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1.
Circulation ; 141(4): 285-300, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31707831

RESUMO

BACKGROUND: Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared with adult cardiomyocytes. Immaturity of iPSC-derived cardiomyocytes may be a significant barrier to clinical translation of cardiomyocyte cell therapies for heart disease. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of rapamycin (mTOR)-signaling pathway plays a key role in nutrient sensing and growth. We hypothesized that transient inhibition of the mTOR-signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. METHODS: Cardiomyocytes were differentiated from 3 human iPSC lines using small molecules to modulate the Wnt pathway. Torin1 (0 to 200 nmol/L) was used to inhibit the mTOR pathway at various time points. We quantified contractile, metabolic, and electrophysiological properties of matured iPSC-derived cardiomyocytes. We utilized the small molecule inhibitor, pifithrin-α, to inhibit p53 signaling, and nutlin-3a, a small molecule inhibitor of MDM2 (mouse double minute 2 homolog) to upregulate and increase activation of p53. RESULTS: Torin1 (200 nmol/L) increased the percentage of quiescent cells (G0 phase) from 24% to 48% compared with vehicle control (P<0.05). Torin1 significantly increased expression of selected sarcomere proteins (including TNNI3 [troponin I, cardiac muscle]) and ion channels (including Kir2.1) in a dose-dependent manner when Torin1 was initiated after onset of cardiomyocyte beating. Torin1-treated cells had an increased relative maximum force of contraction, increased maximum oxygen consumption rate, decreased peak rise time, and increased downstroke velocity. Torin1 treatment increased protein expression of p53, and these effects were inhibited by pifithrin-α. In contrast, nutlin-3a independently upregulated p53, led to an increase in TNNI3 expression and worked synergistically with Torin1 to further increase expression of both p53 and TNNI3. CONCLUSIONS: Transient treatment of human iPSC-derived cardiomyocytes with Torin1 shifts cells to a quiescent state and enhances cardiomyocyte maturity.

2.
Circulation ; 140(5): 390-404, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31311300

RESUMO

BACKGROUND: Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. METHODS: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. RESULTS: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. CONCLUSIONS: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.

3.
Clin Drug Investig ; 39(9): 899-908, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31190195

RESUMO

BACKGROUND AND OBJECTIVE: Little evidence exists regarding the marginal decrease in health-related quality of life (HRQoL) in relation to the presence of hypertension among a Hispanic population based on US population-based research. METHOD: This cross-sectional study used data from the 2014 to 2015 Medical Expenditure Panel Survey (MEPS). The target population was comprised of Hispanic community-dwelling residents with hypertension in the USA. The independent variable was the presence of hypertension. The dependent variable was HRQoL, which was measured using the Short Form-12 (SF-12) physical health composite scale (PCS) and mental health composite scale (MCS). RESULTS: A total of 13,933 members of the Hispanic population met the study inclusion criteria, and the estimated population size was 36,440,400 Hispanics. Among them, 82.9% did not have any hypertensive condition (n = 11,466), while 17.7% had some hypertensive condition (n = 2467). SF-12 PCS scores (95% CI) were 46.62 (45.68-47.57) in the Hispanic population with hypertension and 51.62 (51.1-52.14) in the Hispanic population without hypertension. SF-12 MCS scores (95% CI) were 52.67 (52.07-53.27) in patients without hypertension and 50.35 (49.45-51.26) in the Hispanic population with hypertensive conditions. CONCLUSION: The presence of hypertension was associated with lower HRQoL in the Hispanic population. Based on our findings, we suggest that healthcare providers should monitor a hypertensive minority population for anxiety and mood disorders and recommend psychiatric assessment and treatment if appropriate.


