Better therapeutic effect of oral administration of GS441524 compared with GC376.

FIP is a fatal feline disease caused by FIPV. Two drugs (GS441524 and GC376) target FIPV and have good therapeutic effect when administered by subcutaneous injection. However, subcutaneous injection has limitations compared with oral administration. Additionally, the oral efficacy of the two drugs has not been determined. Here, GS441524 and GC376 were shown to efficiently inhibit FIPV-rQS79 (recombination virus with a full-length field type I FIPV and the spike gene replaced with type II FIPV) and FIPV II (commercially available type II FIPV 79-1146) at a noncytotoxic concentration in CRFK cells. Moreover, the effective oral dose was determined via the in vivo pharmacokinetics of GS441524 and GC376. We conducted animal trials in three dosing groups and found that while GS441524 can effectively reducing the mortality of FIP subjects at a range of doses, GC376 only reducing the mortality rate at high doses. Additionally, compared with GC376, oral GS441524 has better absorption, slower clearance and a slower rate of metabolism. Furthermore, there was no significant difference between the oral and subcutaneous pharmacokinetic parameters. Collectively, our study is the first to evaluate the efficacy of oral GS441524 and GC376 using a relevant animal model. We also verified the reliability of oral GS441524 and the potential of oral GC376 as a reference for rational clinical drug use. Furthermore, the pharmacokinetic data provide insights into and potential directions for the optimization of these drugs.

Development of indigestible IgA antibody for restoring microbiome balance

Dysbiosis, especially in the gut plays a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. At mucosal surfaces, mucosal polymeric immunoglobulin A（IgA）antibodies are known to be important to regulate the gut microbiota as well as to exclude infection induced by pathogenic bacteria or virus such as influenza and SARS-CoV-2（severe acute respiratory syndrome coronavirus 2）. Since the 1970s, oral administration of IgA or IgG antibodies has been performed against infectious enteritis caused by pathogenic Escherichia coli or Clostridioides difficile. However, none of them has been successfully developed as an antibody drug up to now. Although IgA is well known to modulate the gut commensal microbiota, the therapeutic IgA drugs to treat dysbiosis has not been developed. Here, we discuss the advantages of therapeutic IgA antibodies.Alternate :抄録Dysbiosisは、健康な微生物叢と比較した微生物組成の変化であり、腸内微生物多様性の減少および微生物分類群の変化を特徴とする。腸内のdysbiosisはまた、炎症性腸疾患、結腸直腸がん、心血管疾患、肥満、糖尿病および多発性硬化症を含むさまざまな疾患の病因において重要な役割を果たすと提唱されている。腸の多量体免疫グロブリンA（IgA）抗体は、腸内微生物叢を調節するだけではなく、病原性細菌、インフルエンザやSARS-CoV-2（重症急性呼吸器症候群コロナウイルス2）などのウイルス感染を粘膜部位から排除するのに重要であることが、多くのエビデンスから示されている。1970年代以降、治療用IgAまたはIgGの経口投与試験が、主に病原性大腸菌またはディフィシル菌によって引き起こされる感染性腸炎を治療するために行われてきた。しかし、現在まで臨床応用として開発に成功したものはない。腸内病原体に対する防御機能に加えて、IgAは腸内共生微生物叢を調節して共生に導くことがよく知られているが、dysbiosisを治療するためのIgA治療薬の開発も進んでいない。本稿では、治療用IgA抗体の利点とその開発について議論する。

Improved virus inhibition by microencapsulated monoclonal antibody against porcine epidemic diarrhea virus

