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Repurposing drugs

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https://www.readbyqxmd.com/read/29679606/regulatory-pitfalls-and-opportunities-when-repurposing-for-inhalation-therapy
#1
Svetlana Lyapustina
This article reviews regulatory considerations for companies wishing to develop drugs for delivery via the respiratory tract (e.g., by oral inhalation or intranasally) using molecules previously approved for a different therapeutic indication and/or a different delivery route. Conceptually, such repurposing has many medical and business advantages, but turning promising ideas into real products requires overcoming a number of practical challenges. Obtaining regulatory approval to market a candidate product comes at the end of a product development, but being aware of the regulatory requirements is necessary before the development even starts...
April 18, 2018: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/29679241/therapeutic-approaches-to-type-i-interferonopathies
#2
REVIEW
Marc Bienias, Normi Brück, Constanze Griep, Christine Wolf, Stefanie Kretschmer, Barbara Kind, Victoria Tüngler, Reinhard Berner, Min Ae Lee-Kirsch
To review recent scientific advances and therapeutic approaches in the expanding field of type I interferonopathies. Type I interferonopathies represent a genetically and phenotypically heterogenous group of disorders of the innate immune system caused by constitutive activation of antiviral type I interferon (IFN). Clinically, type I interferonopathies are characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic nucleic acid sensors...
April 20, 2018: Current Rheumatology Reports
https://www.readbyqxmd.com/read/29671878/targeting-autophagy-in-cancer
#3
REVIEW
Angelique V Onorati, Matheus Dyczynski, Rani Ojha, Ravi K Amaravadi
Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. Early results from clinical trials that repurposed hydroxychloroquine for cancer have suggested that autophagy inhibition may be a promising approach for advanced cancers. In this review of the literature, the authors present fundamental advances in the biology of autophagy, approaches to targeting autophagy, the preclinical rationale and clinical experience with hydroxychloroquine in cancer clinical trials, the potential role of autophagy in tumor immunity, and recent developments in next-generation autophagy inhibitors that have clinical potential...
April 19, 2018: Cancer
https://www.readbyqxmd.com/read/29669855/squalene-epoxidase-drives-nafld-induced-hepatocellular-carcinoma-and-is-a-pharmaceutical-target
#4
Dabin Liu, Chi Chun Wong, Li Fu, Huarong Chen, Liuyang Zhao, Chuangen Li, Yunfei Zhou, Yanquan Zhang, Weiqi Xu, Yidong Yang, Bin Wu, Gong Cheng, Paul Bo-San Lai, Nathalie Wong, Joseph J Y Sung, Jun Yu
Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase ( SQLE ) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet-induced HCC...
April 18, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29669541/three-dimensional-models-of-mycobacterium-tuberculosis-proteins-rv1555-rv1554-and-their-docking-analyses-with-sildenafil-tadalafil-vardenafil-drugs-suggest-interference-with-quinol-binding-likely-to-affect-protein-s-function
#5
Pallabini Dash, M Bala Divya, Lalitha Guruprasad, Kunchur Guruprasad
BACKGROUND: Earlier based on bioinformatics analyses, we had predicted the Mycobacterium tuberculosis (M.tb) proteins; Rv1555 and Rv1554, among the potential new tuberculosis drug targets. According to the 'TB-drugome' the Rv1555 protein is 'druggable' with sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) drugs. In the present work, we intended to understand via computer modeling studies, how the above drugs are likely to inhibit the M.tb protein's function. RESULTS: The three-dimensional computer models for M...
April 18, 2018: BMC Structural Biology
https://www.readbyqxmd.com/read/29666812/tumor-progression-the-neuronal-input
#6
REVIEW
Marco Arese, Federico Bussolino, Margherita Pergolizzi, Laura Bizzozero, Davide Pascal
One of the challenges of cancer is its heterogeneity and rapid capacity to adapt. Notwithstanding significant progress in the last decades in genomics and precision medicine, new molecular targets and therapies appear highly necessary. One way to approach this complex problem is to consider cancer in the context of its cellular and molecular microenvironment, which includes nerves. The peripheral nerves, the topic of this review, modulate the biological behavior of the cancer cells and influence tumor progression, including the events related to the metastatic spread of the disease...
