Biomedical subjects

M S Roberts

Publications and source records attributed to M S Roberts.

At least 37 records · Page 2Linked to original sources

PubMed2001

Probing the effect of vehicles on topical delivery: understanding the basic relationship between solvent and solute penetration using silicone membranes.

PURPOSE: In the present study we examined the relationship between solvent uptake into a model membrane (silicone) with the physical properties of the solvents (e.g., solubility parameter, melting point, molecular weight) and its potential predictability. We then assessed the subsequent topical penetration and retention kinetics of hydrocortisone from various solvents to define whether modifications to either solute diffusivity or partitioning were dominant in increasing permeability through solvent-modified membranes. METHODS: Membrane sorption of solvents was determined from weight differences following immersion in individual solvents, corrected for differences in density. Permeability and retention kinetics of 3H-hydrocortisone, applied as saturated solutions in the various solvents, were determined over 48 h in horizontal Franz-type glass diffusion cells. RESULTS: Solvent sorption into the membrane could be related to differences in solubility parameters, MW and hydrogen bonding (r2=0.76). The actual and predicted volume of solvent sorbed into the membrane was also found to be linearly related to Log hydrocortisone flux, with changes in both diffusivity and partitioning of hydrocortisone observed for the different solvent vehicles. CONCLUSIONS: A simple structure-based predictive model can be applied to the sorption of solvents into silicone membranes. Changes in solute diffusivity and partitioning appeared to contribute to the increased hydrocortisone flux observed with the various solvent vehicles. The application of this predictive model to the more complex skin membrane remains to be determined.

Administration, Topical↗

PubMed2001

Multidisciplinary case conference reviews: improving outcomes for nursing home residents, carers and health professionals.

AIM OF STUDY: This study sought to determine whether multidisciplinary case conference reviews improved outcomes for nursing home residents, and the effects of this team approach to resident care on carers, including the hands-on carers employed by the nursing home, and health professionals. METHOD: 245 residents of three Canberra nursing homes were enrolled in this non-randomised controlled trial. The intervention consisted of sessions of three case conference reviews held between 10/4/96 and 4/12/96. These sessions were attended by the General Practitioners (GPs) of the residents discussed, the GP project officer from the ACT Division of General Practice, a clinical pharmacist, senior nursing staff, other health professionals e.g. physiotherapist, and occasionally the resident concerned or their representative. At each review, a case presentation by the resident's GP was followed by a multidisciplinary discussion of all aspects, medical and non-medical, of the resident's care. The review concluded with a management plan for the resident. In total 75 residents were reviewed. MAIN OUTCOME MEASURES: Medication use and cost, and mortality. RESULTS: One month after the reviews were completed comparisons between those who were reviewed and those who were not showed non-significant reductions in medication orders, medication cost, and mortality in the reviewed group. Many of the 92 recommendations in the management plans that were carried out benefited the residents (n = 37) and/or carers (n = 24). The responses of the GPs and the Directors of Nursing to the reviews were overwhelmingly positive. CONCLUSION: Recommendations arising from multidisciplinary case conferences were carried out to the benefit of patients and carers. Given the support shown by key stakeholders, multidisciplinary conferences should be used more.

Aged↗

PubMed2001

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer.

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have previously shown that systemic treatment of neonatal mucopolysaccharidosis type VII (MPS VII) mice with recombinant adeno-associated virus (AAV) vectors results in relatively long-term expression of beta-glucuronidase (GUSB) in multiple tissues, and a reduction in lysosomal storage. Here, we demonstrate that therapeutic levels of enzyme persist for at least 1 year following a single intravenous injection of virus in neonatal MPS VII mice. The level and distribution of GUSB expression achieved is sufficient to prevent the development of many aspects of clinical disease over the life of the animal. Following treatment, bone lengths, weights and retinal function were maintained at nearly normal levels throughout the life of the animal. In addition, significant improvements in survival and auditory function were seen in AAV-treated MPS VII mice when compared with untreated mutant siblings. These data suggest that AAV-mediated gene transfer in the neonatal period can lead to prevention of many of the clinical symptoms associated with MPS VII in the murine model of this disease.

Animals↗

PubMed2001

Outcomes of a randomized controlled trial of a clinical pharmacy intervention in 52 nursing homes.

