Viral Drug Research Articles

Biomimetic lung-on-a-chip to model virus infection and drug evaluation

Viral infectious diseases remain a global public health problem. The rapid and widespread spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) has had a severe impact on the global economy and human activities, highlighting the vulnerability of humans to viral infectious diseases and the urgent need to develop new technologies and effective treatments. Organ-on-a-chip is an emerging technology for constructing the physiological and pathological microenvironment of human organs in vitro and has the advantages of portability, high throughput, low cost, and accurate simulation of the in vivo microenvironment. Indeed, organ-on-a-chip provides a low-cost alternative for investigating human organ physiology, organ diseases, toxicology, and drug efficacy. The lung is a main target organ of viral infection, and lung pathophysiology must be assessed after viral infection and treatment with antiviral drugs. This review introduces the construction of lung-on-a-chip and its related pathophysiological models, focusing on the in vitro simulation of viral infection and evaluation of antiviral drugs, providing a developmental direction for research and treatment of viral diseases.

Impact of Human Immunodeficiency Virus and Recreational Drugs on Cognitive Functions.

This prospective study characterizes the structural and metabolic cerebral correlates of cognitive impairments found in a preclinical setting that considers the lifestyle of young European men exposed to human immunodeficiency virus (HIV), including recreational drugs. Simultaneous structural brain magnetic resonance imaging (MRI) and positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) were acquired on a hybrid PET-MRI system in 23 asymptomatic young men having sex with men with HIV (HIVMSM; mean age, 33.6 years [range, 23-60 years]; normal CD4+ cell count, undetectable viral load). Neuroimaging data were compared with that of 26 young seronegative men under HIV preexposure prophylaxis (PrEPMSM), highly well matched for age and lifestyle, and to 23 matched young seronegative men (controls). A comprehensive neuropsychological assessment was also administered to the HIVMSM and PrEPMSM participants. HIVMSM had lower performances in executive, attentional, and working memory functions compared to PrEPMSM. No structural or metabolic differences were found between those 2 groups. Compared to controls, HIVMSM and PrEPMSM exhibited a common hypometabolism in the prefrontal cortex that correlated with the level of recreational drug use. No structural brain abnormality was found. Abnormalities of brain metabolism in our population of young HIVMSM mainly relate to recreational drug use rather than HIV per se. A complex interplay between recreational drugs and HIV might nevertheless be involved in the cognitive impairments observed in this population.

PCSK9 Inhibitor: Safe Alternative to Fill the Treatment Gap in Statin-Limited Conditions?

Lipid-lowering therapy is of great importance in reducing the burden of atherosclerotic cardiovascular disease. Statins act as first-line therapy in the current lipid management guidelines. However, statin use is limited in (1) statin-induced adverse events, including statin-associated muscle symptoms, new-onset diabetes mellitus, drug-induced liver injuries, acute kidney injuries, cognitive effects, hemorrhagic strokes, and cataracts; (2) special populations, including pregnant and lactating patients, patients with decompensated cirrhosis, and patients on dialysis; (3) coadministration with statin-interactive drugs, such as anti-human immunodeficiency virus drugs, anti-hepatitis C virus drugs, and immunosuppressive drugs. These considerable statin-limited groups are in urgent need of safer alternative lipid-lowering options. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are attracting widespread attention for their documented safety in general populations and superior lipid-lowering properties. Therefore, questions have been raised whether PCSK9 inhibitors could be a safe alternative in patients who are intolerant to statin therapy. In this review, we discuss the safety of PCSK9 inhibitors in statin-limited conditions. We conclude that PCSK9 inhibitors are a safe alternative lipid-lowering therapy in various statin-limited conditions. Furthermore, we identify several limitations in the current literature and suggest future directions, for the refinement of lipid management regimens.

Viral infections and drug hypersensitivity.

Virus infections and T-cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i): drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T-cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T-cell activation and symptoms. There is a situation where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity by killing herpes peptide-expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.

High Level of Pretreatment and Acquired Human Immunodeficiency Virus Drug Resistance in El Salvador: A Nationally Representative Survey, 2018-2019.

