Oral Administration Research Articles

A Phase 1 Study to Evaluate the Absorption, Metabolism, and Disposition of Dordaviprone in Healthy Adult Participants.

Dordaviprone (ONC201) is a novel, small-molecule imipridone with antitumor activity in patients with a glioma. Six healthy male participants received a single 625-mg (100-µCi) oral dose of [14C]-dordaviprone. Blood, plasma, urine, and feces were collected up to 288hours after dosing and analyzed by liquid scintillation counting. Metabolite profiles were evaluated using liquid chromatography-radiometric detection, and metabolite identification was accomplished by liquid chromatography with tandem mass spectrometry. Concentrations of drug-derived radioactivity in blood and plasma peaked at 1 hour after dosing and were below the limit of quantitation by 72hours (whole blood) to 96hours (plasma) after dosing. Seventy-one percent of the administered radioactivity was recovered in urine and 20% in feces. In plasma, the major circulating compounds were dordaviprone and the inactive metabolite ONC207, each contributing approximately one third of the total radioactivity area under the curve. Of the 19 metabolites identified in plasma, no other single metabolite contributed more than 10% to the total radioactivity area under the curve. Unchanged dordaviprone was a minor component in excreta (less than 0.3%), with multiple metabolites identified in urine and feces. Given the lack of dordaviprone in excreta and the metabolites formed, the primary route for dordaviprone elimination was through urinary excretion of oxidative metabolites.

Structure-Guided Design of Pyrazolopyrimidinones as Highly Potent and Selective Allosteric SHP2 Inhibitors.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays crucial roles in various biological processes and has become a promising target for cancer therapy. In this work, we presented the structure-guided design of new allosteric SHP2 inhibitors, leading to the identification of the pyrazolopyrimidinone derivatives TK-684 and TK-685. Both compounds were highly potent and selective allosteric SHP2 inhibitors (TK-684: SHP2WT IC50 = 2.1 nM; Ki = 0.89 nM; TK-685: SHP2WT IC50 = 1.5 nM; Ki = 0.87 nM), likely binding to the "tunnel" allosteric site of SHP2. By targeting SHP2-mediated AKT and ERK signaling pathways, TK-684 and TK-685 suppressed cell proliferation and induced apoptosis in esophageal cancer cells. Additionally, oral administration of TK-685 demonstrated good antitumor effects in the KYSE-150 xenograft mouse model, with a T/C value of 76.8%. Collectively, the pyrazolopyrimidinone derivatives represent promising lead compounds for the treatment of esophageal cancer, where SHP2 is dysregulated.

Pterostilbene Exhibits Broad-Spectrum Antiviral Activity by Targeting the Enterovirus Capsid, Inactivating Viral Particles, Blocking Viral Binding, and Protecting Mice From Lethal EV-A71 Challenge.

Human enteroviruses (EVs) are a major public health issue worldwide owing to their potential to cause respiratory illnesses, hand-foot-and-mouth disease, and severe neurological complications. Currently, no effective drugs or multivalent vaccines are available. Pterostilbene (Pte), a naturally occurring compound found in blueberries and other plants, is a type of stilbene with a similar structure to resveratrol. Pterostilbene exerts antioxidant, anti-inflammatory, and anticancer properties. However, few studies have explored its antiviral activity. This study aimed to investigate the anti-enteroviral effect and mechanisms of Pte against EV-A71 and EV-D68. Cytotoxicity and antiviral assays were performed to assess the safety of Pte to cells and its antiviral effects against enteroviruses. Viral attachment, inactivation assays, cellular receptor binding, western blotting, time-of-addition and time-of-removal assays, particle stability thermal release assay, and molecular docking were performed to elucidate the antiviral mechanisms of Pte. Additionally, we validated the antiviral effects of Pte using invivo experiments. Among the stilbenes examined, Pte exerted a broad-spectrum inhibitory effect on various enteroviruses, including EV-A71, EV-D68, and coxsackieviruses at 40 μM, without cytotoxicity. Mechanistically, Pte significantly inhibited enteroviral attachment, inactivated viral particles, blocked viral binding to its receptors, and increased virion stability. Molecular docking analysis revealed that Pte occupied a hydrophobic pocket in viral protein 1, indicating a strong binding affinity and acting as an efficient inhibitor. Notably, sequence alignment of multiple enteroviruses indicated that the Pte-interacting residues in VP1 were highly conserved. Invivo studies demonstrated that oral administration of Pte significantly alleviated infection symptoms and reduced mortality in hSCARB2 transgenic mice. Pte possesses potential application as a broad-efficacy antiviral drug against enteroviral infections.

