Quantification of Chemical Uptake into the Skin by Vibrational Spectroscopies and Stratum Corneum Sampling.

Evaluation of the bioavailability of drugs intended to act within the skin following the application of complex topical products requires the application of multiple experimental tools, which must be quantitative, validated, and, ideally and ultimately, sufficiently minimally invasive to permit use in vivo. The objective here is to show that both infrared (IR) and Raman spectroscopies can assess the uptake of a chemical into the stratum corneum (SC) that correlates directly with its quantification by the adhesive tape-stripping method. Experiments were performed ex vivo using excised porcine skin and measured chemical disposition in the SC as functions of application time and formulation composition. The quantity of chemicals in the SC removed on each tape-strip was determined from the individually measured IR and Raman signal intensities of a specific molecular vibration at a frequency where the skin is spectroscopically silent and by a subsequent conventional extraction and chromatographic analysis. Correlations between the spectroscopic results and the chemical quantification on the tape-strips were good, and the effects of longer application times and the use of different vehicles were clearly delineated by the different measurement techniques. Based on this initial investigation, it is now possible to explore the extent to which the spectroscopic approach (and Raman in particular) may be used to interrogate chemical disposition deeper in the skin and beyond the SC.

Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling.

Predicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm-2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h "uptake" period, and (b) following a 6-h "clearance" period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm-2 dose compared to those of 2 and 10 mg cm-2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm-2 h-1 and 0.07 h-1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined.

Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

Modeling the Effect of HIV/AIDS Stigma on HIV Infection Dynamics in Kenya.

Stigma toward people living with HIV/AIDS (PLWHA) has impeded the response to the disease across the world. Widespread stigma leads to poor adherence of preventative measures while also causing PLWHA to avoid testing and care, delaying important treatment. Stigma is clearly a hugely complex construct. However, it can be broken down into components which include internalized stigma (how people with the trait feel about themselves) and enacted stigma (how a community reacts to an individual with the trait). Levels of HIV/AIDS-related stigma are particularly high in sub-Saharan Africa, which contributed to a surge in cases in Kenya during the late twentieth century. Since the early twenty-first century, the United Nations and governments around the world have worked to eliminate stigma from society and resulting public health education campaigns have improved the perception of PLWHA over time, but HIV/AIDS remains a significant problem, particularly in Kenya. We take a data-driven approach to create a time-dependent stigma function that captures both the level of internalized and enacted stigma in the population. We embed this within a compartmental model for HIV dynamics. Since 2000, the population in Kenya has been growing almost exponentially and so we rescale our model system to create a coupled system for HIV prevalence and fraction of individuals that are infected that seek treatment. This allows us to estimate model parameters from published data. We use the model to explore a range of scenarios in which either internalized or enacted stigma levels vary from those predicted by the data. This analysis allows us to understand the potential impact of different public health interventions on key HIV metrics such as prevalence and disease-related death and to see how close Kenya will get to achieving UN goals for these HIV and stigma metrics by 2030.

Approximating optimal controls for networks when there are combinations of population-level and targeted measures available: chlamydia infection as a case-study.

Using a modified one-dimensional model for the spread of an SIS disease on a network, we show that the behaviour of complex network simulations can be replicated with a simpler model. This model is then used to design optimal controls for use on the network, which would otherwise be unfeasible to obtain, resulting in information about how best to combine a population-level random intervention with one that is more targeted. This technique is used to minimise intervention costs over a short time interval with a target prevalence, and also to minimise prevalence with a specified budget. When applied to chlamydia, we find results consistent with previous work; that is maximising targeted control (contact tracing) is important to using resources effectively, while high-intensity bursts of population control (screening) are more effective than maintaining a high level of coverage.

Exploring short-term responses to changes in the control strategy for Chlamydia trachomatis.

Chlamydia has a significant impact on public health provision in the developed world. Using pair approximation equations we investigate the efficacy of control programmes for chlamydia on short time scales that are relevant to policy makers. We use output from the model to estimate critical measures, namely, prevalence, incidence, and positivity in those screened and their partners. We combine these measures with a costing tool to estimate the economic impact of different public health strategies. Increasing screening coverage significantly increases the annual programme costs whereas an increase in tracing efficiency initially increases annual costs but over time reduces costs below baseline, with tracing accounting for around 10% of intervention costs. We found that partner positivity is insensitive to changes in prevalence due to screening, remaining at around 33%. Whether increases occur in screening or tracing levels, the cost per treated infection increases from the baseline because of reduced prevalence.