Assuntos
Hispano-Americanos , Hipertensão/fisiopatologia , Qualidade de Vida , Adulto , Estudos Transversais , Feminino , Humanos , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados Unidos
4.
Clin Drug Investig ; 39(8): 703-712, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102109

RESUMO

BACKGROUND AND OBJECTIVE: A systematic review and meta-analysis were performed to determine the cumulative effect of pharmacist-led transitions of care on the 30-day all-cause readmission rates of patients with congestive heart failure with the objective to isolate and assess the effect of pharmacy intervention to a condition-specific service. Previous studies that review pharmacist-led transitional care services involve multiple condition-specific services or a pharmacy service integrated into the healthcare team that presents complications in interpreting the independent effectiveness of component services by pharmacy professionals. METHODS: A systematic review was conducted using articles identified from MEDLINE, CINAHL, Web of Science, Embase, the Cochrane Library, and clinicaltrials.gov databases for studies on congestive heart failure readmission rates based on transitions of care pharmacist services using detailed inclusion and exclusion criteria. Abstracts were screened for outcome of interest and appropriate transitions of care program structure. Practice and patient characteristics were described and compared to identify current practice trends. A meta-analysis was then performed utilizing previously identified studies from systematic analysis that reported the required data to calculate the effect size. Evidence was reviewed and appraised according to the Newcastle-Ottawa Scale for cohort studies. RESULTS: The database search produced 443 potential articles for inclusion. Six articles were identified for inclusion in the systematic review based on abstract screening. Of the six articles included in the systematic review, three studies met inclusion criteria for a meta-analysis. Two studies in the meta-analysis stated a significant reduction in the 30-day all-cause readmission rate for patients with congestive heart failure, while the third depicted a reduction in readmission that was found to be non-significant. The pooled effect of the included articles found that pharmacist-led transitions of care services for patients with congestive heart failure had an increased odds to have lower all-cause readmission rates of patients with congestive heart failure (odds ratio = 2.19, 95% confidence interval 1.50-3.20). Based on the meta-analysis of three studies, pharmacist-led transitions of care services significantly reduced the odds of 30-day all-cause readmission rates in patients with congestive heart failure compared with standard-of-care discharge protocols. CONCLUSION: Results of the meta-analysis demonstrate the capacity for pharmacist-led transitions of care programs to reduce 30-day all-cause readmission rates in patients with congestive heart failure compared with non-pharmacist discharge care. The financial implications of transitions of care pharmacist involvement have yet to be validated. In general, existing database search results highlight the lack of evidence detailing specific clinical outcomes of pharmacist-led transitions of care services in distinct chronic conditions. Future studies may serve to compare patient-centered outcomes between condition-specific services or across disciplines to provide the most cost-effective delivery of care.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Readmissão do Paciente , Farmacêuticos , Doença Crônica , Estudos de Coortes , Análise Custo-Benefício , Assistência à Saúde , Insuficiência Cardíaca/diagnóstico , Humanos , Alta do Paciente
5.
Mol Metab ; 16: 76-87, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30120064

RESUMO

OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.


Assuntos
Ciclopentanos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Ciclopentanos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humulus/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina/fisiologia , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
6.
Anal Bioanal Chem ; 410(24): 6141-6154, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29744562

RESUMO

Due to the unique physicochemical properties exhibited by materials with nanoscale dimensions, there is currently a continuous increase in the number of engineered nanomaterials (ENMs) used in consumer goods. However, several reports associate ENM exposure to negative health outcomes such as cardiovascular diseases. Therefore, understanding the pathological consequences of ENM exposure represents an important challenge, requiring model systems that can provide mechanistic insights across different levels of ENM-based toxicity. To achieve this, we developed a mussel-inspired 3D microphysiological system (MPS) to measure cardiac contractility in the presence of ENMs. While multiple cardiac MPS have been reported as alternatives to in vivo testing, most systems only partially recapitulate the native extracellular matrix (ECM) structure. Here, we show how adhesive and aligned polydopamine (PDA)/polycaprolactone (PCL) nanofiber can be used to emulate the 3D native ECM environment of the myocardium. Such nanofiber scaffolds can support the formation of anisotropic and contractile muscular tissues. By integrating these fibers in a cardiac MPS, we assessed the effects of TiO2 and Ag nanoparticles on the contractile function of cardiac tissues. We found that these ENMs decrease the contractile function of cardiac tissues through structural damage to tissue architecture. Furthermore, the MPS with embedded sensors herein presents a way to non-invasively monitor the effects of ENM on cardiac tissue contractility at different time points. These results demonstrate the utility of our MPS as an analytical platform for understanding the functional impacts of ENMs while providing a biomimetic microenvironment to in vitro cardiac tissue samples. Graphical Abstract Heart-on-a-chip integrated with mussel-inspired fiber scaffolds for a high-throughput toxicological assessment of engineered nanomaterials.


