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.

Improvement and characterization of oral absorption behavior of clofazimine by SNEDDS: Quantitative evaluation of extensive lymphatic transport.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular-luminal perfused small intestine-liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.

Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects.

BACKGROUND: Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules. METHODS: This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects (n = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h-30 min, 4-30 min, 6 h-30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC0-24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (Cmax) (secondary endpoint). RESULTS: Compared with an overnight pre-dose fast (reference arm: night-30 min), shorter pre-dose fasting times in the 2 h-night, 2 h-30 min, 4 h-30 min, and 6 h-30 min treatment arms resulted in significantly lower semaglutide AUC0-24h and Cmax after the 10th dose (estimated treatment ratio ranges: 0.12-0.43 and 0.11-0.44, respectively; p < 0.0001 for all comparisons). Semaglutide AUC0-24h and Cmax after the 10th dose were similar for the 2 h-30 min and 2 h-night treatment arms. CONCLUSION: This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04513704); registered August 14, 2020.

Oral semaglutide is a human glucagon-like peptide-1 analogue that has been approved for the treatment of type 2 diabetes. It has been established that taking oral semaglutide with food or large volumes of water decreases absorption of the drug in the body. Current prescribing information instructs taking oral semaglutide on an empty stomach (known as the fasting state), with 120 mL/4 oz of water, then waiting for at least 30 min before consuming any food, water, or taking other oral medications. This study investigates whether different dosing schedules for oral semaglutide could potentially offer more flexibility to patients in the timing of their oral semaglutide dosing. The trial, conducted in healthy volunteers, compares the dosing schedule described in the prescribing information with different fasting times before (pre-dose) and after (post-dose) taking oral semaglutide during the day or evening, to see if there were any effects on the concentration of drug in the body. Compared to the recommended overnight fasting period, shorter pre-dose fasting periods of 2­6 h with a 30-min post-dose fast considerably reduced semaglutide exposure in the body. Similarly, semaglutide exposure was also reduced with a 2-h pre-dose fast combined with post-dose overnight fasting. These findings further support the current prescribing information, which states that patients should take their oral semaglutide dose after an overnight fast.

Characterization of in-vivo human metabolites of the oral nucleoside anti-COVID-19 drug VV116 using UHPLC-Orbitrap-MS.

VV116 is an oral nucleoside anti-COVID-19 drug undergoing clinical trials in China. We aimed to characterize its metabolites in plasma, urine, and feces of healthy Chinese male subjects after a single oral administration of 400 mg VV116, by using UHPLC-UV-Orbitrap-MS. After oral administration, VV116 was almost completely converted into the metabolite 116-N1. Seventeen other metabolites produced by the subsequent metabolism of 116-N1 were also detected, including 6 phase I metabolites and 11 phase II metabolites resulting from hydrolysis, oxidative deamination, oxidation, and CN-group removal and conjugations. The results were exploratory. The major metabolite of VV116 in human plasma and urine was 116-N1, the main metabolites in feces were M2 and 116-N1. We then synthesized a reference M2 standard and confirmed its structure by MS and NMR.

A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Oral Bioactive Self-Nanoemulsifying Drug Delivery Systems of Remdesivir and Baricitinib: A Paradigmatic Case of Drug Repositioning for Cancer Management.

Oral anticancer therapy mostly faces the challenges of low aqueous solubility, poor and irregular absorption from the gastrointestinal tract, food-influenced absorption, high first-pass metabolism, non-targeted delivery, and severe systemic and local adverse effects. Interest has been growing in bioactive self-nanoemulsifying drug delivery systems (bio-SNEDDSs) using lipid-based excipients within nanomedicine. This study aimed to develop novel bio-SNEDDS to deliver antiviral remdesivir and baricitinib for the treatment of breast and lung cancers. Pure natural oils used in bio-SNEDDS were analyzed using GC-MS to examine bioactive constituents. The initial evaluation of bio-SNEDDSs were performed based on self-emulsification assessment, particle size analysis, zeta potential, viscosity measurement, and transmission electron microscopy (TEM). The single and combined anticancer effects of remdesivir and baricitinib in different bio-SNEDDS formulations were investigated in MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. The results from the GC-MS analysis of bioactive oils BSO and FSO showed pharmacologically active constituents, such as thymoquinone, isoborneol, paeonol and p-cymenene, and squalene, respectively. The representative F5 bio-SNEDDSs showed relatively uniform, nanosized (247 nm) droplet along with acceptable zeta potential values (+29 mV). The viscosity of the F5 bio-SNEDDS was recorded within 0.69 Cp. The TEM suggested uniform spherical droplets upon aqueous dispersions. Drug-free, remdesivir and baricitinib-loaded bio-SNEDDSs (combined) showed superior anticancer effects with IC50 value that ranged from 1.9-4.2 µg/mL (for breast cancer), 2.4-5.8 µg/mL (for lung cancer), and 3.05-5.44 µg/mL (human fibroblasts cell line). In conclusion, the representative F5 bio-SNEDDS could be a promising candidate for improving the anticancer effect of remdesivir and baricitinib along with their existing antiviral performance in combined dosage form.

