scholarly journals New In Vitro Methodology for Kinetics Distribution Prediction in the Brain. An Additional Step towards an Animal-Free Approach

Animals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3521
Author(s):  
Bárbara Sánchez-Dengra ◽  
Isabel González-Álvarez ◽  
Marta González-Álvarez ◽  
Marival Bermejo
Keyword(s):  
Brain Homogenate ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
New Drugs ◽  
In Vitro Tests ◽  
Unbound Fraction ◽  
Standard Tool ◽  
New Formulation ◽  
The Brain

The development of new drugs or formulations for central nervous system (CNS) diseases is a complex pharmacologic and pharmacokinetic process; it is important to evaluate their access to the CNS through the blood−brain barrier (BBB) and their distribution once they have acceded to the brain. The gold standard tool for obtaining this information is the animal microdialysis technique; however, according to 3Rs principles, it would be better to have an “animal-free” alternative technique. Because of that, the purpose of this work was to develop a new formulation to substitute the brain homogenate in the in vitro tests used for the prediction of a drug’s distribution in the brain. Fresh eggs have been used to prepare an emulsion with the same proportion in proteins and lipids as a human brain; this emulsion has proved to be able to predict both the unbound fraction of drug in the brain (fu,brain) and the apparent volume of distribution in the brain (Vu,brain) when tested in in vitro permeability tests. The new formulation could be used as a screening tool; only the drugs with a proper in vitro distribution would pass to microdialysis studies, contributing to the refinement, reduction and replacement of animals in research.

scholarly journals Effects of Experimental Hyperlipidemia on the Pharmacokinetics of Tadalafil in Rats

2012 ◽  
Vol 15 (4) ◽  
pp. 528 ◽  
Author(s):  
Joo Hyun Lee ◽  
Ju-Hee Oh ◽  
Young-Joo Lee
Keyword(s):  
Erectile Dysfunction ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Poloxamer 407 ◽  
Time Curve ◽  
Unbound Fraction ◽  
Therapeutic Implications ◽  
Experimental Hyperlipidemia ◽  
Increased Risk

Purpose. Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. Methods. Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. Results. Hyperlipidemia dramatically increased tadalafil’s the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. Conclusions. The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1616
Author(s):  
Nicoletta di Leo ◽  
Stefania Moscato ◽  
Marco Borso' ◽  
Simona Sestito ◽  
Beatrice Polini ◽  
...  
Keyword(s):  
High Performance ◽  
In Vitro Model ◽  
New Drugs ◽  
Therapeutic Approaches ◽  
Neuroprotective Effects ◽  
Pharmacological Response ◽  
Preliminary Study ◽  
Vitro Model ◽  
The Brain

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

scholarly journals A study on Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty in a Japanese laboratory of biochemistry and molecular biology in 1990s: An attempt for TCM modernization

2021 ◽  
pp. 1-21
Author(s):  
Jiankang Liu
Keyword(s):  
Qing Dynasty ◽  
Brain Homogenate ◽  
Modern Technology ◽  
Toxicity Tests ◽  
Brain Functions ◽  
Great Progress ◽  
Theoretical Evidence ◽  
The Brain

Traditional Chinese Medicine (TCM) modernization has been proposed for many years, but the progress is still slow due to both ideological and technical obstacles. When I went to Japan in 1989, I found Japan has made a great progress on TCM by using modern technology. Therefore, I have studied a fine extract prepared from medicinal herbs (renamed Yi-Zhi-Yi-Shou, YZYS), a prescription of Dowager Cixi’s Yanling-Yishou-Dan of Qing Dynasty, with the current drug investigation strategies. I examined its antioxidant activity both in vitro and in vivo. The in-vitro studies found that YZYS possesses strong antioxidant capacity, such as scavenging various kinds of free radicals, and inhibits free radical-induced peroxidation of brain homogenate, microsomes, mitochondria, amino acids, deoxyribose and DNA. The in-vivo study with immobilization-induced emotional stress in rats, showed that YZYS effectively inhibits stress-induced stomach ulcers and oxidative damage in plasma and the brain. In addition, YZYS is shown to be non-toxic in both acute and chronic toxicity tests. These studies demonstrate that YZYS is a potent natural antioxidant and offer theoretical evidence for the beneficial effect of YZYS on health and brain functions, and that TCM prescriptions can be studied scientifically as modern medical drugs.

scholarly journals Synthesis and AChE Inhibitory Activity of Novel Thiazolylhydrazone Derivatives

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2392 ◽  
Author(s):  
Derya Osmaniye ◽  
Begüm Nurpelin Sağlık ◽  
Ulviye Acar Çevik ◽  
Serkan Levent ◽  
Betül Kaya Çavuşoğlu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
New Drugs ◽  
Brain Diseases ◽  
Structure Identification ◽  
Ache Inhibitor ◽  
In Vitro Tests ◽  
Active Inhibitor