Orally Administered ZnxCeyO2/Se Hydrogel with Effective Antioxidant Activity for Treating Inflammatory Bowel Disease by Inhibiting Ferroptosis.

Oxidative stress leads to intestinal barrier damage, which induces immune responses to occur and further promotes oxidative stress exacerbating inflammatory bowel disease (IBD). In this work, the multifunctional ZnxCeyO2/Se (ZCSO) nanozyme wrapped with acid-resistant calcium alginate hydrogel designed for oral administration is prepared. The ZCSO nanozyme can promote the activation of the Nrf2 oxidative stress pathway, then significantly improve the efficiency of scavenging reactive oxygen species (ROS) and up-regulate the protein expression of glutathione peroxidase 4 (GPx4), which is closely related to the inhibition of ferroptosis. In addition, the ZCSO nanozyme inhibiting the growth of some pathogenic bacteria proliferating due to oxidative stress shows a positive regulation of the intestinal flora and reduces the secretion of pro-inflammatory factors and the levels of inflammatory macrophages, achieving the significant preventive and delayed therapeutic effect of colitis mice. Consequently, the distinctive properties of ZCSO nanozyme render it a promising candidate for the treatment of IBD by effectively scavenging ROS, thereby interrupting the detrimental cycle between oxidative stress and immune response, ultimately promoting the proliferation of epithelial cells to reestablish the integrity of the intestinal mucosal barrier.

The prophylactic anti-aging effect of aspirin (acetylsalicylic acid) on oxidative stress-induced damage in the buccal mucosa of D-galactose-induced aged rats

Most living organisms experience time-dependent functional deterioration as they age. To combat aging, aspirin was proposed as an already well-studied drug. However, its antiaging effect is neither well studied nor understood. So, this study intended to assess the proposed antiaging effect of aspirin. Three groups of seven adult male albino rats were established. The control group received saline, the aging model group got a daily single D-galactose subcutaneous injection (300 mg/kg), and the aspirin group consisted of D-galactose-induced aged rats that received a daily aspirin oral dose (60 mg/kg). Drugs were given for 8 weeks. Then, malondialdehyde (MDA) blood level was evaluated, and rats were euthanized. Buccal mucosa samples were obtained for inducible nitric oxide synthase (iNOS) gene expression, histopathological, ultrastructural, and comet analyses. MDA blood level, iNOS gene expression and DNA damage examined by comet assay displayed a significant reduction in the aspirin group when compared to the aging model group. Histopathological and ultrastructural results showed that aspirin ameliorated most of the degenerative signs caused by D-galactose. Thus, it was deduced that aspirin had promising results as an antiaging pharmaceutical agent. However, more studies are needed regarding its translation to human trials.

