Advances in Microbial Exopolysaccharides: Present and Future Applications.

Microbial exopolysaccharides (EPSs) are receiving growing interest today, owing to their diversity in chemical structure and source, multiple functions, and immense potential applications in many food and non-food industries. Their health-promoting benefits for humans deserve particular attention because of their various biological activities and physiological functions. The aim of this paper is to provide a comprehensive review of microbial EPSs, covering (1) their chemical and biochemical diversity, including composition, biosynthesis, and bacterial sources belonging mainly to lactic acid bacteria (LAB) or probiotics; (2) their technological and analytical aspects, especially their production mode and characterization; (3) their biological and physiological aspects based on their activities and functions; and (4) their current and future uses in medical and pharmaceutical fields, particularly for their prebiotic, anticancer, and immunobiotic properties, as well as their applications in other industrial and agricultural sectors.

Synbiotic Agents and Their Active Components for Sustainable Aquaculture: Concepts, Action Mechanisms, and Applications.

Aquaculture is a fast-emerging food-producing sector in which fishery production plays an imperative socio-economic role, providing ample resources and tremendous potential worldwide. However, aquatic animals are exposed to the deterioration of the ecological environment and infection outbreaks, which represent significant issues nowadays. One of the reasons for these threats is the excessive use of antibiotics and synthetic drugs that have harmful impacts on the aquatic atmosphere. It is not surprising that functional and nature-based feed ingredients such as probiotics, prebiotics, postbiotics, and synbiotics have been developed as natural alternatives to sustain a healthy microbial environment in aquaculture. These functional feed additives possess several beneficial characteristics, including gut microbiota modulation, immune response reinforcement, resistance to pathogenic organisms, improved growth performance, and enhanced feed utilization in aquatic animals. Nevertheless, their mechanisms in modulating the immune system and gut microbiota in aquatic animals are largely unclear. This review discusses basic and current research advancements to fill research gaps and promote effective and healthy aquaculture production.

Synbiotics and Their Antioxidant Properties, Mechanisms, and Benefits on Human and Animal Health: A Narrative Review.

Antioxidants are often associated with a variety of anti-aging compounds that can ensure human and animal health longevity. Foods and diet supplements from animals and plants are the common exogenous sources of antioxidants. However, microbial-based products, including probiotics and their derivatives, have been recognized for their antioxidant properties through numerous studies and clinical trials. While the number of publications on probiotic antioxidant capacities and action mechanisms is expanding, that of synbiotics combining probiotics with prebiotics is still emerging. Here, the antioxidant metabolites and properties of synbiotics, their modes of action, and their different effects on human and animal health are reviewed and discussed. Synbiotics can generate almost unlimited possibilities of antioxidant compounds, which may have superior performance compared to those of their components through additive or complementary effects, and especially by synergistic actions. Either combined with antioxidant prebiotics or not, probiotics can convert these substrates to generate antioxidant compounds with superior activities. Such synbiotic-based new routes for supplying natural antioxidants appear relevant and promising in human and animal health prevention and treatment. A better understanding of various component interactions within synbiotics is key to generating a higher quality, quantity, and bioavailability of antioxidants from these biotic sources.

Applications of Probiotic-Based Multi-Components to Human, Animal and Ecosystem Health: Concepts, Methodologies, and Action Mechanisms.

Probiotics and related preparations, including synbiotics and postbiotics, are living and non-living microbial-based multi-components, which are now among the most popular bioactive agents. Such interests mainly arise from the wide range and numerous beneficial effects of their use for various hosts. The current minireview article attempts to provide an overview and discuss in a holistic way the concepts, methodologies, action mechanisms, and applications of probiotic-based multi-components in human, animal, plant, soil, and environment health. Probiotic-based multi-component preparations refer to a mixture of bioactive agents, containing probiotics or postbiotics as main functional ingredients, and prebiotics, protectants, stabilizers, encapsulating agents, and other compounds as additional constituents. Analyzing, characterizing, and monitoring over time the traceability, performance, and stability of such multi-component ingredients require relevant and sensitive analytical tools and methodologies. Two innovative profiling and monitoring methods, the thermophysical fingerprinting thermogravimetry-differential scanning calorimetry technique (TGA-DSC) of the whole multi-component powder preparations, and the Advanced Testing for Genetic Composition (ATGC) strain analysis up to the subspecies level, are presented, illustrated, and discussed in this review to respond to those requirements. Finally, the paper deals with some selected applications of probiotic-based multi-components to human, animal, plant, soil and environment health, while mentioning their possible action mechanisms.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Bulk and Surface Wettability Characteristics of Probiotic Powders in Their Compressed Disc and Packed-Bed Column Forms.

