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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 β-1b), we evaluated the heterogeneity of treatment effect of interferon-β1b 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-β1b and lopinavir–ritonavir and 38 received placebo. Interferon-β1b 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-β1b and lopinavir–ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843). [ABSTRACT FROM AUTHOR]

Background: Inhibition of papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is projected to terminate its replication. Hence, these proteases represent viable therapeutic targets. Methods: Sixty-one flavonoids with reported activities against other RNA viruses were selected and docked in PLpro and 3CLpro. Flavonoids with better binding energies compared to reference inhibitors (lopinavir and ritonavir) in their interaction with PLpro and 3CLpro were selected for drug-likeness and ADMET analysis. The best representative flavonoid for each protease from the ADMET filtering analysis was subjected to molecular dynamics simulations (MDS) and clustering analysis of the trajectory files. Results: Licorice, ugonin M, procyanidin, silymarin, and gallocatechin gallate had better binding energies (-11.8, -10.1, -9.8, -9.7 and -9.6 kcal/mol respectively) with PLpro compared to lopinavir and ritonavir (-9.1 and -8.5 kcal/mol respectively). Also, isonymphaeol B, baicalin, abyssinone II, tomentin A, and apigetrin had better binding energies (-8.7, -8.3, -8.2, -8.1, and -8.1 kcal/mol respectively) with 3CLpro compared to lopinavir and ritonavir (-7.3 and -7.1 kcal/mol respectively). These flavonoids interacted with the proteases via hydrogen and non-hydrogen bonding. Of these flavonoids, silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics in silico. These two flavonoids exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. Conclusion: Silymarin and isonymphaeol B are proposed for further studies as compounds with potential activities against SARS-CoV-2. Highlights: • Flavonoids displayed varying affinities for PLpro and 3CLpro of SARS-CoV-2 • They interacted via hydrogen and non-hydrogen bonds; nine and twenty-seven flavonoids had better binding affinities for PLpro and 3CLpro respectively than lopinavir and ritonavir • Silymarin and isonymphaeol B demonstrated most favourable combination of attributes in terms of binding energies, compliance with Lipinski rule for drug-likeness and favourable pharmacokinetics. • Silymarin and isonymphaeol B exhibited appreciable degree of structural stability, maintaining strong interaction with residues in the different representative clusters selected during the MDS run. [ABSTRACT FROM AUTHOR]

Purpose: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). Method: Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. Results: Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. Conclusion: In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. Subject and method: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, "SARS-CoV-2," "COVID-19," "antivirals," "therapy"), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. Results: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. Discussion: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds. [ABSTRACT FROM AUTHOR]

Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. [ABSTRACT FROM AUTHOR]

Background Liver injury has been documented independently in novel coronavirus disease 2019 (COVID-19) patients and patients treated with lopinavir-ritonavir. Objective to investigate the drug-induced liver injury associated with lopinavir-ritonavir among the patients with COVID-19. Methods We conducted a disproportionality analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) between 2020Q1 and 2021Q1 to evaluate the association between lopinavir-ritonavir and risk of drug-induced liver injury (or severe drug-induced liver injury) and calculated their reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results A total of 3,425 cases of drug-induced liver injury were reported in 19,782 patients with COVID-19. The ROR for drug-induced liver injury was 2.99 (2.59-3.46), 3.16 (2.68-3.73), and 5.39 (4.63-6.26) when comparing lopinavir-ritonavir with all other drugs, hydroxychloroquine/chloroquine only, and remdesivir, respectively. For severe drug-induced liver injury, RORs for lopinavir-ritonavir provided evidence of an association compared with all other drugs (3.98; 3.15-5.05), compared with hydroxychloroquine/chloroquine only (5.33; 4.09-6.94), and compared with remdesivir (3.85; 3.03-4.89). Conclusions In the FAERS, we observed a disproportional signal for drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19. [ABSTRACT FROM AUTHOR]

Lopinavir-ritonavir combination is being used for the treatment of SARS-CoV-2 infection. A low dose of ritonavir is added to other protease inhibitors to take advantage of potent inhibition of cytochrome (CYP) P450 3A4, thereby significantly increasing the plasma concentration of coadministered lopinavir. Ritonavir also inhibits CYP2D6 and induces CYP2B6, CYP2C19, CYP2C9, and CYP1A2. This potent, time-dependent interference of major hepatic drug-metabolizing enzymes by ritonavir leads to several clinically important drug-drug interactions. A number of patients presenting with acute coronary syndrome and acute heart failure may have SARS-CoV-2 infection simultaneously. Lopinavir-ritonavir is added to their prescription of multiple cardiac medications leading to potential drug-drug interactions. Many cardiology, pulmonology, and intensivist physicians have never been exposed to clinical scenarios requiring co-prescription of cardiac and antiviral therapies. Therefore, it is essential to enumerate these drug-drug interactions, to avoid any serious drug toxicity, to consider alternate and safer drugs, and to ensure better patient care. [ABSTRACT FROM AUTHOR]

