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This study examined the effect of live yeast (Saccharomyces cerevisiae; LYS) supplementation on rumen solubility and systemic bioavailability of Mg, P, Ca, Cd, and Pb in the serum and tissues of fattening lambs fed a total mixed ration. The 60-day feeding trial involved 24 fattening lambs randomly assigned to three treatments receiving 0.0, 1.5, or 3.0 g of LYS per animal daily. Results indicated that yeast supplementation, at either level, did not significantly (p > 0.05) affect ruminal mineral solubility. However, 3 g yeast significantly (p < 0.05) increased meat Ca and Pb concentrations while decreasing meat P and meat Cd and serum Pb levels, indicating improved systemic meat Ca utilization and heavy metal clearance through reducing meat Cd and serum Pb accumulations by 34.4% and 95%, respectively. Serum Ca, P, and Mg levels increased compared with baseline, whereas Pb decreased and Cd remained unchanged. Correlation analysis revealed significant interactions among minerals and heavy metals, suggesting that LYS modulates their absorption and metabolism through shared pathways or competitive interactions. However, elevated lead in meat warrants further investigation. In conclusion, live yeast supplementation can serve as an effective probiotic additive to enhance mineral metabolism and reduce heavy metal risk in fattening lambs.HighlightsLive yeast (Saccharomyces cerevisiae) supplementation boosted Ca bioavailability in blood and meat, leading to improved mineral utilization in fattening sheep.Phosphorus levels exhibited a dynamic response, with serum levels rising and meat levels falling at higher yeast doses, indicating potential changes in systemic retention.Cadmium accumulation in meat decreased linearly (up to 34.4%) with yeast supplementation, suggesting partial clearance benefits.Yeast dramatically reduced lead (Pb) concentrations in serum (up to 60.24%; from 249 to 99 ug/L), indicating a robust protective clearance effect.Serum Ca, P, and Mg concentrations increased, and Pb levels decreased post 60 days’ intervention of supplementation, whereas Cd remained unchanged.The mineral solubility in the ruminal remained largely unchanged, which confirms that the influence of yeast primarily has a postruminal or systemic effect.Live yeast plays a crucial role in regulating macromineral-heavy metal dynamics, either positively through a shared absorption pathway or negatively through mineral interactions (correlations highlighted).

Bioavailability is an ancient but effective terminology by which the entire therapeutic efficacy of a drug directly or indirectly relays. Despite considering general plasma bioavailability, specific organ/tissue bioavailability will pave the path to broad spectrum dose calculation. Clear knowledge and calculative vision on bioavailability can improve the research and organ-targeting phenomenon. This article comprises a detailed introduction on bioavailability along with regulatory aspects, kinetic data and novel bioformulative approaches to achieve improved organ specific bioavailability, which may not be readily related to blood plasma bioavailability.

Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form. Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications. Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

Beclomethasone dipropionate (BDP) is an anti-inflammatory corticosteroid that is rapidly metabolized to the pharmacologically active monoester, beclomethasone-17-monopropionate (17-BMP). Recently, a hydrofluoroalkane (HFA)–propelled nasal aerosol formulation of BDP was developed to treat allergic rhinitis. However, the pharmacokinetic profile of BDP HFA nasal aerosol has not been previously investigated. This study evaluated and compared the systemic levels of 17-BMP and BDP after a single dose of intranasally administered or orally inhaled BDP HFA in healthy subjects. In this single-center, randomized, open-label, 3-period crossover study, healthy subjects received single doses of intranasal BDP HFA (80 and 320 μg) and orally inhaled BDP HFA (320 μg). The primary pharmacokinetic parameters assessed were area under the concentration-time curve until the last measurable value (AUClast) and Cmax for 17-BMP. For AUClast and Cmax, point estimates for treatment differences and CIs were calculated on the log scale and then exponentiated to provide estimates of the geometric mean ratios (GMRs) and associated CIs. Thirty subjects were randomized to receive study medication (aged 18–45 years, 66.7% male). Mean plasma concentrations of 17-BMP after intranasal administration of BDP HFA (for both 80- and 320-μg doses) were substantially lower than that of orally inhaled BDP HFA (320 μg) across all time points. Mean AUClast values of 17-BMP for intranasal 80 μg, intranasal 320 μg, and orally inhaled 320 μg were 295.8, 1139.7, and 4140.3 pg·hr/mL, respectively. Mean Cmax values were 92.1, 262.7, and 1343.7 pg/mL, respectively. The GMR of AUClast for 17-BMP with intranasal BDP HFA 320 μg versus orally inhaled BDP HFA 320 μg was 0.275, indicating substantially lower systemic bioavailability with intranasal administration than with oral inhalation. Similarly, the GMR of AUClast for 17-BMP with intranasal BDP HFA 80 μg versus 320 μg was 0.260, suggesting approximate dose proportionality (4-fold difference). Pharmacokinetic results for BDP were similar to those seen for 17-BMP. All doses of intranasal and orally inhaled BDP HFA were well tolerated, and no treatment-related adverse events were reported. The results of this study suggest that 80 and 320 μg BDP HFA nasal aerosols have substantially lower systemic bioavailability than 320 μg orally inhaled BDP HFA in healthy subjects. All treatments were well tolerated. ClinicalTrials.gov identifier: NCT01537692.