Absolute oral bioavailability and possible metabolic pathway of panduratin A from Boesenbergia rotunda extract in beagle dogs.

CONTEXT: Attempts are ongoing to develop medications to fight against the COVID-19 pandemic. Our previous study revealed the in vitro anti-SARS-CoV-2 activity of fingerroot [Boesenbergia rotunda (L.) Mansf. (Zingiberaceae)] and its phytochemical, panduratin A. OBJECTIVE: To investigate the pharmacokinetic profiles of panduratin A as a pure compound and in a fingerroot extract formulation in beagle dogs. MATERIALS AND METHODS: A total of 12 healthy dogs were randomly divided into three groups, a single dose of 1 mg/kg panduratin A by intravenous and multiple doses of 5 and 10 mg/kg panduratin A fingerroot extract formulation by oral administration for seven consecutive days. The plasma concentration of panduratin A was determined by LCMS. RESULTS: The peak concentrations of a single dose of 5 and 10 mg/kg panduratin A fingerroot extract formulation were 12,416 ± 2,326 and 26,319 ± 8,221 µg/L, respectively. Increasing the oral dose of fingerroot extract formulation, equivalent to panduratin A 5-10 mg/kg, showed dose proportionality, with an approximately 2-fold increase in Cmax and AUC. The absolute oral bioavailability of panduratin A in the fingerroot extract formulation was approximately 7-9%. The majority of panduratin A was biotransformed into several products via oxidation and glucuronidation, and predominantly excreted via the faecal route. CONCLUSION: The oral formulation of fingerroot extract was safe in beagle dogs, and increasing dose showed dose proportionality in terms of the systemic exposure of panduratin A. This information will support the phytopharmaceutical product development of fingerroot extract against the COVID-19 pandemic.

A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation.

Direct-acting oral anticoagulant (DOAC) use has increased dramatically since their introduction because of the growing evidence of proven efficacy and enhanced safety compared with warfarin and the low-molecular-weight heparins in the general population. Unfortunately, there is a dearth of quality data regarding the safety and efficacy of the DOACs in patients awaiting organ transplant and those who received a solid organ transplant. This review aims to evaluate the available literature and considerations regarding anticoagulation use in transplant recipients, focusing on preoperative, perioperative, and postoperative DOAC use.

A validated LC-MS/MS method for clinical pharmacokinetics and presumptive phase II metabolic pathways following oral administration of Andrographis paniculata extract.

Andrographis paniculata, a medicinal plant in Thailand national list of essential medicines, has been proposed for treatment of patients with mild to moderate coronavirus disease 2019. This study aims to develop a highly selective and sensitive liquid chromatography triple quadrupole tandem mass spectrometry method for quantitative determination of major diterpenoids in plasma and urine with application in pharmacokinetics. Chromatographic separation was performed on C18 column using a gradient mobile phase of water and acetonitrile. Mass spectrometry was analyzed using multiple reaction monitoring with negative ionization mode. This validated analytical method was very sensitive, less time consuming in analysis, and allowed the reliability and reproducibility on its application. The clinical pharmacokinetics was evaluated after single oral administration of A. paniculata extract (calculated as 60 mg of andrographolide). The disposition kinetics demonstrated that major diterpenoids could enter into systemic circulation, but they are mostly biotransformed (phase II) into conjugated glucuronide and sulfate metabolites. These metabolites are predominantly found in plasma and then extremely eliminated, in part through urinary excretion. The successful application of this analytical method supports its suitable uses in further clinical benefits after oral administration of A. paniculata.

Absorption, distribution, metabolism and excretion of 14C-Emvododstat following a single oral dose in rats and dogs.

Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19.Following an oral dose administration in Long-Evans rats, 14C-emvododstat-derived radioactivity was widely distributed throughout the body, with the highest distribution in the endocrine, fatty, and secretory tissues and the lowest in central nervous system.Following a single oral dose of 14C-emvododstat in rats, 54.7% of the dose was recovered in faeces while less than 0.4% of dose was recovered in urine 7 days post-dose. Emvododstat was the dominant radioactive component in plasma and faeces.Following a single oral dose of 14C-emvododstat in dogs, 75.2% of the dose was recovered in faeces while 0.5% of dose was recovered in urine 8 days post-dose. Emvododstat was the dominant radioactive component in faeces, while emvododstat and its two metabolites (O-desmethyl emvododstat and emvododstat amide bond hydrolysis product) were the major circulating radioactivity in dog plasma.

