Biomedical subjects

M S Roberts

Publications and source records attributed to M S Roberts.

At least 55 records · Page 3Linked to original sources

PubMed2000

Antiviral therapies for herpes zoster infections. Are they economically justifiable?

Antiviral treatment of herpes zoster is controversial because of uncertain benefits and relatively high costs. Most studies show that antiviral therapy lessens acute herpes zoster symptoms and postherpetic neuralgia (PHN). Current clinical recommendations support antiviral treatment of severely symptomatic herpes zoster in all adults, and mild herpes zoster in those 50 or 60 years of age or older. However, it is unclear if these recommended strategies are cost effective. Published studies of herpes zoster costs and the effect of antiviral therapy on costs and quality of life have significant variation in study design and results, as well as many shortcomings in the data. Thus, definitive economic recommendations cannot be made based on the present data. Another approach, which we have used, is to develop a 'reference case' analysis using decision-analysis techniques and the available data to estimate the incremental cost effectiveness of antiviral treatment in patients of differing age and herpes zoster severity. In the baseline analysis, parameter values and assumptions were consistently slightly biased against antiviral use. Effectiveness was measured in quality-adjusted life years (QALYs). We assumed that antiviral treatment did not change PHN risk, but decreased PHN duration in patients older than 50 years. PHN risk increased with age and with acute herpes zoster severity as seen in published data. Mild acute herpes zoster was assumed to have a utility value of 0.9 and severe acute herpes zoster a value of 0.7 on a scale where 0 = death and 1 = perfect health. Treating mildly symptomatic acute herpes zoster cost $US89,200/QALY gained in 40-year-olds, $US47,700/QALY in 60-year-olds and $US40,700/QALY in 70-year-olds (1995 values). Results were most sensitive to variation of antiviral costs (baseline $US134), but changes in acute symptom relief, PHN risk, duration, costs and utility, and antiviral effect on PHN duration increased costs/QALY above $US50,000 in 60- and 70-year-olds in extremes of parameter ranges. However, no variation resulted in treatment of mild illness in 40-year-olds to fall below $US50,000/QALY gained. Treatment of severe acute herpes zoster cost $US29,700, $US18,000 and $US16,500/QALY gained in 40-, 60- and 70-year-olds, respectively. Results were sensitive to variation of antiviral costs (> $US225) and acute symptom relief (< 21%) in 40-year-olds. Based on this analysis, antiviral therapy of herpes zoster seems economically justifiable for mildly symptomatic acute herpes zoster in patients aged 50 years and older, and for severely symptomatic acute herpes zoster in all adults.

Acute Disease↗

PubMed2000

Experimental methods for studying drug uptake in the head and brain.

A number of techniques have been developed to study the disposition of drugs in the head and, in particular, the role of the blood-brain barrier (BBB) in drug uptake. The techniques can be divided into three groups: in-vitro, in-vivo and in-situ. The most suitable method depends on the purpose(s) and requirements of the particular study being conducted. In-vitro techniques involve the isolation of cerebral endothelial cells so that direct investigations of these cells can be carried out. The most recent preparations are able to maintain structural and functional characteristics of the BBB by simultaneously culturing endothelial cells with astrocytic cells. The main advantages of the in-vitro methods are the elimination of anaesthetics and surgery. In-vivo methods consist of a diverse range of techniques and include the traditional Brain Uptake Index and indicator diffusion methods, as well as microdialysis and positron emission tomography. In-vivo methods maintain the cells and vasculature of an organ in their normal physiological states and anatomical position within the animal. However, the shortcomings include renal and hepatic elimination of solutes as well as the inability to control blood flow. In-situ techniques, including the perfused head, are more technically demanding. However, these models have the ability to vary the composition and flow rate of the artificial perfusate. This review is intended as a guide for selecting the most appropriate method for studying drug uptake in the brain.

Animals↗

PubMed2000

Can tissue drug concentrations be monitored by microdialysis during or after isolated limb perfusion for melanoma treatment?