Most probiotic-based products are available in powder particles under different solid-state forms. Such diversity can affect the probiotic stability, viability, and performance at different stages of processing, storage, and use. Here, we apply complementary physical chemistry techniques to characterize the bulk and surface properties of probiotic powder particles under different forms and report quantitative results of a highly concentrated multistrain reference product. The solid particle morphology, size/shape distribution, and the powder surface wettability in the compressed disc and porous packed bed forms are successively measured by sessile drop and capillary rise techniques. A complete wettability of the disc surface is observed through equilibrium contact angle measurements for various solvents, whereas the associated capillary rise data exhibit two regimes: a power law regime for the first few moments followed by a second regime, which can be described using Darcy's law. The use of this modeling approach shows the possibility of assessing the particle-packed bed permeability and porosity. These results open a new route of the structure-activity relationship study on the impact of probiotic solid particles on their functionalities and performance in promoting health benefits, related particularly to the human and animal gut permeability. This statement also strengthens the idea of using the compressed disc technique for easily performing probiotic wettability measurements.

Enhanced dopamine renal responsiveness in patients with hypertension.

The purpose of the study was to compare the renal effects of low doses of exogenous dopamine to assess the responsiveness of renal dopaminergic receptors in normotensive and hypertensive subjects. Eight hypertensive patients and seven normotensive volunteer subjects were studied. Inulin and para-aminohippuric (PAH) clearances, natriuresis, and fractional excretion of sodium increased significantly after intravenous dosing with dopamine (2 micrograms/min/kg) in both groups. These increases were significantly higher in hypertensive than in normotensive subjects: 31.8% +/- 3.7% vs. 16.2% +/- 1.2% for inulin clearance (P less than 0.01), 83.3% +/- 10.5% vs. 41.1% +/- 3.4% for PAH clearance (P less than 0.01), and 331% +/- 38% vs. 216% +/- 26% for natriuresis (P less than 0.01). These findings suggest hyperresponsiveness to dopamine during hypertension. This enhanced response to exogenous dopamine can be considered as a further argument favoring the existence of a deficit in dopaminergic activity during hypertension. Dopamine also induced a significant reduction in blood pressure and increased heart rate in hypertensive subjects but no significant change in blood pressure and heart rate occurred in normotensive subjects.

ACTH secretion from isolated hypophysial anterior lobes of male and female newborn rats: effects of corticotrophin-releasing factor, arginine vasopressin and oxytocin alone or in combination.

ACTH release by the anterior pituitary lobes of 8-day-old newborn rats (males and females) in the presence of rat corticotrophin-releasing factor (rCRF), arginine vasopressin (AVP) and oxytocin, given alone or in association, was measured in vitro. Rat CRF and AVP induced a dose-dependent release of ACTH in both sexes, while oxytocin was unable to stimulate ACTH secretion except at the highest dose tested. No sex-related difference was noted for any of the responses. Oxytocin (1 nmol/l) potentiated the response to rCRF (0.20 nmol/l) by the anterior pituitary lobes of females but not by those of males. This oxytocin potentiation was abolished when female newborn rats were injected at birth with testosterone (1 mg). AVP (1 nmol/l) alone stimulated ACTH release from the anterior pituitary lobes of the newborn rats of both sexes and markedly potentiated the ACTH response to rCRF. Although no difference between the sexes was noted for basal levels of AVP and oxytocin in the hypothalamus, the neurointermediate lobe and the peripheral plasma, the present data on the sex-related effect of oxytocin on the newborn adenohypophysis could, in part, explain why ACTH release in response to ether stress was previously reported to be more lasting in females than in males on day 8 postpartum.

Diltiazem increases steady state digoxin serum levels in patients with cardiac disease.

Diltiazem has been reported to decrease or not to affect digoxin elimination. The effects of diltiazem on steady state concentrations of digoxin was evaluated in eleven patients with congestive heart failure receiving this drug for at least two weeks. The mean trough digoxin was 1.11 +/- 0.18 ng/ml before the coadministration of diltiazem (180 mg/day). This concentration increased to 1.54 +/- 0.22 ng/ml after three days and to 1.54 +/- 0.23 ng/ml after seven days of coadministration (P less than 0.01). Clinically, no patient showed signs of digitalis toxicity. Creatinine clearance was unchanged. The present results show that when diltiazem is added to a regimen that includes digoxin, steady state concentrations of this glycoside may increase.

Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.

OBJECTIVES: Although the existence of a deep compartment for metformin has long been hypothesized, there is still little direct information concerning metformin distribution in individual tissues in man. The only available study involves chronic metformin therapy. In that study, the measurement of metformin in erythrocytes provided a reliable indicator of metformin distribution and of potential accumulation. To determine the kinetics of metformin in plasma and in erythrocytes after acute oral administration, we performed the present study in healthy subjects after a single oral dose of metformin and compared the pharmacokinetics parameters in erythrocytes to those in plasma. METHODS: Six nondiabetic participants took the study dose of 850 mg metformin at 8: 00 AM after a non-standardized breakfast (i.e., as recommended in clinical practice). Blood samples were collected for metformin measurement in plasma and in erythrocytes at 0, 1, 2, 3, 4, 6, 9, 24, 33, 48, 57, and 72 h. RESULTS: Maximum metformin concentration was attained at 3.0 +/- 0.3 h in plasma and 4.7 +/- 0.5 h in erythrocytes. This difference was not significant. Metformin concentrations peaked at a maximum almost 6 times higher in plasma than in erythrocytes (1.7 +/- 0.1 and 0.3 +/- 0.0 mg/l, respectively). However, because the elimination half-life of metformin was much longer in erythrocytes (23.4 +/- 1.9 h vs. 2.7 +/- 1.2 h), there was no difference in area under the curve between plasma and erythrocytes. The distribution volume (plasma) was calculated to be 146 +/- 11 l. Plasma and erythrocytes concentration-time curves showed that metformin was not detectable in plasma 24 hours after the oral administration, while it remained detectable in erythrocytes up to 48 hours. Metformin concentrations crossed approximately 13 hours after having reached their maximum values in plasma, approximately 16 h after metformin intake. CONCLUSION: Having demonstrated the rapid elimination of metformin from plasma and its slow disappearance from erythrocytes, the presents results should contribute to adjustment of metformin dosage to renal function, assessment of drug compliance, and retrospective analysis (when blood samples are drawn with delay) of the link between metformin and development of lactic acidosis. Most importantly, the present findings should help to ascertain the optimal dosage of metformin, particularly in elderly patients.

Pharmacokinetics and ascitic fluid penetration of piperacillin in cirrhosis.

The pharmacokinetics of piperacillin were evaluated in seven healthy volunteers, eight cirrhotic patients without ascites and 11 cirrhotic patients with sterile ascites after a single 15-min intravenous infusion of 4 g of the drug. In ascitic patients, piperacillin rapidly entered the peritoneal fluid. Peritoneal concentrations were higher than 10 mg/l from 0.5 to 8 h after the infusion. Disappearance rate of piperacillin was slower in the ascitic fluid than in plasma. The plasma half life of piperacillin was more prolonged in cirrhotic patients that in control subjects. This difference was more marked in ascitic patients for whom half life was twice as high as in volunteers (1.95 versus 0.91 h; P less than 0.01).

Serum bupivacaine concentrations and transplacental transfer following repeated epidural administrations in term parturients during labour.

Bupivacaine is the most widely used local anaesthetic in obstetrics for epidural analgesia. Nineteen women (mean age 26.9 +/- 5.3 years) who underwent epidural analgesia during labour were included in this study. All parturients received a first injection of 21.8 +/- 2.5 mg 0.25% plain bupivacaine. The following administrations were given on request: 0.25% concentration was used when cervix uteri was supple, and a 0.375% concentration when it was tonic. Blood samples were collected 5 min after the first injection and then every 30 min until delivery. At delivery blood samples were collected from the infant umbilical cord vein and from the arm vein of the mother. Bupivacaine was assayed by high pressure liquid chromatography. Serum data were analyzed for each patient using a non-compartmental model. Bupivacaine was rapidly detected in serum, and maximal concentration was reached between 5 and 35 min. Pharmacokinetic parameters were estimated in 17 women after the first injection: 87 +/- 35 min for elimination half-life, 60 +/- 19 L for apparent volume of distribution and 0.5 +/- 0.3 L/min for plasmatic clearance. For a mean total duration of labour and total dose administered of respectively 222 +/- 115 min and 57.1 +/- 28.7 mg the mean value of the foeto-maternal ratio was 0.29 +/- 0.10. The infant maximal serum concentration was 0.26 microgram/mL. No side effects were spontaneously reported by the parturients and all infants had an Apgar score of 10 at 5 min after the delivery. We confirm the fast systemic absorption and rapid elimination of bupivacaine which may be used without risk of acute toxicity both in mother and child, even when it is used in a 0.375% concentration.