Potential Advantages of Pharmaceutical Technology in the Preparation of Faecal Microbial Transplant

The gut microbiome, a complex ecosystem of microorganisms, has gained significant attention for its profound impact on human health. Alterations in the gut microbiota have been linked to various diseases, from infectious to inflammatory and metabolic disorders. This review article describes faecal microbiota transplantation (FMT), a promising therapeutic approach to restore a disrupted gut microbiome, involves transferring stool from a healthy donor to a recipient. While FMT has demonstrated efficacy in treating recurrent Clostridioides difficile infection (rCDI), its potential is being explored in other conditions, such as inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Traditionally, faecal material has been administered through invasive procedures like colonoscopy or nasogastric tube. However, with the growing interest in this therapy, less invasive delivery methods, such as oral administration of FMT in acid-resistant capsules, are being developed. Despite promising results, several challenges remain, including the lack of standardized protocols for FMT and regulatory oversight in this field.

Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a lethal and aggressive cancer with an extremely poor prognosis. Recent preclinical, clinical and genomic studies have highlighted the role of Hippo-Yap pathway in the progression of GBM. In addition, it has been identified that YAP plays a major role in creating immune suppressive tumor microenvironment facilitating drug resistance, recurrence, and metastasis of GBM tumors. Herein, we report that 'moxidectin' an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence data shows that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. Inhibition of MEK-ERK by moxidectin ultimately led to blockade of the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex in various GBM cells. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in an intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. Interestingly, moxidectin enhanced antigen presentation in the tumor draining lymph nodes (TDLN) and reduced pro-tumorigenic macrophage population in brain, indicating that it might play a role in modulating the immune response. Chronic moxidectin treatment did not cause any toxicity in mice based on our toxicological evaluation. Moxidectin is an FDA approved drug, findings from our study will promote its clinical investigation as a potential therapeutic agent for GBM patients.

A Protocol for Fecal Microbiota Transplantation Using Freeze-Dried Capsules: Dosage and Outcomes in 171 Dogs with Chronic Enteropathy

Background: In veterinary medicine, fecal microbiota transplantation (FMT) shows promise for treating chronic enteropathy (CE) in dogs, but standardized protocols for dosage, preparation, and administration are lacking. This study aimed to evaluate the efficacy of freeze-dried FMT capsules (cFMT) and to investigate the existence of a possible optimal dosage for dogs with CE. Methods: A multicenter prospective study was conducted on 171 dogs with CE, treated with freeze-dried FMT capsules (100 mg for dogs ≤ 10 kg, 200 mg for dogs > 10 kg). The dosage of freeze-dried FMT material was expressed in different ways, to investigate the effect of putative active principles. Clinical outcomes were assessed by classifying dogs as responders (R) or non-responders (NR) based on veterinary evaluations from a questionnaire, along with changes in the CIBDAI score and variations in 15 clinical signs of chronic enteropathy (CE). Data were collected before and 15 days after treatment. Results: Of the 111 dogs included in the final analysis, 82% showed a positive clinical response, with no significant differences in clinical response between capsule sizes or dosage, irrespective of how it was expressed. Conclusion: Effective dosage range for cFMT administration in dogs affected by CE was defined. The oral administration of 100 mg of freeze-dried cFMT daily for a month was shown to be sufficient to achieve an 80% response rate. Further studies are needed to explore additional factors that may influence the overall effectiveness of cFMT in treating CE.

Evaluation of Safety, Pharmacokinetic, and Pharmacodynamic Characteristics of a Novel Dual mGluR5/5-HT2AR Antagonist (VVZ-2471) in a Randomized, Double-Blind, First-in-Human Study.

