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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.

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.

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.

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.

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

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

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.

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.

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.

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.

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.

Baclofen is a γ-aminobutyric acid-B receptor agonist used for control of spastic muscle activity and as a treatment for alcohol abuse. The review of the nonclinical database suggested a data gap for potential carcinogenicity following long-term use. Regulatory requirements for pharmaceutical safety testing of cancer-causing potential have historically included 2-year rodent studies in rats and mice. The availability of transgenic models with greater specificity and sensitivity to carcinogens provides safety testing alternatives that align with the 3Rs. The carcinogenicity of baclofen was evaluated in CB6F1-TgrasH2 transgenic mice following daily oral administration at 45, 90, and 180 mg/kg/d for 26 weeks, preceded by a 2-week drug-conditioning period. There were no treatment-related palpable masses or neoplastic findings, and survival rates were not affected by the baclofen treatment. In conclusion, baclofen was considered as noncarcinogenic in CB6F1-TgrasH2 mice, which is consistent with results previously obtained in a 2-year rat study.

ObjectiveThe understanding of acceptability of existing dosage forms is limited in most of the world and hinders the development of acceptable, age‐appropriate medicines. The attributes of paediatric medicine acceptability may differ from country to country based on culture, healthcare infrastructure and health policies. This study was designed to map the acceptability of oral medicines in paediatric patients treated in hospital in India.MethodsAn observational, cross-sectional study was conducted in patients aged below 18 years and taking any form of oral medication. Acceptability scores were obtained using CAST–ClinSearch Acceptability Score Test tool.Findings490 patients were recruited and 193 evaluations of different pharmaceutical products available in 20 dosage forms and 7 routes of administration were studied. Oral liquids (50%) and tablets (35%) were the most commonly prescribed and administered forms. Regardless of the therapeutic class and age, the oral liquids were ‘positively accepted’ in infants and toddlers. Acceptability of tablets improved with age and appeared to be generally good from the age of 6.ConclusionThis study indicates the limited progress towards adoption of age-appropriate dosage forms in India and thus impact on the acceptability of existing oral dosage forms. The key challenges posed by the adoption of age-appropriate formulations in India are (1) awareness of importance of appropriate administration and acceptability of medicines to children in India, (2) availability of age-appropriate dosage forms and (3) lack of child-appropriate medicine policies.

Protoapigenone, a unique class of natural flavonoid, exerted significant cytotoxic and antitumoral activities. A simple, sensitive, and rapid LC–MS/MS method for the quantification of protoapigenone in plasma was developed and validated to obtain the pharmacokinetic profile of protoapigenone in beagle dogs. Ethyl acetate-10% ammonium hydroxide (2:1, v/v) was employed for liquid–liquid extraction (recovery > 90%). Under optimal conditions, chromatographic resolution was achieved on a C18 column using acetonitrile and 10 mM ammonium formate in water (9:1, v/v), as mobile phase at a flow rate of 0.5 ml/min. The established method presented good linearity, selectivity, accuracy, and precision in the range of 0.2–100 ng/ml. Finally, this method was successfully applied to a pharmacokinetic study in beagle dogs following oral administration of protoapigenone.

We previously reported a 39-year-old man who presented with pulmonary and cerebral Cryptococcus gattii (genotype VGIIa) infection and was successfully treated with liposomal amphotericin B and flucytosine induction therapy. Following induction therapy, oral fluconazole treatment was initiated as consolidation therapy. However, the patient complained of progressively worsening headache, presenting an elevated cerebrospinal fluid (CSF) cell count. The minimum inhibitory concentrations of the CSF isolate were 8 and 0.12 μg/mL for fluconazole and voriconazole, respectively. The oral administration of voriconazole for more than 18 months alleviated his symptoms. Voriconazole might be useful for controlling refractory cases of C. gattii infection.

Bruton’s tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B‐cell receptor and Fc‐receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood‐brain barrier and potently inhibits BTK in microglial cells isolated from the CNS. A first‐in‐human randomized, double‐blind, placebo‐controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well‐tolerated in the study and all treatment‐related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half‐life of ~ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an enzyme‐linked immunosorbent assay‐based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady‐state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

Leishmaniasis urgently needs new oral treatments, as it is one of the most important neglected tropical diseases that affects people with poor resources. The drug discovery pipeline for oral administration currently discards entities with poor aqueous solubility and permeability (class IV compounds in the Biopharmaceutical Classification System, BCS) such as the diselenide 2m, a trypanothione reductase (TR) inhibitor. This work was assisted by glyceryl palmitostearate and diethylene glycol monoethyl ether-based nanostructured lipid carriers (NLC) to render 2m bioavailable and effective after its oral administration. The loading of 2m in NLC drastically enhanced its intestinal permeability and provided plasmatic levels higher than its effective concentration (IC50). In L. infantum-infected BALB/c mice, 2m-NLC reduced the parasite burden in the spleen, liver, and bone marrow by at least 95% after 5 doses, demonstrating similar efficacy as intravenous Fungizone. Overall, compound 2m and its formulation merit further investigation as an oral treatment for visceral leishmaniasis.

