Press Release | Novel Biomarkers and Therapeutic Targets for Atherosclerotic Cardiovascular Diseases

 

Cardiovascular diseases (CVDs) are proven to be the leading cause of deaths throughout the world. If statistics are reviewed, almost four out of five deaths are due to myocardial infarction or stroke. Efforts to prevent CVD have little effect on the decrease of the number of CVD related deaths despite many medical advances. Therefore, the search for new and even better therapies and treatments for the betterment of those who are suffering from CVD is still in progress. The field of metabolomics has offered a good solution for these diseases. Metabolomic biomarkers help clinicians to identify the risk of CVD and take preventive measures before the diseases can surface. Early diagnosis of CVD is a good sign for a patient’s recovery and also for their health. Therefore, there is a need to establish reliable, sensitive and non-invasive biomarkers which can serve as therapeutic targets for prevention and treatment of CVD.

In this study, analytical techniques are discussed along with the workflow that is used in untargeted metabolomics. Case studies that highlight the use of untargeted metabolomics in CVD research are also identified. Five of the case studies show approaches to identify untargeted metabolomics and apply this information in clinical situations. Analysis was conducted for the prediction of cardiovascular disease risk, myocardial ischemia, transient ischemic attack, incident coronary heart disease, and myocardial infarction risk. The use of the untargeted metabolomics for risk assessment is still relatively new and there is still a need for future advancements in metabolomics technologies. Read full press release to find out more at: https://www.eurekalert.org/pub_releases/2018-12/bsp-nb122518.php

 

Untargeted Metabolomics in the Discovery of Novel Biomarkers and Therapeutic Targets for Atherosclerotic Cardiovascular Diseases

The article by Dr. Geoff H. Werstuck et al. is published in Cardiovascular & Hematological Disorders-Drug Targets, Volume 18, Issue 3, 2018. To obtain this article, please visit: http://www.eurekaselect.com/161468

PRESS RELEASE – Asthma management: Allocating duties

The article by Dr. Giuseppe Madonia and Dr. Ursula Madonia is published in Current Respiratory Medicine Reviews

IMAGE: BETTER AND SYSTEMATIC STRATEGIES IN DIAGNOSIS, PHENOTYPING AND THERAPY ARE AVAILABLE IN A SPECIALISTIC DEDICATED SETTING AND CAN HELP IN ASTHMA MANAGEMENT. view more 

CREDIT: DR. GIUSEPPE MADONIA, DR. URSULA MADONIA AND BENTHAM SCIENCE PUBLISHERS

 

The privilege to operate in a specialist asthma clinic allows for a light to be shed on the persistence of the many pitfalls in the management of this condition, which continue despite the recommendations of the numerous authoritative guidelines produced and spread in the last decades. Asthma heterogeneity and variability make it extremely difficult to be optimally managed, also in a specialist environment.

Many factors contribute to overcomplicate things: correct diagnosis and, if necessary, a differential one (e.g. COPD, vocal cord disfunction, congestive heart failure, emotional dyspnea, for example); characterization and education of the so-called poor perceiver; creation of a partnership with the patient; etc…

In other words, it is necessary to spend time on every single patient and his/her particular form of asthma and to formulate a more or less stringent plan of follow-up. That being said, it appears clear how the role of physicians is particularly challenging in managing comfortably this complexity and the burden produced by it. Overcoming these obstacles will be the result of knowledge, dedication, constancy and acquired experience. A recent National Institute for Health and Care Excellence (NICE) guideline suggests the best practice in asthma management directly to general practitioners assuming however that “putting recommendations into practice can take time”.

Almost all patients with a suspect of asthma will have their first evaluation in a primary care setting. But a single general practitioner physician will not regularly observe, in his daily practice, such a patient. Concurrently, it is unclear how many spirometry tests he will do in a month: possibly not enough to guarantee an acceptable level of expertise in such a key role test. It will likely be very difficult to acquire the optimal background level appropriate to smoothly manage asthma condition – especially in such a busy, diverse and eclectic environment .

The few considerations just briefly exposed make it reasonable to assume that, paradoxically, it could be better, in future guidelines on the topic, to typify when a respiratory physician – taking into account the local health system – can refer an asthmatic patient to the primary care colleague (and not vice versa).

