scholarly journals Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jean-Sélim Driouich ◽  
Maxime Cochin ◽  
Guillaume Lingas ◽  
Grégory Moureau ◽  
Franck Touret ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Exposure ◽  
Clinical Evidence ◽  
Antiviral Effect ◽  
Dose Effect ◽  
Plasma Drug ◽  
Hamster Model ◽  
Viral Genomes ◽  
Antiviral Efficacy ◽  
Repurposed Drugs

AbstractDespite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we use a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment is initiated before or simultaneously to infection, favipiravir has a strong dose effect, leading to reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlates with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. Antiviral efficacy is achieved with plasma drug exposure comparable with those previously found during human clinical trials. Notably, the highest dose of favipiravir tested is associated with signs of toxicity in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.

scholarly journals Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model

2020 ◽  
Author(s):  
Jean-Sélim Driouich ◽  
Maxime Cochin ◽  
Guillaume Lingas ◽  
Grégory Moureau ◽  
Franck Touret ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Exposure ◽  
Clinical Evidence ◽  
Antiviral Effect ◽  
Dose Effect ◽  
Hamster Model ◽  
Viral Genomes ◽  
Antiviral Efficacy ◽  
Weight Losses ◽  
Repurposed Drugs

AbstractDespite no or limited pre-clinical evidence, repurposed drugs are massively evaluated in clinical trials to palliate the lack of antiviral molecules against SARS-CoV-2. Here we used a Syrian hamster model to assess the antiviral efficacy of favipiravir, understand its mechanism of action and determine its pharmacokinetics. When treatment was initiated before or simultaneously to infection, favipiravir had a strong dose effect, leading to dramatic reduction of infectious titers in lungs and clinical alleviation of the disease. Antiviral effect of favipiravir correlated with incorporation of a large number of mutations into viral genomes and decrease of viral infectivity. The antiviral efficacy observed in this study was achieved with plasma drug exposure comparable with those previously found during human clinical trials and was associated with weight losses in animals. Thereby, pharmacokinetic and tolerance studies are required to determine whether similar effects can be safely achieved in humans.

Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease

2020 ◽  
Vol 26 (30) ◽  
pp. 3733-3747 ◽  
Author(s):  
Mariana Ferreira-Duarte ◽  
Joana Beatriz Sousa ◽  
Carmen Diniz ◽  
Teresa Sousa ◽  
Margarida Duarte-Araújo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endothelial Dysfunction ◽  
Bowel Disease ◽  
Clinical Evidence ◽  
High Cardiovascular Risk ◽  
Considerable Evidence ◽  
Chronic Inflammatory Condition ◽  
Inflammatory Bowel ◽  
Repurposed Drugs ◽  
Main Effects

The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.

scholarly journals Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 557
Author(s):  
Deanna M. Mudie ◽  
Aaron M. Stewart ◽  
Jesus A. Rosales ◽  
Nishant Biswas ◽  
Molly S. Adam ◽  
...  
Keyword(s):  
Solid Dispersion ◽  
Drug Exposure ◽  
Ph Effect ◽  
Hydroxypropyl Methylcellulose ◽  
Amorphous Solid ◽  
Gastric Ph ◽  
Patient Treatment ◽  
Oral Exposure ◽  
Amorphous Solid Dispersion ◽  
Plasma Drug

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

scholarly journals Extrapolation of pharmacokinetics and pharmacodynamics of sunitinib in children with gastrointestinal stromal tumors

2021 ◽  
Author(s):  
Reza Khosravan ◽  
Steven G. DuBois ◽  
Katherine Janeway ◽  
Erjian Wang
Keyword(s):  
Body Size ◽  
Solid Tumors ◽  
Gastrointestinal Stromal Tumors ◽  
Drug Exposure ◽  
Tumor Type ◽  
Plasma Drug ◽  
Safety And Efficacy ◽  
Stromal Tumors ◽  
Mixed Effects Modeling ◽  
Starting Dose

Abstract Purpose The starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors. Methods Integrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure–response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored. Results Two-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure. Conclusion Based on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.