Direct vascular actions of methyclothiazide and indapamide in aorta of spontaneously hypertensive rats.

In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretics methyclothiazide (MCTZ), the hydrochlorothiazide (HCTZ), and the thiazide-related diuretic indapamide (IND) on contractile responses to norepinephrine (NE) and arginine vasopressin (AVP) of aortic rings from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Changes in the tension of aortic ring preparations were measured isometrically. MCTZ (10(-4) M) induced endothelium-dependent inhibition of the vasoconstrictor responses to NE and AVP only in aortas from SHR, and the maximal vasoconstrictive effect of NE and AVP was decreased by 59 +/- 11% and 32.3 +/- 13%, respectively. Indapamide (10(-4) M) also induced endothelium-dependent inhibition of the contractile response to AVP in aortic rings from SHR, and the maximal vasoconstrictive effect of AVP was decreased by 33 +/- 5%. In contrast, HCTZ did not inhibit the contractile response to either NE or AVP, even at the highest concentration. This study provides evidence that methyclothiazide and indapamide inhibit the contractile response induced by norepinephrine and/or arginine vasopressin on SHR aortic preparations via an endothelium-dependent mechanism.

[Renin-angiotensin-aldosterone system inhibition: pharmacologic rationale and evaluations of drug combinations]. / Inhibition du système rénine-angiotensine-aldostérone: rationnel pharmacologique et évaluation des associations thérapeutiques.

First-line antihypertensive monotherapy is effective in normalizing blood pressure in approximatively 50 per cent of patients. Normalization in the remaining patients may require a combination of two or more drugs. This review considers the rationale and the evaluation of combinations with drugs interacting with the renin-angiotensin system (i.e. angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists) with other drugs. The combinations may be justified when giving an additive or synergistic action and when reducing clinical or metabolic side-effects. Recent developments concern the potential benefit of combining ACEI and angiotensin receptor antagonists.

[Clinical and pharmacokinetic study of pefloxacin in spontaneous ascitic fluid infections]. / Etude clinique et pharmacocinétique de la péfloxacine dans les infections spontanées du liquide d'ascite.

Ten patients with spontaneous ascitic fluid infections received intravenously 400 mg of pefloxacin for pharmacokinetic evaluation of the drug and its diffusion into peritoneal space. The patients were then treated with oral pefloxacin (400 mg every 36 h except for icteric patients: 48 h) during 21 days. Total body clearance was decreased (0.66 +/- 0.16 ml/min/kg) and elimination half life was increased as compared to that observed in normal subject (28.2 +/- 7.6 h), the longest half-lives being observed in the cases with the most severe alteration of hepatic function. Peritoneal concentrations were higher than 1 microgram/ml (i.e. exceeding the minimal inhibitory concentrations for most of the bacterial species involved in ascitic fluid infections) from the first half-hour after infusion to at least 36 hours. 9 of the 10 cases were cured. Pefloxacin provided a well spaced rythm of administration is a suitable antibacterial drug for ascitic fluid infections in cirrhotic patients with two advantages: its effectiveness against Enterobacteriaceae and an oral administration.

[Comparison of the fluoride bioavailability from two oral preparations of monofluorophosphate disodium in combination with various calcium salts]. / Comparaison de la biodisponibilité du fluor à partir de deux préparations orales de monofluorophosphate disodique en association avec différents sels de calcium.

We studied, in twelve healthy volunteers, the pharmacokinetics of inorganic fluoride and calcium variations in serum and urine, parathormone variations in serum after administration of two oral preparations containing 100 mg of disodium monofluorophosphate (13.2 mg F as element) with different calcium salts (500 mg Ca as element). Fluoride was estimated in serum and urine with an ion specific electrode. The fluoride bioavailability from two preparations is identical with an areas under the curve corresponding to 61.05 and 62.53 mumols.l-1 h (after deduction of physiological fluoride concentrations) and urinary fluoride excretion after 72 hours corresponding to 266.6 and 246.1 mumols. The plasma peak appearance is rapid (one hour) and similar. The significant increase of urinary Ca-Creat ratio (70 to 100%) is identical four hours after drug administration. In the same way, a significant and early decrease of intact PTH in serum, measured with chemiluminometric method, was observed from two drugs. From these observations we may conclude that the two preparations are biologically equivalent.