Objective: To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients. Methods: Concentrations of lopinavir/ritonavir were assayed by an accredited LC-MS/MS method. The population pharmacokinetics of lopinavir was described using non-linear mixed-effects modeling (NONMEM version 7.4). After determination of the base model that better described the data set, the influence of covariates (age, body weight, height, body mass index (BMI), gender, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C reactive protein (CRP), and trough ritonavir concentrations) was tested on the model. Results: From 13 hospitalized patients (4 females, 9 males, age = 64 ± 16 years), 70 lopinavir/ritonavir plasma concentrations were available for analysis. The data were best described by a one-compartment model with a first-order input (KA). Among the covariates tested on the PK parameters, only the ritonavir trough concentrations had a significant effect on CL/F and improved the fit. Model-based simulations with the final parameter estimates under a regimen lopinavir/ritonavir 400/100 mg b.i.d. showed a high variability with median concentration between 20 and 30 mg/L (Cmin/Cmax) and the 90% prediction intervals within the range 1–100 mg/L. Conclusion: According to the estimated 50% effective concentration of lopinavir against SARS-CoV-2 virus in Vero E6 cells (16.7 mg/L), our model showed that at steady state, a dose of 400 mg b.i.d. led to 40% of patients below the minimum effective concentration while a dose of 1200 mg b.i.d. will reduce this proportion to 22%. [ABSTRACT FROM AUTHOR]

Background: Patients hospitalised with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2; coronavirus 2019 disease (COVID-19)] infection are frequently older with co-morbidities and receiving polypharmacy, all of which are known risk factors for drug–drug interactions (DDIs). The pharmacological burden may be further aggravated by the addition of treatments for COVID-19. Objective: The aim of this study was to assess the risk of potential DDIs upon admission and during hospitalisation in patients with COVID-19 treated at our hospital. Methods: We retrospectively analysed 502 patients with COVID-19 (mean age 61 ± 16 years, range 15–99) treated at our hospital with a proven diagnosis of SARS-CoV-2 infection hospitalised between 21 February and 30 April 2020 and treated with at least two drugs. Results: Overall, 68% of our patients with COVID-19 were exposed to at least one potential DDI, and 55% were exposed to at least one potentially severe DDI. The proportion of patients experiencing potentially severe DDIs increased from 22% upon admission to 80% during hospitalisation. Furosemide, amiodarone and quetiapine were the main drivers of potentially severe DDIs upon admission, and hydroxychloroquine and particularly lopinavir/ritonavir were the main drivers during hospitalisation. The majority of potentially severe DDIs carried an increased risk of cardiotoxicity. No potentially severe DDIs were identified in relation to tocilizumab and remdesivir. Conclusions: Among hospitalised patients with COVID-19, concomitant treatment with lopinavir/ritonavir and hydroxychloroquine led to a dramatic increase in the number of potentially severe DDIs. Given the high risk of cardiotoxicity and the scant and conflicting data concerning their efficacy in treating SARS-CoV-2 infection, the use of lopinavir/ritonavir and hydroxychloroquine in patients with COVID-19 with polypharmacy needs to be carefully considered. [ABSTRACT FROM AUTHOR]

Objectives: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. Methods: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. Results: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). Conclusions: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT 04251871 at www.clinicaltrials.gov) [ABSTRACT FROM AUTHOR]

Introduction and Objective: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. Methods: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. Results: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95–1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. Conclusions: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available. [ABSTRACT FROM AUTHOR]

Lopinavir (LPV), a well-known drug administered in human immunodeficiency virus (HIV) infection, has shown limitation for pediatric treatment owing to poor aqueous solubility that gives rise to limited oral bioavailability and short plasma half-life (5–6 h). Polymers such as polyethylene glycol (PEG) have been used as drug carriers to improve their solubility. This study reports the preparation of polyethylene glycol (5,000) succinate (PEG–Suc–LPV) conjugate of LPV by the esterification method. The disappearance of the 3,395 cm−1 (O–H stretch of COOH) band for Polyethylene glycol (5,000) succinate (PEG–Suc)confirms the formation ester linkage with the OH group of LPV which is also confirmed by 1H NMR analysis. The XRD for the conjugate showed a broad, amorphous peak while pure PEG, Suc, LPV are crystalline. DSC analysis showed that the conjugate exhibited new broad and diffuse peaks, confirming that they did exist in an amorphous state as multiple complexes. The conjugate showed improved solubility and activity with reduced toxicity compared to pure LPV. The solubility of LPV increased significantly from 80 to 318 ppm. Furthermore, an aquatic toxicity test using Danio rerio showed that the conjugate had a lower LC50 (60.8 ppm) when compared to the pure LPV drug LC50 (6.42 ppm). These results suggest PEG–Suc conjugate of LPV as an efficient carrier for enhanced hydrophilicity and anti-HIV property of LPV. [ABSTRACT FROM AUTHOR]