The pharmacokinetic profiling of active compounds is necessary for drug development and application. Approaches to a pharmacokinetic study based on biological markers are alternatives to traditional approaches based on chromatographic methods. The aim of the study was to compare two analytical approaches to pharmacokinetics investigation for an example of sitagliptin in rabbits after one dose oral administration. The method for sitagliptin quantification in rabbit plasma samples based on a correlation between its concentration and dipeptidyl peptidase IV activity was proposed, validated, and applied. The high-performance liquid chromatography (HPLC)-ultraviolet (UV) method was also validated and applied for the same sample analysis. The plasma pharmacokinetics of sitagliptin after oral administration to the rabbits in one dose was characterized after two analytical assays. The close values of the main pharmacokinetic parameters were obtained after two approaches. The nontraditional approach based on correlation of special marker activity and active substance concentration appears to be more sensitive than HPLC-UV. Thus, the sitagliptin concentrations determined by biomarker assay were higher than the lower limit of quantification (LLOQ) for a longer period (more timepoints) than after the HPLC-UV assay. This feature may influence the values of some calculated concentration-dependent (area under the curve [AUC]0-t , etc.) and time-dependent parameters (mean residence time [MRT], T1/2 , etc.). The values of Tmax obtained by the two approaches were similar and adequate for oral drug administration that confirms the correctness of biomarker selection for pharmacokinetics assessment. The obtained results on the example of sitagliptin confirms that the biomarker approach is adequate and applicable for a pharmacokinetics study. Similar approaches may be effective for individual compounds and complex mixtures when it is difficult or impossible to analyze them traditionally by chromatographic methods.

Aluminum oxide nanoparticles (Al2O3NPs) are one class of widely used nanomaterials. However, the teratogenicity toxicity of Al2O3NPs in mammal remains poorly understood. This study was aimed to evaluate the teratogenicity of Al2O3NPs in Sprague Dawley (SD) rats by gavage and to compare the effects of Al2O3NPs to those of equivalent dose of microscale aluminum oxide (bulk Al2O3). Sixty pregnant rats were randomly divided into 5 groups and treated with 100 and 200 mg/kg body weight (bw) Al2O3NPs (30 nm), 200 mg/kg bulk Al2O3, deionized water (as the negative control), and 300 mg/kg aspirin (as the positive control). Rats were exposed daily by oral gavage from the 7th day of gestation for 10 consecutive days and sacrificed on the 20th day of gestation. Results of the study showed that there were no significant effects of Al2O3NPs on pregnant rats (clinical signs, body weight, food consumption, ovary and uterus weight, number of corpora lutea) and fetuses (body weight, sex, body length, tail length, skeletal and visceral development). Under the experimental conditions of the present study, 10 consecutive days of repeated oral administration of Al2O3NPs at doses of up to 200 mg/kg/day did not induce any treatment-related teratogenicity in SD rats. Accordingly, the NOAEL was determined to be 200 mg/kg Al2O3NPs (106 mg Al/kg bw/day) in rats. The teratogenic effects of Al2O3NPs in rats were comparable to those of the bulk Al2O3 of same doses (200 mg/kg).

Chlorella is a green alga consumed as a dietary food supplement in pulverized form. In addition to its high nutritional value, it is also reported as an excellent detoxifying agent. The Chlorella powder has been reported for removal of mercury, cadmium, and radioactive strontium from the body. The present study evaluated the toxic effect of Chlorella powder (source: Chlorella vulgaris) in Swiss albino mice at acute and sub-acute (28 days repeated dose) doses. In acute and sub-acute oral toxicity studies, mice were administered orally with Chlorella powder at single (2000 mg kg−1) and repeated (1000 mg kg−1, once daily for 28 days) doses, respectively. During the study, mice were observed for clinical signs and mortality, weekly body weight, feed and water consumption, and biochemical, hematological, organ weight, and histological parameters. In the acute oral toxicity study, the test item Chlorella produced no change in clinical signs, and no morbidity or mortality was observed throughout the study period. The change in weekly body weight was statistically insignificant compared to the vehicle control group. In the sub-acute oral toxicity study, no statistically significant changes were observed in behavior, body weight, feed and water consumption, and biochemical, hematological, organ weight, and histological parameters compared to vehicle control mice. No morbidity or mortality was observed during the study period. Oral administration of Chlorella at acute and repeated doses in mice showed no toxicity or adverse effect. The No Observed Adverse Effect Level was estimated to be 1000 mg kg−1 body weight per day for male and female mice.

