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Biomedical subjects

Michael S Roberts

Publications and source records attributed to Michael S Roberts.

At least 37 records · Page 2Linked to original sources

Medication reviews in the community: results of a randomized, controlled effectiveness trial.

AIMS: To examine the effectiveness of a multidisciplinary service model delivering medication review to patients at risk of medication misadventure in the community. METHODS: The study was carried out in three Australian states; Queensland, New South Wales and Western Australia, and conducted as a randomized, controlled effectiveness trial with the general practitioner (GP) as the unit of randomization. In total, 92 GPs, 53 pharmacists and 400 patients enrolled in the study. The multidisciplinary service model consisted of GP education, patient home visits, pharmacist medication reviews, primary healthcare team conferences, GP implementation of action plans in consultation with patients, and follow-up surgery visits for monitoring. Effectiveness was assessed using the four clinical value compass domains of (i) functional status, (ii) clinical outcomes, (iii) satisfaction and (iv) costs. The domains of functional status (assessed by the health-related quality of life measure SF-36 subscales) and clinical outcomes (as assessed by adverse drug events (ADEs), number of GP visits, hospital services and severity of illness) were measured at baseline and endpoint. Satisfaction was measured by success in implementation and by participant satisfaction at endpoint, and costs (as assessed using medication and healthcare service costs, less intervention costs) were measured preintervention and during the trial. In addition, process evaluation was conducted for intervention patients, in which problems and recommendations from the medication reviews were described. RESULTS: The model was successfully implemented with 92% of intervention GPs suggesting that the model had improved the care of participating patients, a view shared by 94% of pharmacists. In addition, positive trends in clinical outcomes (ADEs and severity of illness) and costs (an ongoing trend towards reduction in healthcare service costs) were evident, although the trial was limited to a 6-month intervention time. No differences between intervention and control groups were identified for the health-related quality of life domain. The cost-effectiveness ratio for the intervention based on cost savings, reduced adverse events and improved health outcomes was small. The most common problems identified in the medication reviews were potential adverse drug reactions, suboptimal monitoring and adherence/lack of concordance issues. In total, 54.4% of recommendations were enacted, and 23.9% were implemented precisely as recommended in the medication review. Follow-up evaluation showed that 70.9% of actions had a positive outcome, 15.7% no effect and 3.7% had a negative outcome. CONCLUSIONS: Most studies emphasize efficacy and the best achievable clinical outcomes rather than whether an intervention will be effective in practice. The current trial showed that three of the four domains in the clinical value compass showed trends of improvement or were indeed improved in the relatively short follow-up period of the trial, suggesting that a service based on this model could achieve similar benefits in practice. A domiciliary medication review programme similar to this model has now been implemented into national Australian practice, where GPs and pharmacists are reimbursed by the Australian government for the provision of these services.

Adult↗

Detection of surfactant protein A (SP-A) and surfactant protein D (SP-D) in equine synovial fluid with immunoblotting.

Once considered unique to the lung, surfactant proteins have been clearly identified in the intestine and peritoneum and are suggested to exist in several other organs. In the lung, surfactant proteins assist in the formation of a monolayer of surface-active phospholipid at the liquid-air interface of the alveolar lining, reducing the surface tension at this surface. In contrast, surface-active phospholipid adsorbed to articular surfaces has been identified as the load-bearing boundary lubricant of the joint. This raises the question of whether surfactant proteins in synovial fluid (SF) are required for the formation of the adsorbed layer in normal joints. Proteins from small volumes of equine SF were resolved by 1- and 2-dimensional polyacrylamide gel electrophoresis and detected by Western blotting to investigate the presence of surfactant proteins. The study showed that surfactant proteins A and D (SP-A and SP-D) are present in the SF of normal horses. We suggest that, like surface-active phospholipid, SP-A and SP-D play a significant role in the functioning of joints. Next will be clarification of the roles of surfactant proteins as disease markers in a variety of joint diseases, such as degenerative joint disease and inflammatory problems.

Animals↗

Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs.

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pKa values of drugs. Lipophilicity and pKa determined hepatic drug retention: a drug with low pKa and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pKa and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pKa and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pKa basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.

Animals↗

Transdermal penetration of vasoconstrictors--present understanding and assessment of the human epidermal flux and retention of free bases and ion-pairs.

