Preclinical Development for Suspensions

2009 ◽  
pp. 127-176 ◽  
Author(s):  
Sudhakar Garad ◽  
Jianling Wang ◽  
Yatindra Joshi ◽  
Riccardo Panicucci
Keyword(s):  
Preclinical Development

118-LB: Preclinical Development of IDG-16177 as a Potent GPR40 Agonist for Treatment of Type 2 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 118-LB
Author(s):  
JONG MIN YOON ◽  
DOHEE KIM ◽  
DON-GIL LEE ◽  
KYUNG MI AN ◽  
MYONG JAE LEE ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Preclinical Development

Recent Advances in the Development of Broad-Spectrum Antiprotozoal Agents

2020 ◽  
Vol 27 ◽  
Author(s):  
Antonio Moreno-Herrera ◽  
Sandra Cortez-Maya ◽  
Virgilio Bocanegra-Garcia ◽  
Bimal Krishna Banik ◽  
Gildardo Rivera
Keyword(s):  
Giardia Lamblia ◽  
Heterocyclic Compounds ◽  
Trichomonas Vaginalis ◽  
Mechanisms Of Action ◽  
Parasitic Infections ◽  
Parasitic Diseases ◽  
Pharmacological Treatments ◽  
Preclinical Development ◽  
Leishmania Spp ◽  
Effective Drugs

: Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatment is limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.

Quantitative relations between structure and antiinflammatory activity of aryloxoalkanoic acids

1988 ◽  
Vol 53 (8) ◽  
pp. 1862-1872 ◽  
Author(s):  
Miroslav Kuchař ◽  
Eva Maturová ◽  
Bohumila Brunová ◽  
Jaroslava Grimová ◽  
Hana Tomková ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Structural Changes ◽  
Antiinflammatory Activity ◽  
Structural Parameters ◽  
Considerable Effect ◽  
Antiinflammatory Effect ◽  
Prolonged Action ◽  
Preclinical Development ◽  
Indicator Variables ◽  
Inhibitory Activities

The antiinflammatory effect of a series of aryloxoalkanoic acids II and of their biphenyl derivatives III was examined by measuring the inhibition of the development of carageenan- and adjuvant-induced edemas. The quantitative relations between the antiinflammatory effect and physicochemical and structural parameters of the compounds tested were evaluated. The equations obtained by the method of regression analysis showed a significant linear dependence of both inhibitory activities on the lipophilicity of the compounds and a considerable effect of some structural changes as expressed by indicator variables. The antiinflammatory effect is especially enhanced in both tests by the presence of a cyclic substituent at the aromatic ring. The high antiinflammatory effect of biphenylyl derivatives III is paralleled by their prolonged action. The prolongation of the effect is most likely a result of a suitable biotransformation of acid III to an efficient metabolite. The structural requirements which resulted from both the regression analysis and from the hypothesis of biotransformation of acids III were utilized in the synthesis of suitably substituted biphenylyloxoalkanoic acids. By this approach derivatives IIIe-i were obtained some of which showed a high antiinflammatory and also protracted effect. 4-(2',4'-Difluorbiphenylyl)-4-oxo-2-methylbutanoic acid (VÚFB-16 066, Flobufen) was chosen for further preclinical development.

scholarly journals Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

2021 ◽  
Vol 22 (2) ◽  
pp. 477
Author(s):  
Guendalina Froechlich ◽  
Chiara Gentile ◽  
Luigia Infante ◽  
Carmen Caiazza ◽  
Pasqualina Pagano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Reproductive System ◽  
Tumor Cell Line ◽  
Breast Tumors ◽  
Oncolytic Viruses ◽  
Female Reproductive System ◽  
Viral Glycoprotein ◽  
Preclinical Development ◽  
Biological Drugs

Background: HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. Results: We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

2021 ◽  
Vol 14 (3) ◽  
pp. 203 ◽  
Author(s):  
Shurong Hou ◽  
Juan Diez ◽  
Chao Wang ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
De Novo ◽  
Selective Inhibitors ◽  
Preclinical Development ◽  
Starting Point ◽  
Good Starting Point ◽  
Parallel Screening ◽  
Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.

