Kwang Choon Yee

Elevated plasma glutathione peroxidase concentration in acute severe asthma: Comparison with plasma glutathione peroxidase activity, selenium and malondialdehyde

Objective. To investigate plasma glutathione peroxidase concentration, glutathione peroxidase activity, plasma selenium and oxidative stress in acute severe asthma. Material and methods. The study was case‐control in design, with cases presenting to the emergency department with acute severe asthma and controls randomly selected from a larger cross‐sectional study. Plasma malondialdehyde (MDA) was used as a measure of oxidative stress and plasma selenium was measured using ICP‐MS. Glutathione peroxidase (GPx) activity was analysed using a colorimetric GPx assay and plasma GPx level was measured by enzyme‐linked immunosorbent assay (ELISA). Results. Fifteen cases [mean (range) predicted peak expiratory flow rate (PEFR) of 43% (20–69)] and 15 matched controls were recruited. MDA levels (mean±SD) were higher in acute asthma subjects (1.30±0.56 µmol/L) than in controls (0.86±0.53 µmol/L; p<0.05). There were no differences between cases and controls for selenium (99±34 µg/L versus 109±17 µg/L) or for GPx activity (39±25 nmol min−1 mL−1 versus 38±24 nmol min−1 mL−1), however, GPx plasma levels measured by ELISA were higher in cases than controls (22.5±10.8 mg/L versus 13.8±7.3 mg/L; p<0.05). Conclusions. Patients with acute severe asthma demonstrated increased MDA levels but no differences in plasma selenium levels or GPx activity. GPx levels measured by ELISA were elevated in severe asthma. These results are consistent with an adaptive up‐regulation of GPx to protect against oxidative stress.

SULT 1A3 single-nucleotide polymorphism and the single dose pharmacokinetics of inhaled salbutamol enantiomers: are some athletes at risk of higher urine levels?

The study was designed to investigate the effect of a common genetic variation of the main salbutamol metabolizing enzyme SULT1A3 (single nucleotide polymorphism 105A>G, rs1975350) on the stereoselective pharmacokinetics of salbutamol. Subjects were administered a 400 µg dose of inhaled salbutamol via a large volume spacer and blood samples were collected over 4 h. Plasma levels of (R)- and (S)-salbutamol were determined by an enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Twenty-five subjects with asthma were recruited and underwent SULT1A3 genotyping, from which four SNP homozygote (GG) subjects and nine wild-type (AA) subjects were selected to participated in the pharmacokinetic investigation. There were no differences in pharmacokinetic parameters (t1/2 , Cmax , AUC0-4h ) between SNP and wild-type genotypes for either the R- or S-enantiomer. Observed Cmax of R- and S-salbutamol [mean (SD)] was 0.64 (0.30) ng/mL and 1.32 (0.98) ng/mL, respectively. The mean t1/2 of R- and S-salbutamol was estimated at 2.94 (1.17) h and 7.86 (6.14) h respectively. The AUC0-4h of R- and S-salbutamol was 14.0 (6.8) and 38.3 (19.5) ng/mL.h respectively. In conclusion, the common SULT1A3 SNP 105A>G is not an important determinant of salbutamol enantiomer pharmacokinetics under normal clinical use and does not place some individuals at greater risk of accumulation in the body.

Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle

Significant enhancement of skeletal muscle function has been observed with racemic albuterol (salbutamol). There is now general acceptance that the R-albuterol enantiomer elicits the pharmacological response, both in the lungs and extrapulmonary, while S-albuterol is pharmacologically inert. The objective of this study was to investigate the distribution of (R/S)-albuterol enantiomers into skeletal and cardiac muscle. Initially oral dosing was undertaken in neonatal mice administered a maximum tolerable dose of racemic albuterol. An in vivo infusion rat model was employed for the investigation of albuterol uptake into skeletal and cardiac muscle over 4 h. Tissue concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). From the oral dosing model, mean (±SD) levels of racemic albuterol after 5 days were 915 (±293) ng/mL in plasma, 2574 (±196) ng/g in muscle, and 53 (±6.6) ng/g in brain with enantioselective partitioning (muscle:plasma ratio of 5.7 and 1.7 for R- and S-albuterol, respectively). In the infusion model, enantioselective disposition was observed in skeletal muscle (muscle:plasma ratio of 1.2-1.7 and 0.6-0.7 for R- and S-albuterol, respectively) and in cardiac muscle (4.1 and 0.5, respectively). In conclusion, there is greater partitioning of active (R)-albuterol than inactive (S)-albuterol into both skeletal and cardiac muscle compared to plasma. These findings have relevance for albuterol sports doping, cardiac effects, and therapeutic use in muscle wasting diseases. Furthermore, the greater muscle partitioning of the active R-albuterol, and the availability of pure R-albuterol formulations highlight shortcomings in doping control measures using non-enantioselective assays.

