Clinical Pharmacology in Sarcoidosis: How to Use and Monitor Sarcoidosis Medications.

When sarcoidosis needs treatment, pharmacotherapy is usually required. Although glucocorticoids work reliably and relatively quickly for sarcoidosis, these drugs are associated with numerous significant side effects. Such side effects are common in sarcoidosis patients, as the disease frequently has a chronic course and glucocorticoid treatment courses are often prolonged. For these reasons, corticosteroid-sparing and corticosteroid-replacing therapies are often required for sarcoidosis. Unfortunately, many healthcare providers who care for sarcoidosis patients are not familiar with the use of these agents. In this manuscript, we provide a review of the pharmacotherapy of sarcoidosis. We discuss the mechanism of action, dosing, side-effect profile, approach to monitoring and patient counselling concerning glucocorticoids, and the common alternative drugs recommended for use in the recent European Respiratory Society (Lausanne, Switzerland) Sarcoidosis Treatment Guidelines. We also discuss the use of these agents in special situations including hepatic insufficiency, renal insufficiency, pregnancy, breastfeeding, vaccination, and drug-drug interactions. It is hoped that this manuscript will provide valuable practical guidance to clinicians who care for sarcoidosis patients.

Patient Perception of Cardiovascular Risk in Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have higher incidence of cardiovascular diseases (CVDs) compared with age- and sex-matched controls. The objective of our study was to measure the knowledge of patients with RA about the association between their disease and cardiovascular (CV) risk and to measure the frequency of counseling by physicians based on patient report. METHODS: A telephone survey was conducted among patients with RA enrolled in the Consortium of Rheumatology Researchers of North America RA registry to collect data on medical and social history and on knowledge about CVD risk in RA and how they learned about that risk. Multivariable logistic regression models were performed to determine the factors associated with patients' knowledge and factors influencing likelihood of physician counseling. The odds ratios (ORs) represent adjusted multivariable results. RESULTS: Of 185 patients with RA included in the study, 87 patients (47%) were aware that RA was a CV risk factor. Older age (OR 0.6; 95% confidence interval [CI] 0.4-0.8 per decade) and smoking (OR 0.4; 95% CI 0.1-0.9) were associated with low awareness, whereas disease duration of more than 10 years (OR 5.2; 95% CI 2.2-12.1) was positively associated with patient knowledge. Counseling by physicians, mostly rheumatologists, on CV risk in RA was reported by 47 patients (25%). Disease duration of more than 10 years (OR 3.9; 95% CI 1.2-13.1) was positively associated with patient-reported counseling. Patients with hypertension were less likely to report counseling (OR 0.4; 95% CI 0.2-0.9). CONCLUSION: Our study demonstrated low patient awareness of CV risk with RA and low rates of patient-reported counseling by physicians. This is an unmet need in clinical practice, which may be overcome by multimodal approaches such as developing websites, organizing symposiums, and involving health care providers at various levels.

The development of sarcoidosis in patients receiving daclizumab: A case series from multiple clinical trials.

INTRODUCTION: Several drugs have been associated with druginduced sarcoidosis-like reactions (DISRs) that are clinically indistinguishable from sarcoidosis. Daclizumab is a humanized monoclonal IgG1 antibody that binds to CD25 that has been studied for the treatment of multiple sclerosis (MS). During MS clinical trials of daclizumab, 12 subjects developed clinical conditions potentially consistent with sarcoidosis. Therefore, an independent adjudication committee of individuals with expertise in sarcoidosis was organized to determine the likelihood of these cases representing sarcoidosis. METHODS: The adjudication committee consisted of a pulmonologist, pathologist, and radiologist with clinical experience in sarcoidosis. The committee had access to the subjects' laboratory data, narratives of all suspect adverse reaction reports, radiographic imaging and histology from biopsies. A priori, a grading system was developed to determine criteria to establish the likelihood that the patient had developed sarcoidosis. RESULTS: The adjudication confirmed sarcoidosis in 11/12 subjects. The committee's decisions were unanimous in all cases. Biopsies were available in 7/11 of these. In the 4 subjects who did not have a biopsy, they all had presentations, clinical findings, and/or laboratory findings that were highly specific for sarcoidosis. Alternative causes for these clinical findings were reasonably excluded in all cases. The lung (8/11) and skin (6/11) were the most common organs involved. The mean daclizumab dose given when signs or symptoms of sarcoidosis occurred was 5413 ±â€¯2704 mg and the median time from first daclizumab dose was 996 days. The incidence rate of developing sarcoidosis in those participating in these daclizumab trials was 154/100,000 patient-years compared with incidence rates of sarcoidosis in the United States of 3.2-17.8/100,000/year. These data suggest that these sarcoidosis cases may have represented DISRs related to daclizumab therapy. CONCLUSIONS: Given the clinical presentation and subsequent evaluation of these 11 subjects, we suspect that they had DISRs from daclizumab.