Porcine epidemic diarrhea virus (PEDV) has been affecting the swine industry, especially in suckling pigs in with a high mortality rate. Among all the strategies to overcome PEDV, boosting mucosal immunity in pig intestine via oral administration appears to be more efficient than other routes. However, there are biological obstacles such as acidic environment that could damage biologics, a product from organisms often used for PEDV treatment. The plant-derived 2C10 monoclonal antibody (mAb) from Nicotiana benthamiana produced by transient expression was revealed as one of the potential candidates against PEDV through oral delivery. Herein, we demonstrated the calcium-alginate microencapsulation system to protect the 2C10 mAb from the harsh condition in the stomach and to be released the 2C10 mAb when arriving in the intestine. The pH-responsive encapsulated 2C10 mAb microbeads were constructed from the calcium-alginate system. The microbeads were well-tolerated under the acidic environment of simulated gastric fluid (SGF) and were digested under the alkaline condition of simulated intestinal fluid (SIF). The encapsulated 2C10 mAb in the SPF-treated microbeads exhibited high virus neutralization efficiency in Vero cells when compared to the unencapsulated 2C10 mAb treated by SPF that cannot neutralize the virus. For these reasons, calcium-alginate microencapsulation system is an attractive platform to be considered as a candidate for the next generation of oral vaccine development.

A pilot study on controlling Coronavirus disease 2019 (COVID-19) inflammation using melatonin supplement

No effective antiviral drugs and vaccines are available for the treatment of patients with severe coronavirus 2019 (COVID-19). Therefore, available, safe, and inexpensive drugs and supplements such as melatonin are among the proposed options for controlling inflammation. We did a randomized, single-blind study in Imam Khomeini Hospital between June 30, 2020, and August 5, 2020. Mild to moderate COVID-19 patients aged 25-65 years were eligible to enter the study based on chest CT scan, clinical symptoms, and physician diagnosis. The intervention group was prescribed 6 mg of oral melatonin for 2 weeks, which consumed half an hour before bedtime every night in low light conditions. Clinical symptoms and C-reactive protein (CRP) were measured before and after treatment in the melatonin received and control(regular medications)groups. Among screened patients with COVID-19, 14 patients were assigned to receive melatonin, and 17 patients were considered as controls. A significant difference (p=0.005) between CRP 1 and CRP 2 levels (before and after using melatonin) was found in the melatonin group while this difference (p=0.069) was not significant in the control group. Also, the percentage of recovery (based on symptoms) in patients who took melatonin was higher than that of patients in the control group (85.7%VS 47.1%). The result of this study confirmed the effectiveness of melatonin in mild to moderate outpatients with COVID-19. More clinical trials on elderly, diabetic, obese patients and severe cases are suggested in future studies.

Predictors of in-hospital mortality in COVID-19: a study across two peripheral district general hospitals in UK

Aim: The mortality from Coronavirus Disease 2019 (COVID-19) has remained a significant medical challenge. Internationally, patient demographics and pre-existing co-morbidities are significant determinants of mortality from COVID-19. The mortality-risk in a local population is difficult to determine. The objective of our study is to examine the risk posed by epidemiological and demographic variables, and co-morbidities in our local population. Method: A retrospective, observational study was conducted on confirmed COVID-19 patients, identified from the local microbiology database. A search of the electronic patient records was performed to collect demographic details and co-morbidities. Chi-square test and logistic regression analysis of the demographic variables and co-morbidities were utilised to calculate the predictive-risk for in-hospital mortality of adult COVID-19 patients. Results: Final analysis included 263 samples. Univariate logistic regression analysis was performed using age as an independent categorical predictor with two cohorts - those <60 and those 60 years old. Age (X2 =17.12, p<0.001) was found to be an independent predictor of mortality - this was independent of sex (X2 =1.784, p<0.182). Charlson Comorbidity Index (CCI) score was found to be a significant predictor of adverse outcome. The odds of death for patients with CCI scores 0-4 was less than half (44.8%) of those with CCI scores 5 (p=0.005). Patients with no pre-existing medical conditions had a lower mortality-risk (OR=0.181, p=0.022) than those with known medical conditions. Pre-existing renal disease predicted a poor outcome (OR=1.996, p=0.027). The odds of death for the patients coming from their own-home was only 26% of the odds for those from a longterm care-home. Long-term care facility, advanced age (OR=1.058, p <0.001), and long-term oral steroid (OR=3.412, p=0.016) use were all associated with a poor prognosis. Conclusion: People aged 60 years, residence in a long-term care-home, pre-existing renal diseases, a high CCI score and long-term oral steroids use were associated with an increased mortality-risk.