Background: There is no identified pharmacological therapy for COVID-19 patients, where potential therapeutic strategies are underway to determine effective therapy under such unprecedented pandemic. Therefore, combination therapies may have the potential of alleviating the patient's outcome. This study aimed at comparing the efficacy of two different combination regimens in improving outcomes of patients infected by novel coronavirus (COVID-19). Methods: This is a single centered, retrospective, observational study of 60 laboratory-confirmed COVID-19 positive inpatients (≥18 years old) at two wards of the Baqiyatallah Hospital, Tehran, Iran. Patient's data including clinical and laboratory parameters were recorded. According to the drug regimen, the patients were divided into two groups; group I who received regimen I consisting azithromycin, prednisolone, naproxen, and lopinavir/ritonavir and group II who received regimen II including meropenem, levofloxacin, vancomycin, hydroxychloroquine, and oseltamivir. Results: The oxygen saturation (SpO2) and temperature were positively changed in patients receiving regimen I compared to regimen II (P = 0.013 and P = 0.012, respectively). The serum level of C-reactive protein (CRP) changed positively in group I (P < 0.001). Although there was a significant difference in platelets between both groups (75.44 vs 51.62, P < 0.001), their change did not clinically differ between two groups. The findings indicated a significant difference of the average length of stay in hospitals (ALOS) between two groups, where the patients under regimen I showed a shorter ALOS (6.97 vs 9.93, P = 0.001). Conclusion: This study revealed the beneficial effect of the short-term use of low-dose prednisolone in combination with azithromycin, naproxen and lopinavir/ritonavir (regimen I), in decreasing ALOS compared to regimen II. Since there is still lack of evidence for safety of this regimen, further investigation in our ongoing follow-up to deal with COVID-19 pneumonia is underway. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 59-year-old female patient was on treatment with lopinavir/ritonavir and dexamethasone. Topics include the remdesivir is the first small molecule against SARSCoV-2 approved for use in hospitalized patients with COVID-19. Topics include the pharmacokinetic data have demonstrated that the remdesivir main metabolite is predominantly renally, and the remdesivir is not recommended in adults with an estimated glomerular filtration rate less than 30 mL/min.

The role of therapeutic drug monitoring in pediatric antiretroviral therapy is unclear. A little pharmacokinetic datum from clinical practice exists beyond controlled approval studies including clinically stable children. The aim of this study is to quantify LPV exposure of critically ill infants in an ICU and—by identifying risk factors for inadequate exposure—to define sensible indications for TDM in pediatric HIV care; in addition, assume total drug adherence in ICU to compare LPV exposure with a setting of unknown adherence. In this prospective investigation, 15 blood samples from critically ill infants in the pediatric ICU at Tygerberg Hospital were analyzed for LPV-serum concentrations. They were then compared to those of 22 blood samples from out-patient children. Serum-level measurements were performed with an established high-performance liquid chromatography method. All LPV-serum levels of ICU patients were higher than a recommended Ctrough (= 1.000 ng/ml), 60% of levels were higher than Cmax (8.200 ng/ml). Partly, serum levels reached were extremely high (Maximum: 28.778 ng/ml). Low bodyweight and age correlated significantly with high LPV concentrations and were risk factors for serum levels higher than Cmax. Significantly fewer serum levels from infants in ICU care (mean: 11.552 ng/ml ± SD 7760 ng/ml) than from out-patient children (mean: 6.756 ng/ml ± SD 6.003 ng/ml) were subtherapeutic (0 vs. 28%, p = 0.008). Under total adherence in the ICU group, there were no subtherapeutic serum levels, while, in out-patient, children with unknown adherence 28% of serum levels were found subtherapeutic. Low bodyweight and age are risk factors for reaching potentially toxic LPV levels in this extremely fragile population. TDM can be a reasonable tool to secure sufficient and safe drug exposure in pediatric cART. [ABSTRACT FROM AUTHOR]

Background: Drug-drug interaction (DDIs) are evaluated using pharmacokinetic (PK) simulation models, clinical studies, and scientific publications throughout drug development. DDIs with Norvir (ritonavir) and combination products (eg, Kaletra [lopinavir/ritonavir]) containing ritonavir as a PK enhancer are relevant, because these drugs could affect exposures of CYP3A4 substrates. Application of algorithms proactively identified recently approved drugs, which potentially cause adverse outcomes when given with drugs containing ritonavir. Methods: An evidence-based medicine technology platform was used to identify newly approved products. PK-related information from the products’ prescribing information was reviewed to identify DDIs with ritonavir. Algorithms were used to further evaluate PK, clinical, and postmarketing information pertinent to the interaction to determine if prescribing information required revision. Results: From January 1, 2014, through December 31, 2015, 39 newly approved drugs were identified as having potential interactions with Norvir and/or Kaletra. Ten drugs were excluded, 19 drugs went through initial screening, and 10 drugs underwent in-depth algorithm-based analyses for DDIs. No changes to prescribing information for Norvir or Kaletra were recommended from evaluation of the DDIs. Regulatory concurrence with AbbVie decisions was 93.1% (27/29, 93.1%); in 6.9% (2/29, 6.9%) of the evaluated interactions, at least 1 local regulatory authority disagreed with recommendations, requiring label changes to incorporate the DDI information. Conclusions: This proactive algorithmic approach identifies and complements existing methods used to detect DDIs with newly approved products. Additionally, this approach facilitates timely communication of risks to patients and healthcare providers via label revisions, publications, or other regulatory communications. [ABSTRACT FROM AUTHOR]