For further information on the research study, please visit: http://www.eurekaselect.com/160581

PRESS RELEASE – Zinc oxide-graphene solar cells could provide new opportunities

The article by Dr. Hieu P. T. Nguyen et al. is published in Current Nanomaterials, 2018

Researchers from NJIT (New Jersey Institute of Technology, New Jersey, USA) in collaboration with researchers from CSIR-CECRI (Central Scientific Industrial Research Institute – Central Electrochemical Research Institute, Tamil Nadu, India) have fabricated a new kind of dye sensitized solar cells (DSSC) based on zinc oxide-graphene (ZnO-G) composites, having a flake like morphology. The polyol approach used for synthesis of the composite material can be envisioned for future low-cost, transparent and flexible solar cells that will be installed on surfaces including windows, roofs in the near future.

The novel technique for the fabrication has been developed by a 3rd year Ph.D. student Moab Rajan Philip and Dr. Hieu P Nguyen, Assistant Professor in the Electrical and Computer Engineering Department of NJIT and is reported in Current Nanomaterials-Bentham Science Publishers. The paper is co-authored by Rupesh K Babu, V. Krishnakumar and T. Bui who are researchers in CSIR-CECRI and NJIT respectively.

Zinc Oxide (ZnO) is a multifunctional semiconductor material that can be fabricated at low temperatures. The wide energy bandgap, radiation resistance, high chemical stability, and high excitation binding energy leads to ZnO offering huge potential in applications involving sensors, light-emitting diodes (LEDs), piezoelectric devices, solar cells, short wavelength lasers and transistors. In addition, ZnO offers superior electrical and optical properties that include high electron mobility in the order of 1500 cm2V-1s-1 at room temperature, a wide band gap energy of 3.3 eV and a high exciton (electron-hole) binding energy of 60 meV. Graphene, which is one of the most exciting 2D materials known to man, exhibits superior properties such as ultrahigh electron mobility, large surface area, high chemical and thermal stability, excellent electrical and optical properties. The ZnO-G composites exhibited in the study significantly enhanced photoluminescence which was around 8 times stronger than that of ZnO samples, attributed to the contribution of plasmonic effect of graphene in ZnO-G. It has been reported that the drawback of poor catalytic activity in ZnO due to its photoelectron recombination is known can be overwhelmed by the incorporation of graphene into ZnO matrix thereby improving its photodegradation efficiency and reducing photoelectron recombination. The latter reasons along with the ZnO-G composite’s photosensitivity, electron transport capability, chemical stability and better light adsorption make it an interesting material for the future era electronic devices.

“We’ve demonstrated that devices based on ZnO-G have an excellent conversion efficiency compared to ZnO”- Moab and Prof. Nguyen (lead authors of the paper) says. The conversion efficiency of ZnO-G DSSCs is greatly increased compared to that of the bare ZnO devices which are 0.438% and 0.067%, respectively. Moreover the authors add that the low-cost polyol process, in addition to being simple and facile, do have the benefits of being environmentally friendly along with large scale production. The team studied the fabricated samples via characterization techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), laser raman spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), photoluminescence spectroscopy (PL) and dye sensitized solar cell (DSSC) studies. Moab adds “The initial work is promising and excellent and might pave the way for future investigations into similar material oxide material systems will help us to reach potential long term real applications.” Prof. Hieu comments that “The high surface area hexagonal wurtzite ZnO particles thus fabricated by inexpensive and environmentally friendly polyol route can ultimately lead to being used as a suitable anode material in DSSCs as well as an excellent catalyst/adsorbent.”

For more information on this research study, please visit: http://www.eurekaselect.com/161876

PRESS RELEASE – Molecular basis of neural memory — reviewing ‘neuro-mimetic’ technologies

This article by Dr. Gerard Marx and Dr. Chaim Gilon is published in Neuroscience and Biomedical Engineering, Volume 6, 2018

 

The overwhelming quest in cognitive science has been (and still is) to scientifically describe mental processes on a molecular level, notably memory and intelligence, and attempt to mimic them technologically. But really ‘intelligent’ computers can only arise from an appreciation of neural reality with credible principles about the nature of neural mentation.