This study aimed to investigate pharmacokinetics of fluoxetine in horses and validate a method for liquid chromatography mass spectrometry analysis of serum levels. Fluoxetine pharmacokinetics were determined using 10 healthy, adult horses. Fluoxetine pharmacokinetics following a single oral dose (0.25 mg/kg) were determined using blood samples collected prior to and at several time points over 7 days following administration. Serum concentrations of fluoxetine and its bioactive metabolite norfluoxetine were measured using liquid chromatography coupled to an accurate mass/high-resolution mass spectrometer. Pharmacokinetic parameters were estimated using a noncompartmental model. Time to maximum serum concentration and serum half-life of fluoxetine was 1.5 and 15.6 h, respectively. Steady-state serum concentrations were evaluated using five horses each receiving fluoxetine (0.25 mg/kg, PO, q24hrs) for 8 weeks and were found to be 62.9 ± 25.5 ng/ml on average. Norfluoxetine was not detected in any sample.

Reproductive toxicity is a major challenge associated with aluminum (Al) exposure. Therefore, this study aimed to investigate the effects of zinc oxide nanoparticle (ZnONP) treatment on Al-induced reproductive toxicity in rats. Thirty-two adult male albino rats were allocated into four equal groups as follows: control, AlCl3 orally administered group (100 mg/kg bwt), ZnONPs injected intraperitoneally (i.p.) group (4 mg/kg bwt), and ZnONPs + AlCl3–treated group. The treatment was daily extended for 42 consecutive days. Oral administration of AlCl3 showed an oxidative damage confirmed by an increase in malondialdehyde and nitric oxide levels and superoxide dismutase activity and accompanied by a decrease in glutathione content and catalase activity. Also, AlCl3 administration increased the pro-inflammatory mediator tumor necrosis factor-alpha. Furthermore, significant declines in the levels of serum male reproductive hormones testosterone, luteinizing hormone, and follicle-stimulating hormone in AlCl3-intoxicated rats were noticed. In parallel, severe histopathological alterations were observed in testis tissues. Additionally, the immunohistochemical analysis showed that AlCl3 administration potentiates cell death in the testicular tissue by elevating the immunostaining intensity signal for the pro-apoptotic protein, cysteinyl aspartate specific protease-3 (caspase-3) and a marked depletion in the cell proliferation expression marker, Ki-67, in germinal cells of AlCl3-treated group. On the other hand, the daily i.p. injection to rats with ZnONPs before AlCl3 was found to ameliorate the reproductive toxicity induced by Al administration through reducing the testicular oxidative stress and improving the inflammatory, apoptotic, and reproductive markers as well as histopathological alterations in the testis. These results suggest that ZnONPs could be used as an alternative agent to minimize the reproductive toxicity associated with Al exposure through its antioxidant, anti-inflammatory, anti-apoptotic, and reproductive modulatory activities.

Introduction: In recent years as a result of the observation that the toxic effects of boron and its products have increased intensive studies have been initiated in our country and in the world regarding its effects, especially in the central nervous system, digestive system and reproductive system. The aim was to determine the histopathological changes caused by boric acid in rat testis, liver, kidney and brain tissues by light microscopy after oral administration of toxic dose of acute boric acid. Material and Methods: In the study, 1000 mg/kg/day boric acid was given orally for 7 days to 12-week-old 30 male albino SpragueDawley rats in total with an average weight of 285 g. Twelve male albino Sprague-Dawley rats of approximately the same weight and age were used as controls. At the end of the seventh day testes, liver, kidney and brain tissues were isolated from the animals. Results: At the end of the experiment, it was determined that the experimental group had significant body weight loss compared to the control group. Likewise, testicular, liver and kidney weights of the experimental group were decreased compared to the controls. In the histopathological examination performed with light microscopy in the testis, liver, kidney and brain tissues taken, congestion in the vascular bed of the testicular tissue and cellular degeneration at different rates were observed in paraffin sections and semi-thin sections. Conclusion: It was observed that acute boric acid administration, together with its widespread toxic effect, caused histopathological changes by inhibiting spermatogenesis, especially in testicular tissue.

The objective of this study was to investigate the single- and multiple-dose pharmacokinetics of chelerythrine (CHE) and its metabolite, dihydrochelerythrine (DHCHE), after oral and IM administrations in pigs.Six crossbreed (Landrace × Large White) female pigs (7-8 weeks old; 24.1 ± 2.6 kg bw) administered oral and IM CHE at a dose of 0.1 mg/kg orally and intramuscularly in a cross-over design. Multiple oral administration was performed at 0.1 mg/kg a time, three times a day at 8-h intervals for three consecutive days. Blood samples were collected from the anterior vena cava and placed into heparinized centrifuge tubes before dosing (time 0 h) and at different times after oral and IM administrations. Pre-treatment plasma was analysed by high-performance liquid chromatography-tandem mass spectrometry.After IM administration, CHE and DHCHE rapidly reached peak concentrations (