VVZ-2471 is a dual-target compound that simultaneously inhibits both metabotropic glutamate receptor subtype 5 and serotonin receptor subtype 2A. Preclinical studies have supported VVZ-2471 as a promising candidate for opioid use disorder. This study aimed to evaluate the safety and pharmacokinetic (PK)-pharmacodynamic (PD) characteristics of VVZ-2471 capsules in healthy Korean adults. A phase I, double blind, placebo controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted in healthy adult males. In the SAD study, participants received a single oral dose of VVZ-2471 ranging from 25 to 600 mg, including a satellite food-effect group receiving 200 mg. In the MAD study, participants received 200 mg once daily (QD), 200 mg twice daily, and 400 mg QD for 7 days. Plasma and urine samples were collected for the PK analyses. Safety analysis was based on adverse events, clinical laboratory tests, vital signs, physical examinations, 12-lead electrograms, oxygen saturation monitoring, and the Beck Depression Inventory-II test. The potential of VVZ-2471 for treating addiction was explored using a well-established questionnaire on smoking urges (QSU-Brief) consisting of ten items. A total of 49 and 24 healthy Korean adult males completed the SAD and MAD study, respectively. The overall demographic characteristics of participants who received VVZ-2471 or placebo in the SAD and MAD studies were generally comparable. Following a single oral dose of VVZ-2471 up to 600 mg, the area under the concentration-time curve (AUC) increased proportionally with the dose. After repeated administration, the accumulation ratio of VVZ-2471 ranged from 1.4 to 2.0. In the fed state, the maximum plasma concentration and AUC of VVZ-2471 decreased to 0.78-fold and 0.61-fold, respectively, compared with the fasting state. Urinary excretion was marginal. The most common adverse events were nausea and dizziness. Among 29 smokers, participants given VVZ-2471 at 200 mg or higher had reduced smoking urges compared with the placebo. VVZ-2471 was well tolerated up to a single oral dose of 600 mg and a daily oral dose of 400 mg for 7 days. While preliminary, a trend of reducing smoking urges was observed in the VVZ-2471 group. Clinical Research Information Service (CRiS), Republic of Korea (a primary registry in the World Health Organization (WHO) Registry Network) identifier no. KCT000889.

Tuneable dissolution profile of tinidazole through thermoplastic polymer composites in low temperature 3D printing settings for pharmaceutical additive manufacturing applications.

In this study the first-time introduction of Kollidon® 25 (K25) thermoplastic polymer, which was not earlier explored in PBF-based 3D printing technology along with the simultaneous usage of Kollidon® SR (KSR) to form a thermoplastic polymer composite for the development of tunable solid oral dosage form (SODFs). In addition to this, a novel laser-absorbing dye i.e., Pigment Green 7 (PG-7) was also introduced to facilitate the laser sintering process of the used thermoplastic polymer composites. Sintered tablets obtained from the used thermoplastic polymer bed composites were systematically characterized using various analytical tools and in vitro examinations as well. The physicochemical characterization of all sintered tablet batches (B1-B7) was within the acceptable limit. Thermal and chemical analyses revealed no detrimental physical or chemical interactions between the components, as well as after exposure of sintered tablet batches to laser and temperature. Powder X-ray diffraction diffractograms suggested a change in the native state of tinidazole (TNZ, used as an active pharmaceutical ingredient) to amorphous due to the exposure of sintering parameters. Scanning electron microscopy micrographs of all batches showed intense fusion of the particles in the polymer composite. The sintered tablet batches B1 to B7 exhibited a drug content ranging from 90.36 ± 4.32% to 99.36 ± 1.24%. TNZ released in an acidic medium for up to 2.0 h from different sintered tablets were around 100% to 12% from B1 to B7 batches, respectively following alkaline medium for up to 12.0 h. TNZ release pattern was fine tuned in accordance with the changes in the composition ratio of Kollidon® 25 and Kollidon® SR polymers in order to get quick release to sustained release. This prepared unique thermoplastic pharmaceutical grade polymer composite might broaden the range of materials accessible for PBF-mediated 3D printing in pharmaceutical industrial applications in near future.

