scholarly journals Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies

2021 ◽  
Author(s):  
Sebastian Bauer ◽  
George D. Demetri ◽  
Ensar Halilovic ◽  
Reinhard Dummer ◽  
Christophe Meille ◽  
...  
Keyword(s):  
Partial Response ◽  
Disease Control ◽  
Time Course ◽  
Oral Treatment ◽  
Preliminary Evidence ◽  
Disease Control Rate ◽  
In Vivo Studies ◽  
Hematologic Toxicity ◽  
Next Generation

Abstract Background CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). Methods Fifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. Results No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. Conclusions Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. Translational relevance Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.

Effects of Probiotics in the Management of Infected Chronic Wounds: From Cell Culture to Human Studies

2020 ◽  
Vol 15 (3) ◽  
pp. 193-206
Author(s):  
Brognara Lorenzo ◽  
Salmaso Luca ◽  
Mazzotti Antonio ◽  
Di M. Alberto ◽  
Faldini Cesare ◽  
...  
Keyword(s):  
Chronic Wounds ◽  
Animal Experiments ◽  
Multidrug Resistant ◽  
Preliminary Evidence ◽  
Human Studies ◽  
In Vivo Studies ◽  
Resistant Bacteria ◽  
Keywords Probiotics

Background: Chronic wounds are commonly associated with polymicrobial biofilm infections. In the last years, the extensive use of antibiotics has generated several antibiotic-resistant variants. To overcome this issue, alternative natural treatments have been proposed, including the use of microorganisms like probiotics. The aim of this manuscript was to review current literature concerning the application of probiotics for the treatment of infected chronic wounds. Methods: Relevant articles were searched in the Medline database using PubMed and Scholar, using the keywords “probiotics” and “wound” and “injuries”, “probiotics” and “wound” and “ulcer”, “biofilm” and “probiotics” and “wound”, “biofilm” and “ulcer” and “probiotics”, “biofilm” and “ulcer” and “probiotics”, “probiotics” and “wound”. Results: The research initially included 253 articles. After removal of duplicate studies, and selection according to specific inclusion and exclusion criteria, 19 research articles were included and reviewed, accounting for 12 in vitro, 8 in vivo studies and 2 human studies (three articles dealing with animal experiments included also in vitro testing). Most of the published studies about the effects of probiotics for the treatment of infected chronic wounds reported a partial inhibition of microbial growth, biofilm formation and quorum sensing. Discussion: The application of probiotics represents an intriguing option in the treatment of infected chronic wounds with multidrug-resistant bacteria; however, current results are difficult to compare due to the heterogeneity in methodology, laboratory techniques, and applied clinical protocols. Lactobacillus plantarum currently represents the most studied strain, showing a positive application in burns compared to guideline treatments, and an additional mean in chronic wound infections. Conclusions: Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings such as infected chronic wounds, large, long-term clinical trials are still lacking, and further research is needed.

scholarly journals Characterization of Weissella viridescens UCO-SMC3 as a Potential Probiotic for the Skin: Its Beneficial Role in the Pathogenesis of Acne Vulgaris

2021 ◽  
Vol 9 (7) ◽  
pp. 1486
Author(s):  
Marcela Espinoza-Monje ◽  
Jorge Campos ◽  
Eduardo Alvarez Villamil ◽  
Alonso Jerez ◽  
Stefania Dentice Maidana ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Treatment ◽  
Acne Vulgaris ◽  
Topical Administration ◽  
In Vivo Studies ◽  
Mice Model ◽  
Cutibacterium Acnes ◽  
Snail Helix Aspersa

