Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (ION and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that ON and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.

A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.

Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody-associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG (P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.

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Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis

Objectives To develop and validate an international set of classification criteria for primary Sjogren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS

Methods We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgement We then validated the performance of the classification criteria in a separate cohort of patients

Results The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm2, each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤01 mL/min, each scoring 1 Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS Sensitivity and specificity against clinician-expert—derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively

Conclusion Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well suited as criteria for enrolment in clinical trials

https://ard.bmj.com/content/annrheumdis/76/1/9.full.pdf

2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome A consensus and data-driven methodology involving three international patient cohorts

Pathogenetic insights from the treatment of rheumatoid arthritis.

Perturbed cellular metabolism has been increasingly associated with fibroblast activation in fibrosis. A deeper understanding of metabolic rewiring might help to unravel the interplay between the metabolic and fibrotic pathways in systemic sclerosis (SSc).We aimed to identify transcriptomic alterations in metabolic pathway-related genes in fibrotic SSc skin and unravel whether fibroblasts could contribute to the perturbed skin metabolic networks in SSc.We integrated transcriptomic microarray data from skin (clinically affected forearm and non-affected back skin) of 76 SSc patients and 26 healthy controls (HC, forearm skin) from three distinct cohorts (GSE:45485, 59785, 9285/32413). Differentially expressed (DE) genes (FDR<0.05) between healthy and SSc skin were identified using the limma package. The supervised gene set enrichment analysis (GSEA) was based on DE genes using the clusterProfiler package, focusing on metabolic pathways. Transcriptional changes in SSc skin were compared to the TGFβ-induced changes in transcriptomes of primary human skin fibroblasts, measured by RNA-seq and scRNA-seq. For these experiments, cultured healthy skin fibroblasts were treated or not with TGFβ for 24h.Pathway enrichment analysis of DE gene in skin transcriptomes identified multiple alterations of metabolic pathways in SSc skin (Figure 1A) compared to healthy skin, pointing to enhanced pyrimidine/folate metabolism and suppressed lipid metabolism in SSc skin. Steroid hormone biosynthesis (AKR1, DHRS11, CYP1A2, SULT2B1, HSD1, EHTM2, HSD11B2), fatty acid synthesis (FASN1, FADS1, FADS2, ELOVL, SCD5, PTPLB), and fatty acid degradation (ACAT1/2, ACADS, ACAA1/2, ACADM, ACSL3) were the main downregulated lipid metabolism pathways in SSc skin, particularly in patients with the inflammatory intrinsic gene expression subset. The latter changes were detected in the affected and non-affected SSc skin, suggesting that altered lipid metabolism is a generalized feature of the SSc skin. Furthermore, pathway enrichment analysis of TGFβ-induced transcriptional changes in skin fibroblasts, as detected by RNA-seq and scRNA-seq, suggested that TGFβ-driven reprogramming could significantly contribute to the lipid metabolism perturbations in SSc skin (Figure 1B, C). Specifically, STRING analysis revealed that TGFβ suppressed metabolic networks of glycerophospholipids, arachidonic acid, and fatty acids in cultured skin fibroblasts (Figure 1D).Our data suggest perturbed lipid metabolic networks in SSc skin and identify skin fibroblasts, exposed to profibrotic milieu, as likely contributors to the altered lipid metabolism in SSc. These results might pave the way to a deeper understanding of the interplay between the metabolic and fibrotic pathways in SSc. Integrating these data with future metabolomic and single-cell studies could accelerate the discovery of potential metabolic targets in SSc.Figure 1.A) Enriched metabolic pathways in SSc skin compared to healthy skin based on DE gene expression. Downregulated GO biological processes in TGFβ-treated cultured healthy skin fibroblasts based on RNAseq (B) and scRNAseq (C) analyses. D) STRING pathway enrichment analysis of downregulated genes (RNA-Seq) linked to lipid metabolism in TGFβ-stimulated skin fibroblasts.We would like to acknowledge Foundation for Research in Rheumatology (FOREUM) and University Medical Centre Ljubljana for financial support.Blaž Burja: None declared, Hubert Rehrauer: None declared, Dominique Paul: None declared, Michael Whitfield: None declared, Matija Tomsic: None declared, Ziga Rotar: None declared, Mark Robinson: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant Siences, Amgen,AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL.Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec,Mitsubishi Tanabe, MSD, Novartis, Prometheus, Redxpharna, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim, Katja Lakota: None declared, Mojca Frank Bertoncelj: None declared.

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Matija Tomšič

Papers

Pos0626 perturbed lipid metabolism is a central metabolic reprogramming hub in systemic sclerosis