Safety of Credelio Quattro™ (lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets) in dogs infected with adult heartworms (Dirofilaria immitis)

BackgroundCredelio Quattro (lotilaner, moxidectin, praziquantel, and pyrantel chewable tablets) is a novel endectocide for monthly oral administration in dogs. The safety of Credelio Quattro was investigated in dogs with pre-existing patent heartworm (Dirofilaria immitis) infections. Heartworm preventive products are tested in heartworm-positive dogs as rapid microfilarial and adult worm death can lead to serious clinical reactions, including death.MethodsThis was a gender-stratified, randomized, placebo-controlled, blinded, parallel group design study. Prior to study, dogs were surgically implanted with 10 male and 10 female adult D. immitis worms (Georgia III isolate). After confirming a patent infection, dogs were randomized into three groups (placebo control, 1×, or 3× the maximum recommended labeled dose of Credelio Quattro) consisting of eight dogs each. Treatment was administered on three consecutive monthly occasions. The assessment of safety was based on body weight, physical examinations, clinical observations on the days of dosing, general health observations, microfilariae (MF) counts, and D. immitis antigen testing. On the last day of study, the heart, lungs, and pleural and peritoneal cavities were examined for adult D. immitis worms.ResultsCredelio Quattro was well tolerated. Emesis occurred in the 3× group only. Diarrhea was observed in all groups at various times throughout the study. Owing to the timing of events relative to dosing, emesis and diarrhea were possibly related to treatment; however, all dogs recovered quickly and without treatment. No signs of avermectin toxicity or hypersensitivity reactions were observed in any dog. Compared with control, Credelio Quattro reduced the concentration of circulating MF on study day 1 by 38.8% for the 1× group and significantly reduced MF by 73.3% for the 3× group. MF reduction remained significant for both groups at all subsequent time points.ConclusionsCredelio Quattro, when administered at 1× and 3× the maximum recommended label dose, was well tolerated following three consecutive monthly administrations to heartworm-positive dogs. Although Credelio Quattro caused a rapid reduction in microfilaria counts, no adverse effects related to microfilaria reduction were observed, and there was no effect on adult worms in this study.Graphical abstract

Artificial Mitochondrial Nanorobots Deliver Energy In Vivo by Oral Administration.

Delivering energy in vivo is essential for treating mitochondrial damage-related diseases. Current methods, including natural mitochondrial transplantation and artificial energy delivery systems, lack non-destructive, external energy-free, and clinically viable potential solutions. Here, artificial mitochondrial nanorobots (AMNs) carrying high-energy phosphate bonds rebuild the in vivo energy supply system to provide energy. Using ischemic heart disease (IHD) as an energy-deficient disease model and the oral route, which has high patient compliance and facilitates long-term administration, to investigate the therapeutic efficacy of AMNs. AMNs remain stable in the gastrointestinal tract, cross the intestinal barrier via a barrier-crossing unit, and target damaged heart tissue and cardiomyocytes using a motion unit chemotactically. Intracellularly, their energy-generating unit provides high-energy phosphate bonds for ATP synthesis (duration 12h), while synergistically reducing inflammation and restoring cell viability. At the same frequency of administration, oral AMNs (50mgkg-1) match intravenous AMNs (10 mgkg-1) in therapeutic efficacy, offering a convenient approach to improving cardiac function. Transcriptomics confirm that 200µg AMNs emulate 5 × 10⁶ natural mitochondria, restoring energy metabolism and structural function in damaged hearts at the genetic level. This innovative design opens a new pathway for the construction of artificial energy delivery systems in vivo.

Diosmetin Attenuates Painful Symptoms Caused by Antineoplastics Paclitaxel and Anastrozole in Mice.