Modelling formation of a drug reservoir in the stratum corneum and its impact on drug monitoring using reverse iontophoresis.

Reverse iontophoresis is a relatively new technique for non-invasive drug monitoring in the body. It involves a small electrical current being passed through the skin to facilitate the movement of small charged ions and polar molecules on the skin's surface where the amount of drug can then be measured and hence an accurate estimate of the blood concentration can be made. In vivo studies for several molecules show that initially large amounts of drug are extracted from the body, which are unrelated to the magnitude of the blood concentration; over time the fluxes of extraction decrease to a level proportional to the steady state blood concentration. This suggests that, at first, the drug is being extracted from some source other than the blood; one such candidate for this source is the dead cells which form the stratum corneum. In this paper, we construct two related mathematical models; the first describes the formation of the drug reservoir in the stratum corneum as a consequence of repeated drug intake and natural death of skin cells in the body. The output from this model provides initial conditions for the model of reverse iontophoresis in which charged ions from both the blood and the stratum corneum reservoir compete for the electric current. Model parameters are estimated from data collected for lithium monitoring. Our models will improve interpretation of reverse iontophoretic data by discriminating the subdermal from the skin contribution to the fluxes of extraction. They also suggest that analysis of the skin reservoir might be a valuable tool to investigate patients' exposure to chemicals including therapeutic drugs.

Exploring the impact of target cell heterogeneity on HIV loads in a within-host model.

HIV can be transmitted from blood plasma or semen of an infected male. Viral loads in blood plasma are routinely measured, but the same is not true of semen. Even before drug treatment, viral loads have been shown to be different in the two body compartments (blood and genital tract), and this heterogeneity may be exacerbated by treatments using those antiretroviral drugs which have different efficacies in the two compartments. In addition to this heterogeneity, and despite highly effective drugs (in the blood) low-level viral replication is commonly reported for HIV patients as are differences in drug resistant mutation patterns in the two compartments. In this paper we investigate the effect of target cell heterogeneity between compartments on HIV viral loads using a within-host model that includes wildtype and drug resistant strains of HIV. We find that modelling target cell heterogeneity in the blood and male genital tract gives different viral loads in the two compartments prior to treatment and allows low-level viral loads to persist during therapy even if drug penetration is good. The model also allows coexistence of the two viral strains (in the absence of a mutation mechanism) with different dominance patterns in each body compartment. Our results suggest that monitoring of blood plasma viral strains may not give an accurate picture of the strains of HIV being transmitted between individuals and that continued research into the nature of HIV target cells in the male genital tract would be beneficial.

Relating coupled map lattices to integro-difference equations: dispersal-driven instabilities in coupled map lattices.

Recently there has been a great deal of interest within the ecological community about the interactions of local populations that are coupled only by dispersal. Models have been developed to consider such scenarios but the theory needed to validate model outcomes has been somewhat lacking. In this paper, we present theory which can be used to understand these types of interaction when population exhibit discrete time dynamics. In particular, we consider a spatial extension to discrete-time models, known as coupled map lattices (CMLs) which are discrete in space. We introduce a general form of the CML and link this to integro-difference equations via a special redistribution kernel. General conditions are then derived for dispersal-driven instabilities. We then apply this theory to two discrete-time models; a predator-prey model and a host-pathogen model.

Applications of biological control in resistant host-pathogen systems.

Insect pest species can have devastating effects on crops. Control of these insect pests is usually achieved by using chemical insecticides. However, there has been much cause for concern with their overuse. Consequently, research has been carried out into alternative forms of control, in particular biological control methods. Recent laboratory studies have indicated that these natural forms of control can induce resistant strains of insect pest. In this paper we present a discrete-time host-pathogen model to describe the interaction between a host (insect species) that can develop a resistant strain and a pathogen (biological control) that can be externally applied to the system. For this model we use a single-state variable for the host population. We show that the proportion of resistance in the population impacts on the viability of the host population. Moreover, when the host population does persist, we explore the interaction between host susceptibility and host population levels. The different scenarios which arise are explained ecologically in terms of trade-offs in intrinsic growth rates, disease susceptibility and intraspecific host competition for the resistant subclass.