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Multisystemic inflammatory syndrome (Mis-C) has emerged in May 2020 as a serious complication of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). A total of 6 children presented to tertiary care hospitals with Mis-C, of which 5 (83%) have died during hospitalization. All included patients presented with respiratory symptoms (ranged from mild to severe acute respiratory distress syndrome) and gastrointestinal symptoms. Most of the patients are known to have medical illnesses. Pediatric Risk of Mortality (PRISM) IV score ranged from 3 to 87. All patients developed acidosis and varying stages of acute kidney injury and electrolyte disturbances. All were treated for coagulopathy, thrombocytopenia, bacterial infections as well as antiviral medications (either ritonavir or lopinavir). Most patients had chest X-ray changes either unilateral or bilateral lung changes. Multisystemic inflammatory syndrome is a rare, yet serious complication of SARS-CoV2 infection in children. Multisystem involvement should be anticipated and promptly treated. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection, commonly called COVID-19, has taken a jump from being rarely talked about to becoming a household name. Making it to history as the 5th global pandemic, this public health crisis has taken millions of lives all over the world. Right from the identification of patient zero, the pandemic has unfolded in waves of infection, triggering a domino effect that has impacted all aspects of life. Global efforts have been underway to combat this pandemic and minimize its repercussions, resulting in the development of efficient vaccines and drugs to treat the disease and control the spread of infection. However, making the benefits of these efforts available to everyone and walking the path towards the end of the pandemic remains a challenge. Keeping this in view, this review intends to present a summary of the sequential development of the pandemic, the recent advancements in the field of diagnostics and treatment, and the challenges that continue to remain in overcoming this public health crisis. It can be understood that the task of controlling and managing the impact of such a massive pandemic goes well beyond the boundaries of what present-day technology and advancements in the field of medicine and health care can offer. A collaborative and integrative approach between academic, scientific, social, and economic factors, along with close supervision and reinforcement of the current public safety protocols, can help to ensure a better management strategy to control the progression of COVID-19. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic response has been hindered by the absence of an efficient antiviral therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The reason why the previous preventative approach to COVID-19 solely through vaccines has failed could be a lack of understanding of how quickly the SARS-CoV-2 virus evolves. Given the absence of specific treatments for the virus, efforts have been underway to explore treatment options. Drug repurposing involves identifying new therapeutic uses for approved drugs, proving to be a time-saving strategy with minimal risk of failure. In this study, we report the successful use of a multidrug approach in patients with COVID-19. Successful administration of multidrug therapy, such as combinations of hydroxychloroquine and azithromycin, doxycycline and ivermectin, or ivermectin, doxycycline, and azithromycin, has been reported. Multidrug therapy is effective because of the differing mechanisms of action of these drugs, and it may also mitigate the emergence of drug-resistant SARS-CoV-2 strains. The medicines were lopinavir/ritonavir (Kaletra), bamlanivimab (monoclonal antibody), glycopyrrolate-formoterol (Bevespi), ciclesonide (Alvesco), famotidine (Pepcid), and diphenhydramine (Benadryl). [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of Aikeqing (AKQ), a compound of Chinese medicine, on drugmetabolizing activity and on the pharmacokinetic parameters of HIV-1 protease inhibitors lopinavir (LPV) and ritonavir (RTV) in Kaletra tablets. Methods Human liver microsomes were co-incubated with mixed probes AKQ. HPLC-MS was employed to measure the content of probe. Half-inhibitory concentration (IC50) of AKQ on different subtypes of cytochrome P450 enzymes involved in drug metabolism of liver microsomes was calculated. The P450 subtype, whose activity was significantly inhibited by AKQ was then identified. HPLC-MS analytical method for simultaneous determination of LPV and RTV in rat plasma was established. SD rats were orally given AKQ or vehicle once a day for 7 consecutive days. After half an hour of the last gavage of AKQ, the rats were given Kaletra by intragastric administration. Then, the blood concentration of LPV and RTV were measured and the effect of AKQ on pharmacokinetic parameters of LPV and RTV were analyzed. Results The methanol extract of AKQ at the concentrations of 0~500 µg·mL-1 showed inhibitory effects on the metabolic activity of CYP2D6, CYP2C8、 CYP2E1, CYP2C19, CYP1A2, CYP2B6, CYP2C9 and CYP3A4, with IC50 values of 7.7, 75.3, 144.0, 99.5, 43.5, 104.5, 49.3 and 204.9 µg·mL-1, respectively. An HPLC-MS/MS method was established for simultaneous quantification of LPV and RTV in blood samples. LPV and RTV showed linear relationships in the ranges of 30～ 10 000 ng·mL-1 and 3~1 000 ng·mL-1, respectively. The lowest limits of quantification were 30 ng·mL-1 and 3 ng·mL-1. Intra-day and inter-day precision were all less than 5%, and the accuracy of LPV and RTV was in the range of 96.3%~109%. The extraction recovery rates were not less than 88.7%, the matrix effects were 93.8%~105.0%, and the plasma samples were stable. Compared with Kaletra group, there was no significant changes in noncompartmental model parameters including AUC0-t, AUC0-∞, MRT0-t, t1/2z, tmax, Vz/F, Clz/F and Cmax of LPV in AKQ + Kaletra group (P＞0.05). But MRT0-∞ was found to be obviously affected by AKQ (P＜0.05). All pharmacokinetic parameters of RTV showed no significant change in AKQ+ Kaletra group (P＞0.05). Conclusion Aikeqing exhibited varying degrees of inhibitory effects on 8 human drug-metabolizing cytochromes P450, especially CYP2D6. A human-equivalent dose of Aikeqing does not affect the pharmacokinetic parameters of lopinavir and ritonavir in rats. [ABSTRACT FROM AUTHOR]

Cambodia has experienced exponential economic growth in recent years and is expected to graduate from least developed country (LDC) status within the next decade. Membership of the World Trade Organization (WTO) will require Cambodia to grant product and process patents for pharmaceuticals upon LDC graduation. This study aims to measure the impact of the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) on the price of HIV and hepatitis C medicine in Cambodia once it graduates from LDC status and is obliged to make patents available for pharmaceutical products and processes. Using scenarios based on likely outcomes of accession to the TRIPS Agreement, it measures the impact on the price of the HIV treatment program and compares that impact with the hepatitis C treatment program. Graduation from LDC status would be expected to result in a modest increase in the cost of the antiretroviral (ARV) treatment program and very large increases in the cost of the direct acting antivirals (DAA) treatment program. If annual treatment budgets remain constant, patent protection could see 1,515 fewer people living with HIV able to access ARV treatment and 2,577 fewer people able to access DAA treatment (a drop in treatment coverage of 93%). [ABSTRACT FROM AUTHOR]

