| 1. |
- Tulp, Martin, et al.
(author)
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Functional versus chemical diversity: is biodiversity important for drug discovery?
- 2002
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In: TIPS - Trends in Pharmacological Sciences. - 0165-6147 .- 1873-3735. ; 23:5, s. 225-231
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Journal article (peer-reviewed)abstract
- Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of ‘biodiversity prospecting’, which will, possibly, endanger fragile ecosystems in the search for rare species.
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| 2. |
- Arnberg, Niklas
(author)
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Adenovirus receptors : implications for targeting of viral vectors
- 2012
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier. - 0165-6147 .- 1873-3735. ; 33:8, s. 442-448
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Research review (peer-reviewed)abstract
- Cancer, cardiovascular disease, and infectious diseases are all global health threats. To combat these diseases with gene therapies, adenovirus-based vectors have been developed. Although certain clinical trials appear successful, there is an obvious need to improve the efficacy of most adenovirus-based vectors. For the most commonly used vector (based on type 5; Ad5), a main problem is its accumulation in the liver, which can be attributed to interactions with specific host factors. The diverse tropism for types other than Ad5 implies that vectors based on alternative types could have advantages. The numerous interactions of different adenoviruses with host molecules - such as the recently identified desmoglein-2 receptor - may cause novel and unexpected obstacles, but also may provide possibilities for vectors based on alternative types. This review provides an update of new and previously known molecules that mediate cellular attachment of human adenoviruses and discusses how these may influence the targeting of adenovirus-based vectors.
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| 3. |
- Attwood, Misty M., et al.
(author)
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Orphan Drugs and Their Impact on Pharmaceutical Development
- 2018
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 39:6, s. 525-535
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Research review (peer-reviewed)abstract
- High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.
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| 4. |
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| 5. |
- Baijnath, Sooraj, et al.
(author)
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Advances in spatial mass spectrometry enable in-depth neuropharmacodynamics
- 2022
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier. - 0165-6147 .- 1873-3735. ; 43:9, s. 740-753
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Research review (peer-reviewed)abstract
- Mass spectrometry imaging (MSI) is a powerful technique that combines the abil-ity of microscopy to provide spatial information about multiple molecular species with the specificity of mass spectrometry (MS) for unlabeled mapping of analytes in diverse biological tissues. Initial pharmacological applications focused on drug distributions in different organs, including the compartmentalized brain. However, recent technological advances in instrumentation, software, and chemical tools have allowed its use in quantitative spatial omics. It now enables visualization of distributions of diverse molecules at high lateral resolution in studies of the pharmacokinetic and neuropharmacodynamic effects of drugs on functional biomolecules. Therefore, it has become a versatile technique with a multitude of applications that have transformed neuropharmacological re-search and enabled research into brain physiology at unprecedented resolution, as described in this review.
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| 6. |
- Banerjee, Debarshi, et al.
(author)
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Adding nanotechnology to the metastasis treatment arsenal
- 2019
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In: TIPS - Trends in Pharmacological Sciences. - Cambridge, Massachusets : Elsevier. - 0165-6147 .- 1873-3735. ; 40:6, s. 403-418
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Research review (peer-reviewed)abstract
- Metastasis is a major cause of cancer-related mortality, accounting for 90% of cancer deaths. The explosive growth of cancer biology research has revealed new mechanistic network information and pathways that promote metastasis. Consequently, a large number of antitumor agents have been developed and tested for their antimetastatic efficacy. Despite their exciting cytotoxic effects on tumor cells in vitro and antitumor activities in preclinical studies in vivo, only a few have shown potent antimetastatic activities in clinical trials. In this review, we provide a brief overview of current antimetastatic strategies that show clinical efficacy and review nanotechnology-based approaches that are currently being incorporated into these therapies to mitigate challenges associated with treating cancer metastasis.
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| 7. |
- Blennow, Kaj, 1958, et al.
(author)
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Amyloid biomarkers in Alzheimer's disease.
