Size control of ropivacaine nano/micro-particles by soft-coating with peptide nanosheets for long-acting analgesia.

Rationale: To meet the need of long-acting analgesia in postoperative pain management, slow-releasing formulations of local anesthetics (LAs) have been extensively investigated. However, challenges still remain in obtaining such formulations in a facile and cost-effective way, and a mechanism for controlling the release rate to achieve an optimal duration is still missing. Methods: In this study, nanosheets formed by a self-assembling peptide were used to encapsulate ropivacaine in a soft-coating manner. By adjusting the ratio between the peptide and ropivacaine, ropivacaine particles with different size were prepared. Releasing profile of particles with different size were studied in vitro and in vivo. The influence of particle size and ropivacaine concentration on effective duration and toxicity were evaluated in rat models. Results: Our results showed that drug release rate became slower as the particle size increased, with particles of medium size (2.96 ± 0.04 µm) exhibiting a moderate release rate and generating an optimal anesthetic duration. Based on this size, formulations at different ropivacaine concentrations generated anesthetic effect with different durations in rat sciatic nerve block model, with the 6% formulation generated anesthetic duration of over 35 h. Long-acting analgesia up to 48 h of this formulation was also confirmed in a rat total knee arthroplasty model. Conclusion: This study provided a facile strategy to prepare LA particles of different size and revealed the relationship between particle size, release rate and anesthetic duration, which provided both technical and theoretical supports for developing long-acting LA formulations with promising clinical application.

Metal oxide nanocage as drug delivery systems for Favipiravir, as an effective drug for the treatment of COVID-19: a computational study.

This paper is a summary of research that looks at the potential of fullerene-like (MO)12 nanoclusters (NCs) in drug-carrying systems using density functional theory. Favipiravir/Zn12O12 (- 34.80 kcal/mol), Favipiravir/Mg12O12 (- 34.98 kcal/mol), and Favipiravir/Be12O12 (- 30.22 kcal/mol) were rated in order of drug adsorption degrees. As a result, Favipiravir attachment to (MgO)12 and (ZnO)12 might be simple, increasing Favipiravir loading efficiency. In addition, the quantum theory of atoms in molecules (QTAIM) assessment was utilized to look at the interactions between molecules. The FMO, ESP, NBO, and Eads reactivity patterns were shown to be in excellent agreement with the QTAIM data. The electrostatic properties of the system with the biggest positive charge on the M atom and the largest Eads were shown to be the best. This system was shown to be the best attraction site for nucleophilic agents. The findings show that (MgO)12 and (ZnO)12 have great carrier potential and may be used in medication delivery.

Effects of fatty acid metabolites on nocturia.

Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (ClockΔ19/Δ19) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in ClockΔ19/Δ19 mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in ClockΔ19/Δ19 than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.

Determination of favipiravir in human plasma using homogeneous liquid-liquid microextraction followed by HPLC/UV.

Background: Favipiravir is an antiviral drug that was recently approved for the management of COVID-19 infection. Aim: This work aimed to develop a new method, using sugaring-out induced homogeneous liquid-liquid microextraction followed by HPLC/UV for the determination of favipiravir in human plasma. Materials & methods: The optimum extraction conditions were attained using 500 µl of tetrahydrofuran as an extractant and 1400 mg of fructose as a phase-separating agent. Results: The developed method was validated according to the US FDA bioanalytical guidelines and was found linear in the range of 25-80,000 ng/ml with a correlation coefficient of 0.999. Conclusion: These results showed that the developed method was simple, easy, valid and adequately sensitive for determination of favipiravir in plasma for bioequivalence studies.

Menthol-assisted homogenous liquid-liquid microextraction for HPLC/UV determination of favipiravir as an antiviral for COVID-19 in human plasma.