Human immunodeficiency virus drug resistance (HIVDR) can negatively impact the effectiveness of antiretroviral therapy (ART). We aimed to estimate the prevalence of pretreatment HIVDR (PDR) among ART initiators and the prevalence of viral load (VL) suppression and acquired HIVDR among individuals receiving ART for 12 ± 3 months (ADR12) and ≥48 months (ADR48) in El Salvador. Nationally representative cross-sectional PDR, ADR12 and ADR48 surveys were conducted among adults with HIV from October 2018 to August 2019, following World Health Organization-recommended methods. Demographic and clinic data and blood specimens were collected. Two hundred sixty participants were enrolled in the PDR survey, 230 in ADR12 and 425 in ADR48. Twenty-seven percent (95% confidence interval [CI], 17.1%-39.9%) of ART initiators had PDR to efavirenz or nevirapine. The prevalence of VL suppression was 88.8% (95% CI, 83.1%-92.8%) in ADR12 and 80.5% (95% CI, 76.6%-84.0%) in ADR48 surveys. Among people with HIV receiving a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens and with unsuppressed VL, the prevalence of ADR to efavirenz or nevirapine was 72.0% (95% CI, 32.3%-93.3%) and 95.0% (68.5%-99.4%) in the ADR12 and ADR28 surveys, respectively. ADR12 to boosted protease inhibitors (PI/r) or integrase strand transfer inhibitors (INSTIs) was not observed. ADR48 was 1.3% (95% CI, 0.2%-9.6%) and 2.1% (0.3%-13.7%), respectively. Programmatic improvements in ART delivery are urgently needed in El Salvador to address the high levels of resistance to efavirenz or nevirapine among ART initiators and the low VL suppression prevalence among individuals on treatment.

ODP499 Myxedema Coma: A Challenging Presentation of an Uncommon Disease

Abstract Myxedema coma is a rare diagnosis but if not early recognized, this medical emergency possesses a high mortality rate. Over the years, it has been described predominantly in elderly women with history of hypothyroidism and as a precipitant factor that converges to evolve in a full presentation. We report a case of myxedema coma in a young male without risks for this disease. A 38 y/o Latin-American male with medical history ofhepatitis C virus and intravenous drug abuser that was brought to the emergency department after being found in the streets. The patient was agitated, oriented only to person, had slurred speech and reports last dose of heroin was two days ago. Denied other condition or medications. Vital signs BP 103/90mmHg, pulse: 41 bpm, T: 35.8°C RR: 19 rpm, SPO2: 99% at room air and BMI: 23.9. kg/m 2 . Physical examination pertinent for a disheveled male with anasarca, diffused dry skin with piloerection without surgery scars, non-palpable nor tender thyroid gland, bilateral exophthalmos, decreased bowel sound, positive fluid wave and abdomen diffusely tender to palpation with bilateral lower extremities infected ulcers. Blood workup showed impaired renal function, severe azotemia, hyponatremia, hypoglycemia and normocytic anemia. TSH 147uIU/mL. Imaging studies remarkable for bilateral pleural effusions, intestinal ileus, and negative brain CT scan. Patient was admitted with diagnosis of uremic encephalopathy, drug withdrawal and soft skin tissue infection. Patient was treated with emergent hemodialysis, drug withdrawal measures and IV antibiotics. Despite treatment, patient's clinical condition began to decline. He was found obtunded requiring endotracheal intubation. TSH was persistently elevated in 55.7uIU/mL with suppressed free T4 <0.42ng/dL. Patient noted with persistent sinus bradycardia, hypothermia, ileus, ascites, bilateral pleural effusions, and hypotension. Patient was consulted to endocrinology department who evaluated the overall clinical presentation and myxedema coma was diagnosed. He was treated with levothyroxine 100mg IV for two days, but eventually developed multiorgan failure and unfortunately died. Myxedema coma is a complication of severe hypothyroidism that slows down the functions of multiple organs and directly affects their function. It is an endocrinologic emergency that leads to decline of the clinical presentation of patients. The epidemiology favors this presentation in patients with history of hypothyroidism, more specifically elderly women. Multiple conditions may present with similar signs and symptoms. Physicians must be aware that myxedema coma must be suspected in a patient with altered mental status, hypothermia, hypoglycemia, hypotension, anasarca among others even in the presence of more common conditions and in rare populations like our patient. Opioid Induced Endocrinopathies still remain a complication that is underdiagnosed. The aim of this case is to createmedical awareness on the importanceto consider myxedema coma in patients with Opioid abuse and withdrawal. Presentation: No date and time listed