Antiviral therapies are integral in the fight against SARS‐CoV‐2 (i.e. severe acute respiratory syndrome coronavirus 2), the causative agent of COVID‐19. Antiviral therapeutics can be divided into categories based on how they combat the virus, including viral entry into the host cell, viral replication, protein trafficking, post‐translational processing, and immune response regulation. Drugs that target how the virus enters the cell include: Evusheld, REGEN‐COV, bamlanivimab and etesevimab, bebtelovimab, sotrovimab, Arbidol, nitazoxanide, and chloroquine. Drugs that prevent the virus from replicating include: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, and Kaletra. Drugs that interfere with protein trafficking and post‐translational processing include nitazoxanide and ivermectin. Lastly, drugs that target immune response regulation include interferons and the use of anti‐inflammatory drugs such as dexamethasone. Antiviral therapies offer an alternative solution for those unable or unwilling to be vaccinated and are a vital weapon in the battle against the global pandemic. Learning more about these therapies helps raise awareness in the general population about the options available to them with respect to aiding in the reduction of the severity of COVID‐19 infection. In this 'A Guide To' article, we provide an in‐depth insight into the development of antiviral therapeutics against SARS‐CoV‐2 and their ability to help fight COVID‐19. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed. This graphical abstract is centered by co–crystal structure of SARS-CoV-2 Mpro, highlighting the theme of "non-covalent inhibitors targeting Mpro". The surrounding boxes display some representative medicinal chemistry strategies and active compounds concluded in the article. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and purpose: The COVID‐19 pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2), rapidly spread across the globe. Tremendous efforts have been mobilized to create effective antiviral treatment options to reduce the burden of the disease. This article summarizes the available knowledge about the antiviral drugs against SARS‐CoV‐2 from a neurologist's perspective. Methods: We summarize neurological aspects of antiviral compounds against SARS‐CoV‐2 with full, conditional, or previous marketing authorization by the European Medicines Agency (EMA). Results: Nirmatrelvir/ritonavir targets the SARS‐CoV‐2 3c‐like protease using combinatorial chemistry. Nirmatrelvir/ritonavir levels are affected by medications metabolized by or inducing CYP3A4, including those used in neurological diseases. Dysgeusia with a bitter or metallic taste is a common side effect of nirmatrelvir/ritonavir. Molnupiravir is a nucleotide analog developed to inhibit the replication of viruses. No clinically significant interactions with other drugs have been identified, and no specific considerations for people with neurological comorbidity are required. In the meantime, inconsistent results from clinical trials regarding efficacy have led to the withdrawal of marketing authorization by the EMA. Remdesivir is a viral RNA polymerase inhibitor and interferes with the production of viral RNA. The most common side effect in patients with COVID‐19 is nausea. Remdesivir is a substrate for CYP3A4. Conclusions: Neurological side effects and drug interactions must be considered for antiviral compounds against SARS‐CoV‐2. Further studies are required to better evaluate their efficacy and adverse events in patients with concomitant neurological diseases. Moreover, evidence from real‐world studies will complement the current knowledge. [ABSTRACT FROM AUTHOR]

Background: The current absence of gold‐standard or all‐aspect favorable therapies for COVID‐19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well‐designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N‐acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID‐19. Methods: Two 30‐person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study. Results: At the end of the study, a further decrease in C‐reactive protein was observed in the NAC group (P = 0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P > 0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C‐reactive protein), and lower mortality in hospitalized patients with COVID‐19. Conclusion: The NAC could be more effective as prophylactic or adjuvant therapy in stable non‐severe cases of COVID‐19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID‐19 or its therapy‐related side effects. [ABSTRACT FROM AUTHOR]

Our research aimed to analyze the application and outcome of several common antiviral drugs and the traditional Chinese medicine formulations for COVID-19 during the early months (January 20, 2020 to December 30, 2020) of the epidemics in China. Patients were clinically classified into mild, common, severe, and critical types based on their clinical symptoms, pulmonary imaging findings, and complications. During the study period, antiviral treatment was administered to 482 patients, with 342 patients receiving a combination of traditional Chinese and Western medicine, accounting for 80.60% and 57.19% of the discharged COVID-19 patients (598 cases), respectively. The main treatment consisted of monotherapy with lopinavir/ritonavir, arbidol, and chloroquine phosphate, with a need to change the treatment regimen in 29.88% of patients. Three traditional Chinese medicine formulations--Huoxiangzhengqi Liquid, Lianhuaqingwen Jiaonang, and Shufeng Jiedu Jiaonang--were used for COVID-19 treatment and showed good curing effects for patients with mild common clinical classification. Antiviral-related adverse effects were experienced by a total of 142 patients (29.46%). To sum up, antiviral and TCM treatments remain the mainstays of therapy for COVID-19 and show good effects. [ABSTRACT FROM AUTHOR]

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb–drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a -null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid. Drug- and herb-mediated activation of PXR upregulates the expression of CYP3A4/5 resulting in the increased metabolism and decreased systemic exposure of Paxlovid (NMV/r). [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: The ongoing global COVID-19 pandemic, caused by the SARS-CoV-2 virus, has generated significant apprehensions in maternalfetal medicine. Initially considered to affect the respiratory system primarily, recent findings have indicated that the pandemic has far-reaching implications for various physiological functions, particularly in pregnant individuals. This study focused on examining the influence of COVID-19 on placental histopathology in pregnant women infected with SARS-CoV-2. Material and Methods: We conducted a comparative study involving two groups of pregnant women with similar demographic characteristics: a group testing positive for COVID-19 (n=31) and a control group of COVID-19-negative pregnant women (n=31). After delivery, placental tissues were collected and subjected to comprehensive histopathological examination to determine any potential alterations in the placenta induced by SARS-CoV-2 infection. Results: Our study revealed substantial histopathological alterations in pregnant women with COVID-19 placentas. Notably, the COVID-19 group displayed a higher incidence of cesarean deliveries, possibly due to concerns related to maternal-fetal transmission and respiratory complications. Furthermore, neonates born to mothers in the COVID-19 group had significantly lower birth weights. Several placental histopathological changes, including villous fibrin deposits, thrombosis, intervillous hemorrhage, agglutination, avascular fibrotic villi, and syncytial knots, were markedly increased in the COVID-19 group, indicating compromised fetal blood circulation. Although not statistically significant, trends toward elevated villous infarction, fetal vascular malperfusion, and chorioamnionitis were observed. Conclusion: Our study underscores the potential risks associated with COVID-19 on placental health, maternal well-being, and neonatal outcomes. We must understand the underlying physiological mechanisms behind these pathological changes to provide optimal maternal-fetal care during this ongoing crisis. Comprehensive and multicentric studies are urgently required to confirm and expand our findings. [ABSTRACT FROM AUTHOR]