Favipiravir is a promising antiviral agent that has been recently approved for treatment of COVID-19 infection. In this study, a menthol-assisted homogenous liquid-liquid microextraction method has been developed for favipiravir determination in human plasma using HPLC/UV. The different factors that could affect the extraction efficiency were studied, including extractant type, extractant volume, menthol amount and vortex time. The optimum extraction efficiency was achieved using 300 µL of tetrahydrofuran, 30 mg of menthol and vortexing for 1 min before centrifuging the sample for 5 min at 3467g. Addition of menthol does not only induce phase separation, but also helps to form reverse micelles to facilitate extraction. The highly polar favipiravir molecules would be incorporated into the hydrophilic core of the formed reverse micelle to be extracted by the non-polar organic extractant. The method was validated according to the FDA bioanalytical method guidelines. The developed method was found linear in the concentration range of 0.1 to 100 µg/mL with a coefficient of determination of 0.9992. The method accuracy and precision were studied by calculating the recovery (%) and the relative standard deviation (%), respectively. The recovery (%) was in the range of 97.1-103.9%, while the RSD (%) values ranged between 2.03 and 8.15 %. The developed method was successfully applied in a bioequivalence study of Flupirava® 200 mg versus Avigan® 200 mg, after a single oral dose of favipiravir administered to healthy adult volunteers. The proposed method was simple, cheap, more eco-friendly and sufficiently sensitive for biomedical application.

Favipiravir-induced cutaneous adverse reactions in patients infected with COVID-19.

Favipiravir (FVP) has been used for treatment of COVID-19 in many countries. We analysed the incidence of FVP-induced cutaneous adverse reactions (CARs) in patients infected with COVID-19 who were hospitalized at Bamrasnaradura Infectious Diseases Institute, a principal centre of emerging infectious disease in Thailand, and who presented with cutaneous eruption following FVP prescription. We identified five cases of FVP-induced CARs: two patients with maculopapular rash, two with urticarial rash, and one with Stevens-Johnson syndrome. The median interval between FVP treatment and rash occurrence was 7 days and the mean duration of the rash was 5 days. This report highlights that FVP can induce CARs, particularly eruptions, in COVID-19-infected patients. Clinicians should be aware of this possible drug-related allergy, and it should be excluded as a cause of rash during FVP treatment of COVID-19.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

The therapeutic efficacy of quercetin in combination with antiviral drugs in hospitalized COVID-19 patients: A randomized controlled trial.

In this study, the therapeutic efficacy of quercetin in combination with remdesivir and favipiravir, were evaluated in severe hospitalized COVID-19 patients. Our main objective was to assess the ability of quercetin for preventing the progression of the disease into critical phase, and reducing the levels of inflammatory markers related to SARS-Cov-2 pathogenesis. Through an open-label clinical trial, 60 severe cases were randomly divided into control and intervention groups. During a 7-day period, patients in the control group received antivirals, i.e., remdesivir or favipiravir, while the intervention group was treated with 1000 mg of quercetin daily in addition to the antiviral drugs. According to the results, taking quercetin was significantly associated with partial earlier discharge and reduced serum levels of ALP, q-CRP, and LDH in the intervention group. Furthermore, although the values were in normal range, the statistical outputs showed significant increase in hemoglobin level and respiratory rate in patients who were taking quercetin. Based on our observations, quercetin is safe and effective in lowering the serum levels of ALP, q-CRP, and LDH as critical markers involved in COVID-19 severity. However, according to the non-significant borderline results in comparing the mortality, the ICU-admission rate, and the duration of ICU-admission, further studies can be helpful to compensate the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments.

RAS induced senescence of skin keratinocytes is mediated through Rho-associated protein kinase (ROCK).