- 2015
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In: Trends in pharmacological sciences. - : Elsevier BV. - 1873-3735 .- 0165-6147. ; 36:5, s. 297-309
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Journal article (peer-reviewed)abstract
- Aggregation of amyloid-β (Aβ) into oligomers, fibrils, and plaques is central in the molecular pathogenesis of Alzheimer's disease (AD), and is the main focus of AD drug development. Biomarkers to monitor Aβ metabolism and aggregation directly in patients are important for further detailed study of the involvement of Aβ in disease pathogenesis and to monitor the biochemical effect of drugs targeting Aβ in clinical trials. Furthermore, if anti-Aβ disease-modifying drugs prove to be effective clinically, amyloid biomarkers will be of special value in the clinic to identify patients with brain amyloid deposition at risk for progression to AD dementia, to enable initiation of treatment before neurodegeneration is too severe, and to monitor drug effects on Aβ metabolism or pathology to guide dosage. Two types of amyloid biomarker have been developed: Aβ-binding ligands for use in positron emission tomography (PET) and assays to measure Aβ42 in cerebrospinal fluid (CSF). In this review, we present the rationales behind these biomarkers and compare their ability to measure Aβ plaque load in the brain. We also review possible shortcomings and the need of standardization of both biomarkers, as well as their implementation in the clinic.
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| 8. |
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| 9. |
- Epstein, David H., et al.
(author)
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Science-Based Actions Can Help Address the Opioid Crisis
- 2018
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In: TIPS - Trends in Pharmacological Sciences. - : ELSEVIER SCIENCE LONDON. - 0165-6147 .- 1873-3735. ; 39:11, s. 911-916
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Journal article (other academic/artistic)abstract
- The epidemic of addiction and over-dose is real. Addiction among pain patients accounts for only a small proportion but a large number. Scientific opinion leaders can be most effective on two fronts, each relatively low-tech: dissemination and oversight of empirically established treatments, and promulgation of social-science-based strategies for population-level prevention.
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| 10. |
- Evers, Bastiaan, et al.
(author)
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Targeting homologous recombination repair defects in cancer
- 2010
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 31:8, s. 372-380
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Research review (peer-reviewed)abstract
- DNA repair is essential for cells to maintain genome stability in an environment that constantly produces DNA damage. There is a growing appreciation that defects in homologous recombination repair underlie hereditary and sporadic tumourigenesis, and that deficiency in this pathway may dictate the sensitivity of tumours to certain DNA-damaging agents. Homologous recombination deficiency (HRD) may therefore prove to be a diagnostic criterion per se if appropriate biomarkers become available to identify these tumours. In addition, homologous recombination-deficient tumours are more sensitive to inhibition of other DNA repair pathways through so-called 'synthetic lethal interactions', a principle that is currently being tested in clinical trials. Finally, homologous recombination repair-deficient cells may have an increased dependency on certain cell-cycle checkpoints, which can be therapeutically exploited. Here we describe recent advances in strategies to identify and target HRD tumours, approaches to overcome resistance, and combinatory strategies to optimize treatment outcome.
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| 11. |
- Fowler, Christopher J.
(author)
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Anandamide uptake explained?
- 2012
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 33:4, s. 181-185
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Research review (peer-reviewed)abstract
- The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol are removed from the extracellular space by a process of cellular uptake followed by metabolism. Although the enzymes responsible for endocannabinoid metabolism have been well characterised, the processes involved in uptake have been the subject of much controversy. Recent studies, however, have identified intracellular transport proteins (fatty acid binding proteins 5 and 7, heat shock protein 70, albumin, and fatty acid amide hydrolase-like AEA transporter protein) that shuttle AEA from the plasma membrane to its metabolic enzymes. Proteins such as the fatty acid amide hydrolase-like anandamide transporter protein may be useful targets for novel therapeutic strategies aimed at potentiating AEA signalling. In this article I review the current state of the art of endocannabinoid uptake.
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| 12. |
- Fowler, Christopher J.
(author)
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Has FLAT fallen flat?
- 2014
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:2, s. 51-52
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Journal article (other academic/artistic)
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| 13. |
- Fowler, Christopher J.
(author)
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NSAIDs : eNdocannabinoid stimulating anti-inflammatory drugs?
- 2012
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 33:9, s. 468-473
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Research review (peer-reviewed)abstract
- Read any pharmacology textbook and the message is clear: nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of cyclooxygenase (COX) and thereby the production of prostaglandins. However, evidence is accumulating that NSAIDs involve the endocannabinoid system in their actions, and that such effects may pave the way towards the design of new analgesics that are not plagued with the gastrointestinal and cardiovascular adverse actions that are associated with this class of drugs. In this Opinion article, our current understanding of the involvement of the endocannabinoid system in the actions of NSAIDs is described, and the ways in which this can lead to novel drug development is discussed.