Cancer patients often experience painful symptoms as an adverse effect resulting from various factors, including antineoplastic therapy. Paclitaxel is a chemotherapeutic agent used to treat solid tumours and, unfortunately, causes acute and chronic peripheral neuropathic pain in patients. Anastrozole is an antineoplastic used to treat hormone receptor-positive breast cancer and causes musculoskeletal pain symptoms. The therapies used to control these pain symptoms have limited efficacy and cause adverse effects, highlighting the importance of finding new treatments. Diosmetin is a flavonoid that has shown efficacy in neuropathic, nociplastic, and inflammatory pain models. Therefore, we verified the antinociceptive effects of diosmetin on nociceptive parameters induced by paclitaxel and anastrozole. We investigated the effects of diosmetin (0.015, 0.15 and 1.5 mg/kg; oral route (p.o.)) on nociceptive parameters (mechanical and cold allodynia and pain affective‑motivational behaviour) induced by a single and repeated paclitaxel (1 mg/kg, intraperitoneal (i.p.)) administrations, as well as on the pain-like symptoms (mechanical allodynia, muscle strength, and pain affective‑motivational behaviour) of a single administration of anastrozole (0.2 mg/kg, p.o.) and the combination of both antineoplastics in mice. Diosmetin reduced the nociceptive parameters induced by paclitaxel and anastrozole. In addition, we observed that anastrozole exacerbated the mechanical allodynia induced by paclitaxel, an effect that was also reversed by diosmetin. These results suggest that diosmetin may be an effective therapeutic alternative for the treatment of painful symptoms caused by antineoplastic drugs, such as paclitaxel and anastrozole.

Patient Age and Antibiotic Formulation Administration in the Pediatric Emergency Department.

Oral antibiotics are the most prescribed medication in the United States. We sought to describe the distribution of oral antibiotic formulation administration among children in the emergency department (ED). We performed a retrospective single-center study of children presenting to a pediatric ED. We included encounters for children (<18 years) discharged from the ED between 2016 and 2022 and prescribed one of 7 common antibiotics in oral suspension or tablet/capsule forms, excluding children with an enteral feeding tube or complex neuromuscular conditions. We analyzed encounters for children administered an antibiotic in the ED and antibiotic prescriptions. We determined the age at which the proportion of children given a tablet or capsule equaled or exceeded the proportion of those given a suspension. We identified 12,900 eligible encounters (median age: 4.3 years, interquartile range: 1.7 to 8.1 years; 51.5% boys). The most common diagnoses were infectious ear disorders (22.6%), infectious mouth and throat disorders (9.1%), infectious skin, dermatologic and soft tissue disorders (6.6%), and infectious nose and sinus disorders (6.2%). For all antibiotics administered in the ED (n = 3809 encounters; 52.6% for amoxicillin), the age threshold at which more children were prescribed the tablet/capsule than the suspension formulation was 14 years. This threshold for each antibiotic was 16 years for amoxicillin, 13 years for amoxicillin-clavulanate, 11 years for azithromycin, 14 years for cefdinir, 12 years for cephalexin, 11 years for clindamycin, and 10 years for trimethoprim-sulfamethoxazole. Findings were similar for encounters discharged from the ED with an antibiotic prescription. We identified age-related differences in antibiotic formulations in a pediatric ED. These findings can inform prescribing practices to optimize medication adherence and treatment effectiveness through clinical decision support and shared decision-making and may be especially useful during periods of formulation shortages or when planning for clinical research.

Review on Implantable Drug Delivery System

In the past, medications were commonly given orally in the form of liquids or powders. However, to address the challenges associated with oral drug administration, alternative dosage forms were developed. Over time, the need arose for drug delivery systems capable of providing a consistent release of medication directly to the site of action. This led to the creation of drug delivery technologies aimed at enhancing the therapeutic effects of drugs while making them safer, more effective, and reliable. Implantable drug delivery systems (IDDS) are one such innovation currently used in treatment. These systems offer several key benefits, including targeted and steady drug release, reduced dosage requirements, fewer side effects, and improved treatment outcomes. Thanks to advancements in sustained release formulations, medications that once required multiple daily doses can now be administered weekly or even annually. Early studies have demonstrated that these systems are more effective than traditional treatment methods. Nonetheless, a major drawback is their high-cost relative to their benefits, which limits their widespread adoption. Furthermore, many newly developed implants are still in early stages and need thorough clinical testing before they can be used routinely in healthcare settings