Recombinant mannan-binding lectin (MBL) for therapy

2003 ◽  
Vol 31 (4) ◽  
pp. 763-767 ◽  
Author(s):  
J.C. Jensenius ◽  
P.H. Jensen ◽  
K. McGuire ◽  
J.L. Larsen ◽  
S. Thiel
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Clinical Evidence ◽  
Human Cell Line ◽  
Innate Immune ◽  
Genetically Determined ◽  
Micro Organisms ◽  
Mannan Binding Lectin ◽  
Binding Lectin ◽  
Increased Susceptibility

Mannan-binding lectin (MBL) is a plasma protein involved in the innate immune response. It binds to a number of micro-organisms and promotes killing of these through complement activation either directly or through opsonization. Clinical evidence indicates that in a variety of situations genetically determined low MBL levels are associated with increased susceptibility to infections. Infusions of plasma-derived MBL into MBL-deficient individuals was found to be safe in preliminary trials, but we considered that sufficient production and product safety could only be achieved through synthesis of recombinant MBL. A transfected human cell line produces MBL showing the same biological activity as plasma-derived MBL, and an essentially identical profile on MS. The production has been scaled up and clinical trials will start this year.

Causes of Increased Plasma Creatine Kinase Activity after Surgery

1974 ◽  
Vol 20 (3) ◽  
pp. 340-342 ◽  
Author(s):  
Kannika S Phornphutkul ◽  
Sinn Anuras ◽  
Raymond S Koff ◽  
Leonard B Seeff ◽  
Donald L Mahler ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Enzyme Activity ◽  
Drug Exposure ◽  
Kinase Activity ◽  
Clinical Evidence ◽  
Creatine Kinase Activity ◽  
Drug Reactions ◽  
Ornithine Carbamoyl Transferase ◽  
Elective Surgical Procedures ◽  
Plasma Creatine Kinase

Abstract To determine whether drug reactions might play a role in postoperatively increased plasma enzyme activity, we measured creatine kinase (CK), and ornithine carbamoyl transferase (OCT) activities immediately before and on the 1st, 4th, and 8th day after 343 elective surgical procedures performed on 327 patients who had received various drugs pre-operatively. We saw no overt clinical evidence of muscle damage, but plasma CK activity was significantly increased on the first postoperative day. Plasma OCT activity was not significantly altered. We found no relationship between prior drug exposure and in creased CK activity, but the administration of general rather than regional anesthesia and the duration of anesthesia during surgery were closely related to increased CK activity. Halothane or succinylcholine administration during operation was also associated with a significant increase in CK activity in subjects whose pre-operative CK activity was normal. In contrast, subjects with increased pre-operative CK activities did not show this response to halothane or succinylcholine.

Trimetrexate: a second generation folate antagonist in clinical trial.

1987 ◽  
Vol 5 (12) ◽  
pp. 2032-2040 ◽  
Author(s):  
J T Lin ◽  
J R Bertino
Keyword(s):  
Clinical Trials ◽  
Antitumor Activity ◽  
Pneumocystis Pneumonia ◽  
Dose Effect ◽  
Small Cell Lung ◽  
Phase Ii Trials ◽  
Neck Tumors ◽  
Nonhematologic Toxicity ◽  
Leucovorin Rescue ◽  
New Treatment

Trimetrexate is a promising new lipophilic antifolate with antitumor and antimicrobial activity, which is currently undergoing clinical trials. It differs from methotrexate in its transport and intracellular retention, and may be useful against tumors resistant to methotrexate because of impaired transport or deficient polyglutamylation. In preclinical studies, it has demonstrated a broader spectrum of antitumor activity than methotrexate, and appears to have synergistic antitumor activity when combined with a number of other agents. In clinical trials, the primary toxicity has been hematologic, with rapid recovery and no evidence of cumulative dose effect. Nonhematologic toxicity has been sporadic. Preliminary results of phase II trials indicate activity against breast, non-small-cell lung, and head and neck tumors. In addition, trimetrexate with simultaneous leucovorin rescue appears to be a promising new treatment for pneumocystis pneumonia in AIDS patients, with minimal toxic side effects.