Simple Summary: We explored the potential of targeting the enzyme cytochrome P450 (CYP450) in colorectal cancer (CRC) using lopinavir/ritonavir. Various experimental methods in a preclinical phase were employed to assess the effects of lopinavir/ritonavir on CRC. The study found that inhibiting CYP450 reduced cell proliferation, induced cell death, and suppressed cell migration. Lopinavir/ritonavir also inhibited tumor growth and fibrosis. These results suggest that targeting CYP450 with lopinavir/ritonavir has therapeutic potential in CRC and highlight the need for further research in this area. Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC. [ABSTRACT FROM AUTHOR]

HTLV-I-associatedmyelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <300 nm) while maintaining their immunomodulatory activity. Therefore, we investigated the role of soluble and exosomal ICPs in HTLV-1 associated neuroinflammation. For the very first time, we demonstrate a unique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors inHAM/TSP sera, and in purified exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. These ICPs were found to be co-localized with the endosomal sorting complex required for transport (ESCRT) pathway proteins and exhibited functional binding with their respective ligands. Viral proteins and cytokines (primarily IFNγ) were found to be present in purified exosomes. IFNγ exposure enhanced the release of ICP molecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantly inhibited this process. HTLV-1 b-Zip protein (HBZ) has been linked to factors that enhance EV release and concurrent knockdown here led to the reduced expression of ESCRT associated genes (e.g., Hrs, Vsp4, Alix, Tsg101) as well as abrogated the release of ICP molecules, suggesting HBZ involvement in this process. Moreso, exosomes from OSP2 cells adversely affected CD8 T-cell functions by diminishing levels of cytokines and cytotoxic factors. Collectively, these findings highlight exosomemediated immunomodulation of T-cell functions with HBZ and ESCRT pathways as an underlying mechanism in the context of HTLV-1-induced neuroinflammation. [ABSTRACT FROM AUTHOR]

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020–2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir–ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir–ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has affected over 760 million individuals worldwide, resulting in more than 6.8 million reported deaths. Early detection of patient deterioration can assist in predicting outcomes and prioritizing healthcare services based on evidence-based indicators. Interleukin-6 (IL-6) is a cytokine that plays a role in the inflammatory process, making it a potential parameter for assessing a patient's inflammatory state. This study aimed to analyze the characteristics, laboratory profiles, and IL-6 levels of COVID-19 patients. This study used a retrospective cohort study design with medical record data. The characteristics (n=68) and IL-6 levels (n=52) of the patients on the first, third, and sixth days of treatment were recorded consecutively. The mean age of the patients was 49 years, with the majority being male (72%) and the most prevalent comorbidity being hypertension (29%). The average duration of hospitalization was 10.94 days. Shortness of breath was the most commonly reported symptom (45.6%). The medians of neutrophil-lymphocyte ratio, C-reactive protein, procalcitonin, ferritin, and D-dimer were above normal. Significant differences were observed in lymphocytes (p=0.046), procalcitonin (p=0.023), and D-dimer (p=0.000) between survivor and non-survivor patients. Significant dynamic changes in IL-6 levels were observed from the first day to the sixth day (p=0.014) and from the third day to the sixth day (p=0.041). In conclusion, risk stratification, laboratory profiles, and IL-6 levels play a role in assessing the severity and outcomes of COVID-19 patients. [ABSTRACT FROM AUTHOR]

Introduction: Drug-drug cocrystals of Lopinavir and Ritonavir were designed and characterized. In view of literature, Ritonavir increases the oral bioavailability of Lopinavir in low dosage. Aim: The present research aimed to improve the solubility, dissolution, and oral bioavailability of Lopinavir through a cocrystallization approach using Ritonavir as a coformer. Materials and Methods: Cocrystallization was carried out using wet grinding and solvent evaporation methods. Prepared Cocrystals were examined and evaluated using characterization methods such as DSC, PXRD, FTIR, Polarized light microscopy, % Drug content, FE-SEM, Micromeritics properties, Solubility, Dissolution, and Stability studies as per ICH guidelines. Results: Developed cocrystals were showed superior solubility and dissolution as compared to pure drug. After 48 hr, aqueous solubility of Lopinavir and Ritonavir co-amorphous formulation (LRCWG) was increased 3.7-fold in the wet grinding method, while Lopinavir and Ritonavir Cocrystals Prepared by Solvent Evaporation Method (LRCSE) indicated 5.9-fold increase compared to pure drug. The co-amorphous formulation was developed using wet grinding showed 86% drug release at 60 min, and cocrystals synthesized through solvent evaporation method showed 94% of drug release. Conclusion: Cocrystals produced using solvent evaporation approach were stable and showed excellent physico-chemical characteristics. The study concluded that the cocrystallization approach would prove to be a successful method to improve physico-chemical and mechanical properties. [ABSTRACT FROM AUTHOR]