Structure-Based Design and Molecular Simulations of Some Quercetin-Based Drugs as Repurposable Inhibitors of SARS-CoV-2 Main Protease

In this study, virtual screening and molecular dynamics (MD) protocols were applied to screen 2826 FDA-approved natural product drugs from the Selleckchem.com library for prospective inhibitors of the SARS-CoV-2 main protease. From the virtual screening through HTVS, SP and XP docking analysis, hyperoside, rutin hydrate, rutoside and quercitrin displayed a stronger binding affinity with respective XP docking scores of –11.389, –11.340, –11.087 and –10.232 kcal/mol than co-crystallized N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide (HWH) and positive inhibitors, lopinavir and ritonavir which scored –5.493, –6.463 and –6.221 kcal/mol respectively. Selectively, the binding free energy, MMGB(SA) of hyperoside and rutin hydrate was observed as –21.55 and –25.82 kcal/mol respectively compared to lopinavir and ritonavir with –17.66 and –5.28 kcal/mol respectively. Consistently, the selected drugs displayed good thermodynamics conformational stability, thus, recommended as promising repurposable inhibitors of the SARS-CoV-2 main protease amenable for further studies. HIGHLIGHTS Main protease of the SARS-CoV-2 represents a plausible target for mitigating viral replication Natural repurposable drugs are safer and cheaper for combating COVID-19 Hyperoside, rutin hydrate and quercitrin displayed strong binding and stability with the viral main protease They are recommended as repurposable inhibitors of SARS-CoV-2 main protease for further studies GRAPHICAL ABSTRACT

Design of a novel multiple epitope-based vaccine: an immunoinformatics approach to combat monkeypox

Monkeypox virus is an infectious agent that causes fever, Pneumonitis encephalitis, rash, lymphadenopathy and bacterial infection. The current outbreak of monkeypox has reawakened the global health concern. In the current situation of increasing viral infection, no vaccine or drug is available for monkeypox. Thus, there is an urgent need for viable vaccine development to prevent viral transmission by boosting human immunity. Herein, using immunoinformatics approaches, a multi-epitope vaccine was constructed for the Monkeypox virus. In this connection, B-Cell and T-cell epitopes were identified and joined with the help of adjutants and linkers. The vaccine construct was selected based on promising vaccine candidates and immunogenic potential. Further epitopes were selected based on antigenicity score, non-allergenicity and good immunological properties. Molecular docking reveals strong interactions between TLR-9 and the predicted vaccine construct. Finally, molecular dynamics simulations were performed to evaluate the stability and compactness of the constructed vaccine. The MD simulation results demonstrated the significant stability of the polypeptide vaccine construct. The predicted vaccine represented good stability, expression, immunostimulatory capabilities and significant solubility. Design vaccine was verified as efficient in different computer-based immune response investigations. Additionally, the constructed vaccine also represents a good population coverage in computer base analysis. Communicated by Ramaswamy H. Sarma

COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics.

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT: Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment.

Frequency of CYP2B6 Alleles in Major Iranian Ethnicities, Affecting Response to Efavirenz.

Efavirenz is an antihuman immunodeficiency virus (HIV) drug metabolized by cytochrome P450 2B6 (CYP2B6) enzyme. Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. Polymorphisms of this gene play a crucial role in the metabolism of drugs such as Efavirenz. This study aims to evaluate the frequency of three clinically significant CYP2B6 polymorphisms (CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T)) in three major Iranian ethnicities. One hundred forty-seven participants from three main Iranian ethnicities were included in this study. After DNA extraction, CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T) were genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). The frequency of the mutated allele in the Iranian population for CYP2B6 ∗ 6 (516G > T) was 41.50 (95% CI: 35.81, 47.36), which was significantly lower than in Kurds (59.62, 95% CI: 45.10, 72.99). Similarly, Kurds had a higher frequency of mutated allele of CYP2B6 ∗ 5 (1459C > T) (46.15%, 95% CI: 32.23, 60.53) than in Iranians (24.49%, 95% CI: 19.68, 29.82). The frequency of A and G alleles of CYP2B6 ∗ 4 (785A > G) was 62.59% (95% CI: 56.78, 68.13) and 37.41 (95% CI: 31.87, 43.22), respectively. Kurds are at higher risk of adverse drug reactions (ADRs) and insufficient anti-HIV response compared to other Iranians.