Previously, we isolated lactic acid bacteria from the slime of the garden snail Helix aspersa Müller and selected Weissella viridescens UCO-SMC3 because of its ability to inhibit in vitro the growth of the skin-associated pathogen Cutibacterium acnes. The present study aimed to characterize the antimicrobial and immunomodulatory properties of W. viridescens UCO-SMC3 and to demonstrate its beneficial effect in the treatment of acne vulgaris. Our in vitro studies showed that the UCO-SMC3 strain resists adverse gastrointestinal conditions, inhibits the growth of clinical isolates of C. acnes, and reduces the adhesion of the pathogen to keratinocytes. Furthermore, in vivo studies in a mice model of C. acnes infection demonstrated that W. viridescens UCO-SMC3 beneficially modulates the immune response against the skin pathogen. Both the oral and topical administration of the UCO-SCM3 strain was capable of reducing the replication of C. acnes in skin lesions and beneficially modulating the inflammatory response. Of note, orally administered W. viridescens UCO-SMC3 induced more remarkable changes in the immune response to C. acnes than the topical treatment. However, the topical administration of W. viridescens UCO-SMC3 was more efficient than the oral treatment to reduce pathogen bacterial loads in the skin, and effects probably related to its ability to inhibit and antagonize the adhesion of C. acnes. Furthermore, a pilot study in acne volunteers demonstrated the capacity of a facial cream containing the UCO-SMC3 strain to reduce acne lesions. The results presented here encourage further mechanistic and clinical investigations to characterize W. viridescens UCO-SMC3 as a probiotic for acne vulgaris treatment.

Trajectory-Based Tissue Engineering for Cartilage Repair: Correlation Between Maturation Rate and Integration Capacity

2013 ◽  
Author(s):  
Matthew B. Fisher ◽  
Nicole Söegaard ◽  
David R. Steinberg ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Time Course ◽  
Biomechanical Properties ◽  
Time Dependent ◽  
In Vivo Studies ◽  
Surgical Approaches ◽  
General Hypothesis ◽  
Vitro Assay

Given the limitations of current surgical approaches to treat articular cartilage injuries, tissue engineering (TE) approaches have been aggressively pursued over the past two decades. Although biochemical and biomechanical properties on the order of the native tissue have been achieved (1–5), several in-vitro and in-vivo studies indicate that increased tissue maturity may limit the ability of engineered constructs to remodel and integrate with surrounding cartilage, although results are highly variable (2, 6–8). Thus, “static” measures of construct maturity (e.g. compressive modulus) upon implantation may not be the best indicators of in-vivo success, which likely requires implanted TE constructs to mature, remodel, and integrate with the host over time to achieve optimal results. We recently introduced the concept of “trajectory-based” tissue engineering (TB-TE), which is based on the general hypothesis that time-dependent increases in construct maturation in-vitro prior to implantation (i.e. positive rates) may provide a better predictor of in-vivo success (9). As a first step in evaluating this concept, in the current study we hypothesized that time-dependent increases in equilibrium modulus (a metric of growth) would be correlated to ability of constructs to integrate to cartilage using an in-vitro assay. To test this hypothesis, the current objective was to determine and model the time course of maturation of TE constructs during in-vitro culture and to assess the ability of these constructs to integrate to cartilage at various points during their maturation.

Systemic telomerase gene therapy delivered via targeted lipidic nanoparticles

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13025-13025 ◽  
Author(s):  
A. Goldkorn ◽  
B. Hann ◽  
M. Hayes ◽  
D. C. Drummond ◽  
D. B. Kirpotin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Time Course ◽  
Cancer Metastasis ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Control Group ◽  
Telomerase Rna ◽  
Single Chain ◽  
Dna Nanoparticles