[Convulsions associated with the administration of excessive dose of ceftazidime in patients with renal failure]. / Crises convulsives associées à l'administration de doses excessives de ceftazidime chez des patients en insuffisance rénale.

Central neurological diseases caused by beta-lactamins are usually associated with excessive dosages in patients with renal failure. Two case reports of convulsive encephalopathy in patients treated with ceftazidime, show the absolute necessity of adapted posology, in case of renal dysfunction. In one case, we could follow plasma levels of ceftazidime during hemodialysis, and calculated the pharmacokinetic parameters. We conclude that extra renal epuration is an efficient technique in case of acute ceftazidime intoxication.

[Neurologic side effects of fluoroquinolones. Apropos of 9 cases concerning pefloxacin]. / Effets indésirables neurologiques des fluoroquinolones. A propos de 9 observations concernant la péfloxacine.

Neurological side-effects were a limiting factor with older quinolones. Although they appear to be less frequent with the newer fluoroquinolones, we observed nine such cases at Amiens University Hospital over a four-year period. The patients were six women and three men, with a mean age of 61 years. They received a mean dose of 800 mg/day of pefloxacin. Four had septic shock, one left ventricular failure, and seven had signs of cholestasis (signs of liver failure were absent). Neurological manifestations occurred between 24 hours and seven days after starting treatment and disappeared within 24 to 48 hours of stopping the drug or reducing the dosage. They included myoclonia (3 cases), convulsions (2 cases, one with concomitant theophylline), delirium and agitation (2 cases, one in a patient on steroids) and confusion (3 cases). Plasma drug levels were determined in six patients and were above normal peak levels (10 micrograms/ml) in five. Pefloxacin was measured in the cerebrospinal fluid in two cases (8.7 and 15.0 micrograms/ml). Neurological manifestations during pefloxacin treatment are probably related to overdose (plasma levels were above normal in 5/6 cases), possibly being favoured by cholestasis (7/9 cases) and/or hemodynamic factors (5/9). Symptoms can resolve when the pefloxacin dosage is reduced.

[Perinatal influence of sex hormones on the differential activation of corticotrope function during stress in the male and female]. / Influence périnatale des hormones sexuelles sur l'activation différentielle de la fonction corticotrope au cours d'un stress chez le mâle et la femelle.

The stress-induced activation of the corticostimulating function of the pituitary gland was noted to vary according to sex in both the adult and the newborn. The pituitary response in testosterone or estradiol-injected females at the time of birth was similar to that of intact males, in contrast, the castration of the males performed just before the postnatal surge of plasma testosterone was unable to modify at the 8th day, the male characteristic evolution in response to ether inhalation. Present data suggest--in the male, prenatal differentiation of the neuroendocrine pathways involved in the pattern of ACTH release in response to ether inhalation, probably in correlation with the peak of plasma testosterone on day 19 of gestation--in the female, the existence of androgen--sensitive structures in early postnatal life. An alpha stimulatory effect of norepinephrine on these neuroendocrine pathways was suggested. Present report also discuss--the catecholaminergic control of CRF X producing neurons--the sex dependent AVP and/or oxytocin (OT) release induced by a stress--the AVP and OT potentiation of CRF-induced ACTH release.

Liquid crystalline phases induced by the hydroxyl group stereochemistry of amphiphilic carbohydrate bicatenary derivatives.

Liquid crystals (LCs) may exist in different phases depending upon the orientational and positional orders of molecules in the material. Here, we demonstrate that the class of LC state induced by amphiphilic carbohydrate bicatenary derivatives is strictly hydroxyl group stereochemistry-dependent. This statement results from the experimental and theoretical investigations of surface film (2D) and bulk solid (3D) thermal behavior of synthetic stereoisomers n-tetradecyl (α-D-n-tetradecyl) galacto- and gluco-pyranosiduronate, with an axial (GalA-C(14/14)) or equatorial (GlcA-C(14/14)) hydroxyl group at the fourth carbon, respectively. Surface pressure-area isotherms (283-310 K), differential scanning calorimetry thermograms (223-573 K), and polarized optical textures (298-363 K) reveal that GlcA-C(14/14) organizes as a smectic LC-like phase (positional or lateral order), whereas the analogous stereoisomer GalA-C(14/14) behaves as a nematic LC-like phase (orientational order). Thermodynamic investigations and molecular dynamics models computed under similar temperature conditions provide consistent data with physical properties resulting from experimental approaches.