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| 14. |
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| 15. |
- Högberg, Liselotte Diaz, et al.
(author)
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The global need for effective antibiotics : challenges and recent advances
- 2010
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 31:11, s. 509-515
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Research review (peer-reviewed)abstract
- The emerging problem of antibiotic resistance is a serious threat to global public health. The situation is aggravated by a substantial decline in the research and development of antibacterial agents. Hence, very few new antibacterial classes are brought to market when older classes lose their efficacy. There has been renewed and growing attention within policy groups to: (i) address the problem; (ii) discuss incentives for the development of urgently needed new treatments; (iii) preserve the efficacy of existing therapeutic options. We briefly review the basic principles of antibiotic resistance, and contrast the increasing resistance to the dwindling antibacterial 'pipeline'. We also highlight some recent policy initiatives aiming to secure the future need of effective antibiotics.
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| 16. |
- Ingeiman-Sundberg, M
(author)
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Interview with Magnus Ingelman-Sundberg
- 2015
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In: Trends in pharmacological sciences. - : Elsevier BV. - 1873-3735 .- 0165-6147. ; 36:2, s. 65-67
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Journal article (other academic/artistic)
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Jespers, Willem, et al.
(author)
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Structural Mapping of Adenosine Receptor Mutations : Ligand Binding and Signaling Mechanisms
- 2018
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 39:1, s. 75-89
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Research review (peer-reviewed)abstract
- The four adenosine receptors (ARs), A(1), A(2A), A(2B), and A(3), constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A(2A) and inactive conformations of the A(1) ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.
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| 22. |
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| 23. |
- Järver, Peter, et al.
(author)
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In vivo biodistribution and efficacy of peptide mediated delivery
- 2010
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 31:11, s. 528-535
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Research review (peer-reviewed)abstract
- To transverse the plasma membrane and gain access to the cellular interior is one of the major obstacles for many novel pharmaceutical molecules. Since the late 1990 s, cell-penetrating peptides (CPPs) have been utilized as transport vectors for a broad spectrum of 'biological cargoes', ranging from inert gold particles to multifaceted macromolecules such as proteins and plasmids. Numerous studies have shown that CPPs are efficient carriers for bioactive cargoes in vitro. However, even though CPPs are versatile transport vectors, this does not guarantee they can be developed into useful pharmaceutical molecules. Nevertheless, recent progress in the field has shown CPPs to be effective for in vivo delivery with retained biological activity of a wide variety of bioactive cargoes into virtually any mammalian tissue. This review will focus on recent developments and applications for CPP delivery and distribution in vivo.
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| 24. |
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| 25. |
- Kurland, Lisa, et al.
(author)
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Using genotyping to predict responses to anti-hypertensive treatment
- 2005
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 26:9, s. 443-7
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Journal article (peer-reviewed)abstract
- Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Matsson, Pär, et al.
(author)
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Quantifying the impact of transporters on cellular drug permeability.
- 2015
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:5, s. 255-262
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Journal article (peer-reviewed)abstract
- The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters.
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| 31. |
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| 32. |
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| 33. |
- Perland, Emelie, et al.
(author)
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Classification Systems of Secondary Active Transporters
- 2017
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In: TIPS - Trends in Pharmacological Sciences. - : ELSEVIER SCIENCE LONDON. - 0165-6147 .- 1873-3735. ; 38:3, s. 305-315
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Research review (peer-reviewed)abstract
- Membrane-bound solute carrier (SLC) transporter proteins are vital to the human body, as they sustain homeostasis by moving soluble molecule as nutrients, drugs, and waste across lipid membranes. Of the 430 identified secondary active transporters in humans, 30% are still orphans, and systematic research has been requested to elaborate on their possible involvement in diseases and their potential as drug targets. To enable this, the various classification systems in use must be understood and used correctly. In this review, we describe how various classification systems for human SLCs are constructed, and how they overlap and differ. To facilitate communication between researchers and to avoid ambiguities, everyone must clearly state which classification system they are referring to when writing scientific articles.
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| 34. |
- Pirmohamed, Munir, et al.
(author)
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Oral anticoagulation : a critique of recent advances and controversies
- 2015
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 36:3, s. 153-163
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Research review (peer-reviewed)abstract
- There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.