Isolated limb perfusion (ILP) with melphalan is used to treat recurrent melanoma. This study aimed to develop a microdialysis technique for melphalan tissue concentration measurement during ILP. The effects of melphalan concentration (50-600 microg/ml), microdIalysis flow rate (0.55-17.5 microl/min), probe length (5-50 mm) and temperature (25-41.5 degrees C) on in vitro recovery were studied. In addition, in vivo recovery was measured in rat hindlimbs perfused with melphalan using 50 mm microdialysis probes implanted subcutaneously and into muscle. Both dialysate and tissue sample melphalan concentrations were determined by high performance liquid chromatography. The in vitro recovery of melphalan was not affected by melphalan concentration or temperature, but increased with probe length and decreased with flow rate. The melphalan concentrations in subcutaneous and muscle dialysates were not significantly different. A linear relationship was found between tissue dialysate concentrations and actual tissue concentrations of melphalan (r2 = 0.97). Microdialysis is a potential method for tissue drug monitoring which may assist in the efficacious use of cytotoxics in human ILP.

Animals↗

PubMed1999

The back diffusion of glucose across human skin in vitro.

For diabetic patients, blood glucose monitoring is an important part in the management of their disease, however the acquisition of blood requires the use of invasive and often painful methods, and the development of a technique that removes these problems would represent a major advance. The uppermost membrane of the skin, the stratum corneum, has been shown to be the main barrier to percutaneous absorption, but there have been claims that polar water-soluble compounds diffuse across it via aqueous pathways. In this study, skin diffusion cells were used to investigate the back diffusion of tritiated water and the convective transport of 3H-glucose across full thickness human skin after the application of a number of different materials to the stratum corneum. Significant amounts of 3H-glucose back diffused only after complete removal of the stratum corneum by tape stripping, and it is likely that any future attempts to monitor blood glucose levels using non-physical techniques will require a certain degree of damage to the stratum corneum. The extraction through the skin of tritiated water and 3H-glucose after the application of solutions with different osmotic pressures were consistent with the theory that solutions with high osmotic pressures dehydrate the stratum corneum which suggests that passive transport of these radiolabelled molecules through porous pathways was insignificant.

Blood Glucose↗

PubMed1999

Behavior and therapeutic efficacy of beta-glucuronidase-positive mononuclear phagocytes in a murine model of mucopolysaccharidosis type VII.

Bone marrow transplantation (BMT) is relatively effective for the treatment of lysosomal storage diseases. To better understand the contribution of specific hematopoietic lineages to the efficacy of BMT, we transplanted beta-glucuronidase-positive mononuclear phagocytes derived from either the peritoneum or from bone marrow in vitro into syngeneic recipients with mucopolysaccharidosis type VII (MPS VII). Cell surface marking studies indicate that the bone marrow-derived cells are less mature than the peritoneal macrophages. However, both cell types retain the ability to home to tissues rich in cells of the reticuloendothelial system after intravenous injection into MPS VII mice. The half-life of both types of donor macrophages is approximately 7 days, and some cells persist for at least 30 days. In several tissues, therapeutic levels of beta-glucuronidase are present, and histopathologic analysis demonstrates that lysosomal storage is dramatically reduced in the liver and spleen. Macrophages intravenously injected into newborn MPS VII mice localize to the same tissues as adult mice but are also observed in the meninges and parenchyma of the brain. These data suggest that macrophages play a significant role in the therapeutic efficacy of BMT for lysosomal storage diseases and may have implications for treatments such as gene therapy.

Animals↗

PubMed1999

Interconnected-tubes model of hepatic elimination: steady-state considerations.

In the interconnected-tubes model of hepatic transport and elimination, intermixing between sinusoids was modelled by the continuous interchange of solutes between a set of parallel tubes. In the case of strongly interconnected tubes and for bolus input of solute, a zeroth-order approximation led to the governing equation of the dispersion model. The dispersion number was expressed for the first time in terms of its main physiological determinants: heterogeneity of flow and density of interconnections. The interconnected-tubes model is now applied to steady-state hepatic extraction. In the limit of strong interconnections, the expression for output concentrations is predicted to be similar in form to those predicted by the distributed model for a narrow distribution of elimination rates over sinusoids, and by the dispersion model in the limit of a small dispersion number D(N). More generally, the equations for the predicted output concentrations can be expressed in terms of a dimensionless 'heterogeneity number'H(N), which characterizes the combined effects of variations in enzyme distribution and flow rates between different sinusoids, together with the effects of interconnections between sinusoids. A comparative analysis of the equations for the dispersion and heterogeneity numbers shows that the value of H(N)can be less than, greater than or equal to the value of D(N)for a correlation between distributions of velocities and elimination rates over sinusoids, anticorrelation between them, and when all sinusoids have the same elimination rate, respectively. Simple model systems are used to illustrate the determinants of H(N)and D(N).

Animals↗

PubMed1999

Structure-hepatic disposition relationships for phenolic compounds.

