Combination Of Antiviral Drugs Research Articles

Comparison of Outcomes of Bell’s Palsy Patients Treated with Steroid and Steroid with Antiviral Drug in a Tertiary Care Hospital

Background: Bell’s palsy is the most common acute mononeuropathy associated with idiopathic unilateral facial weakness, characterized by facial asymmetry. Though steroids have effectiveness in managing Bell’s palsy, the use of antiviral is still debatable. Objective: To compare the outcome of Bell’s palsy with treatment by steroid versus combination of steroid and antiviral drugs. Methodology: A prospective analytical study was performed on 84 patients with acute Bell’s palsy attending at Neurology outpatient department of Mymensingh Medical College Hospital from July 2014 to June 2016. The patients were divided into two groups purposively after initial assessment as per House-Brackmann grading system (HBS). Group-I patients were treated with oral prednisolone and oral valacyclovir and Group-II patients were treated with oral prednisolone only. Both groups received facial exercises as per demonstration and proper eye care throughout the study period. Follow-up was done after 2 weeks, 4 weeks and 3 months for collection of data about recovery according to reassessment. Results: The analysis revealed that recovery rates at all 3 follow-ups were higher in the combination group than that of the prednisolone-only group [29(67.44%) versus 18 (43.90%) at 2nd week follow-up, 35(81.39%) versus 25(60.97%) at 4th week follow up and 40 (93.02%) versus 30(73.17%) at 3rd month follow-up]. Moreover, the expected recovery rate was higher in severe Bell’s palsy patients in the combination group than in steroid-alone group (22, 88.0% complete recovery versus 13, 54.17% complete recovery at the end of 3 months of treatment) [p=0.034]. haemorrhagic shock, spinal cord damage, septic shock and crush syndrome. Conclusion: The study showed antiviral (valacyclovir) plus steroid (prednisolone) to be more effective than steroid (prednisolone) alone in the treatment of Bell’s palsy. Moreover, outcome was more favorable in combination groups presenting with severe disease. Lessen their severity. Journal of Monno Medical College December, 2023; 9 (2):58-62

Hepatitis C virus-induced differential transcriptional traits in host cells after persistent infection elimination by direct-acting antivirals in cell culture.

Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.

Ji Desheng Snake Medicine for Herpes Zoster

Objective: to evaluate the clinical efficacy and application value of Ji Desheng snake medicine in the treatment of herpes zoster by Meta-analysis. Methods: CNKI, WANFANG, VIP, PubMed, The Cochrane Library and Embase were searched to identify available articles (up to January 2024). The included articles were subjected to data extraction and bias risk evaluation, and ＲevMan5.3 software was used to evaluate the efficacy and safe recovery time. Results: Nine articles involving 459 patients were finally included. Meta-analysis showed that Ji Desheng snake medicine combined with conventional treatment could improve and shorten the disease recovery time of patients [MD = − 3.30, 95%CI (-5.50, -1.1%), P < 0.05]. Ji Desheng snake medicine combined with routine treatment tended to improve the curative effect, and the difference was not statistically significant [RR = 1.11, 95%CI (0.99, 1.24), P = 0.12]. Conclusion: Ji Desheng snake medicine combined with conventional antiviral therapy can shorten the course of herpes zoster, suggesting that the combination of Ji Desheng snake medicine and conventional antiviral drugs should be considered in the clinical treatment of herpes zoster. However, due to the large differences in the included literature, we should treat the research results carefully, and large sample size and high-quality literature are needed to further confirm its clinical efficacy.

