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Retrospective evidence drawn from real‐world experience of a medicine's use outside its labelled indication is one of a number of techniques used in drug repurposing (DRP). Relying as it does on large numbers of real incidences of human experience, rather than individual case reports with limited statistical support, preclinical experiments with poor translatability or in silico associations, which are early‐stage hypotheses, it represents the best validated form of DRP. Cancer is the most frequent of such DRP examples (e.g. aspirin in pancreatic cancer, hazard ratio = 0.25). This approach can be combined with pathway analysis to provide first‐in‐class treatments for complex diseases. Alternatively, it can be combined with prospective preclinical studies to uncover a validated mechanism for a new indication, after which a repurposed molecule is chemically optimized. [ABSTRACT FROM AUTHOR]

DrugRepurposing Online is a database of well-curated literature examples of drug repurposing, structured by reference to compounds and indications, via a generalisation layer (within specific datasets) of mechanism. References are categorised by level of relevance to human application to assist users in prioritising repurposing hypotheses. Users can search freely between any two of the three categories in either direction; results can then be extended to the third category. The concatenation of two (or more) direct relationships to create an indirect, hypothetical new repurposing relationship is intended to offer novel and non-obvious opportunities that can be both patented and efficiently developed. A natural language processing (NLP) powered search capability extends the opportunities from the hand-curated foundation to identify further opportunities., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS., Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes., Results: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44)., Conclusions: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23)., (© 2023. The Author(s).)

Background: Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans., Methods: Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion., Results: Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment., Conclusions: Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact., Methods: This is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics., Discussion: The current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay., Trial Status: Protocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks., Trial Registration: ClinicalTrials.gov NCT04794088 . Registered on 11 March 2021., (© 2022. The Author(s).)

Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA-Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA-Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5.

Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates., (Copyright © 2015 Elsevier B.V. All rights reserved.)

There are nearly 2000 patent and peer-reviewed literature-based examples of drug repurposing to be found at http://www.drugrepurposing.info/; yet there has recently been a spate of experimental techniques used to predict new drug repurposing opportunities. This review questions whether these new methods - from computerised modelling of drug-target interactions to retrospective analysis of clinical experience - merely add testable hypotheses without addressing their inherent validity, or whether they also partially validate the new uses so that the predictions are more likely to be successfully developed. In addition, ontological methods take existing information and link two known facts to create an unknown association. These can both enhance other methods of repurposing and provide patented, commercial products, including several case historical examples., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The increasing realization that many existing drugs do indeed provide opportunities for additional therapeutic indications suggests we should not only be alert for this potential among marketed drugs but also within the pool of developmental drugs, of which (owing to attrition) there are many more examples in existence. We present examples of drug repurposing by retrospective clinical trial analysis and suggest that this strategy presents a promising way of rescuing failed developmental candidates. We contend that the commercial barriers to successful drug rescue are less problematic than for drug repurposing. We indicate practical means for mining data from past clinical trials, either for new indications or for specific patient groups., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Pharmaceutical R&D is notoriously risky, lengthy and costly; moreover, it does not always produce products of blockbuster status. The conventional route of fully discovering, developing and marketing a new chemical entity is followed by the large pharmaceutical companies, whereas other organizations in the pharmaceutical sector--such as generic or specialty companies and biotechnology companies--only operate over portions of the full R&D process. Here, we compare the ten-year financial performance of these three subsectors through their price/earnings ratios and their return on capital metrics to understand which of these strategic alternatives offered the best return to investors., (2009 Elsevier Ltd. All rights reserved.)

New chemical entity discovery and development is a long, expensive and risky way of producing new therapeutics. An alternative approach, namely finding new uses for existing drugs, offers substantial advantages in terms of cost, time and risk, and represents a highly attractive strategy to drug discovery. Patents protecting the new use may also be obtained. There are multiple different classes of such R and D programs, depending on whether the original development is still protected by composition of matter patents, and whether the compound was ever fully developed/marketed for its original indication. There are also shortened R and D programs for new uses for stereoisomers and metabolites of existing drugs. Case histories in all areas are presented.

