Exenatide is a glucagon-like peptide 1 receptor agonist, which has recently received FDA approval in the US for the treatment of Type 2 diabetes. Exenatide is an incretin mimetic that improves glycaemic control in patients with diabetes through acute mechanisms, such as glucose-dependent stimulation of insulin secretion, suppression of inappropriate glucagon secretion and slowing of gastric emptying, as well as chronic mechanisms that include enhancement of β-cell mass in rodent studies and weight loss and inhibition of food intake in humans. This article reviews the mechanisms of exenatide action, as well as its efficacy in the treatment of Type 2 diabetes. 相似文献
We evaluated the pharmacodynamic effects of apremilast in 69 patients who were included in biomarker subanalyses of a phase 2b study that demonstrated the long‐term safety and efficacy of apremilast in Japanese adults with moderate to severe psoriasis. The association between cytokine levels and Psoriasis Area and Severity Index (PASI) improvement was evaluated using linear regression and Spearman’s rank correlation coefficient analysis. At baseline, median plasma levels of interleukin (IL)‐17A, IL‐17F and IL‐22 were elevated versus reference values for healthy individuals, whereas tumor necrosis factor‐α levels were close to normal. With apremilast 30 mg b.i.d., there were significant associations between percentage change in PASI score and percentage change in IL‐17A, IL‐17F and IL‐22 levels at week 16. Findings demonstrate that the efficacy of apremilast in psoriasis is associated with inhibition of key cytokines involved in the pathology of psoriasis. 相似文献
Introduction: Treatment of HIV infection has consistently evolved in the last three decades. A steady improvement in efficacy tolerability, safety, and practical aspects of treatment intake has made HIV infection much easier to manage over the long term, and in optimal treatment conditions the life expectancy of persons living with HIV infection now approaches the values of the general population. The last category of antiretrovirals to be fully developed for clinical use is the one of strand-transfer integrase inhibitors (INSTIs).
Areas covered: In this review, the evolution of the knowledge on INSTIs use in the clinical setting is reviewed, analyzed, and interpreted. Emphasis is placed on the properties possibly accounting for several superiority results achieved by INSTIs in non-inferiority designed comparative clinical trials, which led to their inclusion as first line options in all versions of HIV therapeutic guidelines.
Expert commentary: Some unprecedented clinical-pharmacological properties of INSTIs, such as their rapid and sustained action against HIV replication, the optimal tolerability and safety profile and a clinically proven robust genetic barrier are the main factors justifying the successful clinical use of INSTIs. Based on these unique features, novel INSTIs-based treatment modalities are being developed, including the reduction of antiretroviral regimens to two drugs only. 相似文献
Severe sepsis often leads to multiple organ dysfunction syndromes (MODS) with acute kidney injury (AKI). AKI affects approximately, 35% of Intensive Care Unit patients, and most of these are due to sepsis. Mortality rate of sepsis-induced AKI is high. Inappropriate use of antimicrobials may be responsible for higher therapeutic failure, mortality rates, costs and toxicity as well as the emergence of resistance. Antimicrobial treatment is particularly difficult due to altered pharmacokinetic profile, dynamic changes in patient''s clinical status and, in many cases, need for renal replacement therapy. This article aims to describe the appropriate antimicrobial dosing and reviews the factors contributing to the difficulties in establishing precise guidelines for antimicrobial dosing in sepsis-induced AKI patients. Search strategy: Text material was collected by systematic search in PubMed, Google (1978–2013) for original articles. 相似文献
What is known and Objective: Dexmedetomidine is a selective alpha2‐adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects. Methods: A randomized, double‐blind, placebo‐controlled study with three parallel dosage groups was conducted. Twenty‐four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 μg/kg/h for 10 min followed by 0·17 μg/kg/h for 50 min (low dose), 6 μg/kg/h for 10 min followed by 0·34 μg/kg/h for 50 min (middle dose) and 3·7 μg/kg/h for 35 min followed by 0·7 μg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non‐compartmental methods (WinNonlin®), and a population PK model was developed using nonmem ®. The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment. Results: Six subjects were assigned to each of the three active treatment group or placebo group. The AUClast of the low‐, middle‐ and high‐dose group were 1096·8 ± 119·9 (mean ± SD) ng*h/L, 2643·0 ± 353·2 ng*h/L and 5600·6 ± 411·0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two‐compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19·9 (age/27)0·954, peripheral volume of distribution (L) = 59·4, clearance (L/h) = 33·7 (albumin level/4·3)1·42 and inter‐compartment clearance (L/h) = 67·7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable. What is new and Conclusion: Dexmedetomidine shows linear PK characteristics and dose‐dependent sedative effects. A two‐compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians. 相似文献
The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied. 相似文献