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In the last 20 years, the development of stimuli-responsive drug delivery systems (DDS) has received great attention. Hydrogel microparticles represent one of the candidates with the most potential. However, if the role of the cross-linking method, polymer composition, and concentration on their performance as DDS has been well-studied, still, a lot needs to be explained regarding the effect caused by the morphology. To investigate this, herein, we report the fabrication of PEGDA–ALMA-based microgels with spherical and asymmetric shapes for 5-fluorouracil (5-FU) on-demand loading and in vitro pH-triggered release. Due to anisotropic properties, the asymmetric particles showed an increased drug adsorption and higher pH responsiveness, which in turn led to a higher desorption efficacy at the target pH environment, making them an ideal candidate for oral administration of 5-FU in colorectal cancer. The cytotoxicity of empty spherical microgels was higher than the cytotoxicity of empty asymmetric microgels, suggesting that the gel network’s mechanical proprieties of anisotropic particles were a better three-dimensional environment for the vital functions of cells. Upon treatment with drug-loaded microgels, the HeLa cells’ viability was lower after incubation with asymmetric particles, confirming a minor release of 5-FU from spherical particles.

White spot syndrome virus (WSSV) is one of the most concerning pathogens in penaeid shrimp and can cause severe loss in shrimp aquaculture worldwide. Among the WSSV structural proteins, VP15, a DNA-binding protein located in the WSSV nucleocapsid, is an antiviral protein candidate to protect kuruma shrimp (Marsupenaeus japonicus) from WSSV infection. We identified that the truncated VP15, VP15

Background and aim Campomanesia xanthocarpa Berg. (Myrtaceae) present several pharmacological actions, but there are no reports on its antidepressant-like potential. This study investigated the antidepressant-like effect and mechanism of action of Campomanesia xanthocarpa seeds extract obtained from supercritical CO2 (40 °C, 250 bar). Experimental procedure Mice were orally treated with the extract 1 h before the TST. To investigate the involvement of the monoaminergic system in the antidepressant-like activity of the extract, pharmacological antagonists were administered prior to the acute oral administration of the extract (60 mg/kg). Also, the interaction of the extract with antidepressants was assessed in the tail suspension test (TST). The in vitro inhibitory potential of C. xanthocarpa seeds extract towards MAO A and MAO B enzymes was tested in vitro. Results and conclusion Animals treated with Campomanesia xanthocarpa seeds extract showed a significant reduction in the immobility time in the TST. Mice pretreatment with SCH23390, sulpiride, prazosin, yohimbine, and p-chlorophenylalanine prevented the anti-immobility effect of the extract in the TST. The combined administration of sub-effective doses of the extract with imipramine, bupropion and fluoxetine significantly reduced mice immobility time in the TST. The extract showed MAO A inhibitory activity (IC50 = 151.10 ± 5.75 μg/mL), which was greater than that toward MAO B (IC50 > 400 μg/mL). The extract of Campomanesia xanthocarpa seeds obtained by supercritical CO2 shows antidepressant-like activity, which relies on the activation of the monoaminergic neurotransmission (serotoninergic, dopaminergic and noradrenergic), suggesting that this species might represent a resource for developing new antidepressants.

Objective: To compare the difference in the clinical therapeutic effect on dysmenorrhea in the patients with adenomyosis between acupuncture and ibuprofen sustained release capsules. Methods: A total of 40 patients were randomized into an acupuncture group and an ibuprofen group, 20 cases in each one. The treatment was given consecutively for 3 menstrual cycles and the follow-up lasted for 2 menstrual cycles. The score of visual analogue scale (VAS) at the most painful time during menstruation, menstrual flow, the score of COX menstrual symptom scale (CMSS) and the score of endometriosis health profile-5 (EHP-5), as well as the patients’ satisfaction and acceptance were compared between the two groups. Results: Three menstrual cycles after treatment, the VAS score at the most painful time, menstrual flow, CMSS score and EHP-5 score were all lower than those before treatment in either group, with statistical significance (all P 0.05), the menstrual flow was lower (P > 0.05), CMSS score was higher (P 0.05). The score of the patients’ satisfaction and acceptance in the acupuncture group were all higher than the ibuprofen group (both P Conclusion: Acupuncture is effective for analgesia and symptom-relief and the long-term effect is superior to the oral administration of ibuprofen.

Aims: The aim of the study was to evaluate the antihyperglycemic effect of Chenopodium quinoa. Background: Chenopodium quinoa is a pseudocereal plant with several medicinal properties. Objective: The goal of this investigation was to determine the antihyperglycemic activity of Chenopodium quinoa in both normal and streptozotocin (STZ)-induced diabetic rats. Methods: In this study, the effect of the aqueous extract of Chenopodium quinoa seeds (AECQS) (60 mg/kg) on blood glucose levels was evaluated in both normal and diabetic rats after a single (6 hours) and repeated oral administration (7 days of treatment). The effect of this herb on glucose tolerance and lipid profile was also studied. Additionally, histopathological examination of the liver was carried out using the Hematoxylin-Eosin method. Furthermore, the in vitro antioxidant activity as well as, preliminary phytochemical screening and quantification of some secondary metabolites (phenolic compounds, flavonoids and tannins) were performed according to standard methods. Results: AECQS produced a significant lowering effect on plasma glucose levels in STZ-induced diabetic rats. In addition, this extract exhibited a remarkable amelioration on hepatic histopathology in diabetic rats. In addition, the extract exerted a remarkable antioxidant activity which could be due to the presence of some compounds found in this herb. Conclusion: In conclusion, this study demonstrates that the aqueous extract of Chenopodium quinoa seeds has a favorable effect in controlling diabetes mellitus.

Aim: The present study was aimed to developed and optimize the self-nano emulsifying drug delivery system of α-pinene (ALP-SNEDDS) and evaluate its in-vivo anti-Parkinson's activity. Background: Different lipid-based drug delivery technologies have been researched to upgrade drug bioavailability and expand their clinical adequacy upon oral administration. Self-emulsifying drug delivery systems (SEDDS) have pulled in developing the interest specifically for self nano emulsifying drug delivery systems (SNEDDS). Objective: The present work was attempted to improve the bioavailability of the ALP by defining the role of self-nano emulsifying formulations for its neuroprotective effect. Method: Miscibility of the ALP was estimated in various excipient components to select the optimized combination. Self-nano emulsification, thermodynamic stability, the effect of dilution on robustness, optical clarity, viscosity, and conductivity tests were performed. The in-vivo anti-Parkinson's activity of the ALP-SNEDDS formulations were done using Pilocarpine antagonism induced Parkinsonism in rodents. Behavioral tests like tremulous jaw movements, body temperature, salivation, and lacrimation are performed. Result: Two optimized formulations, composed of Anise oil, Tween 80, and Transcutol-HP of Oil: Smix ratio (4:6 and 3:7) were selected. The Smix ratio for both the formulation was 2:1. The particle size was found to consistent with the increase in dilution. The mean negative zeta potential of the formulations was found to be increased with an increase in dilution. The TEM images of the formulations revealed spherical shape of the droplet. The in-vitro drug release profile was found to be significant as compared to plain ALP suspension. Conclusion: The results of in-vivo studies indicate that nanosizing and enhanced solubilization of oral ALP-SNEDDS formulations significantly improved the behavioral activities compared to plain ALP suspension.