March 2018: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29666146/identification-of-circadian-clock-modulators-from-existing-drugs
#7
T Katherine Tamai, Yusuke Nakane, Wataru Ota, Akane Kobayashi, Masateru Ishiguro, Naoya Kadofusa, Keisuke Ikegami, Kazuhiro Yagita, Yasufumi Shigeyoshi, Masaki Sudo, Taeko Nishiwaki-Ohkawa, Ayato Sato, Takashi Yoshimura
Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone)...
April 17, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29665951/statistical-considerations-for-pediatric-multidrug-resistant-tuberculosis-efficacy-trials
#8
S Kim, J A Seddon, A J Garcia-Prats, G Montepiedra
The inclusion of newly licensed or repurposed drugs in regimens to treat children for multidrug-resistant tuberculosis (TB) may lead to treatment that is shorter than traditional regimens and composed only of oral medications. As an all-oral regimen may be more acceptable and have a better safety profile than current regimens, demonstrating non-inferiority may be satisfactory. Demonstrating non-inferior efficacy requires setting a non-inferiority margin and safeguarding study assay sensitivity. Multi-arm, multistage designs may currently not be appropriate in pediatric trials because of the lack of sensitive and specific intermediate outcomes...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29665949/current-status-of-pharmacokinetic-and-safety-studies-of-multidrug-resistant-tuberculosis-treatment-in-children
#9
A J Garcia-Prats, E M Svensson, E D Weld, H S Schaaf, A C Hesseling
After decades of neglect, data are finally becoming available on the appropriate, safe dosing of key second-line anti-tuberculosis drugs used for treating multidrug-resistant tuberculosis (MDR-TB) in children, including levofloxacin (LVX), moxifloxacin (MFX), linezolid (LZD) and delamanid (DLM). Much needed data on some novel and repurposed drugs are still lacking, including for bedaquiline (BDQ), pretomanid (PTM) and clofazimine (CFZ). We review the status of pharmacokinetic (PK) and safety studies of key anti-tuberculosis medications in children with MDR-TB, identify priority knowledge gaps and note ongoing work to address those gaps, in the context of planning for an efficacy trial in children with MDR-TB...
May 1, 2018: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/29661867/triclosan-is-an-aminoglycoside-adjuvant-for-the-eradication-of-pseudomonas-aeruginosa-biofilms
#10
Michael M Maiden, Alessandra M Agostinho Hunt, Mitchell P Zachos, Jacob A Gibson, Martin E Hurwitz, Martha H Mulks, Christopher M Waters
One of the most important clinical obstacles in cystic fibrosis (CF) is antibiotic treatment failure due to biofilms produced by Pseudomonas aeruginosa The ability of this pathogen to survive eradication by tobramycin and pathoadapt into a hyper-biofilm state leading to chronic infections is key to its success. Retrospective studies have demonstrated that preventing this pathoadaptation by improving eradication is essential to extend the lives of CF patients. To identify adjuvants that enhance tobramycin eradication of P...
April 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29661129/spidr-small-molecule-peptide-influenced-drug-repurposing
#11
Matthew D King, Thomas Long, Daniel L Pfalmer, Timothy L Andersen, Owen M McDougal
BACKGROUND: Conventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates...
April 16, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29659015/possible-repurposing-of-pyrvinium-pamoate-for-the-treatment-of-mesothelioma-a-pre-clinical-assessment
#12
Marcella Barbarino, Daniele Cesari, Riccardo Intruglio, Paola Indovina, Asadoor Namagerdi, Franca Maria Bertolino, Maria Bottaro, Delaram Rahamani, Cristiana Bellan, Antonio Giordano
Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, whose incidence is increasing worldwide. Unfortunately, no effective therapies are currently available and the prognosis is extremely poor. Recently, the anti-helminthic drug pyrvinium pamoate has attracted a strong interest for its anti-cancer activity, which has been demonstrated in many cancer models. Considering the previously established inhibitory effect of pyrvinium pamoate on the Wnt/β-catenin pathway and given the important role of this pathway in MM, we investigated the potential anti-tumor activity of this drug in MM cell lines...