Thermal polymerization (TP) and electropolymerization (EP) are the two methods used in this study to explore the molecular imprinting process. To detect the antiviral medication lopinavir (LPV), an inhibitor of enzyme HIV-1 protease that is co-formulated with ritonavir (RTV) to extend its half-life in the body, with greater precision, these methods were merged with an electrochemical sensor. The sensors were created on glassy carbon electrodes (GCE) based on molecularly imprinted polymers (MIP) using TP with methacrylic acid (MAA) functional monomer and EP with p -aminobenzoic acid (PABA) functional monomer. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and electrochemical methods were utilized to examine the technical features of the suggested sensors. For both approaches, the necessary optimization investigations were carried out. Different LPV concentrations, ranging from 1.0 pM to 17.5 pM in drug solution and commercial human serum samples, were used to validate the analytical efficiency of the two sensors and compare their electroanalytical behaviour. For TP-LPV@MIP/GCE and EP-LPV@MIP/GCE, the corresponding limit of detection (LOD) was 2.68 × 10−13 M (0.169 pg mL−1) and 1.79 × 10−13 M (0.113 pg mL−1) in standard solutions, and 2.87 × 10−13 M (0.180 pg mL−1) and 2.91 × 10−13 M (0.183 pg mL−1) in serum samples. For the measurement of LPV in tablet form and serum samples, the proposed TP-LPV@MIP/GCE and EP-LPV@MIP/GCE sensors provide good recovery, demonstrating 99.85–101.16 % and 100.36–100.97 % recovery, respectively. The imprinting factor was utilized to demonstrate the selectivity of the suggested sensors by utilizing several anti-viral drugs that are structurally comparable to LPV. Additionally, the constructed sensors were examined for the potential impacts of interferences and the stability during the storage. [Display omitted] • The first use of MIP-based electrochemical sensors for LPV measurement. • Comparing two distinct MIP approaches (thermal and electropolymerization). • Precise and reliable assessment of biological and pharmacological tablets. • MIP-based sensor offers great selectivity along with excellent sensitivity. [ABSTRACT FROM AUTHOR]

Seeking an alternative approach for detecting adverse drug reactions (ADRs) in coronavirus patients (COVID-19) and enhancing drug safety, a retrospective study of six months was conducted utilizing an electronic medical record (EMR) database to detect ADRs in hospitalized patients for COVID-19, using "ADR prompt indicators" (APIs). Consequently, confirmed ADRs were subjected to multifaceted analyses, such as demographic attribution, relationship with specific drugs and implication for organs and systems of the body, incidence rate, type, severity, and preventability of ADR. The incidence rate of ADRs is 37%, the predisposition of organs and systems to ADR is observed remarkably in the hepatobiliary and gastrointestinal systems at 41.8% vs. 36.2%, p < 0.0001, and the classes of drugs implicated in the ADRs are lopinavir-ritonavir 16.3%, antibiotics 24.1%, and hydroxychloroquine12.8%. Furthermore, the duration of hospitalization and polypharmacy are significantly higher in patients with ADRs at 14.13 ± 7.87 versus 9.55 ± 7.90, p < 0.001, and 9.74 ± 5.51 versus 6.98 ± 4.36, p < 0.0001, respectively. Comorbidities are detected in 42.5% of patients and 75.2%, of patients with DM, and HTN, displaying significant ADRs, p-value < 0.05. This is a symbolic study providing a comprehensive acquaintance of the importance of APIs in detecting hospitalized ADRs, revealing increased detection rates and robust assertive values with insignificant costs, incorporating the hospital EMR database, and enhancing transparency and time effectiveness. [ABSTRACT FROM AUTHOR]

Artemisinin‐based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether‐lumefantrine in HIV‐uninfected and HIV‐infected children living in a high‐transmission region of Uganda. HIV‐infected children were on efavirenz‐, nevirapine‐, or lopinavir‐ritonavir‐based antiretroviral regimens, with daily trimethoprim‐sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42‐day follow‐up and incorporated genotyping into a time‐to‐event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy‐seven children contributed 364 episodes to the model (186 HIV‐uninfected and 178 HIV‐infected), with recurrent microscopy‐detectable parasitemia detected in 176 episodes by day 42. The final model was a two‐compartment model with first‐order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir‐ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV‐uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5‐fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV‐infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa. [ABSTRACT FROM AUTHOR]

PURPOSE: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer. METHODS: Physiologically based pharmacokinetic modeling was used to conduct virtual clinical trials with a parallel group study design in the presence and absence of ritonavir (100 mg twice daily for 5 days). The magnitude and time course of changes in KI exposure when coadministered with ritonavir was evaluated as the primary outcome. RESULTS: Dosing of ritonavir resulted in a > 2-fold increase in steady-state area under the plasma concentration-time curve and maximal concentration for six of the 10 KIs. When the KI was coadministered with ritonavir, dose reductions to between 10% and 75% of the original dose were required to achieve an area under the plasma concentration-time curve within 1.25-fold of the value in the absence of ritonavir. CONCLUSION: To our knowledge, this study provides the first data to assist clinicians' understanding of the drug interaction risk associated with administering ritonavir-containing COVID-19 therapies to patients with cancer who are currently being treated with KIs. These data may support clinicians to make more informed dosing decisions for patients with cancer undergoing treatment with KIs who require treatment with ritonavir-containing COVID-19 antiviral therapies. These data may support clinicians to make more informed dosing decisions for patients with cancer undergoing treatment with kinase inhibitors who require treatment with ritonavir-containing COVID-19 antiviral therapies. [ABSTRACT FROM AUTHOR]

COVID-19, caused by SARS-CoV-2, requires new approaches to control the disease. Programmed cell death protein (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) play important roles in T-cell exhaustion in severe COVID-19. This study evaluated the frequency of whole blood lymphocytes expressing PD-1 and CTLA-4 in COVID-19 patients upon admission to the intensive care unit (ICU) (i.e., severe) or infection ward (i.e., moderate) and after 7 days of antiviral therapy. COVID-19 patients were treated with either favipiravir or Kaletra (FK group, 11 severe and 11 moderate) or dexamethasone plus remdesivir (DR group, 7 severe and 10 moderate) for 7 days in a pilot study. Eight healthy control subjects were also enrolled. The frequency of PD-1 + and CTLA4 + lymphocytes in whole blood was evaluated by flow cytometry. Patients on DR therapy had shorter hospital stays than those on FK therapy. The frequency of PD-1 + lymphocytes in the FK group at baseline differed between COVID-19 patients and healthy controls, while the frequency of both PD-1 + and CTLA-4 + cells increased significantly 7 days of FK therapy. The response was similar in both moderate and severe patients. In contrast, the frequency of PD-1 + and CTLA-4 + lymphocytes varied significantly between patients and healthy controls before DR treatment. DR therapy enhanced PD-1 + but not the CTLA-4 + frequency of these cells after 7 days. We show that the frequency of PD-1 and CTAL-4-bearing lymphocytes during hospitalization was increased in Iranian ICU COVID-19 patients who received FK treatment, but that the frequency of CTLA-4 + cells was higher at baseline and did not increase in patients who received DR. The effectiveness of DR treatment may reflect differences in T-cell activation or exhaustion status, particularly in CTLA-4-expressing cells. [ABSTRACT FROM AUTHOR]

