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PubMed2025

A Causal Effect of Serum 25(OH)D Level on Appendicular Muscle Mass: Evidence From NHANES Data and Mendelian Randomization Analyses.

BACKGROUND: Low serum vitamin D status was reported to be associated with reduced muscle mass; however, it is inconclusive whether this relationship is causal. This study used data from the National Health and Nutrition Examination Survey (NHANES) and two-sample Mendelian randomization (MR) analyses to ascertain the causal relationship between serum 25-hydroxyvitamin D [25(OH)D] and appendicular muscle mass (AMM). METHODS: In the NHANES 2011-2018 dataset, 11 242 participants (5588 males and 5654 females) aged 18-59 years old were included, and multivariant linear regression was performed to assess the relationship between 25(OH)D and AMM measured by dual-energy X-ray absorptiometry. In two-sample MR analysis, 167 single nucleotide polymorphisms significantly associated with serum 25(OH)D at the genome-wide association level (p < 5 × 10-8) were applied as instrumental variables (IVs) to assess vitamin D effects on AMM in the UK Biobank (417 580 Europeans) using univariable and multivariable MR (MVMR) models. RESULTS: In the NHANES dataset, serum 25(OH)D concentrations were positively associated with AMM (β = 0.013, SE = 0.001, p < 0.001) in all participants, after adjustment for age, race, season of blood collection, education, income, body mass index and physical activity. In stratification analysis by sex, males (β = 0.024, SE = 0.002, p < 0.001) showed more pronounced positive associations than females (β = 0.003, SE = 0.002, p = 0.024). In univariable MR, genetically higher serum 25(OH)D levels were positively associated with AMM in all participants (β = 0.049, SE = 0.024, p = 0.039) and males (β = 0.057, SE = 0.025, p = 0.021), but only marginally significant in females (β = 0.043, SE = 0.025, p = 0.090) based on IVW models was noticed. No significant pleiotropy effects were detected for the IVs in the two-sample MR investigations. In MVMR analysis, a positive causal effect of 25(OH)D on AMM was observed in the total population (β = 0.116, SE = 0.051, p = 0.022), males (β = 0.111, SE = 0.053, p = 0.036) and females (β = 0.124, SE = 0.054, p = 0.021). CONCLUSIONS: Our results suggested a positive causal effect of serum 25(OH)D concentration on AMM; however, more researches are warranted to unveil the underlying biological mechanisms and evaluate the effects of vitamin D intervention on AMM.

Humans↗

PubMed2006

Determination of polycyclic aromatic hydrocarbons in olive oil by a completely automated headspace technique coupled to gas chromatography-mass spectrometry.

A new and completely automated method for the determination of ten relevant polycyclic aromatic hydrocarbons (PAHs) in olive oil is proposed using an extraction by the headspace (HS) technique. Quantification and confirmation steps are carried out by gas chromatography-mass spectrometry (GC-MS) combining simultaneously selected-ion monitoring (SIM) and tandem mass spectrometry (MS/MS). This combination offers on one hand an increased sensitivity and on the other hand, selective and reliable qualitative information. Sample pretreatment or clean-up are not necessary because the olive oil sample is put directly into an HS vial, automatically processed by HS and introduced into the GC-MS instrument for analysis. Because of its high selectivity and sensitivity, a triple-quadrupole (QqQ) detector coupled with the gas chromatograph allows us to limit handling. Each sample is completely processed in approximately 63 min (45 min for HS isolation and 18 min for GC-MS determination), a reduced time compared with previously published methods. The chemical and instrumental variables were preliminarily optimized using uncontaminated olive oil samples spiked with 25 microg kg(-1) of each target compound. The final method was validated to ensure the quality of the results. The precision was satisfactory, with relative standard deviation (RSD) values in the range 3-9%. Recovery rates ranged from 96 to 99%. Limits of detection (LOD) were calculated as 0.02-0.06 microg kg(-1) and the limits of quantification (LOQ) were obtained as 0.07-0.26 microg kg(-1). It must be mentioned that the LOD and LOQ are much lower than the maximum levels established by the European Union (EU) in oils and fats intended for direct human consumption or for use as an ingredient in foods, which are set at 2 microg kg(-1). All the figures of merit are completely in accordance with the latest EU legislation. This fact makes it possible to consider the proposed method as a useful tool for the control of PAHs in olive oils.

Food Analysis↗

PubMed2026

Subtype-Specific Causal Effects of C16 and C24 Ceramides on Heart Failure: Evidence From Univariable and Multivariable Mendelian Randomization Analyses.

Ceramides (Cer) are bioactive lipids implicated in cardiovascular disease (CVD), yet their subtype-specific causal effects remain unclear. We performed a two-sample Mendelian randomization (MR) analysis using publicly available GWAS summary statistics to investigate the effects of C16:0-ceramide homologs (Cer16:0) and C24:1-ceramide homologs (Cer24:1) on six CVD outcomes. Instrumental variables were rigorously selected, and multiple MR methods were applied to ensure robust inference. Univariable MR identified a significant inverse association between Cer(d18:1/24:1) and heart failure (HF), which remained significant after false discovery rate correction. In contrast, the association for Cer(d17:1/16:0) did not remain significant after correction. No causal associations were observed for other CVD outcomes. When aggregating subtypes, genetically predicted higher total Cer16:0 levels were associated with increased HF risk, while no significant association was found for total Cer24:1. Multivariable MR further demonstrated that the protective effect of Cer(d18:1/24:1) on HF was robust, while estimates for C16 subtypes were attenuated and sensitive to model specification. In conclusion, our findings support a stable protective role of Cer(d18:1/24:1) in HF and highlight the complexity of subtype-specific effects among structurally related ceramides. These results underscore the importance of considering ceramide heterogeneity in cardiovascular research. Further studies are warranted to validate these findings and explore their clinical implications.

Ceramides↗

PubMed2004

Are Colombian sickness funds cream skimming enrollees? An analysis with suggestions for policy improvement.

One of the primary objectives of Colombian social health insurance reform was to increase competition among for-profit insurers. Unfortunately, the flat capitated formula creates an opportunity for sickness funds to maximize reimbursement gains by cream skimming--selecting against unhealthy individuals. This paper explores sickness fund selection behavior to evaluate the efficiency losses associated with the introduction of managed competition in Colombia. Data from a 1997 Colombian household survey are analyzed with a bivariate probit model with partial observability using instrumental variables. The model yields some evidence of sickness fund selection based on health status. Public policy options to discourage risk selection by health status are discussed.

Colombia↗

PubMed2006

Does sex education affect adolescent sexual behaviors and health?

This study examines whether offering sex education to young teenagers affects several measures of adolescent sexual behavior and health: virginity status, contraceptive use, frequency of intercourse, likelihood of pregnancy, and probability of contracting a sexually transmitted disease. Using data from the National Longitudinal Study of Adolescent Health, I find that while sex education is associated with adverse health outcomes, there is little evidence of a causal link after controlling for unobserved heterogeneity via fixed effects and instrumental variables. These findings suggest that those on each side of the ideological debate over sex education are, in a sense, both correct and mistaken. Opponents are correct in observing that sex education is associated with adverse health outcomes, but are generally incorrect in interpreting this relationship causally. Proponents are generally correct in claiming that sex education does not encourage risky sexual activity, but are incorrect in asserting that investments in typical school-based sex education programs produce measurable health benefits.

Adolescent↗

PubMed2005

Exercise manages fatigue during breast cancer treatment: a randomized controlled trial.

Fatigue is the most prevalent and debilitating symptom experienced by breast cancer patients receiving adjuvant chemotherapy or radiation therapy and few evidence-based treatments are available to manage this distressing side-effect. The purpose of this multi-institutional randomized controlled trial was to determine the effects of exercise on fatigue levels during treatment for breast cancer. Sedentary women (N=119) with Stage 0-III breast cancer receiving outpatient adjuvant chemotherapy or radiation therapy were randomized to a home-based moderate-intensity walking exercise program or to usual care for the duration of their cancer treatment. Of participants randomized to exercise, 72% adhered to the exercise prescription; 61% of the usual care group adhered. The intention-to-treat analysis revealed no group differences in part because of a dilution of treatment effect as 39% of the usual care group exercised and 28% of the exercise group did not. When exercise participation was considered using the data analysis method of instrumental variables with principal stratification, a clinically important and statistically significant (p=0.03) effect of exercise on pretest-to-posttest change in fatigue levels was demonstrated. Adherence to a home-based moderate-intensity walking exercise program may effectively mitigate the high levels of fatigue prevalent during cancer treatment.

Adult↗

PubMed2005

Correlated errors in biased surrogates: study designs and methods for measurement error correction.

A measurement error model proposed previously allows for correlations between subject-specific biases and between random within-subject errors in the surrogates obtained from two modes of measurement. However, most of these model parameters are not identifiable from the standard validation study design, including, importantly, the attenuation factor needed to correct for bias in relative risk estimates due to measurement error. We propose validation study designs that permit estimation and inference for the attenuation factor and other parameters of interest when these correlations are present. We use an estimating equations framework to develop semi-parametric estimators for these parameters, exploiting instrumental variables techniques. The methods are illustrated through application to data from the Nurses' Health Study and Health Professionals' Follow-up Study, and comparisons are made to more restrictive models.

Bias↗

PubMed2005

Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.

In traditional epidemiological studies the association between phenotype (risk factor) and disease is often biased by confounding and reverse causation. As a person's genotype is assigned by a seemingly random process, genes are potentially useful instrumental variables for adjusting for such bias. This type of adjustment combines information on the genotype-disease association and the genotype-phenotype association to estimate the phenotype-disease association and has become known as Mendelian randomization. The information on genotype-disease and genotype-phenotype may well come from a meta-analysis. In such a synthesis, a multivariate approach needs to be used whenever some studies provide evidence on both the genotype-phenotype and genotype-disease associations. This paper presents two multivariate meta-analytical models, which differ in their treatment of the heterogeneities (between-study variances). Heterogeneities on the genotype-phenotype and genotype-disease associations may be highly correlated, but a multivariate model that parameterizes the heterogeneity directly is difficult to fit because that correlation is poorly estimated. We advocate an alternative model that treats the heterogeneities on genotype-phenotype and phenotype-disease as being independent. This model fits readily and implicitly defines the correlation between the heterogeneities on genotype-phenotype and genotype-disease. We show how either maximum likelihood or a Bayesian approach with vague prior distributions can be used to fit the alternative model.

Coronary Disease↗

PubMed2006

Random effects logistic models for analysing efficacy of a longitudinal randomized treatment with non-adherence.

We present a random effects logistic approach for estimating the efficacy of treatment for compliers in a randomized trial with treatment non-adherence and longitudinal binary outcomes. We use our approach to analyse a primary care depression intervention trial. The use of a random effects model to estimate efficacy supplements intent-to-treat longitudinal analyses based on random effects logistic models that are commonly used in primary care depression research. Our estimation approach is an extension of Nagelkerke et al.'s instrumental variables approximation for cross-sectional binary outcomes. Our approach is easily implementable with standard random effects logistic regression software. We show through a simulation study that our approach provides reasonably accurate inferences for the setting of the depression trial under model assumptions. We also evaluate the sensitivity of our approach to model assumptions for the depression trial.

Humans↗

PubMed2006

Rater bias in a blinded randomized placebo-controlled psychiatry trial.

Rater bias occurs when rater knowledge of treatment assignment modifies the outcome assessment. Raters may be unconsciously influenced by inclinations for or against a particular treatment and consequently may give a more or less generous assessment depending upon these biases. Blinding of raters by keeping raters unaware of treatment assignment is one way to limit bias influencing assessment due to knowledge of treatment assignment. Unblinding may be particularly problematic in efficacy studies comparing placebo to drugs and/or non-drug psychotherapy treatments where subjects may reveal drug side-effects or mention their therapist by name, thus unblinding their treatment assignment. We present a new instrumental variable statistical approach for assessing the association between success in blinding and its impact on efficacy estimates of active drug and/or cognitive behavioural psychotherapy versus placebo in the multicentre comparative treatment study of panic disorder. Despite the uncertainty involved in assessing bias that may be unobserved and unconscious, we will show how to derive a bound for the impact of rater bias.

Bias↗

PubMedDate not supplied

A method for the analysis of repeated binary outcomes in randomized clinical trials with non-compliance.

When analysing repeated binary data from randomized trials, the model-based approaches, such as generalized estimating equations, are frequently used. Such methods ignore compliance information and give the model-based intention-to-treat estimate of treatment effect. In this paper, the design-based (randomization-based) semi-parametric estimation procedure is given in the estimation of causal risk difference. The resulting risk difference estimator is interpreted as an extension of the instrumental variables estimator for a binary outcome which has the causal interpretation. Extension of the proposed method to stratified analysis is given for data from stratified randomization or meta-analysis. It yields a Mantel-Haenszel type risk difference estimator. As a special case of stratified analysis, the pattern mixture model which stratifies the data by pattern of missing data is performed. Application of the proposed method to a trial in which endpoints were the occurrences of fever over three courses is provided. The same ideas are applied to the causal risk ratio estimation.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2025

A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.

Peripheral facial paralysis (PFP) is a common neurological disorder characterized by facial-nerve dysfunction. Identifying therapeutic targets and understanding the molecular and cellular mechanisms underlying PFP are crucial for developing effective treatment strategies. This study combined Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq) to explore potential therapeutic candidates and their roles in PFP pathophysiology. The MR analysis included 1925 publicly available plasma protein cis-heritability instruments. Instrumental variables were selected for MR analysis to identify plasma proteins associated with PFP, followed by colocalization analysis to evaluate shared genetic variants between the identified proteins and PFP. After the initial identification of plasma proteins associated with Bell's palsy using MR analysis, a rat model of facial-nerve injury was established to further dissect underlying mechanisms at cellular and molecular levels. Using scRNA-seq technology, we delved deeply into cellular Heterogeneity and dynamic changes in gene expression in the facial-nerve nucleus tissues under both injured and control conditions, thereby achieving a systematic study ranging from macroscopic genetic associations to microscopic cellular functions. Finally, expression patterns were preliminarily validated by performing in vitro immunofluorescence analysis on the facial-nerve nucleus samples of SD rats. The MR analysis results identified 30 plasma proteins significantly associated with PFP, with nine target genes showing differential expression in the scRNA-seq data. Colocalization analysis demonstrated that slit guidance Ligand 2 (SLIT2), semaphorin 4D (SEMA4D), EGF containing fibulin extracellular matrix protein 1 (EFEMP1), and sprouty related EVH1 domain containing 2 (SPRED2) shared causal variants with PFP. SLIT2 was highly expressed in the microglia and inhibitory neurons in the experimental group, whereas SEMA4D showed elevated expression across multiple glial cell types in the same group. In contrast, EFEMP1 and SPRED2 showed distinct expression patterns in fibroblasts and oligodendrocytes. The role of SLIT2 has been previously well-documented in many central nervous system diseases. However, for the first time, this study detected SLIT2 alteration after facial-nerve injury. Altered intercellular signaling, particularly enhanced SLIT2-ROBO signaling between neurons and glial cells, was observed in the PFP group. Pseudotime analysis revealed dynamic SLIT2 expression during microglia and inhibitory neuron differentiation, mirroring changes in ROBO1 expression. Immunofluorescence analysis of rat facial-nerve nucleus samples verified that SLIT2 protein levels were significantly increased in the facial-nerve nuclei of injured samples. In conclusion, despite the fact that this study is primarily founded on animal models and despite notable differences existing between animals and humans in terms of the facial motor nucleus, this study successfully identified SLIT2 as potential therapeutic targets for PFP. The SLIT2-ROBO axis stands out as a particularly promising candidate. SLIT2 may play a role in modulating neuroimmune interactions and promoting nerve repair. These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

Animals↗

PubMed2005

The impact of subsidized health insurance for the poor: evaluating the Colombian experience using propensity score matching.

This paper evaluates the impact of Colombia's subsidized health insurance program (SUBS) on medical care utilization. Colombia's SUBS program is a demand-side subsidy intended for low-income families, where the screening of beneficiaries takes place in decentralized locations across the country. Due to the self-selection problems associated with non-experimental data, we implement Propensity Score Matching (PSM) methods to measure the impact of this subsidy on medical care utilization. By combining unique household survey data with community and regional data, we are able to compute propensity scores in a way that is consistent with both the local government's decision to offer the subsidy, and with the individual's decision to accept the subsidy. Although the application of PSM using these rich datasets helps to achieve a balance between the treatment and control groups along observable dimensions, we also present instrumental variable estimates to control for the potential endogeneity of program participation. Using both methods, we find that Colombia's subsidized insurance program greatly increased medical care utilization among the country's poor and uninsured. This evidence supports the case for other Latin American countries implementing similar subsidy programs for health insurance for the poor.

Adolescent↗

PubMed2025

Mendel randomization confirmed gastroesophageal reflux disease may increase the risk of mental disorders.

BACKGROUND: The potential causal relationship between gastroesophageal reflux disease (GERD) and mental disorder was analyzed using the mendelian randomization (MR) method. METHODS: Data are derived from genome-wide association study (GWAS) summary data, using gastroesophageal reflux disease (GERD) as the exposure factor. Single nucleotide polymorphisms (SNPs) significantly associated with GERD were selected as instrumental variables (IVs), and mental disorders (bipolar disorder, major depression, Alzheimer's disease, anorexia nervosa, anxiety, and obsessive-compulsive disorder) were used as outcome variables. The inverse variance weighted (IVW) method is used as the main analysis method, and MR-Egger regression, weighted median (WM) method, simple mode and weighted mode are used as supplementary methods for Mendelian randomization (MR) analysis. Cochran's Q test and P value are used to quantify heterogeneity, MR-Egger regression was used to evaluate the multilevel effect test of SNPs, and leave-one-out method to determine whether there are potential SNPs, and to evaluate the stability of the results. Odds ratio (OR) and 95% confidence interval (CI) were used as effect indicators to evaluate whether there is a causal relationship between GERD and mental disorders. RESULTS: IVW demonstrated a causal relationship between GERD and bipolar disorder (OR = 1.70, 95%CI = 1.39-2.09, P < 0.05) and anorexia nervosa (OR = 0.71, 95%CI = 0.52-0.99, P < 0.05). Furthermore, there is a weak causal relationship between GERD and major depression (OR = 1.01, 95%CI = 1.01-1.02, P < 0.05) and anxiety (OR = 1.01, 95%CI = 1.01-1.01, P < 0.05). Similarly, there is no evidence of a causal relationship between GERD and Alzheimer's disease (OR = 0.95, 95%CI = 0.87-1.03, P > 0.05) or obsessive-compulsive disorder (OR = 0.95, 95%CI = 0.67-1.36, P > 0.05). Cochran's Q test for heterogeneity shows that there is no significant heterogeneity (P > 0.05) for bipolar disorder, anxiety, and obsessive-compulsive disorder. However, major depression, Alzheimer's disease, and anorexia nervosa have some degree of heterogeneity (P < 0.05). Horizontal pleiotropic analysis showed that the P values for six mental disorders (0.750, 0.296, 0.154, 0.798, 0.893, 0.451) were all greater than 0.05. Leave-one-out analysis and funnel plot showed that MR analysis results can be considered relatively stable. All F are > 10, indicating no weak IVs bias. CONCLUSION: GERD can obviously increase the risk of bipolar disorder; the increased risk of anxiety disorder is very slight. There is no clear evidence to support the causal relationship between GERD and four other mental disorders, including major depression, Alzheimer's disease, anorexia nervosa, and obsessive-compulsive disorder.

Humans↗

PubMed1992

Moratorium-achievement (MAMA) cycles in lifespan identity development: value orientations and reasoning system correlates.

Three important questions emerging in identity research are: Why do only some persons with Foreclosed identities move on to Identity Achievement? Why do some Identity Achievement persons move "back" to Foreclosure? How can life-span identity re-formulation be accounted for? This study proposes that individual's positions on two variables, "instrumental vs. experiential orientation" and formistic vs. dialectrical thinking, may be important in answering these questions. Among 60 university students, 23 males and 37 females, those in an identity status characterized by formation and maintenance of structure (Foreclosure) were instrumentally-oriented while those characterized by openness to change and revision (Moratorium) were experientially-oriented. Similarly, more Moratoriums than other statuses were high in dialectic thinking. These results are discussed in terms of their theoretical implications for life-span identity development.

Adult↗

PubMed1990

Air pollution, cigarette smoking, and the production of respiratory health.

Previous studies of the determinants of respiratory health have treated both smoking and air pollution as being exogenous. Using an instrumental variables approach, we estimate a simple production technology in which smoking is treated as being endogenously determined. Doing so, we find, increases the predicted absolute effects of smoking on respiratory health; relative to air pollution, smoking becomes a more important determinant when it is treated as an endogenous variable.

Absenteeism↗

PubMed2026

Exploring causal associations between autoimmune diseases and hearing loss: a mendelian randomization study.