AIMS: To evaluate whether a year long clinical pharmacy program involving development of professional relationships, nurse education on medication issues, and individualized medication reviews could change drug use, mortality and morbidity in nursing home residents. METHODS: A cluster randomised controlled trial, where an intervention home was matched to three control homes, was used to examine the effect of the clinical pharmacy intervention on resident outcomes. The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in south-east Queensland and north-east New South Wales, Australia. The outcome measures were: continuous drug use data from government prescription subsidy claims, cross-sectional drug use data on prescribed and administered medications, deaths and morbidity indices (hospitalization rates, adverse events and disability indices). RESULTS: This intervention resulted in a reduction in drug use with no change in morbidity indices or survival. Differences in nursing home characteristics, as defined by cluster analysis with SUDAAN, negated intervention-related apparent significant improvements in survival. The use of benzodiazepines, nonsteroidal anti-inflammatory drugs, laxatives, histamine H2-receptor antagonists and antacids was significantly reduced in the intervention group, whereas the use of digoxin and diuretics remained similar to controls. Overall, drug use in the intervention group was reduced by 14.8% relative to the controls, equivalent to an annual prescription saving of A64 dollars per resident (approximately 25 pound sterling). CONCLUSIONS: This intervention improved nursing home resident outcomes related to changes in drug use and drug-related expenditure. The continuing divergence in both drug use and survival at the end of the study suggests that the difference would have been more significant in a larger and longer study, and even more so using additional instruments specific for measuring outcomes related to changes in drug use.

Age Distribution↗

PubMed2001

Can increasing the viscosity of formulations be used to reduce the human skin penetration of the sunscreen oxybenzone?

The effect of adding thickening agents on the penetration of a sunscreen benzophenone-3 through epidermal and a high-density polyethylene membrane was studied using both very thick (infinite dose) and thin (in use) applications. Contradictory results were obtained. Thickening agents retard skin penetration, in a manner consistent with a diffusional resistance in the formulation, when applied as an infinite dose. In contrast, when applied as in thin (in use) doses, thickening agents promote penetration, most likely through greater stratum corneum diffusivity arising from an enhanced hydration by the thicker formulations. The two key implications from this work are (i) a recognition of the danger in the potential extrapolation of infinite dosing to in use situations, and (ii) to recognize that thicker formulations may sometimes enhance the penetration of other topical agents when applied "in use".

Benzophenones↗

PubMed2001

Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy.

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.

Aged↗

PubMed2001

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat.

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 microg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 microg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Animals↗

PubMed2001

Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: transmembrane exchange and cytoplasmic binding process.

This work studied the structure-hepatic disposition relationships for cationic drugs of varying lipophilicity using a single-pass, in situ rat liver preparation. The lipophilicity among the cationic drugs studied in this work is in the following order: diltiazem > propranolol > labetalol > prazosin > antipyrine > atenolol. Parameters characterizing the hepatic distribution and elimination kinetics of the drugs were estimated using the multiple indicator dilution method. The kinetic model used to describe drug transport (the "two-phase stochastic model") integrated cytoplasmic binding kinetics and belongs to the class of barrier-limited and space-distributed liver models. Hepatic extraction ratio (E) (0.30--0.92) increased with lipophilicity. The intracellular binding rate constant (k(on)) and the equilibrium amount ratios characterizing the slowly and rapidly equilibrating binding sites (K(S) and K(R)) increase with the lipophilicity of drug (k(on): 0.05--0.35 s(-1); K(S): 0.61--16.67; K(R): 0.36--0.95), whereas the intracellular unbinding rate constant (k(off)) decreases with the lipophilicity of drug (0.081--0.021 s(-1)). The partition ratio of influx (k(in)) and efflux rate constant (k(out)), k(in)/k(out), increases with increasing pK(a) value of the drug [from 1.72 for antipyrine (pK(a) = 1.45) to 9.76 for propranolol (pK(a) = 9.45)], the differences in k(in/kout) for the different drugs mainly arising from ion trapping in the mitochondria and lysosomes. The value of intrinsic elimination clearance (CL(int)), permeation clearance (CL(pT)), and permeability-surface area product (PS) all increase with the lipophilicity of drug [CL(int) (ml x min(-1) x g(-1) of liver): 10.08--67.41; CL(pT) (ml x min(-1) x g(-1) of liver): 10.80--5.35; PS (ml x min(-1) x g(-1) of liver): 14.59--90.54]. It is concluded that cationic drug kinetics in the liver can be modeled using models that integrate the presence of cytoplasmic binding, a hepatocyte barrier, and a vascular transit density function.

Algorithms↗

PubMed2001

Hepatocyte [3H]-palmitate uptake: effect of albumin surface charge modification.

The role of plasma proteins on the cellular uptake of lipophilic substrates has perplexed investigators for many years. We tested the hypothesis that an ionic interaction between the protein-ligand complex and hepatocyte surface may be responsible for supplying more ligand to the cell for uptake. The surface-charged groups on albumin were modified to yield proteins having a range of isoelectric points (ALB, ALBs, ALBm, ALBe had values of 4.8-5.0, 4.5-4.7, 3.0-3.5, 8.4-8.6, respectively). [3H]-Palmitate uptake studies were performed with adult rat hepatocyte suspensions using similar unbound ligand fractions in the presence of the different binding proteins. Mass spectrometry, isoelectric focusing (pI), and heptane:water partitioning were used to determine protein molecular weight, pI, and protein-palmitate equilibrium binding constant, respectively. Hepatocyte [3H]-palmitate clearance in the presence of ALBs and ALBm were significantly lower (p < 0.05) than ALB, whereas [3H]-palmitate clearance in the presence of ALBe was significantly higher (p < 0.05) than ALB. The data were consistent with the notion that ionic interactions between extracellular protein-ligand complexes and the hepatocyte surface facilitate the uptake of long-chain fatty acids.

Albumins↗

PubMed2000

The cost-effectiveness of sildenafil.

BACKGROUND: Coverage of sildenafil by health insurance plans is a contentious issue. OBJECTIVE: To evaluate the cost-effectiveness of sildenafil treatment for erectile dysfunction. DESIGN: A Markov decision model to estimate the incremental cost-effectiveness of sildenafil compared with no drug therapy. DATA SOURCES: Values for the efficacy and safety of sildenafil and quality-of-life utilities were obtained from the published medical literature. Base-case values were chosen to bias against sildenafil use. TARGET POPULATION: Men 60 years of age with erectile dysfunction. TIME HORIZON: Lifetime. PERSPECTIVE: Societal and third-party payer. INTERVENTION: Sildenafil or no treatment in identical hypothetical cohorts. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: The cost per QALY gained for sildenafil treatment compared with no therapy was $11,290 from the societal perspective and $11,230 from the third-party payer perspective. RESULTS OF SENSITIVITY ANALYSIS: From the societal perspective, the cost per QALY gained associated with sildenafil was less than $50,000 if treatment-related morbidity was less than 0.8% per year, mortality was less than 0.55% per year, treatment was successful in more than 40.2% of patients, or sildenafil cost less than $244 per month. The results were sensitive to variation of erectile dysfunction utilities, but cost per QALY gained was less than $50,000 if successful treatment increased utility values by 0.05 or more on a scale of 0 (death) to 1 (perfect health). CONCLUSIONS: In an analysis biased against use of sildenafil, the cost-effectiveness of sildenafil treatment compared favorably with that of accepted therapies for other medical conditions.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2000

Cost effectiveness of vaccination strategies in adults without a history of chickenpox.

PURPOSE: Some authorities recommend varicella antibody testing or vaccination for adults without a history of chickenpox, but the cost effectiveness of these interventions is uncertain. SUBJECTS AND METHODS: Using a Markov decision model, we estimated the cost effectiveness of three strategies for adults with no history of chickenpox: no vaccination, varicella antibody testing followed by vaccination for those without antibody, and vaccinating all. Societal and third-party payer perspectives were taken, with costs and benefits discounted at 3% per year. Assumptions for the baseline analysis were chosen to bias against no vaccination. RESULTS: In the baseline analysis for 20- to 29-year-old patients, testing followed by vaccination compared with no vaccination is cost saving from a societal perspective and costs $6,670 per quality-adjusted life-year (QALY) gained from a third-party payer perspective. When less favorable assumptions are used, results are sensitive to the rates of compliance with vaccination follow-up; testing followed by vaccination costs more than $50,000 per QALY if <75% comply. For patients 30 years of age and older, the incremental cost of testing followed by vaccination is at least $97,100 per QALY compared with no vaccination, with costs greater than $50,000 per QALY unless testing costs less than $7.73, the chickenpox case-fatality rate is >0.067% (baseline 0.025%), or immunity with no chickenpox history is <25% (baseline 71%). In either age group, vaccinating all has an incremental cost of $2 to $16 million per QALY gained compared with testing followed by vaccination. CONCLUSION: Testing followed by vaccination for varicella in US adults aged 20 to 29 years may be cost effective by conventional criteria but is sensitive to rates of compliance with vaccination protocols. Testing or vaccination of older adults is expensive but may be cost effective in patients with lower probabilities of immunity or in those who have a greater risk of complications from chickenpox.

