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.

Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton\'s tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.

OBJECTIVE: Paxlovid is effective in reducing COVID-19 hospitalization and mortality. This study characterized Paxlovid use and evaluated racial/ethnic disparities over time among community-dwelling adults at high risk of progression to severe COVID-19 disease.
METHODS: This retrospective cohort study used the National COVID Cohort Collaborative (N3C) data and included individuals aged 18 years or older diagnosed with COVID-19 between January 2022 and December 2023. The study cohort included nonhospitalized individuals who were at high risk of COVID-19 progression, and selected the first COVID-19 episode in each quarter, including reinfection episodes. Paxlovid use was defined as receiving Paxlovid within ±5 days of a COVID-19 diagnosis. We used descriptive statistics to characterize Paxlovid use overall and by calendar quarter and race/ethnicity. We used a generalized estimating equations (GEE) models to quantify the association of race/ethnicity with Paxlovid use controlling for age, gender, and clinical characteristics.
RESULTS: Among 1 264 215 individuals at high risk of disease progression (1 404 607 episodes), Paxlovid use increased from 1.2% in January-March 2022 to 35.1% in October-December 2023. Paxlovid use was more common among non-Hispanic White individuals (23.9%) than non-Hispanic Black (16.5%) and Latinx/e (16.7%) patients. After adjusting age, gender, and clinical characteristics, Paxlovid use was less likely among non-Hispanic Black (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.68-0.70) and Latinx/e (OR 0.72, CI 0.71-0.73) patients than non-Hispanic White patients.
CONCLUSIONS: Among a large, diverse cohort of community-dwelling individuals with COVID-19, nearly two out of three eligible individuals did not receive Paxlovid, and minoritized racial/ethnic groups were less likely to use Paxlovid than their non-Hispanic White individuals.

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).

OBJECTIVE: This study seeks to identify demographic and clinical factors prompting clinician prescribing of nirmatrelvir/ritonavir to pediatric patients for management of coronavirus disease 2019 (COVID-19) infection.
METHODS: Patients aged 12 to 17 years with a COVID-19 infection and nirmatrelvir/ritonavir prescription during an outpatient clinical encounter within a PEDSnet-affiliated institution between January 2022 and August 2023 were identified using electronic health record data. A multivariate logistic regression analysis was used to estimate odds of nirmatrelvir/ritonavir prescription after adjusting for various factors.
RESULTS: A total of 20 959 patients aged 12 to 17 years were diagnosed with a COVID-19 infection on the basis of an electronic health record-documented positive polymerase chain reaction or antigen test or diagnosis during an outpatient clinical visit. Of these patients, 408 received a nirmatrelvir/ritonavir prescription within 5 days of diagnosis. Higher odds of nirmatrelvir/ritonavir treatment were associated with having chronic or complex chronic disease (chronic: odds ratio [OR] 2.50 [95% confidence interval (CI) 1.83-3.38]; complex chronic: OR 2.21 [95% CI 1.58-3.08]). Among patients with chronic disease, each additional body system conferred 1.18 times higher odds of treatment (95% CI 1.10-1.26). Compared with non-Hispanic white patients, Hispanic patients (OR 0.61 [95% CI 0.44-0.83]) had lower odds of treatment.
CONCLUSIONS: Children with chronic conditions are more likely than those without to receive nirmatrelvir/ritonavir prescriptions. However, nirmatrelvir/ritonavir prescribing to children with chronic conditions remains infrequent. Pediatric data concerning nirmatrelvir/ritonavir safety and effectiveness in preventing severe disease and hospitalization are critical optimizing clinical decision-making and use among children.

Despite emerging evidence indicating that molecular SARS-CoV-2 tests performed on saliva have diagnostic sensitivity and specificity comparable to those observed with nasopharyngeal swabs (NPSs), most in vivo follow-up studies on the efficacy of drugs against SARS-CoV-2 have been performed on NPSs, not considering saliva as a possible alternative matrix. For this reason, in this study, we used, in parallel, saliva and NPS samples for the detection of SARS-CoV-2 by real-time RT-PCR in patients receiving Tixagevimab/Cilgavimab, Nirmatrelvir/Ritonavir, or Sotrovimab as a treatment against SARS-CoV-2. Our results showed a good correlation between the NPS and saliva samples for each drug; moreover, comparable changes in the cycle threshold (Ct) levels in saliva and NPSs were observed both 7 days and 30 days after treatment, thus confirming that the saliva represents a good matrix for in vivo follow-up studies verifying the effectiveness of treatments against SARS-CoV-2.

In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.

BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies.
METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations.
RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2.
CONCLUSIONS: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

Among immunocompromised hosts, leukemia patients, and hematopoietic cell transplant recipients are particularly vulnerable, facing challenges in balancing coronavirus disease 2019 (COVID-19) management with their underlying conditions. In this How I Treat article, we discuss how we approach severe acute respiratory syndrome coronavirus 2 infections in daily clinical practice, considering the existing body of literature and for topics where the available data are not sufficient to provide adequate guidance, we provide our opinion based on our clinical expertise and experience. Diagnostic approaches include nasopharyngeal swabs for polymerase chain reaction testing and chest computed tomography scans for symptomatic patients at risk of disease progression. Preventive measures involve strict infection control protocols and prioritizing vaccination for both patients and their families. Decisions regarding chemotherapy or hematopoietic cell transplantation in leukemia patients with COVID-19 require careful consideration of factors such as COVID-19 severity and treatment urgency. Treatment protocols include early initiation of antiviral therapy, with nirmatrelvir/ritonavir or remdesivir. For cases of prolonged viral shedding, distinguishing between viable and non-viable viruses remains challenging but is crucial for determining contagiousness and guiding management decisions. Overall, individualized approaches considering immune status, clinical presentation, and viral kinetics are essential for effectively managing COVID-19 in leukemia patients.

The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However, discrepancies in the information on drug interaction are reported between J-PI and foreign databases. This study aimed to evaluate various information sources on N/r drug interactions. We categorized and compared information on N/r drug interactions from the J-PI, prescribing information from foreign regulatory agencies, guidance from the National Institutes of Health and University Health Network, the Ontario coronavirus disease 2019 (COVID-19) Science Advisory Table, University of Liverpool, Lexicomp, and the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS). We assessed information quantity, missing data in J-PI, predicted change of the area under the blood concentration-time curve (AUC) for nirmatrelvir or co-administered drugs, and the information source consistency. From these information sources, we compiled a dataset with 115 contraindications and 203 precautions for N/r co-administration, and 51 contraindications are missing in J-PI. Among them, at least 12 drugs have large predicted AUC changes with N/r (AUC ≥5-fold or <1/5 of the baseline value). Nine of these 12 drugs are included as contraindications in Lexicomp and the JSPHCS. The consistency among the information sources is low. Information in the J-PI alone may be insufficient and Lexicomp or the JSPHCS guidelines should be useful because of their large amounts of information and wide coverage of drugs with large AUC changes. Due to low source consistency, multiple sources are needed for clinical management.