PURPOSE: As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). METHODS: We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin. RESULTS: As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 +/- 11.7 microg/cm2/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 +/- 2.3 and 12.0 +/- 1.6 microg/cm2/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 +/- 0.6, 7.8+/- 0.8 and 1.1 +/- 0.1 respectively. Transdermal transport of VC's is discussed. CONCLUSIONS: Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.

Administration, Cutaneous↗

Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro.

PURPOSE: The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects. METHODS: The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log Koct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm3)1/2. RESULTS: Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log Koct 2.96). CONCLUSION: An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.

Administration, Cutaneous↗

Development of a quality use of medicines coding system to rate clinical pharmacists' medication review recommendations.

OBJECTIVE: To develop a 'quality use of medicines' coding system for the assessment of pharmacists' medication reviews and to apply it to an appropriate cohort. METHOD: A 'quality use of medicines' coding system was developed based on findings in the literature. These codes were then applied to 216 (111 intervention, 105 control) veterans' medication profiles by an independent clinical pharmacist who was supported by a clinical pharmacologist with the aim to assess the appropriateness of pharmacy interventions. The profiles were provided for veterans participating in a randomised, controlled trial in private hospitals evaluating the effect of medication review and discharge counselling. The reliability of the coding was tested by two independent clinical pharmacists in a random sample of 23 veterans from the study population. MAIN OUTCOME MEASURE: Interrater reliability was assessed by applying Cohen's kappa score on aggregated codes. RESULTS: The coding system based on the literature consisted of 19 codes. The results from the three clinical pharmacists suggested that the original coding system had two major problems: (a) a lack of discrimination for certain recommendations e.g. adverse drug reactions, toxicity and mortality may be seen as variations in degree of a single effect and (b) certain codes e.g. essential therapy were in low prevalence. The interrater reliability for an aggregation of all codes into positive, negative and clinically non-significant codes ranged from 0.49-0.58 (good to fair). The interrater reliability increased to 0.72-0.79 (excellent) when all negative codes were excluded. Analysis of the sample of 216 profiles showed that the most prevalent recommendations from the clinical pharmacists were a positive impact in reducing adverse responses (31.9%), an improvement in good clinical pharmacy practice (25.5%) and a positive impact in reducing drug toxicity (11.1%). Most medications were assigned the clinically non-significant code (96.6%). In fact, the interventions led to a statistically significant difference in pharmacist recommendations in the categories; adverse response, toxicity and good clinical pharmacy practice measured by the quality use of medicine coding system. CONCLUSION: It was possible to use the quality use of medicine coding system to rate the quality and potential health impact of pharmacists' medication reviews, and the system did pick up differences between intervention and control patients. The interrater reliability for the summarised coding system was fair, but a larger sample of medication regimens is needed to assess the non-summarised quality use of medicines coding system.

Aged↗

Unexpected clobetasol propionate profile in human stratum corneum after topical application in vitro.

PURPOSE: The validity of using drug amount-depth profiles in stratum corneum to predict uptake of clobetasol propionate into stratum corneum and its transport into deeper skin layers was investigated. METHODS: In vitro diffusion experiments through human epidermis were carried out using Franz-type glass diffusion cells. A saturated solution of clobetasol propionate in 20% (V/V) aqueous propylene glycol was topically applied for 48 h. Steady state flux was calculated from the cumulative amount of drug permeated vs. time profile. Epidermal partitioning was conducted by applying a saturated drug solution to both sides of the epidermis and allowing time to equilibrate. The tape stripping technique was used to define drug concentration-depth profiles in stratum corneum for both the diffusion and equilibrium experiments. RESULTS: The concentration-depth profile of clobetasol propionate in stratum corneum for the diffusion experiment is biphasic. A logarithmic decline of the drug concentration over the first four to five tape strips flattens to a relatively constant low concentration level in deeper layers. The drug concentration-depth profile for the equilibrium studies displays a similar shape. CONCLUSIONS: The shape of the concentration-depth profile of clobetasol propionate is mainly because of the variable partitioning coefficient in different stratum corneum layers.

Administration, Topical↗

Bovine-serum-albumin-containing receptor phase better predicts transdermal absorption parameters for lipophilic compounds.