Background: Clinicians and patients want to know the benefits and harms of outpatient treatment options for SARS-CoV-2 infection.Purpose: To assess the benefits and harms of 12 different COVID-19 treatments in the outpatient setting.Data Sources: Epistemonikos COVID-19 L·OVE Platform, searched on 4 April 2022.Study Selection: Two reviewers independently screened abstracts and full texts against a priori-defined criteria. Randomized controlled trials (RCTs) that compared COVID-19 treatments in adult outpatients with confirmed SARS-CoV-2 infection were included.Data Extraction: One reviewer extracted data and assessed risk of bias and certainty of evidence (COE). A second reviewer verified data abstraction and assessments.Data Synthesis: The 26 included studies collected data before the emergence of the Omicron variant. Nirmatrelvir-ritonavir and casirivimab-imdevimab probably reduced hospitalizations (1% vs. 6% [1 RCT] and 1% vs. 4% [1 RCT], respectively; moderate COE). Nirmatrelvir-ritonavir probably reduced all-cause mortality (0% vs. 1% [1 RCT]; moderate COE), and regdanvimab probably improved recovery (87% vs. 72% [1 RCT]; moderate COE). Casirivimab-imdevimab reduced time to recovery by a median difference of 4 days (10 vs. 14 median days [1 RCT]; high COE). Molnupiravir may reduce all-cause mortality, sotrovimab may reduce hospitalization, and remdesivir may improve recovery (low COE). Lopinavir-ritonavir and azithromycin may have increased harms, and hydroxychloroquine may result in lower recovery rates (low COE). Other treatments had insufficient evidence or no statistical difference in efficacy and safety versus placebo.Limitation: Many outcomes had few events and small samples.Conclusion: Some antiviral medications and monoclonal antibodies may improve outcomes for outpatients with mild to moderate COVID-19. However, the generalizability of the findings to the currently dominant Omicron variant is limited.Primary Funding Source: American College of Physicians. (PROSPERO: CRD42022323440). [ABSTRACT FROM AUTHOR]

Introduction: Although a long time past since COVID-19 was broken out, it is hard to determine which pharmacological combination regimen is more efficacious. The present study aimed to evaluate the efficacy of lopinavir/ritonavir (LPV/r) plus interferon (IFN) beta-1a regimen compared to the hydroxychloroquine (HCQ) regimen in moderately ill patients with COVID-19. Methods: A multiple-centre retrospective observational case-controlled study was performed between March and September 2020, including adults with confirmed COVID-19. The patients were categorised into age- and sex-matched two groups; LPV/r plus IFN beta-1a (n = 102) and HCQ (n = 298) regimens. Clinical outcomes and mortality rates were compared between the groups. Results: LPV/r plus interferon (INF) beta-1a regimen had improved none of the clinical outcomes and mortality rate compared to the HCQ regimen. The length of stay (LOS) in the hospital and the need for oxygen therapy were slightly worse in the LPV/r plus INF beta-1a regimen (4.73 ± 2.93 days, 63%) than in the HCQ group (3.74 ± 3.30 days, 48.3%). No statistically significant difference was observed between the two groups in care of intensive care unit (ICU) admission, LOS in ICU, the need for non-invasive ventilation and the need for invasive mechanical ventilation as well as in-hospital mortality rate. Conclusions: LPV/r plus IFN beta-1a regimen did not show any meaningful improvement in clinical outcomes or mortality compared to the HCQ regimen. Larger randomised controlled trials are needed to assess the efficacy of this combination further. [ABSTRACT FROM AUTHOR]

Background Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. Methods A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. Results From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2–19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P <.001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. Conclusions Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. Clinical Trials Registration NCT03162107. [ABSTRACT FROM AUTHOR]

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: 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. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) has affected over 145 million infected people and 3 million deaths worldwide. There has been limited data to recommend either for or against use of antiviral regimens in mild COVID-19 patients. This study aimed to compare clinical outcomes between mild COVID-19 patients receiving antiviral drugs and those without. Method: Thai patients diagnosed with COVID-19 at field hospital affiliated to Thammasat University Hospital, Thailand were evaluated between January 1, 2020 and April 13, 2021. Patients’ data, clinical presentation, past medical history, laboratory results, and treatment outcomes were extensively reviewed. Results: Five hundred patients with positive tests were included in the study. The mean age was 35.9 years; 46% males. There were 225 (45%), 207 (41.4%), 44 (8.8%), 18 (3.6%), 6 (1.2%) patients with asymptomatic, mild, moderate, severe, and critical COVID-19, respectively. Of 207 mild COVID-19 patients, 9 (4.3%) received lopinavir/ritonavir or darunavir/ritonavir, 17 (8.2%) received favipiravir, while 175 (84.5%) had only supportive care. Mild COVID-19 patients receiving antiviral treatment had longer median length of hospital stay [13 days (IQR 11–14) vs. 10 days (IQR 8–12), p < 0.001] than patients having only supportive treatment. Antiviral drug use was significantly associated with longer hospital stay (>10 days) in mild COVID-19 patients (OR 5.52; 95%CI 2.12–14.40, p < 0.001). Adverse drug reactions such as diarrhea, abdominal pain, and hepatitis were also demonstrated in our COVID-19 patients with antiviral treatments. Majority of patients (97.6%) recovered without any complications and were discharged home. Two deaths were caused by acute respiratory distress syndrome from severe COVID-19 pneumonia. Conclusion: Antiviral treatment could not provide superior clinical outcomes to supportive care in mild COVID-19 patients. Mild COVID-19 patients receiving antiviral medication had longer length of hospital stay than those without. Standard supportive care and regular monitoring of disease progression might be keys for successful management of mild COVID-19.

