The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.
Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.
Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS. 相似文献
This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation. 相似文献
The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide.We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery. 相似文献
ContextPalliative care is gaining ground globally and is endorsed in high-level policy commitments, but service provision, supporting policies, education, and funding are incommensurate with rapidly growing needs.ObjectivesThe objective of this study was to describe current levels of global palliative care development and report on changes since 2006.MethodsAn online survey of experts in 198 countries generated 2017 data on 10 indicators of palliative care provision, fitted to six categories of development. Factor analysis and discriminant analysis showed the validity of the categorization. Spearman correlation analyses assessed the relationship with World Bank Income Level (WBIL), Human Development Index (HDI), and Universal Health Coverage (UHC).ResultsNumbers (percentages) of countries in each development category were as follows: 1) no known palliative care activity, 47 (24%); 2) capacity-building, 13 (7%); 3a) isolated provision, 65 (33%); 3b) generalized provision, 22 (11%); 4a) preliminary integration into mainstream provision, 21 (11%); 4b) advanced integration, 30 (15%). Development levels were significantly associated with WBIL (rS = 0.4785), UHC (rS = 0.5558), and HDI (rS = 0.5426) with P < 0.001. Net improvement between 2006 and 2017 saw 32 fewer countries in Categories 1/2, 16 more countries in 3a/3b, and 17 more countries in 4a/4b.ConclusionPalliative care at the highest level of provision is available for only 14% of the global population and is concentrated in European countries. An 87% global increase in serious health-related suffering amenable to palliative care interventions is predicted by 2060. With an increasing need, palliative care is not reaching the levels required by at least half of the global population. 相似文献
AbstractThis research explores how the level of consumers’ need for cognition (NFC) is associated with celebrity endorser credibility and examines its effects on advertising-related attitudes. A 3 (endorser types: actor/actress, athlete, TV personality/talent) × 2 (endorser’s gender) factorial experiment with 435 Japanese consumers was conducted. Concerning Japanese OTC drug advertising, lower NFC individuals perceived celebrity endorsers as more credible in comparison to higher NFC individuals. The main effects of NFC and endorser type on endorser credibility existed; however, no interaction between the two variables was found. The endorser type had an influence on attitudes toward ads and the advertised brand. 相似文献
Osteoarthritis (OA) is a highly prevalent joint disease that is associated with pain, loss of function, and high direct and indirect economic costs. The current therapeutic options are inadequate, providing only a moderate symptom relief without the possibility of disease modification. While treatment options and personalized medicines are increasing for many complex diseases, OA drug development has been impeded by the advanced state of disease at the time of diagnosis and intervention, heterogeneity in both symptoms and rates of progression, and a lack of validated biomarkers and relevant outcome measures. This review article summarizes the OA landscape, including therapies in development as potential OA treatments, potential biomarkers undergoing evaluation by the US Food and Drug Administration, and a summary of current OA treatment guidelines, with a particular focus on the knee OA. 相似文献