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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]

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]

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]

The new Coronavirus (SARS-CoV-2) created a pandemic in the world in late 2019 and early 2020. Unfortunately, despite the increasing prevalence of the disease, there is no effective drug for the treatment. A computational drug repurposing study would be an appropriate and rapid way to provide an effective drug in the treatment of the coronavirus disease of 2019 (COVID-19) pandemic. In this study, the inhibitory potential of more than 50 antiviral drugs on three important proteins of SARS-CoV-2, was investigated using the molecular docking method. By literature review, three important proteins, including main protease, RNA-dependent RNA polymerase (RdRp), and spike, were selected as the drug targets. The three-dimensional (3D) structure of protease, spike, and RdRp proteins was obtained from the Protein Data Bank. Proteins were energy minimized. More than 50 antiviral drugs were considered as candidates for protein inhibition, and their 3D structure was obtained from Drug Bank. Molecular docking settings were defined using Autodock 4.2 software and the algorithm was executed. Based on the estimated binding energy of docking and hydrogen bond analysis and the position of drug binding, five drugs including, indinavir, lopinavir, saquinavir, nelfinavir, and remdesivir, had the highest inhibitory potential for all three proteins. According to the results, among the mentioned drugs, saquinavir and lopinavir showed the highest inhibitory potential for all three proteins compared to the other drugs. This study suggests that saquinavir and lopinavir could be included in the laboratory phase studies as a two-drug treatment for SARS-CoV-2 inhibition. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease 2019 (COVID-19), appeared in the United States over 1 year ago. This virus has a wide range of presentations, from being asymptomatic to causing severe acute respiratory syndrome, which can lead to death. It has led to a worldwide effort to find effective treatments, from repurposed medications to new discoveries, as well as the push to develop effective vaccines. As the race to fight this pandemic unfolds, this column provides what is currently available to combat this virus, how it has been utilized in the pregnant population, and what data have been made available about how these treatments affect fetal development and the neonate. [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]

Objective: To compare 48-week changes in bone mineral density (BMD) and body fat distribution between patients continuing lopinavir/ritonavir and two NRTIs and those switching to lopinavir/ritonavir and lamivudine. Methods: Substudy of a randomized, open-label, multicenter OLE study was carried out. Adult HIV-infected patients with <50 copies/mL for ≥6 months were randomized (1:1) to continue lopinavir/ritonavir and two NRTIs or switching to lopinavir/ritonavir and lamivudine. Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 48 weeks to measure bone composition and body fat distribution in both the groups. Results: Forty-one patients (dual-therapy, n = 23; triple-therapy, n = 18) of 239, who received at least one dose of study medication, completed the study: median age, 42 years, 71% male, 73% Caucasian. At week 48, total BMD increased by 1.04% (95% CI, 0.06 to 2.01%) among patients switching to dual-therapy, whereas no significant changes occurred in patients maintaining triple-therapy. Dual-therapy and older age were independently associated with total BMD increase. Among patients discontinuing tenofovir-DF, a significant increase was seen in total BMD (1.43; 95% CI, -0.04 to 2.91) and total hip (1.33%; 95% CI, 0.44 to 2.22%). A non-statistically significant decrease in femoral and spinal BMD was observed in patients who discontinued abacavir and in those continuing triple-therapy. Regarding fat distribution, no significant changes were seen in both the treatment groups. Discussion: BMD increased following switching to lopinavir/ritonavir plus lamivudine in HIV-infected patients on suppressive triple-therapy with lopinavir/ritonavir and two NRTIs including tenofovir-DF. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To determine if switching virologically suppressed patients on a regimen containing lopinavir/r (LPV/r) or fosamprenavir (FPV/r) to darunavir/r (DRV/r) or atazanavir/r (ATV/r) results in improved TGs while maintaining virological suppression. Methods: Eligibility criteria were undetectable HIV RNA ≥12 weeks, no PI resistance, receiving LPV/r (n =46) or FPV/r (n =3) plus nucleosides, and fasting TGs >200mg/dl. Patients were randomized to either QD ATV/r or DRV/r (maintaining the same nucleosides). Primary endpoint was change in TGs from baseline to week 24. Results: 66 were screened, 51 enrolled and two withdrew consent after randomization. 24 patients received ATV/r; 25 received DRV/r. Baseline mean CD4 cell count was 569; HIV RNA was <50copies/mL in 88% of subjects. Mean baseline TGs were 326mg/dl in ATV/r arm and 342mg/dl in DRV/r arm. TGs declined from baseline to week 24 by 108mg/dl (p <0.001) with a non-significant difference by arm: −88mg/dl in the ATV/r arm and −126mg/dl in the DRV/r arm. At week 24, 55% of ATV/r and 48% of DRV/r subjects had TGs <200mg/dl (OR 1.3; Difference 7%, 95% CI: −22% to 35%). Total and HDL cholesterol decreased and LDL increased (non-significantly). Baseline quality of life (QOL) was 83% and remained high at week 24 (84%). No differences between the groups in CD4 cell counts or HIV RNA levels were noted. Conclusions: Patients with high TGs who switched from LPV/r or FPV/r to DRV/r or ATV/r had improved TGs, while maintaining virological suppression and high adherence and QOL. [Copyright &y& Elsevier]

