Distinct B cell subsets in Peyer’s patches convey probiotic effects by Limosilactobacillus reuteri

Background Intestinal Peyer’s patches (PPs) form unique niches for bacteria-immune cell interactions that direct host immunity and shape the microbiome. Here we investigate how peroral administration of probiotic bacterium Limosilactobacillus reuteri R2LC affects B lymphocytes and IgA induction in the PPs, as well as the downstream consequences on intestinal microbiota and susceptibility to inflammation. Results The B cells of PPs were separated by size to circumvent activation-dependent cell identification biases due to dynamic expression of markers, which resulted in two phenotypically, transcriptionally, and spatially distinct subsets: small IgD+/GL7−/S1PR1+/Bcl6, CCR6-expressing pre-germinal center (GC)-like B cells with innate-like functions located subepithelially, and large GL7+/S1PR1−/Ki67+/Bcl6, CD69-expressing B cells with strong metabolic activity found in the GC. Peroral L. reuteri administration expanded both B cell subsets and enhanced the innate-like properties of pre-GC-like B cells while retaining them in the sub-epithelial compartment by increased sphingosine-1-phosphate/S1PR1 signaling. Furthermore, L. reuteri promoted GC-like B cell differentiation, which involved expansion of the GC area and autocrine TGFβ-1 activation. Consequently, PD-1-T follicular helper cell-dependent IgA induction and production was increased by L. reuteri, which shifted the intestinal microbiome and protected against dextran-sulfate-sodium induced colitis and dysbiosis. Conclusions The Peyer’s patches sense, enhance and transmit probiotic signals by increasing the numbers and effector functions of distinct B cell subsets, resulting in increased IgA production, altered intestinal microbiota, and protection against inflammation.

Population Pharmacokinetics Modeling of Levofloxacin In Rabbit By Intravenous Bolus Injection and Peroral Administration

The population-based approach has been widely applied to describe the pharmacokinetic profile of many drugs. The aim of this current research was to study the implementation of the population-based pharmacokinetics of levofloxacin in rabbits administered by intravenous bolus injection and peroral delivery. Modeling analyses were performed using Monolix, one of the alternative tools for the population-based approach. Monolix works based on the Stochastic Approximation Expectation-Maximization (SAEM) method. The analysis was performed based on the population model using one-compartmental and two-compartmental disposition models. The combination error model was used during the analyses. Modeling appropriateness was determined based on the goodness of fit analyses, i.e., 1) the individual fit, 2) the observed versus population prediction values; and 3) the observed versus individual prediction values Plasma concentration profiles of levofloxacin by intravenous bolus injection and oral administration are better described by an appropriate model using a two-compartmental disposition model. All goodness of fit analyses demonstrates the power of the chosen model. However, the estimated disposition parameter values obtained based on the intravenous bolus injection and peroral administration are different for each subject. To confirm this phenomenon, we performed a simultaneous fitting of all intravenous bolus as well as peroral administration data. The goodness of fit analyses indicates an adequate fitting of all data.

Design of Mucoadhesive Strips for Buccal Fast Release of Tramadol

Tramadol hydrochloride is a synthetic analogue of codeine and shows activity on the central nervous system as an opioid agonist and inhibitor of serotonin and norepinephrine reuptake. It has been used for controlling moderate to severe pain. Mucoadhesive fast-dissolving films can present greater drug availability and patient acceptance when compared to the systems of peroral administration. The films were prepared using the solvent casting method with ethylcellulose, polyvinylpyrrolidone and poly(vinyl alcohol). The effect of each polymer concentration was investigated using a 2³ factorial design with repetition at the central point. The formulations were subjected to physicochemical, mechanical, ex vivo mucoadhesive and in vitro drug release profile analysis. These properties were dependent on the polymeric composition (independent factors) of each system. The optimized formulations showed good macroscopic characteristics, improved resistance to bending, rigidity, rapid swelling up to 60 s, improved mechanical and mucoadhesive characteristics, and also fast dissolving and tramadol release. The optimized formulations constitute platforms and strategies to improve the therapy of tramadol with regard to availability at the site of application, considering the necessity of rapid pain relief, and show potential for in vivo evaluation.