13025 Background: Most human cancers possess elevated telomerase activity that promotes proliferation. We developed 2 telomerase-targeting gene constructs: telomerase RNA containing a mutated template sequence (MT-hTer), and short interfering RNA (siRNA) targeting endogenous wild type telomerase RNA. When co-expressed in cancer cell lines and xenografts, MT-hTer/siRNA synergizes to cause rapid cell death (Li, S et al. Cancer Research 2004). Here, we tested the in vivo efficacy of MT-hTer/siRNA delivered systemically via antibody-targeted lipidic nanoparticles in a breast cancer metastasis model. Methods: Nude mice received intracardiac injection of luc+MCF7-C18 breast carcinoma cells ectopically overexpressing HER2 and luciferase. After 3 days, the mice were treated with a single 100 μg i.v. injection of either MT-hTer/siRNA-GFP or control (GFP-only) plasmid formulated into lipid-DNA nanoparticles conjugated to an internalizing anti-HER2 single chain antibody (Genosphere, TM) (Hayes, M et al. Gene Therapy 2005). A third group received saline (PBS) as a vehicle control. Cancer progression was monitored non-invasively via biophotonic imaging (Xenogen) of tumor luciferase signal. Results: By week 2 the PBS control group showed luciferase signal elevation that increased exponentially during the study. Similarly, the GFP-only control group developed significant luciferase signal elevation by week 3, with continued rise at all subsequent time points. In contrast, the MT-hTer/siRNA-GFP group experienced a decreased luciferase signal by week 2, which remained consistently low throughout the experimental time course. There were no observed treatment-related toxicities. Conclusions: In pilot in vivo studies, telomerase therapy dramatically inhibited tumor formation in mice after systemic delivery with cancer-targeting lipid-DNA nanoparticles. Expanded preclinical studies are underway. [Table: see text]

The Fibrinolytic Potential of the Normal Primate following the Generation of Thrombin In Vivo

1990 ◽  
Vol 63 (03) ◽  
pp. 476-481 ◽  
Author(s):  
Alan R Giles ◽  
Michael E Nesheim ◽  
Steven W Herring ◽  
Hugh Hoogendoorn ◽  
David C Stump ◽  
...  
Keyword(s):  
Time Course ◽  
Factor Xa ◽  
Lipid Vesicles ◽  
Experimental Period ◽  
In Vivo Studies ◽  
Full Time ◽  
Primate Model ◽  
Fibrinolytic Potential

SummaryParameters of the fibrinolytic system were studied in a primate model where the generation of thrombin was promoted in vivo. The procoagulant stimulus used was a combination of human factor Xa in combination with phosphatidylcholine/phos-phatidylserine lipid vesicles (PCPS) as the source of coagulant active phospholipid. The dosage of each component was formulated to provide a gradation of thrombin generating potential assessed prior to in vivo study in an in vitro clotting assay. These ranged from 25.25 - 36.60 pMole/kg (factor Xa) and 18.85 - 56.30 nMole/kg (PCPS). In each case, the ratio of the dose of factor Xa/PCPS was maintained at 0.65 (pMole factor Xa/ nMole PCPS). Individual dosage combinations producing recalcification clotting times in vitro of 15, 20, 25 and 30 s were used in detailed in vivo studies. Previous studies in dogs had confirmed the thrombin generating potential of factor Xa/PCPS infusions and demonstrated an associated activation ot protein C and increased fibrinolytic activity. This has now been extensively characterized in the chimpanzee as follows: 10 min after the infusion of the highest dose (36.6 pMole factor Xa/56.3 nMole PCPS kg bodyweight), the level of circulating t-PA had risen to 900 ng/ml (antigen), 885 IU/ml (functional). Dosage was observed with the lowest dose of 12.25 pMole factor Xa and 18.85 nMole PCPS being associated with relatively minor increases in circulating t-PA activity. There were no changes in u-PA at any dosage during the full time course of the experimental period (90 min). Plasminogen activation was also apparent with alpha-2 antiplasmin levels falling to 30 - 40% of pre-infusion levels at the highest dosages. There was also a significant consumption of fibrinogen and evidence of active fibrinolysis manifested by major increases in the levels of FDP, D-dimer and B-beta 1-42. The data strongly suggested that this was predominantly fibrinolysis rather than fibrinogenolysis and that the fibrinolytic response observed resulted from a major release of t-PA from available stores consequent to thrombin generation and presumably subsequent fibrin generation. These data illustrate the enormous fibrinolytic potential of the intact normal primate and may provide a model for study of the mechanism(s) by which the regulation of t-PA availability can be up- or down-regulated in health and disease.

