12 was completed by October 2020 (during the COVID-19 pandemic). RESULTS: At baseline, 109 and 34 participants completed surveys and interviews, respectively; 87% were male; 35% were Black or African American. All participants who remained in the study at month 12 (n = 102) maintained HIV-1 RNA <50 copies/ml; two participants withdrew due to injection-related reasons. Mean total scores measuring acceptability and appropriateness of cabotegravir + rilpivirine LA were high at baseline (4.5-4.6 out of 5) and month 12 (4.7-4.9). At month 12, 74% of participants reported nothing interfered with receiving LA injections; injection pain or soreness was the most common concern (15%). Time spent in the clinic and coming to the clinic for monthly injections was very or extremely acceptable after 12 months for most participants (93% and 87%, respectively), with 64% reporting having spent ≤30 minutes in the clinic for injection visits. At month 12, 92% of participants preferred LA injections to daily oral tablets (3%); 97% plan to continue LA treatment going forward. In month 12 interviews, 24 (77%) of 31 participants reported the COVID-19 pandemic did not impact their ability to receive treatment. CONCLUSIONS: Once-monthly cabotegravir + rilpivirine LA was highly acceptable among PLHIV who were virologically suppressed on a stable antiretroviral regimen and interested in trying LA therapy, with few participants reporting challenges receiving LA injections. Implementation data from CUSTOMIZE suggest that monthly LA injections provide a convenient and appealing treatment option for PLHIV.

Determinants of Survival of HIV Patients Receiving Dolutegravir: A Prospective Cohort Study in Conflict-Affected Bunia, Democratic Republic of Congo.

This study aims to determine the factors influencing HIV-related mortality in settings experiencing continuous armed conflict atrocities. In such settings, people living with HIV (PLHIV), and the partners of those affected may encounter specific difficulties regarding adherence to antiretroviral therapy (ART), and retention in HIV prevention, treatment, and care programs. Between July 2019 and July 2021, we conducted an observational prospective cohort study of 468 PLHIV patients treated with Dolutegravir at all the ART facilities in Bunia. The probability of death being the primary outcome, as a function of time of inclusion in the cohort, was determined using Kaplan-Meier plots. We used the log-rank test to compare survival curves and Cox proportional hazard modeling to determine mortality predictors from the baseline to 31 July 2021 (endpoint). The total number of person-months (p-m) was 3435, with a death rate of 6.70 per 1000 p-m. Compared with the 35-year-old reference group, older patients had a higher mortality risk. ART-naïve participants at the time of enrollment had a higher mortality risk than those already using ART. Patients with a high baseline viral load (≥1000 copies/mL) had a higher mortality risk compared with the reference group (adjusted hazard ratio = 6.04; 95% CI: 1.78-20.43). One-fourth of deaths in the cohort were direct victims of armed conflict, with an estimated excess death of 35.6%. Improving baseline viral load monitoring, starting ART early in individuals with high baseline viral loads, the proper tailoring of ART regimens and optimizing long-term ART, and care to manage non-AIDS-related chronic complications are recommended actions to reduce mortality. Not least, fostering women's inclusion, justice, peace, and security in conflict zones is critical in preventing premature deaths in the general population as well as among PLHIV.

Perspectives of healthcare providers on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings from a Hybrid III Implementation-effectiveness study (CUSTOMIZE).

INTRODUCTION: CUSTOMIZE evaluated the implementation of long-acting (LA) cabotegravir + rilpivirine, a novel healthcare provider-administered injectable antiretroviral therapy regimen, in diverse US healthcare settings. Findings from staff-study participants (SSPs) through 12 months of implementation are reported. METHODS: CUSTOMIZE was a phase IIIb, 12-month, single-arm, hybrid III implementation-effectiveness study conducted from July 2019 to October 2020 at eight US clinics of five clinic types: private practice (n = 2), federally qualified health centre (n = 2), university (n = 2), AIDS Healthcare Foundation (n = 2) and health maintenance organization (n = 1). Eligible patient participants received monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. At baseline, month 4 and month 12, SSPs (n = 3 each per clinic), including physicians, nurses or injectors, and administrators, completed quantitative surveys and semi-structured interviews to assess implementation outcomes (acceptability, appropriateness and feasibility of intervention measures), programme sustainability and SSP perceptions of, attitudes towards, and expectations for cabotegravir + rilpivirine LA. Month 12 data collection occurred during the COVID-19 pandemic. RESULTS: In surveys, SSPs reported high mean total scores for acceptability, appropriateness and feasibility of cabotegravir + rilpivirine LA implementation at baseline (4.43, 4.52 and 4.38 of 5, respectively) and month 12 (4.45, 4.61 and 4.46 of 5, respectively), regardless of clinic type. At month 12, SSPs were positive about the implementation sustainability (mean Program Sustainability Assessment Tool score, 5.83 out of 7). At baseline, SSPs' top concern was patients' ability to maintain monthly appointments (81%); at month 12, 39% had this concern. The proportion of SSPs reporting patient injection pain or soreness as a barrier was consistent at month 12 versus baseline (48% vs. 46%). Most (78%) SSPs reported optimal implementation of cabotegravir + rilpivirine LA in their clinics was achieved in 1-3 months. In interviews, SSP-reported strategies for successful implementation included teamwork, using a web-based treatment planner and having a designated person to track appointment scheduling. In month 12 interviews, SSP-reported structural changes needed for implementation included changing clinic hours and purchasing refrigerators. CONCLUSIONS: In CUSTOMIZE, cabotegravir + rilpivirine LA was successfully implemented across a range of US healthcare settings. Barriers were mitigated with minor process adjustments.