Oral Administration of Universal Bacterium-Vectored Nucleocapsid-Expressing COVID-19 Vaccine is Efficacious in Hamsters.

Oral delivery of an inexpensive COVID-19 (coronavirus disease 2019) vaccine could dramatically improve immunization rates, especially in low- and middle-income countries. Previously, we described a potential universal COVID-19 vaccine, rLVS ΔcapB/MN, comprising a replicating bacterial vector, LVS (live vaccine strain) ΔcapB, expressing the highly conserved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) membrane and nucleocapsid (N) proteins, which, when administered intradermally or intranasally, protects hamsters from severe COVID-19-like disease after high-dose SARS-CoV-2 respiratory challenge. Here, we show that oral administration of the vaccine also protects against high-dose SARS-CoV-2 respiratory challenge; its protection is comparable to that of intradermal, intranasal, or subcutaneous administration. Hamsters were protected against severe weight loss and lung pathology and had reduced oropharyngeal and lung virus titers. Protection against weight loss and histopathology by the vaccine, which in mice induces splenic and lung cell interferon gamma in response to N protein stimulation, was correlated in hamsters with pre-challenge serum anti-N TH1-biased IgG (IgG2/3). Thus, rLVS ΔcapB/MN has potential as an oral universal COVID-19 vaccine. IMPORTANCE The COVID-19 pandemic continues to rage into its fourth year worldwide. To protect the world's population most effectively from severe disease, hospitalization, and death, a vaccine is needed that is resistant to rapidly emerging viral variants of the causative agent SARS-CoV-2, inexpensive to manufacture, store, and transport, and easy to administer. Ideally, such a vaccine would be capable of oral administration, especially in resource-poor countries of the world where there are shortages of needles, syringes and trained personnel to administer injectable vaccines. Here, we show that oral administration of a bacterium-vectored vaccine meeting all these criteria protects naturally susceptible Syrian hamsters from severe COVID-19-like disease, including severe weight loss and lung pathology, after high-dose SARS-CoV-2 respiratory challenge. As the vaccine is based upon inducing immunity to highly conserved SARS-CoV-2 membrane and nucleocapsid proteins, as opposed to the rapidly mutating Spike protein, it should remain resistant to newly emerging SARS-CoV-2 variants.