A function called ‘Memory’ is central to the intelligence of both computers and brains, though each type arise from quite different processes. For example, computers processes (computation) and memory are well characterized theoretically (information theory) and practically (manufacture of memory chips). But as there is no binary code for emotions, the computer is deficient of any emotive quality. By contrast, biologic neurons and neural nets remember on the basis of multinary (not binary) processes. They experience emotive states that confer meaning (value) to all stimuli. But what are the details of the biologic neural process?

To clarify these, Marx & Gilon propose a tripartite mechanism of neural memory and provide a chemographic description. It involves the interactions of neurons with their surrounding extracellular matrix (nECM) and dopants, comprising trace metals (copper, zinc, etc) and neurotransmitters (more than 100 NTs). The NTs elicit both physiologic reactions and psychic states. Essentially, the neuron forms metal-centered complexes within the surrounding nECM, to encode cognitive units of information (cuinfo). Thus, neural memory is stored outside the highly extended cell, but readily available for recall.

Within that context, Marx & Gilon review the IBM Brain Chip and the Blue Brain Project, both being technologies which represent themselves as mimicking biologic neural systems, one as a chip, the other as a simulation. But both are found wanting, due to their inappropriate modeling of neuron morphology and the lack of emotive qualifiers. Consequently, the demotive IBM Brain Chip and the Blue Brain Simulation are inadequate actual and virtual constructs of neural systems and cannot be said to be truly ‘neuromimetic’.

Marx & Gilon propose a novel, but credible biochemical model, a tripartite mechanism for neural memory. This implies a ‘paradigm shift’ for cognitive science, a new way of thinking about mental processes. Expectedly, the tripartite model could help steer the development of technologies truer to neurobiology and neurochemistry.

For more information about the research, please visit: http://www.eurekaselect.com/159732

 

 

PRESS RELEASE – Pterocarpanquinones and carbapterocarpans with anti-tumor activity against MDR leukemias

The article by Dr. Vivian M. Rumjanek et al. is published in Anti-Cancer Agents in Medicinal Chemistry, 2018

IMAGE: INSIGHTS INTO THE BIOLOGICAL EVALUATION OF PTEROCARPANQUINONES AND CARBAPTEROCARPANS WITH ANTI-TUMOR ACTIVITY AGAINST MDR LEUKEMIAS. view more

Careful thinking must be put since the very first days of the design of a new drug candidate to consider variables such as cost-effectiveness, novelty, side effects and the peculiarity of the disease to be treated. Cancer, as a multifactorial sum of diseases, present challenges since its high mutational background often grants tumor cells varying mechanisms to sustain cellular proliferation. Our group, consisting on researchers with different backgrounds as well, resorted to nature to find chemical groups that would present good in vivo tolerance with possibilities for further development. Pterocarpans, secondary metabolites derived mainly from isoflavonoids of the Papilionoideae subfamily of the Leguminosae plant family, served this purpose. They possess anti-inflammatory and antineoplastic properties along with a highly ‘moddable’ scaffold comprising phenolic rings. Addition of two prime pharmacophores such as naphthoquinones and sulfonamides added new mechanisms of antineoplastic action, since the first display prooxidant activity and the latter are described to inhibit tubulin polymerization and tyrosine kinases. Considering this, the resulting molecules LQB-118 and LQB-223 would likely induce toxicity to a variety of tumor cells.