Luminescent mesoporous nanoreservoirs for the effective loading and intracellular delivery of therapeutic drugs.

Development of biocompatible and multifunctional nanocarriers is important for the therapeutic efficacy of drug molecules in the treatment of disease and tissue repair. A novel nanocarrier of luminescent hollowed mesoporous silica (L-hMS) was explored for the loading and controlled delivery of drugs. For the synthesis of L-hMS, self-activated luminescence hydroxyapatite (LHA) was used as a template. Different thicknesses (∼ 7-62 nm) of mesoporous silica shell were obtained by varying the volume of silica precursor and the subsequent removal of the LHA core, which resulted in hollow-cored (size of ∼ 40 nm × 10 nm) mesoporous silica nanoreservoirs, L-hMS. While the silica shell provided a highly mesoporous structure, enabling an effective loading of drug molecules, the luminescent property of LHA was also well preserved in both the silica-shelled and the hollow-cored nanocarriers. Doxorubicin (DOX), used as a model drug, was shown to be effectively loaded onto the mesopore structure and within the hollow space of the nanoreservoir. The DOX release was fairly pH-dependent, occurring more rapidly at pH 5.3 than at pH 7.4, and a long-term sustainable delivery over the test period of 2weeks was observed. The nanoreservoir exhibited favorable cell compatibility with low cytotoxicity and excellent cell uptake efficiency (over 90%). Treatment of HeLa cells with DOX-loaded L-hMS elicited a sufficient degree of biological efficacy of DOX, as confirmed in the DOX-induced apoptotic behaviors, including stimulation in caspase-3 expression, and was even more effective than the direct DOX treatment. Overall, the newly developed L-hMS nanoreservoirs may be potentially useful as a multifunctional (luminescent, mesoporous and biocompatible) carrier system to effectively load and sustainably deliver small molecules, including anticancer drugs.

Silica-based mesoporous nanoparticles for controlled drug delivery.

Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles.

Conceptualizing functional cognition in stroke.

BACKGROUND: Up to 65% of individuals demonstrate poststroke cognitive impairments, which may increase hospital stay and caregiver burden. Randomized stroke clinical trials have emphasized physical recovery over cognition. Neuropsychological assessments have had limited utility in randomized clinical trials. These issues accentuate the need for a measure of functional cognition (the ability to accomplish everyday activities that rely on cognitive abilities, such as locating keys, conveying information, or planning activities). OBJECTIVE: The aim of the study was to present the process used to establish domains of functional cognition for development of computer adaptive measure of functional cognition for stroke. METHODS: Functional cognitive domains involved in identifying relevant neuropsychological constructs from the literature were conceptualized and finalized after advisory panel feedback from experts in neurology, neuropsychology, aphasiology, clinical trials, and epidemiology. RESULTS: The following 17 domains were proposed: receptive aphasia, expressive aphasia, agraphia, alexia, calculation, visuospatial, visuoperceptual, visuoconstruction, attention, language usage, executive functions, orientation, processing speed, memory, working memory, mood, awareness and abstract reasoning. The advisory panel recommended retaining the first 12 domains. Recommended changes included: to address only encoding and retrieval of recent information in the memory domain; to add domains for limb apraxia and poststroke depression; and to keep orientation as a separate domain or reclassify it under memory or attention. The final 10 domains included: language, reading and writing, numeric/calculation, limb praxis, visuospatial function, social use of language, emotional function, attention, executive function, and memory. CONCLUSION: Conceptualizing domains of functional cognition is the first step in developing a computer adaptive measure of functional cognition for stroke. Additional steps include developing, refining, and field-testing items, psychometric analysis, and computer adaptive test programming.

Measuring stroke impact with SIS: construct validity of SIS telephone administration.

