scholarly journals In Vivo Pharmacodynamics of a New Triazole, Ravuconazole, in a Murine Candidiasis Model

2003 ◽  
Vol 47 (4) ◽  
pp. 1193-1199 ◽  
Author(s):  
D. Andes ◽  
K. Marchillo ◽  
T. Stamstad ◽  
R. Conklin
Keyword(s):  
Protein Binding ◽  
Time Course ◽  
Treatment Success ◽  
Peak Level ◽  
Experimental Models ◽  
Free Drug ◽  
In Vivo Studies ◽  
Time Curve ◽  
Percent Time

ABSTRACT In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for the AUC/MIC ratio as the PK/PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio, R 2 = 91%; peak/MIC ratio, R 2 = 85%; percent time above the MIC, R 2 = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean ± SD = 20.3 ± 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.

scholarly journals In Vivo Pharmacokinetics and Pharmacodynamics of a New Triazole, Voriconazole, in a Murine Candidiasis Model

2003 ◽  
Vol 47 (10) ◽  
pp. 3165-3169 ◽  
Author(s):  
D. Andes ◽  
K. Marchillo ◽  
T. Stamstad ◽  
R. Conklin
Keyword(s):  
Protein Binding ◽  
Treatment Efficacy ◽  
Treatment Success ◽  
Peak Level ◽  
Free Drug ◽  
In Vivo Studies ◽  
Mouse Serum ◽  
Time Curve ◽  
Elimination Half

ABSTRACT In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (R 2 for AUC/MIC ratio = 82%, R 2 for peak level/MIC ratio = 63%, R 2 for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean ± standard deviation, 24 ± 17 [P = 0.45]). These AUC/MIC ratios observed for free drug are similar to those observed for other triazoles in this model.

scholarly journals Pharmacodynamics of a New Triazole, Posaconazole, in a Murine Model of Disseminated Candidiasis

2004 ◽  
Vol 48 (1) ◽  
pp. 137-142 ◽  
Author(s):  
D. Andes ◽  
K. Marchillo ◽  
R. Conklin ◽  
Gopal Krishna ◽  
Farkad Ezzet ◽  
...  
Keyword(s):  
Protein Binding ◽  
Murine Model ◽  
Treatment Efficacy ◽  
Time Course ◽  
Dose Range ◽  
Treatment Success ◽  
Free Drug ◽  
Peak Serum ◽  
In Vivo Studies

ABSTRACT Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to ∞ values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R 2 = 83%; peak serum drug/MIC ratio R 2 = 85%; time that serum levels of posaconazole remained above the MIC R 2 = 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 μg/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean ± SD = 16.9 ± 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.

scholarly journals In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model

2007 ◽  
Vol 52 (2) ◽  
pp. 539-550 ◽  
Author(s):  
D. Andes ◽  
D. J. Diekema ◽  
M. A. Pfaller ◽  
R. A. Prince ◽  
K. Marchillo ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Time Course ◽  
Dose Range ◽  
Treatment Success ◽  
In Vivo Studies ◽  
Serum Drug Concentration ◽  
Time Curve ◽  
Maximum Serum ◽  
Dosing Regimens

ABSTRACT Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC0-24] to the MIC, and the ratio of the maximum serum drug concentration [C max] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max/MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max/MIC and AUC/MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 μg/ml) to determine if similar C max/MIC and AUC0-24/MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.

scholarly journals Pharmacodynamics of the New Des-F(6)-Quinolone Garenoxacin in a Murine Thigh Infection Model

2003 ◽  
Vol 47 (12) ◽  
pp. 3935-3941 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Time Course ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Strain Atcc ◽  
Time Curve ◽  
Gram Negative ◽  
Percent Time ◽  
Dosing Regimens ◽  
Resistant Strains

ABSTRACT Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 106.5 to 106.7 CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R 2= 71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]).In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 105.9 to 107.2 CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4μ g/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios ± standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 ± 18, 81± 37, and 33 ± 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.

scholarly journals Pharmacodynamics of the New Fluoroquinolone Gatifloxacin in Murine Thigh and Lung Infection Models

2002 ◽  
Vol 46 (6) ◽  
pp. 1665-1670 ◽  
Author(s):  
D. Andes ◽  
W. A. Craig
Keyword(s):  
Time Course ◽  
Peak Level ◽  
Lung Infection ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Infection Models ◽  
The Family ◽  
Multiple Pathogens

ABSTRACT Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 106.5 to 107.4 CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log10 numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R 2 = 90 to 94% for the three organisms, whereas R 2 = 70 to 81% for peak level/MIC and R 2 = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 106.5 to 107.4 CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 108.3 CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 μg/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean ± standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 ± 21, 52 ± 20, and 36 ± 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection.

scholarly journals Comparative pharmacokinetics, distributions in tissue, and interactions with blood proteins of conventional and sterically stabilized liposomes containing 2',3'-dideoxyinosine.

1996 ◽  
Vol 40 (1) ◽  
pp. 225-229 ◽  
Author(s):  
P Harvie ◽  
A Désormeaux ◽  
M C Bergeron ◽  
M Tremblay ◽  
D Beauchamp ◽  
...  
Keyword(s):  
Protein Binding ◽  
Intravenous Injection ◽  
Half Life ◽  
Peak Level ◽  
Free Drug ◽  
Systemic Clearance ◽  
Blood Proteins ◽  
Sterically Stabilized Liposomes

The pharmacokinetics and distribution in tissue of 2',3'-dideoxyinosine (ddI) encapsulated in sterically stabilized liposomes have been evaluated in rats. Most of the sterically stabilized liposomes concentrated in the spleen with a peak level at 24 h after their intravenous injection. An extended half-life in plasma was observed for sterically stabilized liposomes (14.5 h) compared with that of conventional liposomes (3.9 h). The systemic clearance of ddI incorporated in sterically stabilized liposomes was 180 times lower than that of the free drug. The levels of in vitro and in vivo protein binding on both conventional and sterically stabilized liposomes were also evaluated. Results suggest that the amount of proteins associated with liposomes might not be the only factor involved in the in vivo clearance of liposomes, as this process may also be influenced by the nature of the bound blood proteins.

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.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

scholarly journals The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3088
Author(s):  
Mariana Matias ◽  
Jacinta O. Pinho ◽  
Maria João Penetra ◽  
Gonçalo Campos ◽  
Catarina Pinto Reis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Drug Evaluation ◽  
Three Dimensional ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Murine Models ◽  
In Vivo Experiments ◽  
Novel Therapeutic Strategies

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

scholarly journals Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 180 ◽  
Author(s):  
Aroha B. Sánchez ◽  
Beatriz Clares ◽  
María J. Rodríguez-Lagunas ◽  
María J. Fábrega ◽  
Ana C. Calpena
Keyword(s):  
Side Effects ◽  
Redox State ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Histological Evaluation ◽  
Sodium Diclofenac ◽  
Cox 2

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs.

Sign in / Sign up

Export Citation Format

Share Document