Multidrug resistance (MDR), the major hurdle to a successful therapy outcome, would present additional challenges. Diverse mechanisms act in MDR to evade drug-induced apoptosis: changes in cell cycle and metabolic adaptation to the insult exerted by chemotherapeutics, upregulation of protective responses such as resistance to oxidative stress and antiapoptotic proteins (IAPs) and increase in the activity of efflux transporter proteins. These adaptations are dynamic and highly variable among tumor subtypes, in a way that drug design projects often show its shortcomings when MDR is considered. Our results indicated otherwise; in leukemic cells, inhibition induced by the hybrid pterocarpanquinone LQB-118 did not seem to associate with blockade on a particular phase of the cell cycle. On solid tumors, however, an increase in the G2/M phase was observed. On leukemias, suppression of the master cell cycle regulator FoxM1 produced changes in diverse phases of the cell cycle according to the cell subtype; on prostate cancer downregulation of cyclins B1 and D1 were present. Regarding protective responses, LQB-118 was able to overcome two of the most effective in dealing with cellular stress, increases in glutathione to counter oxidative damage and upregulation of survivin and XIAP to evade apoptosis. This profile would likely be associated to inhibition of a broad, upstream transcriptional regulator, and NF?B emerged as the cellular target of LQB-118. In addition, the effect of this compound was increased when autophagy was promoted with rapamycin, and no changes manifested when this pathway was inhibited with chloroquine. Downstream apoptotic responses were observed accordingly, such as calcium leakage from the endoplasmic reticulum, mitochondrial outer membrane depolarization, caspases’ and PARP activation, and DNA fragmentation.

It became clear that LQB-118 was able to ‘tweak’ its mode of action and exert toxicity to different tumor cells. The multiple pathways affected are the reflection of the way the particular cell tries to circumvent the insult produced by this drug. This could partially be explained by the hybrid nature of LQB-118, in which both its pterocarpan and quinone scaffolds act in synergy for the bioactivation of this drug, producing oxidative and/or alkylating damage depending on the intrinsic biological feature of the tumor subtype. This would be nothing out of ordinary if this resulted in unacceptable toxicity to healthy organisms. Our group performed extensive studies on normal mice with diverse immunologic backgrounds, and this compound was able to reach its final targets in vivo, reducing tumor growth sparing normal cells. A similar outcome was observed on both healthy and neoplastic cells from leukemic patients at the National Cancer Institute of Brazil. Our compounds were designed to be effective in cells with MDR phenotype; as such, it was important to evaluate their efficacy on cells overexpressing ABC proteins. Given their isoflavonoid origin, LQB-118 was able to circumvent high levels of ABCB1 protein expression and functional activity, a profile that was maintained on LQB-223, the carba-derivative that was designed not to repeat the same molecular mechanisms displayed by LQB-118 (thus avoiding the non-innovative ‘me-too’ molecules). LQB-223 acted regardless of both ABCB1 and ABCC1 overexpression in leukemias as well as breast cancer cells, being of broader scope than LQB-118. Owing to its sulfonamide moiety, LQB-223 was demonstrated to bind to the minor groove of DNA, and recent yet unpublished results suggest DNA topoisomerases and ?-tubulin as targets of this carbapterocarpan, expanding its use.

Tracing back to the origins of the compounds, the diverse natures of our research group and the variety of prime chemical groups employed resulted in compounds with a myriad of mechanisms, adaptable to diverse phenotypes of drug resistance. The radical innovation applied to a prototypical chemical structure propose LQB-118 and LQB-223 as antineoplastic drug candidates directed to drug-resistant neoplasias, with good selectivity and interesting mechanistic features.

For more information, please visit: http://www.eurekaselect.com/161464

PRESS RELEASE – Targeting inflammation to prevent preterm birth

A molecule named rytvela decreases uteroplacental inflammation, prevents preterm birth and improves perinatal outcomes through biased antagonism of the IL-1 receptor (functional selectivity)

Preterm birth (PTB) affects more than 10% of pregnancies worldwide and is the leading cause of neonatal mortality. Current treatments target myometrial contractility and are largely ineffective at improving perinatal outcomes. Myometrial contractions represent the final stage of a long process of uterine activation orchestrated by in utero inflammatory processes. If triggered prematurely (e.g. by infection), inflammation inevitably leads to preterm labor, with the timing of onset being inversely correlated with adverse neonatal outcomes and associated lifelong complications. Interleukin-1 (IL-1) is a major proinflammatory cytokine that has been firmly linked to human PTB and fetal organ injuries.