Antiretroviral (ARV) treatment may induce metabolic complications in HIV patients on long-term therapy that can affect bone health. In this study, the effects of the ARVs Stavudine (d4T), Tenofovir (TDF) and Lopinavir/ritonavir (LPV/r) on bone metabolism and lipodystrophy were directly compared in rats to negate the consequences of HIV-associated confounding factors. Healthy 12-14-week-old male Wistar rats (n = 40) were divided into four treatment groups and received an oral animal equivalent dose of either Stavudine (6.2 mg/kg/day), TDF (26.6 mg/kg/day), LPV/r (70.8 mg/kg/day) or water (Control 1.5 mL water/day) for a period of 9 weeks. Whole-body DXA measurements, a biomechanical three-point breaking test and histomorphometric analysis were performed on the femurs and tibias at the end of the treatment period. Stavudine monotherapy was found to be associated with decreased femoral bone mineral density that translated into reduced bone strength, whereas histomorphometric analysis demonstrated that Stavudine induces an imbalance in bone metabolism at tissue level, evident in higher resorption (eroded surfaces, osteoclast surfaces and osteoclast number) and lower formation parameters (osteoblast surfaces and osteoid surfaces). This was less clear in the rats treated with either TDF or LPV/r. Furthermore, both Stavudine and TDF treatment resulted in significant bone marrow adiposity, although no significant redistribution of body fat was noted in the treated rats compared to controls. The data from this study suggest that in the absence of HIV-associated factors, LPV/r is less detrimental to bone metabolism compared to Stavudine and TDF. [ABSTRACT FROM AUTHOR]

A series of new urea and thiourea derivatives of lopinavir intermediate 7a-k was designed and synthesized from lopinavir intermediate by treating various biopotent isocyanates and isothiocyanates in the presence of base, 1,4-dimethyl piperazine, and their biological activity was evaluated . The bio-assay revealed that the compounds exhibited moderate to good antimicrobial and antioxidant activities; particularly, 7k showed high activity against Staphylococcus aureus. Further, to know the binding interactions of the title products with protease enzyme, molecular studies were performed, which revealed that 7j exhibited high binding affinity towards the enzyme cysteine protease from Staphylococcus aureus. The results from in vitro studies revealed that they can be used as effective antimicrobial and antioxidant agents. Furthermore, molecular docking studies shown very good interaction. Graphical Abstract: [ABSTRACT FROM AUTHOR]

A 50-year-old male patient with comorbid human immunodeficiency virus developed a relapse of bipolar disorder after a switch from oral aripiprazole 10 mg/day to intramuscular aripiprazole depot 200 mg every 28 days plus oral aripiprazole 5 mg/day. The patient was concomitantly taking lopinavir, saquinavir, ritonavir, silybum marianum extract, and omeprazole. Only 1 week after the switch, the patient developed mood swings, irritability, depressive mood, and lack of drive. The oral aripiprazole was increased again to stabilize the patient. The measured trough drug concentration of aripiprazole was low and may be correlated to the relapse. When oral aripiprazole was increased back to 10 mg again, the depressive symptoms subsided. The dose of the next depot injection was increased to 300 mg and that of oral aripiprazole decreased back to 5 mg/day. Because trough drug concentrations were still low after 28 days, the depot dose was increased to 400 mg every 28 days, which is double that recommended in the prescriber's information. Two months after the initial switch from oral to intramuscular aripiprazole, the patient's mood stabilized on aripiprazole depot 400 mg every 28 days. More clinical data, especially regarding the pharmacokinetic drug interactions of aripiprazole depot are needed to improve dosing recommendations, and prevent relapses or adverse drug events. Genetic polymorphisms may play an important role in the clinical relevance of drug interactions concerning aripiprazole depot. [ABSTRACT FROM AUTHOR]