Lactobacillus paracasei Expressing Porcine Trefoil Factor 3 and Epidermal Growth Factor: A Novel Approach for Superior Mucosal Repair

Trefoil factor 3 (TFF3) and epidermal growth factor (EGF) exert a promotive effect on the functions of intestinal epithelial cells and offer protection to the intestinal mucosa. Lactobacillus paracasei can ameliorate intestinal mucosal damage. In this study, pPG-pTFF3/27-2, pPG-pEGF/27-2, and pPG-pTE/27-2 were constructed to express porcine TFF3, EGF, and a fusion protein (pTE). Functional assays showed they promoted Immortalized Porcine Enterocyte Cell line J2 (IPEC-J2) proliferation and migration, with pTE having a greater migratory effect. In dextran sulfate sodium (DSS)-induced colitis mice, oral administration of pPG-pTE/27-2 reduced colitis, improved mucosal integrity, increased the expression of tight-junction proteins and the serum level of Interleukin-10 (IL-10), and decreased the levels of pro-inflammatory Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-1β (IL-1β). These results imply that recombinant L. paracasei 27-2 strains engineered to express pTFF3 and pEGF represent a promising approach for augmenting intestinal epithelial cell function and facilitating mucosal restitution, and they possess significant potential in the treatment of intestinal mucosal injury and inflammatory bowel disease (IBD).

Florfenicol-induced dysbiosis impairs intestinal homeostasis and host immune system in laying hens

BackgroundDespite growing concerns about the adverse effects of antibiotics in farm animals, there has been little investigation of the effects of florfenicol in laying hens. This study examined the effect of florfenicol on the intestinal homeostasis, immune system, and pathogen susceptibility of laying hens.ResultsThe oral administration of florfenicol at field-relevant levels for 5 d resulted in a decrease in the gut microbiota genera Lactobacillus, Bacillus, and Bacteroides, indicating the development of intestinal dysbiosis. The dysbiosis led to decreased mRNA levels of key regulators peroxisome proliferator-activated receptor gamma (PPAR-γ) and hypoxia-inducible factor-1α (HIF-1α), compromising intestinal hypoxia. Intestinal homeostasis was also disrupted, with decreased expression of Occludin and Mucin 2 (Muc2) genes combined with increased gut epithelial permeability. The breakdown in intestinal homeostasis and immune function provided a favorable environment for opportunistic bacteria like avian pathogenic Escherichia coli (APEC), culminating in systemic infection. Immunologically, florfenicol treatment resulted in increased proportion and absolute number of MRC1L-B+ monocytes/macrophages in the spleen, indicating an exacerbated infection. Furthermore, both the proportion and absolute number of γδ T cells in the lamina propria of the cecum decreased. Treatment with florfenicol reduced butyrate levels in the cecum. However, the administration of butyrate before and during florfenicol treatment restored factors associated with intestinal homeostasis, including PPAR-γ, Occludin, and Muc2, while partially restoring HIF-1α, normalized intestinal hypoxia and gut permeability, and reversed immune cell changes, suppressing APEC systemic infection.ConclusionThe uncontrolled and widespread use of florfenicol can negatively affect intestinal health in chickens. Specifically, florfenicol was found to impair intestinal homeostasis and immune function in laying hens, including by reducing butyrate levels, thereby increasing their susceptibility to systemic APEC infection. The development of strategies for mitigating the adverse effects of florfenicol on gut health and pathogen susceptibility in laying hens is therefore essential.

