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Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

ABSTRACT: Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively (P < 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection in ex vivo challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.

SUBMITTER: Xiao P

PROVIDER: S-EPMC5740373 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

Xiao Peng P Gumber Sanjeev S Marzinke Mark A MA Date Abhijit A AA Hoang Thuy T Hanes Justin J Ensign Laura M LM Wang Lin L Rohan Lisa L Fuchs Edward J EJ Hendrix Craig C Villinger Francois F

Antimicrobial agents and chemotherapy 20171221 1

Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and <i>ex vivo</i> efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of I ...[more]

PMID: 29084755

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Project description:Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive spectroscopic technique that generates signal-enhanced fingerprint vibrational spectra of small molecules. However, without rigorous control of SERS substrate active sites, geometry, surface area, or surface functionality, SERS is notoriously irreproducible, complicating the consistent quantitative analysis of small molecules. While evaporatively prepared samples yield significant SERS enhancement resulting in lower detection limits, the distribution of these enhancements along the SERS surface is inherently stochastic. Acquiring spatially resolved SERS spectra of these dried surfaces, we have shown that this enhancement is governed by a power law as a function of analyte concentration. Consequently, by definition, there is no true mean of SERS enhancement, requiring an alternative approach to achieve reproducible quantitative results. In this study, we introduce a new method of analysis of SERS data using a cumulative distribution function (CDF). The antiviral drug tenofovir (TFV) in an aqueous matrix was quantified down to a clinically relevant concentration of 25 ng/mL using hydroxylamine-reduced silver colloids evaporated to dryness. The data presented in this study provide a rationale for the benefits of combining a novel statistical approach using CDFs with simple and inexpensive experimental techniques to increase the precision, accuracy, and analytical sensitivity of aqueous TFV quantification by SERS. TFV calibration curves generated using CDF analysis showed higher analytical sensitivity (in the form of a normalized calibration curve average slope increase of 0.25) compared to traditional SERS intensity calculations. A second aliquot of nanoparticles and analyte dried on the SERS surface followed by CDF analysis showed further analytical sensitivity with a normalized calibration curve slope increase of 0.23 and decreased variation among replicates represented by an average standard deviation decrease of 0.02 with a second aliquot. The quantitative analysis of SERS data using CDFs presented here shows promise to be a reproducible method for quantitative analysis of SERS data, a significant step toward implementing SERS as an analytical method in clinical and industrial settings.

Project description:BackgroundReduction of gross diarrhea rate in excess of that seen over time with intravenous therapy and appropriate antibiotics is not usually achieved by oral glucose-electrolyte rehydration therapy for cholera and cholera-like diarrheas.Methodology and principal findingsThis prospective randomized clinical trial at a tertiary referral hospital in southern India was undertaken to determine whether amylase resistant starch, substituting for glucose in hypo-osmolar oral rehydration solution, would reduce diarrhea duration and weight in adults with acute severe dehydrating diarrhea. 50 adult males with severe watery diarrhea of less than three days' duration and moderate to severe dehydration were randomized to receive hypo-osmolar ORS (HO-ORS) or HO-ORS in which amylase resistant high amylose maize starch 50g/L substituted for glucose (HAMS-ORS). All remaining therapy followed standard protocol. Duration of diarrhea (ORS commencement to first formed stool) in hours was significantly shorter with HAMS-ORS (median 19, IQR 10-28) compared to HO-ORS (median 42, IQR 24-50) (Bonferroni adjusted P, P(adj)<0.001). Survival analysis (Kaplan-Meier) showed faster recovery from diarrhea in the HAMS-ORS group (P<0.001, log rank test). Total diarrhea fecal weight in grams (median, IQR) was not significantly lower in the HAMS-ORS group (2190, 1160-5635) compared to HO-ORS (5210, 2095-12190) (P(adj) = 0.08). However, stool weight at 13-24 hours (280, 0-965 vs. 1360, 405-2985) and 25-48 hours (0, 0-360 vs. 1080, 55-3485) were significantly lower in HAMS-ORS compared to HO-ORS group (P(adj) = 0.048 and P = 0.012, respectively). ORS intake after first 24 hours was lower in the HAMS-ORS group. Subgroup analysis of patients with culture isolates of Vibrio cholerae indicated similar significant differences between the treatment groups.ConclusionsCompared to HO-ORS, HAMS-ORS reduced diarrhea duration by 55% and significantly reduced fecal weight after the first 12 hours of ORS therapy in adults with cholera-like diarrhea.Trial registrationCurrent Controlled Trials ISRCTN72841333.

Dataset Information

Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

Publications

Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

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