The availability of widespread contractual services led to the birth of the virtual company in the 1990s. As the concept has matured, and the biotechnology sector diversified, interchange of intellectual property in the form of collaborative and license arrangements opens up still further the opportunities for outsourced forms of pharmaceutical R&D.

V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic., (Copyright 2003 Elsevier Science Ltd.)

The most recent meeting organized by the Society for Medicines Research, entitled Improving Medicines Through Drug Delivery, was held at the National Heart and Lung Institute in London on July 5, 2001. Drug delivery is increasingly becoming a central technology in the research and development of better medicines. This is so for at least three reasons. First, new drugs are being derived from complex biological molecules that are not readily amenable to oral delivery. Second, improved medicine is recognized as requiring better dosing regimens for the patient. Both compliance and preference are improved by reduced dosing frequency, and it is rare for new products to require three-times-daily administration. Lastly, drug delivery technology has come a long way in the past 20 years, beyond controlled-release pharmaceuticals to polymer conjugates and dry powder-inhaled proteins., ((c) 2001 Prous Science. All rights reserved.)

It has recently become apparent that mitochondria play a pivotal role in the process of cell death. In the absence of adenosine 5'-triphosphate (ATP) cells die by necrosis, but if sufficient ATP is available, a cascade of changes is initiated that lead to a much more orderly process of cell death (apoptosis). In addition to providing energy to the cell, mitochondria serve to sequester Ca(2+). Excessive accumulation of Ca(2+) leads to the formation of reactive oxygen species, together with the opening of the mitochondrial permeability transition pore, which depolarizes the mitochondria and leads to mitochondrial swelling. This may also provide a mechanism for the release of cytochrome c from the intermembrane space, although it is clear that there are probably other mechanisms also. Cytochrome c normally functions as part of the respiratory chain, but when released into the cytosol it becomes a critical component of the apoptosis execution machinery, where it activates caspases (cysteine aspartate proteases) and (if ATP is available) causes apoptotic cell death. The regulation of mitochondrial function by proteins related to Bcl-2 is also discussed, together with the prospects for the development of new therapies for disorders associated with cell death.

On December 3, 1998, the Society for Medicines Research held a meeting entitled Trends in Medicinal Chemistry at the National Heart and Lung Institute, London. The meeting was conceived to alert researchers to compounds in early development or new discoveries likely to lead to new approaches to disease treatment in the near future. Presentations covered potential therapies for CNS disorders, through immune disease and cancer to cardiovascular diseases. Specific new discoveries described at the meeting included the antipsychotic agent ORG-23366; the anticonvulsants SB-204269, SB-258229 and SB-270664; the tyrosine kinase inhibitors CT-5269 and CT-4694; VEGF inhibitors from Zeneca; the elastase inhibitor GW-311616A; a serine protease inhibitor from Roche; the MMPI D-2163; two antimigraine follow-ons to rizatriptan, L-775606 and L-785103; the P(2T) inhibitor AR-C69931MX and a follow-on compound; and the PDE5 inhibitor sildenafil., ((c) 1998 Prous Science. All rights reserved.)

The Society for Medicines Research organized a one-day meeting on antiobesity drugs on March 26, 1998, in London. Current environmental risks for obesity include an increase in the proportion of fat consumption--especially an increase in the fat-to-carbohydrate ratio--and an increase in a sedentary life-style without an appropriate lowering in food intake. Energy balance plays a pivotal role of in the control of body stores. Knowing the mechanisms of the control of energy intake and energy expenditure provides explanations for the incidence of obesity and also possible sites for drug intervention. The genetic basis for obesity is complex, with the probability of a number of interacting genes being involved (polygenic inheritance). Each of the main components of the energy balance relationship has a distinct genetic basis. The ob gene was first identified in 1994 by Friedman, and its product is leptin, which may well be a potential target for obesity treatment. Speakers at the meeting highlighted various targets that hold promise in developing pharmacological treatments for obesity: increasing the activity of satiety factors (CCK-8, GPL-1, ACTH, alphaMSH and 5-HT acting on 5-HT(2C) receptors); inhibiting orexigenic agents (NPY, MCH, galanin); targeting thermogenesis (beta(3)-adrenergic agonists and uncoupling proteins); targeting fat absorption; and targeting neuropeptides. Some of the compounds developed to act on these sites are now becoming available., ((c) 1998 Prous Science. All rights reserved.)