The era of gene therapy: From preclinical development to clinical application

2021 ◽  
Author(s):  
Nabil A. Alhakamy ◽  
David T. Curiel ◽  
Cory J. Berkland
Keyword(s):  
Gene Therapy ◽  
Clinical Application ◽  
Preclinical Development

scholarly journals Intrapulmonary vaccination with delta-inulin adjuvant stimulates non-polarised chemotactic signalling and diverse cellular interaction

2021 ◽  
Author(s):  
Kia C. Ferrell ◽  
Erica L. Stewart ◽  
Claudio Counoupas ◽  
Thomas M. Ashhurst ◽  
Warwick J. Britton ◽  
...  
Keyword(s):  
Γδ T Cells ◽  
Mucosal Vaccine ◽  
Cellular Interaction ◽  
Respiratory Pathogens ◽  
Preclinical Development ◽  
Cell Recruitment ◽  
Mait Cells ◽  
Attractive Option ◽  
Early Inflammatory Response ◽  
Chemotactic Factors

AbstractThere is an urgent need for novel vaccination strategies to combat respiratory pathogens. Mucosal vaccine delivery is an attractive option as it directly targets the site of infection; however, preclinical development has been hindered by a lack of suitable mucosal adjuvants and a limited understanding of their immune effects in the lung environment. Herein, we define the early immune events following the intrapulmonary delivery of a vaccine incorporating the adjuvant delta-inulin. Analysis of the early inflammatory response showed vaccine-induced innate cell recruitment to lungs and local lymph nodes (LN) was transient and non-polarised, correlating with an increase in pulmonary chemotactic factors. Use of fluorescently labelled adjuvant revealed widespread tissue dissemination of adjuvant particles, coupled with broad cellular uptake and transit to the lung-draining LN by a range of innate immune cells. Mass cytometric analysis revealed extensive phenotypic changes in innate and adaptive cell subsets induced by vaccination; this included identification of unconventional lymphocytes such as γδ-T cells and MAIT cells that increased following vaccination and displayed an activated phenotype. This study details a comprehensive view of the immune response to intrapulmonary adjuvant administration and provides pre-clinical evidence to support delta-inulin as a suitable adjuvant for pulmonary vaccines.

scholarly journals The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1123
Author(s):  
Elsa Ghirardini ◽  
Francesco Calugi ◽  
Giulia Sagona ◽  
Federica Di Vetta ◽  
Martina Palma ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Human Condition ◽  
Clinical Aspects ◽  
Missense Mutations ◽  
Preclinical Development ◽  
Creatine Transporter Deficiency ◽  
Therapeutic Development ◽  
Transporter Deficiency ◽  
Scientific Challenge ◽  
Slc6a8 Gene

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

scholarly journals Bringing Advanced Therapies for Parkinson’s Disease to the Clinic: The Scientist’s Perspective

2021 ◽  
pp. 1-6
Author(s):  
Mark Tomishima ◽  
Agnete Kirkeby
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Phase I Clinical Trials ◽  
Preclinical Models ◽  
Preclinical Development ◽  
Dopaminergic Medication ◽  
Gene Therapies ◽  
Advanced Therapies ◽  
New Phase

After many years of preclinical development, cell and gene therapies have advanced from research tools in the lab to clinical-grade products for patients, and today they constitute more than a quarter of all new Phase I clinical trials for Parkinson’s disease. Whereas efficacy has been convincingly proven for many of these products in preclinical models, the field is now entering a new phase where the functionality and safety of these products will need to stand the test in clinical trials. If successful, these new products can have the potential to provide patients with a one-time administered treatment which may alleviate them from daily symptomatic dopaminergic medication.

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