Nintedanib vs pirfenidone in the management of COVID-19 lung fibrosis: A single-centre study.

BACKGROUND: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS). METHODS: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 ⩽ 96% and CTSS ⩾ 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS. RESULTS: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 µg/mL (normal <0.5 µg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01. CONCLUSION: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

Impact of apixaban treatment discontinuation on the risk of hospitalization among patients with nonvalvular atrial fibrillation and COVID-19.

INTRODUCTION: This study evaluated the risk of hospitalization among nonvalvular atrial fibrillation (NVAF) patients with an outpatient COVID-19 diagnosis who discontinued vs continued apixaban treatment. METHODS: Adult patients with NVAF with an apixaban prescription prior to an outpatient COVID-19 diagnosis were identified from Optum Clinformatics claims database (1 April 2020-31 March 2021). Continuers were those who continued apixaban as of the index date (date of initial outpatient COVID-19 diagnosis) and discontinuers were those who had the last day of apixaban supply on or before index. Patients were followed from COVID-19 diagnosis to change of continuation/discontinuation status, switch, death, end of continuous coverage or study end, whichever occurred first. Inverse probability treatment weighting (IPTW) was performed to balance cohorts. Cox proportional hazard models were used to compare the risk of all-cause hospitalization and hospitalization for ischemic stroke (IS), venous thromboembolism (VTE), myocardial infarction (MI), bleeding and mortality. RESULTS: A total of 7869 apixaban patients with COVID-19 were included: 6676 continuers (84.8%) and 1193 discontinuers (15.2%). Compared with continuers, discontinuers had a higher risk of all-cause hospitalization (hazard ratio [HR]: 1.23; 95% confidence interval [CI]: 1.08-1.40), IS (HR: 2.00; 95% CI: 1.03-3.87), VTE (HR: 2.37; 95% CI: 1.06-5.27) and mortality (HR: 2.28; 95% CI: 1.85-2.80). There were no significant differences in the risk of MI (HR: 1.01; 95% CI: 0.54-1.90) or bleeding-related hospitalization (HR: 1.13; 95% CI: 0.73-1.76). CONCLUSION: NVAF patients with COVID-19 who discontinued apixaban had a higher risk of hospitalization and thrombotic events vs those who continued apixaban, with no significant difference in bleeding-related hospitalization.

Emerging Roles of the Iron Chelators in Inflammation.

Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern.

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology.

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a "magic bullet" drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.

Coexistence of SARS-CoV-2 and cerebrovascular diseases: does COVID-19 positivity trigger cerebrovascular pathologies?

The objectives of this study were to determine the prevalence of cerebrovascular diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and to assess the pharmacological agents used in such cases as reported in the literature. Patient files were retrospectively scanned to determine the prevalence of neurological symptoms of the central nervous system (headache, dizziness, lack of smell and taste, numbness in arms and legs, change in consciousness, muscle weakness, loss of urine and stool control) and cerebrovascular diseases (ischemic cerebrovascular diseases, cerebral venous sinus thrombosis, intracerebral hemorrhage, subarachnoid/subdural hemorrhage) in 2019 novel coronavirus (2019-nCoV) disease (COVID-19) cases (n = 20,099). The diagnostic laboratory, radiology examinations and treatments applied to these cases were recorded. The data from studies presenting cerebrovascular diseases associated with SARS-Cov-2, which constituted 0.035% of all cases, were systematically evaluated from electronic databases. During the treatment of cerebrovascular diseases, it was discovered that high doses of enoxaparin sodium anti-Xa are combined with apixaban or acetylsalicylic acid or clopidogrel or piracetam, and mannitol, in addition to SARS-CoV-2 treatment modalities. While neurological symptoms of the central nervous system are uncommon in cases of SARS-CoV-2 infection, cerebrovascular diseases are far less common, according to the findings of this study. Acute cerebral ischemia was discovered to be the most common cerebrovascular disease associated with SARS-CoV-2. The mortality rate increases with the association between SARS-CoV-2 and cerebrovascular disease.