April 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29658795/an-update-and-systematic-review-on-drug-therapies-for-the-treatment-of-refractory-chronic-cough
#13
Nicole M Ryan, Anne E Vertigan, Surinder S Birring
Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain. Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC...
April 16, 2018: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29653129/delivering-drugs-to-the-lungs-the-history-of-repurposing-in-the-treatment-of-respiratory-diseases
#14
Stephen P Newman
The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects...
April 10, 2018: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/29650251/exploring-the-molecular-mechanisms-of-traditional-chinese-medicine-components-using-gene-expression-signatures-and-connectivity-map
#15
Minjae Yoo, Jimin Shin, Hyunmin Kim, Jihye Kim, Jaewoo Kang, Aik Choon Tan
BACKGROUND AND OBJECTIVE: Traditional Chinese Medicine (TCM) has been practiced over thousands of years in China and other Asian countries for treating various symptoms and diseases. However, the underlying molecular mechanisms of TCM are poorly understood, partly due to the "multi-component, multi-target" nature of TCM. To uncover the molecular mechanisms of TCM, we perform comprehensive gene expression analysis using connectivity map. METHODS: We interrogated gene expression signatures obtained 102 TCM components using the next generation Connectivity Map (CMap) resource...
April 4, 2018: Computer Methods and Programs in Biomedicine
https://www.readbyqxmd.com/read/29649433/repurposing-sex-steroids-and-related-drugs-as-potential-treatment-for-parkinson-s-disease
#16
REVIEW
Mélanie Bourque, Marc Morissette, Thérèse Di Paolo
Parkinson's disease (PD) is a neurodegenerative disorder for which a greater prevalence and incidence is described in men. This suggests a protective effect of sex hormones in the brain. Therefore, steroids and drugs to treat endocrine conditions could have additional application for PD. Here, we review the protective effect of sex hormones, particularly estrogens, progesterone, androgens and dehydroepiandrosterone, in animal models of PD and also in human studies. Data also support that drugs affecting estrogen neurotransmission such as selective estrogen receptor modulators or affecting steroid metabolism with 5α-reductase inhibitors could be repositioned for treatment of PD...
April 9, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29642960/cyp51-as-drug-targets-for-fungi-and-protozoan-parasites-past-present-and-future
#17
Galina I Lepesheva, Laura Friggeri, Michael R Waterman
The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14α-demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus...
April 12, 2018: Parasitology
https://www.readbyqxmd.com/read/29628139/drug-repurposing-in-kidney-disease
#18
REVIEW
Usha Panchapakesan, Carol Pollock
Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease...
April 6, 2018: Kidney International
https://www.readbyqxmd.com/read/29626533/the-repurposing-of-ivermectin-for-malaria-a-prospective-pharmacokinetics-based-virtual-clinical-trials-assessment-of-dosing-regimen-options
#19
Raj Badhan, Zaril Zakaria, Olusola Olafuyi
Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance attention has turned towards ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiologically-based pharmacokinetic model in healthy adults (20-50 years) and paediatric (3-5 years/15-25 kg) subjects and in a representative adult malaria population group (Thailand). Dosing optimisation demonstrated a twice daily for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and paediatric...
April 4, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29625966/identification-of-st3agl4-mfhas1-csnk2a2-and-cd226-as-loci-associated-with-systemic-lupus-erythematosus-sle-and-evaluation-of-sle-genetics-in-drug-repositioning
#20
Yong-Fei Wang, Yan Zhang, Zhengwei Zhu, Ting-You Wang, David L Morris, Jiangshan Jane Shen, Huoru Zhang, Hai-Feng Pan, Jing Yang, Sen Yang, Dong-Qing Ye, Timothy J Vyse, Yong Cui, Xuejun Zhang, Yujun Sheng, Yu Lung Lau, Wanling Yang
OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. METHODS: We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci...
April 6, 2018: Annals of the Rheumatic Diseases
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