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Using modeling to help understand vaginal microbicide functionality and create better products.

ABSTRACT: A summary is presented of a range of mathematical models that relate to topical microbicidal molecules, applied vaginally to inhibit HIV transmission. These models contribute to the fundamental understanding of the functioning of those molecules, as introduced in different delivery systems. They also provide computational tools that can be employed in the practical design and evaluation of vaginal microbicide products. Mathematical modeling can be implemented, using stochastic principles, to understand the probability of infection by sexually transmitted HIV virions. This provides a frame of reference for the deterministic models of the various processes that underlie HIV transmission and its inhibition, including: the temporal and spatial history of HIV migration from semen to vaginal epithelial surfaces and thence to the underlying stroma; the time and spatial distribution of microbicidal drugs as delivered by various vehicles (e.g., gels, rings, films, and tablets)-this is central to understanding microbicide product pharmacokinetics; and the time and space history of the drug interactions with HIV directly and with host cells for HIV within the vaginal environment-this informs the understanding of microbicide pharmacodynamics. Models that characterize microbicide functionality and performance should and can interface with both in vitro and in vivo experimental studies. They can serve as a rapidly applied, inexpensive tool, to facilitate microbicide R&D, in advance of more costly and time consuming clinical trials.

SUBMITTER: Katz DF

PROVIDER: S-EPMC3337038 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Using modeling to help understand vaginal microbicide functionality and create better products.

Katz David F DF Gao Yajing Y Kang Meng M

Drug delivery and translational research 20110517 3

A summary is presented of a range of mathematical models that relate to topical microbicidal molecules, applied vaginally to inhibit HIV transmission. These models contribute to the fundamental understanding of the functioning of those molecules, as introduced in different delivery systems. They also provide computational tools that can be employed in the practical design and evaluation of vaginal microbicide products. Mathematical modeling can be implemented, using stochastic principles, to und ...[more]

PMID: 22545245

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Project description:Treatment for osteoporosis in the community in patients who were operated for hip fracture appears to be suboptimal at best. Evidence regarding treatment beyond the 1st year after surgery is scarce. We examined the association between discharge recommendations for treatment of osteoporosis in patients suffering from hip fractures and treatment beyond the 1st year.We performed a retrospective observational cohort study in patients age 50 to 90 years operated for osteoporotic hip fractures between the years 2008 and 2014. We investigated the correlation between discharge recommendations and rates of osteoporosis treatment postdischarge 1 to 7 years, and the influence of osteoporosis diagnosis upon treatment. Exclusion criteria besides age included high-energy trauma, pathologic or periprosthetic fractures, and patients deceased within 1-year postsurgery.A total of 602 patient files were examined. Univariate analysis showed that, of 283 patients who were prescribed dietary supplementation of vitamin D and calcium, a significantly higher percentage of patients received treatment if they had a recommendation (50.3% vs 36.1%, P = 0.0005), were diagnosed (43.8% vs 14.4%, P?<?0.0001), or were of female gender (84.1% vs 57.3%, P?<?0.0001). Multivariate analysis showed that the odds ratio (OR) for receiving treatment compared with the control group (patients without a recommendation and a diagnosis) was higher among patients who had both a recommendation and a treatment (OR = 5.4, P?<?0.0001) than the group with a diagnosis only (OR = 4.75, P?<?0.0001) or a recommendation only (OR = 2.06, P = 0.0006).A formal recommendation for osteoporosis treatment in the discharge letters of patients who suffered hip fragility fractures increases treatment rate of osteoporosis in the community compared with patients without a recommendation. Patients who receive such a recommendation but also have a formal coded diagnosis of osteoporosis in their medical files have an even higher chance of receiving treatment in the community. Our observations may assist in amplifying the overall treatment rates, which are still undoubtedly low.

Project description:Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection ("percent protected"). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.

Dataset Information

Using modeling to help understand vaginal microbicide functionality and create better products.

Publications

Using modeling to help understand vaginal microbicide functionality and create better products.

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