OBJECTIVES: The purpose of this study was to examine the construct validity of the Stroke Impact Scale (SIS) using telephone mode of administration. METHODS: Stroke patients were identified using national VA administrative data and ICD-9 codes in 13 participating VA hospitals. Stroke was confirmed by reviewing electronic medical records. Patients were administered SIS by telephone at 12-weeks post-stroke, and administered the Functional Independence Measure (FIM) and SF-36V at 16 weeks post-stroke. The instrument's convergent validity and its ability to differentiate between groups of stroke patients with different disability levels were examined using Pearson's correlations and Kruskal-Wallis one way ANOVA tests. RESULTS: All the relevant relationships yielded high correlation coefficients with statistical significance: 0.86 for FIM-motor vs. SIS-ADL, and 0.77 for PF in SF-36V vs. SIS-PHYSICAL. The SIS presented better score discrimination and distribution for different severity of stroke than FIM and SF-36V without severe ceiling and floor effects. Kruskal-Wallis tests showed the Physical Component Score of SF-36V did not discriminate any disability levels. Physical functioning (PF) in SF-36V, FIM-motor, SIS-PHYSICAL, SIS-16, and SIS-ADL showed better discrimination in person's functioning. The pairwise comparisons showed that SIS-PHYSICAL, SIS-16, and SIS-ADL discriminated more Rankin levels than FIM-motor and PF in SF-36V. CONCLUSIONS: SIS telephone survey had superior convergent validity and was better at differentiating between groups of stroke patients with different disability levels than the FIM and SF-36V with no evidence of ceiling and floor effects. Telephone administration of SIS would be a useful and cost-effective method to follow-up community dwelling veterans with stroke.

Measuring stroke impact with the stroke impact scale: telephone versus mail administration in veterans with stroke.

OBJECTIVES: The purpose of this study was to examine response rate, mode effects, and reliability of the Stroke Impact Scale (SIS) in a veteran stroke population using mail and telephone modes of administration. METHODS: Patients who had suffered a stroke were identified using national VA administrative data and International Classification of Diseases, 9th Revision codes in 13 participating Veterans Affairs hospital. Stroke was confirmed by reviewing electronic medical records. Patients were randomized to SIS administration by mail or telephone at 12-weeks after their stroke. Comparison of response rate, nonresponse bias, domain scores, administration costs, and instrument reliability were performed. RESULTS: Four hundred fifty-eight patients with stroke were identified, validated, and randomly assigned into 2 administration groups. No significant cluster effect was observed. Response rates for mail and telephone were 45% and 69%, respectively. Mail nonresponders were more likely to have had severe stokes, cognitive deficits, and be unmarried. No difference was observed between telephone responders and nonresponders. Responders in mail and telephone modes were not different, and the SIS score distribution did not indicate the presence of mode effects. Test-retest reliability was good to excellent in the mail group (0.77-0.99) except social participation (0.62). Test retest reliability was excellent in the telephone mode (0.90-0.99) except emotion (0.68). CONCLUSIONS: Telephone mode of survey administration yielded a higher response rate, less bias in responder selection, and higher test-retest reliability. The cost of telephone administration was 2 times the cost of mail. Mode effects in SIS score distribution were not observed in this study but additional research with larger sample sizes is needed to provide more definitive evidence.

Disability measures in stroke: relationship among the Barthel Index, the Functional Independence Measure, and the Modified Rankin Scale.

BACKGROUND AND PURPOSE: Residual disability after stroke presents a major economic and humanistic burden. To quantify disability in patients, activities of daily living (ADL; Barthel Index [BI], and motor component of Functional Independence Measure [M-FIM]) and categorical disability measures (Modified Rankin Scale [MRS]) are used. The purpose of this study is to examine the predicting ability of ADL measures to global disability scale. METHODS: Kansas City Stroke Study data were used for the present study. Correlation coefficient, Kruskal-Wallis test, and polytomous logistic regression analysis were applied to examine the relationship between the ADL measure and global disability scale. Model fit statistics were examined to verify logistic regression appropriateness. A categorization scheme, which minimized the false-positive response rate, was selected as the optimal categorizing system. RESULTS: The 3 measures were highly correlated. Both BI and M-FIM differentiated disability better in lower than higher disability. In logistic regression, BI differentiated 4 disability levels; M-FIM differentiated 3 levels in MRS. However, on the basis of results of the Kruskal-Wallis and multiple comparison tests, we suspect that M-FIM may have the potential to predict MRS categories better with a different model. CONCLUSIONS: The proposed categorization scheme can serve as a translation between measures. However, because of the ceiling effect of BI and M-FIM, the translation could not be completed for all 6 levels of MRS. No apparent variation over time in the categorization scheme was observed. Further research needs to be conducted to develop better prediction models explaining the relationship between M-FIM and MRS.