Stroke was always a disease that threatened human life and health worldwide. We reported the synthesis of a new type of hyaluronic acid-modified multi-walled carbon nanotube. Then, we produced hydroxysafflor yellow A-hydroxypropyl-β-cyclodextrin phospholipid complex water-in-oil nanoemulsion with hyaluronic acid-modified multi-walled carbon nanotubes and chitosan (HC@HMC) for oral treatment of an ischemic stroke. We measured the intestinal absorption and pharmacokinetics of HC@HMC in rats. We found that the intestinal absorption and the pharmacokinetic behavior of HC@HMC was superior to that of HYA. We measured intracerebral concentrations after oral administration of HC@HMC and found that more HYA crossed the blood–brain barrier (BBB) in mice. Finally, we evaluated the efficacy of HC@HMC in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice. In MCAO/R mice, oral administration of HC@HMC demonstrated significant protection against cerebral ischemia-reperfusion injury (CIRI). Furthermore, we found HC@HMC may exert a protective effect on cerebral ischemia-reperfusion injury through the COX2/PGD2/DPs pathway. These results suggest that oral administration of HC@HMC may be a potential therapeutic strategy for the treatment of stroke.

The delivery of curcumin (CUR) using the solid dispersion system (CUR solid dispersions; C-SDs) has been shown to improve CUR bioavailability. However, it is unclear how different particle sizes of C-SDs affect the bioavailability and biological activities of CUR. Hence, we prepared C-SDs in different sizes using food-grade excipients and evaluated their bioavailability and biological activities. By pulverizing large particle sizes of C-SDs using zirconia beads, we successfully prepared C-SDs I-IV (particle size: (I) 120, (II) 447, (III) 987, (IV) 1910 nm). When administrated orally in rats, the bioavailability of CUR was increased with decreasing C-SDs size, most likely by improving its solubility in micelles. When administrated intravenously in rats, blood concentrations of CUR were increased with increasing particle size, suggesting that larger C-SDs presumably control the metabolic conversion of CUR. In RAW264 cells, more CUR was taken up by cells as their sizes reduced, and the more potent their anti-inflammatory activities were, suggesting that smaller C-SDs were taken up through a number of cellular uptake pathways. Altogether, the present study showed an evident effect of C-SDs size on their bioavailability and anti-inflammatory activities—information that serves as a basis for improving the functionality of CUR.

In this study, the effect of oral administration of chaste tree fruit (CTF) extract was evaluated on growth performance, hematological indices, serum biochemical parameters, and the expression of growth and appetite-related genes in goldfish (Carassius auratus). The fry (N = 300; 2.40 ± 0.12 g) were randomly dispersed into 12 aquaria and fed with different levels of CTF extract (0 (control), 0.5%, 1.0%, and 1.5%) for 56 days. At the end of the trial, the highest body weight gain and the lowest feed conversion ratio were observed in the fish fed with 1.5% CTF extract (P 0.05). The levels of aspartate transaminase and lactate dehydrogenase were decreased by increasing the supplementation levels of CTF extract and the lowest values were obtained in 1.5% CTF extract diet (P

BACKGROUND The increase in patients suffering from type I hypersensitivity, including hay fever and food allergy, is a serious public health issue around the world. Recent studies have focused on allergy prevention by food factors with fewer side effects. The purpose of this study was to evaluate the effect of dietary glucosylceramide from pineapples (P-GlcCer) on type I hypersensitivity and elucidate mechanisms. RESULTS Oral administration of P-GlcCer inhibited ear edema in passive cutaneous anaphylaxis reaction. In a Caco-2/RBL-2H3 co-culture system, P-GlcCer inhibited β-hexosaminidase release from RBL-2H3 cells. The direct treatment of P-GlcCer on RBL-2H3 did not affect β-hexosaminidase release, but sphingoid base moiety of P-GlcCer did. These results predicted that sphingoid base, a metabolite of P-GlcCer, through the intestine inhibited type I hypersensitivity by inhibiting mast cell degranulation. In addition, the inhibitory effects of P-GlcCer on ear edema and degranulation of RBL-2H3 cells were canceled by pretreatment of leukocyte mono-immunoglobulin-like receptor 3 (LMIR3)-Fc, which can block LMIR3-mediated inhibitory signals. CONCLUSION It was demonstrated that a sphingoid base, one of the metabolites of P-GlcCer, may inhibit mast cell degranulation by binding to LMIR3. The oral administration of P-GlcCer is a novel and attractive food factor that acts directly on mast cells to suppress allergy. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Rotundic acid (RA), an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb. (Aquifoliaceae), possesses diverse bioactivities. To further study its pharmacokinetics, a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry (LC-QqQ-MS/MS) method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard (IS). Plasma and tissue samples were subjected to one-step protein precipitation. Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C18 column (4.6 mm × 50 mm, 5 μm) under gradient conditions with eluents of methanol:acetonitrile (1:1, V/V) and 5 mM ammonium formate:methanol (9:1, V/V) at 0.5 mL/min. Multiple reaction monitoring transitions were performed at m/z 487.30 → 437.30 for RA and m/z 256.10 → 227.10 for IS in the negative mode. The developed LC-QqQ-MS/MS method exhibited good linearity (2–500 ng/mL) and was fully validated in accordance with U.S. Food and Drug Administration bioanalytical guidelines. Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral (10, 20, and 40 mg/kg) and intravenous (10 mg/kg) administration of RA. Tissue distribution was studied following oral administration at 20 mg/kg. The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1% to 19.4%. RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver. In conclusion, this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats, which could provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.

Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B−NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.

Summary Thalidomide is a medication that has been in existence for over half a century, and has proven to be useful and effective in severe dermatological conditions. For dermatologists, the ability of thalidomide to reduce the levels of the cytokine tumour necrosis factor-α, along with its immunomodulatory and anti-angiogenic properties, is of great significance, with the added advantage of being an oral medication. Its use is of course strictly monitored, owing to its potential adverse effects (AEs), particularly teratogenicity, with precautions taken to ensure its safe and correct use by both prescriber and patient. In this review, we look at the background and mechanism of action of thalidomide, provide an overview of conditions it can be used for with case examples, explain the potential AEs and monitoring requirements, and discuss future developments.

Through the boost of the natural medicinal market, individuals began to use a variety of organic materials in the marketed herbal preparation. Lagerstroemia speciosa (LS) leaves are known as banaba. People have been using a decoction of LS leaves as antidiabetic. The study aimed to investigate the acute and sub-acute oral toxicity of LS in Sprague-Dawley rats. The acute toxicity was determined by a single oral dose of LS (2000 mg/kg). Therein animal behaviour and mortality rate were observed for 14 days. The LS (200 mg/kg) was given for 28 days daily in the sub-acute study. The body weight, organ weight, food, water intake, biochemical, haematological parameters, and histopathology were studied. The findings of this study showed no mortality or morbidity was found in acute and sub-acute toxicity studies in rats. Additionally, no significant variations were found in the respective weight of organ, haematological and biochemical parameters of treated groups with reference to the control group. Moreover, no visible histological changes were detected in the liver of treated groups with reference to the control. In conclusion, the oral administration of LS did not fabricate any major toxic effect in rats. No toxic consequences were reported during acute and sub-acute toxicity investigations. Overall, LS is a safe, natural bio-actives as studied. Further investigations of cytotoxicity and genotoxicity of the above drug(s) or their combinations may be executed for appreciative safety.