Cardiovascular Risk Assessment in Prediabetes and Undiagnosed Diabetes Mellitus Study: International Collaboration Research Overview

The study aims to develop a screening protocol for the risk of future cardiovascular disease and diabetes mellitus in people with prediabetes and undiagnosed diabetes; and to establish a framework for early identification and intervention of prediabetes including strategies for holistic management and monitoring of progression. The first phase is to identify prediabetes and undiagnosed diabetes in volunteers who are ≥18-years-old for 5 years. Point-of-care testing and questionnaire will be used to screen for prediabetes and cardiovascular disease. We anticipate screening more than 2000 individuals of both genders by the end of first phase. The second and third phases which shall run for 5-10 years will be longitudinal study involving participants identified in the first phase as having prediabetes without dyslipidaemia, or clinically established cardiovascular disease. The second phase shall focus on preventive management of risk of progress to diabetes with explicit diagnosis of cardiovascular disease. Oxidative stress measurements will be performed cum evaluation of the use of antioxidants, exercise, and nutrition. The third phase will include probing the development of diabetes and cardiovascular disease. Binomial logistic regression would be performed to generate and propose a model chart for the assessment of cardiovascular disease risk in prediabetes.

Albuterol enantiomer levels, lung function and QTc interval in patients with acute severe asthma and COPD in the emergency department

BackgroundThis observational study was designed to investigate plasma levels of albuterol enantiomers among patients with acute severe asthma or COPD presenting to the emergency department, and the relationship with extra-pulmonary cardiac effects (QTc interval) and lung function. Recent reviews have raised concerns about the safety of using large doses of β2-agonists, especially in patients with underlying cardiovascular comorbidity. It has been demonstrated that significant extrapulmonary effects can be observed in subjects given nebulised (R/S)-albuterol at a dose of as little as 6.5 mg.MethodsBlood samples were collected and plasma/serum levels of (R)- and (S)-albuterol enantiomers were determined by LC-MS and LC-MS/MS assay. Extra-pulmonary effects measured at presentation included ECG measurements, serum potassium level and blood sugar level, which were collected from the hospital medical records.ResultsHigh plasma levels of both enantiomers were observed in some individuals, with median (range) concentrations of 8.2 (0.6-24.8) and 20.6 (0.5-57.3) ng/mL for (R)- and (S)- albuterol respectively among acute asthma subjects, and 2.1 (0.0-16.7) to 4.1 (0.0-36.1) ng/mL for (R)- and (S)- albuterol respectively among COPD subjects. Levels were not associated with an improvement in lung function or adverse cardiac effects (prolonged QTc interval).ConclusionsHigh plasma concentrations of albuterol were observed in both asthma and COPD patients presenting to the emergency department. Extra-pulmonary cardiac adverse effects (prolonged QTC interval) were not associated with the plasma level of (R)- or (S)-albuterol when administered by inhaler in the emergency department setting. Long-term effect(s) of continuous high circulating albuterol enantiomer concentrations remain unknown, and further investigations are required.

Drug-disease interactions: narrative review of aspirin in gastric ulcer

ABSTRACT Introduction: Drug-disease interactions include the impact of a drug and a particular disease condition on each other. However, the current practice in addressing drug-disease interaction is unbalanced and mostly limited to how the drug worsens the disease or health condition. Areas covered: Aspirin and gastric ulcer interaction are used as an example to illustrate this concept, especially the narration of how disease affects drug efficacy. The number of molecules that make up 100 mg of aspirin is identified with a view to discuss the pharmacokinetics, especially in terms of absorption and distribution. Using hypothetical scenarios, the pharmacodynamics in co-morbidities that could involve gastric ulcer and aspirin are also discussed. Expert opinion: There seems to be oversight in definition and description of drug-disease interaction, which is often limited to ‘how drug exacerbates disease’. The implication of this limited definition is that the discussions, research and teaching of the topic either lacks information, or are not clear on ‘how disease affects drug efficacy’. For example, gastric ulcer has the potential to enhance absorption, bioavailability and therapeutic effects of aspirin, but this is rarely discussed in preference to the probability of gastro-intestinal bleeding side-effect.

Over‐the‐counter drugs for pre‐menstrual syndrome: is the pharmacist still part of the picture?

Pre‐menstrual syndrome (PMS) includes a wide range of symptoms, affects women of reproductive age and often leads to self‐diagnosis and self‐medication. Many products are available from the community pharmacy for PMS symptoms without a doctors prescription.