Background: The COVID-19 pandemic has increased online purchases and heightened interest in existing treatments. Dexamethasone, hydroxychloroquine, and lopinavir-ritonavir have been touted as potential COVID-19 treatments.Objective: This study assessed the availability of 3 potential COVID-19 treatments online and evaluated the safety and marketing characteristics of websites selling these products during the pandemic.Methods: A cross-sectional study was conducted in the months of June 2020 to August 2020, by searching the first 100 results on Google, Bing, and Yahoo! mimicking a US consumer. Unique websites were included if they sold targeted medicines, were in English, offered US shipping, and were free to access. Identified online pharmacies were categorized as rogue, unclassified, or legitimate based on LegitScript classifications. Patient safety characteristics, marketing techniques, price, legitimacy, IP addresses, and COVID-19 mentions were recorded.Results: We found 117 websites: 30 selling dexamethasone (19/30, 63% rogue), 39 selling hydroxychloroquine (22/39, 56% rogue), and 48 selling lopinavir-ritonavir (33/48, 69% rogue). This included 89 unique online pharmacies: 70% were rogue (n=62), 22% were unapproved (n=20), and 8% were considered legitimate (n=7). Prescriptions were not required among 100% (19/19), 61% (20/33), and 50% (11/22) of rogue websites selling dexamethasone, lopinavir-ritonavir, and hydroxychloroquine, respectively. Overall, only 32% (24/74) of rogue websites required prescriptions to buy these medications compared with 94% (31/33) of unapproved and 100% (10/10) of legitimate websites (P<.001). Rogue sites rarely offered pharmacist counseling (1/33, 3% for lopinavir-ritonavir to 2/22, 9% for hydroxychloroquine). Drug warnings were unavailable in 86% (6/7) of unapproved dexamethasone sites. It was difficult to distinguish between rogue, unapproved, and legitimate online pharmacies solely based on website marketing characteristics. Illegitimate pharmacies were more likely to offer bulk discounts and claim price discounts, yet dexamethasone and hydroxychloroquine were more expensive online. An inexpensive generic version of lopinavir-ritonavir that is not authorized for use in the United States was available online offering US shipping. Some websites claimed hydroxychloroquine and lopinavir-ritonavir were effective COVID-19 treatments despite lack of scientific evidence. In comparing IP addresses to locations claimed on the websites, only 8.5% (7/82) matched their claimed locations.Conclusions: The lack of safety measures by illegitimate online pharmacies endanger patients, facilitating access to medications without appropriate oversight by health care providers to monitor clinical response, drug interactions, and adverse effects. We demonstrated how easy it is to go online to buy medications that are touted to treat COVID-19 even when current clinical evidence does not support their use for self-treatment. We documented that illegitimate online pharmacies sidestep prescription requirements, skirt pharmacist counseling, and make false claims regarding efficacy for COVID-19 treatment. Health care professionals must urgently educate the public of the dangers of purchasing drugs from illegitimate websites and highlight the importance of seeking treatment through authentic avenues of care. [ABSTRACT FROM AUTHOR]

Background: Treatments for coronavirus disease 2019 (COVID-19) are limited by suboptimal efficacy.Methods: From January 30, 2020 to March 23, 2020, we conducted a non-randomised controlled trial, in which all adult patients with laboratory-confirmed COVID-19 were assigned to three groups non-randomly and given supportive treatments: Group A, Lopinavir-Ritonavir; Group B, Huashi Baidu Formula (a Chinese medicineformula made by the China Academy of Chinese Medical Sciences to treat COVID-19, which is now in the clinical trial period) and Lopinavir-Ritonavir; and Group C, Huashi Baidu Formula. The use of antibiotics, antiviruses, and corticosteroids was permitted in Group A and B. Traditional Chinese medicine injections were permitted in Group C. The primary outcomes were clinical remission time (interval from admission to the first time the patient tested negatively for novel coronavirus or an obvious improvement was observed from chest CT) and clinical remission rate (number of patients whose clinical time was within 16 days/total number of patients).Results: A total of 60 adult patients with COVID-19 were enrolled at sites in Wuhan, China, and the sample size of each group was 20. In Groups A, B and C, the clinical remission rates were 95.0%%(19/20), 100.0%%(20/20) and 100.0%%(20/20), respectively. Compared with Groups A and B, the clinical remission time of Group C was significantly shorter (5.9 days vs. 10.8 days, p < 0.05; 5.9 days vs. 9.7 days, p < 0.05). There was no significant difference among Groups A, B, and C in terms of the time taken to be released from quarantine. The clinical biochemical indicators and safety indexes showed no significant differences among the three groups.Conclusions: Our findings suggest that Lopinavir-Ritonavir has some efficacy in the treatment of COVID-19, and the Huashi Baidu Formula might enhance this effect to an extent. In addition, superiority was displayed in the treatment of COVID-19 through a combination of the Huashi Baidu Formula and traditional Chinese medicine injection. In future, well-designed prospective double-blinded randomised control trials are required to confirm our findings. [ABSTRACT FROM AUTHOR]