Role of lipid peroxidation in H2O2-induced renal epithelial (LLC-PK1) cell injury

1995 ◽  
Vol 268 (1) ◽  
pp. F30-F38 ◽  
Author(s):  
A. K. Salahudeen
Keyword(s):  
Lipid Peroxidation ◽  
Renal Cell ◽  
Time Course ◽  
Cell Injury ◽  
Thiobarbituric Acid ◽  
Alpha Tocopherol ◽  
In Vivo Studies ◽  
Sequence Of Events

The exact sequence of events or mechanisms by which H2O2 induces renal cell injury remains undetermined. Specifically, whether the attendant lipid peroxidation is a cause or an effect remains unclear. Employing H2O2 and LLC-PK1 cells, we tested the hypothesis that lipid peroxidation is a seminal event and that its inhibition is cytoprotective. In a time course study, lipid peroxidation (thiobarbituric acid reaction) and degradation (release of [3H]arachidonic acid) preceded H2O2-induced cytolysis (51Cr and lactate dehydrogenase release). The role of preceding lipid peroxidation in cytolysis was examined with lipid radical scavengers. alpha-Tocopherol and lazaroid compound 2-methyl aminochroman dose-dependently inhibited H2O2-induced lipid peroxidation and prevented cytolysis. 2-Methyl aminochroman cytoprotection was associated with blockade of lipid degradation. 21-Aminosteroid, another lazaroid, also inhibited lipid peroxidation and prevented cytolysis. These findings provide evidence that lipid alterations contribute to H2O2-mediated LLC-PK1 injury and, for the first time, demonstrate the potency of lazaroids in a renal cell line. In vivo studies with lazaroids may define the role of lipid peroxidation in acute renal injury models.

Daratumumab (Dara) and hyperfractionated cyclophosphamide (HyperCy)/dexamethasone (Dex) with and without carfilzomib (Car) for the treatment of relapsed/refractory multiple myeloma (RRMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20528-e20528
Author(s):  
Brandon R. Shank ◽  
Brian Primeaux ◽  
Sandra B. Horowitz ◽  
Erin K. Yeung ◽  
Irene Y. Lee ◽  
...  
Keyword(s):  
Partial Response ◽  
Disease Control ◽  
Progression Free Survival ◽  
Organ Damage ◽  
Median Number ◽  
Published Data ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
End Organ Damage ◽  
Grade 3

e20528 Background: RRMM can be associated with high disease burden and/or end organ damage requiring rapid disease control. Our group has previously published data with hyperCy-bortezomib (bor)-doxorubicin-dex (Tabchi et al. 2019) for such patients (pts). Dara, a monoclonal antibody targeting CD38, has limited overlapping toxicities with cytotoxic chemotherapy, making it an attractive partner for hyperCy-dex. We report our retrospective experience of pts treated with dara-hyperCy-dex ± car. Methods: Between 5/2016-8/2019, 53 pts were treated with dara (16 mg/kg IV d1,8,15,22)-hyperCy (300-350 mg/m2 IV q12h x 6-8 doses d1-3/4)-dex (20-40 mg IV/PO d1-4, 8-11, 15-18, 22-23) alone (27 records), or with car (20 mg/m2 IV d1-2, 27-36 mg/m2 IV d8-9, 15-16) (32 records) on 28 day cycles. Pts received growth factor, anti-fungal, anti-bacterial, anti-viral, and peptic ulcer prophylaxis. High-risk MM (HRMM) was defined by t(4;14), t(14;16), and/or del 17p. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Each instance of treatment (tx) started > 60 days from the previous cycle start date was counted as a separate record. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were assessed per pt, based on earliest administration date. Results: Median age of pts was 61 (26-77) years. Median number of prior therapies was 4 (1-18). Previous exposure to both lenalidomide and pomalidomide (93%), both bor and car (83%), and dara (64%) was frequent. HRMM was present in 20/42 evaluable pts. After a median of 1 cycle (1-5), ORR was 63%, with ≥ very good partial response in 24%. DCR was 86%. Median PFS was 4.3 months. Median OS was 9.7 months. Grade 3-4 hematologic toxicities included 66% neutropenia, 66% anemia, and 68% thrombocytopenia. Grade 3-4 non-hematologic toxicities included 42% febrile neutropenia, 19% bacteremia, and 15% pneumonia. Within 60 days of tx, 7 pts underwent autologous stem cell transplant (ASCT), and 7 pts died. Conclusions: Dara-hyperCy-dex ± car demonstrates a high ORR and DCR in heavily treated and HRMM, allowing bridging of some pts to ASCT. High rates of hematologic toxicity and risk of infection are manageable with twice weekly monitoring for transfusion support, as well as early detection and intervention for infections. Rates of end organ damage reversal will be presented.

