Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study.

OBJECTIVES: To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic. METHODS: This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves. RESULTS: A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials. CONCLUSIONS: The effective dissemination of evidence-based and concerted recommendations seems to have allowed an optimized management of COVID-19 drug therapies in the context of this emerging infection with rapidly evolving therapeutic questions.

Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3.

Previous use of a mechanistic static model to accurately quantify the increased rosuvastatin exposure due to drug-drug interaction (DDI) with coadministered atazanavir underpredicted the magnitude of area under the plasma concentration-time curve ratio (AUCR) based on inhibition of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1. To reconcile the disconnect between predicted and clinical AUCR, atazanavir and other protease inhibitors (darunavir, lopinavir and ritonavir) were evaluated as inhibitors of BCRP, OATP1B1, OATP1B3, sodium taurocholate cotransporting polypeptide (NTCP) and organic anion transporter (OAT) 3. None of the drugs inhibited OAT3, nor did darunavir and ritonavir inhibit OATP1B3 or NTCP. All drugs inhibited BCRP-mediated estrone 3-sulfate transport or OATP1B1-mediated estradiol 17ß-D-glucuronide transport with the same rank order of inhibitory potency (lopinavir>ritonavir>atazanavir>>darunavir) and mean IC50 values ranging from 15.5 ± 2.80 µM to 143 ± 14.7 µM or 0.220 ± 0.0655 µM to 9.53 ± 2.50 µM, respectively. Atazanavir and lopinavir also inhibited OATP1B3- or NTCP-mediated transport with a mean IC50 of 1.86 ± 0.500 µM or 65.6 ± 10.7 µM and 5.04 ± 0.0950 µM or 20.3 ± 2.13 µM, respectively. Following integration of a combined hepatic transport component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above for atazanavir, the newly predicted rosuvastatin AUCR reconciled with the clinically observed AUCR confirming additional minor involvement of OATP1B3 and NTCP inhibition in its DDI. The predictions for the other protease inhibitors confirmed inhibition of intestinal BCRP and hepatic OATP1B1 as the principal pathways involved in their clinical DDI with rosuvastatin.

Brief Report: Long-Term Clinical, Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in Botswana: A Nonrandomized Controlled Clinical Trial.

BACKGROUND: Early antiretroviral treatment (ART) improves outcomes in children, but few studies have comprehensively evaluated the impact of ART started from the first week of life. METHODS: Children diagnosed with HIV within 96 hours of life were enrolled into the Early Infant Treatment Study in Botswana and followed on ART for 96 weeks. Nevirapine, zidovudine, and lamivudine were initiated; nevirapine was switched to lopinavir/ritonavir between weeks 2-5 in accordance with gestational age. Clinical and laboratory evaluations occurred at weeks 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. FINDINGS: Forty children initiated ART at a median of 2 (IQR 2, 3) days of life; 38 (95%) completed follow-up through 96 weeks, and 2 (5%) died between 12 and 24 weeks. ART was well tolerated; 9 children (24%) experienced a grade 3 or 4 hematologic event, and 2 (5%) required treatment modification for anemia. The median 96-week CD4 count was 1625 (IQR 1179, 2493) cells/mm 3 with only 5/38 (13%) having absolute counts <1000 cells/mm 3 . Although 23 (61%) had at least one visit with HIV-1 RNA ≥40 copies/mL at or after 24 weeks, 28 (74%) had HIV-1 RNA <40 copies/mL at the 96-week visit. Median cell-associated HIV-1 DNA at 84/96-week PBMCs was 1.9 (IQR 1.0, 2.6) log 10 copies/10 6 cells. Pre-ART reservoir size at birth was predictive of the viral reservoir at 84/96 weeks. INTERPRETATION: Initiation of ART in the first week of life led to favorable clinical outcomes, preserved CD4 cell counts, and low viral reservoir through 96 weeks of life.

Virologic status and pattern of drug resistance mutation among ART-experienced HIV-infected patients in Butuo County, China.