Purpose: Amorphous solid dispersions (ASDs) formulated with acid-insoluble (enteric) polymers form suspensions in acidic media where the polymer is largely insoluble. However, a small amount of drug can dissolve and a supersaturated solution may be generated. The goal of this study was to gain insight into the leaching mechanisms of both drug and polymer from the suspended particles, studying the impact of solution additives such as surfactants. Methods: ASDs were prepared by spray drying lopinavir (LPV) with an enteric polymer, either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or hydroxypropylmethylcellulose phthalate (HPMCP). Four surfactants and a suspending agent were added to the liquid media to evaluate the effect of these excipients on leaching. pH 3 and pH 5 buffers were used to investigate the effect of pH. Results: The extent of drug leaching from the amorphous formulation was proportional to the crystalline solubility of the drug in the same medium. All surfactants promoted solubilization of LPV with the exception of poloxamer and sodium dodecyl sulfate-HPMCP combinations. A small amount of polymer ionization significantly enhanced LPV leaching in solutions containing an ionic surfactant. Conclusions: The mechanism of enhanced leaching appeared to be solubilization, with the apparent supersaturation remaining the same for systems containing the same polymer. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral treatment (ART) with ritonavir-boosted protease inhibitor monotherapy (rb-PMT) remains a potentially attractive strategy for treatment simplification in HIV-infected individuals. However, long-term follow-up in particular with respect to HIV-RNA suppression in cerebrospinal fluids (CSF) is still lacking. Methods: Patients who participated in one of the three monotherapy trials [indinavir/r, ATARITMO (atazanavir/r), MOST (lopinavir/r)] at our HIV clinic and remained successfully suppressed during the entire trial (plasma < 50 copies/mL, CSF < 100 copies/mL) were offered to continue their monotherapy under close monitoring. While on rb-PMT, patients were asked to provide CSF samples in yearly or 2-yearly intervals. All patients fully suppressed in plasma and CSF for at least 12 months were included in the analysis. Patients demonstrating any failure in plasma or CSF resumed triple combined ART. Results: A total of 27 patients (5 women and 22 men) fulfilled the entry criteria. The median follow-up time was 4.8 (1.1-10.9) years with an overall experience of 139 patient-years on monotherapy. Eleven of 27 (41 %) patients (2 women and 9 men) developed virologic failure (1 in plasma only, 4 in CSF only, 4 both in plasma and CSF and 2 in plasma with CSF not available). Plasma failure occurred in 7 patients after a median follow-up of 25 (13-32) months, and CSF failure in 8 patients after a median follow-up of 30 (14-64) months. Seven patients are still on rb-PMT with atazanavir/r. Failure was associated with shorter duration of fully suppressed plasma viral load prior to starting ( p < 0.022). Conclusion: For selected patients, rb-PMT might be a valid long-term treatment strategy. Nevertheless, even after 12 months of full HIV-RNA suppression, more than 1/3 of patients may still develop failure in either plasma or CSF. Given the observation of isolated CSF failure, treatment monitoring with regular lumbar puncture should be recommended in rb-PMT. Only monotherapy with atazanavir/r was successful beyond 39 months. Monotherapy failure was significantly associated with a shorter duration of complete HIV-RNA suppression in plasma prior to rb-PMT start. Further investigation is needed to better identify predictors for patients that will qualify for successful long-term rb-PMT. [ABSTRACT FROM AUTHOR]

Resistance to antiretroviral drugs has been a major obstacle for long-lasting treatment of HIV-infected patients. The development of models to predict drug resistance is recognized as useful for helping the decision of the best therapy for each HIV+ individual. The aim of this study was to develop classifiers for predicting resistance to the HIV protease inhibitor lopinavir using a probabilistic neural network (PNN). The data were provided by the Molecular Virology Laboratory of the Health Sciences Center, Federal University of Rio de Janeiro (CCS-UFRJ/Brazil). Using bootstrap and stepwise techniques, ten features were selected by logistic regression (LR) to be used as inputs to the network. Bootstrap and cross-validation were used to define the smoothing parameter of the PNN networks. Four balanced models were designed and evaluated using a separate test set. The accuracies of the classifiers with the test set ranged from 0.89 to 0.94, and the area under the receiver operating characteristic (ROC) curve (AUC) ranged from 0.96 to 0.97. The sensitivity ranged from 0.94 to 1.00, and the specificity was between 0.88 and 0.92. Four classifiers showed performances very close to three existing expert-based interpretation systems, the HIVdb, the Rega and the ANRS algorithms, and to a k-Nearest Neighbor. [ABSTRACT FROM AUTHOR]

This paper examines a global campaign in which transnational advocacy networks challenged the monopoly rights of Abbott Laboratories over the antiretroviral drug Kaletra. It focuses on the cases of Colombia and Ecuador and analyzes the different trajectories of the campaign in the two countries and how each trajectory contributed differently to the global outcome. In both of these cases, I show that activism operated in an 'inverse boomerang' pattern, by which an international NGO reached out to local allies to expand its global coalition, prioritizing its agenda over other domestic considerations. I argue that in cases where transnational campaigns are initiated globally, there is a potential mismatch between global and domestic goals and that the campaigns' contribution to global norm-making depends on the type of relationship established between international advocates and domestic actors. Such relationships are in turn influenced by the political and economic context and the institutional arrangements of each country. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP) 3A4 has been considered to be the most important enzyme system for metabolism of lopinavir/ritonavir (LPV/r), a widely used HIV protease inhibitor (PI) recommended during pregnancy. Herein we present a clinical case of a pregnant HIV-infected woman who was taking standard doses of LPV/r, 400/100 mg twice daily. The trough plasma concentrations for LPV were fourfold above that recommended for PI-pretreated patients and toxicity associated with LPV/r and PI regimens was observed. These high concentrations continued after delivery in spite of a dosage reduction. The pharmacogenetic analysis revealed a genetic polymorphism in the CYP3A4 gene that encodes a non-functional protein. The pharmacokinetic study could indicate the occurrence of a phenomenon of non-linear pharmacokinetics which would justify why dosage reduction after pregnancy did not proportionally affect the patient's degree of exposure to the drug. In addition, an increment in CYP3A activity during pregnancy could explain lower LPV/r exposure during this period compared to postpartum, despite the impaired activity of CYP3A4 caused by the polymorphism. [ABSTRACT FROM AUTHOR]

