European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
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Resveratrol (RES), chemically known as 3,5,4'-trihydroxy-trans-stilbene, is a promising multi-targeted anti-oxidative and anti-inflammatory natural polyphenol. Preclinical studies showed its biological activities against the pathogens of sexually transmitted diseases causing vaginal inflammation and infections. Due to its low solubility and poor bioavailability, the optimal therapeutic uses are limited. ⋯ The anti-oxidative activities of RES and its corresponding liposomal formulation were also compared by measuring enhanced superoxide dismutase (SOD) activities in lipopolysaccharide (LPS)-induced J774A.1 cells. In vitro anti-inflammatory activities were compared by measuring nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in LPS-induced J774A.1 cells. Liposomal RES was found to exhibit stronger anti-oxidative and anti-inflammatory activities than RES solution.
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Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. ⋯ The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.
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Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. ⋯ Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
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Clinical Trial
Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration--a dose escalation study.
To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. ⋯ A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.
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Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured. ⋯ This model was subsequently applied on literature data on methotrexate brain distribution in other healthy and diseased rats (brainECF), healthy dogs (CSF) and diseased children (CSF) and adults (brainECF and CSF). Important differences between brainECF and CSF kinetics were found, but we have found that inhibition of Mrp/Oat/Oatp-mediated active transport processes does not significantly influence the relationship between brainECF and CSF fluid methotrexate concentrations. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, combined with advanced mathematical modeling is a most valid approach to develop SBPK models that allow for revealing the mechanisms underlying the relationship between brainECF and CSF concentrations in health and disease.