OBJECTIVES: To assess the virological outcomes, prevalence of HIV drug resistance mutation (DRM), and correlates in Butuo County. METHODS: We conducted a cross-sectional study. Virological failure (VF) was defined as HIV-1 RNA ≥1000 copies/mL and on antiretroviral therapy (ART) for ≥6 months. Genotypic drug resistance was performed among VF cases. Correlates of DRM were identified using multivariate logistic regression. RESULTS: The overall virological suppression rate was 85.3%; DRM was detected in 42.6% (517/1215) VF cases and 6.2% of the sample patients. A total of 90.9% of patients were infected with HIV-1 CRF07_BC subtype. The prevalence of DRM to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were 46.0% and 96.9%, respectively. The most prevalent mutation for NRTI was M184V (84.5%). Lamivudine (3TC), emtricitabine (FTC), and abacavir (ABC) had the highest resistance rates. For NNRTI, K103N (60.7%), nevirapine (NVP), and efavirenz (EFV) had the highest resistance rates and cross resistance to rilpivirine (RPV), doravirine (DOR), and etravirine (ETR). Ritonavir boosted lopinavir (LPV/r) resistance rate was extremely low. The occurrence of DRM was associated with age at ART ≤18 years, baseline CD4 count ≤200 cells/mL, NVP-based regimen, and ART duration >3 years. CONCLUSION: A relatively high proportion of VF and broad DRM for NRTI and NNRTI were observed, causing high-level resistance to first-line NRTI, NNRTI, and next generation NNRTI. Our findings necessitate the implementation of scaling up virological monitoring, adherence support, and timely switching to an LPV/r-containing regimen when patients with VF to reduce the occurrence of DRM.

Lopinavir/ritonavir for treatment of non-hospitalized patients with COVID-19: a randomized clinical trial.

OBJECTIVES: Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19. METHODS: This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1). RESULTS: Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups. CONCLUSION: LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04372628.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Method validation and clinical application for the quantification of lopinavir, efavirenz, and ritonavir in breast milk using liquid chromatography tandem mass spectrometry.

A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been validated for quantification of three antiretroviral drugs (efavirenz [EFV], lopinavir [LPV], and ritonavir [RTV]) from human breast milk. The samples were extracted employing protein precipitation method using methanol as precipitating agent. The supernatant was evaporated and reconstituted before injecting into the chromatograph and separated on a biphenyl column. Calibration curves for the three tested antiretroviral drugs were linear (r ≥ 0.999) over the range examined. The inter- and intra-day coefficients of variation (CV) were ≤15% for efavirenz, lopinavir, and ritonavir. Mean recovery ranged from 96% to 105% and no major matrix effects were observed. This validated LC-MS/MS method was efficiently applied to determine EFV, LPV, and RTV concentrations in breast milk from Human Immunodeficiency Virus (HIV)-positive breastfeeding mothers. This assay requires a simple sample processing method with a short run time, making it well suited for high-throughput routine clinical or research purposes.

Epidemiology, diagnosis and treatment of early COVID-19 patients in Jiaxing City, Zhejiang Province, China, January to March 2020.

BACKGROUND: Imported Coronavirus disease 2019 (COVID-19) patients pose a huge challenge to the prevention and control of the epidemic in prefecture-level cities in China. However, the treatment strategies at that time were mainly empirical and far from perfect. Hence, this study aims to summarize the clinical characteristics, diagnosis and treatment of all COVID-19 patients in Jiaxing City in 2020. METHODS: The clinical data of 42 patients diagnosed with COVID-19 in Jiaxing City, Zhejiang Province from January 23, 2020 to March 4, 2020 were retrospectively analyzed. Epidemiological history and sociodemographic data were collected. Laboratory parameters, imaging and disease progression, treatment methods, efficacy and adverse reactions of COVID-19 cases were recorded. Then, the clinical characteristics as well as diagnosis and treatment were statistically analyzed. RESULTS: The median age of 42 patients was 47 years old, including 24 males (57.1%) and 18 females (42.9%). There were 21 first-generation cases, 29 cases (69%) of clustering onset related to first-generation cases, and 28 cases without any underlying diseases. Radiographic progression was reported in 17 patients (40.5%) (progression duration, 2-11 days; median progression duration, 3.8 days; average progression duration, 4.59-2.48 days). The main clinical symptoms include fever (78.6%) and cough (64.3%). A total of 37 patients (88.10%) received arbidol combined with lopinavir/ritonavir or darunavir/cobicistat. Of these, 22 patients (52.4%) took a combination with moxifloxacin tablets, and 20 patients (47.6%) took combined hormone therapy. Seventeen patients (40.48%) reported diarrhea, nausea, vomiting, rash, and other adverse drug reactions. A total of 38 patients improved (90.5%). The hospital stays of 36 patients ranged from 7 to 33 days, with a median of 19 days (19.00-7.33 days on average). The virus nucleic acid test result return time was 1 to 32 days, with a median of 15.5 days (14.41-8.61 days on average). CONCLUSIONS: Most of the imported COVID-19 patients in Jiaxing City were of the first generation, mainly cluster onset, and the epidemiological characteristics were relatively simple. Arbidol combined with lopinavir/ritonavir or darunavir/cobicistat was the main treatment strategy for the initial treatment of COVID-19.