ACKNOWLEDGEMENT TO REFEREES

The most popular 2022 articles to date, in terms of downloads from SpringerLink, are: * The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders * A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication * Cannabis-Based Medicines and Medical Cannabis for Chronic Neuropathic Pain * Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression * Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment * Potential Role of Curcumin for the Treatment of Major Depressive Disorder * Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment * Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judic ious Prescribing * New Oral Drugs for Migraine * A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schiz ophrenia Social media sharing and other online mentions of information are additional metrics with which to measure the reach of articles. Results from the Randomized Phase III REST-ON Trial * Potential Role of Curcumin for the Treatment of Major Depressive Disorder * Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment The quality of published articles is also testament to the significant efforts of the peer reviewers, whose commitment ensures that the journal's content is held to the highest possible standard. Moussa, USA Suresh Muthukumaraswamy, New Zealand Kjell-Morten Myhr, Norway Ahmed Nadeem, Saudi Arabia Michael R. Nadorff, USA Jadwiga Najib, USA David N. Neubauer, USA Fabricio Ferreira de Oliveira, Brazil Giovanni Ostuzzi, Italy Lucas H. Overeem, Germany Paolo Palmisciano, USA Sagun Parakh, Australia Daniele Pastori, Italy Friedemann Paul, Germany Michael Paulzen, Germany Santiago Perez-Lloret, Argentina Jamir Pitton Rissardo, Brazil Werner Poewe, Austria Emilio Portaccio, Italy Wei Qiu, China Susana Quijano-Roy, France Emanuel Raschi, Italy John Read, UK Gary Remington, Canada Uwe Reuter, Germany Johan Reutfors, Sweden Paul Rolan, Australia Simona Rolla, Italy Benjamin Rolland, France Francisco Romo-Nava, USA Stephan Rüegg, Switzerland Henricus Ruhe, The Netherlands Gabriele Sachs, Austria Hiroyuki Sakata, Japan Cristina Sampaio, Portugal Ley Sander, UK Joan Santamaría, Spain Jerome Sarris, Australia Sebastiaan Sassen, The Netherlands Takehito Sato, Japan An-Sofie Schoonjans, Belgium Rudy Schreiber, The Netherlands Mieke H.J. Schulte, The Netherlands Peter F.J. Schulte, The Netherlands Mehmet Güney Şenol, Turkey Ancor Serrano Afonso, Spain Raghuraman M. Sethuraman, India Rahul Shukla, India Alessio Signori, Italy Balwinder Singh, USA Dan Siskind, Australia J. Robert Sneyd, UK Karin Söderberg-Löfdal, Sweden Anand Srinivasan, India Joseph F. Standing, UK Richard R. Stark, Australia Mark A. Stein, USA Thomas P. Stern, USA Pasquale Striano, Italy Cliff H. Summers, USA Raoul Sutter, Switzerland Takefumi Suzuki, Japan Enzo Tagliazucchi, Argentina Hiroyoshi Takeuchi, Japan Emma Tallantyre, UK Xiangdong Tang, China Aina Teniente Serra, Spain David Ternant, France Morgane Thomsen, Denmark Eduardo Fidel Tizzano, Spain Lawrence Toll, USA Duong Tran, Australia Louis-Eric Trudeau, Canada Marit Tveito, Norway Alp Ucok, Turkey Emily Uebbing, USA Nicole Van Bergen, Australia Judy Van de Water, USA Arnold van der Lee, The Netherlands Nathalie van der Velde, The Netherlands Ruben van Eijk, The Netherlands Vincent van Pesch, Belgium Jan Versijpt, Belgium Michail Vikelis, Greece Antonio Vita, Italy Viktor von Wyl, Switzerland Howard Weiner, USA Gail Winger, USA Elaine C. Wirrell, USA David C. Yeomans, USA V. Wee Yong, Canada Gaetano Zaccara, Italy Atefeh Zandifar, Islamic Republic of Iran Ifrah Zawar, USA Nicole Ziliotto, Italy We gratefully acknowledge all of the members of the journal's Honorary Editorial Board, who have acted as peer reviewers and authors, and have provided guidance on journal content, policy and processes: David S. Baldwin, University of Southampton, Southampton, England Robert L. Barkin, North Shore University Health System and Rush University, Chicago, IL, USA Thomas R.E. Barnes, Imperial College London, London, England Michael Berk, Deakin University, Geelong, VIC, Australia Meir Bialer, The Hebrew University of Jerusalem, Jerusalem, Israel José Biller, Loyola University Chicago, Maywood, IL, USA Francesco Brigo, Hospital of Merano (SABES-ASDAA), Merano, Italy Henry Brodaty, Prince of Wales Hospital, Randwick, NSW, Australia Martin J. Brodie, West Glasgow Ambulatory Care Hospital, Glasgow, Scotland Matthew Carpenter, Medical University of South Carolina, Charleston, SC, USA Marc C. Chamberlain, University of Washington, Seattle, WA, USA David R. Coghill, Royal Children's Hospital Melbourne, and University of Melbourne, Parkville, VIC, Australia Samuele Cortese, University of Southampton, Southampton, England Mervyn J. Eadie, University of Queensland, Brisbane, QLD, Australia Susanna Every-Palmer, University of Otago, Wellington, New Zealand Martin R. Farlow, Indiana University School of Medicine, Indianapolis, IN, USA Giovanni A. Fava, University of Bologna, Bologna, Italy Susan H. Fox, University Health Network, Toronto, ON, Canada George T. Grossberg, St Louis University School of Medicine, St. Louis, MO, USA David Gurwitz, Tel-Aviv University, Tel Aviv, Israel Martina Hahn, University Hospital Frankfurt, Frankfurt, Germany Göran Hajak, University of Regensburg, Regensburg, Germany Hans-Peter Hartung, Heinrich-Heine University, Dusseldorf, Germany Tomas Kalincik, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia Joshua T. Kantrowitz, Columbia University, New York, NY, USA David Kemp, Case Western Reserve University, Cleveland, OH, USA Susan G. Kornstein, Virginia Commonwealth University, Richmond, VA, USA Patrick Kwan

