In vivo Receptor Occupancy and Plasma Concentration of Pranidipine, a Potent and Long-Acting Dihydropyridine Calcium Antagonist

Pharmacology ◽  
1999 ◽  
Vol 59 (4) ◽  
pp. 171-182 ◽  
Author(s):  
Shizuo Yamada ◽  
Shinya Uchida ◽  
Akihiko Urayama ◽  
Ryohei Kimura
Keyword(s):  
Calcium Antagonist ◽  
Plasma Concentration ◽  
Receptor Occupancy ◽  
Dihydropyridine Calcium Antagonist ◽  
Long Acting

Antihypertensive Activity of OPC-13340, a New Potent and Long-Acting Dihydropyridine Calcium Antagonist, in Rats

1990 ◽  
Vol 15 (5) ◽  
pp. 836-844 ◽  
Author(s):  
Natsuki Nakayama ◽  
Kazumi Ikezono ◽  
Toyoki Mori ◽  
Shuji Yamashita ◽  
Sunao Nakayama ◽  
...  
Keyword(s):  
Calcium Antagonist ◽  
Antihypertensive Activity ◽  
Dihydropyridine Calcium Antagonist ◽  
Long Acting

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

2014 ◽  
Vol 28 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Khanum Ridler ◽  
Roger N Gunn ◽  
Graham E Searle ◽  
Julien Barletta ◽  
Jan Passchier ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Human Brain ◽  
Dose Range ◽  
Receptor Occupancy ◽  
Repeat Dose ◽  
Dose Selection ◽  
Dose Administration ◽  
Single Dose Administration

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [11C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration–occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration–occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

scholarly journals OPC-13340, a New Potent and Long-Acting Dihydropyridine Calcium Antagonist

1991 ◽  
Vol 9 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Natsuki Nakayama ◽  
Katsumi Ikezono ◽  
Naoki Fujio ◽  
Hiroyuki Sasabe ◽  
Keisuke Kitaura ◽  
...  
Keyword(s):  
Calcium Antagonist ◽  
Dihydropyridine Calcium Antagonist ◽  
Long Acting

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

2019 ◽  
Vol 15 ◽  
Author(s):  
Xingzhou Li ◽  
Tianhong Zhang ◽  
Wu Zhong
Keyword(s):  
Plasma Concentration ◽  
Development Strategy ◽  
Parent Compound ◽  
Systemic Exposure ◽  
Parent Drug ◽  
New Drugs ◽  
Structure Modification ◽  
Design Synthesis ◽  
Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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