Summary Objective Our objective was to evaluate the absorption of finasteride administered by oral and topical routes for treatment of androgenetic alopecia, by means of computer simulations using the GastroPlus ® software. Material and methods In vivo plasma concentration profile of oral administration of finasteride 1 mg tablets from the literature was used in the software to build a compartmental pharmacokinetic model that was extrapolated to simulate topical administration of finasteride 0.25% solution in the scalp. Results were compared to literature and other drug concentrations (0.1% and 1%) were also predicted. Results Compared to literature data, predictive plasma curve from oral administration of finasteride 1 mg showed good correlation, R2=0.992, and Cmax=4.6769 ng/mL. Simulations of topical administration in the scalp for finasteride 0.25% solution showed good correlation, R2=0.908, and Cmax=0.04325 ng/mL when compared to literature data. Topical administration was also simulated at concentrations 0.1% and 1%, both with low plasma concentrations. Conclusion The results obtained in this study suggest that topical finasteride is a potential treatment for androgenetic alopecia in the concentrations analyzed using computer simulations in GastroPlus ®.

Aims: The aim of the study was to assess the effect of Cleome arabica on lipid metabolism. Background: Cleome arabica (L.) is a medicinal plant used traditionally by the population of North Africa for managing diabetes mellitus. Objective: This study was designed to evaluate the antidyslipidemic and antiatherogenic capacities of Cleome arabica (L.) in normal and streptozotocin(STZ)-induced diabetic rats. Methods: The hypolipidemic, antihyperglycemic and antiatherogenic effects of oral administration of the aqueous extract of Cleome arabica (CAAE) (100 mg/kg) were evaluated in normal and diabetic rats. In addition, the quantification of polyphenols, flavonoids and tannins as well as the antioxidant activity were performed. Results : The results showed that the extract (CAAE) revealed an antidyslipidemic action by attenuating plasma levels of Total Cholesterol (TC), Triglycerides (TGs), Low-Density Lipoprotein cholesterol (LDL-c), Very low-density lipoprotein cholesterol (VLDL-c) and glucose. Additionally, CAAE exhibited a potent antiatherogenic activity by reducing Atherogenic Coefficient (AC), Castelli’s Risk index-I (cri-I), and Castelli’s Risk Index-II (CRI-II). Furthermore, the findings indicated that CAAE is abundant with polyphenols, flavonoids and tannins, and exhibited an important antioxidant capacity. Conclusion: The study demonstrates that aqueous Cleome arabica extract was able to ameliorate lipid abnormalities associated with diabetes mellitus. This pharmacological activity might be due to the antioxidant capacities of phytochemical compounds.

Objective: This study was performed to determine the effects of stress after road transportation and oral administration of chromium and meloxicam on growth performance, plasma cortisol, serum metabolites, and behavior in dairy calves.Methods: A total of 50 Holstein heifers (average body weight [BW]: 172±4.19 kg; average age: 5.53±0.12 months) were randomly assigned to five groups including NL (not transported + D-lactose; 1 mg/kg BW), TL (transported + D-lactose; 1 mg/kg BW), TC (transported + chromium; 0.5 mg/kg dry matter [DM] feed), TM (transported + meloxicam; 1 mg/kg BW), and TMC (transported + combination of meloxicam and chromium; 1 mg/kg BW and 0.5 mg/kg DM, respectively). Doses of D-lactose monohydrate, meloxicam, and chromium were prepared for oral administration by suspension in 15 mL of water in a 20-mL dosing syringe. Blood was collected before transportation, immediately after 120 km of transportation (IAT), and at 6, 24, and 48 h after transportation.Results: Neither transportation nor administration of meloxicam and/or chromium affected (p = 0.99) average daily gain and feed intake. Plasma cortisol concentrations in the NL group (average 0.13 and 0.18 nmol/L, respectively) were lower (p

Heta Dinesh Bhatt,1 Steve A McClain,2 Hsi-Ming Lee,1 Thomas Zimmerman,3 Jie Deng,4 Francis Johnson,5 Ying Gu,6 Lorne M Golub1 1Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USA; 2Department of Dermatology and Department of Emergency Medicine, Stony Brook University, and McClain Laboratories LLC, Smithtown, NY, 11787, USA; 3Division of Laboratory Animal Resources (DLAR) at Stony Brook, Stony Brook University, Stony Brook, NY, 11794, USA; 4Department of Orthodontics, School of Stomatology, Peking University, Beijing, People’s Republic of China; 5Department of Chemistry and Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA; 6Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USACorrespondence: Heta Dinesh Bhatt, Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USA, Tel +1 646 715-2925, Fax +1 631 632-9705, Email drhetabhatt@gmail.comPurpose: CMC 2.24, a chemically modified curcumin, was developed as a novel, pleiotropic MMP-inhibitor to treat various inflammatory/collagenolytic diseases including periodontitis. To date, this compound has shown efficacy in vitro, in cell culture, and in vivo (oral administration) in mice, rats and dogs. In preparation for possible Phase I human clinical trials, the current study describes the maximum-tolerated-dose (MTD), pharmacokinetics (PK), and toxicology of CMC 2.24 in the rat model.Methods: For the MTD study, 30 Sprague-Dawley rats were randomly distributed into 5 groups (3M/3F per group): Placebo (vehicle; carboxymethylcellulose) and CMC 2.24 at various doses (50, 100, 500, 1000 mg/kg/day), were administered once daily by oral gavage for 5 days. For the PK study, 24 rats were administered either Placebo or CMC 2.24 (100mg/kg/day) once daily for 28 days or only once (500 or 1000 mg/kg). Analysis of this test compound was done using LC/MS/MS for PK evaluation on blood samples drawn from rats at multiple time points. The animals were sacrificed after 5 or 28 days of treatment, and blood chemistry and serology were analyzed. Major organs (heart, lung, liver, kidney, spleen, intestine, brain) were histologically examined at necropsy.Results: Orally administered, CMC 2.24 did not produce significant changes in body weight, food consumption or adverse events in the MTD and toxicology studies. Moreover, no obvious pathologic changes were observed based on histology, hematology, serum biochemistry, or necropsy compared to placebo-treated controls. The PK study demonstrated a peak-blood concentration (Cmax) at 45 mins after oral administration of 2.24 and a serum half-life of 10 hours.Conclusion: In conclusion, CMC 2.24, orally administered to rats once a day, appears to be safe and effective at a wide range of doses, consistent with efficacy previously demonstrated in studies on animal models of various collagenolytic diseases, such as periodontitis, diabetes and cancer.Keywords: novel compound, MMP-inhibitor, oral administration, toxicology

Cypermethrin is a potent pyrethroids insecticide causing different pathological features when exposed to mammal. Vitamins are used as nutrient supplements and in clinical studies as medical intervention in some disease conditions. This study was designed to investigate the possible protective effect of vitamin C and E on Cypermethrin induced nephrotoxicity in wistar albino rats. Twenty-eight (28) wistar albino rats were sorted into four groups of seven rats per groups were used in this study. Group A serves as the control and received distilled water orally. Group B, C and D were administered 25mg/kg body weight cypermethrin orally. Group C and D were treated daily with 40mg/kg body weight vitamin C and 20mg/kg body weight vitamin E respectively by oral administration while group B was left untreated for 14 days. Cypermethrin significantly (P

1. The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [14C] cetagliptin.2. The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and feces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.3. Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulfate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and feces at low levels, except that metabolite M640B was not detected in feces. All metabolites were observed with < 10% of parent compound systemic exposure after oral administration.

