High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth.

Int J Parasitol Drugs Drug Resist. 2018 Feb 16;8(1):137-144

Authors: Bowden GD, Land KM, O'Connor RM, Fritz HM

Abstract
The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036-0.12; 95% CI] or 21.9 ng/ml [12.1-40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection.

PMID: 29547840 [PubMed - as supplied by publisher]

Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology: Applications for Drug Repurposing.

Front Physiol. 2018;9:151

Authors: de Anda-Jáuregui G, Guo K, McGregor BA, Hur J

Abstract
The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space.

PMID: 29545755 [PubMed]

New opportunities for kinase drug repurposing and target discovery.

Br J Cancer. 2018 Mar 16;:

Authors: Knapp S

Abstract
Protein kinases are major drug targets for oncology. The large size of the kinome, active site conservation and the influence of activation states on drug binding complicates the analysis of their cellular mode of action. In a recent article in Science, Klaeger et al. analysed cellular targets of 243 drug candidates providing a large repository of data for drug repurposing.

PMID: 29545596 [PubMed - as supplied by publisher]

Therapeutic Effect of Quinacrine, an Anti-protozoan Drug, by Selective Suppression of p-CHK1/2 in p53-negative Malignant Cancers.

Mol Cancer Res. 2018 Mar 15;:

Authors: Park S, Oh AY, Cho JH, Yoon MH, Woo TG, Kang S, Lee HY, Jung Y, Park BJ

Abstract
Quinacrine (QNC), anti-protozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest anti-tumor effects of QNC through suppression of NF-κB and activation of p53. This study, demonstrates the anti-cancer effect of QNC via a novel pathway through the elimination of check point kinase 1/2 (Chk1/2) under p53 inactivated conditions. Inhibition of p53, by PFT-α or siRNA, promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G2/M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed anti-tumor effects in a Villin-Cre;p53+/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53-/- xenografts.
IMPLICATIONS: Quinacrine has been used for the past over 70 years without obvious side-effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies.

PMID: 29545477 [PubMed - as supplied by publisher]

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CYP2D6 Pharmacogenetics Testing and Post-Cesarean Section Pain Scores-a Preliminary Study.

Pain Med. 2018 Mar 12;:

Authors: Ribeiro C, Quinta R, Raposo A, Valentim A, Albuquerque J, Grazina M

Abstract
Objective: Prospective observational study to analyze CYP2D6 pharmacogenetics in 55 Portuguese adult parturients undergoing elective cesarean section and to investigate the association between CYP2D6 alleles and pain score.
Methods: DNA was extracted from peripheral blood by standard methods. Genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number determination with TaqMan probes by real-time polymerase chain reaction (PCR). Allele duplications were confirmed (long PCR and PCR-restriction fragment length polymorphism). Theoretical metabolic profiles prediction was based on genetic data and activity scores. Association was investigated between genotypes and predicted phenotypes with pain scores. Statistical analysis was performed by using a χ2 test, and significance was set at P < 0.05.
Results: The percentage of poor, intermediate, extensive, and ultrarapid metabolizers found were 9%, 38%, 46%, and 7%, respectively. The results reveal a positive association between alleles *4, *10, and pain.
Conclusions: A positive association was found between predicted reduced or null activity of CYP2D6 and increased pain. It can be hypothesized that if CYP2D6 activity is reduced, tyramine metabolism will decrease, resulting in reduced formation of endogenous dopamine. Consequently, activation of the signal transduction pathways that controls pain and analgesic effect may be reduced, leading to an increase in pain. Therefore, we would recommend CYP2D6 genotyping to anticipate the needs for analgesia, which will help to adjust opioid dose and maximize clinical efficacy while reducing side effects.

PMID: 29546421 [PubMed - as supplied by publisher]

Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients.

J Immunol Res. 2018;2018:2780272

Authors: Sukasem C, Chaichan C, Nakkrut T, Satapornpong P, Jaruthamsophon K, Jantararoungtong T, Koomdee N, Sririttha S, Medhasi S, Oo-Puthinan S, Rerkpattanapipat T, Klaewsongkram J, Rerknimitr P, Tuchinda P, Chularojanamontri L, Tovanabutra N, Puangpetch A, Aekplakorn W

Abstract
The HLA-B∗15:02 allele has been reported to have a strong association with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Thai patients. The HLA-B alleles associated with carbamazepine-induced maculopapular exanthema (MPE) and the drug reaction with eosinophilia and systemic symptoms (DRESS) among the Thai population have never been reported. The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case-control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepine-tolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B∗15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04-25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10-13; OR (95% CI) = 70.91(19.67-255.65)) when compared with carbamazepine-tolerant controls. Carbamazepine-induced SJS/TEN also showed an association with HLA-B∗15:21 allele (P = 0.013; OR (95% CI) = 9.54 (1.61-56.57)) when compared with carbamazepine-tolerant controls. HLA-B∗58:01 allele was significantly related to carbamazepine-induced MPE (P = 0.007; OR (95% CI) = 4.73 (1.53-14.66)) and DRESS (P = 0.0315; OR (95% CI) = 7.55 (1.20-47.58)) when compared with carbamazepine-tolerant controls. These alleles may serve as markers to predict carbamazepine-induced cADRs in the Thai population.

PMID: 29546073 [PubMed - in process]

Porokeratotic eccrine and hair follicle nevus: a report of two cases and review of the literature.

An Bras Dermatol. 2017;92(5 Suppl 1):121-125

Authors: Agulló-Pérez AD, Resano-Abarzuza MÁ, Córdoba-Iturriagagoitia A, Yanguas-Bayona JI

Abstract
Porokeratotic eccrine and hair follicle nevus is a very rare non-hereditary disorder of keratinization with eccrine and hair follicle involvement with only 9 cases described in the literature. In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome. Herein we report 2 cases of porokeratotic eccrine and hair follicle nevus and review the existing cases in the Spanish and English literature.

PMID: 29267468 [PubMed - indexed for MEDLINE]