The sensitivities of PDE-4 enzymes from smooth muscle and inflammatory cell sources from different species to a range of structurally diverse compounds were compared. All inflammatory cell PDE-4 sources displayed good crosscorrelations in their sensitivity to inhibition by these compounds. Similarly, PDE-4 enzymes from smooth muscle sources were well-correlated; however, there was no crosscorrelation between PDE-4 from smooth muscle sources and those of inflammatory cell sources, possibly reflecting differences in subcellular location of enzymes as well as subtype expression. The present study concludes that PDE-4 preparations from smooth muscle sources as well as those from inflammatory cell sources may be used to model the potential smooth muscle cell relaxing properties and anti-inflammatory properties of a compound in relation to human asthma.

PC12 is a rat pheochromocytoma cell line which has been increasingly used as a model system for both neural differentiation and chromaffin cell function. PC12 cells have been reported to synthesize dopamine and norepinephrine, but not epinephrine. We have found that PC12 cells do synthesize small amounts of epinephrine and that dexamethasone increases both epinephrine content as well as phenylethanolamine-N-methyltransferase (PNMT) activity. These results suggest that the PC12 cell line may be useful in the investigation of the regulation of PNMT.

Muscimol is one of the most potent agonist ligands at the gamma-aminobutyric acidA (GABAA) receptor. Analysis of its chemical structure showed it to be a candidate for photoaffinity labeling. In practice, UV irradiation at 254 nm both changed the UV spectrum of muscimol and induced an irreversible binding of [3H]-muscimol to rat cerebellar synaptosomal membrane. After 10 min of irradiation, using 10 nM [3H]muscimol, the specific portion of this binding was 270 fmol/mg protein. (Nonspecific binding was defined as that arising in the presence of 1 mM GABA.) Specific binding increased asymptotically up to 100 nM [3H]muscimol. Irradiation of the membranes themselves did not significantly alter the KD or Bmax of reversible [3H]muscimol binding. However, irradiation of [3H]muscimol reduced its capacity subsequently to photolabel the membranes by 86 +/- 3%. Dose-dependent inhibition of binding was observed with muscimol, GABA, and bicuculline methiodide; with 10 nM [3H]muscimol maximum inhibition was 70% of total labeling and the order of potencies of these three compounds was characteristic of labeling to the GABAA receptor. Baclofen, l-glutamate, and diazepam exerted no effect at high concentrations. SDS-PAGE of the photolabeled membranes indicated specific incorporation of radioactivity into two molecular-weight species. One failed to enter the separating gel, implying a molecular weight greater than 250,000 daltons (250 kD). The molecular weight of the other was identified by fluorography to be about 52,000 daltons (52 kD).

In synaptosomal membranes from rat cerebellum, additive responses to adenylate cyclase activity are observed between the beta adrenergic receptors present on the Purkinje cells and the adenosine A-1 receptors or gamma-aminobutyric acid B (GABAB) receptors, which are both associated with the granule cells. In contrast, nonadditive responses are found with the activation of the adenosine A-1 and the GABAB receptors. Because both receptors are mainly associated with the same cell type, the nonadditive response indicates an interaction between the adenosine A-1, GABAB receptors and the adenylate cyclase. The present study suggests that the nonadditivity results from a limited number of adenylate cyclase catalytic units, which both receptor systems share. This conclusion was derived indirectly by showing that 1) a GABAB agonist did not affect the adenosine A-1 recognition site; 2) both receptors additively activated the high-affinity guanosine 5'-triphosphatase, which is believed to reflect the activation of the inhibitory guanine nucleotide unit; and 3) the nonadditivity was still observed after stimulation of adenylate cyclase activity with forskolin.