The in vivo fate of drugs conjugated to macromolecules inevitably depends on that of macromolecules. However, the in vivo fate of macromolecules also may be altered by conjugation to drugs. For the efficient design of carboxymethyldextran (CMD) conjugates of a new analgesic drug, DA5018, we investigated whether the chemical modifications alter the pharmacokinetics and tissue distribution of CMD itself. [(14)C]CMD, oxidized [(14)C]CMD ([(14)C]OCMD), [(14)C]OCMD conjugates of DA5018 ([(14)C]OCMD-DA5018) and [(14)C]OCMD conjugates of ethanolamine ([(14)C]OCMD-EA) were prepared and their molecular sizes were compared by size exclusion HPLC. The pharmacokinetics, biliary excretion, and tissue distribution of total radioactivity were compared after intravenous administration of each CMD derivative, 2.0 MBq/kg, to rats. The effective molecular sizes of CMD derivatives decreased in the order of [(14)C]CMD, [(14)C]OCMD-DA5018, [(14)C]OCMD, and [(14)C]OCMD-EA. After administration of each derivative, the mean AUC values of total radioactivity decreased with the decrease in the effective molecular size. The values of CL, Vss, and the amount of total radioactivity excreted in 24-hr urine increased considerably with the decrease in the effective molecular size. The tissue-to-plasma ratios of total radioactivity remaining in heart, liver, lung, kidney, and spleen at 24 hr also increased in the opposite order of the effective molecular size. Taken together, all these results demonstrate that the chemical modifications and physicochemical properties of attached chemicals can alter the pharmacokinetics and tissue distribution of CMD. One possible reason might be the difference in the effective molecular size of various CMD derivatives. Our study demonstrates that it may be necessary to consider the effect of chemical modification on the in vivo fate of macromolecules in designing macromolecular drug conjugates.

01 Jun 2001·Archives of Pharmacal ResearchQ3 · MEDICINE

Enhanced skin permeation of a new capsaicin derivative (DA-5018) from a binary vehicle system composed of isopropyl-myristate and Ethoxydiglycol

Q3 · MEDICINE

Article

Author: Eung Doo Lee ; Won Bae Kim ; Chang-Koo Shim ; Min-Hwa Lee ; Suk-Jae Chung ; Bong Jin Cha

DA-5018, a recently synthesized capsaicin analog, appears to possess potent analgesic activity when administered topically. The objective of this study is to test the feasibility of the topical administration of this compound. Specifically, our goal was to identify vehicle system that permit a reasonable transdermal permeation of the compound in mice. Among the vehicles examined, isopropyl myristate (IPM) showed the largest in vitro permeability across the intact skin (83.6 +/- 5.42 microl/cm2/h). However, due to the limited solubility of DA-5018 in IPM (0.53 mg/ml), the maximal flux from the IPM medium remained at only 44.3 +/- 2.87 microg/cm2/hr. In order to increase the flux, addition of better solvents for DA-5018 was attempted, under the assumption that flux is the result of both solubility and permeability. Ethoxydiglycol (EG) and oleic acid (OA) were selected as examples of good solvents. The addition of EG or OA to IPM at a 1:1 volume ratio resulted in a comparable increase in the solubility of the compound (i.e., to 61.1 and 50.2 mg/ml for EG and OA, respectively). However, the addition of EG at a 1:1 volume ratio, for example, increased the flux 6.3 fold (i.e., 279 microg/cm2/hr), while OA, at a 1:1 volume ratio, decreased the flux 5 fold (i.e., 9.26 microg/cm2/hr). The mechanism of this discrepancy between EG and OA was investigated by measuring the permeabilty of DA-5018 across the stratum corneum-removed skin of the mouse, under the hypothesis that the viable skin layer may serve as a barrier for the permeation of lipophilic substances such as DA 5018. The permeability of DA-5018, from the medium of EG or OA, across the viable skin differed greatly for EG (0.41 microl/cm2/hr) and OA (0.086 microl/cm2/hr), suggesting that a higher permeability across the viable skin layer is needed for the second solvents. The maximum flux across the intact skin was achieved for DA-5018 when EG was added to IPM at a 1:1 volume ratio. Thus, the use of a binary system appears to be the bes approach for realizing the transdermal delivery of DA-5018 at a reasonable rate.

01 Feb 2001·Neuroscience LettersQ4 · MEDICINE

Differences in sensitivity of vanilloid receptor 1 transfected to human embryonic kidney cells and capsaicin-activated channels in cultured rat dorsal root ganglion neurons to capsaicin receptor agonists

Q4 · MEDICINE

Article

Author: Mi Jeong Kwon ; Hawon Cho ; Uhtaek Oh ; So Yeon Cho ; Sun Wook Hwang ; Myeong Hyeon Wang ; Jae Soo Shin ; Soon Youl Lee

Heterologously expressed vanilloid receptor 1 (VR1), a cloned cDNA encoding for capsaicin (CAP)-sensitive currents, resembles the native CAP channels in cultured sensory neurons in channel property. But, the pharmacological profile of VR1 to various CAP analogs is not known. The stable expression of VR1 in human embryonic kidney (HEK) cells was generated and confirmed by reverse transcription-polymerase chain reaction and Western blots. VR1 expressed in HEK cells retained single-channel properties similar to those of the native channels. When concentration-response relationships were compared, CAP and DA-5018.HCl, a synthetic analog of CAP, exhibited a greater potency in activating VR1 than the native channels in sensory neurons. In contrast, resiniferatoxin and its analog, phorbol 12-phenylacetate 13-acetate 20-homovanillate, was more potent in activating the CAP-activated channels in cultured sensory neurons than VR1. Thus, the difference in pharmacological profiles of VR1 and the native channels suggests the possible presence of subtypes of the CAP receptor or regulatory mechanisms associated with VR1.

100 Deals associated with Davasaicin

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Diabetic Neuropathies	Phase 2	KR	Dong-A Pharmaceutical Co., Ltd.	-
Neuralgia, Postherpetic	Phase 2	-	Stiefel Laboratories, Inc.	-
Neuralgia, Postherpetic	Phase 2	-	Dong-A Pharmaceutical Co., Ltd.	-
Pain	Phase 2	KR	Dong-A Pharmaceutical Co., Ltd.	-
Pruritus	Phase 2	KR	Dong-A Pharmaceutical Co., Ltd.	-
Neuralgia	Discovery	KR	Dong-A Pharmaceutical Co., Ltd.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

Davasaicin

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation