scholarly journals Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym

2020 ◽  
Vol 175 (2) ◽  
pp. 292-300
Author(s):  
Diane M Longo ◽  
Lisl K M Shoda ◽  
Brett A Howell ◽  
Vladimir Coric ◽  
Robert M Berman ◽  
...  
Keyword(s):  
Clinical Data ◽  
Liver Toxicity ◽  
Hepatic Metabolism ◽  
In Vitro Toxicity ◽  
Oral Tablet ◽  
Test Parameters ◽  
First Pass ◽  
Function Test ◽  
Lateral Sclerosis

Abstract For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels > 3× ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 versus conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable with that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with interindividual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared with oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism.

Resveratrol: nanocarrier-based delivery systems to enhance its therapeutic potential

Nanomedicine ◽  
2020 ◽  
Author(s):  
Gurinder Singh
Keyword(s):  
Water Solubility ◽  
Therapeutic Potential ◽  
Hepatic Metabolism ◽  
Enterohepatic Recirculation ◽  
Systemic Delivery ◽  
First Pass ◽  
High Doses ◽  
Sites Of Action

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic compound existing in trees, peanuts and grapes and exhibits a broad spectrum of promising therapeutic activities, but it is unclear whether this entity targets the sites of action after oral administration. In vivo applicability of resveratrol has limited success so far, mainly due to its incompetent systemic delivery resulting from its low water solubility, poor bioavailability and short biological half-life. First-pass metabolism and presence of enterohepatic recirculation create doubt on the biological application of high doses typically used for in vitro trials. To augment bioavailability, absorption and uptake of resveratrol by cellular internalization, countless approaches have been implemented which involve the use of nanocarriers. Nanocarriers are a well-known delivery system used to reduce first-pass hepatic metabolism, overcome enterohepatic recirculation and accelerate the absorption of drugs via lymphatic pathways.

scholarly journals Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

2020 ◽  
Vol 10 (20) ◽  
pp. 7283 ◽  
Author(s):  
Atheer Zgair ◽  
Yousaf Dawood ◽  
Suhaib M. Ibrahem ◽  
Hyun-moon Back ◽  
Leonid Kagan ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Hepatic Metabolism ◽  
Hydrolysis Time ◽  
Testosterone Undecanoate ◽  
Main Site ◽  
Cell Homogenate ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

The bioavailability of orally administered drugs could be impacted by intestinal and hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug of testosterone, is significantly subjected to first-pass metabolism. However, the individual contribution of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the current study was to predict the metabolic contribution of each site. The hydrolysis–time profiles of TU incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the “well-stirred” model, the fraction of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min, which was applied in a “Q gut” model to estimate the fraction of TU that would escape intestinal first-pass metabolism (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal metabolism, while 91% can pass through hepatic metabolism. Hence, compared to the liver, the intestinal wall is the main site where TU is significantly metabolised during first-pass effect.

scholarly journals In vitro Intestinal Absorption and First-pass Intestinal and Hepatic Metabolism of Cycloastragenol, a Potent Small Molecule Telomerase Activator

2010 ◽  
Vol 25 (5) ◽  
pp. 477-486 ◽  
Author(s):  
Jing Zhu ◽  
Stephanie Lee ◽  
Maurice K.C. Ho ◽  
Yueqing Hu ◽  
Haihong Pang ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Small Molecule ◽  
Hepatic Metabolism ◽  
First Pass

scholarly journals Evaluation of the Liver Toxicity of Pterocephalus hookeri Extract via Triggering Necrosis

Toxins ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 142 ◽  
Author(s):  
Rui Wang ◽  
Zhaoyue Dong ◽  
Xiaolong Zhang ◽  
Jingxin Mao ◽  
Fancheng Meng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Toxicity ◽  
Folk Medicine ◽  
Tibetan Medicine ◽  
In Vitro Toxicity ◽  
Interacting Protein ◽  
Butanol Extract ◽  
Comparison Research