Adult↗

PubMed2000

Commentary: using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics.

The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyama in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application.

Algorithms↗

PubMed2000

Kinetics of propranolol uptake in muscle, skin, and fat of the isolated perfused rat hindlimb.

The tissue distribution kinetics of a highly bound solute, propranolol, was investigated in a heterogeneous organ, the isolated perfused limb, using the impulse-response technique and destructive sampling. The propranolol concentration in muscle, skin, and fat as well as in outflow perfusate was measured up to 30 min after injection. The resulting data were analysed assuming (1) vascular, muscle, skin and fat compartments as well mixed (compartmental model) and (2) using a distributed-in-space model which accounts for the noninstantaneous intravascular mixing and tissue distribution processes but consists only of a vascular and extravascular phase (two-phase model). The compartmental model adequately described propranolol concentration-time data in the three tissue compartments and the outflow concentration-time curve (except of the early mixing phase). In contrast, the two-phase model better described the outflow concentration-time curve but is limited in accounting only for the distribution kinetics in the dominant tissue, the muscle. The two-phase model well described the time course of propranolol concentration in muscle tissue, with parameter estimates similar to those obtained with the compartmental model. The results suggest, first that the uptake kinetics of propranolol into skin and fat cannot be analysed on the basis of outflow data alone and, second that the assumption of well-mixed compartments is a valid approximation from a practical point of view (as, e.g., in physiological based pharmacokinetic modelling). The steady-state distribution volumes of skin and fat were only 16 and 4%, respectively, of that of muscle tissue (16.7 ml), with higher partition coefficient in fat (6.36) than in skin (2.64) and muscle (2.79).

Adipose Tissue↗

PubMed2000

An isolated in-situ rat head perfusion model for pharmacokinetic studies.

PURPOSE: To develop a viable, single pass rat head perfusion model useful for pharmacokinetic studies. METHODS: A viable rat head preparation, perfused with MOPS-buffered Ringer's solution, was developed. Radiolabelled markers (red blood cells, water and sucrose) were injected in a bolus into the internal carotid artery and collected from the posterior facial vein over 28 minutes. The double inverse Gaussian function was used to estimate the statistical moments of the markers. RESULTS: The viability of the perfusion was up to one hour, with optimal perfusate being 2% bovine serum albumin at 37 degrees C, pH 7.4. The distribution volumes for red blood cells, sucrose and water (from all studies, n = 18) were 1.0 +/- 0.3 ml, 6.4 +/- 4.2 ml and 18.3 +/- 11.9 ml, respectively. A high normalised variance for red blood cells (3.1 +/- 2.0) suggests a marked vascular heterogeneity. A higher normalised variance for water (6.4 +/- 3.3) is consistent with additional diffusive/permeability limitations. CONCLUSIONS: Analysis of the physiological parameters derived from the moments suggested that the kinetics of the markers were consistent with distribution throughout the head (weight 25 g) rather than just the brain (weight 2 g). This model should assist in studying solute pharmacokinetics in the head.

Animals↗

PubMed2000

Cytoplasmic binding and disposition kinetics of diclofenac in the isolated perfused rat liver.

1. The binding kinetics of diclofenac to hepatocellular structures were evaluated in the perfused rat liver using the multiple indicator dilution technique and a stochastic model of organ transit time density. 2. The single-pass, in situ rat liver preparation was perfused with buffer solution (containing 2% albumin) at 30 ml min(-1). Diclofenac and [(14)C]-sucrose (extracellular reference) were injected simultaneously as a bolus dose into the portal vein (six experiments in three rats). An analogous series of experiments was performed with [(14)C]-diclofenac and [(3)H]-sucrose. 3. The diclofenac outflow data were analysed using three models of intracellular distribution kinetics, assuming (1) instantaneous distribution and binding (well-mixed model), (2) 'slow' binding at specific intracellular sites after instantaneous distribution throughout the cytosol (slow binding model), and (3) 'slowing' of cytoplasmic diffusion due to instantaneous binding (slow diffusion model). 4. The slow binding model provided the best description of the data. The rate constants for cellular influx and sequestration were 0.126+/-0. 026 and 0.013+/-0.009 s(-1), respectively. The estimated ratio of cellular initial distribution volume to extracellular volume of 2.82 indicates an almost instantaneous distribution in the cellular water space, while the corresponding ratio of 5.54 estimated for the apparent tissue distribution volume suggests a relatively high hepatocellular binding. The non-instantaneous intracellular equilibration process was characterized by time constants of the binding and unbinding process of 53.8 and 49.5 s, respectively. The single-pass availability of diclofenac was 86%. The results obtained with [(14)C]-diclofenac and [(3)H]-sucrose were not statistically different.