Alzheimer’s disease (AD) is the most common of the degenerative brain diseases and is described together with the impairment of cognitive function. Patients with AD lose the capability to code new memories, and life conditions are extremely difficult. The development of new drugs in this area continues at a great pace. A novel series of thiazole-piperazine hybrids, aimed against Alzheimer’s disease (AD), have been synthesized. The structure identification of synthesized compounds was elucidated by 1HNMR, 13C-NMR, and LCMSMS spectroscopic methods. The inhibitory potential of the synthesized compounds on cholinesterase enzymes was investigated. The compounds 3a, 3c and 3i showed significant inhibitory activity on the acetylcholinesterase (AChE) enzyme. On the other hand, none of the compounds showed significant inhibitory activity on the butyrylcholinesterase (BChE) enzyme. In addition to enzyme inhibition studies, enzyme kinetic studies were performed to observe the effects of the most active inhibitor compounds on the substrate–enzyme relationship. In addition to in vitro tests, docking studies also indicated that compound 3c potentially acts as a dual binding site AChE inhibitor.

scholarly journals Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents

2014 ◽  
Vol 70 (3) ◽  
pp. 857-867 ◽  
Author(s):  
Suresh B. Lakshminarayana ◽  
Tan Bee Huat ◽  
Paul C. Ho ◽  
Ujjini H. Manjunatha ◽  
Véronique Dartois ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Volume Of Distribution ◽  
Metabolic Stability ◽  
New Drugs ◽  
Pharmacokinetic Parameters ◽  
Lipinski’S Rule ◽  
Drug Classes ◽  
Human Pharmacokinetic

Abstract Objectives The discovery and development of TB drugs has met limited success, with two new drugs approved over the last 40 years. Part of the difficulty resides in the lack of well-established in vitro or in vivo targets of potency and physicochemical and pharmacokinetic parameters. In an attempt to benchmark and compare such properties for anti-TB agents, we have experimentally determined and compiled these parameters for 36 anti-TB compounds, using standardized and centralized assays, thus ensuring direct comparability across drugs and drug classes. Methods Potency parameters included growth inhibition, cidal activity against growing and non-growing bacteria and activity against intracellular mycobacteria. Pharmacokinetic parameters included basic physicochemical properties, solubility, permeability and metabolic stability. We then attempted to establish correlations between physicochemical, in vitro and in vivo pharmacokinetic and pharmacodynamic indices to tentatively inform future drug discovery efforts. Results Two-thirds of the compounds tested showed bactericidal and intramacrophage activity. Most compounds exhibited favourable solubility, permeability and metabolic stability in standard in vitro pharmacokinetic assays. An analysis of human pharmacokinetic parameters revealed associations between lipophilicity and volume of distribution, clearance, plasma protein binding and oral bioavailability. Not surprisingly, most compounds with favourable pharmacokinetic properties complied with Lipinski's rule of five. Conclusions However, most attempts to detect in vitro–in vivo correlations were unsuccessful, emphasizing the challenges of anti-TB drug discovery. The objective of this work is to provide a reference dataset for the TB drug discovery community with a focus on comparative in vitro potency and pharmacokinetics.

IN VITRO METABOLISM OF STEROID HORMONES BY CHICKEN BRAIN

1974 ◽  
Vol 75 (2) ◽  
pp. 410-416 ◽  
Author(s):  
Takao Nakamura ◽  
Yuichi Tanabe
Keyword(s):  
Steroid Hormones ◽  
Brain Homogenate ◽  
Hydroxysteroid Dehydrogenase ◽  
In Vitro Metabolism ◽  
Differential Centrifugation ◽  
White Leghorn ◽  
Chicken Brain ◽  
The Brain

ABSTRACT The brains of 14-month-old White Leghorn cocks were homogenized, fractionated by differential centrifugation, and used as enzymatic materials. When [4-14C]pregnenolone was incubated with the brain homogenate, the substrate was recovered without conversion. After incubation of [4-14C] progesterone with the brain homogenate, it was converted to 5α-pregnanedione and 3α-hydroxy-5α-pregnan-20-one. When [4-14C]17α-hydroxyprogesterone was incubated with the brain homogenate, it was metabolized to androstenedione, 3α, 17α-dihydroxy-5α-pregnan-20-one and 17α,20α-dihydroxy-4-pregnen-3-one. [4-14C] Androstenedione was metabolized to 5α-androstanedione, testosterone, androsterone, epiandrosterone and 5α-androstanediol; and [4-14C]testosterone was metabolized to androstenedione, 5β-dihydrotestosterone and 5β-androstanediol in the chicken brain. The enzymatic pattern in the brain of cocks was characterized by high activities of the 17β-hydroxysteroid dehydrogenase. Δ4-5β- and Δ5-5β-hydrogenase which acted on both C19- and C21-steroids, but was lacking in Δ5-3β-hydroxysteroid dehydrogenase associated with the Δ5a-Δ4isomerase, and 17α-hydroxylase.