Based on the hypothesis that limited receptor solubility of lipophilic compounds may result in lower observed permeability parameters, the aim of this study was to determine the in vitro human epidermal permeability coefficients and membrane retention of a series of aliphatic alcohols (C1-C10, log p-0.72 to 4.06) using two different receptor solutions (water and 4% bovine serum albumin in phosphate-buffered saline). Aqueous solutions of radiolabeled alcohols were dosed into the stratum corneum side of membranes mounted in side-by-side glass diffusion cells. Appearance of alcohol in the receptor compartment filled with either of the two solutions was monitored over a 7 h period when both stratum corneum (assessed by tape stripping) and the remaining epidermis levels of radioactivity were determined. In a separate study the degree of binding of alcohols to 4% bovine serum albumin was determined. The data showed increased receptor phase solubility in the bovine serum albumin solution and higher permeability coefficients for the more lipophilic alcohols in the series. No changes were seen in the partitioning of the alcohols from the vehicle into either the stratum corneum or tape-stripped epidermis with the two receptor phases; however, a decrease in the amount of the more lipophilic alcohols partitioning into the water receptor phase from the tape-stripped epidermis was observed. We conclude that bovine serum albumin receptor phase allows better estimation of real permeability parameters for lipophilic compounds due to its increased solubility capacity and we question whether permeability parameters for lipophilic solutes from older data sets based on aqueous receptor phases are completely reliable.

Alcohols↗

Determination of the effect of lipophilicity on the in vitro permeability and tissue reservoir characteristics of topically applied solutes in human skin layers.

In order to establish the relationship between solute lipophilicity and skin penetration (including flux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2-C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum flux and permeability coefficients are compared for each membrane and estimates of alcohol diffusivity are made based on flux/concentration data and also the related tissue resistance (the reciprocal of permeability coefficient) for each membrane type. The permeability coefficient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coefficients were related to logP, and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No difference was measured in the diffusivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower diffusivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone.

Alcohols↗

Community-level physiological profiling performed with an oxygen-sensitive fluorophore in a microtiter plate.

Community-level physiological profiling based upon fluorometric detection of oxygen consumption was performed on hydroponic rhizosphere and salt marsh litter samples by using substrate levels as low as 50 ppm with incubation times between 5 and 24 h. The rate and extent of response were increased in samples acclimated to specific substrates and were reduced by limiting nitrogen availability in the wells.

Biosensing Techniques↗

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites.

Disposition kinetics of [(3)H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [(3)H]palmitate and its low-molecular-weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [(3)H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. A slow-diffusion/bound model was found to better describe the hepatic disposition of unchanged [(3)H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female > clofibrate-treated male > female > male. Levels of other intrahepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low-molecular-weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [(3)H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [(3)H]palmitate and its low-molecular-weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intrahepatic proteins.

Albumins↗

Catheter effects in organ perfusion experiments.

In a typical isolated organ perfusion experiment, a substance is injected upstream of an organ and then collected at some distance downstream. To reach the organ from the injection site, and then from the organ to the collector, a solute passes through catheters, usually tubes with circular cross-sections. Catheters cause distortion to the concentration-time profile of the perfusion. In this paper, we analyse catheter distribution kinetics from a mathematical point of view, develop the function most suitable for modeling this distribution and successfully apply this function to experimental data.

Catheterization↗

A compartmental model of hepatic disposition kinetics: 1. Model development and application to linear kinetics.

The conventional convection-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 bloodflow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity of the liver is not straightforward and requires numerical solution of partial differential equation, which is not available in standard nonlinear regression analysis software. In this paper, we describe an alternative compartmental model representation of hepatic disposition (including elimination). The model allows the use of standard software for data analysis and accurately describes the outflow concentration-time profile for a vascular marker after bolus injection into the liver. In an evaluation of a number of different compartmental models, the most accurate model required eight vascular compartments, two of them with back mixing. In addition, the model includes two adjacent secondary vascular compartments to describe the tail section of the concentration-time profile for a reference marker. The model has the added flexibility of being easy to modify to model various enzyme distributions and nonlinear elimination. Model predictions of F, MTT, CV2, and concentration-time profile as well as parameter estimates for experimental data of an eliminated solute (palmitate) are comparable to those for the extended convection-dispersion model.

Animals↗

Pro re nata medication for psychoses: the knowledge and beliefs of doctors and nurses.

