scholarly journals Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular Heart Disease in Humans: Regulatory Considerations

2017 ◽  
Vol 45 (3) ◽  
pp. 381-388 ◽  
Author(s):  
Thomas Papoian ◽  
Gowraganahalli Jagadeesh ◽  
Muriel Saulnier ◽  
Natalie Simpson ◽  
Arippa Ravindran ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Heart Disease ◽  
Valvular Heart Disease ◽  
Serotonin Receptor ◽  
Term Treatment ◽  
In Vitro Assays ◽  
Drug Induced ◽  
Safety Margins ◽  
Long Term Treatment

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on Ki values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC50 or EC50/human fCmax values for determining whether known 5-HT2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.

Valvular Heart Disease Associated with Long-term Treatment by Methysergide: a Case Report

Therapies ◽  
2014 ◽  
Vol 69 (3) ◽  
pp. 255-257 ◽  
Author(s):  
Michel Andréjak ◽  
Catherine Szymanski ◽  
Sylvestre Maréchaux ◽  
Elise Arnalsteen ◽  
Valérie Gras ◽  
...  
Keyword(s):  
Heart Disease ◽  
Case Report ◽  
Valvular Heart Disease ◽  
Term Treatment ◽  
Long Term Treatment

Drug-Induced Mesovarial Leiomyomas in the Rat—A Review and Additional Data

1993 ◽  
Vol 12 (1) ◽  
pp. 13-22 ◽  
Author(s):  
W. A. Kelly ◽  
R. J. Marler ◽  
J. H. Weikel
Keyword(s):  
Tumor Development ◽  
Term Treatment ◽  
Adrenergic Stimulation ◽  
Drug Induced ◽  
Continuous Administration ◽  
Suspensory Ligament ◽  
Stimulant Drugs ◽  
Uterine Muscle ◽  
Long Term Treatment

Leiomyomas developed in the ovarian suspensory ligament (costo-uterine muscle) of rats after long-term treatment with several beta2-adrenoceptor stimulant drugs. The response was evidently related to excessive adrenergic stimulation of a tissue with a high density of β2-receptors; was inhibited by β blockade; and was directly related to in vitro pharmacologic potency. Tumor development was dependent on continuous administration of adequate dosages to a susceptible strain of rat. Histologically, all tumors were benign and none were malignant. After many years of clinical experience, there are no known reports of this response in human patients receiving β2-adrenoceptor-stimulant drugs.

Recent Progress in Prediction Systems for Drug-induced Liver Injury Using in vitro Cell Culture

2020 ◽  
Vol 14 ◽  
Author(s):  
Shogo Ozawa ◽  
Toshitaka Miura ◽  
Jun Terashima ◽  
Wataru Habano ◽  
Seiichi Ishida
Keyword(s):  
Cell Culture ◽  
Recent Progress ◽  
Inflammatory Cells ◽  
Protein Adducts ◽  
In Vitro Assays ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Culture Systems ◽  
Cell Culture Systems

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. Objective: In this study, the recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as for the limitations of in vitro cell culture systems for DILI research. Methods: Information related to DILI was collected through a literature search of the PubMed database. Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4+ helper T lymphocytes and recognition by CD8+ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells, or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILIinducing drugs with approximately 50% sensitivity and 90% specificity. Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.

scholarly journals Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

2021 ◽  
Vol 22 (12) ◽  
pp. 6570
Author(s):  
Yue Lv ◽  
Rui-Can Cao ◽  
Hong-Bin Liu ◽  
Xian-Wei Su ◽  
Gang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Reserve ◽  
Primordial Follicle ◽  
Term Treatment ◽  
New Drugs ◽  
Gene Profiling ◽  
Primordial Follicles ◽  
Long Term Treatment ◽  
Follicle Activation