Objectives Research about the effects of magnesium (Mg) supplementation on chronic kidney disease-mineral bone disorder (CKD-MBD) among hemodialysis (HD) patients is controversial. Thus, we conducted a meta-analysis to examine Mg supplementation's effects on CKD-MBD in patients requiring dialysis. Methods The PubMed and EMBASE databases were searched for English language studies up to September 2020. The main indicators of our study were changes in serum Mg, calcium (Ca), phosphate, parathyroid hormone (PTH), and C-reactive protein levels, and carotid intima-media thickness (CIMT) after Mg supplementation. Mg efficacy was evaluated by weighted mean difference (WMD) and confidence intervals (CIs), and subgroup analyses of intervention type and intervention duration were also performed. Results Eight eligible studies comprising 309 HD patients were included in our meta-analysis. Mg supplementation alone produced a negative effect on serum PTH levels (WMD = −236.56; 95% CI −349.71 to −123.41) and CIMT (WMD = −0.18; 95% CI −0.34 to −0.01). A subgroup analysis based on intervention type showed a significant improvement in serum Mg (WMD = 1.08; 95% CI 0.51-1.64) and Ca (WMD = −0.50; 95% CI −0.77 to −0.23) levels when Mg was administered via dialysate and oral medication, respectively. Different intervention durations had no effect on serum Mg levels. Mg supplementation had no significant effect on serum phosphate (WMD = −0.25; 95% CI −0.64 to 0.14) and C-reactive protein levels (WMD = −0.02; 95% CI −2.80 to 2,76). Conclusions Our results showed that Mg supplementation alone could improve CKD-MBD by regulating serum Ca and PTH metabolism and decreasing CIMT among HD patients.

Objective: Based on the expression changes in the TGF-β/ALK5/Smad2/3 signal transduction pathway, the repair of cartilage injury in the rabbit knee joint was investigated and evaluated by oral administration of naringin in combination with acellular dermal matrix implantation. Methods: First, twenty New Zealand white rabbits were randomly divided into five groups: a sham operation group (Sham group), a model group (Mod group), a naringin group (Nar group), an acellular dermal matrix group (ADM group), a naringin ​+ ​acellular dermal matrix group (Nar/ADM group). After the 12th week, the repaired tissues were assessed for histomorphology and repair content of the repaired site by observing the morphological characteristics of articular cartilage. The International Cartilage Repair Society (ICRS)'s macroscopic evaluation of the cartilage repair scale and the quantitative scoring repair effect of the modified O'Driscoll grading system were used as evaluation criteria. In addition, the structure of the rabbit knee joint was evaluated by micro-CT scan, histological staining (H & E staining, Alcian blue staining, Safranin-O staining) and immunohistochemical staining (TGF-β2 immunostaining, TGF-β3 immunostaining, Sox-9 immunostaining). Results: ① The observation of the repair morphology of joint defect tissues showed that the repair effects of the Nar and ADM groups were better than that of the Mod group, and the repair effect of Nar/ADM group was the best (P

Introduction: Probiotics, including lactobacilli, have immunomodulatory activities with promising effects on inflammatory diseases. In this study, we evaluate the effect of Enterococcus durans (Edu) and three various strains of lactobacilli (Lacto-mix), including L. rhamnosus, L. casei, and L. plantarum, to prevent Experimental Autoimmune Encephalomyelitis (EAE) features Methods: C57BL/6 female mice were inoculated with Myelin Oigodendrocyte Glycoprotein (MOG35-55) in CFA (complete Freund’s adjuvant) to induce EAE. Five groups (n=6 in each group) of animals received saline or probiotics by oral gavage with 200 µL of lactobacilli (1.5×108 CFU/mL) for 2 weeks before the immunization and during the test for one month. Results: Histopathological studies showed an increase in infiltration of inflammatory cells and destruction of the myelin membrane in the EAE group but a decrease in inflammatory cells in the probiotic-treated animals. Pro-inflammatory cytokines (Interleukin [IL]-17 and Interferon [IFN]-γ) concentration in the supernatant of the brain and spinal cord tissues showed a significant increase in the EAE compared with the normal saline group (P

Background: Exenatide(EXE) is an anti-hyperglycemic agent approved for treating type 2 diabetes by the Food and Drug Administration(FDA). However, twice-daily injection of exenatide is inconvenient for most of the patients. Objective: In this study, biotinylated trimethylated chitosan(Bio-TMC) based nanoparticles were proposed to promote oral absorption of exenatide. Realizing the oral administration of exenatide is very important to alleviate patient suffering and improve patient compliance. Methods: Bio-TMC was synthesized, and the chemical structure was characterized by Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy. Nanoparticles were prepared through polyelectrolyte interaction in the presence of sodium Tripolyphosphate (TPP) and hydroxypropyl methylcellulose phthalate (HP-55). Formulations were physically and chemically characterized. In vitro release was investigated in different pH media. In vivo antidiabetic activities of biotin modified and non-biotin modified chitosan were evaluated in db/db mice. Results: EXE-loaded Bio-TMC/HP-55 nanoparticles were spherical in shape with a mean diameter of 156.2 nm and zeta potential of +11.3 mV. The drug loading efficiency and loading content were 52.38% and 2.08%, respectively. In vitro release revealed that EXE-loaded Bio-TMC/HP-55 nanoparticles were released faster in pH 1.2 than pH 6.8 (63.71% VS 50.12%), indicating that nanoparticles have enteric characteristics. Antidiabetic activity study revealed that after oral administration to diabetic mice, the relative pharmacological bioavailability (FPharm%) of the biotin modified nanoparticles was found to be 1.27-fold higher compared to the unmodified ones, and the hypoglycemic effect was also found to be better. Conclusion: Bio-TMC/HP-55 nanoparticles are feasible as oral drug carriers of exenatide and have the potential to be extended to other drugs that are not readily oral, such as monoclonal antibodies, vaccines, genes, etc. These would be beneficial to the pharmaceutical industry. Further research will focus on the biodistribution of Bio-TMC/HP-55 nanoparticles after oral administration.

Mechanisms linking ingested pollutants to increased incidence of allergy are poorly understood. We report that mice exposed to low doses of cadmium develop higher IgE responses following oral allergen sensitization and more severe allergic symptoms upon allergen challenge. The environmentally relevant doses of this pollutant also induced oxidative/inflammatory responses in the gut of SPF, but not germ-free mice. Interestingly, the increased IgE responses correlated with stimulation of the vitamin D3-metabolizing enzymes CYP27B1 and CYP24A1 in the gut and increased luminal levels of oxidized vitamin D3 metabolites that are not ligands of the vitamin D receptor. Inhibition of CYP27B1 and CYP24A1 via oral administration of pharmacological inhibitors reduced IgE responses induced in mice orally exposed to cadmium. Our findings identify local alteration of vitamin D signaling as a new mechanism for induction of IgE responses by environmental pollutants. They also identify vitamin D3-metabolizing enzymes as therapeutic targets for the treatment of allergy.