Cellular senescence is a well-documented response to oncogene activation in many tissues. Multiple pathways are invoked to achieve senescence indicating its importance to counteract the transforming activities of oncogenic stimulation. We now report that the Rho-associated protein kinase (ROCK) signaling pathway is a critical regulator of oncogene-induced senescence in skin carcinogenesis. Transformation of mouse keratinocytes with oncogenic RAS upregulates ROCK activity and initiates a senescence response characterized by cell enlargement, growth inhibition, upregulation of senescence associated ß-galactosidase (SAßgal) expression, and release of multiple pro-inflammatory factors comprising the senescence-associated secretory phenotype (SASP). The addition of the ROCK inhibitor Y-27632 and others prevents these senescence responses and maintains proliferating confluent RAS transformed keratinocyte cultures indefinitely. Mechanistically, oncogenic RAS transformation is associated with upregulation of cell cycle inhibitors p15Ink4b , p16Ink4a , and p19Arf and downregulation of p-AKT, all of which are reversed by Y-27632. RNA-seq analysis of Y-27632 treated RAS-transformed keratinocytes indicated that the inhibitor reduced growth-inhibitory gene expression profiles and maintained expression of proliferative pathways. Y-27632 also reduced the expression of NF-κB effector genes and the expression of IκBζ downstream mediators. The senescence inhibition from Y-27632 was reversible, and upon its removal, senescence reoccurred in vitro with rapid upregulation of cell cycle inhibitors, SASP expression, and cell detachment. Y-27632 treated cultured RAS-keratinocytes formed tumors in the absence of the inhibitor when placed in skin orthografts suggesting that factors in the tumor microenvironment can overcome the drive to senescence imparted by overactive ROCK activity.

Anti-inflammatory activity of palmitoylethanolamide ameliorates osteoarthritis induced by monosodium iodoacetate in Sprague-Dawley rats.

Novel treatment strategies are urgently required for osteoarthritis (OA). Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide with analgesic and anti-inflammatory effects. We aimed to examine its effect on OA and elucidate the molecular mechanism of actions in monosodium iodoacetate (MIA)-induced OA Sprague-Dawley rats. The experimental animals were divided into normal control group (injected with saline + treated with phosphate-buffered saline (PBS), NOR), control group (injected with MIA + treated with PBS, CON), 50 or 100 mg/kg body weight (BW)/day PEA-treated group (injected with MIA + treated with 50 or 100 mg of PEA/kg BW/day, PEA50 or PEA100), and positive control group (injected with MIA + treated with 6 mg of diclofenac/kg BW/day, DiC). The changes in blood parameters, body parameters, gene expression of inflammatory mediators and cytokines, knee thickness, and joint tissue were observed. Oral administration of PEA had no adverse effects on the BW, liver, or kidneys. PEA reduced knee joint swelling and cartilage degradation in MIA-induced OA rats. The serum levels of leukotriene B4, nitric oxide, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and prostaglandin E2 considerably reduced in the PEA100 group compared with those in the CON group. In the synovia of knee joints, the mRNA expression of iNOS, 5-Lox, Cox-2, Il-1ß, Tnf-α, and Mmp-2, -3, -9, and -13 apparently increased with MIA administration. Meanwhile, Timp-1 mRNA expression apparently decreased in the CON group but increased to the normal level with PEA treatment. Thus, PEA can be an effective therapeutic agent for OA.

Co-Ultra PEALut Enhances Endogenous Repair Response Following Moderate Traumatic Brain Injury.

This study aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®), composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in vivo model of traumatic brain injury (TBI) and patients affected by moderate TBI. An increase in neurogenesis was seen in the mice at 72 h and 7 d after TBI. The co-ultra PEALut treatment helped the neuronal reconstitution process to restore the basal level of both novel and mature neurons; moreover, it induced a significant upregulation of the neurotrophic factors, which ultimately led to progress in terms of memory recall during behavioral testing. Moreover, our preliminary findings in a clinical trial suggested that Glialia® treatment facilitated neural recovery on working memory. Thus, co-ultra PEALut (Glialia®) could represent a valuable therapeutic agent for intensifying the endogenous repair response in order to better treat TBI.

Effectiveness of favipiravir in COVID-19: a live systematic review.