In a review article published in Current Pharmaceutical Design, Nadeau-Vallée et al. summarize the most recent evidence on the efficacy of molecules that target IL-1 to prevent PTB. Of all inhibitors of IL-1, the selective IL-1 receptor inhibitor rytvela (all-d heptapeptide) stands out preclinically as superiorly potent, effective, and safe in the prevention of PTB and its consequences. “Rytvela exerts benefits in decreasing uteroplacental inflammation, decreasing premature birth, prolonging gestation, increasing fetal survival, and improving fetal and neonatal outcome including that of the neurodevelopment” says Dr. Sylvain Chemtob, neonatologist, researcher, and principal author of the article. “Other than preventing preterm labor, rytvela also decreases inflammation inside the fetal compartment and in fetal organs, which is of significant importance because numerous neonatal conditions have been linked to inflammation independent of prematurity. Antenatal treatment with rytvela results in normalisation of lung, intestine and cerebral pathology scores during development and at adulthood”.

The effects of rytvela have been validated in vitro in murine and human uterine and immune cells, and in vivo in numerous murine models of PTB. Mechanistically, rytvela binds on a site remote from the binding site of IL-1 and act as a biased ligand by selectively inhibiting the p38/JNK/AP-1 pathway while preserving the activity of transcription factor NF-kB. This innovative mechanism of action may help decrease adverse effects (e.g. immunosuppression) which are particularly undesirable in the context of pregnancy.

Read more here: http://www.eurekaselect.com/155176

PRESS RELEASE – LC-MS/MS Identification and characterization of biodegradation products of Nitroproston

This article by Dr. Natalia Vladimirovna Mesonzhnik et al. is published in Drug Metabolism Letters, Volume 12, 2018

Nitroproston (11(S),15(S)-dihydroxy-9-keto-5Z,13E-prostadienoic acid 1?,3?-dinitroglycerol ester) is a novel prostaglandin-based compound with potential application in obstructive respiratory diseases such as asthma and obstructive bronchitis. Its pharmacological activity is provided by combined multi-target action on prostanoid EP4 receptors and soluble guanylylcyclase. Nitroproston is bearing a prostaglandin E2 (PGE2) moiety modified by an additional NO-donating fragment of glycerol-1,3-dinitrate (1,3-GDN) via ester bond and can be consider as nitrated derivative of glycerol ester of PGE2 ? the natural COX-2 metabolite of endogenous cannabinoid-like molecule 2-arachidonoyl glycerol. The presence of NO-donating fragment extremely changes pharmacological properties of PGE2. Nitroproston is more than 20-fold as active as prostaglandin E2 in the relaxation of respiratory muscles. Due to this enhanced myorelaxant activity Nitroproston is well tolerated by asthmatic subjects and is the first-in-class pharmaceutical candidate for therapy of asthma attacks utilized both prostanoid and NO receptors.

Despite the fact that Nitroproston has been extensively studied using various pharmacological models, its biological stability is still unknown. Thereby, the main aim of the present study was to evaluate Nitroproston stability in vitro, as well as to identify and characterize its biodegradation products. The principal in vitro biodegradation products of Nitroproston were identified using liquid chromatography/ion trap – time-of-flight mass-spectrometry (LC-HRMS/MS). The postulated structure of metabolites was confirmed using authentic reference standards. Rat, rabbit and human plasma and human whole blood samples were used for comparative in vitro degradation study. Nitroproston and its biodegradation products in biological samples were measured by target liquid chromatography/triple-stage quadrupole mass spectrometry (LC-MS/MS).

LC-HRMS/MS of spiked rat plasma samples clearly indicated the presence of two main metabolites of Nitroproston – 1,3-GDN and PGE2, the later can undergo dehydration to cyclopentenone prostaglandins. The applied LC-HRMS/MS screening method did not reveal the presence of biodegradation products of Nitroproston with one nitro-group or PGE2 glycerol ester. We assume that nitrate esters are more resistant to enzymatic hydrolysis in rat plasma than carboxyl ester moieties.