Precise oral dosing in rodents is usually achieved by intragastric gavage. If performed incorrectly due to technical difficulties, inexperience, or animal resistance, oral gavage may have animal welfare implications such as esophageal and gastric rupture and aspiration. The stress that is induced by this procedure can also lead to confounding results. In several animal models, drug vehicles must be sugar-free, deliver drugs in a specific formulation, and sometimes supply water. Gelatin has all of these properties. The current study aimed to evaluate the use of gelatin vehicles with different sensory features as an alternative to oral gavage. We investigated the time taken by 2 different inbred mouse strains, FVB/N and C57BL/6J, to ingest sugar-free gelatin pellets of varying flavors. Results showed that FVB/N mice took more time to eat the unflavored, strawberry and diet-flavored gelatin pellets than did C57BL/6J mice. Both strains showed low preference for lemon flavor, with the same ingestion times after the second day. This study showed that the C57BL/6J mice are more likely to eat gelatin than are FVB/N mice, and that the 2 strains of mice show a lower preference for lemon flavoring as compared with other flavors. This method of voluntarily oral administration offers an alternative to gavage for studies that use oral dosing studies.

Background Skin rash often occurs upon oral administration of amoxicillin in children, due to non-immediate hypersensitivity. However, information on delayed hypersensitivity to amoxicillin is scarce. Moreover, the appropriate diagnostic method and actual diagnostic rate of delayed hypersensitivity to amoxicillin among Japanese children are unclear. We conducted intradermal tests (IDTs) and drug provocation tests (DPTs) and retrospectively investigated the proportion of children with a definitive diagnosis of non-immediate hypersensitivity to amoxicillin. We then evaluated the characteristics of patients with a positive allergic workup. Methods We enrolled children referred for suspected findings of mild or moderate non-immediate hypersensitivity to amoxicillin between August 2018 and March 2020. If the IDT in the delayed phase was negative, DPT with amoxicillin (60–90 mg/kg/day) was performed for 7 days. Non-immediate hypersensitivity to amoxicillin was defined when IDT or DPT was positive. We evaluated the potential of the drug-induced lymphocyte stimulation test (DLST) to reveal hypersensitivity to amoxicillin. Results This study enrolled 27 children. Fourteen children (52%) had hypersensitivity to amoxicillin, of whom 12 had positive IDTs and two had positive DPTs. No differences in age, sex, history of allergic disease, days from oral use to symptom onset, type of rash at symptom onset, generalized rash, and DLST results were observed between the hypersensitivity and non-hypersensitivity groups. Conclusions Examination should be performed for children with mild or moderate reactions because positive cases have no significant features and half of the suspected cases are negative.

Here, we report on the development of lipid-based nanostructures containing zidovudine (1 mg/mL) and lamivudine (0.5 mg/mL) for oral administration in the pediatric population, eliminating the use of organic solvents, which is in accordance with green chemistry principles. The formulations were obtained by ultrasonication using monoolein (MN) or phytantriol (PN), which presented narrow size distributions with similar mean particle sizes (~150 nm) determined by laser diffraction. The zeta potential and the pH values of the formulations were around −4.0 mV and 6.0, respectively. MN presented a slightly higher incorporation rate compared to PN. Nanoemulsions were obtained when using monoolein, while cubosomes were obtained when using phytantriol, as confirmed by Small-Angle X-ray Scattering. The formulations enabled drug release control and protection against acid degradation. The drug incorporation was effective and the analyses using an electronic tongue indicated a difference in palatability between the nanotechnological samples in comparison with the drug solutions. In conclusion, PN was considered to have the strongest potential as a novel oral formulation for pediatric HIV treatment.

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of 125I-AP with and without bromosulfalein and by intravenous administration of 125I-AP. The uptake of 125I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, 125I-AP was easily excreted in the urine when administered intravenously. The accumulation of 125I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both 125I-AP and bromosulfalein than those receiving only 125I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral 125I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder.

(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between “good” and “bad” formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs.

Cell-culture-based drug tests are usually performed in an instantaneous delivery manner. However, in vivo pharmacokinetic studies have shown a steady increase in the concentration of bioactive compounds in the plasma following oral administration, with the maximum concentration observed after several hours. Here, a novel palm-sized syringe pump powered by the manual winding of a spring was utilized for sustained delivery of chlorogenic acid (CHA) to lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages over 2 h. When delivered in a sustained manner and simulating the in vivo pharmacokinetics following oral administration, CHA showed a stronger inhibitory effect on LPS-induced expression of inducible nitric oxide synthase and the transcription and secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α. It also enhanced the mRNA expression of the gene encoding heme oxygenase 1. The suppression of phosphorylation of p38 but not the nuclear translocation of nuclear factor-κB was affected by the sustained delivery of CHA. High-performance liquid chromatography analysis indicated that the sustained delivery model showed a higher concentration of CHA in the conditioned medium two hours after starting the delivery. A stronger anti-inflammatory effect of CHA was observed upon sustained delivery to the cell medium, simulating an in vivo pharmacokinetic release profile following oral administration.

For oral drug delivery the stability of liposomes against intestinal bile salts is of key importance. Here, asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering (MALLS) and a differential refractive index (dRI) detector was employed to monitor structural re-arrangement of liposomes upon exposure to the model bile salt taurocholate. For comparison, a conventional stability assay was employed using a hydrophilic marker and size exclusion chromatography (SEC) to separate released from liposome-entrapped dye. Calcein-containing liposomes with and without cholesterol were compared in terms of their in vitro stability upon exposure to bile salts by separating liposomes from co-existing colloidal species emerging after stress test using AF4/MALLS/dRI. Dynamic light scattering (DLS) was utilized in parallel. Our AF4/MALLS/dRI results suggested that exposure of egg-phospholipid liposomes to bile salts at physiological concentrations led to the formation of two new species of colloidal associates, likely (mixed) micelles. Subjecting cholesterol-containing liposomes to the same bile media did not lead to any new colloidal structures, indicating increased stability of these liposomes. Our SEC-based release assay largely confirmed these findings, indicating that AF4/MALLS/dRI is a suitable technique for prediction of in vitro oral stability of liposomal formulations. Moreover, the powerful AF4/MALLS/dRI technique appears promising to improve the understanding of the underlying mechanisms during bile salt-induced liposomal breakdown.

IntroductionIn the last few years, different formulations containing cannabidiol (CBD) were tested with regard to its efficacy on chronic pain, refractory epilepsy, anxiety, aggressive behavior and atopic dermatitis in dogs. CBD is generally administered orally, but its low bioavailability, probably due to a first-pass metabolism, represents a great limitation. The aim of this study was to evaluate if CBD bioavailability increases after oral transmucosal administration (OTM) compared to oral treatment.MethodsTwelve dogs diagnosed with mild chronic pain were enrolled in the study and treated once orally or OTM (6 dogs/group) with a pure CBD in oil formulation at a dosing rate of 1 mg/kg b.w. At prefixed time points, blood samples were collected to define CBD plasma concentrations vs. time profiles, and the main pharmacokinetics parameters were obtained by non-compartmental model.ResultsCBD Cmax, Tmax, terminal half-life and AUC0 − t were 206.77 ± 167 and 200.33 ± 158.33 ng/mL, 2.17 ± 0.98 and 1.92 ± 1.11 h, 2.67 ± 0.53 and 2.62 ± 0.64 h, 647.51 ± 453.17, and 536.05 ± 370.21 h*ng/mL, following oral and OTM administration, respectively. No significant difference in pharmacokinetic parameters were observed between treatments.DiscussionThe OTM administration did not increase cannabidiol bioavailability compared to oral treatment. The almost perfectly superimposable mean plasma concentrations of cannabidiol following the two treatments suggests that CBD is not able to be adsorbed by the oral mucosa or that its absorption is very scarce, and that CBD is swallowed and absorbed in the gastrointestinal tract.

