| 1. |
- Mohammadi, Elyas, et al.
(författare)
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Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9, s. 1-24
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Forskningsöversikt (refereegranskat)abstract
- Simple Summary Drug repurposing is an accelerated route for drug development and a promising approach for finding medications for orphan and common diseases. Here, we compiled databases that comprise both computationally- or experimentally-derived data, and categorized them based on quiddity and origin of data, further focusing on those that present high throughput omic data or drug screens. These databases were then contextualized with genome-wide screening methods such as CRISPR/Cas9 and RNA interference, as well as state of art systems biology approaches that enable systematic characterizations of multi-omic data to find new indications for approved drugs or those that reached the latest phases of clinical trials. Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
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| 2. |
- Di Gennaro, A., et al.
(författare)
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Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:8, s. 1907-1912
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Tidskriftsartikel (refereegranskat)abstract
- Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
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| 3. |
- Turanli, Beste, et al.
(författare)
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Drug Repositioning for Effective Prostate Cancer Treatment
- 2018
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-kappa B inhibition, Wnt/beta - Catenin pathway inhibition, DNMT1 inhibition, and GSK-3 beta inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.
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| 4. |
- Xin, D. L., et al.
(författare)
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Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task
- 2017
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Ingår i: BMC Neuroscience. - : BioMed Central. - 1471-2202. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
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| 5. |
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| 6. |
- Altay, Özlem, et al.
(författare)
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Current Status of COVID-19 Therapies and Drug Repositioning Applications
- 2020
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Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 23:7
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Tidskriftsartikel (refereegranskat)abstract
- The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
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| 7. |
- Tjäderborn, Micaela, 1983-
(författare)
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Psychoactive prescription drug use disorders, misuse and abuse : Pharmacoepidemiological aspects
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: There is a widespread and increasing use of psychoactive prescription drugs, such as opioid analgesics, anxiolytics, hypnotics and anti-epileptics, but their use is associated with a risk of drug use disorder, misuse and abuse. Today, these are globally recognized and emerging public health concerns.Aim: The aim of this thesis is to estimate the prevalence of psychoactive prescription drug (PPD) use disorders, misuse and abuse, and to investigate the association with some potential risk factors.Methods: A study using register data from forensic cause of death investigations investigated and described cases of fatal unintentional intoxication with tramadol (Study I). Based on register data on spontaneously reported adverse drug reactions (ADRs) reported cases of tramadol dependence were investigated and summarised (Study II). In a study in suspected drug-impaired drivers with a toxicology analysis confirming the intake of one out of five pre-specified PPDs, the prevalence of non-prescribed use was assessed and associated factors were investigated (Study III). From a cohort of patients initiating prescribed treatment with pregabalin, using data on prescription fills, a study investigated longitudinal utilisation patterns during five years with regards to use of the drug above the maximum approved daily dose (MAD), and factors associated with the utilisation patterns (Study IV).Results: In the first study, 17 cases of unintentional intoxications were identified, of which more concerned men, the median age was 44 years and the majority used multiple psychoactive substances (alcohol, illicit drugs and prescription drugs). The second study identified 104 spontaneously reported cases of tramadol dependence, in which more concerned women, the median age was 45 years, and a third reported a history of substance abuse and 40% of past psychoactive medication use. In the third study, more than half of the individuals suspected of drug-impaired driving used the drug without a recent prescription. Non prescribed use was most frequent in users of benzodiazepines and tramadol, and was more likely in younger individuals and in multiple-substance users. In the last paper five longitudinal utilisation patterns were found in pregabalin users, with two patterns associated with a particularly high risk of doses above the maximum approved dosing recommendation. This pattern of use was associated with male sex, younger age, non-urban residency and a recent prescribed treatment with an antiepileptic or opioid analgesic drug.Conclusions: This thesis shows that psychoactive prescription drug use disorders, misuse and abuse occur and may have serious and even fatal consequences. The prevalence varies between different drugs and populations. Abuse and misuse seem to be more common in young people. Fatal intoxications and misuse of prescribed drugs may be more common in men, while drug use disorders following prescribed treatment may be more common in women and non-prescribed use equally distributed between women and men. Individuals with a history of mental illness, substance use disorder or abuse, or of past use of psychoactive medications are likely important risk groups. In summary, the findings suggest a potential for improvements in the utilisation of psychoactive prescription drugs. The results may be useful in the planning of clinical and regulatory preventive interventions to promote the rational, individualised and safe use of such drugs.
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| 8. |
- Salomé, Nicolas, et al.
(författare)
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Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats
- 2009
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 612:1-3, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 mu g) in a dose-dependent manner with a total blockade at concentraions of 0.4 mu g and 8 mu g for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 mu g). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 mu M)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fast mass in clincal studies.
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| 9. |
- Bondesson, Åsa ÅB, et al.
(författare)
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A structured questionnaire to assess patient compliance and beliefs about medicines taking into account the ordered categorical structure of data
- 2009
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Ingår i: Journal of Evaluation In Clinical Practice. - : Wiley. - 1356-1294 .- 1365-2753. ; 15:4, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE, AIMS AND OBJECTIVE: The objectives were to describe and evaluate the structured medication questionnaire and to improve data handling of results from the Morisky four-item scale for patient compliance and Beliefs about Medicines Questionnaire-specific (BMQ-specific). METHODS: A questionnaire was developed with the purpose of being used when identifying medication errors and assessing patient compliance to and beliefs about medicines. RESULTS: A majority of the respondents (62%; CI 45-77%) had at least one medication error. Assuming that all items are equally important in the Morisky four-item scale we presented four alternative ways to create a unidimensional global scale. A two-dimensional global scale was also constructed. The results from the BMQ-specific were presented in different ways, all taking into account that the scale has ordered verbal categories: at the level addressing each specific question, at the sub-scales 'concern' and 'necessity' level and at the global level. CONCLUSIONS: The structured medication questionnaire can be used in daily practice as a tool to identify drug-related problems. The choice of how to use and present data from those scales in research depends on patient characteristics and how discriminating one would like the scales to be.
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| 10. |
- Ekqvist, David, et al.
(författare)
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Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin : a study protocol of a phase II clinical trial (HighShort-RP)
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C-max) and area under the concentration-time curve (AUC(0-24h)) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC(0-24h) and main secondary endpoint is safety.Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.
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