Assuntos
Bivalves , Coração/efeitos dos fármacos , Dispositivos Lab-On-A-Chip , Nanofibras/toxicidade , Nanoestruturas/toxicidade , Tecidos Suporte , Adesivos , Animais , Células Cultivadas , Técnicas In Vitro , Indóis/química , Microscopia Eletrônica de Varredura , Miócitos Cardíacos/citologia , Poliésteres/química , Polímeros/química , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier
7.
Invest Ophthalmol Vis Sci ; 59(5): 1704-1716, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29610853

RESUMO

Purpose: The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. Methods: Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354. Results: sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted. Conclusions: MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.


Assuntos
Anti-Hipertensivos/farmacologia , Ativadores de Enzimas/farmacologia , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Administração Oftálmica , Animais , Anti-Hipertensivos/administração & dosagem , Células Cultivadas , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ativadores de Enzimas/administração & dosagem , Glaucoma/fisiopatologia , Humanos , Imuno-Histoquímica , Macaca fascicularis , Hipotensão Ocular/tratamento farmacológico , Soluções Oftálmicas , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Coelhos , Malha Trabecular/metabolismo
8.
SLAS Discov ; 22(10): 1239-1245, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28787579

RESUMO

Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is becoming an important technology to determine the distribution of drugs and their metabolites in the tissue of preclinical species after dosing. Interest in IMS is growing in the ophthalmology field, but little work to this point has been done to investigate ocular drug transit using this technology. Information on where and how a drug is distributing through the eye is important in understanding efficacy and whether it is reaching the desired target tissue. For this study, ocular distribution of brimonidine was investigated in rabbits following topical administration. Brimonidine has been shown to lower intraocular pressure and is approved to treat glaucoma, the second leading cause of blindness in the world. We have developed IMS methods to assess transit of topically administered brimonidine from the anterior to the posterior segment of rabbit eyes. Using IMS, brimonidine was detected in the cornea, aqueous humor, iris, and posterior segments of the eye. The distribution of brimonidine suggests that the route of transit following topical administration is mainly through the uvea-scleral route. This study demonstrates that IMS can be applied to assess ocular transit and distribution of topically administered drugs.


Assuntos
Tartarato de Brimonidina/farmacologia , Olho/efeitos dos fármacos , Imagem Tridimensional , Espectrometria de Massas , Animais , Coelhos , Processamento de Sinais Assistido por Computador , Fatores de Tempo
9.
Clin Drug Investig ; 37(10): 957-963, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28735450

RESUMO

BACKGROUND AND OBJECTIVES: Despite the introduction of Medicare Part D (MPD) and 2012 Affordable Care Act (ACA), patients have a cost burden due to increases in drug prices. To overcome cost barriers, some patients purchase their medications from Canadian online pharmacies as Canadian prescription drug prices are believed to be lower than US prescription drug prices. The objective of this study was to determine which top 100 Medicare drugs can be imported to the USA legally, and to determine which type of prescription drug would be more beneficial to be purchased from Canadian online pharmacies. Moreover, we also deemed it important to compare MPD beneficiary annual expenses with expenses patients would have when obtaining their prescriptions from Canadian online pharmacies. METHODS: We conducted a cost analysis from a patient perspective. A list of the top 100 Medicare drugs was compiled and information on drug prices was collected from three Canadian online pharmacies and four MPD plans in Virginia. The annual cost of each Medicare drug and percent change between Canadian online pharmacies and MPD were compared. RESULTS: A total of 78 drugs from the top 100 Medicare drugs were included in the final analysis. Seventy-six prescription drugs (97.4%) that could be purchased from Canadian online pharmacies showed a significantly lower average drug price percent change of -72.71% (P < 0.0001). The heart health/blood pressure subgroup had the highest number of drugs that could be purchased from Canadian online pharmacies. CONCLUSION: The majority of prescription drugs can be purchased at lower prices from Canadian online pharmacies when compared to Medicare beneficiaries' potential expenses. Purchasing medications from Canadian online pharmacies may be a viable option to address cost barriers.