It is unknown if, compared to a triple drug antiretroviral therapy, boosted protease inhibitor monotherapy leads to worse results in specific neuropsychological processes. In our study, we included patients virologically suppressed (≥1 year), on antiretroviral therapy, without concomitant major neurocognitive confounders, receiving boosted lopinavir or darunavir as monotherapy ( n = 96) or as triple therapy with two nucleoside reverse transcriptase inhibitors ( n = 95). All patients underwent a comprehensive neuropsychological test battery (14 neuropsychological measures, covering seven domains). Both groups were compared in average score distributions and rates of neuropsychological deficits. Similar comparisons were conducted only for patients with neurocognitive impairment. In the adjusted analysis, we found only small differences between groups in the entire sample: better verbal learning ( p = 0.02; d = 0.28) and verbal recall scores ( p < 0.01; d = 0.25) in patients on boosted protease inhibitor monotherapy and slightly better motor skills with dominant hand ( p = 0.02; d = 0.23) scores in patients on triple therapy. No greater proportion of deficits in the protease inhibitor monotherapy group was found in any neuropsychological measure. In neurocognitively impaired patients, we found similar outcomes in verbal learning, verbal recall, and motor skills with dominant hand but with larger effect sizes. Close similarities in the neurocognitive pattern between groups question the clinical relevance of the number of neuroactive drugs included in the regimen. These results also suggest that peripheral viral load control may be a good indicator of brain protection. [ABSTRACT FROM AUTHOR]

Background and Objective: Antiretroviral drug regimen choice may influence changes in body composition. The objective of this study was to compare changes in body composition between ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted lopinavir (LPV/r) over 96 weeks using data from a substudy of CASTLE, which compared once-daily ATV/r with twice-daily LPV/r, both in combination with tenofovir disoproxil fumarate/emtricitabine in treatment-naïve patients with HIV-1 infection. Methods: We examined 224 patients (125 on ATV/r; 99 on LPV/r) at baseline, 48 and 96 weeks using dual-energy X-ray absorptiometry and computerised tomography. Results: In the lowest baseline body mass index (BMI) group, there were significantly greater gains at week 96 for ATV/r than for LPV/r in subcutaneous adipose tissue and in visceral adipose tissue (VAT). By week 96, patients with lowest baseline CD4 cell counts on ATV/r had 28 % increases in VAT versus 14 % reductions for patients receiving LPV/r. Those with the lowest baseline BMI on ATV/r had 19 % increases in VAT versus reductions of 5 % for patients on LPV/r. In the highest baseline BMI group, the mean increase in triglycerides was 6 and 70 % in the ATV/r and LPV/r arms, respectively. Compared with baseline, an increase in proportion of patients with high waist circumference (WC)/high triglycerides at 96 weeks was noted in both treatment arms, but this increase was numerically greater with LVP/r (18 %) than with ATV/r (11 %). Conclusion: Truncal fat gains on ATV/r primarily led to increases in WC, which may reflect return to health, while on LPV/r increases in WC and triglycerides occurred. Changes in body composition with antiretroviral therapy are influenced by treatment choice and baseline characteristics. [ABSTRACT FROM AUTHOR]

The article focuses on prediction of lopinavir/ritonavir effectiveness in COVID-19 patients which a recall of basic pharmacology concepts. Topics include the population pharmacokinetic analysis of lopinavir/ritonavir concentrations has collected in 13 coronavirus disease 2019 (COVID-19), and the patients demonstrated that a dose of lopinavir of 400 mg twice daily led to 40% of patients below the minimum effective concentration.