Embracing change in acute health settings: patients’ experience of a pop-up day care unit in a Nightingale Hospital

AimsThe coronavirus disease (COVID-19) pandemic imposed unprecedented disruption to global health care service delivery. Healthcare settings had to rapidly implement social-distancing measures to reduce disease transmission, primarily prioritising emergency treatment over routine care. The impact upon paediatric ambulatory care settings was considerable, forcing hospitals to restructure traditional provision and to explore new initiatives.A pop-up paediatric day care unit was set up at the Nightingale Hospital, Bristol (NHB). This temporary unit aimed to mitigate against anticipated delays in diagnosis and treatment for children with allergic disease and inflammatory bowel disease.The aim of this study was to collate patients’ and family/carer’s experience feedback in order to understand the acceptability and viability of these innovative initiatives for ambulatory care in alternative settings, outside acute hospitals.MethodsA 12 bedded area Day Care Unit was developed at the NHB. The Day Care Unit operated fortnightly between December 2020 and March 2021, supporting patients from the paediatric allergy and the paediatric gastroenterology specialities.Patients were carefully selected following strict criteria. At the end of their test/treatment, patients and carers were invited by their named nurse to complete an evaluation via an online form.Results72 responses were collated. The children underwent a range of procedures from: supervised feeds, food challenges, sublingual immunotherapy, omalizumab injections, infliximab infusion, outpatient appointment, skin prick test and flu vaccination. 23 (31.9%) of the patients had to drive less than 5 miles to the NHB, 33 (45.8%) drove 5-10 miles and 16 (22.2%) more than 10 miles.All responses (72) found NHB acceptable and 70 (97%) would be happy to return. 63 (90.3%) would prefer to attend the NHB or had no preference for their appointments. All comments were positive focusing on good management and organisation as well as on the friendly, calm and safe environment. Families particularly valued the close and free parking. Any negative comments related to the signposting to venue, the lack of catering facilities and the number of toilets.ConclusionAlternative ambulatory services have been a successful means of managing a potential crisis in access to healthcare. The pop-up service model was highly acceptable to families and provokes consideration of the need to investigate future similar initiatives as potential alternative models to maximise capacity in acute settings. It was an environment in which families felt safe and well-cared for, was more easily accessible than a city centre busy hospital and allowed the clinical team the opportunity to work more closely than usual. This highlights the need for selected hospital services to consider looking further afield in order to ensure the provision of equitable healthcare in line with the NHS Forward plan.

Challenges and opportunities in current vaccine technology and administration: A comprehensive survey examining oral vaccine potential in the United States.