OBJECTIVE: To examine the knowledge and beliefs of doctors and nurses in inpatient psychiatric units about pro re nata (PRN) (as needed) medications for psychotic disorders. METHODS: Medical (n = 44) and nursing (n = 80) staff in two metropolitan public hospital units completed a structured questionnaire about their use of PRN psychotropic medications on one occasion during the four months from March-June 1999. RESULTS: Nurses selected more indications for PRN antipsychotics than doctors (3.49 vs 2.72, p < 0.05), whereas doctors selected more indications for PRN benzodiazepines (3.77 vs 3.19, p < 0.05). The groups did not differ in the number of selected indications for using anticholinergics. For agitation, the majority of nurses viewed both benzodiazepines (56%) and antipsychotics (86%) as effective, with 60% preferring an antipsychotic. For the acute control of psychotic symptoms, 99% of nurses believed antipsychotics were effective and 58% benzodiazepines, with 87% preferring an antipsychotic. A large majority of doctors viewed both PRN benzodiazepines, 94%,and antipsychotics, 81%, as effective for agitation, and 55% preferred to use a benzodiazepine. For psychotic symptoms, 80% believed PRN antipsychotics were effective, but only 32% viewed benzodiazepines as effective, and 64% preferred to use an antipsychotic. Nursing staff identified more non-pharmacological techniques for managing both agitation and psychotic symptoms and reported using these more often than doctors. Junior staff, both nursing and medical, had less knowledge of non-pharmacological alternatives to PRN medication than senior staff. CONCLUSIONS: Disparities existed between doctors and nurses views on the indications for PRN medication in the acute management of psychoses, thus it is important for doctors to specify indications when writing PRN prescriptions. Despite evidence for the safety and effectiveness of benzodiazepines, there was widespread reluctance to use them as PRN medication in acute psychoses. Beliefs of some staff about PRN medications were at odds with the known properties of these medicines. Educational interventions for both nurses and doctors are required to achieve best practice in PRN medication.

Antipsychotic Agents↗

Pro re nata medication for psychoses: an audit of practice in two metropolitan hospitals.

OBJECTIVE: To examine the use of pro re nata (PRN) (as needed) medication in hospitalized patients with psychotic disorders. METHODS: Retrospective chart reviews were conducted at two large public psychiatry units situated in inner city general hospitals. Pro re nata medication prescription, administration and outcomes were examined during inpatient episodes of care for 184 consecutive admissions of patients diagnosed with a psychotic disorder. Patient demographics, diagnoses, and regularly prescribed medication were also recorded. All admissions were drawn from a three-month period from December 1998-February 1999. RESULTS: The most prevalent diagnoses were schizophrenia related disorders (n = 111) and mania (n = 34). Substance use disorders (n = 49) were the most common comorbid dis-orders. Pro re nata medication was administered during the acute phase of 82% of admissions. Drugs prescribed Pro re nata were mostly typical antipsychotics, benzodiazepines and/or anti-cholinergics. Coprescription of typical antipsychotics PRN with regularly scheduled atypical antipsychotics was common (64%). Pro re nata medications accounted for 31% of the total antipsychotic dose and 28% of the total anxiolytic dose administered during acute treatment. Higher daily doses of PRN medication were given to manic patients, males, younger patients and those with substance use disorders. Pro re nata prescriptions usually specified a maximum daily dose (87%) but rarely gave indications for use (6%). Administration records frequently lacked a specified reason for use (48%) or a notation of outcome (64%). Unit staff noted medication-related morbidity in 37% of patients receiving PRN medication, compared to 3% of patients receiving only regularly scheduled medication. Extrapyramidal symptoms (EPS) were most frequently associated with administration of PRN haloperidol (Relative Risk vs other PRN medications = 5.61, 95% CI = 2.36-13.73). CONCLUSIONS: Pro re nata medications comprised a significant part of the treatment which psychotic patients received. The common practice of coprescribing PRN typical antipsychotics with scheduled atypical antipsychotics is potentially problematical since administration of PRN medication is associated with significant medication related morbidity. Preferential use of benzodiazepines as PRN agents may minimize this morbidity and foster subsequent compliance with regularly prescribed antipsychotics.

Adolescent↗

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver.

Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl(4)-treated group (phenobarbital with CCl(4) treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of (3)H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl(4)-treated rats were found to have the smallest vascular space, extravascular albumin space, (3)H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of (3)H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses.

Albumins↗