Background/Aims: Recent data indicate the presence of liver enzyme abnormalities in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the clinical features and treatment outcomes of COVID-19 patients with abnormal liver enzymes. Methods: We performed a retrospective, multicenter study of 874 COVID-19 patients admitted to five tertiary hospitals from February 20 to April 14, 2020. Data on clinical features, laboratory parameters, medications, and treatment outcomes were collected until April 30, 2020, and compared between patients with normal and abnormal aminotransferases. Results: Abnormal aminotransferase levels were observed in 362 patients (41.1%), of which 94 out of 130 (72.3%) and 268 out of 744 (36.0%) belonged to the severe and non-severe COVID- 19 categories, respectively. The odds ratios (95% confidence interval) for male patients, patients with a higher body mass index, patients with severe COVID-19 status, and patients with lower platelet counts were 1.500 (1.029 to 2.184, p=0.035), 1.097 (1.012 to 1.189, p=0.024), 2.377 (1.458 to 3.875, p=0.001), and 0.995 (0.993 to 0.998, p>0.001), respectively, indicating an independent association of these variables with elevated aminotransferase levels. Lopinavir/ ritonavir and antibiotic use increased the odds ratio of abnormal aminotransferase levels after admission (1.832 and 2.646, respectively, both p

In the SARS-CoV-2 pandemic, the so far two most effective approved antivirals are the protease inhibitors nirmatrelvir, in combination with ritonavir (Paxlovid) and ensitrelvir (Xocova). However, antivirals and indeed all antimicrobial drugs are sooner or later challenged by resistance mutations. Studying such mutations is essential for treatment decisions and pandemic preparedness. At the same time, generating resistant viruses to assess mutants is controversial, especially with pathogens of pandemic potential like SARS-CoV-2. To circumvent gain-of-function research with non-attenuated SARS-CoV-2, a previously developed safe system based on a chimeric vesicular stomatitis virus dependent on the SARS-CoV-2 main protease (VSV-Mpro) was used to select mutations against ensitrelvir. Ensitrelvir is clinically especially relevant due to its single-substance formulation, avoiding drug-drug interactions by the co-formulated CYP3A4 inhibitor ritonavir in Paxlovid. By treating VSV-Mpro with ensitrelvir, highly-specific resistant mutants against this inhibitor were selected, while being still fully or largely susceptible to nirmatrelvir. We then confirmed several ensitrelvir-specific mutants in gold standard enzymatic assays and SARS-CoV-2 replicons. These findings indicate that the two inhibitors can have distinct viral resistance profiles, which could determine treatment decisions. [Display omitted] • A safe, surrogate virus system was developed to generate SARS-CoV-2-Mpro mutants. • Mutants were generated against the protease inhibitor Xocova® (ensitrelvir). • Some mutants were specific for ensitrelvir with no cross-resistance to nirmatrelvir. • The S1′ subpocket of Mpro was a hot spot for ensitrelvir-specific mutations. [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]

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Objectives: The COVID-19 pandemic necessitates time-sensitive policy and implementation decisions regarding new therapies in the face of uncertainty. This study aimed to quantify consequences of approving therapies or pursuing further research: immediate approval, use only in research, approval with research (eg, emergency use authorization), or reject.Methods: Using a cohort state-transition model for hospitalized patients with COVID-19, we estimated quality-adjusted life-years (QALYs) and costs associated with the following interventions: hydroxychloroquine, remdesivir, casirivimab-imdevimab, dexamethasone, baricitinib-remdesivir, tocilizumab, lopinavir-ritonavir, interferon beta-1a, and usual care. We used the model outcomes to conduct cost-effectiveness and value of information analyses from a US healthcare perspective and a lifetime horizon.Results: Assuming a $100 000-per-QALY willingness-to-pay threshold, only remdesivir, casirivimab-imdevimab, dexamethasone, baricitinib-remdesivir, and tocilizumab were (cost-) effective (incremental net health benefit 0.252, 0.164, 0.545, 0.668, and 0.524 QALYs and incremental net monetary benefit $25 249, $16 375, $54 526, $66 826, and $52 378). Our value of information analyses suggest that most value can be obtained if these 5 therapies are approved for immediate use rather than requiring additional randomized controlled trials (RCTs) (net value $20.6 billion, $13.4 billion, $7.4 billion, $54.6 billion, and $7.1 billion), hydroxychloroquine (net value $198 million) is only used in further RCTs if seeking to demonstrate decremental cost-effectiveness and otherwise rejected, and interferon beta-1a and lopinavir-ritonavir are rejected (ie, neither approved nor additional RCTs).Conclusions: Estimating the real-time value of collecting additional evidence during the pandemic can inform policy makers and clinicians about the optimal moment to implement therapies and whether to perform further research. [ABSTRACT FROM AUTHOR]

Amongst our patients, the addition of Kaletra has led to a partial response in half of the cases, and 5 of the 12 patients achieved stable disease who were otherwise progressing on CFZ-based treatment. As per IMWG criteria, six (50%) of the patients achieved a partial response (PR) to treatment, five patients (42%) achieved stable disease (SD), whilst one had disease progression (PD) despite therapy. Treatment failure resulted from progression for 6 patients (50%), treatment cessation for two patients (17%), and death for two patients (17%). [Extracted from the article]

Purpose: A number of research articles has been published evaluating safety and efficacy of drugs against COVID-19. This study was undertaken to collate and review the information regarding common proposed anti- viral drugs for easy reference. Methods: The literature was search was done using terms like severe acute respiratory syndrome or SARS-CoV-2 or 2019-nCoV or SARS-CoV or COVID-19 in combination with drugs or treatment or pharmaco-therapy using PubMed and google scholar to identify relevant articles. Results: Despite showing good early results, hydroxychloroquine and lopinavir-ritonavir has not shown clinical benefit in randomized controlled trials. However lopinavir in combination with other drugs specially interferon is being investigated. Remdesivir has shown positive effect in terms of clinical improvement and continued to being investigated alone or in combination with other drugs. Favipiravir has shown mixed results and more data from adequately powered study is needed to prove its efficacy. Conclusions: Many drugs which showed positive effect in initial studies could not replicate the same benefit in large randomized controlled trials. There is need to evaluate efficacy and safety of drugs based on high quality evidence before allowing it to be used in general population.

The DUALIS study demonstrated efficacy and safety of switching to dolutegravir plus ritonavir-boosted darunavir (DRV/r) (2DR) as compared to standard-of-care-therapy with two nucleoside reverse transcriptase inhibitors + DRV/r (3DR) in pretreated people living with HIV (PLWH), 48 weeks after switching. This DUALIS sub-study investigates health-related-quality-of-life (HrQoL) in this study-population. The Hospital Anxiety and Depression Scale (HADS) and the Medical Outcome Survey-HIV (MOS-HIV) were used assessing anxiety and depression symptoms, respectively HrQoL. Data were collected at baseline, 4, 24, and 48 weeks after randomization. Outcome scores were dichotomized and used as criteria in longitudinal models identifying differential developments. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as main measures of effects. ORs<1 indicate better results for HADS, and worse for MOS-HIV scores in the 2DR compared to 3DR group. In total, 263 subjects were randomized and treated (2DR n=131, 3DR n=132; median age 48 years). Significant different progressions could only be found for HADS-Depression scores (OR=.87, 95% CI:.78,.98, p=.02). While HADS-Depression scores decreased in the 2DR group, they increased in 3DR group. This sub-study showed no disadvantages regarding HrQoL in PLWH after switching to DTG+DRV/r. Considering lifelong requirements for antiretroviral medication, close attention to HrQL is required. [ABSTRACT FROM AUTHOR]