Target LC-MS/MS quantitative analysis was used to quantify the amount of Nitroproston and its major biodegradation products in rodent’s plasma. The degradation was higher in rat plasma where only 5 % of parent Nitroproston was identified at the first moment of incubation. Similar pattern was observed for rabbit plasma where half-life (T1/2) of Nitroproston was about 2.0 minutes. Additionally, whole human blood and plasma samples were taken to perform stability and blood cell distribution study. Nitroproston biodegradation rate for human plasma was the slowest (T1/2 = 2.1 h) among tested species, but occurred more rapidly in whole blood (T1/2 = 14.8 min). Nitroproston was distributed between human RBCs and plasma with partition ratio of 0.82. These data suggest that metabolism of drug candidate in human whole blood was mainly associated with an enzymes located in RBC fraction. The observed interspecies variability highlights the need of suitable animal model selection for Nitroproston follow-up PK/PD studies. Our findings do not exclude that Nitroproston may be relatively stable in human after inhalation and may exert its therapeutic actions either as a whole drug molecule or as a prostaglandin E2 and nitric oxide prodrugs thanks to its active metabolites.

Nitroproston is being developed as a drug candidate for relief of bronchial asthma. The key principle of the action of Nitroproston is not only the effect on two targets having similar pharmacological activity with respect to bronchial smooth muscle, but also the synchronization of the pharmacological activity when the prostaglandin E2 is the driver of the donor part releasing the NO in the activity sites. Due to this, a powerful synergy of pharmacological activity is achieved and the dose of PGE2 drops sharply, which brings us back to the possibility of starting new and more successful attempts to use the of NO donating PGE2 derivatives for relief the bronchial asthma.

For more information about the research, please visit: http://www.eurekaselect.com/160373/article

Press Release – The clinical and experimental research on the treatment of endometriosis with thiostrepton

This article by Dr. Ping Jin et al. is published in Anti-Cancer Agents in Medicinal Chemistry, Volume 18, 2018

Forkhead Box M1 (FOXM1), which known as Trident, HNF-3, HFH-11, MPP2, and Win, is a transcriptional factor that plays an important role in cell proliferation, differentiation, and transformation. As one of the early up-regulated proteins in cancerogenesis, FOXM1 is frequently activated in tumors. This research studied the expression and the possible mechanism of FOXM1 and evaluated the effects of thiostrepton in an endometriotic rat model.

The research concluded two part. On the one hand, we constructed the rats model of endometriosis. Observed the expression of FOXM1 in endometriosis tissues. Explored the possible mechanism of FOXM1 action, like EKR?FOXM1 and MMP9 Signaling Pathway. Fifty female Wistar rats were surgically induced with endometriosis. After 4 weeks of observation, twenty and thirty rats were randomly allocated to an ovariectomized (OVX) group and a treatment group, respectively. The OVX group was ovariectomized and randomly divided into an OVX-estrogen group and a control (OVX -oil) group. All rats were allowed a resting period of 3 days prior to any operation. The rats in the estrogen group were given estradiol (20 μg/kg, 0.1 ml /d), while the control group was treated with an equivalent amount of sesame oil. Every group was injected with subcutaneous injection for 7 days. Our results showed that FOXM1 is enrich in nucleus of an ectopic endometrium when compared with an eutopic uterus. Furthermore, we found that an ERK/FOXM1/matrix metalloproteinase-9 (MMP9) signaling pathway might result in the establishment and development of endometriosis.

On the other hand, thiostrepton is a small-molecule inhibitor of the transcription factor FOXM1. We evaluated the effects of thiostrepton in an endometriotic rat model. The treatment group was randomly divided into three groups to receive the following: TST at 150 mg/kg, ip.; TST at 250 mg/kg, ip.; or sterile normal saline, ip. The groups received these dosages every 2 days for 2 weeks. Lesion growth, histological examination, and protein expression were subsequently analyzed using caliper measurement, histology, immunostaining, and Western blot after each rat received an injection in its own group. Our results showed that a thiostrepton concentration dependently reduced the expression of FOXM1, MMP9 and Bcl-2 in endometriotic lesions of the treated rats. Statistical significance was accepted for a value of P < 0.05.

In conclusion, we postulate that thiostrepton could inhibit the endometriotic lesions, at least in part, by decreasing the FOXM1 expression and exerting a pro-apoptotic effect. We reported for the first time that FOXM1 expresses in experimental endometriosis rat and thiostrepton may also be suitable for the administration of endometriosis by inhibiting the growth of endometriotic implants.