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

scholarly journals Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2607
Author(s):  
Yuzhen Gao ◽  
Jingjing Cao ◽  
Pan Xing ◽  
Ralf Altmeyer ◽  
Youming Zhang
Keyword(s):  
Respiratory Syncytial Virus ◽  
Confidence Interval ◽  
The Elderly ◽  
Term Treatment ◽  
Fusion Inhibitors ◽  
Long Term Treatment ◽  
Statistical Program ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

scholarly journals Development of a Bioartificial Vascular Pancreas

2021 ◽  
Vol 12 ◽  
pp. 204173142110277
Author(s):  
Edward X Han ◽  
Juan Wang ◽  
Mehmet Kural ◽  
Bo Jiang ◽  
Katherine L Leiby ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Pancreatic Islets ◽  
Vascular Graft ◽  
Term Treatment ◽  
Diffusion Limitations ◽  
Human Scale ◽  
Arterial Blood ◽  
Long Term Treatment

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

Long-Term Treatment with Pivmecillinam in Patients with Recurrent Bacteriuria

1982 ◽  
Vol 10 (3) ◽  
pp. 179-182
Author(s):  
B Bresky ◽  
K Lincoln
Keyword(s):  
Escherichia Coli ◽  
Adverse Effect ◽  
Renal Function ◽  
Term Treatment ◽  
The Body ◽  
End Of Treatment ◽  
Long Term Treatment ◽  
Tract Infections

Thirty out-patients with chronic recurrent urinary tract infections, who had failed to respond to 10 days treatment with either pivmecillinam and/or amoxycillin, received a 3-month course of pivmecillinam at a dose of 200 mg, three times daily. Twenty-seven patients had bacteriuria due to Enterobacteriaceae, mainly Escherichia coli, sensitive to mecillinam in vitro. Pivmecillinam eradicated all the initial urinary pathogens. Reinfections occurred during treatment in three patients, who remained asymptomatic. Four subjects complained of gastro-intestinal side-effects, and therapy was withdrawn in three instances. Another three patients described unusual adverse events towards the end of the course of treatment, described as an odd sensation in the body and a desire for salt. The sensation disappeared a few days after the end of treatment. Treatment with pivmecillinam had no adverse effect on haematopoietic, hepatic or renal function.

Free fatty acids normalize a rosiglitazone-induced visfatin release

2006 ◽  
Vol 291 (5) ◽  
pp. E885-E890 ◽  
Author(s):  
Dominik G. Haider ◽  
Friedrich Mittermayer ◽  
Georg Schaller ◽  
Michaela Artwohl ◽  
Sabina M. Baumgartner-Parzer ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Term Treatment ◽  
Double Blind ◽  
Lipid Infusion ◽  
Major Mechanism ◽  
Insulin Mimetic ◽  
Long Term Treatment ◽  
Plasma Ffa

The detrimental effect of elevated free fatty acids (FFAs) on insulin sensitivity can be improved by thiazolidinediones (TZDs) in patients with type 2 diabetes mellitus. It is unknown whether this salutary action of TZD is associated with altered release of the insulin-mimetic adipocytokine visfatin. In this study, we investigated whether visfatin concentrations are altered by FFA and TZD treatment. In a randomized, double-blind, placebo-controlled, parallel-group study 16 healthy volunteers received an infusion of triglycerides/heparin to increase plasma FFA after 3 wk of treatment with rosiglitazone (8 mg/day, n = 8) or placebo ( n = 8), and circulating plasma visfatin was measured. As a corollary, human adipocytes were incubated with synthetic fatty acids and rosiglitazone to assess visfatin release in vitro. The results were that rosiglitazone treatment increased systemic plasma visfatin concentrations from 0.6 ± 0.1 to 1.7 ± 0.2 ng/ml ( P < 0.01). Lipid infusion caused a marked elevation of plasma FFA but had no effect on circulating visfatin in controls. In contrast, elevated visfatin concentrations in subjects receiving rosiglitazone were normalized by lipid infusion. In isolated adipocytes, visfatin was released into supernatant medium by acute addition and long-term treatment of rosiglitazone. This secretion was blocked by synthetic fatty acids and by inhibition of phosphatidylinositol 3-kinase or Akt. In conclusion, release of the insulin-mimetic visfatin may represent a major mechanism of metabolic TZD action. The presence of FFA antagonizes this action, which may have implications for visfatin bioactivity.

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