The combination of pleconaril, rupintrivir, and remdesivir efficiently inhibits enterovirus infections in vitro, delaying the development of drug-resistant virus variants

Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed toxicity and efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro. We identified several novel, synergistic two-drug and three-drug combinations that demonstrated significant inhibition of enterovirus infections in vitro. Specifically, the triple-drug combination of pleconaril, rupintrivir, and remdesivir exhibited remarkable efficacy against echovirus (EV) 1, EV6, EV11, and coxsackievirus (CV) B5, in human lung epithelial A549 cells. This combination surpassed the effectiveness of single-agent or dual-drug treatments, as evidenced by its ability to protect A549 cells from EV1-induced cytotoxicity across seven passages. Additionally, this triple-drug cocktail showed potent antiviral activity against EV-A71 in human intestinal organoids. Thus, our findings highlight the therapeutic potential of the pleconaril-rupintrivir-remdesivir combination as a broad-spectrum treatment option against a range of enterovirus infections. The study also paves the way towards development of strategic antiviral drug combinations with virus family coverage and high-resistance barriers.

Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics

The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2.

Rapid and validated UHPLC method for simultaneous determination of sofosbuvir, ledipasvir and paracetamol as commonly repurposed drugs for COVID-19 treatment: application in spiked human plasma

BackgroundSofosbuvir/ledipasvir (SOF/LDV), a combination of antiviral drugs, has been recently repurposed for COVID-19 management, according to Food and Drug Administration approval. Paracetamol (PAR) identified as a first-line antipyretic for COVID-19 symptoms' management. The use of these three drugs together has significantly influenced the management of COVID-19 by providing symptomatic relief via inhibiting viral activity. A validated ultra-high performance liquid chromatographic (UHPLC) method has been introduced for the quantification of these repurposed drugs in COVID-19 treatment. This novel chromatographic method allows the simultaneous detection of SOF, LDV, and PAR in bulk. Additionally, the method has been applied to determine the levels of SOF and LDV in human plasma samples with PAR used as an internal standard.ResultsA new UHPLC method was developed, using a mobile phase with a combination of acetonitrile and 0.1% orthophosphoric acid in a proportion of 42:58 (v/v).Flow rate was set at 0.4 ml/min, and UV detection was adjusted at 254 nm. The concentration of SOF, LDV, and PAR were measured by their corresponding peak areas, and showed linear relationships between concentration and peak area within the ranges of (5–60) µg/ml for SOF, (2–22) µg/ml for LDV, and (1–22) µg/ml for PAR. The presented UHPLC method was used to quantify the amounts of SOF, LDV, and PAR in both bulk samples and human plasma samples being spiked with the mentioned analytes. The elution process was completed within 4 min, with retention times of 3.28 min for SOF, 2.28 min for LDV, and 1.70 min for PAR. The method showed high separation selectivity, with an injection volume of 1µl. The precision, accuracy and repeatability of the method were found to be within acceptable limits.ConclusionThe recently developed method has been successfully validated in accordance with the guidelines set by the International Council for Harmonization (ICH). This validation process ensures that the method is suitable for routine quality control analysis, making it convenient for regular use.

Utility and feasibility of Phosphodiesterase inhibitors in the treatment COVID-19 patients

Phosphodiesterase inhibitors (PDE inhibitors) are a class of drugs that have been used for various medical conditions, primarily in the treatment of cardiovascular and pulmonary diseases, but they have also been explored for their potential utility in the management of COVID-19. Some PDE inhibitors, such as theophylline, have anti-inflammatory properties. In COVID-19, there is an excessive immune response that can lead to cytokine storms and inflammation in the lungs. PDE inhibitors may help modulate the immune response, potentially reducing inflammation. PDE inhibitors can lead to vasodilation and bronchodilation. In COVID-19, the virus can cause respiratory distress, and PDE inhibitors might help improve oxygenation and reduce breathing difficulties. Some studies suggest that PDE inhibitors can interfere with viral replication. By inhibiting certain phosphodiesterases, these drugs might impact the ability of the virus to reproduce in host cells. PDE inhibitors are often considered in combination with other medications. The combination of antiviral drugs and anti-inflammatory agents may be more effective in treating COVID-19 patients with severe symptoms. While some preclinical studies and small clinical trials have shown promising results, larger, well-designed clinical trials are necessary to confirm the effectiveness of PDE inhibitors in treating COVID-19. PDE inhibitors can have side effects, such as gastrointestinal issues, cardiovascular effects, and interactions with other medications. Their safety and potential for adverse reactions in COVID-19 patients need further evaluation. The feasibility of using PDE inhibitors in COVID-19 treatment may depend on patient profiles, including their underlying medical conditions, severity of illness, and potential contraindications. The use of PDE inhibitors for COVID-19 is subject to regulatory approval in different countries. Health authorities and regulatory agencies evaluate the safety and efficacy of medications for specific indications. while there is ongoing interest in the potential utility of PDE inhibitors in treating COVID-19 patients, their feasibility and safety as a part of COVID-19 treatment protocols are still under investigation. It's important for healthcare providers and researchers to continue conducting rigorous studies to determine their role and to consider the overall clinical context and individual patient characteristics in treatment decisions. Patients should consult with their healthcare professionals for the most up-to-date information and guidance on COVID-19 treatments.