For more information, please visit: http://www.eurekaselect.com/158859

PRESS RELEASE – Pharmacogenetics of angiotensin-converting enzyme inhibitors for Alzheimer’s disease

This article by Dr. Fabricio Ferreira de Oliveira et al. is published in Current Alzheimer Research, Volume 15, Issue 4, 2018

The angiotensin-converting enzyme is an amyloid-ß-degrading enzyme. While angiotensin-converting enzyme inhibitors could increase amyloid-ß accumulation, they might also slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia. In this study from São Paulo, Brazil, we aimed to investigate whether ACE polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with Alzheimer’s disease dementia, while also taking APOE haplotypes and anti-hypertensive treatment with angiotensin-converting enzyme inhibitors into account for stratification. Overall, 193 consecutive patients with late-onset Alzheimer’s disease dementia were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with angiotensin-converting enzyme inhibitors. Almost 94% of all patients used cholinesterase inhibitors, whereas 155 had arterial hypertension, and 124 used angiotensin-converting enzyme inhibitors. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 — T and rs4291 — A, or for APOE4- carriers of rs1800764 — T or rs4291 — T, angiotensin-converting enzyme inhibitors slowed cognitive decline independently of blood pressure variations, possibly by way of central and peripheral effects. APOE4+ carriers were not responsive to treatment with angiotensin-converting enzyme inhibitors. In conclusion, angiotensin-converting enzyme inhibitors may slow cognitive decline for patients with Alzheimer’s disease dementia, more remarkably for APOE4- carriers of specific ACE genotypes. Future trials should prospectively compare angiotensin-converting enzyme inhibitors according to their brain-penetrating properties since the start of anti-hypertensive therapy, with measurements of cerebrospinal fluid and serum levels and activity of the angiotensin-converting enzyme, as well as genetic profiles and neuroimaging parameters.

For more information on this research, please visit: http://www.eurekaselect.com/156397/article

 

PRESS RELEASE – Cytochrome P450 3A4 induction

This article by Dr. Elena K. Schneider is published in Drug Metabolism Letters, Volume 12, 2018

Cystic fibrosis (CF) is the most common, genetically acquired, life-shortening chronic illness affecting young Australians today. There is no cure, and patients with CF undergo life-long and extremely costly medical treatments. Orkambi (Vertex Pharmaceuticals), the novel lumacaftor-ivacaftor combination is the first CF therapeutic that treats the CF disease itself. Worryingly, a number of conflicting reports have emerged that overshadow the clinical efficacy of this important first-in class drug. As there are no other therapeutic alternative we must optimize its use to increase efficacy while minimizing side-effects.

‘Since releases of ivacaftor-lumacaftor combination several red-flags have been raised that highlight the clinical efficacy of this combination strategy maybe be limited due to antagonistic drug-drug interactions. Our lab is invested in shedding light on the pharmacology of cystic fibrosis transmembrane conductions regulator (CFTR) drugs and we have investigated potential cytochrome interactions of ivacaftor, its major metabolites lumacaftor and tezacaftor’ says Dr Elena K Schneider, a Research Fellow from the University of Melbourne, Department of Pharmacology & Therapeutics.

In the last couple of years, Dr Schneider and her lab group have intensively worked on the pharmacology of two new breakthrough CF medications, ivacaftor and lumacaftor and is now able to provide a pharmacological and analytical platform for clinicians to improve patients’ outcomes by optimization of therapy. For example, Dr Schneider found that lumacaftor and ivacaftor-M6 metabolite markedly induced the activity of cytochrome CYP3A4; however, not ivacaftor-M1 and the novel CFTR modulator tezacaftor. She hypothesized that the cytochrome P450 3A4 induction (lumacaftor versus ivacaftor) potentially results in significantly reduced plasma concentration of ivacaftor in patients receiving Orkambi therapy which could explain the reduced efficacy. In addition to the above, Dr Schneider is looking at ADME parameters of CFTR modulators including pharmacokinetic/pharmacodynamic parameters.

Dr Elena Schneider, research fellow at University of Melbourne, is working to fill this gap in knowledge. She aims to optimise the current treatment options and improving the lives of CF patients.

For more information about the research study, please visit: http://www.eurekaselect.com/160801