This study provides a snapshot of the current vaccine business ecosystem, including practices, challenges, beliefs, and expectations of vaccine providers. Our team focused on providers' firsthand experience with administering vaccines to determine if an oral vaccine (e.g. pill or oral-drop) would be well-received. We interviewed 135 healthcare providers and vaccine specialists across the US, focusing questions on routine vaccinations, not COVID-19 vaccines. Improving workflow efficiency is a top concern among vaccine providers due to shrinking reimbursement rates-determined by pharmacy benefit managers (PBMs)-and the time-intensiveness of injectable vaccines. Administering injectable vaccines takes 23 minutes/patient on average, while dispensing pills takes only 5 minutes/patient. An average of 24% of patients express needle-fear, which further lengthens the processing time. Misaligned incentives between providers and PBMs could reduce the quality and availability of vaccine-related care. The unavailability of single-dose orders prevents some rural providers from offering certain vaccines. Most interviewees (74%) believe an oral vaccine would improve patient-provider experience, patient-compliance, and workflow efficiency, while detractors (26%) worry about the taste, vaccine absorption, and efficacy. Additional research could investigate whether currently non-vaccinating pharmacies would be willing to offer oral vaccines, and the impact of oral vaccines on vaccine acceptance.

Antiviral effect and anti-COVID-19 potential of immunobiotics

Immunobiotics, a group of probiotics, have the effect of anti-infection by regulating immune function, which can be added in in foods or used to make adjuvants or medicines (biologics). Immunobiotics can stimulate the mucosal immune system of the body, regulate innate and acquired immunity and exert non-specific anti-microbial (bacterial and viral) infection effects through oral, nasal mucosa, sublingual and other routes, but the immune regulation function of immunobiotics is species-specific. Oral administration of Lactobacillus plantarum GUANKE stimulated the increase and maintenance of SARS-CoV-2 neutralization antibodies in mice even 6 months after immunization. When L. plantarum GUANKE was given immediately after SARS-CoV-2 vaccination, the level of SARS-COV-2 specific neutralizing antibody in bronchoalveolar lavage increased by 8 times in mice, which improved the local and systematic cellular immune response to SARS-CoV-2 of mice. Clinical studies have found that immunobiotics have the auxiliary effect in the treatment of COVID-19 by mitigating the symptoms and increase the level of SARS-CoV-2 specific antibody of the patients. It is necessary to conduct research and evaluation for the appropriate guideline of immunobiotics use as erly as possible to provide a new option for the prevention and control of COVID-19.

Hypoxemic COVID-Pneumonia, Diabetes Mellitus: Combination of Tailored Prednisone, Colchicine, Antithrombotics, Diuretic Improves Prognosis (CocAA-CoLa PLUS Study)

In patients (pts) with diabetes mellitus (DM) , Covid-pneumonia mortality rate >20% has been reported. A low fixed dose of intravenous dexamethasone (Dx) for days (RECOVERY study, 6 mg/d, i.e 0.5 mg/kg/d prednisone equivalent) has been shown to effectively reduce Covid-pneumonia mortality. In an observational study, prognosis was improved with an oral combination of prednisone fixed dose (1mg/kg/d) , direct anticoagulant/aspirin/colchicine/furosemide (DOAACF) . We hypothesized prednisone tailored doses driven by clinical evolution (extra 1mg/kg/d for every increase of O2 flow) added-on DOAACF for days would decrease morbi-mortality. In our monocentric, retrospective study (03.2020-05.2021) , pts with Covid-pneumonia requiring O2 out of the Intensive Care Unit (ICU) were included. According to the Physicians discretionary caring decisions, a control group (no corticoid) , a Dx group, an oral tailored prednisone ≥1mg/kg/d-DOAACF group were compared. The primary endpoint was Day 28 ICU requirement or mortality. Out of 3pts included for hypoxemic Covid-pneumonia, 132 pts had DM (43%) (control n = 28;Dx n = 46;tailored prednisone-DOAACF n = 58) : median age 69y;Males/Females 2.8;BMI 28 kg/m2;cardiovascular history 40%;median SpO2 at room air 92%;median maximal O2 flow 4L/min. Pts characteristics were non statistically different. Prednisone median dose (1.5mg/kg/d) and aspirin-colchicine-furosemide use were significantly higher in the tailored prednisone-DOAACF group in which events rate (12%) was significantly lower (control 50%, p = 0.0003, Dx 37%, p = 0.004) . In the tailored group, no statistical difference observed with pts without DM (13.3%, p = 1) . Out of the ICU, in pts with DM, a five oral drugs combination made of tailored prednisone ≥1mg/kg/d, anti-inflammatory, antithrombotics, diuretic improves hypoxemic Covid-pneumonia prognosis. A randomized trial is needed.