scholarly journals Breakpoints for the Classification of Anti-Candida Compounds in Antifungal Screening

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Danielle da Nóbrega Alves ◽  
Alana Rodrigues Ferreira ◽  
Allana Brunna Sucupira Duarte ◽  
Ana Karoline Vieira Melo ◽  
Damião Pergentino de Sousa ◽  
...  
Keyword(s):  
Candida Species ◽  
Classification Scheme ◽  
New Drugs ◽  
In Vitro Tests ◽  
Exclusion Criteria ◽  
Drug Candidates ◽  
Antifungal Potential ◽  
Reference Strains

Introduction. The absence of a standardized classification scheme for the antifungal potency of compounds screened against Candida species may hinder the study of new drugs. This systematic review proposes a scheme of interpretative breakpoints for the minimum inhibitory concentration (MIC) of bioactive compounds against Candida species in in vitro tests. Materials and Methods. A literature search was conducted in the PubMed, Scopus, Web of Science, Lilacs, and SciFinder databases for the period from January 2015 to April 2020. The following inclusion criterion was used: organic compounds tested by the microdilution technique according to the Clinical and Laboratory Standards Institute protocol against reference strains of the genus Candida. A total of 545 articles were retrieved after removing duplicates. Of these, 106 articles were selected after applying the exclusion criteria and were evaluated according to the number of synthesized molecules and their chemical classes, the type of strain (reference or clinical) used in the antifungal test, the Candida species, and the MIC (in μg/mL) used. Results. The analysis was performed based on the median, quartiles (25% and 75%), maximum, and minimum values of four groups: all strains, ATCC strains, C. albicans strains, and C. albicans ATCC strains. The following breakpoints were proposed to define the categories: MIC < 3.515   μ g / mL (very strong bioactivity); 3.516-25 μg/mL (strong bioactivity); 26-100 μg/mL (moderate bioactivity); 101-500 μg/mL (weak bioactivity); 500-2000 μg/mL (very weak bioactivity); and >2000 μg/mL (no bioactivity). Conclusions. A classification scheme of the antifungal potency of compounds against Candida species is proposed that can be used to identify the antifungal potential of new drug candidates.

Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

Identification of a Transversely Isotropic Material Model for White Matter in the Brain

2012 ◽  
Author(s):  
Yuan Feng ◽  
Ruth J. Okamoto ◽  
Ravi Namani ◽  
Guy M. Genin ◽  
Philip V. Bayly
Keyword(s):  
Brain Injury ◽  
White Matter ◽  
Mechanical Anisotropy ◽  
Accurate Information ◽  
In Vitro Tests ◽  
Fiber Direction ◽  
Structural Anisotropy ◽  
Axonal Fiber ◽  
The Brain

Axonal fiber tracts in white matter of the brain form anisotropic structures. It is assumed that this structural anisotropy causes mechanical anisotropy, making white matter tissue stiffer along the axonal fiber direction. This, in turn, will affect the mechanical loading of axonal tracts during traumatic brain injury (TBI). The goal of this study is to use a combination of in-vitro tests to characterize the mechanical anisotropy of white matter and compare it to gray matter, which is thought to be structurally and mechanically isotropic. A more complete understanding of the mechanical anisotropy of brain tissue will provide more accurate information for computational simulations of brain injury.

CORTICOSTEROIDOGENESIS IN THE FRESH WATER AND SALINE-MAINTAINED DUCK (ANAS PLATYRHYNCHOS)

1965 ◽  
Vol 32 (3) ◽  
pp. 329-336 ◽  
Author(s):  
E. M. DONALDSON ◽  
W. N. HOLMES
Keyword(s):  
Fresh Water ◽  
Salt Solution ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Unit Weight ◽  
Secretory Rate ◽  
Corticosterone Secretion ◽  
Significant Difference

SUMMARY No differences were observed in the patterns of adrenal steroidogenesis in vitro by ducks maintained on fresh water or on a hypertonic salt solution. Determinations in vivo of the biological half-life of corticosterone showed no significant difference between ducks maintained on or loaded with saline and fresh water controls. An increase in the apparent volume of distribution of corticosterone was, however, observed in birds loaded with the salt solution after maintenance on fresh water or salt solution. Estimations were made of the secretory rate of corticosterone in vivo. In the ducks maintained on the salt solution an increased adrenal weight was responsible for the enhanced secretory rate but ducks maintained on fresh water and loaded with saline secreted corticosterone at a higher rate per unit weight of adrenal. The implications of the increased rate of corticosterone secretion are discussed in relation to the known dependence of nasal gland function in marine birds on a functional adrenal gland.

Sign in / Sign up

Export Citation Format

Share Document