OBJECTIVE: The causal relationship between Autoimmune Diseases (ADs) and Hearing Loss (HL) remains unclear. This study investigates whether genetic predispositions associated with ADs contribute to HL risk. METHODS: Mendelian Randomization (MR) analysis was conducted to explore the causal effects of ADs on HL. SNPs from Genome-Wide Association Studies (GWAS) were used as instrumental variables for ADs, including Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), Ankylosing Spondylitis (AS), Multiple Sclerosis (MS), Crohn's Disease (CD), and Ulcerative Colitis (UC). Outcome data included Sensorineural Hearing Loss (SNHL), Conductive Hearing Loss (CHL), Mixed conductive and sensorineural Hearing Loss (MHL), and Sudden Idiopathic Hearing Loss (SIHL). MR analyses employed Inverse Variance Weighted (IVW) as the primary method, supplemented with MR-Egger, weighted median, and weighted mode. Heterogeneity, pleiotropy, and sensitivity were evaluated using Cochran's Q test, MR-Egger regression, MR-PRESSO, and leave-one-out analysis. RESULTS: The IVW method identified nine significant associations: MS-SIHL (OR = 1.0494, 95% CI 1.0072-1.0934), AS-CHL (OR = 1.2832, 95% CI 1.0643-1.5472), AS-MHL (OR = 1.5994, 95% CI 1.3696-1.8678), AS-SNHL (OR = 1.1903, 95% CI 1.1104-1.276), AS-SIHL (OR = 1.481, 95% CI 1.22-1.798), SLE-CHL (OR = 1.0593, 95% CI 1.0116-1.1092), UC-MHL (OR = 1.0907, 95% CI 1.0027-1.1865), CD-CHL (OR = 1.0529, 95%CI: 1.0074-1.1005), and CD-SIHL (OR = 1.0597, 95% CI 1.0177-1.1034). Among these, outliers were detected only in AS-SNHL. After outlier removal, the AS-SNHL association remained significant (OR = 1.1722, p < 0.00001), with resolved heterogeneity and pleiotropy. No heterogeneity and pleiotropy were found for the other associations. CONCLUSION: This study identified nine significant AD-HL associations, emphasizing the need for targeted screening and management of HL in individuals with AD. LEVEL OF EVIDENCE: Level 5.

Humans↗

PubMed2006

Characterization of hot-melt extruded drug delivery systems for onychomycosis.

The objectives of this investigation were to study the physico-chemical properties of hot-melt extruded (HME) films for onychomycosis and to determine the stability of the model antifungal drug incorporated within these films. The influence of etching and instrument variables on the bioadhesion of these drug delivery systems for the human nail was also studied. Six 250 g batches (F1-F6) of hydroxypropyl cellulose (HPC) and/or poly(ethylene oxide) films containing ketoconazole (20%) were extruded using a Killion extruder (Model KLB-100). The thermal properties of HME films were investigated using differential scanning calorimetry (DSC). Scanning electron microscopy (SEM) was used to examine the surface morphology of the films and X-ray diffraction (XRD) was used to investigate the crystalline properties of the drugs, physical mixtures as well as the HME films. Stability studies were performed on the films stored at 25 degrees C/60%RH. The bioadhesive properties of these films were investigated on the human nail (ex vivo) using a Texture Analyzer. The nail samples tested were either non-treated (control) or treated with an etching gel. The parameters measured were peak adhesion force (PAF) and area under the curve (AUC). The Hansen solubility parameter was calculated using a combination of Hoy and Hoftyzer/Van Krevelen methods to estimate the likelihood of drug-polymer miscibility. SEM provided direct physical evidence of the physical state of the drug within the films. The theoretical post-extrusion content of ketoconazole remaining in the six film batches ranged from 90.3% (+/-2.2) to 102.4% (+/-9.0) for up to 6 months and from 83.9% (+/-3.6) to 91.6% (+/-3.0) for up to 12 months. Bioadhesion studies of HPC film tested on 'etched' nails recorded significantly higher PAF and AUC than that of the non-treated 'control' nails. Ketoconazole was found to be relatively stable during the extrusion process. Melting points corresponding to the crystalline drugs were not observed in the processed films. The Hansen solubility parameters predicted miscibility between the polymers and the drug. The predictions of the solubility parameters were in agreement with DSC, XRD and SEM results. Bioadhesion measurements of the film on the human nail substrate were generally higher for the etched nails than that of the control nails.

Adhesiveness↗