Examination of the Impact of CYP3A4/5 on Drug–Drug Interaction between Schizandrol A/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach

Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug–drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes’ inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.

Tailoring Tofacitinib Oral Therapy in Rheumatoid Arthritis: The TuTOR App

To support the management of rheumatoid arthritis (RA) patients treated with tofacitinib, we designed the TuTOR (tailoring tofacitinib oral therapy in rheumatoid arthritis) mobile app. The impact of the app on medical adherence was evaluated using a crossover design alternating a paper-diary and the TuTOR App. Twenty patients with RA (mean age at inclusion, 59 ± 13 years) were included in the study. A statistically significant decrease in DAS28 was observed since the first month of therapy (mean DAS28 at baseline, 3.9 ± 1 vs. 1° month 3.1 ± 1, p = 0.0016). Similarly, the numerical rating scale (NRS) of perceived activity of disease and subjective fatigue progressively decreased. No differences were reported in DAS28 or NRS between the TuTOR app and the paper-diary groups. A significant decrease was observed in HAQ during the follow-up (baseline 1.38 ± 1.11 vs. six months 0.83 ± 0.9;p = 0.01). When filling out the self-reporting questionnaires, most of the patients (82%) preferred the TuTOR App helping them to remember to take the pills. Furthermore, 82% of patients used the app regularly (vs. 53% for the paper diary). Three patients suspended tofacitinib due to gastrointestinal intolerance. Both digital and paper devices can help maximize adherence to therapy;however, the TuTOR app was preferred by the patients for its simplicity and immediacy.

2-Deoxy D-Glucose, the new drug to fight COVID-19

The molecular structure of 2-Deoxy D-Glucose is exactly like D-Glucose except for the fact that the former has no hydroxyl group on the carbon atom at the position 2 but instead has a hydrogen atom. Glucose can be of two types: one which turns the plane of the polarized light, when passed through its solution in water, towards right is called Dextrorotatory or D-Glucose and the other which turns it towards left is called Levorotatory or LGlucose. Chemists call glucose as an aldohexose, indicating that it is made up of six carbon atoms, one of which is an aldehyde group and the rest contain hydrogen atoms and hydroxyl groups. In other words, it has one oxygen atom less than D-Glucose and therefore, is called 2-Deoxy-D-Glucose. The Drugs Controller General of India granted approval (May 17 2021) for use of 2 DG drug after it went through too extensive successful clinical trials. Now, the drug has been recommended to be used in moderate cases which have to be taken orally mixed with water, 2 times a day for 5 to 7 days. It showed that the drug was able to reduce oxygen dependency by the third day and reduce the hospital stay considerably.

Oral SARS-CoV-2 Spike Protein Recombinant Yeast Candidate Prompts Specific Antibody and Gut Microbiota Reconstruction in Mice.

A recent study showed that patients with coronavirus disease 2019 (COVID-19) have gastrointestinal symptoms and intestinal flora dysbiosis. Yeast probiotics shape the gut microbiome and improve immune homeostasis. In this study, an oral candidate of yeast-derived spike protein receptor-binding domain (RBD) and fusion peptide displayed on the surface of the yeast cell wall was generated. The toxicity and immune efficacy of oral administration were further performed in Institute of Cancer Research (ICR) mice. No significant difference in body weights, viscera index, and other side effects were detected in the oral-treated group. The detectable RBD-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more complex microbiota were detected from oral administration mice compared with those of the control group. Interestingly, the recombinant yeast was identified in female fetal of the high-dose group. These results revealed that the displaying yeast could fulfill the agent-driven immunoregulation and gut microbiome reconstitution. The findings will shed light on new dimensions against SARS-CoV-2 infection with the synergistic oral agents as promising non-invasive immunization and restoring gut flora.