Background: The ARTEMIS trial compared first-line antiretroviral therapy (ART) with lopinavir/ritonavir (LPV/r) to darunavir plus ritonavir (DRV + RTV) for HIV-1-infected subjects. In order to fully assess the implications of this study, economic modelling extrapolating over a longer term is required. Objective: The aim of this study was to simulate the course of HIV and its management, including the multiple factors known to be of importance in ART. Methods: A comprehensive discrete event simulation was created to represent, as realistically as possible, ART management and HIV outcomes. The model was focused on patients for whom clinicians believed that LPV/r or DRV + RTV were good options as a first regimen. Prognosis was determined by the impact of initial treatment on baseline CD4+ T-cell count and viral load, adherence, virological suppression/failure/rebound, acquired resistance mutations, and ensuing treatment changes. Inputs were taken from trial data (ARTEMIS), literature and, where necessary, stated assumptions. Clinical measures included AIDS events, side effects, time on sequential therapies, cardiovascular events, and expected life-years lost as a result of HIV infection. The model underwent face, technical and partial predictive validation. Treatment-naive individuals similar to those in the ARTEMIS trial were modelled over a lifetime, and outcomes with first-line DRV + RTV were compared with those with LPV/r, both paired with tenofovir and emtricitabine. Up to three regimen changes were permitted. Drug prices were based on wholesale acquisition cost. Outcomes were lifetime healthcare costs (in 2011 US dollars) from the US healthcare system perspective and quality-adjusted life-years (QALYs) (discounted at 3 % per annum). Results: Choice of LPV/r over DRV + RTV as initial ART resulted in nearly identical clinical outcomes, but distinctly different economic consequences. Starting with an LPV/r regimen potentially results in approximately US$25,000 discounted lifetime savings. Accumulated QALYs for LPV/r and DRV + RTV were 12.130 and 12.083, respectively (a 19-day difference). In sensitivity analyses, net monetary benefit ranged from US$12,000 to US$31,000, favouring LPV/r (base case US$27,762). Conclusions: A comprehensive simulation of lifetime course of HIV in the USA indicated that using LPV/r as first-line therapy compared with DRV + RTV may result in cost savings, with similar clinical outcomes. [ABSTRACT FROM AUTHOR]

We compared rates of neurocognitive impairment (NCI) among 93 Thai adults failing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy (cART) before and after switching to lopinavir/ritonavir monotherapy (mLPV/r) vs. tenofovir/lamivudine/LPV/r (TDF/3TC/LPV/r). Participants completed the Color Trails 1 and 2, Digit Symbol, and Grooved Pegboard at weeks 0, 24, and 48. We calculated z-scores using normative data from 451 healthy HIV-negative Thais. We defined NCI as performance of <-1 SD on ≥2 tests. The Thai depression inventory was used to capture depressive symptoms. Lumbar puncture was optional at week 0 and 48. At baseline, median (IQR) age was 36.9 (32.8-40.5) years, and 46 % had primary school education or lower. The median CD4 count was 196 (107-292) cells/mm, and plasma HIV RNA was 4.1 (3.6-4.5) log copies/ml. Almost all (97 %) had circulating recombinant CRF01_AE. At baseline, 20 (47 %) of the mLPV/r vs. 22 (44 %) of TDF/3TC/LPV/r arms met NCI criteria ( p = 0.89). The frequency of NCI at week 48 was 30 vs. 32 % ( p = 0.85) with 6 vs. 7 % ( p = 0.85) developing NCI in the mLPV/r vs. TDF/3TC/LPV/r arms, respectively. Having NCI at baseline and lower education each predicted NCI at week 48. Depression scores at week 48 did not differ between arms ( p = 0.47). Cerebrospinal fluid HIV RNA of <50 copies/ml at 48 weeks was observed in five out of seven in mLPV/r vs. three out of four in TDF/3TC/LPV/r arm. The rates of NCI and depression did not differ among cases failing NNRTI-based cART who received mLPV/r compared to LPV/r triple therapy. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate whether the addition of enfuvirtide to standard highly active antiretroviral therapy (HAART) could confer immunovirological benefits in human immunodeficiency virus (HIV)-infected very late presenters. The current study is an open comparative therapeutic trial of standard protease inhibitor (PI)-based HAART ± additional enfuvirtide in treatment-naïve deeply immunologically impaired HIV-positive patients. Methods: Very late presenters (CD4 <50/mm), without tuberculosis and neoplasms, were alternatively allocated to two nucleoside reverse transcriptase inhibitors (NRTIs) and lopinavir/ritonavir without (control arm, CO) or with (ENF arm) enfuvirtide 90 mg bid. Enfuvirtide was administered until the achievement of viral load <50 copies/ml and for at least 24 weeks. The primary objective was the magnitude of CD4+ cell recovery at 6 months. HIV RNA was intensively monitored in the first month, and, thereafter, monthly, as for CD4+ cell count and percentage, clinical data, and plasma drug concentrations. Results: Of 22 enrolled patients (11 per arm), 19 completed the study (10 in the ENF arm). Baseline CD4+ cell counts and % were comparable, with 20 CD4+/mm (12-37) and a percentage of 3.3 (1.7-7.1) in the ENF arm, and 16 CD4+/mm (9-29) and a percentage of 3.1 (2.3-3.8) in the CO arm, respectively. The baseline viral load was also comparable between the two arms, with 5.77 log10 (5.42-6) and 5.39 log10 (5.06-6) in the ENF and CO arms, respectively. Enfuvirtide recipients had higher CD4+ percentage at week 8 (7.6 vs. 3.6%, p = 0.02) and at week 24 (10.7 vs. 5.9%, p = 0.02), and a greater CD4+ increase at week 24 (207 vs. 134 cells/mm, p = 0.04), with 70% of enfuvirtide intakers versus 12.5% of controls who achieved a CD4+ cell count >200/mm ( p = 0.01). At 48 weeks, patients in the ENF arm had CD4+ cell counts higher than controls (251 vs. 153cells/mm, p = 0.04) and were also found to be faster in reaching a CD4 cell count over 200/mm: 18 (8-24) versus 48 (36-108) weeks ( p = 0.01). Viral load decay at week 4 was greater in the ENF arm (−3 vs. −2.2 log, p = 0.04), while the proportion of patients with viral load <50 copies/ml at week 24 was comparable. Conclusions: In this pilot study, the addition of enfuvirtide to a lopinavir-based HAART was shown to be associated with a significantly faster and greater immunological recovery in newly discovered HIV-positive patients with very low CD4+ cell counts. Induction strategies using an enfuvirtide-based approach in such subjects warrant further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Chronic hepatitis C is an emerging issue in the management of human immunodeficiency virus (HIV) disease because both diseases have the same route of transmission, leading to a very high prevalence of hepatitis C virus (HCV)-coinfection in the HIV-positive patient population. Lopinavir is extensively metabolized by the hepatic cytochrome P450 3A4, and the pharmacokinetics of this protease inhibitor (PI) could be influenced by liver impairment. However, data currently available on the impact of HCV-coinfection on lopinavir plasma concentrations are both limited and conflicting. Methods: This was an observational, open-label study in which adult HIV-infected outpatients on stable antiretroviral treatment that included two nucleoside reverse transcriptase inhibitors (NRTIs) plus lopinavir/ritonavir for at least 4 weeks were asked to participate. The trough plasma concentration ( C) of lopinavir and ritonavir was assessed at steady state by a validated high-performance liquid chromatography-tandem mass spectrometry method. Results: A total of 65 HIV-positive patients were enrolled in the study. These patients were stratified into two groups based on the absence/presence of HCV-coinfection: 45 were monoinfected (HIV+/HCV−) and 20 were coinfected (HIV+/HCV+). The lopinavir C in plasma was comparable between HIV+/HCV+ and HIV+/HCV− patients, without any statistically significant difference (geometric mean ratio 0.89, 95% confidence interval 0.61-1.42; p = 0.581). The mean ritonavir C was also comparable in the two groups. Almost all samples were found to be within the therapeutic plasma level range (97% in HIV+/HCV− group and 100% in HIV+/HCV+ group). No correlation was found between lopinavir plasma levels and adverse events (such as diarrhoea and hypertriglyceridaemia) or immune-virological parameters of HIV disease. Conclusions: Among the HIV-positive patients participating in this study, the pharmacokinetics of lopinavir/ritonavir did not significantly change in those HIV-positive patients coinfected with HCV and in the absence of liver cirrhosis. [ABSTRACT FROM AUTHOR]