Tuberculosis is a highly contagious disease caused by Mycobacterium tuberculosis. It affects about 10 million people each year and is still one of the leading causes of death worldwide. About 2 to 3 billion people (equivalent to 1 in 3 people in the world) are infected with latent tuberculosis. Moreover, multidrug-resistant, extensively drug-resistant, and totally drug-resistant strains of M. tuberculosis are increasing. Therefore, it is urgent and necessary to develop new anti-tuberculosis drugs that are different from existing drugs to combat antibiotic-resistant M. tuberculosis. With this background, we aimed to develop probiotics as anti-tuberculosis drugs. Here we report the anti-tuberculosis effect of Pediococcus acidilactici PMC202 isolated from young radish kimchi, a traditional Korean fermented food. Under co-culture conditions, PMC202 inhibited the growth of M. tuberculosis. In addition, PMC202 inhibited the growth of drug-sensitive and resistant M. tuberculosis infecting macrophages at a concentration that did not show cytotoxicity and showed a synergistic effect with isoniazid. In the 2-week repeated oral administration toxicity study using mice, PMC202 did not cause weight change or specific clinical symptoms. The result of 16S rRNA-based metagenomics analysis confirmed that dysbiosis was not induced in bronchoalveolar lavage fluid after oral administration of PMC202. The anti-tuberculosis effect of PMC202 was found to be related to the reduction of nitric oxide. These results indicate that PMC202 could be used as an anti-tuberculosis drug candidate with the potential to replace current chemical-based drugs. However, more extensive toxicity, mechanism of action, and animal efficacy studies with clinical trials are needed.

BACKGROUND AND OBJECTIVE Benign Prostatic Hyperplasia (BPH) is a prevalent disease among older men caused by abnormal proliferation of the prostatic cells. Findings indicate an association between dyslipidemia and BPH. This study aimed at evaluating the effect of ethanol extract of Sphenostylis stenocarpa seed on the lipid profile of rats with testosterone propionate-induced BPH. MATERIALS AND METHODS A total of 25 male Wistar rats randomized into five groups of five rats each were used. BPH was induced in the rats by subcutaneous injection of testosterone propionate in olive oil for 28 days. The test rats (after BPH induction) were treated with ethanol extract of the plant seed at doses of 200 and 400 mg kg-1 b.wt. The concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triacylglycerol were evaluated on the sera of the rats. RESULTS The BPH control rats (model group) showed a significant (p

The lack of an appropriate analytical approach characterizing metabolites from dietary proteins may prevent further studies that could clarify their health benefits. In this study, we attempted to establish a novel analytical assay of peptide metabolites from glycinin using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), in combination with the amine derivatization technique with coumarin (Cou). Cou (30 mmol/L) derivatization of peptides under rapid (30 min) and mild (25 °C, pH 8.5) conditions caused higher MS detection of the peptides as compared to nonderivatized peptides. In addition, an MS shift of the target by Cou derivatization (+202.0 m/z) can help to easily discriminate peptide metabolites in glycinin-administered blood, by comparing the MALDI-MS spectra of Cou-derivatized plasma with those of preadministered blood. After the oral administration of glycinin (100 mg/kg) to Sprague-Dawley rats, 15 di- to tetrapeptides were successfully characterized as glycinin-derived metabolites, demonstrating that the proposed Cou-tagged MALDI-MS is an appropriate characterization technique for peptide metabolites.

A new rapid ultra-high performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry method was established for the qualitative analysis of absorbed ingredients and metabolites of Zhimu-Huangbai herb pair, which is used to treat type 2 diabetes mellitus. A total of 16 absorbed ingredients and 11 metabolites were identified in normal and type 2 diabetes mellitus rats, respectively. Such findings indicated that the diabetic model had no effect on the type of components in plasma. Seven absorbed ingredients and 11 metabolites were first identified after the oral administration of Zhimu-Huangbai herb pair. Thereafter, ultra-high performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry and liquid chromatography-API4000+ triple quadrupole mass spectrometer methods were established and validated for pharmacokinetic comparative studies of seven major bioactive components in normal and type 2 diabetes mellitus rats. Partial pharmacokinetic parameters in the plasma of type 2 diabetes mellitus rats were significantly different from those in normal rats. To our knowledge, this is the first comparison of absorbed ingredients and metabolites of Zhimu-Huangbai herb pair, and its used in pharmacokinetic studies between normal and type 2 diabetes mellitus rats. Ultimately, our findings provide insights into the clinical usage of Zhimu-Huangbai herb pair. This article is protected by copyright. All rights reserved.

Cognition maintenance is essential for healthy and safe life if sleep deprivation happens. Armodafinil is a wake-promoting agent against sleep deprivation related disorders. However, only the tablet formulation is available, which may limit its potential in some circumstances. Here, we report the synthesis of a new formulation of armodafinil, microneedle patches, which can be conveniently used by any individual and removed in time if not wanted. To produce the needles of higher mechanical strength and higher drug loading, polyvinylpyrrolidone (PVP) K90 was used to fabricate armodafinil-loaded microneedles by applying the mold casting method after dissolving in methanol and drying. The higher mechanical strength was validated by COMSOL Multiphysics® software stimulation and universal mechanical testing machines. The obtained armodafinil microneedles can withstand a force of 70 N and penetrate the skin to a depth of 230 μm, and quickly released the drug within 1.5 h in vitro. The pharmacokinetic analysis showed that microneedle administration can maintain a more lasting and stable blood concentration as compared to oral administration. After the treatment of sleep deprived mice with microneedles, the in vivo pharmacodynamics study clearly demonstrated that armodafinil microneedles could eliminate the effects of sleep deprivation and improve the cognitive functions of sleep-deprived mice. A self-administered, high drug-loaded microneedle patch were prepared successfully, which appeared to be highly promising in preserving cognition by transdermal administration.