scholarly journals In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Rafael A. Guerra ◽  
Marcos P. Silva ◽  
Tais C. Silva ◽  
Maria C. Salvadori ◽  
Fernanda S. Teixeira ◽  
...  
Keyword(s):  
Egg Production ◽  
Oral Treatment ◽  
Drug Repurposing ◽  
In Vivo Studies ◽  
Content Type ◽  
Low Concentrations ◽  
Parasitic Flatworm ◽  
And Control

ABSTRACT Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.

scholarly journals Silver Nanoparticles-Composing Alginate/Gelatine Hydrogel Improves Wound Healing In Vivo

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 390 ◽  
Author(s):  
Flavia Resende Diniz ◽  
Romerito Cesar A. P. Maia ◽  
Lucas Rannier Andrade ◽  
Luciana Nalone Andrade ◽  
Marco Vinicius Chaud ◽  
...  
Keyword(s):  
Wound Healing ◽  
Silver Nanoparticles ◽  
Sodium Alginate ◽  
Time Course ◽  
In Vivo Studies ◽  
Natural Polymers ◽  
Cutaneous Lesions ◽  
Cutaneous Wounds ◽  
Healing Tissue

Polymer hydrogels have been suggested as dressing materials for the treatment of cutaneous wounds and tissue revitalization. In this work, we report the development of a hydrogel composed of natural polymers (sodium alginate and gelatin) and silver nanoparticles (AgNPs) with recognized antimicrobial activity for healing cutaneous lesions. For the development of the hydrogel, different ratios of sodium alginate and gelatin have been tested, while different concentrations of AgNO3 precursor (1.0, 2.0, and 4.0 mM) were assayed for the production of AgNPs. The obtained AgNPs exhibited a characteristic peak between 430–450 nm in the ultraviolet-visible (UV–Vis) spectrum suggesting a spheroidal form, which was confirmed by Transmission Electron Microscopy (TEM). Fourier Transform Infra-red (FT–IR) analysis suggested the formation of strong intermolecular interactions as hydrogen bonds and electrostatic attractions between polymers, showing bands at 2920, 2852, 1500, and 1640 cm−1. Significant bactericidal activity was observed for the hydrogel, with a Minimum Inhibitory Concentration (MIC) of 0.50 µg/mL against Pseudomonas aeruginosa and 53.0 µg/mL against Staphylococcus aureus. AgNPs were shown to be non-cytotoxic against fibroblast cells. The in vivo studies in female Wister rats confirmed the capacity of the AgNP-loaded hydrogels to reduce the wound size compared to uncoated injuries promoting histological changes in the healing tissue over the time course of wound healing, as in earlier development and maturation of granulation tissue. The developed hydrogel with AgNPs has healing potential for clinical applications.

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