We performed a systematic review and meta-analysis for the effectiveness of Favipiravir on the fatality and the requirement of mechanical ventilation for the treatment of moderate to severe COVID-19 patients. We searched available literature and reported it by using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Until June 1, 2021, we searched PubMed, bioRxiv, medRxiv, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar by using the keywords "Favipiravir" and terms synonymous with COVID-19. Studies for Favipiravir treatment compared to standard of care among moderate and severe COVID-19 patients were included. Risk of bias assessment was performed using Revised Cochrane risk of bias tool for randomized trials (RoB 2) and ROBINS-I assessment tool for non-randomized studies. We defined the outcome measures as fatality and requirement for mechanical ventilation. A total of 2702 studies were identified and 12 clinical trials with 1636 patients were analyzed. Nine out of 12 studies were randomized controlled trials. Among the randomized studies, one study has low risk of bias, six studies have moderate risk of bias, and 2 studies have high risk of bias. Observational studies were identified as having moderate risk of bias and non-randomized study was found to have serious risk of bias. Our meta-analysis did not reveal any significant difference between the intervention and the comparator on fatality rate (OR 1.11, 95% CI 0.64-1.94) and mechanical ventilation requirement (OR 0.50, 95% CI 0.13-1.95). There is no significant difference in fatality rate and mechanical ventilation requirement between Favipiravir treatment and the standard of care in moderate and severe COVID-19 patients.

Selective MOR activity of DAPEA and Endomorphin-2 analogues containing a (R)-γ-Freidinger lactam in position two.

The use of α-amino-γ lactam of Freidinger (Agl) may serve as an impressive method to increase the biological stability of peptides and an appropriate tool to elucidate their structure-activity relationships. The endomorphin-2 (EM-2) and [D-Ala2, des-Leu5] enkephalin amide (DAPEA) are two linear opioid tetrapeptides agonists of MOR and MOR/DOR respectively. Herein, we investigated the influence of the incorporation of (R/S)-Agl in position 2 and 3 on the biological profile of the aforementioned products in vitro and in vivo. Receptor radiolabeled displacement and functional assays were used to measure in vitro the binding affinity and receptors activation of the novel analogues. The mouse tail flick and formalin tests allowed to observe their antinociceptive effect in vivo. Data revealed that peptide A2D was able to selectively bind and activate MOR with a potent antinociceptive effect after intracerebroventricular (i.c.v.) administration, performing better than the parent compounds EM-2 and DAPEA. Molecular docking calculations helped us to understand the key role exerted by the Freidinger Agl moiety in A2D for the interaction with the MOR binding pocket.

Fluorescence of ocular surface in a Covid -19 patient after Favipiravir treatment: a case report.

BACKGROUND: Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report. CASE PRESENTATION: A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant. CONCLUSION: We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.

Favipiravir treatment prolongs the survival in a lethal mouse model intracerebrally inoculated with Jamestown Canyon virus.

BACKGROUND: Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus that causes acute febrile illness, meningitis, and meningoencephalitis, primarily in North American adults. Currently, there are no available vaccines or specific treatments against JCV infections. METHODOLOGY/PRINCIPAL FINDINGS: The antiviral efficacy of favipiravir (FPV) against JCV infection was evaluated in vitro and in vivo in comparison with that of ribavirin (RBV) and 2'-fluoro-2'-deoxycytidine (2'-FdC). The in vitro inhibitory effect of these drugs on JCV replication was evaluated in Vero and Neuro-2a (N2A) cells. The efficacy of FPV in the treatment of JCV infection in vivo was evaluated in C57BL/6J mice inoculated intracerebrally with JCV, as per the survival, viral titers in the brain, and viral RNA load in the blood. The 90% inhibitory concentrations (IC90) of FPV, RBV, and 2'-FdC were 41.0, 61.8, and 13.6 µM in Vero cells and 20.7, 25.8, and 8.8 µM in N2A cells, respectively. All mice infected with 1.0×104 TCID50 died or were sacrificed within 10 days post-infection (dpi) without treatment. However, mice treated with FPV for 5 days [initiated either 2 days prior to infection (-2 dpi-2 dpi) or on the day of infection (0 dpi-4 dpi)] survived significantly longer than control mice, administered with PBS (p = 0.025 and 0.011, respectively). Moreover, at 1 and 3 dpi, the virus titers in the brain were significantly lower in FPV-treated mice (0 dpi-4 dpi) versus PBS-treated mice (p = 0.002 for both 1 and 3 dpi). CONCLUSIONS/SIGNIFICANCE: Although the intracerebral inoculation route is thought to be a challenging way to evaluate drug efficacy, FPV inhibits the in vitro replication of JCV and prolongs the survival of mice intracerebrally inoculated with JCV. These results will enable the development of a specific antiviral treatment against JCV infections and establishment of an effective animal model.