Seasonal coronavirus infections trigger NLRP3 inflammasome activation in macrophages but is therapeutically targetable

Seasonal coronaviruses widely circulate in the global population, and severe complications can occur in specific vulnerable populations. Little is known on their pathogenic mechanisms and no approved treatment is available. Here, we present anecdotal evidence that the level of IL-1β, a hallmark of inflammasome activation, appears elevated in a subset of seasonal coronavirus infected patients. We found that cultured human macrophages support the full life cycle of three cultivatable seasonal coronaviruses. Their infections effectively activate NLRP3 inflammasome activation through TLR4 ligation and NF-κB activation. This activation can be attenuated by specific pharmacological inhibitors and clinically used medications including dexamethasone and flufenamic acid. Interestingly, combination of antiviral and anti-inflammatory drugs simultaneously inhibit seasonal coronavirus-triggered inflammatory response and viral replication. Collectively, these findings show that the TLR4/NF-κB/NLRP3 axis drives seasonal coronavirus triggered-inflammatory response, which in turn represents a viable therapeutic target.

Antibiotics and Antivirals in COVID-19: Clinical Outcomes

The clinical manifestations of COVID-19 disease are mainly caused by an irregular host response associated with excessive expression of inflammatory markers. Patients with mild, moderate, and severe symptoms of COVID-19 with or without comorbidities use a combination of antiviral drugs and antibiotics. This study aimed to determine the relationship between the use of antiviral drugs and antibiotics on the clinical outcomes of COVID-19 patients. The research design used a cross-sectional study with retrospective data collection. The inclusion criteria were COVID-19 patients hospitalized at Panti Waluya Sawahan Malang Hospital with or without comorbidities, positive RT-PCR results, and receiving antibiotic and antiviral therapy. The clinical outcome is a patient improvement if the length of stay is 14 days, and the patient worsens if it is >14 days. There is no relationship between antibiotics and antiviral drugs on the clinical outcomes of COVID-19 patients (p>0,05).
 Highlights:
 
 Excessive expression of inflammatory markers contributes to the clinical manifestations of COVID-19.
 Combination therapy of antiviral drugs and antibiotics is commonly used for COVID-19 patients.
 The study found no significant relationship between the use of antibiotics and antiviral drugs and the clinical outcomes of COVID-19 patients
 
 Keywords: antibiotics, antiviruses, COVID-19, clinical improvement, clinical deterioration

Simultaneous Determination of Nirmatrelvir and Ritonavir in Human Plasma by HPLC-MS/MS