Animals↗

PubMed2000

The effect of occlusion on epidermal penetration of parabens from a commercial allergy test ointment, acetone and ethanol vehicles.

The efficacy of topical allergy screening systems relies on the ability of test agents to effectively penetrate the stratum corneum from applied vehicles and reach the viable cells involved in the cutaneous immune response system. There is very little evidence in the dermatologic literature to justify the choice and suitability of vehicles used in many allergy test systems and the effectiveness of occlusion, reported to have variable effects on solute penetration, often employed in combination with these systems. In this study we evaluated the in vitro human epidermal penetration of a mixture of paraben ester preservatives from a commercially available test ointment and two commonly employed solvent vehicles (acetone and ethanol), together with the effect of occlusion on the rate of delivery from these systems. Parabens were applied as finite doses (5 mg per cm2) to epidermal membranes mounted in horizontal Franz-type diffusion cells. At intervals of 2 h for a total of 10 h the receptor phase (20% ethanol in distilled water) was completely removed and replaced. Occlusion was effected by the placement of a piece of high density polyethylene (20 microm) over the application site immediately after dosing. Concentrations of parabens in receptor fluid and remaining in the epidermis at the end of the study were determined by high-performance liquid chromatography. There was a significant change in the epidermal flux of parabens from each of the vehicles following occlusion. Whereas increases were observed for the acetone and ethanol vehicles a decrease was seen following occlusion of the ointment formulation. Changes in flux appeared to result from a significant decrease in the epidermal partitioning of the esters following occlusion of the ointment and primarily by an increase in paraben epidermal diffusivity (estimated from changes in flux/retention) following occlusion of the solvent vehicles. These studies show that the effects of occlusion are strongly vehicle dependent, having wide implications for optimization of this technique with a range of topically applied solutes.

Cell Membrane Permeability↗

PubMed2000

Ion-pair formation as a strategy to enhance topical delivery of salicylic acid.

An in-vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion-pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physicochemical properties of the counter-ions and salicylate flux was examined. It was found that flux can be related to the conductivity associated with the penetrant solution, molecular size of the counter-ion and lipophilicity expressed as either octanol/water partition coefficient of the ion pairs or the carbon chain-length of the counter-ions. Equations have been developed to predict salicylate flux from these physicochemical parameters.

Administration, Cutaneous↗

PubMed2000

Effect of ion pairing with alkylamines on the in-vitro dermal penetration and local tissue disposition of salicylates.

Hydrophilic ionic drugs can be rendered lipophilic by ion-pair formation with hydrophobic counter-ions. This study examines the value of forming ion pairs between anionic salicylate and a series of amines as model cationic counter-ions to facilitate topical delivery and skin penetration. The in-vitro translocation of salicylate ions from a nonaqueous vehicle through human epidermis was estimated in the presence or absence of amines. The distribution into, and accumulation of the salicylate ion in various tissues following topical application to anaesthetised rats were also investigated. Although the epidermal permeation constants of the salicylate-amine ion pairs were lower than that of salicylate itself (enhancement ratios: 0.74-0.87), salicylate retention and localisation in the underlying rat tissues increased in the presence of some of the counter-ions studied. Salicylate concentrations (microg (g tissue)(-1)) in the dermis were 877.2+/-78.6 for salicylate alone and 1098+/-121.9-2586+/-332.5 for salicylate-amine ion pairs. The levels of salicylate in tissues up to the top muscle layer were 1.2-3.7-fold higher in the presence of the counter-ions. It is concluded that, although amine counter-ions have the ability to influence the penetration of salicylate, in-vitro permeability studies do not reflect the in-vivo increases in tissue concentrations resulting from probable changes in systemic clearance.

Administration, Topical↗