Pterocephalus hookeri (C. B. Clarke) Höeck, recorded in the Chinese Pharmacopoeia (2015 version) as a Tibetan medicine for the treatment of various diseases, especially rheumatoid arthritis, was believed to possess a slight toxicity. However, hardly any research has been carried out about it. The present study aimed to evaluate the toxicity in vivo and in vitro. Toxicity was observed by the evaluation of mice weight loss and histopathological changes in the liver. Then, the comparison research between ethyl acetate extract (EAE) and n-butanol extract (BUE) suggested that liver toxicity was mainly induced by BUE. The mechanical study suggested that BUE-induced liver toxicity was closely associated with necrosis detected by MTT and propidium iodide (PI) staining, via releasing lactate dehydrogenase (LDH), reducing the fluidity, and increasing the permeability of the cell membrane. Western blot analysis confirmed that the necrosis occurred molecularly by the up-regulation of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3), as well as the activation of the nuclear factor-kappa-gene binding (NF-κB) signaling pathway in vivo and in vitro. This finding indicated that the liver toxicity induced by BUE from P. hookeri was mainly caused by necrosis, which provides an important theoretical support for further evaluation of the safety of this folk medicine.

Valsartan Loaded Solid Lipid Nanoparticles: Development, Characterization, and In vitro and Ex vivo Evaluation

2011 ◽  
Vol 4 (3) ◽  
pp. 1483-1490
Author(s):  
Krutika K Sawant ◽  
B Parmar ◽  
S A Mandal ◽  
K C Petkar ◽  
L D Patel
Keyword(s):  
Particle Size ◽  
Drug Release ◽  
Zeta Potential ◽  
Solid Lipid Nanoparticles ◽  
Ex Vivo ◽  
Hepatic Metabolism ◽  
Lipid Nanoparticles ◽  
Release Studies ◽  
First Pass

Valsartan is an antihypertensive drug with poor oral bioavailability ranging from 10-35% because of poor solubility, dissolution and most importantly, extensive first pass hepatic metabolism. The present study deals with the development and characterization of Valsartan-loaded solid lipid nanoparticles (VSLNs) to enhance the solubility, bypass the first pass hepatic metabolism, and enhance the lymphatic absorption leading to improved bioavailability. VSLNs were developed using glyceryl behenate (Compritol 888 ATO®) as the lipid and Poloxamer 407 (Pluronic F 127) as the surfactant by the solvent injection method. VSLNs were characterized for mean particle Size (MPS), zeta potential, percentage drug entrapment (PDE), DSC Scans, XRD and TEM analysis. In vitro drug release studies were performed in 0.067 M phosphate buffer of pH 6.8 using dialysis diffusion bag method. Ex vivo drug release studies were also performed for both VSLNs and valsartan suspension in stomach and intestine. The optimized formulation of having the 80 mg lipid, 10 mg drug and 250 mg surfactant was found to have particle size distribution of 142.5 ± 1.859 nm, zeta potential of – 14.3 ± 0.384 mV, and 84.59 ± 0.328% drug entrapment. Based on these results, it is concluded that SLNs show promise for improving the oral bioavailability of valsartan. 

Human liver cell cultivation for long-term in vitro toxicity studies in a miniaturized multi-compartment 3D bioreactor system

2011 ◽  
Vol 49 (01) ◽  
Author(s):  
SA Hoffmann ◽  
M Lübberstedt ◽  
U Müller-Vieira ◽  
D Knobeloch ◽  
A Nüssler ◽  
...  
Keyword(s):  
Liver Cell ◽  
Human Liver ◽  
In Vitro Toxicity ◽  
Cell Cultivation ◽  
Toxicity Studies ◽  
Human Liver Cell ◽  
Bioreactor System

DETERMINATION OF BLOOD CORTICOIDS USING THE IN VITRO RESIN UPTAKE OF 3H-PREDNISOLONE

1968 ◽  
Vol 57 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Hironori Nakajima ◽  
Mitsunori Murala ◽  
Masumitsu Nakata ◽  
Takeshi Naruse ◽  
Seiji Kubo
Keyword(s):  
Thyroid Function Test ◽  
Normal Subjects ◽  
Adrenal Function ◽  
Function Test ◽  
Before And After ◽  
Adrenal Response ◽  
Suppression Test

ABSTRACT The in vitro resin uptake of 3H-prednisolone was used for the determination of blood cortisol after addition of radioactive prednisolone followed by Amberlite CG 400 Type 1 to the test serum, and incubation of the mixture. The radioactivity of the supernatant was compared before and after the addition of the resin. The principle of this method is similar to that of the 131I-triiodothyronine resin uptake for the thyroid function test. The tests for the specificity, reproducibility and sensitivity gave satisfactory results. The mean basal value ± SD of the 3H-prednisolone resin uptake was 35.3 ± 9.2% in normal subjects, and 27.1 ± 4.8% in pregnant women. This method was valid in various adrenal function tests, i. e. the adrenal circadian rhythm, corticotrophin (ACTH) test, dexamethasone suppression test and the adrenal response to lysine-8-vasopressin. It proved to be a sensitive indicator of the adrenal function. These results suggest that this method should be useful for a routine adrenal function test.

