• Biomolecules & Therapeutics
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• 제4권4호
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• pp.364-372
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• 1996

The primary skin and eye irritation test of 0.3% DA-5018 cream, a capsaicin analogue, were carried out in rabbits. As control materials, Zostrix-HP cream (0.075% capsaicin cream) and the base of 0.3% DA-5018 cream were used in the same manners. In the primary skin irritation test, the Primary Irritation Index (P.I.I.) was 1.6, 1.9 and 0.5 in groups treated with 0.3% DA-5018 cream, Zostrix-HP cream and the base of 0.3% DA-5018 cream, respectively. The irritation ratings of 0.3% DA-5018 cream and Zostrix-HP cream were mildly irritating. The base of 0.3% DA-5018 cream was evaluated as a non-irritating material. In the eye irritation test, 0.3% DA-5018 cream and Zostrix-HP cream could be considered as mildly irritating materials. But, the base of 0.3% DA-5018 cream was a non-irritating material. These results suggest that 0.3% DA-5018 cream has mildly irritating activity and its irritancy is similar to that of Zostrix-HP cream.

• Biomolecules & Therapeutics
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• 제4권4호
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• pp.391-397
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• 1996

The aim of this study was to assess the allergenic potential of 0.3% DA-5018 cream, a non-narcotic analgesic agent, using a guinea pig maximization test. Five male and female guinea pigs in the experimental group were sensitized in two steps. First, ,0.3% DA-5018 cream was injected intradermally, and 7 days later, the material was applied topically. After another 2 weeks test material was applied, the skin response was evaluated by visual observation. Five male and female guinea pigs served as cream base group, negative(ultreated) group or positive (2,4-dinitrochlorobenzene, DNCB) group, respectively. 0.3% DA-5018 cream provoked slight erythema in 1 out of 5 cases in male and female guinea pigs sensitized with 0.3% DA-5018 cream or cream base. The animals challenged with cream base also showed slight erythema in 1/5 female guinea pig sensitized with 0.3% 3A-5018 cream or 2/5 male guinea pjgs sensitized with cream base, respectively. Histologically, however, no indication of skin sensitization was observed in all of these cases. The positive control group was sensitized with 0.1% DNCB suspended in olive oil and challenged with 0.01% and 0.1% DNCB ointment, all the animal showed remarkable skin reactions and obvious skin sensitization reactions in a dose dependent manner. From the challenge test it was evident that 0.3% DA-5018 cream did not elicit positive skin reaction interpreted as delayed hypersensitivity reactions, compared with cream base or untreated control group. These findings indicate that allergenic side effects by 0.3% DA-5018 cream is not likely in the clinical use.

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.74-81
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• 1997

DA-5018(N-(3-(3, 4-dimethylphenyl)propyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide) is a new capsaicin derivative under development as topical analgesic agent. The general pharmacological properties of DA-5018 on central nervous, cardiovascular, gastrointestinal and other organ systems were studied in experimental animals. DA-5018 cream (0.3%) had no effects on behavior, hexobarbital-induced sleeping time, body temperature, spontaneous activity, blood pressure, heart rate, intestinal charcoal propulsion, urine volume and electrolyte excretion even at a high dose of 2000 mg/kg in rats. In addition, DA-5Ol8 cream had little skin irritation compared to Zostrix-HP (capsaicin, 0.075%) cream in rabbits. In isolated guinea pig tissue studies, DA-5018 increased the contractility of trachea and ileum and also increased sinus rate of atrium in a range of 10^{-8}-10^{-5}$$ M, but its efficacy as a agonist was weak. These results suggest that DA-5018 cream might be used topically without serious side effects.

• Biomolecules & Therapeutics
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• 제6권1호
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• pp.95-110
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• 1998

A 13-week dermal toxicity test was conducted to assess the toxicity of DA-5018, a capsaicin derivative. Three groups of Sprague-Dawley rats (10-15 males and 10-15 females) were treated with DA-5018 cream daily by dermal application at concentrations of 0.1%, 0.3% or 0.9% as 500 mg/kg for 13 weeks. One further group of rats (15 males and 15 females) received cream base at 500 mg/kg/day and acted as controls. One male receiving 0.3% DA-5018 cream died during the treatment period. But the animal did not show any signs of treatment-related toxicity until death. There were no local skin reaction of application site and systemic reaction to the treatment of DA-5018 creams in all experimental groups throughout treatment and recovery period. Weight gain and food consumption in animals that received DA-5018 creams appeared to be comparable to that of the controls. Laboratory analyses (hematology, urinalysis and opthalmoscopic examination) did not revealed pathological values. In biochemical investigations, an increase of glucose level associated with increased food consumption and some other significant changes were noted in the animals of both sexes received DA-5018 creams. But these changes were not considered to be of toxicological importance. Postmortem examination did not show macroscopic or histological alterations attributable to the DA-5018 treatments. Based on these results, NOAEL(no-observable-adverse-effect level) of DA-5018 cream if estimated to be over 500 mg/tg/day as 0.9% cream.