SARS-CoV-2 Omicron BA.5 infection recurrence after Paxlovid treatment: The first case report in Hunan Province. / 湖南省首例Paxlovidæ²»ç–—æ–°åž‹å† çŠ¶ç— æ¯’å¥¥å¯†å ‹æˆŽBA.5å˜å¼‚æ ªå¤é˜³ç— ä¾‹æŠ¥é“.

We report a case of coronavirus disease 2019 (COVID-19) patient who was cured by oral administration of nirmatrelvir/ritonavir (Paxlovid). The patient was treated with Paxlovid after being first infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5 variant. On the 11th day after SARS-CoV-2 nucleic acid test turned negative, SARS-CoV-2 nucleic acid test was positive again, and the threshold of nucleic acid cycle number was equivalent to that of the first infection. The results of two whole gene sequencing showed that it was the same virus strain infection, suggesting that the case was re-positive. Without specific treatment, SARS-CoV-2 nucleic acid detection in nasopharyngeal swab turned negative. It is not uncommon for Paxlovid to recover after treating COVID-19, and most of the patients can recover without specific treatment. However, it is necessary to further study the mechanism that may lead to the recovery of SARS-CoV-2.

Oral administration of Lactic acid bacteria inhibits PEDV infection in young piglets.

Since the emergence of the highly pathogenic porcine epidemic diarrhea virus (PEDV) strain in 2010, the prevention of porcine epidemic diarrhea (PED) in pig farms remains problematic. To find the reasons behind the high mortality in young piglets, the relative mRNA expression of inflammation-related factors in infected pigs of different ages as well as uninfected pigs were detected by RT-qPCR. The results showed that the mRNA expression of these factors including IL-6 and TNF-α was more increased in infected younger piglets than infected older pigs. To clarify the relationship between these inflammation related factors, the pairwise linear correlation between the relative expression of these factors were analyzed and showed as network mapping with different correlation coefficients. A strong positive correlation was observed between the expression of various factors in 1-week-old piglets. Combined with the difference in mortality of PEDV infection in pigs of different ages, we hypothesized that lactic acid bacteria (LAB) could inhibit PEDV infection in newborn piglets, and an in vivo experiment was carried out. The results of survival rate and wet/dry ratio showed that LAB alleviated PEDV indued mortality and diarrhea. The detection of viral copies and tissue section staining showed less observed viruses in LAB treated pig. RT-qPCR results of gene expression in intestines showed that LAB modulated the gene expression of various host barrier genes, indicating that LAB is potential to inhibit PEDV infection by regulating the host intestinal barrier. However, to use LAB as therapy, how to improve the efficiency on inhibiting PEDV infection needs further studies.

Association between oral anticoagulants and COVID-19-related outcomes: a population-based cohort study.

BACKGROUND: Early evidence has shown that anticoagulant reduces the risk of thrombotic events in those infected with COVID-19. However, evidence of the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes is limited. AIM: To investigate the association between OACs and COVID-19 outcomes in those with atrial fibrillation and a CHA2DS2-VASc score of 2. DESIGN AND SETTING: On behalf of NHS England, a population-based cohort study was conducted. METHOD: The study used primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Cox regression was used to estimate hazard ratios (HRs) for COVID-19 outcomes comparing people with current OAC use versus non-use, accounting for age, sex, comorbidities, other medications, deprivation, and general practice. RESULTS: Of 71 103 people with atrial fibrillation and a CHA2DS2-VASc score of 2, there were 52 832 current OAC users and 18 271 non-users. No difference in risk of being tested for SARS-CoV-2 was associated with current use (adjusted HR [aHR] 0.99, 95% confidence interval [CI] = 0.95 to 1.04) versus non-use. A lower risk of testing positive for SARS-CoV-2 (aHR 0.77, 95% CI = 0.63 to 0.95) and a marginally lower risk of COVID-19-related death (aHR, 0.74, 95% CI = 0.53 to 1.04) were associated with current use versus non-use. CONCLUSION: Among those at low baseline stroke risk, people receiving OACs had a lower risk of testing positive for SARS-CoV-2 and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or unmeasured confounding, including more cautious behaviours leading to reduced infection risk.

VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19.

BACKGROUND: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir). RESULTS: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%). CONCLUSIONS: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.