This study evaluated the effects of yeast supplementation (YS) on trace mineral (TM) concentrations in blood serum, rumen fluid, and meat, as well as on the growth performance of lambs fed a total mixed ration (TMR). In addition, correlations among TM concentrations in different tissues were examined. A total of 24 healthy, growing lambs were randomly assigned to three groups (  = 8/group): YS0.00, YS1.50, and YS3.00 (0.00, 1.50, and 3.00 g yeast/lamb/day). Feed intake and body weight were monitored every four weeks during the 8-week trial. The samples of blood serum, rumen fluid, and meat were analyzed for Fe, Cu, Zn, I, Se, and Co using ICP-OES. In the YS3.00 group, yeast supplementation significantly increased overall roughage intake. However, it decreased feed efficiency, indicating that although animals consumed more, nutrient utilization efficiency was altered. The YS1.50 group showed significantly higher serum levels of Mn, Cu, and Se (  < 0.05). Rumen fluid TM concentrations were significantly affected by treatment, with lower values observed in the YS1.50 and YS3.00 groups compared to the YS0.00 group. A similar pattern was observed in meat, with the YS1.50 group showing significantly higher levels of most TMs, except for I and Cu. Strong positive correlations (  < 0.05) were found between rumen and meat TM concentrations for Mn, Fe, Se, and I, as well as between rumen fluid and serum for Fe and Cu. In conclusion, yeast supplementation at 1.50 g/day increased trace mineral concentrations in serum and meat, with the exception of I and Cu, and improved correlations between rumen fluid and meat for Mn, Fe, Se, and I, as well as between rumen fluid and serum, in the growing lambs.

This chapter focuses on the various prodrug approaches that have been used to overcome many of the pharmaceutical and pharmacokinetic barriers that hinder the optimal delivery of the active drug. The most important requirement in prodrug design is naturally the adequate reconversion of the prodrug to the active drug in vivo at the intended compartment. This prodrug‐drug conversion may take place before absorption, in the GI system, during absorption such as in the GI wall or skin, after absorption, or at the specific site of drug action. A number of enzymes can also be delivered to targeted tissues through antibodies or gene delivery approaches for the activation of subsequently administered prodrugs. Although they are of limited use in small‐molecule pro‐drugs, Schiff bases have been used to conjugate amine‐containing drugs to polymers with carbonyl groups as macromolecular prodrugs for slow release and targeting.

This chapter presents recent evidence to demonstrate that different anthocyanin (ANC) aglycones can differ markedly in terms of bioavailability, absorption, metabolism, metabolic breakdown products, and excretion to produce wide‐ranging impacts on human metabolic health and disease. In more recent years, stable isotope labeling has provided new insights into the complex issue of ANCs disposition after ingestion. ANC deposition in various tissues has been studied in animal models. Several studies have demonstrated that detectable levels of ANCs occur in brain tissue after ingestion. Modern nutritional supplementation with ANCs aimed at metabolic health promotion and disease risk reduction revealed several nutrigenomic biomarkers that might explain how an anthocyanin‐rich diet influences gene transcription, protein expression, and metabolism. Taken together, these new findings provide a strong scientific basis for developing new anthocyanin‐rich foods, cultivars of existing crops, and dietary supplements adapted to the specific needs of consumers and targeted to a specific group of metabolic risk factors.

The choice of a nebulized system for a patient usually depends on the equipment available. To date, there is limited guidance on the selection and use of a nebulizer. We have conducted in vitro tests described within the draft European Standard for Nebulisers (BSEN13544-1; CEN) and correlated these to in vivo pharmacokinetic performance of relative lung and systemic deposition in healthy volunteers. Eight nebulizer systems have been tested. The in vitro analysis used the recommended CEN methods to quantify the total dose available for inhalation as well as the size distribution from which the respirable dose was determined. The draft European Standard methods were slightly modified to use salbutamol rather than a fluoride tracer. For the in vivo study, nine volunteers provided urine samples after 30 min and then pooled for 24 h after the start of each nebulized dose (2.5 mg of salbutamol). Amounts of salbutamol and its metabolite excreted in the urine samples were determined. There was a significant (p = 0.02) correlation between the in vitro respirable dose and the amount of salbutamol excreted in the urine 30 min after the start of nebulization (relative bioavailability of salbutamol to the lung). Also, there was a significant (p < 0.001) correlation between the in vitro dose available for inhalation and the total amount of salbutamol and its metabolites excreted over the 24 h after the start of nebulization (relative bioavailability of salbutamol to the body). The results demonstrate that in vivo/in vitro correlations exist and warrant further investigations. The in vitro methods require further validation with in vivo correlations using patients with different severities of airway obstruction.

This chapter contains sections titled: Introduction Scientific disciplines involved Summary and outlook References

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disease with unknown etiology characterized by multi-organ fibrosis. Despite substantial investigation on SSc-related cellular and molecular mechanisms, effective therapies are still lacking. The skin, lungs, and gut are the most affected organs in SSc, which act as physical barriers and constantly communicate with colonized microbiota. Recent reports have documented a unique microbiome signature, which may be the pathogenic trigger or driver of SSc. Since gut microbiota influences the efficacy and toxicity of oral drugs, evaluating drug–microbiota interactions has become an area of interest in disease treatment. The existing evidence highlights the potential of the microbial challenge as a novel therapeutic option in SSc. In this review, we have summarized the current knowledge about molecular mechanisms of SSc and highlighted the underlying role of the microbiome in SSc pathogenesis. We have also discussed the latest therapeutic interventions using microbiomes in SSc, including drug–microbiota interactions and animal disease models. This review aims to elucidate the pathophysiological connection and therapeutic potential of the microbiome in SSc. Insights into the microbiome will significantly improve our understanding of etiopathogenesis and developing therapeutics for SSc.