Introduction. SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) is expected to remain a persistent global threat. Therefore, development of coronavirus disease 2019 (COVID-19) drugs is the most urgent global issue. Nirmatrelvir and ritonavir combination is an oral antiviral drug combination with activity against SARS-CoV-2. Nirmatrelvir and ritonavir combination is highly efficacious in reducing the risk of COVID-19. The study describes development and validation of high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of nirmatrelvir and ritonavir in human blood plasma. The method could be applied in pharmacokinetic study of nirmatrelvir and ritonavir.Aim. The aim of this study is to develop and validate a HPLC-MS/MS bioanalytical method for the determination of nirmatrelvir and ritonavir in human plasma.Materials and methods. The determination of nirmatrelvir and ritonavir in human plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation. Internal standard: promethazine. Mobile phase: 0.1% formic acid solution in water (Eluent A), 0.1% formic acid in acetonitrile (Eluent B). Column: Phenomenex Luna C18 50 × 2.0 mm, 5 μm. Analytical range: 50.00–10000.00 ng/mL for nirmatrelvir, 5.00–1000.00 ng/mL for ritonavir in human plasma. Ionization source and ionization: electrospray ionization, positive. Detection conditions: 499.90 → 110.10 m/z, 499.90 → 319.20 m/z (nirmatrelvir), 720.90 → 426.00 m/z, 720.90 → 296.20 m/z, 720.90 → 268.10 m/z, 720.90 → 197.10 m/z, 720.90 → 139.90 m/z (ritonavir), 285.15 → 198.05 m/z (promethazine).Results and discussion. This method was validated for selectivity, matrix effect, calibration curve, accuracy, precision, spike recovery, the lower limit of quantification, carry-over effect and stability.Conclusion. The HPLC-MS/MS method for quantitative determination of nirmatrelvir and ritonavir in human plasma was developed and validated. The analytical range was 50.00–10000.00 ng/mL for nirmatrelvir, 5.00–1000.00 ng/mL for ritonavir in human plasma. This method was applied to investigate the pharmacokinetics of nirmatrelvir and ritonavir.

The experience of using sodium aminodihydrophthalazinedione in the complex treatment of a patient with Ramsey – Hunt syndrome

Ramsey-Hunt syndrome is a rather complex interdisciplinary problem for diagnosis and treatment. Often, diagnosis requires the participation of different specialists: otorhinolaryngologists, neurologists, infectionists. Classic manifestations are quite typical (vesicular rash on the skin of the outer ear, on the eardrum, ear pain and lesion of the mimic muscles as a result of peripheral facial nerve paralysis). However, Hunt himself described various variants of pathological changes of the outer ear and pharynx in combination with lesions of the trigeminal, vestibule-cochlear, glossopharyngeal, abducens and vague nerves. The optic nerve is rarely involved, viral encephalitis and vasculitis of the brain may develop. The literature cites traditional treatment schemes that include a combination of antiviral and glucocorticosteroid drugs. However, the duration of the therapy, specific doses of the drugs continue to be discussed. Untimely initiation of antiviral and corticosteroid therapy and/or inadequately selected dosages provoke the progression of the disease, increase the risk of complications and adverse outcomes. The prognosis gets worse when combined with another pathology (diabetes mellitus, oncopathology, HIV infection). Therefore, the search of new Ramsey-Hunt syndrome’s methods and treatment regimens is essential. We have previously described the use of photodynamic therapy in the treatment of this pathology in a patient with a first-time revealed HIV infection. On our opinion, taking into account the herpes-viral etiology of the disease, drugs that have immunomodulatory effect, a protective effect on the affected tissues, regulating the intensity of inflammatory response, can be applied in the therapy of this pathology. The use of the immunomodulatory drug sodium aminodihydrophthalazinedione in complex therapy, especially in patients with a history of aggravating factors, can increase the effectiveness of treatment and reduce the risk of recurrence.

Molecular Mechanisms of Antiviral Agents against Dengue Virus.

Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for the treatment of dengue infections. Evaluations of combinations of antiviral drugs with different mechanisms of action could also lead to the development of synergistic drug combinations for the treatment of dengue at any stage of the infection.

Elucidation of the liver pathophysiology of COVID-19 patients using liver-on-a-chips.