PHARMACOKINETIC PROPERTIES OF A NEW KAPPA-OPIOID ANALGESIC RU-1205 COMPOUND AT A SINGLE PERORAL ADMINISTRATION

The aim of the study is the investigation of the pharmacokinetic properties of the RU-1205 compound, with previously identified kappa-agonistic and analgesic effects, at a single oral administration, as well as comparison of the relationship between its pharmacokinetic and analgesic properties.Materials and methods. Pharmacokinetic parameters of RU-1205 after the oral administration at the dose of 50 mg / kg were investigated using the method of High Performance Liquid Chromatography with determination of the concentration of the compound according to the previously constructed calibration schedule. The indices of the area under the pharmacokinetic curve, clearance, half-life, residence time of the drug molecule in the body, a total (apparent) volume of distribution, as well as the indicator of absolute bioavailability, were calculated. The tissue distribution and excretion of RU-1205 were studied.Potential metabolites of RU-1205 were predicted using the PALLAS 3.00 program. The study of the analgesic activity was carried out on a model of central somatogenic pain with electricalstimulation, with the dynamics assessment of the voltage amplitude of the corresponding reaction of the "tail-flick" reflex.Results. The compound under study is rapidly adsorbed from the gastrointestinal tract, reaching a maximum concentration by the end of the first hour of the study, and is determined in plasma within 12 hours. Its half-life is 17.7 hours. The absolute oral bioavailability is 37.3%. It was found out that the compound is withdrawn within 3-4 days. The main route of excretion is extrarenal. Biotransformation of a substance probably proceeds mainly with the formation of oxidized forms of the initial molecule by reactions of the first phase of metabolic transformation. The analgesic effect is long-lasting: it starts after 15 minutes and lasts for 12 hours with flattening of the curve by the 8th hour.Conclusion. When administered orally, the test substance undergoes a long process of elimination, has the greatest tropism for the elimination organs and undergoes active biotransformation processes in the body of animals. As a result of it, active metabolic products with an analgesic activity are, possibly, formed.

Orodispersible Tablets: A New Trend in Drug Delivery

The oral route is the most popular and favoured method of drug administration. Orodispersible tablets are becoming more common among novel oral drug delivery systems because they increase patient compliance and provide some additional benefits over other oral formulations. They are also strong unit dosage types that, in the presence of saliva, disintegrate in the mouth within a minute due to super disintegrants in the formulation. As a result, this method of drug delivery aids in proper peroral administration of paediatric and geriatric patients who have difficulty swallowing. Various scientists have used various methods to create orodispersible tablets. The compression process is, however, the most popular method of preparation. Molding, melt granulation, phase-transition technique, sublimation, freeze-drying, spray-drying, and the effervescent method are some of the other unique processes. The flavour of these tablets is significant since they dissolve immediately in the mouth. To mask the drug's acidic flavour, a variety of techniques have been used. In this area, a number of scientists have looked at a variety of drugs. They are tested in the fields of stiffness, friability, wetting time, moisture absorption, disintegration test, and dissolution test, much as any other solid dosage types.