Phenolic compounds are widely used in therapeutic, environmental, and industrial applications. The present work seeks to define the hepatic disposition of 11 phenolic compounds with varying lipophilicities and molecular weights. The hepatic disposition kinetics were studied in a once-through in situ rat liver perfusion preparation in order to avoid extra-hepatic metabolism and recirculation effects. The phenols were administered using the impulse-response technique and the time course of hepatic venous effluent concentration was examined by moments and a two-compartment dispersion model. While the extraction of the phenolic compounds was relatively independent of lipophilicity, the estimated permeability-surface area (PS) product for influx of solutes into the hepatocytes could be related to the compounds' octanol-buffer partition coefficients (log Papp). This log PS-logPapp relationship was consistent with that reported earlier for another series of solutes with a wide range of lipophilicity. The metabolites produced from each of the phenolic compounds used in this study had mean transit times similar to those of their corresponding parent phenols, suggesting that the metabolites were not trapped in the liver as a consequence of their higher polarity. It is concluded that the strong solute lipophilicity-toxicity and lipophilicity-skin penetration relationships often seen for aqueous solutions of phenols are not evident for the hepatic extraction of these compounds. Such a conclusion is consistent with the hepatic extraction of phenolic compounds being mainly determined by a blood flow limitation in delivery of the phenol to the liver, rather than the intrinsic liver metabolic enzyme activities at the doses injected.

Anesthesia↗

PubMed1999

An analysis of solute structure-human epidermal transport relationships in epidermal iontophoresis using the ionic mobility: pore model.

This study sought to examine the extent the ionic mobility-pore model, used to describe epidermal iontophoretic structure-permeability relationships, could describe a range of published iontophoretic data. The model incorporates, as determinants of iontophoretic transport, solute size, solute mobility, total current applied, presence of extraneous ions, determined by conductivities of both donor and receptor solutions, permselectivity of the epidermis, as well as a solute pore interaction term which together provided an excellent regression for iontophoretic permeability. The 'pore' radii for solute transport estimated from literature iontophoretic permeabilities using the model ranged from 6.8 to 17 A depending on the degree of hydration and conformation of solute assumed. The pore size range is consistent with transport through the polar intercellular and transappendageal pathway for transport. The pore restriction form of the model better describes the data obtained to date than other models described previously (Yoshida, N.H., Roberts, M.S., Solute molecular size and transdermal iontophoresis across excised human skin. J. Control. Release 25 (1993) 177-195).

Epidermis↗

PubMed1999

Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control?

Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR or IR oxycodone (maximum dose, 400 mg/day) for a period of up to 21 days. In a study of similar design, 57 patients with low back pain were titrated with either CR or IR oxycodone (maximum dose, 80 mg/day) for a period of up to 10 days. The majority of patients in both studies were converted to oxycodone from other opioid analgesics. Results of both studies showed no difference between CR and IR oxycodone with respect to both the percentage of patients achieving stable pain control, the time to achieve stable pain control, and the degree of pain control achieved. Among cancer patients, 85% achieved stable analgesia, 92% with the CR formulation and 79% with the IR formulation. Among noncancer patients, 91% achieved stable pain control, 87% with the CR formulation and 96% with the IR formulation. The most commonly reported adverse effects in both studies were similar for the two formulations and were those anticipated with opioids: nausea, vomiting, constipation, somnolence, dizziness, and pruritus. Nausea and vomiting were the most frequently cited reasons for treatment discontinuations. These studies suggest that dose titration can be accomplished as readily with oral CR oxycodone as with IR oxycodone in patients with chronic, moderate to severe pain.

Adult↗

PubMed1999

Diffusion modeling of percutaneous absorption kinetics. 1. Effects of flow rate, receptor sampling rate, and viable epidermal resistance for a constant donor concentration.

A diffusion model for the percutaneous absorption of a solute through the skin is developed for the specific case of a constant donor concentration with a finite removal rate from the receptor due to either perfusion rate or sampling. The model has been developed to include a viable epidermal resistance and a donor-stratum corneum interfacial resistance. Numerical inversion of the Laplace domain solutions were used for simulations of solute flux and cumulative amount absorbed and to model specific examples of percutaneous absorption. Limits of the Laplace domain solutions were used to define the steady-state flux, lag time, and receptor concentration. Steady-state approximations obtained from the solutions were used to relate the steady-state flux and the effective permeability coefficient to the viable epidermis resistance, a donor-stratum corneum interfacial resistance, receptor removal rate, and partitioning between the receptor and donor phases. The lag time was shown to be dependent on these parameters and on the volume of the receptor phase. It is concluded that curvilinear cumulative amount and flux-time profiles are dependent on the processes affecting percutaneous absorption, the shapes of the profiles reflecting the processes most determining transport.