Novel coronavirus pneumonia (COVID-19) is a respiratory infection caused by infecting lungs and respiratory pathways which has rapidly spread to 216 countries. It is causing serious harm to the world's entire population and a huge social burden, which can spread mainly by droplets produced during coughing and sneezing from animal to animal or human to human. There were no drugs or vaccines available as of May 2020. Though the severity and infectious behavior and mortality rate of COVID-19 led to the discovery of various vaccines and drugs that are available to control COVID-19 pandemic. India has two vaccines: Covishield and Covaxin approved by the Government of India on 2nd January 2021. Of this sudden and lethal disease, the traditional Indian siddha medicine was proficient as an alternative source, in performing differentiation with fewer side effects and better ability to prevent and control. In this article, we have comprehensively analyzed the case study and the efficacy of Indian Siddha medicine Kabasura Kudineer chooranam. Naturally occurring Indian Siddha medicinal (Kabasura Kudineer chooranam) compounds and its treatment as prevention measures so as to provide strategy and suggestions for the disease COVID-19 are discussed. [ABSTRACT FROM AUTHOR]

The drug repurposing of known approved drugs (e.g., lopinavir/ritonavir) has failed to treat SARS-CoV-2-infected patients. Therefore, it is important to generate new chemical entities against this virus. As a critical enzyme in the lifecycle of the coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive target for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with a fragment-based drug design (ADQN–FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from the lead compounds based on our structure-based optimization policy (SBOP). All of the 47 lead compounds obtained directly with our AI model and related derivatives based on the SBOP are accessible in our molecular library. These compounds can be used as potential candidates by researchers to develop drugs against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background: Coronavirus Disease 2019 (COVID-19) is an evolving pandemic that urged the need to investigate various antiviral therapies. This study was conducted to compare efficacy and safety outcomes of darunavir-cobicistat versus lopinavir-ritonavir in treating patients with COVID-19 pneumonia. Methods and findings: This retrospective, multicenter, observational study was conducted on adult patients hospitalized in one of the COVID-19 facilities in Qatar. Patients were included if they received darunavir-cobicistat or lopinavir-ritonavir for at least three days as part of their COVID-19 treatments. Data were collected from patients' electronic medical records. The primary outcome was a composite endpoint of time to clinical improvement and/or virological clearance. Descriptive and inferential statistics were used at alpha level of 0.05. A total of 400 patients was analyzed, of whom 100 received darunavir-cobicistat and 300 received lopinavir-ritonavir. Majority of patients were male (92.5%), with a mean (SD) time from symptoms onset to start of therapy of 7.57 days (4.89). Patients received lopinavir-ritonavir had significantly faster time to clinical improvement and/or virological clearance than patients received darunavir-cobicistat (4 days [IQR 3–7] vs. 6.5 days [IQR 4–12]; HR 1.345 [95%CI: 1.070–1.691], P = 0.011). Patients received lopinavir-ritonavir had significantly faster time to clinical improvement (5 days [IQR 3–8] vs. 8 days [IQR 4–13]; HR 1.520 (95%CI: 1.2–1.925), P = 0.000), and slower time to virological clearance than darunavir-cobicistat (25 days [IQR 15–33] vs. 21 days [IQR 12.8–30]; HR 0.772 (95%CI: 0.607–0.982), P = 0.035). No significant difference in the incidence or severity of adverse events between groups. The study was limited to its retrospective nature and the possibility of covariates, which was accounted for by multivariate analyses. Conclusion: In patients with COVID-19 pneumonia, early treatment with lopinavir-ritonavir was associated with faster time to clinical improvement and/or virological clearance than darunavir-cobicistat. Future trials are warranted to confirm these findings. Trial registration: ClinicalTrials.gov number, NCT04425382. [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]

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID‐19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID‐19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off‐label use of hydroxychloroquine for COVID‐19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection. [ABSTRACT FROM AUTHOR]

The combination of lopinavir/ritonavir remains one of the first-line therapies for the initial antiretroviral regimen in pediatric HIV-infected children. However, the implementation of this recommendation has faced many challenges due to cold-chain requirements, high alcohol content, and unpalatability for ritonavir-boosted lopinavir syrup. In addition, the administration of crushed tablets has shown a detriment for the oral bioavailability of both drugs. Therefore, there is a clinical need to develop safer and better formulations adapted to children's needs. This work has demonstrated, for the first time, the feasibility of using direct powder extrusion 3D printing to manufacture personalized pediatric HIV dosage forms based on 6 mm spherical tablets. H-bonding between drugs and excipients (hydroxypropyl methylcellulose and polyethylene glycol) resulted in the formation of amorphous solid dispersions with a zero-order sustained release profile, opposite to the commercially available formulation Kaletra, which exhibited marked drug precipitation at the intestinal pH. [ABSTRACT FROM AUTHOR]