Assuntos
Custos de Medicamentos/estatística & dados numéricos , Disponibilidade de Medicamentos Via Internet/estatística & dados numéricos , Medicamentos sob Prescrição/economia , Canadá , Custos e Análise de Custo , Prescrições de Medicamentos , Humanos , Seguro de Serviços Farmacêuticos , Medicare , Patient Protection and Affordable Care Act , Estados Unidos
10.
J Res Pharm Pract ; 6(1): 12-15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331860

RESUMO

Recent case reports in medical literatures suggest that more and more second-generation atypical antipsychotics (AAs) have been prescribed for off-label use; quetiapine (Brand name: Seroquel®) showed increase in its trend for off-label use. Little is known about the reasons behind this trend, although historical sedative and hypnotic prescription patterns suggest that despite relatively superior safety profiles of quetiapine (especially for movement disorders), it may be used for treating substance abuse disorder. In addition, recent studies have shown a strong potential for misuse and abuse (MUA) of quetiapine beyond Food and Drug Administration-approved indications. This includes drug-seeking behaviors, such as feigning symptoms, motivated by quetiapine and use of quetiapine in conjunction with alcohol. Quetiapine appears to be the most documented AA with street values bartered illicitly on the street. A recent report from the Drug Abuse Warning Network has shown a high prevalence of quetiapine-related emergency department visits involving MUA. Several other case studies have found that quetiapine causes seeking behaviors observed in substance use disorder. In fact, the majority of quetiapine MUA involved patients diagnosed with substance use disorder. In the absence of a definitive mechanism of action of quetiapine's reinforcing properties, it is imperative to gather robust evidence to support or refute increasing off-label use of AAs.

11.
Jpn J Nurs Sci ; 14(2): 161-170, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27734627

RESUMO

AIM: The purpose of this study was to develop the Diabetes Self-Management Behavior for Older Koreans (DSMB-O). This scale is based on the seven relevant domains that have been identified by the American Association of Diabetes Educators (AADE) and is adjusted for sociocultural and age-related characteristics. METHODS: Four phases were used to develop of the DSMB-O as a criterion-referenced measure. In phases 1 and 2, the DSMB-O adopted the AADE's seven domains and established a self-report questionnaire using a small number of items that are applicable to older Koreans. In phase 3, the DSMB-O was formulated with 16 preliminary items, including seven subitems. By assessing the content validity, 14 items (including five subitems) were selected. The final phase involved evaluating the DSMB-O's psychometric properties, including test-retest reliability, content validity, and criterion-related validity, using data from 150 older Koreans with type 2 diabetes. RESULTS: The coefficients of agreement and Cohen's Kappa for the test-retest reliability test ranged from 0.32 to 1.0 and -0.07 to 1.0, respectively. For the content validity, the values of both the item- and scale-level content validity indices were 1.0. The scores from the DSMB-O were positively correlated with the scores from the Korean version of the Summary of Diabetes Self-Care Activities Questionnaire. CONCLUSION: The DSMB-O is short and easy for older Koreans to use, as well as having acceptable levels of reliability and validity. Hence, the DSMB-O can be a useful tool to evaluate diabetes self-management behaviors in older Koreans with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/reabilitação , Autogestão , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Autocuidado , Inquéritos e Questionários , Estados Unidos
12.
J Med Chem ; 59(10): 4711-23, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27187609

RESUMO

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/normas , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade
13.
J Pharm Sci ; 105(3): 1277-87, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26886320