SARS-CoV-2 induces severe organ damage not only in the lung but also in the liver, heart, kidney, and intestine. It is known that COVID-19 severity correlates with liver dysfunction, but few studies have investigated the liver pathophysiology in COVID-19 patients. Here, we elucidated liver pathophysiology in COVID-19 patients using organs-on-a-chip technology and clinical analyses. First, we developed liver-on-a-chip (LoC) which recapitulating hepatic functions around the intrahepatic bile duct and blood vessel. We found that hepatic dysfunctions, but not hepatobiliary diseases, were strongly induced by SARS-CoV-2 infection. Next, we evaluated the therapeutic effects of COVID-19 drugs to inhibit viral replication and recover hepatic dysfunctions, and found that the combination of anti-viral and immunosuppressive drugs (Remdesivir and Baricitinib) is effective to treat hepatic dysfunctions caused by SARS-CoV-2 infection. Finally, we analyzed the sera obtained from COVID-19 patients, and revealed that COVID-19 patients, who were positive for serum viral RNA, are likely to become severe and develop hepatic dysfunctions, as compared with COVID-19 patients who were negative for serum viral RNA. We succeeded in modeling the liver pathophysiology of COVID-19 patients using LoC technology and clinical samples.

The effect of different direct antivirals on hepatic steatosis in nondiabetic and naïve hepatitis C-infected Egyptian patients

BackgroundHepatitis C is associated with metabolic effects and fatty liver disease. The effect of different direct antivirals on the liver steatosis, and the metabolic profile, still needs to be established. The aim of this study is to determine the effect of achieving the sustained virological response after 12 weeks (SVR-12 weeks) with different combinations of direct antiviral drugs, on the hepatic steatosis, and fibrosis presented by laboratory and transient elastography parameters. Our study population is nondiabetic, chronically infected HCV Egyptian patients and naïve to any form of HCV treatment.MethodsThis cohort study was carried on 100 nondiabetic HCV treatment-naïve patients attending the Hepatology Clinic, in the Gastroenterology and Hepatology Department, Ain Shams University, and Kobry El Koba Military Hospital. The patients were divided into four groups according to their treatment regimens as follows: group A: 25 patients who received sofosbuvir (400 mg) and daclatasvir (60 mg) daily for 12 weeks; group B: 25 patients who received sofosbuvir (400 mg) and ledipasvir (90 mg) daily for 12 weeks; group C: 25 patients who received ombitasvir (12.5 mg), paritaprevir (75 mg), and ritonavir (50 mg) daily for 12 weeks; and group D: 25 patients who received sofosbuvir (400 mg) and simeprevir (150 mg) daily for 12 weeks. All patients were subjected to the following investigations: HCV quantitative PCR before and after 12 weeks of treatment, clinical and laboratory metabolic evaluation including alfa-fetoprotein level, thyroid profile assessment, ferritin level, pelvi-abdominal ultrasound, and FibroScan examination.ResultsAll patients achieved SVR after 12 weeks. FibroScan median decreased (P < 0.001) from 19.29 ± 6.97 kPa at baseline to 14.15 ± 6.48 kPa at SVR12. NAFLD score median increased from 1.88 (1.49–2.22) at baseline to 2.01 (1.61–2.33) after 12 weeks of treatment. The highest level of NAFLD score was in group C, and the lowest was in group B. The BMI mean decreased from 28.31 ± 1.53 at baseline to 28.07 ± 1.52 at SVR12. HbA1C level mean decreased from 5.73 ± 0.23 at baseline to 5.40 ± 0.24 at SVR12. In addition, liver enzymes, cholesterol, triglycerides, APRI score (AST-platelet ratio index), and HBA1C decreased after 12-week treatment with a statistically significant difference, while the mean LDL increased after 12 weeks of treatment.ConclusionsDAAs affect the metabolic profile of the treated patients. There is a noticed improvement in the FibroScan, NAFLD score, and lipid profile after achieving the SVR-12 weeks. However, LDL is increased after viral cure, mostly due to viral-host molecular interaction.

Genotypes of Hepatitis C Virus and Efficacy of Direct-Acting Antiviral Drugs among Chronic Hepatitis C Patients in a Tertiary Care Hospital.