This study aimed to assess the efficacy and safety of different medications available at present for severe coronavirus disease 2019 (COVID‐19) infection. We searched databases for randomized controlled trials (RCTs) published up to April 30, 2021, with Chinese or English language restriction, of medications recommended for patients (aged 18 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). We identified 1855 abstracts and of these included 15 RCTs comprising 3073 participants through database searches and other sources. In terms of efficacy, compared with the standard of care (SOC) group, no significant decrease in ACM was found in α‐lipoic acid, convalescent plasma (CP), azithromycin, tocilizumab, methylprednisolone, interferon beta, CP/SOC, high dosage sarilumab, low dosage sarilumab, remdesivir, lopinavir–ritonavir, auxora, and placebo group. Compared with placebo, we found that a significant decrease in ACM was only found in methylprednisolone (odds ratio [OR]: 0.16, 95% confidence interval [CI]: 0.03–0.75]. With respect to TEAEs, the CP group showed lower TEAEs than placebo (OR: 0.07, 95% CI: 0.01–0.58) or SOC (OR: 0.05, 95% CI: 0.01–0.42) group for the therapy of severe COVID‐19 patients. This study only demonstrated that methylprednisolone was superior to placebo in treating patients with severe COVID‐19 infection. Meanwhile, this further confirmed that the safety of other treatment interventions might be inferior to CP for the therapy of severe COVID‐19 patients. Highlights: We considered addressing direct and indirect comparisons of medications from the angle of severe COVID‐19 infection based on random controlled trials (RCTs)We explored the difference of efficacy and safety of for the pharmaceutical interventions of severe COVID‐19 patients from different control conditions (i.e., placebo and SOC).To date, the findings from this network meta‐analysis may represent much more comprehensive analysis for the medications of severe COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare intensive care unit (ICU) and overall hospital mortality in patients treated with favipiravir and lopinavir-ritonavir for COVID-19. Methods: Data were collected retrospectively between March 10 and May 10, 2020, from patients' records admitted to ICU due to COVID-19. Laboratory data, clinical characteristics, ICU and hospital mortality, ICU and hospital length of stay were compared in patients treated with favipiravir and lopinavir-ritonavir. Results: A total of 100 patients' data were investigated. Favipiravir was used as the treatment for 85% of patients, with the rest treated with lopinavir-ritonavir. Clinical and laboratory data of both antiviral treatment groups were similar. Length of hospital stay was 16 (9-24) days with favipiravir and 8.5 (5-12.5) days with lopinavir-ritonavir (p=0.002). Length of ICU stay for favipiravir and lopinavir-ritonavir groups were 8 (5-15) days and 4 (3-9) days, respectively (p=0.011). ICU mortality was 65.9% for the favipiravir and 80% for lopinavir-ritonavir (p=0.002). Hospital mortality for favipiravir and lopinavir-ritonavir was 67.1% and 80%, respectively (p=0.001). Conclusion: The mortality in patients treated with favipiravir was less than patients treated with lopinavir-ritonavir. Favipiravir needs more attention and trials for its effect to be confirmed. [ABSTRACT FROM AUTHOR]

Abstract The coronavirus disease (COVID-19) pandemic has led to a global struggle to cope with the sheer numbers of infected persons, many of whom require intensive care support or eventually succumb to the illness. The outbreak is managed by a combination of disease containment via public health measures and supportive care for those who are affected. To date, there is no specific anti-COVID-19 treatment. However, the urgency to identify treatments that could turn the tide has led to the emergence of several investigational drugs as potential candidates to improve outcome, especially in the severe to critically ill. While many of these adjunctive drugs are being investigated in clinical trials, professional bodies have attempted to clarify the setting where the use of these drugs may be considered as off-label or compassionate use. This review summarizes the clinical evidence of investigational adjunctive treatments used in COVID-19 patients as well as the recommendations of their use from guidelines issued by international and national organizations in healthcare.

Background: During the first wave of the COVID-19 pandemic, severe patients were treated with the off-label drugs hydroxychloroquine and lopinavir/ritonavir. The aim of the study was to determine the prevalence of potential drug-drug interactions (DDIs) between hydroxychloroquine, lopinavir/ritonavir and concomitant medications used by hospitalized patients treated for COVID-19 in Costa Rica.Methods: We included all patients that received lopinavir/ritonavir or hydroxychloroquine as treatment for COVID-19. Clinical pharmacists reviewed the prescription profile of each patient and determined the probability and severity of any DDI through two databases (The Lexi-Interact program) and the Micromedex online interaction checker. A logistic regression model was used to identify variables associated with the occurrence of potential DDIs.Results: We identified a total of 108 potential DDIs in 34 inpatients (n=34). At least one of these DDIs occurred in 27 patients (79.4%; 95% CI: 65.8-92.9%). A total of 70 DDIs (64.8%) were classified as clinically relevant (grade D or X) by the clinical pharmacists. Only the number of concomitant drugs was associated with the occurrence of a probable DDI. The most common drugs associated with any DDI were fentanyl (n=12, 11.1%), midazolam (n=11, 10.2%), and insulin (n=10, 10.2%).Conclusion: A large proportion of patients treated with hydroxychloroquine and lopinavir/ritonavir for severe COVID-19 were at risk for clinical meaningful DDIs.

Toxoplasmosis is a zoonotic disease of major significant perspectives in public health and veterinary medicine. So far, the available drugs control only the active infection, once the parasite encysts in the tissues, they lose their efficacy. Cytokines; IFN-γ and IL-10, play a critical role in the modulation of toxoplasmic encephalitis and neuro-inflammation in chronic toxoplasmosis. Antiretroviral protease inhibitors applied in the treatment of acquired immunodeficiency syndrome, revealed activity against multiple parasites. Aluvia (lopinavir/ritonavir) (L/R); an aspartyl protease inhibitor, had efficiently treated T. gondii RH strain infection. We investigated the potential activity of L/R against experimental T. gondii infection with a cystogenic Me49 strain in mice, considering the role of IFN-γ and IL-10 in the neuropathology versus pyrimethamine-sulfadiazine combination therapy. Three aluvia regimens were applied; starting on the day of infection (acute phase), 2-week PI (early chronic phase) and eight weeks PI (late chronic phase). L/R reduced the brain-tissue cyst burden significantly in all treatment regimens. It impaired the parasite infectivity markedly in the late chronic phase. Ultrastructural changes were detected in Toxoplasma cyst membrane and wall, bradyzoite membrane and nuclear envelope. The signs of bradyzoite paraptosis and cytoplasmic lipid droplets were observed. L/R had significantly reduced the brain-homogenate levels of IFN-γ and IL-10 in its three regimens however, they could not reach the normal level in chronic phases. Cerebral hypercellularity, perivascular inflammatory response, lymphoplasmacytic infiltrates and glial cellular reaction were ameliorated by L/R treatment. Herein, L/R was proved to possess promising preventive and therapeutic perspectives in chronic cerebral toxoplasmosis. [ABSTRACT FROM AUTHOR]

Several therapeutic regimens for COVID-19 have been studied, such as combination antiviral therapies. We aimed to compare outcome of two types of combination therapies atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. 108 patients with moderate and severe forms of COVID-19 were divided into two groups (each group 54 patients). One group received ATV/r plus hydroxychloroquine, and the other group received hydroxychloroquine plus LPV/r. Then, both groups were evaluated and compared for clinical symptoms, recovery rates, and complications of treatment regimens. Our findings showed a significant increase in bilirubin in ATV/r-receiving group compared to LPV/r receivers. There was also a significant increase in arrhythmias in the LPV/r group compared to the ATV/r group during treatment. Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. There is no significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia were significantly different by application of atazanavir or lopinavir. [ABSTRACT FROM AUTHOR]