RESUMO

We present a systematic evaluation of the Wajima superpositioning method to estimate the human intravenous (i.v.) pharmacokinetic (PK) profile based on a set of 54 marketed drugs with diverse structure and range of physicochemical properties. We illustrate the use of average of "best methods" for the prediction of clearance (CL) and volume of distribution at steady state (VDss) as described in our earlier work (Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):178-191; Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):167-177). These methods provided much more accurate prediction of human PK parameters, yielding 88% and 70% of the prediction within 2-fold error for VDss and CL, respectively. The prediction of human i.v. profile using Wajima superpositioning of rat, dog, and monkey time-concentration profiles was tested against the observed human i.v. PK using fold error statistics. The results showed that 63% of the compounds yielded a geometric mean of fold error below 2-fold, and an additional 19% yielded a geometric mean of fold error between 2- and 3-fold, leaving only 18% of the compounds with a relatively poor prediction. Our results showed that good superposition was observed in any case, demonstrating the predictive value of the Wajima approach, and that the cause of poor prediction of human i.v. profile was mainly due to the poorly predicted CL value, while VDss prediction had a minor impact on the accuracy of human i.v. profile prediction.


Assuntos
Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/metabolismo , Administração Intravenosa/métodos , Animais , Cães , Haplorrinos , Humanos , Ratos , Análise de Regressão , Especificidade da Espécie
14.
Perm J ; 20(1): 74-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26824966

RESUMO

Cutaneous metastasis of rectal cancer is rare. It typically indicates widespread disease and poor prognosis. We report an exceedingly rare case of rectal cancer with metastasis to the skin and review the literature on cutaneous metastasis of rectal cancer. A 47-year-old man presented with stage IV unresectable adenocarcinoma of the rectum and received palliative chemoradiation for local pain control. About a year later he developed extensive skin lesions involving the genital area, bilateral groin, and perineum. Biopsy specimen showed mucinous adenocarcinoma compatible with rectal origin. Palliative treatment with radiation therapy was initiated. The patient responded well to treatment and is still alive more than a year after diagnosis of cutaneous metastasis. Surgeons should maintain strong suspicion of cutaneous metastases when patients with rectal cancer have new or evolving skin lesions.


Assuntos
Adenocarcinoma , Metástase Neoplásica , Neoplasias Retais/patologia , Adenocarcinoma/radioterapia , Idoso , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/radioterapia , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/radioterapia
15.
Perm J ; 19(4): 71-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26517438

RESUMO

Neuroendocrine tumors are either epithelial or neural in origin. Neuroendocrine tumors of the retroperitoneum are mostly metastatic. Primary epithelial neuroendocrine tumors of the retroperitoneum are exceedingly rare. We describe a case of a retroperitoneal tumor that was discovered incidentally during exploratory laparotomy for small-bowel obstruction. Histopathologic and immunochemical analyses of the biopsied mass were consistent with an epithelial neuroendocrine tumor. The tumor was subsequently removed and final analyses confirmed the initial diagnosis. No evidence of lymph nodes or paraganglia were found within the tumor on histologic examination. Extensive evaluation did not reveal any other primary or metastatic lesions. Therefore, the diagnosis of primary epithelial neuroendocrine tumor of the retroperitoneum was made. The literature is reviewed and discussed. To date, this is only the fifth reported case of primary epithelial retroperitoneal neuroendocrine tumor. Although extremely rare, the possibility of such diagnosis should be included in the differential diagnosis of a retroperitoneal tumor.


Assuntos
Tumores Neuroendócrinos/diagnóstico , Neoplasias Retroperitoneais/diagnóstico , Idoso , Feminino , Humanos , Enteropatias/patologia , Necrose , Tumores Neuroendócrinos/patologia , Neoplasias Retroperitoneais/patologia
16.
Res Theory Nurs Pract ; 29(2): 94-112, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26062288