Computer Simulation↗

PubMed1999

Self promotion of deep tissue penetration and distribution of methylsalicylate after topical application.

PURPOSE: To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient triethanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations. METHODS: Flux of salicylate from MeSA and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed. RESULTS: In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers. CONCLUSIONS: Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.

Administration, Topical↗

PubMed1999

Lateral iontophoretic solute transport in skin.

PURPOSE: The lateral iontophoretic transport of three solutes (sodium, ethanolamine, lidocaine) from an active electrode through skin and other tissues to an indifferent electrodes was investigated. METHODS: Anodal epidermal iontophoresis was carried out on an in vivo rat model using constant direct current of 0.38 mA/cm2. Cells were fixed on the epidermis of anesthetized rats at distances of adjacent, 3 cm and 7 cm apart. After iontophoresis, tissues were dissected at I cm intervals between the electrodes. Concentrations of the radiolabelled solutes in tissues were determined by liquid scintillation counting or gamma counting. RESULTS: The concentration of each solutes in the epidermis, dermis and other tissues was found to decrease in an exponential manner with lateral distance from the active electrode to the indifferent electrode. The detectable lateral distance for ethanolamine and lidocaine was less than 2 cm from the donor sites, at which distance the concentrations were not significantly different to those found in the corresponding contralateral site. The lateral drift velocities for all solutes in the epidermis and dermis were consistent with diffusivities of the order of 10(-6) cm2/s. The drift velocity of sodium was greater than either lidocaine or ethanolamine. CONCLUSIONS: The decline in solute concentration with lateral distance is mainly due to clearance from the site of application by the skin's microcirculation and decreases with distance from the active electrode until a baseline concentration, similar to the contralateral tissue concentration is reached.

Animals↗

PubMed1999

A physiological pharmacokinetic model for solute disposition in tissues below a topical below a topical application site.

PURPOSE: Many compounds are applied to the skin with the aim of targeting deeper underlying tissues. This work sought to define the pharmacokinetics of solutes in tissues below a topical application site in terms of perfusate binding, tissue binding and perfusate flow rate. METHODS: The disposition kinetics of diclofenac in a single pass perfused limb preparation after dermal application disposition was studied using dextran and bovine serum albumin (BSA) containing perfusates. A pharmacokinetic model was then developed to relate the tissue retention half lives for diclofenac, diazepam, water, lignocaine and salicylate to their fraction unbound in the tissues, their fraction unbound in the perfusate and the perfusate flow rate. RESULTS: Diclofenac had estimated tissue retention half lives of 18.1 hr and 3.5 hr for the dextran and BSA containing perfusates, respectively. The fraction of diclofenac and other solutes unbound in the tissues correlated with their corresponding fraction unbound in the perfusate. The tissue retention half lives for diclofenac and other solutes could be described in terms of the fraction of solute unbound in the tissues and perfusate, together with the flow rate. CONCLUSION: The tissue pharmacokinetics of solutes below a topical application are a function of their binding in the tissues, binding in perfusate and local blood flow.

Administration, Topical↗

PubMed1999

Modeling of hepatic elimination and organ distribution kinetics with the extended convection-dispersion model.

The conventional convection-dispersion (also called axial dispersion) model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. An extended form of the convection-dispersion model has been developed to adequately describe the outflow concentration-time profiles for vascular markers at both short and long times after bolus injections into perfused livers. The model, based on flux concentration and a convolution of catheters and large vessels, assumes that solute elimination in hepatocytes follows either fast distribution into or radial diffusion in hepatocytes. The model includes a secondary vascular compartment, postulated to be interconnecting sinusoids. Analysis of the mean hepatic transit time (MTT) and normalized variance (CV2) of solutes with extraction showed that the discrepancy between the predictions of MTT and CV2 for the extended and unweighted conventional convection-dispersion models decreases as hepatic extraction increases. A correspondence of more than 95% in F and Cl exists for all solute extractions. In addition, the analysis showed that the outflow concentration-time profiles for both the extended and conventional models are essentially identical irrespective of the magnitude of rate constants representing permeability, volume, and clearance parameters, providing that there is significant hepatic extraction. In conclusion, the application of a newly developed extended convection-dispersion model has shown that the unweighted conventional convection-dispersion model can be used to describe the disposition of extracted solutes and, in particular, to estimate hepatic availability and clearance in both experimental and clinical situations.