[The main aspects of the impact of the new coronavirus infection SARS-CoV-2 on the development of infertility in men].

Since the end of 2019, the world has been overwhelmed by a pandemic of a new coronavirus infection (COVID-19), a disease that damages various organs and systems. Because of the extensive coverage of the population by the infection, the long-term effects of the disease are not well understood, which is of considerable scientific and practical interest. We performed an in-depth analysis and systematization of data from foreign and domestic publications in the Scopus, Web of Science, eLIBRARY, PubMed, Wiley Online Library, and Google Scholar databases were performed. Information searches included original articles, reviews, guidelines, manual comments, and editorials related to the effects of SARS-CoV-2 virus on the male reproductive system. Accumulated clinical evidence suggests that the SARS-CoV-2 virus and the COVID-19 disease it causes have a negative impact on male reproductive health.. Drugs with a negative effect on spermatogenesis are used in the therapy of patients with COVID-19. These include lopinavir, chloroquine and its derivatives, and widely used glucocorticosteroids. Lopinavir and chloroquine have subsequently been excluded from potential COVID-19 therapy. Although available data on the fertility of men with COVID-19 are scarce and the results of published studies are from a limited sample, it is clear that maintaining male reproductive health during the COVID-19 pandemic is a pressing issue in modern medicine and requires further in-depth study. Preconceptional screening should be recommended for men who have undergone COVID-19.

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis.

BACKGROUND: Prior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH. METHODS: LPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated. RESULTS: Rifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended. CONCLUSION: The population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.

Short-term Pregnancy Outcomes After Nirmatrelvir-Ritonavir Treatment for Mild-to-Moderate Coronavirus Disease 2019 (COVID-19).

This is a descriptive study of pregnant patients who received nirmatrelvir-ritonavir therapy from April 16, 2022, through May 18, 2022. Patients were eligible to receive nirmatrelvir-ritonavir if they were diagnosed with mild-to-moderate coronavirus disease 2019 (COVID-19) with symptom onset within 5 days, did not require oxygen therapy or hospital admission, and had no contraindications to nirmatrelvir-ritonavir. During the study time frame, 11 patients were identified as candidates for nirmatrelvir-ritonavir treatment. All patients agreed to nirmatrelvir-ritonavir treatment after a telehealth consultation; seven patients completed the treatment. All patients who received nirmatrelvir-ritonavir experienced symptom resolution without the need for additional care. All but one patient tolerated nirmatrelvir-ritonavir without immediate adverse effects, and no adverse fetal or neonatal effects were observed.

A systematic review and Bayesian network meta-analysis for comparative safety assessment of favipiravir interventions in hospitalized COVID-19 patients.

INTRODUCTION: COVID-19 is a coronavirus-based infectious illness that was first detected at the end of 2019 in Wuhan, China. The novel virus induces severe acute respiratory syndrome (SARS-CoV-2) and has spread globally, resulting in an ongoing pandemic. There is still a lack of evidence for direct comparison of favipiravir therapy. Network meta-analysis (NMA), may incorporate direct and indirect comparisons in a pooled computation while depending on strong assumptions and premises. This study provides evidence-based recommendations on the safety of currently used clinical pharmacological treatments compared to favipiravir for COVID-19 patients. METHODOLOGY: We conducted a systematic review and Bayesian NMA. We searched the primary databases and clinical trials center for reports of short-term, randomized controlled trials (RCTs) of favipiravir for COVID-19 treatment. The primary endpoints here considered were any adverse events observed or reported during the treatment cycle with estimates of odds ratio (OR) and 95% confidence interval (CI), until November 6, 2021. RESULTS: Between January 2020 and July 2021, 908 individuals were randomly assigned to one of the seven active prescription medication regimens or placebo in this study, generating seven direct comparisons on 12 data points. The safety of favipiravir over the four clinically efficacious monotherapies or combinations including tocilizumab, arbidol, lopinavir + ritonavir, and chloroquine remained unknown due to the lack of a significant difference and the limited sample size. CONCLUSIONS: Overall, comparative rankings could assist doctors and guideline developers in decision-making. We have also concluded that the safety of favipiravir requires further attention.

Evaluation of the polymorphic forms of ritonavir and lopinavir in raw materials and co-milled systems.

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid®. Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).

Can transcription factors in the intervertebral disc of lopinavir/ritonavir prevent degeneration in the nucleus pulposus by mediating the regulation of inflammation through signaling pathways?