RESUMO

Development of behavior theory-based health promotion programs is encouraged with the paradigm shift from contents to behavior outcomes. This article describes the development process of the diabetes self-management program for older Koreans (DSME-OK) using intervention mapping (IM) protocol. The IM protocol includes needs assessment, defining goals and objectives, identifying theory and determinants, developing a matrix to form change objectives, selecting strategies and methods, structuring the program, and planning for evaluation and pilot testing. The DSME-OK adopted seven behavior objectives developed by the American Association of Diabetes Educators as behavioral outcomes. The program applied an information-motivation-behavioral skills model, and interventions were targeted to 3 determinants to change health behaviors. Specific methods were selected to achieve each objective guided by IM protocol. As the final step, program evaluation was planned including a pilot test. The DSME-OK was structured as the 3 determinants of the IMB model were intervened to achieve behavior objectives in each session. The program has 12 weekly 90-min sessions tailored for older adults. Using the IM protocol in developing a theory-based self-management program was beneficial in terms of providing a systematic guide to developing theory-based and behavior outcome-focused health education programs.


Assuntos
Diabetes Mellitus/terapia , Educação de Pacientes como Assunto/organização & administração , Autocuidado , Diabetes Mellitus/psicologia , Humanos , Motivação
18.
PLoS One ; 9(9): e108392, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25268237

RESUMO

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.


Assuntos
Anti-Hipertensivos/farmacocinética , Felodipino/farmacocinética , Interações Alimento-Droga/fisiologia , Modelos Estatísticos , Interface Usuário-Computador , Anti-Hipertensivos/sangue , Disponibilidade Biológica , Simulação por Computador , Jejum/fisiologia , Felodipino/sangue , Esvaziamento Gástrico/fisiologia , Trato Gastrointestinal/fisiopatologia , Trânsito Gastrointestinal/fisiologia , Humanos , Absorção Intestinal/fisiologia , Intestinos/fisiologia , Período Pós-Prandial/fisiologia , Medicina de Precisão , Solubilidade
19.
Patient Prefer Adherence ; 8: 219-26, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24627626

RESUMO

PURPOSE: To describe strategies for enhancing information, motivation, and skills related to changes in diabetes self-management behavior among community-dwelling older adults in Korea. PATIENTS AND METHODS: A total of five focus group interviews (three separate focus groups) were conducted with 12 older adults with type 2 diabetes and five diabetes educators. Qualitative content analysis was used. RESULTS: "One's own willingness and ability" emerged as a fundamental belief about the strategies for diabetes self-management. Six major themes under three categories were identified. Under the information category, the recurrent themes were: 1) repeatedly offering detailed knowledge regarding self-management, 2) providing information about current health status, and 3) identifying experiential knowledge of blood glucose control. The recurrent themes in the motivation category were: 1) ensuring a positive attitude regarding self-management, and 2) encouragement or feedback from significant others. Furthermore, in the skills category, we found that the following theme emerged: hands-on skills training with numerical standards. CONCLUSION: This study identified six tailored strategies for enhancing information, motivation, and skills for diabetes self-management behavior changes. These strategies can be used in the development of a culturally sensitive diabetes self-management program for older adults.

20.
Stud Health Technol Inform ; 192: 333-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23920571

RESUMO

According to WHO, pediatric diabetes is a rising global public health problem, with increasing impact on developing nations. This study summarizes a multidimensional, scalable pilot evaluation of a diabetes self-management platform combining mobile technology with social networking to capture four key metrics of Type 1 diabetes self-management, associated social interactions, and gaming features providing targeted feedback to 8 pediatric users. Based on their 2-month interaction with the application, we analyze click-stream data from social interactions, key health metrics, text comments, and usability and satisfaction surveys to evaluate engagement with the platform and effectiveness in controlling blood glucose using a product-process-program framework. Our preliminary results indicate that this framework was successful in demonstrating the potential of the mobile health platform to effectively leverage the growing use of mobile applications and social media to present a unique benefit that engaged pediatric users and provided useful insights for self-health management.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diagnóstico por Computador/métodos , Quimioterapia Assistida por Computador/métodos , Aplicativos Móveis/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Autocuidado/estatística & dados numéricos , Adolescente , Criança , Feminino , Humanos , Projetos Piloto , Validação de Programas de Computador
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