Uji Toksisitas Beberapa Fungisida Nabati terhadap Penyakit Layu Fusarium (Fusarium oxysporum) pada Tanaman Kentang (Solanum tuberosum L.) secara In Vitro (Toxicity Test of several Biofungicides in controlling Fusarium wilt (Fusarium oxysporum) in Potato Plants (Solanum tuberosum L.) by In Vitro)

2019 ◽  
Vol 9 (2) ◽  
pp. 91
Author(s):  
Ghea Dotulong ◽  
Stella Umboh ◽  
Johanis Pelealu
Keyword(s):  
Solanum Tuberosum ◽  
Fusarium Oxysporum ◽  
Fusarium Wilt ◽  
Leaf Extract ◽  
Solanum Tuberosum L ◽  
In Vitro Toxicity ◽  
Potato Plants ◽  
Colony Diameter ◽  
In Vitro Toxicity Test

Uji Toksisitas Beberapa Fungisida Nabati terhadap Penyakit Layu Fusarium (Fusarium oxysporum) pada Tanaman Kentang (Solanum tuberosum L.) secara In Vitro (Toxicity Test of several Biofungicides in controlling Fusarium wilt (Fusarium oxysporum) in Potato Plants (Solanum tuberosum L.) by In Vitro) Ghea Dotulong1*), Stella Umboh1), Johanis Pelealu1), 1) Program Studi Biologi, FMIPA Universitas Sam Ratulangi, Manado 95115*Email korespondensi: [email protected] Diterima 9 Juli 2019, diterima untuk dipublikasi 10 Agustus 2019 Abstrak Tanaman kentang (Solanum tuberosum L.) adalah salah satu tanaman hortikultura yang sering mengalami penurunan dari segi produksi dan produktivitasnya, akibat adanya serangan penyakit layu yang salah satunya disebabkan oleh Fusarium oxysporum. Tujuan penelitian ini adalah mengidentifikasi toksisitas beberapa fungisida nabati dalam mengendalikan penyakit Layu Fusarium (F. oxysporum) pada tanaman kentang (Solanum tuberosum L.) secara In Vitro. Metode Penelitian yang digunakan yaitu metode umpan beracun. Data dianalisis dengan Rancangan Acak Lengkap (RAL) dengan Analisis Varian (ANAVA) yang dilanjutkan dengan menggunakan metode BNT (Beda Nyata Terkecil). Hasil Penelitian, diperoleh nilai toksisitas fungisida nabati tertinggi yaitu pada ekstrak daun sirsak dengan nilai HR (69,44%), kategori berpengaruh, ditandai dengan diameter koloni 2,75 cm (100ppm) dan yang terendah toksisitasnya yaitu pada ekstrak daun jeruk purut dengan nilai HR (49,81%), kategori cukup berpengaruh ditandai dengan diameter koloni 3,75 cm (25ppm). Semakin tinggi konsentrasi yang diujikan maka semakin tinggi toksisitas dari fungisida nabati yang diberikan.Kata Kunci: fungisida nabati, Fusarium oxysporum, tanaman kentang, In Vitro Abstract Potato plants (Solanum tuberosum L.) is one of the horticulture plants which often decreases in terms of production and productivity, due to the attack of wilt, one of which is caused by Fusarium oxysporum. The purpose of this study was to determine the toxicity of several biofungicides in controlling Fusarium wilt (F. oxysporum) in potato plants (Solanum tuberosum L.) in Vitro. The research method used was the In Vitro method with the poison bait method. Data were analyzed by Completely Randomized Design with Variant Analysis (ANAVA), followed by the BNT method. The results showed that the highest biofungicide toxicity value was soursop leaf extract with HR values (69.44%), influential categories, characterized by colony diameter 2.75 cm (100ppm) and the lowest toxicity, namely in kaffir lime leaf extract with a value of HR (49.81%), quite influential category was characterized by colony diameter of 3.75 cm (25ppm). The higher the concentration tested, the higher the toxicity of the biofungicide given.Keywords: biofungicides, Fusarium oxysporum, Potato Plants, In Vitro.

Sign in / Sign up

Export Citation Format

Share Document