OBJECTIVE: This study was conducted to examine whether lopinavir/ritonavir (Lop/r), an HIV protease inhibitor, can improve disc physiology and slow down intervertebral disc (IVD) degeneration through in vitro experimental methods, as well as whether it can suppress inflammation with interleukin-1 beta (IL-1ß) and sex-determining region Y (SRY) protein-related high-mobility group box genes-9 (SOX9) through hypoxia-inducible factor 1-alpha (HIF-1α) and the nuclear factor kappa B (NF-κB) signaling pathway. The aim was to investigate whether Lop/r application is toxic to IVD cells and the microenvironment simultaneously. PATIENTS AND METHODS: Human primary cell cultures were prepared using herniated IVD tissues obtained from patients with lumbar disc hernia who were unresponsive to conservative and medical treatment, and thereby, were operated on. The untreated culture samples served as control group, and the samples treated with Lop/r served as study group. Microscopic evaluations were performed simultaneously using fluorescent and supravital dyes in all groups. In addition to cell viability, toxicity, and proliferation analysis through a commercial kit, IL-1ß, SOX9, HIF-1α, and NF-κB protein expressions were evaluated using Western blotting. In the statistical comparison of the obtained data, an alpha value less than 0.05 was considered significant. RESULTS: Cell proliferation decreased in the Lop/r group, but no cell death was observed (p < 0.05). Moreover, at the end of 72 hours after Lop/r application, IL-1ß and NF-kB protein expressions decreased by 40% and 52%, respectively, while HIF-1α and SOX9 protein expressions increased by 4% and 59%, respectively (p< 0.05). CONCLUSIONS: Although these data were obtained from an in vitro experimental study, it is believed that these findings could make significant contributions to the pharmaco-regenerative treatment modalities of IVD degeneration. Lop/r suppresses the IL-1ß and NF-κB and induces SOX9 and HIF-1α, since these signaling pathways may be related to human IVD degeneration.

Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

BACKGROUND: Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. METHODS AND FINDINGS: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. CONCLUSIONS: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. TRIAL REGISTRATION: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials.

BACKGROUND: To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.

Menthol augmented niosomes for enhanced intestinal absorption of lopinavir.

Lopinavir is effective in treatment of HIV infection but experiences low oral bioavailability due to poor solubility, pre-systemic metabolism, and P-gp intestinal efflux. Co-processing with menthol enhanced its dissolution and intestinal permeability. Niosomes comprising Span 60, cholesterol, and poloxamer 407 were formulated in absence and presence of menthol. These were evaluated for size, morphology, entrapment efficiency (EE%), lopinavir release, and intestinal absorption. The later employed in situ rabbit intestinal absorption model. Niosomes were spherical with vesicle size of 140.2 ± 23 and 148.2 ± 27 nm for standard and menthol containing niosomes, respectively. The EE% values were 94.4% and 96.3% for both formulations, respectively. Niosomes underwent slow release during the time course of absorption with menthol hastening lopinavir release, but the release did not exceed 9%. Niosmoal encapsulation enhanced lopinavir intestinal absorption compared with drug solution. This was reflected from the fraction absorbed from duodenum, which was 24.15%, 73.09%, and 83.23% for solution, standard niosomes and menthol containing vesicles, respectively. These values were 34.32%, 80.8%, and 86.56% for the same formulations in case of jejuno-ileum. Lopinavir absorption from niosomes did not depend on release supporting intact vesicle absorption. The study introduced menthol containing niosomes as carriers for enhanced lopinavir intestinal absorption.

In Silico Evaluation of Natural Flavonoids as a Potential Inhibitor of Coronavirus Disease.

The recent coronavirus disease (COVID-19) outbreak in Wuhan, China, has led to millions of infections and the death of approximately one million people. No targeted therapeutics are currently available, and only a few efficient treatment options are accessible. Many researchers are investigating active compounds from natural plant sources that may inhibit COVID-19 proliferation. Flavonoids are generally present in our diet, as well as traditional medicines and are effective against various diseases. Thus, here, we reviewed the potential of flavonoids against crucial proteins involved in the coronavirus infectious cycle. The fundamentals of coronaviruses, the structures of SARS-CoV-2, and the mechanism of its entry into the host's body have also been discussed. In silico studies have been successfully employed to study the interaction of flavonoids against COVID-19 Mpro, spike protein PLpro, and other interactive sites for its possible inhibition. Recent studies showed that many flavonoids such as hesperidin, amentoflavone, rutin, diosmin, apiin, and many other flavonoids have a higher affinity with Mpro and lower binding energy than currently used drugs such as hydroxylchloroquine, nelfinavir, ritonavir, and lopinavir. Thus, these compounds can be developed as specific therapeutic agents against COVID-19, but need further in vitro and in vivo studies to validate these compounds and pave the way for drug discovery.