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| 35. |
- Rask-Andersen, Mathias, et al.
(author)
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Advances in kinase targeting : current clinical use and clinical trials
- 2014
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In: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
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Research review (peer-reviewed)abstract
- Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
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| 40. |
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| 41. |
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| 42. |
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| 43. |
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| 44. |
- Zuccotti, Annalisa, et al.
(author)
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Structural and functional differences between L-type calcium channels: crucial issues for future selective targeting
- 2011
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In: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 32:6, s. 366-375
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Research review (peer-reviewed)abstract
- Within the family of voltage-gated calcium channels (VGCCs), L-type channels (L-VGCCs) represent a well-established therapeutic target for calcium channel blockers, which are widely used to treat hypertension and myocardial ischemia. L-VGCCs outside the cardiovascular system also control key physiological processes such as neuronal plasticity, sensory cell function (e.g. in the inner ear and retina) and endocrine function (e.g. in pancreatic beta cells and adrenal chromaffin cells). Research into L-VGCCs was stimulated by the discovery that the known L-VGCC isoforms (Ca(V)1.1, Ca(V)1.2, Ca(V)1.3 and Ca(V)1.4) possess different biophysical properties. However, no L-VGCC-isoform-selective drugs have yet been identified. In this review, we examine Ca(V)1.2 and Ca(V)1.3 isoforms at the level of genetic structure, splice variants, post-translational modifications and functional protein coupling. We discuss candidate Ca(V)1.2- and Ca(V)1.3-specific characteristics as future therapeutic targets in individual organs.
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| 45. |
- Grundemar, L, et al.
(author)
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Neuropeptide Y effector systems : perspectives for drug development
- 1994
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In: Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147. ; 15:5, s. 153-159
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Research review (peer-reviewed)abstract
- Neuropeptide Y was isolated in 1982 and has since attracted considerable interest. It is widely distributed in central and peripheral neurones and can produce a multitude of biological effects in the brain and the periphery. For example, the peptide has been associated with stimulation of food and water intake, control of mood, and regulation of central autonomic functions. In the periphery, sympathetic neuropeptide Y plays a role as a vasopressor and vasoconstrictor. Neuropeptide Y acts on at least three distinct receptor types, referred to a Y1, Y2 and Y3. This review by Lars Grundemar and Rolf Håkanson focuses on some neuropeptide Y-dependent mechanisms that may be implicated in certain disorders and may be promising targets for drugs active at neuropeptide Y receptors.
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| 46. |
- Persson, Carl, et al.
(author)
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Eosinophil lysis and free granules: an in vivo paradigm for cell activation and drug development
- 1997
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In: Trends in Pharmacological Sciences. - 0165-6147. ; 18:4, s. 117-123
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Journal article (peer-reviewed)abstract
- Release of cytotoxic granule proteins from activated eosinophil granules is considered to be a key pathogenic mechanism in eosinophilic diseases. Degenerated eosinophils and extracellular eosinophil granules have been repeatedly depicted. The present overview describes evidence that eosinophil lysis and distribution of free eosinophil granules (as opposed to 'classical degranulation') is an important mechanism by which eosinophils affect their surroundings. Here, Carl Persson and Jonas Erjefalt summarize how recent reports on the induction of eosinophil lysis in vivo provide a new paradigm for eosinophil activation and thus constitute a novel basis for pharmacological manipulations in eosinophilic diseases.
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| 47. |
- Persson, Carl, et al.
(author)
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The mouse trap
- 1997
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In: Trends in Pharmacological Sciences. - 0165-6147. ; 18:12, s. 465-467
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Journal article (peer-reviewed)abstract
- Mouse models of asthma are now being used extensively in drug research. However, the successful unravelling of combinatorial interplays of cells and molecules in the murine airways may not be matched by equally successful demonstrations of an asthma-like pathophysiology. Here, Carl Persson, Jonas Erjefalt, Magnus Korsgren and Frank Sundler discuss the fact that major features of asthma may still need to be demonstrated in the airways of allergic mice.
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| 48. |
- Persson, Carl, et al.
(author)
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Unbalanced research
- 2001
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In: Trends in Pharmacological Sciences. - 0165-6147. ; 22:10, s. 538-541
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Journal article (peer-reviewed)
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| 49. |
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| 50. |
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