Opiate-induced Rhabdomyolysis

1985 ◽  
Vol 4 (1) ◽  
pp. 71-74 ◽  
Author(s):  
P.G. Blain ◽  
R.J.M. Lane ◽  
D.N. Bateman ◽  
M.D. Rawlins
Keyword(s):  
Renal Failure ◽  
Creatine Kinase ◽  
Acute Renal Failure ◽  
Clinical Evidence ◽  
Elevated Serum ◽  
Plasma Drug ◽  
Drug Concentrations ◽  
Serum Aspartate Aminotransferase ◽  
Plasma Drug Concentrations ◽  
Serum Myoglobin

Three patients with opiate self-poisoning developed acute muscle damage with elevated serum aspartate aminotransferase and creatine kinase activities, increased serum myoglobin concentrations, raised plasma creatinine concentrations, hypocalcaemia and hyperphosphataemia. These abnormalities gradually resolved over 7-10 days, but recovery was complicated due to the development of acute renal failure (requiring haemodialysis) in one patient. Plasma drug concentrations, shortly after admission, in the patients taking dihydrocodeine and morphine were grossly elevated (184 and 60 μg/l respectively). Clinical evidence of myopathy was minimal in all three patients and muscle biopsy of one patient was normal at 7 days.

Aplidin Cardiac Safety Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4820-4820
Author(s):  
Arturo Soto-Matos ◽  
Sergio Szyldergemajn ◽  
Javier Gomez ◽  
Sonia Extremera ◽  
Bernardo Miguel-Lillo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Multivariate Analysis ◽  
Drug Exposure ◽  
Single Agent ◽  
Fatal Outcome ◽  
Healthy Population ◽  
Qtc Interval ◽  
Cardiac Safety ◽  
Frequent Type

Abstract Abstract 4820 Background Aplidin (plitidepsin) is a cyclic depsipeptide of marine origin, with activity in relapsed/refractory multiple myeloma and T-cell NHL[1],[2]. Some depsipeptides have been linked to increased cardiac toxicity in the literature[3]. PharmaMar Pharmacovigilance and Clinical Trials Data Management databases were reviewed for cardiac adverse events (CAEs) occurring during clinical trials evaluating plitidepsin as single-agent as of November 2008. Data were analyzed for potential risk factors associations with the occurrence of CAE by univariate and multivariate logistic regression analyses. Results Forty-six of the 578 patients (8.0%) treated had at least one CAE. Eleven patients of 578 (1.9%) had CAE related to plitidepsin, none of them with fatal outcome. CAEs were retrospectively classified into 3 main groups after clinical review of all available data. The most frequent type of CAE were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Most events occurred randomly during plitidepsin treatment. Of note, no cases of life-threatening ventricular arrhythmias have been reported to date. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous events (M) (n=6; 1.0%) included all other cardiac events that did not fit into the aforementioned categories. None of the M events was related to plitidepsin Demographic, clinical and pharmacological variables were explored by univariate and multivariate analysis. Significant association was found with prostate or pancreas cancer diagnosis (p=0.002), known baseline cardiac risk factors (p=0.002), myalgia at baseline (p=0.004), lower hemoglobin levels (p= 0.006) and ≥ grade 2 hypokalemia (p=0.006). Multivariate analysis confirmed all these associations. Importantly, treatment related variables, such as plitidepsin dose, number of cycles or schedule of administration did not result in any statistically significant association. Serial ECGs performed before and after plitidepsin administration (n=136) did not show any relevant effect on QTc interval. None of the PK parameters analyzed (Cmax and AUC from day 0 to day 28) had any significant impact on the probability of developing a CAE. Conclusions CAEs observed to date in plitidepsin trials fit into three clinical categories. The most frequent type observed was AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population[4]. All other events were relatively infrequent. No dose-cumulative pattern was observed; moreover, neither plitidepsin dose nor schedule was associated with occurrence of CAEs. Relevant predisposing factors identified in univariate and multivariate analyses were related to patient's baseline and/or disease-related characteristics rather than to drug exposure or treatment-related variables. Data available on 578 adult patients with advanced cancer treated with singe-agent plitidepsin support a favorable cardiac safety profile. Disclosures: Soto-Matos: PharmaMar SAU: Employment. Szyldergemajn:PharmaMar SAU: Employment. Gomez:PharmaMar SAU: Employment. Extremera:PharmaMar SAU: Employment. Miguel-Lillo:PharmaMar SAU: Employment. Alfaro:PharmaMar SAU: Employment. Coronado:PharmaMar SAU: Employment. Lardelli:PharmaMar SAU: Employment. Roy:PharmaMar SAU: Employment. Corrado:PharmaMar SAU: Employment. Yovine:PharmaMar SAU: Employment. Kahatt:PharmaMar SAU: Employment.

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