Hepatitis C virus (HCV) chronic infection is a major causative factor for several chronic liver diseases, including liver cirrhosis, liver cell failure, and hepatocellular carcinoma. The HCV has seven major genotypes. Genotype 4 is the most prevalent genotype in the Middle East, including Saudi Arabia, followed by genotype 1. The HCV genotype affects the response to different HCV treatments and the progression of liver disease. Currently, combinations of direct-acting antiviral drugs (DAAs) approved for the treatment of HCV achieve high cure rates with minimal adverse effects. Because real-world data from Saudi Arabia about the efficacy of DAAs are still limited, this study was conducted to assess the effectiveness of DAAs in treating patients with chronic hepatitis C and to identify the variables related to a sustained virologic response (SVR) in a real-world setting in Saudi Arabia. This prospective cohort study included 200 Saudi patients with chronic HCV who were 18 years of age or older and had been treated with DAAs at King Abdul-Aziz Specialized Hospital in Taif, Saudi Arabia, between September 2018 and March 2021. The response to treatment was assessed by whether or not an SVR had been achieved at week 12 post treatment (SVR12). An SVR12 was reached in 97.5% of patients. SVR12 rates were comparable for patients of different ages, between men and women, and between patients with and without cirrhosis. In addition, the SVR12 rates did not differ according to the infecting HCV genotype. In this study, the presence of cirrhosis and the patient's gender were independent predictors of who would not reach an SVR12 (known here as the non-SVR12 group) according to the results of univariate and multivariate binary logistic regression analyses based on the determinants of SVR12. In this population of patients with chronic HCV infection, all DAA regimens achieved very high SVR12 rates. The patients' gender and the presence of cirrhosis were independent factors of a poor response.

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials.

Combination of the parent analogue of remdesivir (GS-441524) and molnupiravir results in a markedly potent antiviral effect in SARS-CoV-2 infected Syrian hamsters.

Remdesivir was the first antiviral drug to be approved for the treatment of severe COVID-19; followed by molnupiravir (another prodrug of a nucleoside analogue) and the protease inhibitor nirmatrelvir. Combination of antiviral drugs may result in improved potency and help to avoid or delay the development of resistant variants. We set out to explore the combined antiviral potency of GS-441524 (the parent nucleoside of remdesivir) and molnupiravir against SARS-CoV-2. In SARS-CoV-2 (BA.5) infected A549-Dual™ hACE2-TMPRSS2 cells, the combination resulted in an overall additive antiviral effect with a synergism at certain concentrations. Next, the combined effect was explored in Syrian hamsters infected with SARS-CoV-2 (Beta, B.1.351); treatment was started at the time of infection and continued twice daily for four consecutive days. At day 4 post-infection, GS-441524 (50mg/kg, oral BID) and molnupiravir (150mg/kg, oral BID) as monotherapy reduced infectious viral loads by 0.5 and 1.6 log10, respectively, compared to the vehicle control. When GS-441524 (50mg/kg, BID) and molnupiravir (150mg/kg, BID) were combined, infectious virus was no longer detectable in the lungs of 7 out of 10 of the treated hamsters (4.0 log10 reduction) and titers in the other animals were reduced by ∼2 log10. The combined antiviral activity of molnupiravir which acts by inducing lethal mutagenesis and GS-441524, which acts as a chain termination appears to be highly effective in reducing SARS-CoV-2 replication/infectivity. The unexpected potent antiviral effect of the combination warrants further exploration as a potential treatment for COVID-19.

Focal Segmental Glomerulosclerosis caused by Hepatitis B Infection Comorbid with HIV Infection

Glomerulonephritis is an inflammatory condition on renal glomerulus. These entities can manifest as nephrotic syndrome. One of causes of secondary glomerulonephritis is hepatitis B infection. Glomerulonephritis due to hepatitis B only happens in 0.1 – 25% cases, with the focal segmental glomerulosclerosis (FSGS) is rarely reported. We reported 20 years old male with nephrotic syndrome. He was homosexual with history of unprotected sex and multiple partners. From kidney biopsy, we found focal segmental glomerulosclerosis lesion. Blood examination showed he had both hepatitis B (HBV-DNA 1.7x108 IU/mL) and HIV infection (HIV-RNA 820 copies/mL, CD4 839 cell/uL). We treated this patient with combination of anti-viral drugs which consist of tenofovir, lamivudine and efavirenz. After three weeks of treatment, he showed improvement in the clinical symptoms and urinalysis.