Clinical efficacy of the antiviral drug favipiravir in the complex treatment of patients with COVID-19 coronavirus infection

Introduction. It is known that most patients with COVID-19 have a disease of mild to moderate severity and can be treated at home. A potential etiotropic drug in the treatment of such patients is favipiravir. To finally decide on the inclusion of this drug in the international recommendations for the treatment of COVID-19, further studies are needed to assess its effectiveness and safety in patients with COVID-19. The aim of the study was to study the clinical efficacy of favipiravir in the complex therapy of patients with moderate-severity COVID-19 coronavirus infection. Materials and methods. A retrospective analysis of 468 medical records of an inpatient patient with a moderate form of coronavirus infection COVID-19, who were treated at the State Clinical Hospital at the Multi-Specialty Medical Center of the Akimat of Nur-Sultan, the Semey Infectious Diseases Hospital, for the period August-October 2020, was carried out. The experimental (main) group consisted of 40 patients with COVID-19 of moderate severity, who, in addition to standard therapy in accordance with the Clinical Protocol for Diagnosis and Treatment "COVID-19 Coronavirus infection (10th edition with changes from 15.07.2020), were prescribed oral favipiravir at a dose of 1600 mg/12 h on day 1, then 600 mg/12 h on the following days, for a total of 7 days. The comparison group (control group) consisted of 40 patients with moderate CVI who did not receive favipiravir. Descriptive statistics were performed with the calculation of the mean (M) and standard deviation (SD) for quantitative variables;percentages were calculated for qualitative variables. Statistical analysis was performed using Microsoft Excel and IBM SPSS Statistics 20.0. P <0.05 was considered statistically significant. Results and discussion. The present study showed that the early initiation of antiviral therapy with Favipiravir, compared with standard therapy without an antiviral drug, in patients with a moderate form of COVID-19 is associated with a statistically significant clinical improvement and a large percentage of virus elimination from the mucous membranes of the upper respiratory tract according to molecular genetic research. In the group of patients receiving favipiravir, complete remission of the disease with normalization of the main clinical parameters and the absence of complaints for 7 days of hospitalization was significantly more often than in the comparison group. Conclusions. The results obtained showed that Favipiravir is an effective antiviral drug in the complex treatment of COVID-19 coronavirus infection of moderate severity. Early administration of the drug in patients with a moderate form of the disease can prevent the progression of the disease to a more severe condition and the development of complications that require additional medical interventions.

Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products.

Prodrugs are bioreversible, inactive drug derivatives, which have the ability to convert into a parent drug in the body. In the past, prodrugs were used as a last option; however, nowadays, prodrugs are considered already in the early stages of drug development. Optimal prodrug needs to have effective absorption, distribution, metabolism, and elimination (ADME) features to be chemically stable, to be selective towards the particular site in the body, and to have appropriate safety. Traditional prodrug approach aims to improve physicochemical/biopharmaceutical drug properties; modern prodrugs also include cellular and molecular parameters to accomplish desired drug effect and site-specificity. Here, we present recently investigated prodrugs, their pharmaceutical and clinical advantages, and challenges facing the overall prodrug development. Given examples illustrate that prodrugs can accomplish appropriate solubility, increase permeability, provide site-specific targeting (i.e., to organs, tissues, enzymes, or transporters), overcome rapid drug metabolism, decrease toxicity, or provide better patient compliance, all with the aim to provide optimal drug therapy and outcome. Overall, the prodrug approach is a powerful tool to decrease the time/costs of developing new drug entities and improve overall drug therapy.