Preparation of Darunavir Cubosomal Gel to Treat HIV Infections

HIV (human immunodeficiency virus) is a virus that attacks the body's system. AIDS could be a chronic potentially life threatening condition caused by HIV. This article provides a summary of studies assessing the pharmacokinetics of antiretroviral drug Darunavir. Darunavir is a BCS class II drug which inhibits the HIV protease enzyme by forming an inhibitor-enzyme complex there by preventing cleavage of the polyproteins. This research work aims to increase the penetration of Darunavir into deeper layers of skin by formulating cubosomes of Darunavir into a genital Gel that helps in enhancing the Bioavailablity by providing first pass metabolism. Cubosomes were prepared by the Top- down approach (Emulsification method) employing GMO as a lipid phase vehicle, poloxamer 407 as a stabilizer and distill water as an aqueous phase. Darunavir is an antiretro viral drug with good bioavailablity. The prepared cubosomes were characterized by Visual examination, Entrapment efficiency, Particle size, Zeta potential, In-vitro drug release studies. Optimised formulation (F4) showed good response among all the opposite cubosomal preparation. This (F4) cubosomal prepration was made as Gel using Carbopol 974 BP,and are studied for pH, Drug content,and Diffusion studies. Among all the prepration DARf6 was found for example the utmost drug release. This novel cubosomal genital gel would be promising system for effective drug delivery.

Research progress on the antiviral activities of natural products and their derivatives: Structure-activity relationships.

Viruses spread rapidly and are well-adapted to changing environmental events. They can infect the human body readily and trigger fatal diseases. A limited number of drugs are available for specific viral diseases, which can lead to non-efficacy against viral variants and drug resistance, so drugs with broad-spectrum antiviral activity are lacking. In recent years, a steady stream of new viral diseases has emerged, which has prompted development of new antiviral drugs. Natural products could be employed to develop new antiviral drugs because of their innovative structures and broad antiviral activities. This review summarizes the progress of natural products in antiviral research and their bright performance in drug resistance issues over the past 2 decades. Moreover, it fully discusses the effect of different structural types of natural products on antiviral activity in terms of structure–activity relationships. This review could provide a foundation for the development of antiviral drugs.

Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy.

Chronic Ca2+ imaging of cortical neurons with long-term expression of GCaMP-X.

Dynamic Ca2+ signals reflect acute changes in membrane excitability, and also mediate signaling cascades in chronic processes. In both cases, chronic Ca2+ imaging is often desired, but challenged by the cytotoxicity intrinsic to calmodulin (CaM)-based GCaMP, a series of genetically-encoded Ca2+ indicators that have been widely applied. Here, we demonstrate the performance of GCaMP-X in chronic Ca2+ imaging of cortical neurons, where GCaMP-X by design is to eliminate the unwanted interactions between the conventional GCaMP and endogenous (apo)CaM-binding proteins. By expressing in adult mice at high levels over an extended time frame, GCaMP-X showed less damage and improved performance in two-photon imaging of sensory (whisker-deflection) responses or spontaneous Ca2+ fluctuations, in comparison with GCaMP. Chronic Ca2+ imaging of one month or longer was conducted for cultured cortical neurons expressing GCaMP-X, unveiling that spontaneous/local Ca2+ transients progressively developed into autonomous/global Ca2+ oscillations. Along with the morphological indices of neurite length and soma size, the major metrics of oscillatory Ca2+, including rate, amplitude and synchrony were also examined. Dysregulations of both neuritogenesis and Ca2+ oscillations became discernible around 2-3 weeks after virus injection or drug induction to express GCaMP in newborn or mature neurons, which were exacerbated by stronger or prolonged expression of GCaMP. In contrast, neurons expressing GCaMP-X were significantly less damaged or perturbed, altogether highlighting the unique importance of oscillatory Ca2+ to neural development and neuronal health. In summary, GCaMP-X provides a viable solution for Ca2+ imaging applications involving long-time and/or high-level expression of Ca2+ probes.