Adaptive Mutation in the Main Protease Cleavage Site of Feline Coronavirus Renders the Virus More Resistant to Main Protease Inhibitors.

The rapid global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused serious health problems, highlighting the urgent need for antiviral drugs. The viral main protease (Mpro) plays an important role in viral replication and thus remains the target of choice for the prevention or treatment of several viral diseases due to high sequence and structural conservation. Prolonged use of viral protease inhibitors can lead to the development of mutants resistant to those inhibitors and to many of the available antiviral drugs. Here, we used feline infectious peritonitis virus (FIPV) as a model to investigate its development of resistance under pressure from the Mpro inhibitor GC376. Passage of wild-type (WT) FIPV in the presence of GC376 selected for a mutation in the nsp12 region where Mpro cleaves the substrate between nsp12 and nsp13. This mutation confers up to 3-fold resistance to GC376 and nirmatrelvir, as determined by EC50 assay. In vitro biochemical and cellular experiments confirmed that FIPV adapts to the stress of GC376 by mutating the nsp12 and nsp13 hydrolysis site to facilitate cleavage by Mpro and release to mediate replication and transcription. Finally, we demonstrate that GC376 cannot treat FIP-resistant mutants that cause FIP in animals. Taken together, these results suggest that Mpro affects the replication of coronaviruses (CoVs) and the drug resistance to GC376 by regulating the amount of RdRp from a distant site. These findings provide further support for the use of an antiviral drug combination as a broad-spectrum therapy to protect against contemporary and emerging CoVs. IMPORTANCE CoVs cause serious human infections, and antiviral drugs are currently approved to treat these infections. The development of protease-targeting therapeutics for CoV infection is hindered by resistance mutations. Therefore, we should pay attention to its resistance to antiviral drugs. Here, we identified possible mutations that lead to relapse after clinical treatment of FIP. One amino acid substitution in the nsp12 polymerase at the Mpro cleavage site provided low-level resistance to GC376 after selection exposure to the GC376 parental nucleoside. Resistance mutations enhanced FIPV viral fitness in vitro and attenuated the therapeutic effect of GC376 in an animal model of FIPV infection. Our research explains the evolutionary characteristics of coronaviruses under antiviral drugs, which is helpful for a more comprehensive understanding of the molecular basis of virus resistance and provides important basic data for the effective prevention and control of CoVs.

Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs.

The protease inhibitor, ritonavir, is a strong inhibitor of CYP 3A. The drug is used for management of the human immunovirus and is currently part of an oral antiviral drug combination (nirmatrelvir–ritonavir) for the early treatment of SARS‐2 COVID‐19‐positive patients aged 12 years and over who have recognized comorbidities. The CYP 3A enzyme system is responsible for clearance of numerous drugs used in anesthesia (e.g., alfentanil, fentanyl, methadone, rocuronium, bupivacaine, midazolam, ketamine). Ritonavir will have an impact on drug clearances that are dependent on ritonavir concentration, anesthesia drug intrinsic hepatic clearance, metabolic pathways, concentration‐response relationship, and route of administration. Drugs with a steep concentration‐response relationship (ketamine, midazolam, rocuronium) are mostly affected because small changes in concentration have major changes in effect response. An increase in midazolam concentration is observed after oral administration because CYP 3A in the gastrointestinal wall is inhibited, causing a large increase in relative bioavailability. Fentanyl infusion may be associated with a modest increase in plasma concentration and effect, but the large between subject variability of pharmacokinetic and pharmacodynamic concentration changes suggests it will have little impact on an individual patient, especially when used with adverse effect monitoring. It has been proposed that drugs that have no or only a small metabolic pathway involving the CYP 3A enzyme be used during anesthesia, for example, propofol, atracurium, remifentanil, and the volatile agents. That anesthesia approach denies children of drugs with considerable value. It is better that the inhibitory changes in clearance of these drugs are understood so that rational drug choices can be made to tailor drug use to the individual patient. Altered drug dose, anticipation of duration of effect, timing of administration, use of reversal agents and perioperative monitoring would better behoove children undergoing anesthesia.