Humans↗

PubMed1999

Absorption of sunscreens across human skin: an evaluation of commercial products for children and adults.

AIMS: Topical sunscreens are routinely applied to the skin by a large percentage of the population. This study assessed the extent of absorption of a number of common chemical sunscreen agents into and through human skin following application of commercially available products. METHODS: Sunscreen products were applied to excised human epidermis in Franz diffusion cells with the amount penetrating into and across the epidermis assessed by h.p.l.c. for 8 h following application. RESULTS: All sunscreen agents investigated penetrated into the skin (0.25 g m-2 or 14% of applied dose), but only benzophenone-3 passed through the skin in significant amounts (0.08 g m-2 or 10% of the applied dose). With one exception, suncreen agents in corresponding products marketed for adults and children had similar skin penetration profiles. CONCLUSIONS: Whilst limited absorption across the skin was observed for the majority of the sunscreens tested, benzophenone-3 demonstrated sufficiently high penetration to warrant further investigation of its continued application.

Adult↗

PubMed1999

Defining a model to predict the distribution of topically applied growth factors and other solutes in excisional full-thickness wounds.

Controversy over the efficacy of many topical wound treatments, particularly growth factors, is common, with many clinical practitioners still confused as to the real value of these agents. A serious lack of knowledge appears to exist concerning the diffusion and distribution of topically applied solutes in wounds. Without this basic understanding there seems little chance of accurately predicting the therapeutic window of drugs targeted at cellular activities, such as division and chemotaxis, and processes, such as collagen lattice deposition and contraction, occurring below the surface of the granulating layer. This study was designed to determine the absorption and distribution of a number of radiolabeled solutes (water, sodium chloride, lidocaine) and growth factors (basic fibroblast growth factor, epidermal growth factor) applied topically to full-thickness excisional wounds in rats during the early (2 d), mid (7 d), and late (12 d) stages of repair. Results showed that water and sodium penetrated deepest into wound sites and that changes in water distribution and retention in the wound paralleled the healing process. Multiple stepwise regression showed that molecular weight and tissue depth, but not day of healing, were significant factors in predicting the concentration of each solute in wound and underlying tissue sites. This finding was consistent with a tissue diffusion model developed in this study. Basic fibroblast growth factor and epidermal growth factor only penetrated slightly into the upper granulating layers of the wound site, and calculation of therapeutic doses, based on the percentage of applied solute reaching the deeper granulating layers, is presented.

Administration, Topical↗

PubMed1999

Informatics and process improvement. The clinical design unit.

Seeking to integrate departments and services, reduce costs, and enhance quality, administrators at a university medical center implemented a clinical design unit. The authors describe the operations of the unit in testing new processes before rollout to the entire center.

Academic Medical Centers↗

PubMed1999

Relationship of Bacillus subtilis clades associated with strains 168 and W23: a proposal for Bacillus subtilis subsp. subtilis subsp. nov. and Bacillus subtilis subsp. spizizenii subsp. nov.

Earlier phylogenetic studies based on the inferred DNA sequences of the polC, rpoB and gyrA genes suggested that strains of the species Bacillus subtilis formed two clusters, indicating the presence two closely related taxa; one contained the laboratory strain 168 and the other the laboratory strain W23. Significant sexual isolation was found between strain 168 and members of the group containing W23, but no sexual isolation was observed between strain 168 and other members of the 168 group. DNA reassociation between the two groups ranged from 58 to 69% and intragroup DNA relatedness ranged from 82 to 100%. Because group 168 strains were highly related to the B. subtilis type strain, they were considered to be bona fide members of the species. About 99.5% sequence identity was observed between the 16S rRNA genes of the 168 and W23 groups. Ribitol and anhydroribitol were principal cell wall constituents of the W23 but not of the 168 group. These observations revealed two closely related but genetically and phenotypically distinct groups within B. subtilis that correspond to two historically important strains. Subspecies distinction is proposed for the 168 and W23 groups, with the names Bacillus subtilis subsp. subtilis subsp. nov. and Bacillus subtilis subsp. spizizenii subsp. nov., respectively. The type strain of the former is NRRL NRS-744T and the latter NRRL B-23049T.

Bacillus subtilis↗