Favipiravir-Based Ionic Liquids as Potent Antiviral Drugs for Oral Delivery: Synthesis, Solubility, and Pharmacokinetic Evaluation.

Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the ß-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.

Population pharmacokinetics of favipiravir in patients with COVID-19.

The antiretroviral drug favipiravir (FPV) inhibits RNA-dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID-19). However, its pharmacokinetics in patients with COVID-19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography-tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27-89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11-2.2 m2 ), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one-compartment model with first-order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID-19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID-19, but dose-dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.

Randomized clinical trial "olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin": preliminary results.

OBJECTIVE: Approximately 30% of patients with confirmed COVID-19 report persistent smell or taste disorders as long-term sequalae of infection. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with inflammatory changes to the olfactory bulb, and treatments with anti-inflammatory properties are hypothesized to attenuate viral injury and promote recovery of olfaction after infection. Our study investigated the efficacy of a supplement with Palmitoylethanolamide (PEA) and Luteolin to support recovery of olfaction in COVID-19 patients. PATIENTS AND METHODS: We conducted a randomized-controlled pilot study in outpatients with history of confirmed COVID-19 with post-infection olfactory impairment that persisted ≥ 90 days after SARS-CoV-2 negative testing. Patients were randomized to two times a day olfactory rehabilitation alone or weekly olfactory rehabilitation plus daily oral supplement with PEA and Luteolin. Subjects with preexisting olfactory disorders were excluded. Sniffin' Sticks assessments were performed at baseline and 30 days after treatment.  Data on gender, age, and time since infection were collected. Kruskal-Wallis (KW) test was used to compare variances of Sniff scores between groups over time, and Spearman's correlation coefficients were calculated to assess for correlations between Sniff Score and gender or duration of infection. RESULTS: Among 12 patients enrolled (n=7, supplement; n=5, controls), patients receiving supplement had greater improvement in olfactory threshold, discrimination, and identification score versus controls (p=0.01). Time since infection was negatively correlated with Sniff Score, and there was no correlation between gender. CONCLUSIONS: Treatment combining olfactory rehabilitation with oral supplementation with PEA and Luteolin was associated with improved recovery of olfactory function, most marked in those patients with longstanding olfactory dysfunction. Further studies are necessary to replicate these findings and to determine whether early intervention including olfactory rehabilitation and PEA+Luteolin oral supplement might prevent SARS-CoV-2 associated olfactory impairment.

Elbasvir/grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response: A case report and a review of the literature.

Enteral tubes are necessary for certain patients; however, medication absorption can be affected by this route of administration potentially resulting in decreased efficacy. All first-line treatments for Hepatitis C Virus (HCV) infection are only available as tablets and may have decreased absorption if administered via an enteral tube. This report describes the first case of a pegylated interferon and ribavirin treatment-experienced patient who successfully achieved HCV cure after 12 weeks of elbasvir/grazoprevir administered via percutaneous gastrostomy tube. We further review the available pharmacokinetic and clinical literature regarding administration via enteral feeding tubes for all first-line direct-acting antivirals (DAAs). The literature suggests that crushed administration can be considered for DAAs in patients with gastric access. However, caution should be exercised in patients with extragastric enteral tubes and in those with altered gastrointestinal tract anatomy.