Background: MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells. Objective: The objective of this study is to identify and quantify MIDD0301 metabolites in vitro and in vivo and determine the pharmacokinetics of oral, IP, and IV administered MIDD0301. Methods: In vitro conversion of MIDD0301 was performed using liver and kidney microsomes/S9 fractions followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A LC-MS/MS method was developed using synthesized standards to quantify MIDD0301 and its metabolites in urine and feces. Blood, lung, and brain were harvested from animals that received MIDD0301 by oral, IP, and IV administration, followed by LCMS/ MS quantification. Imaging mass spectrometry was used to demonstrate the presence of MIDD0301 in the lung after oral administration. Results: MIDD0301 is stable in the presence of liver and kidney microsomes and S9 fractions for at least two hours. MIDD0301 undergoes conversion to the corresponding glucuronide and glucoside in the presence of conjugating cofactors. For IP and IV administration, unconjugated MIDD0301 together with significant amounts of MIDD0301 glucoside and MIDD0301 taurine were found in urine and feces. Less conjugation was observed following oral administration, with MIDD0301 glucuronide being the main metabolite. Pharmacokinetic quantification of MIDD0301 in blood, lung, and brain showed very low levels of MIDD0301 in the brain after oral, IV, or IP administration. The drug half-life in these tissues ranged between 4-6 hours for IP and oral and 1-2 hours for IV administration. Imaging mass spectrometry demonstrated that orally administered MIDD0301 distributes uniformly in the lung parenchyma. Conclusion: MIDD0301 undergoes no phase I and moderate phase II metabolism.

The objective of this study was to evaluate the effects of oral administration of fiber from the first week of life on the growth and hindgut environment of preweaning calves. Twenty newborn female Holstein calves were divided into 2 groups as control and treatment. Calves in both groups were reared under the same feeding program except for oral fiber administration. Timothy hay and psyllium were mixed at a 50-to-6 ratio as a treatment diet for oral fiber administration. Calves in the treatment group were orally administered 50 g of fiber daily from 3 to 7 d of age and 100 g of fiber from 8 d of age until weaning. Feed intake and occurrence of diarrhea were recorded daily, and body weight (BW) was recorded weekly for the individual calf. Fresh fe-ces were collected from calves at 7, 21, 35, 49, and 56 d of age to analyze fermentation parameters and microbiota to characterize the hindgut environment. Higher fiber intake in the treatment group due to oral administration of timothy and psyllium did not affect the starter intake and achieved higher BW at 21 d of age. The fecal pH, total volatile fatty acid, lactate, and ammonia nitrogen concentrations were not affected by oral fiber administration; meanwhile, the molar propor-tion of propionate was higher in the treatment group at 7 d of age. The difference in fecal microbiota in the calves subjected to the oral administration of fiber was observed within 21 d of life; Lactobacillus spp. and Prevotella spp. showed higher abundance, whereas that of Clostridium perfringens was decreased. These higher abundances of beneficial bacteria and lower abundance of pathogenic bacteria during early life may partly ex-plain the higher BW of calves in the treatment group at 21 d of age. Furthermore, no adverse effect was ob-served for the BW and health status in the treatment group throughout the preweaning period. Therefore, early fiber feeding via oral administration potentially contributes to improving the hindgut environment in newborn calves, which leads to better growth of calves during the early stage of life.

Background: Hypoestes rosea (family: Acanthacea), has been harnessed and utilized for treatment of several ailments. However, there is the paucity of available data on nephrotoxicity associated with this herb. Here, we investigated the phytochemical profile and toxicological effect of H. rosea on Wistar Rats. Methods: Twenty rats (weight range: 75–100 g) were assigned into five study groups, viz; (a) control (without treatment) (b) treatment group 1, orally administered with 50 mg/kg (c) treatment group 2, orally administered with 100 mg/kg (d) treatment group 3, orally administered with 250 mg/kg, and (e) treatment group 4, orally administered with 300 mg/kg of H. rosea, respectively for 28 days of four rats per group. The rats were made unconscious by using oral administration of chloroform. Cardiac punctures were made, and blood samples collected into 10 ml labeled plain container, allowed to clot and spun to harvest serum for determination of sodium, potassium, chloride, bicarbonate, urea and creatinine using colorimetric, back-titrimetric, Urease-Berthelot and Jaffe’s reaction methods respectively. Kidneys of rats were harvested, weighed and immediately fixed in 10% neutral buffered formalin for histological analysis. Result: Mean serum sodium (p = 0.049), potassium (p = 0.007), and urea (p

Treatment options are limited for esophageal carcinoma (EC). G47Δ, a triple-mutated, conditionally replicating herpes simplex virus type 1 (HSV-1), exhibits enhanced killing of tumor cells with high safety features. Here, we studied the efficacy of G47Δ using preclinical models of human EC. In vitro, G47Δ showed efficient cytopathic effects and replication capabilities in all eight human esophageal cancer cell lines tested. In athymic mice harboring subcutaneous tumors of human EC (KYSE180, TE8, and OE19), two intratumoral injections with G47Δ significantly inhibited the tumor growth. To mimic the clinical treatment situations, we established an orthotopic EC model using luciferase-expressing TE8 cells (TE8-luc). An intratumoral injection with G47Δ markedly inhibited the growth of orthotopic TE8-luc tumors in athymic mice. Furthermore, we evaluated the safety of applying G47Δ to the esophagus in mice. A/J mice inoculated intraesophageally or administered orally with G47Δ (107 plaque-forming units [pfu]) survived for more than 2 months without remarkable symptoms, whereas the majority with wild-type HSV-1 (106 pfu) deteriorated within 10 days. PCR analyses showed that the G47Δ DNA was confined to the esophagus after intraesophageal inoculation and was not detected in major organs after oral administration. Our results provide a rationale for the clinical use of G47Δ for treating EC., Graphical abstract, An intratumoral injection with oncolytic herpes virus G47Δ is efficacious in a clinically relevant orthotopic mouse model of esophageal cancer. G47Δ is safe when inoculated intraesophageally in mice, and G47Δ DNA distribution is confined to the esophagus. Intratumoral G47Δ treatment can be a potential therapeutic approach for esophageal cancer patients.

Background: The coccidian protozoan, Caryospora cheloniae, has been associated with severe enteritis and encephalitis in immature farm-raised green turtles (Chelonia mydas) in the Cayman Islands, immature green turtles off the coast of Florida, and immature stranded sea turtles in Australia. An effective anti-coccidial drug that is both orally absorbed and well-distributed throughout the body is needed for treatment of turtles diagnosed with coccidiosis in rehabilitation facilities. Ponazuril is a triazine antiprotozoal drug that is approved in the USA for the treatment of another Apicomplexan, Sarcocystis neurona, and has also been successfully used in the therapy of other coccidian parasites.Aim: To perform an oral dose-ranging pilot study (10-100 mg/kg of body weight ponazuril) in green turtles (N = 9), followed by oral administration of ponazuril at 100 mg/kg body weight (N = 8) to assess its disposition. Another goal of this study was to optimize the method of oral drug administration to green turtles.Method: Plasma ponazuril concentrations were quantified using high performance liquid chromatography (HPLC). Data were fit to standard compartmental models with first order absorption.Results: Ponazuril was absorbed after oral administration at 100 mg/kg BW, with a maximum plasma concentration of 3.3 µg/ml. Dose-dependent pharmacokinetic parameters only weakly correlated with the dose rate, apparently due to considerable pharmacokinetic variability observed between turtles. Administration of ponazuril in gelatin capsules using a balling gun was deemed the least variable and most successful method of drug administration.Conclusion: Further studies are needed to evaluate the safety and efficacy of ponazuril in sea turtles with coccidiosis.

