Evidence for proton-pump inhibitor (PPI)-associated dysbiosis in metabolically unhealthy obesity.

Obesity adversely impacts millions of American adults by predisposing them to significant health risks and further complications. Obesity is differentiated into two groups: metabolically healthy and metabolically unhealthy. In contrast to metabolically healthy counterparts, obese individuals who are metabolically unhealthy display hallmark symptoms of metabolic syndrome (e.g., hypertension, dyslipidemia, hyperglycemia, abdominal obesity). Gastroesophageal reflux disease (GERD) commonly occurs in all obese populations, as do poor dietary habits. Proton-pump inhibitors (PPIs), due to their wide availability, are most often used to treat GERD-related heartburn and other symptoms. Here, we review the evidence on how poor diet as well as short- and long-term use of PPIs adversely affect the gastrointestinal microbiota to cause dysbiosis. Key components of dysbiosis-induced metabolically unhealthy obesity (MUO) associated with PPI use include "leaky gut," systemic low-grade inflammation, and reduced amounts of short-chain fatty acids (SCFAs) such as butyrate that promote metabolic health. The benefit of using probiotics to mitigate PPI-induced dysbiosis and MUO is also discussed.

The pharmacist's role in reducing infusion-related phlebitis.

PURPOSE: Pharmacists oversee parenteral drug preparation and administration in hospitals, clinics, infusion centers, and home infusion settings. Infusion-related phlebitis (IRP), the most common complication of intravenous infusion therapy, significantly impacts therapeutic outcomes, patient satisfaction, cost of care, and provider workload. Here we review the major etiologies of IRP and describe potential pharmacological and nonpharmacological interventions for preventing and managing the condition as well as for improving vascular access health in multiple-drug administration settings. SUMMARY: Many parenterally administered drugs cause phlebitis due to mechanical, chemical, or infectious etiologies. Pharmacists can recommend nonpharmacological strategies to mitigate phlebitis, including -judicious device selection and placement; adjustment of the drug concentration, flow rate, or formulation; infusion site rotation; and use of inline filters to minimize contaminant particulates. Pharmacological treatments for phlebitis include topical, local, and systemic anti-inflammatory and analgesic agents that can reduce symptom severity and prevent further treatment complications or delays. CONCLUSION: Pharmacists can contribute a unique perspective to interprofessional teams tasked with making policy and formulary decisions that minimize the negative impacts of IRP on drug delivery and patient outcomes.

Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers.

STUDY OBJECTIVE: To evaluate the effect of repeated ingestion of grapefruit juice on the systemic availability of itraconazole (ITZ) and hydroxyitraconazole (OHITZ) serum concentrations in subjects administered hydroxypropyl-beta-cyclodextrin-ITZ (HP-beta-CD ITZ) oral solution. DESIGN: Randomized, two-period, crossover study. SETTING: College of pharmacy research unit. SUBJECTS: Twenty healthy, adult volunteers (10 men, 10 women). INTERVENTION: Subjects received 240 ml of regular-strength grapefruit juice from frozen concentrate or bottled purified water 3 times/day for 2 days. On the third day they received a single dose of HP-beta-CD ITZ oral solution 200 mg (20 ml) with 240 ml of the beverage. Two hours after dosing they received another 240 ml of the beverage. MEASUREMENTS AND MAIN RESULTS: Repeated blood samples were drawn for 72 hours after dosing. After a 14-day washout period, subjects were crossed over to the beverage they had not received previously and the above procedure was repeated. There was no difference in peak ITZ concentration (Cmax) or time to Cmax (Tmax). Coadministration of grapefruit juice reduced OHITZ Cmax nearly 10%, but this difference was not statistically significant. It produced a statistically significant increase in ITZ area under the concentration-time curves from 0-48 hours (AUC(0-48)) (17%) and from time zero extrapolated to infinity (AUC(0-infinity)) (19.5%). Apparent oral clearance of ITZ was significantly reduced (14%). Significant changes in OHITZ exposure were not observed; however, grapefruit juice coadministration produced statistically significant decreased mean OHITZ:ITZ AUC(0-48) and AUC(0-infinity) ratios. Grapefruit juice also decreased the mean OHITZ:ITZ Cmax ratio, but the difference was not statistically significant. CONCLUSION: Repeated grapefruit juice consumption moderately affects ITZ systemic availability in subjects administered HP-beta-CD ITZ oral solution. Unlike previous findings with ITZ capsules, changes in the disposition of ITZ and OHITZ after repeated grapefruit juice consumption are consistent with grapefruit juice inhibition of intestinal cytochrome P450 3A4.

Percutaneous permeation of enantiomers and racemates of chiral drugs and prediction of their flux ratios using thermal data: a pharmaceutical perspective.

Albeit pharmacological, pharmacokinetic, and toxicological differences between enantiomeric pairs or between the pure enantiomers and racemate of chiral drugs are known to exist for decades, we are just beginning to realize that there are apparent differences between these species with respect to their percutaneous permeation as well. Such differences in permeation are likely to be enhanced when chiral drugs are formulated with chiral excipients, necessitating a careful assessment of the effect of formulation excipients on the permeation as well as the overall therapeutic outcomes. The in vitro transport data from the preclinical investigations, using laboratory animal models and/or in vitro cell culture systems, must be carefully validated in vivo as there are differences between these models and the human skin. Mathematical models such as MTMT that utilize the interdependence of certain physicochemical characteristics and percutaneous permeability have a predictive value in assessing the flux behavior of enantiomers and racemates.

Effect of Azone upon the in vivo antiviral efficacy of cidofovir or acyclovir topical formulations in treatment/prevention of cutaneous HSV-1 infections and its correlation with skin target site free drug concentration in hairless mice.

The purpose of this study is to examine the influence of Azone upon the skin target site free drug concentration (C(*)) and its correlation with the in vivo antiviral efficacies of cidofovir (HPMPC) and acyclovir (ACV) against HSV-1 infections. Formulations of HPMPC and ACV with or without Azone were used. The in vitro skin flux experiments were performed and the C(*) values were calculated. For the in vivo efficacy studies, hairless mice cutaneously infected with HSV-1 were used and three different treatment protocols were carried out. The protocols were chosen based upon when therapy is initiated and terminated in such a way to assess the efficacy of the test drug to cure and/or prevent HSV-1 infections. A finite dose of the formulation was topically applied twice a day for the predetermined time course for each protocol and the lesions were scored on the fifth day. For ACV formulation with Azone, the C(*) values and hence the in vivo efficacy were much higher than those for that without Azone. In protocol #1, however, early treatment did not increase the in vivo efficacy of ACV when compared with the standard treatment protocol #3. In protocol #2 where the treatment was terminated on the day of virus inoculation, the efficacies for both ACV formulations were completely absent. Although the estimated C(*) values for HPMPC formulations with and without Azone were comparable, formulation with Azone was much more effective than that without Azone in all treatment protocols. HPMPC formulations with Azone at similar flux values were much more effective in "treating and preventing" HSV-1 infections than those without Azone. For ACV formulations, in contrast, addition of Azone has failed to show any effect on the preventive in vivo antiviral efficacy and the enhancement of ACV in vivo antiviral efficacy was merely the skin permeation enhancement effect of Azone.