Reproductive and developmental toxicology studies of iminosugar UV-4

UV-4 (N‐(9‐methoxynonyl)‐1‐deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than virally encoded proteins. This mechanism confers both broad-spectrum activity and low potential for generation of viral drug resistance mutations. Reproductive and developmental studies of UV-4 evaluated effects on fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and pre- and postnatal development including maternal function in rats. All reproductive and developmental studies conducted achieved dose levels where parental toxicity (generally decreased body weight, decreased food consumption and adverse clinical signs) were observed. Toxicokinetic evaluations confirmed UV-4 crossed the placenta exposing fetal rats and rabbits in utero. Adverse findings in reproductive and developmental studies included decreases in sperm motility with histopathology correlates, visceral and skeletal malformations, changes in eye opening, air drop reflex, vaginal opening and preputial separation. The combined results of the fertility and early embryonic developmental study and pre- and postnatal study suggested that there may be an increased risk for male fertility. These effects are similar to those reported in pre-clinical studies of the structurally related drug Miglustat (N-butyl-1-deoxynojirimycin), therefore UV-4 may have risk of developmental or reproductive adverse outcomes in humans similar to existing approved agents in this drug class.

Biolayer Interferometry Analysis for a Higher Throughput Quantification of In-Process Samples of a Rotavirus Vaccine.

Rotavirus A infection is a global leading cause of severe acute gastroenteritis associated with life-threatening diarrheal episodes in infants and young children. The disease burden is being reduced, namely due to a wider access to rotavirus vaccines. However, there is a demand to expand rotavirus vaccination programs, and to achieve this, it is critical to improve high-throughput in-process product quality control and vaccine manufacturing monitoring. Here, we present the development of an analytical method for the quantification of rotavirus particles contained in a licensed vaccine. The binding of rotavirus proteins to distinct glycoconjugate receptors and monoclonal antibodies was evaluated using biolayer interferometry analysis, applied on an Octet platform. The antibody strategy presented the best results with a linear response range within 2.5 × 107–1.0 × 108 particles·mL−1 and limits of detection and quantification of 2.5 × 106 and 7.5 × 106 particles·mL−1, respectively. Method suitability for the quantification of in-process samples was shown using samples from different manufacturing stages and their titers were comparable with the approved CCID(50) method. This cell-free method enables a fast and high-throughput analysis, compatible with time constraints during bioprocess development and it is suitable to be adapted to other viral particle-based drug products.

Honey as a risk factor for erythema multiform: case report

Erythema multiform (EM) is an acute and recurrent hypersensitivity reaction that occurs on the skin and oral mucosa. EM's risk factors include viral infections,drugs, radiation, autoimmune diseases, foodstuffs, and chemicals. Various bee products such as propolis, honey, and bee pollen are believed to have therapeutic effects for various diseases but can trigger allergic reactions. A 31-year-old female patient came to the Oral Medicine clinic with swollen and bleeding lips 2 weeks ago. The patient initially felt her lips were dry and exfoliate, then smeared her lips with honey but they became swollen and painful. The patient felt itchy on hertongue after consuming honey a few months ago. Clinical examination showed edema accompanied by erosive lesions, and ulcers, tend to bleed hemorrhagic crusts on the upper lip to the upper labial mucosa and lower lip. Laboratory examination showed IgE titer increased fourfold, IgG and IgM anti-HSV-1 were negative. The diagnosis was erythema multiforme. The therapy given is 0.9% NaCl compress on the lips using sterile gauze, applying topical corticosteroids to the lips, and educating the patient to not use and consume honey or other bee products. The patient recovered without scarring after two weeks of therapy. It was concluded that honey can be a risk factor for the emergence of EM, so it is very important to eliminate risk factors for the management and prevention of EM recurrence.

Construction of ANbO3 (A= Na, K)/f-carbon nanofiber composite: Rapid and real-time electrochemical detection of hydroxychloroquine in environmental samples

Hydroxychloroquine (HCQ) is a significant viral resistant drug widely acknowledged for its immunomodulatory and anti-inflammatory activities. To minimize the impact of HCQ residues on environmental pathways, exploring control measures is vital. In this regard, electrochemical sensing of HCQ using well-structured functional materials is advantageous. This work aims to provide an economical and sustainable route for the synthesis of ANbO3 (A = Na,K) perovskites via a thymol-menthol-based natural deep eutectic solvent. The as-synthesized NaNbO3 and KNbO3 are pinned to functionalized carbon nanofibers (f-CNF) via an ultrasonication approach. Benefitting from the synergistic effect of rapid electron transfer and improved surface area, enhanced electrochemical activity for NaNbO3@f-CNF/GCE is achieved. The fabricated NaNbO3@f-CNF displays a LOD (DPV = 0.01 μM, i-t = 0.007 μM), wide dynamic range (DPV = 0.09–22.5 μM, i-t = 0.006–35 μM), outstanding selectivity, and reproducibility, proving feasible in real-time analysis with good recovery rates (±97.67–99.81%). The NADES-mediated preparation of perovskites evades the incorporation of traditional toxic solvents and yields atom-efficient ANbO3 (A = Na,K) associated with green solvent templates. This validates the sustainable fabrication of electrode materials with reduced energy stipulations for detecting hazardous drug pollutants in the ecosystem.