It has been shown that the HIV protease inhibitors indinavir and lopinavir may have activity against the human papilloma virus (HPV) type 16 inhibiting HPV E6-mediated proteasomal degradation of p53 in cultured cervical carcinoma cells. However, their mode and site of action is unknown. HPV-negative C33A cervical carcinoma cells and the same cells stably transfected with E6 (C33AE6) were exposed to indinavir and lopinavir at concentrations of 1 mM and 30 μM, respectively. The intracellular distribution of metabolites and metabolic changes induced by these treatments were investigated by Raman microspectroscopic imaging combined with the analysis of cell fractionation products by liquid chromatography-mass spectrometry (LC-MS). A uniform cellular distribution of proteins was found in drug-treated cells irrespective of cell type. Indinavir was observed to co-localise with nucleic acid in the nucleus, but only in E6 expressing cells. Principal components analysis (PCA) score maps generated on the full Raman hypercube and the corresponding PCA loadings plots revealed that the majority of metabolic variations influenced by the drug exposure within the cells were associated with changes in nucleic acids. Analysis of cell fractionation products by LC-MS confirmed that the level of indinavir in nuclear extracts was approximately eight-fold greater than in the cytoplasm. These data demonstrate that indinavir undergoes enhanced nuclear accumulation in E6-expressing cells, which suggests that this is the most likely site of action for this compound against HPV. [ABSTRACT FROM AUTHOR]

The impact of drug–drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69–85%) patients, and in 33 (26%, 95% CI 19–35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10–731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04–0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI. [ABSTRACT FROM AUTHOR]

Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019, which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited supervised molecular dynamics, an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole recognition pathway of Lopinavir, Ritonavir, and Nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease. [ABSTRACT FROM AUTHOR]

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies. [ABSTRACT FROM AUTHOR]