OAR@UM Collection:

Pharmacogenetics of asthma

2015-01-01T00:00:00Z

Title: Pharmacogenetics of asthma Authors: Fenech, Anthony G.; Sayers, Ian; Portelli, Michael A. Abstract: The study of pharmacogenetics has expanded from what were initially casual drug response observations present in families, to a fully-fledged science with direct therapeutic applications, within a timespan of less than 60 years. Within the field of asthma therapeutics, heterogeneity in patient response to therapeutic agents has been reported from various studies, and several genotype associations with specific therapeutic-response phenotypes have been established. There is however much to be accomplished. The future of asthma pharmacogenetics lies in consolidating and validating clinically important pharmacogenes which are relevant to currently available therapy, and to integrate itself into day to day drug management and the drug development process, in order to streamline the discovery of the potential pharmacogenetic relevance of new drugs. This chapter reviews the pharmacogenetics of current asthma therapies, and discusses challenges which need to be addressed in order to enable the optimisation and personalisation of patient management in a genotype-dependent manner.

Gender differences in drug therapy

2019-01-01T00:00:00Z

Title: Gender differences in drug therapy Authors: Fenech, Anthony G.; Petroni Magri, Vanessa Abstract: Therapeutics has steadily evolved over the last two decades, from a broad system designed to target multiple patients with one management approach to a personalized model that focusses on the characteristics of each individual patient and tailors treatment accordingly. In order to achieve the maximum benefit and minimum risk, personalized medicine needs to address multiple individual parameters including pathology, physiology, genetics, comorbidity, sex and gender. While considerable personalized pharmacotherapeutic advances have been made in all fields, sex and gender have somewhat lagged behind. This has possibly been the result of a long-standing premise that females of childbearing age should be generally omitted from clinical trials. This is now changing. For several years, drug regulatory agencies have been advocating the inclusion of both sexes in preclinical and clinical trial design, ensuring adequate statistical power to discriminate sexgender differences. This has led to a gradual but steady increase in published data, which highlights sexually dimorphic differences in the pharmacokinetics, pharmacodynamics, and pharmacogenetics of several drugs. Male and female drug metabolism patterns, gene expression profiles, drug interaction pathways, and adverse drug reaction reporting have all contributed to a corpus of knowledge that needs to be constantly expanded and solidified. Furthermore, this information needs to be understood within the context of gender-bias in adherence to therapy and adverse effect reporting. Adherence to medication is a complex matter based on multiple factors including socioeconomic, health system, and patient-specific factors.; Further sex-gender research is required to consolidate and expand current data, within bench-to-bedside translational application frameworks. This needs to be incorporated into all commercial drug development stages. The inclusion of sex-gender differences in independent research needs to be incentivized through peer-review guidelines, grant application priorities and institutional review boards. This drives prospective study design towards research models capable of generating information that contributes towards the inclusion of sex-gender differences in personalized medicine treatment algorithms.

Selenium, glutathione peroxidase and superoxide dismutase in Maltese asthmatic patients : effect of glucocorticoid administration

1998-01-01T00:00:00Z

Title: Selenium, glutathione peroxidase and superoxide dismutase in Maltese asthmatic patients : effect of glucocorticoid administration Authors: Fenech, Anthony G.; Ellul-Micallef, Roger Abstract: Oxidative processes, mediated by free radical chemistry, are recognized to contribute significantly to the inflammatory pathology of bronchial asthma. This study analysed the degree of defence against reactive oxygen species in Maltese, asthmatic patients and in normal individuals, by measuring plasma selenium concentration, erythrocyte glutathione peroxidase (GSH-Px) activity and erythrocyte superoxide dismutase (SOD) activity, in order to determine their antioxidant status. The effect of glucocorticoids on the status of these antioxidants in patients was also investigated. The measurement of antioxidant status was carried out both in mild (n=22) and severe (n=37) asthmatics, as well as in healthy controls (n=49). The same antioxidant profile was then investigated in a group of 16 severe asthmatics following treatment for 4 weeks with inhaled beclomethasone dipropionate (750 μg twice daily), and in a second group of 16 patients suffering from severe asthma, following 2-weeks treatment with oral prednisolone (15 mg daily during the first week and 10 mg daily during the second). No statistically significant difference was found in the plasma selenium concentrations and erythrocyte glutathione peroxidase activities between patients and controls. Both mild and severe asthmatics, however, exhibited a statistically significant lower erythrocyte superoxide dismutase activity than normal subjects (mild asthmatics: 62.9 (2.9) SOD 525 U/ml, severe asthmatics: 60.6 (1.9) SOD 525 U/ml, normal: 68.5 (1.1) SOD 525 U/ml,P<0.01). Inhaled beclomethasone dipropionate exerted no effect on this antioxidant profile, while prednisolone caused a significant increase in plasma selenium concentration over pretreatment values (pretreatment: 118.3 (4.4) ng/ml, post-treatment: 138.1 (4.6) ng/ml,P<0.01). It is thus suggested that asthmatic patients in Malta might be more susceptible to superoxide-induced damage than normal individuals. The reason for the prednisolone-induced augmentation of plasma selenium could not be determined from this study. It is postulated that the drug may decrease the excretion rate of the element, and may thus exert a positive antioxidant effect in individuals of established low selenium status.

Effects of plant extracts on the transcriptional activity of Nuclear Factor-κB

2021-01-01T00:00:00Z

Title: Effects of plant extracts on the transcriptional activity of Nuclear Factor-κB Authors: Darmanin-Ellul, Rita; Attard, Everaldo; Fenech, Anthony G.; Ellul-Micallef, Roger Abstract: Background and Objective: The Nuclear Factor-κB (NF-κB) family of transcription factors is known to have a central regulatory effect on many physiological processes including the immune response and cell survival. Besides, the modulation of the NF-κB transduction pathway is a principal therapeutic target in cancer and inflammatory disease states. Many natural products have been shown to modulate the transcriptional activity of NF-κB. This research work was aimed at determining the phytochemical content of selected Maltese medicinal plants and investigating their ability to modulate the activity of NF-κB.; Materials and Methods: Extracts with different polarities were prepared from Aloe vera L. (Aloaceae), Jasonia bocconei (Brullo) M. Pardo and R. Morales (Asteraceae), Calendula suffruticosa Vahl (Asteraceae) and Ruta bracteosa DC. (Rutaceae). The extracts were studied for the total content of phenols and alkaloids and DPPH free radical-scavenging activity. Further studies were carried out to investigate extract-induced modulation of the transcriptional activity of NF-κB in human embryonic kidney (HEK293) cells that had been stably transfected with an NF-κB-luciferase reporter construct.; Results: Extracts from Ruta bracteosa caused increased luciferase activity. Besides, significant positive statistical correlations were found between alkaloidal content, increased luciferase activity and increased EC50 values for DPPH free radical scavenging activity.; Conclusion: Polar extracts from Ruta bracteosa with high alkaloidal content exerted increased transcriptional activity of NF-κB. Because of the evidence that links apoptotic cell death with activation of NF-κB in a variety of tumor cells, further studies are warranted, so that the chemotherapeutic potential of the plant could be established.