Subacute Toxicity Studies on Aqueous Stem Extract of Cissus Populnea in Wistar Albino Rats

Cissus populnea is a plant whose medicinal benefits have been well but there is a dearth of studies on subacute toxicity of any part of the plant. The aim of the study is to ascertain the subacute toxicity of the aqueous stem extract of C. populnea in Wistar albino rats. Forty animals (20 males and 20 females) grouped into 8 groups (n=5) (4 males, 4 females) were used. The animals were treated with daily oral doses (125mg/kg, 250mg/kg, and 500mg/kg) of the extract for 28 days, while the control groups received distilled water. The animals were weighed at 7-day intervals. After the test period, the animals were anaesthetised. Blood samples were taken for haematological and biochemical analysis, the organs were harvested and weighed. There was no significant (p&gt;0.05) difference between the weight of the control groups and all the treated groups. Treatment with the various doses of the extract did not cause any significant (p&gt;0.05) changes in the relative organ weight, biochemical parameters, red blood cell count, haemoglobin, and white blood cell count of the experimental animals. Oral administration of the aqueous stem extract of C. populnea in the doses used in this study caused no observable toxic effect on the experimental animals.

Mirabegron induces selective changes in the faecal microbiota of HFHFr rats without altering bile acid composition

IntroductionMetabolic dysfunction-associated steatotic liver (MASL), the initial, asymptomatic stage of the metabolic dysfunction-associated steatotic liver disease, is directly involved in the progression to steatohepatitis. Healthy lifestyle and dietary measures are currently the only treatments for MASL. Given the high prevalence of MASL in the human population, candidate drugs for its prevention or treatment should have an acceptable safety profile. Repurposing drugs already in clinical use could help to identify effective and safe drug treatments for MASL. We have characterized a high-fat, high-fructose rat dietary model of simple hepatic steatosis to evaluate the potential anti-steatotic effect of mirabegron, which is already in clinical use for the treatment of overactive bladder. We have previously reported that mirabegron administration was unable to reduce liver triglyceride content in our rat model.MethodsIn the present work, we analyse stored liver, adipose tissue (perigonadal and brown), serum and faecal samples from our previous study and present new biochemical, faecal metabolomic and microbiome data.Results and discussionWe show that oral administration of mirabegron significantly increases the expression of uncoupling protein 1 in brown adipose tissue and β3-Adrenergic receptor protein in perigonadal white adipose and liver tissues. Furthermore, mirabegron treatment changes the relative abundance of several genus and families of rat faecal microbiota, albeit without restoring the global biodiversity and evenness indexes observed in control rats, as well as faecal bile acids composition. These changes are probably due to a direct effect of mirabegron on the gut microbiome, rather than being mediated by changes in bile acid induced by drug treatment.

Protective Effects of Melatonin and Bee Pollen on Hematotoxicity and Hepatorenal Toxicity Induced by Long-Term Intake of Gabapentin in Female Albino Rats.

Gabapentin (GBN) is an anti-seizure medication that is also used to treat nerve pain and other diseases. However, its misuse is currently a growing worry, as it may pose a significant health danger. The present study aimed to evaluate the protective effect of melatonin (MEL) and bee pollen (BP) as antioxidants against GBN-induced hematotoxicity and hepatorenal toxicity in female Albino rats. In this study, fifty-six adult female albino rats were divided into seven groups (n = 8 each), served as control, GBN, MEL, BP, MEL + GBN, BP + GBN, and MEL + BP + GBN treated groups. Results showed that oral administration of GBN resulted in a hematological toxicity as confirmed by a significant reduction in RBCs, Hb concentration, Ht%, MCV, MCH, platelets as well as altering of leukocyte profiles, WBCs, neutrophils, lymphocytes, monocytes, eosinophils and basophils. The biochemical results of liver and kidney functions showed a significant decrease in serum glucose, total protein, triglycerides, urea and uric acid. However, a significant increase in albumin, cholesterol, creatinine as well as ALP, AST, and ALT liver enzymes compared to the control was found. The oral administration of MEL and BP 12 h before GBN mostly ameliorates the altered hematological and biochemical parameters as well as hepatic and renal histopathological architecture to normal levels. In conclusion, Pre-treatment with MEL and BP, individually or together provided protection against the GBN induced changes in the blood parameters as well as hepatorenal structure and function.