Improved pharmacokinetics of tenofovir ester prodrugs strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism in preclinical models.

Tenofovir (TFV) ester prodrugs, a class of nucleotide analogs (NAs), are the first-line clinical anti-hepatitis B virus (HBV) drugs with potent antiviral efficacy, low resistance rate and high safety. In this work, three marketed TFV ester drugs, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) and tenofovir amibufenamide fumarate (TMF), were used as probes to investigate the relationships among prodrug structures, pharmacokinetic characteristics, metabolic activations, pharmacological responses and to reveal the key factors of TFV ester prodrug design. The results indicated that TMF and TAF exhibited significantly stronger inhibition of HBV DNA replication than did TDF in HBV-positive HepG2.2.15 cells. The anti-HBV activity of TMF was slightly stronger than TAF after 9 days of treatment (EC50 7.29 ± 0.71 nM vs. 12.17 ± 0.56 nM). Similar results were observed in the HBV decline period post drug administration to the HBV transgenic mouse model, although these three TFV prodrugs finally achieved the same anti-HBV effect after 42 days treatments. Furthermore, TFV ester prodrugs showed a correcting effect on disordered host hepatic biochemical metabolism, including TCA cycle, glycolysis, pentose phosphate pathway, purine/pyrimidine metabolism, amino acid metabolism, ketone body metabolism and phospholipid metabolism. The callback effects of the three TFV ester prodrugs were ranked as TMF > TAF > TDF. These advantages of TMF were believed to be attributed to its greater bioavailability in preclinical animals (SD rats, C57BL/6 mice and beagle dogs) and better target loading, especially in terms of the higher hepatic level of the pharmacologically active metabolite TFV-DP, which was tightly related to anti-HBV efficacy. Further analysis indicated that stability in intestinal fluid determined the actual amount of TFV prodrug at the absorption site, and hepatic/intestinal stability determined the maintenance amount of prodrug in circulation, both of which influenced the oral bioavailability of TFV prodrugs. In conclusion, our research revealed that improved pharmacokinetics of TFV ester prodrugs (especially intestinal stability) strengthened the inhibition of HBV replication and the rebalance of hepatocellular metabolism, which provides new insights and a basis for the design, modification and evaluation of new TFV prodrugs in the future.

Liver cirrhosis with its complications: Case report in a young female patient

Liver cirrhosis is a chronic disease characterized by the presence of fibrosis and regeneration of nodules in the liver, the consequence of which is the development of portal hypertension and liver failure. Usually associated with infectious infectious diseases such as viral hepatitis, alcohol consumption, metabolic syndrome, autoimmune processes, storage diseases, toxic substances and drugs. Major complications include gastrointestinal variceal bleeding, ascites, spontaneous bacterial peritonitis infection, hepatorenal syndrome, hepatic encephalopathy, and hepatocellular carcinoma.
 A 23-year-old woman comes to the ER, dr. Soegiri Lamongan with complaints of vomiting blood. The patient also complained of black bloody stools. Referred patient from Intan Medika Hospital with the initial complaint of vomiting blood more than 5 times (± equivalent to one medium drinking bottle) four days ago. On examination also found anemic conjunctiva and found splenomegaly. On abdominal ultrasound examination, the liver was shrunken, the edges were obtuse angles, partially irregular, parenchymal echo intensity was heterogeneous, v.hepatica was normal, liver fibrosis staging was 11.81 kPa, no masses or nodules were seen. The conclusion on endoscopic examination was the presence of grade III esophageal varices, congestive gastropathy, and erosive gastritis.
 Liver cirrhosis is a disease that has various etiologies. Early diagnosis and appropriate treatment in cirrhotic patients with complications is one way to improve patient survival