OBJECTIVE To investigate the effects of a single oral dose of gabapentin on fear-based aggressive behaviors (FABs) in cats during veterinary examinations. ANIMALS 55 healthy pet cats (26 with and 29 without a history of FAB during veterinary visits [FAB and untreated control groups, respectively]). PROCEDURES A standardized 9-step clinical examination protocol (with patient compliance scored from 0 to 9 according to the highest completed step) was tested on untreated control group cats. The protocol was then used in a double-blind, randomized, placebo-controlled, crossover-design trial in which FAB-group cats received owner-administered gabapentin (100 or 200 mg/cat) or placebo capsules 2 hours before the first of 2 veterinary visits and received the alternate treatment before the second visit ≥ 1 day later. Ease of administration (scored from 1 [very difficult] to 4 [very easy]) and adverse effects were recorded. Compliance scores were compared between treatments for the FAB group and between FAB and untreated control groups. Changes in scores between treatments for the FAB group were used to investigate associations between selected variables and the outcome of interest. RESULTS FAB group compliance scores after gabapentin administration (median, 9; range, 0 to 9) were significantly higher than scores after placebo administration (median 0.5; range, 0 to 7) and did not differ from scores for the untreated control group. Owner scores indicated capsule administration was easy. Adverse effects (most commonly drowsiness, myorelaxation, and ataxia) resolved ≤ 10 hours after detection. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested oral administration of gabapentin to cats 2 hours before a veterinary visit can reduce FAB during physical examination, enabling more complete evaluation.

Background: Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The renin-angiotensin system exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of angiotensin (Ang)-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin. Objectives: To evaluate the effects of Ang-(1-7) on GM-induced renal dysfunction in rats. Methods: AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD) was administered by gavage [46 μg/kg HPβCD + 30 μg/kg Ang-(1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected. Results: Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats. Conclusion: Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM.

As a serious neurodegenerative disorder, the prevalence of Parkinson's disease is predicted to dramatically increase in the coming decades. Despite the development of numerous drugs for its treatment, oral administration of levodopa has remained the simplest and most effective pharmacological approach in the management of Parkinson's disease. In this research, the levodopa-imprinted hydrogel was synthesized by reverse emulsion polymerization in the presence of levodopa followed by modification with polypyrrole. The antioxidant activity of amphiphilic non-levodopa-imprinted hydrogel was studied by 2,2-Diphenyl-1-picrylhydrazyl active radicals, which indicated 100% efficiency in the applied amount. Amphiphilic non-levodopa-imprinted hydrogel cytotoxicity was evaluated by MTT assay, which confirmed no significant toxicity after 24 and 48 h even at high concentrations. Moreover, in vitro releasing property of the levodopa-imprinted hydrogel was studied in the pH range of 4 to 7.4, which reached 60 and 80% within 160 h, respectively.

Zhi-zi-chi decoction (ZZCD), a well-known traditional Chinese medicine prescription, is a combination of Gardenia jasminoides fruit (GJF) and fermented soybean (FS). ZZCD has been used for treating depression, insomnia, and other diseases in China for thousands of years. A rapid, accurate, and sensitive ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method was developed for the simultaneous determination of the plasma concentrations of two representative ingredients, namely, geniposide and genistein. Adult Wistar rats were orally administered with ZZCD1 (GJF:FS, 1:1 (w/w), equals to 45.22 mg/kg of geniposide and 1.11 μg/kg of genistein), ZZCD2 (GJF:FS, 1:2 (w/w), equals to 33.31 mg/kg of geniposide and 1.10 μg/kg of genistein), ZZCD3 (GJF:FS, 1:4 (w/w), equals to 25.91 mg/kg of geniposide and 1.06 μg/kg of genistein), ZZCD4 (GJF:FS, 2:1 (w/w), equals to 62.45 mg/kg of geniposide and 0.368 μg/kg of genistein), and ZZCD5 (GJF:FS, 10:1 (w/w), equals to 77.73 mg/kg of geniposide and 0.54 μg/kg of genistein). The analytes were quantified using the multiple reaction monitoring mode with the electrospray ion source in positive (genistein) and negative (geniposide and IS) electrospray ionization. All calibration curves exhibited good linearity (R2 > 0.9992) over the measured ranges. The intra- and inter-day precisions were within 12.32%, and the accuracy ranged from 96.37% to 120.43%. The extraction recovery and matrix effect yielded satisfactory results. The method was successfully applied in a pharmacokinetic study of geniposide and genistein in rat plasma after the oral administration of five different combinations of ZZCDs.

Oral administration is the most popular route for systemic effects due to its ease of ingestion, pain, avoidance, versatility and most importantly, patient compliance. The development of enhanced oral protein delivery technology by mouth dissolving Tablets which may release these drugs in the mouth are very promising for the delivery of high molecular weight protein and peptide. Good mouth feel property of MDDS helps to change the basic view of medication as “bitter pill”, particularly for pediatric patients. To prepare mouth dissolving tablet using SSG & CCM by using Antihypertensive as model drug. Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme and it is a key component of the renin-angiotensin-aldosterone system. The ƛmax of Captopril was determined by scanning the 10µg / ml solution of drug using UV-Spectrophotometer and was found to be 271nm. The linear correlation was found to be 0.9995.The Fast dissolving tablets of captopril were prepared by direct compression method. Captopril can be successfully formulated as mouth dissolving tablets using various super disintegrate in different concentrations by direct compression method. The formulation containing 10% of crospovidone as super disintegrated was found to be outstanding than other formulations in terms of disintegration time and rate of dissolution.

BACKGROUND: Despite the exact etiopathogenesis of psoriasis remains unknown, the increasing or decreasing of some trace elements and oxidative stress status are considered to play a role. In this study, the effect of Lactocare R synbiotic on the serum levels of trace elements including Zn, Cu, Mg, Na, Fe, P, Ca, and K in the patients with mild to moderate psoriasis was investigated. METHODS: Sixty-four patients with mild to moderate psoriasis were included. Patients were randomly divided into treatment (n32) and control (n32) groups. The treatment group received Lactocare R and the control group received a placebo (two times daily for 12 weeks). Eight patients from the intervention group and 18 patients from the control group discontinued the study because of the recent COVID-19 condition. For routine trace element analysis, the blood samples were collected from all patients at the baseline as well as week 12 post-treatment. The serum was then isolated and the serum levels of trace elements including Fe, K, Ca, Mg, P, Zn, Na, and Cu were measured using an automatic electrolyte analyzer. For confirmation of the effect of Lactocare R on the alteration of serum levels of trace elements, intra-group analysis was performed at two interval times: baseline and week 12 post-treatment. RESULTS: The serum levels of K, P, and Ca in the placebo group were significantly higher than that of the treatment group at baseline. Serum levels of Zn and Ca were significantly higher in the treatment group compared to the placebo group at week 12 post-treatment. Moreover, a significantly lower serum level of K, P, and Ca in the treatment group at the baseline compared to the placebo group was compensated on week 12 post-treatment. Intra-group analysis in the treatment group showed that the serum levels of Fe, Ca, Mg, P, Zn, and Na was significantly increased at week 12 post-treatment compared to baseline levels. Whereas, intra-group analysis in the control group showed only Ca has a significant difference between baseline and week 12 post-treatment. CONCLUSION: The serum levels of Fe, Zn, P, Mg, Ca, and Na are increased significantly 12 weeks after oral administration of Lactocare R in psoriatic patients. The serum level of Fe and Cu is affected by sex at pre- and post-treatment. This study supports the concept that Lactocare R exerts beneficial effects in the gastrointestinal tract to improve mineral absorption in psoriatic patients.