Effect of hydrocortisone on hypocorticolism caused by pituitary adenoma

Objectives Pituitary adenoma is a tumor that can cause hormonal secretion problems, including hypocortisolism. Hypocortisolism may result in negative impacts such as an increase in proinflammatory cytokine and immune system activation. Hypocortisolism therapy is performed by giving high-dose hydrocortisone. This case report presented a hypocortisolism therapy using hydrocortisone in a patient with pituitary adenoma. Case presentation A 17-year-old boy was admitted to a hospital due to right-eye vision loss, headache, and swallowing difficulty. During the treatment at the hospital, the patient had light depression. The brain Magnetic Resonance Imaging (MRI) scanning with contrast showed there was a supratentorial axial lesion enlarged from the intrasellar to the suprasellar. The anamnesis and physical examination, as well as laboratory and supporting examinations, showed that the patient was diagnosed to suffer from pituitary macroadenoma. The laboratory examination showed that the size of hypocortisolism was at <0.5 μg/dL (reference value ranges from 4.30–22.40 μg/dL). The patient was treated with hydrocortisone IV therapy at 100 mg/dose administered in the morning and evening for 4 days. Then, the dose tapering off of 100 mg/dose was administered in the morning for 4 days. After that, the patient received hydrocortisone of 20 mg/dose peroral administration in the morning and evening until the patient was discharged from the hospital. Tapering off was performed to prevent the side effects of high-dose hydrocortisone. Besides, the patient was alsounder the Endoscopic Endonasal Transsphenoidal Hypophysectomy (EETH). The cortisol level in the pretreatment was at <0.5 and 5.3 μg/dL during the treatment. There were no side effects of the treatment when the patients were hospitalized. Conclusions The hydrocortisone IV therapy with 100 mg/do was administered in the morning and evening for 4 days, and then the dose tapering off of 100 mg/dose was done in the morning for 4 days. Then, the hydrocortisone therapy of 20 mg/dose peroral administration to the patient with pituitary macroadenoma in the morning and evening to improve the cortisol level. The cortisol level in the pretreatment was at 0.5 and 5.3 μg/dL in the post-treatment.

ACUTE TOXICITY OF A NEW BENZIMIDAZOLE DERIVATIVE WITH ANTITHROMBOGENIC PROPERTIES

The paper presents the results of studying the toxicological profile of a new pharmaceutical substance RU891 with antithrombogenic properties. The minimum toxic dose (TDmin) for RU-891 by peroral administration is 230 mg/kg < TDmin ≤ 460 mg/kg. In experiments on the acute toxicity of the compound RU-891, the nature and severity of its damaging effect on the body of experimental animals were established and the safety of its action was evaluated. When studying the toxic effect of the test sample, the tolerated and toxic doses of RU-891 were determined, and the most sensitive organs and systems of the body were identified.

Distinct B Cell Subsets in Peyer’s Patches Convey Probiotic Effects by Lactobacillus Reuteri

Background: Intestinal Peyer’s patches (PPs) form unique niches for bacteria-immune cell interactions that direct host immunity and shape the microbiome. Here we investigate how peroral administration of probiotic bacterium Lactobacillus reuteri R2LC affects B lymphocytes and IgA induction in the PPs, as well as the downstream consequences on 28 intestinal microbiota and inflammation susceptibility. Results: The B cells of PPs were separated by size to circumvent activation-dependent cell identification biases due to dynamic expression of markers, which resulted in two phenotypically, transcriptionally and spatially distinct subsets: small IgD+/GL7- /S1PR1+/Bcl6, CCR6-expressing pre-germinal center (GC)-like B cells with innate-like functions located subepithelially, and large GL7+/S1PR1-/Ki67+/Bcl6, CD69-expressing B cells with strong metabolic activity found in the GC. Peroral L. reuteri administration expanded both B cell subsets, and enhanced the innate-like properties of pre-GC-like B cells while retaining them in the sub-epithelial compartment by increased sphingosine-1- phosphate/S1PR1 signaling. Furthermore, L. reuteri promoted GC-like B cell differentiation, which involved expansion of the GC area and autocrine TGFβ-1 activation. Consequently, PD-1-T follicular helper cell-dependent IgA induction and production was increased by L. reuteri, which shifted the intestinal microbiome and protected against dextran-sulfate-sodium induced colitis and dysbiosis. Conclusions: The Peyer’s patches sense, enhance and transmit probiotic signals by increasing the numbers and effector functions of distinct B cell subsets, resulting in increased IgA production, altered intestinal microbiota and protection against inflammation.

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1–3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.