• Journal of Pharmaceutical Investigation
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• 제27권1호
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• pp.65-69
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• 1997

To formulate the topical analgesic preparation of a new capsaicin derivative, DA-5018, a skin penetration evaluation system was established and the effect of composition of formulation on skin penetration using this system was evaluated, The effect of massage on hairless mouse skin penetration and inter-day variation of this effect were investigated using test formulations(cream). In massage group, compared with non-massage group, absolute penetration amount of DA-5018 increased and this experimental system was found to be reproducible, The effects of pH of water phase, ratio of oil/water and the concentration of active ingredient in cream on skin penetration were investigated. The permeation of DA-5018 from the cream increased with increasing pH of water phase to 9. But at pH 10, the permeation of DA-5018 decreased, because of the physical instability of the cream. The permeation of DA-5018 from the cream increased with increasing the ratio of oil/water of the cream. The increase of the content of DA-5018 to 0.3% increased the permeation of DA-5018, but at high concentration(1.0%), the permeation of DA5018 decreased, due to the instability of the cream.

• Biomolecules & Therapeutics
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• 제5권2호
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• pp.150-157
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• 1997

Capsaicin cream has been used to attenuate the pain associated with diabetic neuropathy, rheum-atoid arthritis, osteoarthritis and postherpetic neuralgia. But its common side effect, local irritation, limits the use of it and there is still a need for a new analgesic devoid of this side effect. This study was conducted to compare the local irritant effect of DA-5018, a new capsaicin derivative, with that of capsaicin in various animal models and human beings. Capsaicin, applied topically to the mouse ear, produced dose-dependent increase of ear volume and the frequency of ear scratching behavior in mice. Neither ear volume nor scratching behavior was affected by DA-5018. In eye wiping test of rat, DA-5018 was 10 times less irritant than capsaicin. Capsaicin administered intradermally into the rat paw elicited paw lick/lift response with a potency which was three times that of DA-5018. Zostrix-HP (0.075% capsaicin cream), but not DA-50180.3% cream, increased ear volume of rat and induced thermal hyperalgesia in normal and carrageenan inflamed paws. Six day-treatment of Zostrix-HP failed to develop tolerance against this thermal hyperalgesia. In human beings, Zostrix-HP produced burning sensation and itching in more than 90% of volunteers involved and its maximum irritant effect was significantly higher than that of DA-5018 cream. These results suggest that local irritation and burning sensation produced by DA-5018 is much less than capsaicin.

• Archives of Pharmacal Research
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• 제22권6호
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• pp.549-553
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• 1999

The antipruritic effect of DA-5018m a capsaicin derivative, was examined in mice. Male ICR mice were topically pretreated with Zostrix-HP (0.075% capsaicin cream), 0.1%, 0.3% DA-5018 cream or cream base (control) twice daily for 4 days. One hour after the last application, itch was induced either by compound 48/80 ($50{\mu}g$, s.c.) or leukotriene B4 (0.03 nmol, i.d.) injection into the rostral back of the animals, and the number of scratches made by the animals at the injection site was counted for 60 min post-injection. DA-5018 cream (both 0.1 and 0.3%) significantly inhibited compound 48/80-induced scratching when compared with the cream base control (p<0.01), which Zostrix-HP showed minimal inhibition of the scratching behavior. In leukotriene B4-induced itch model, Zostrix-HP and 0.3% DA-5018 cram significantly inhibited the scratching during the first 10-min period (p<0.01). The results suggest that DA-5018 cream can be used as an antipruritic agent and warrant clinical evaluation.

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.82-86
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• 1997

Pharmacokinetics of a new capsaicin analog, DA-5018 were evaluated after a subcutaneous injection or topical application of $[^{14}C]$--labelled or unlabelled DA-5018 to rats and rabbits. After subcutaneous injection of $_{14}$c-labelled or unlabelled DA-5018, 0.5 mg/kg (equivalent to DA-5018) to rats, the plasma total activity peaked at 2 hr with the terminal half life of 5.34 hr, however, unlabelled-DA-5018 peaked at 1 hr with the terminal half life of 1.26 hr. Moreover, the AUC (0.726 versus 0.2337g hr/ml) and MRT (7.82 versus 3.55 hr) increased significantly based on total radioactivity compared with intact DA-5018. Above data indicated that DA-5018 is extensively metabolized in rats and the terminal half- life of the metabolite(5) had a longer half-life than that of DA-5018. The cumulative percentages of biliary excretion of dose after subcutaneous injection of $[^{14}C]$DA-5018 was 40.2%, however, the value was only 2.14% when unlabelled DA-5018 was injected. After topical application of 0.1% or 0.3% $_{14}$C-labelled or unlabelled DA-5018 cream, 500 mg/kg to rats, the plasma and tissue concentrations except applied skin were under the detection limit. After consecutive 7 days topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rats, the plasma concentrations were also under the detection limit. But the urinary excretion of DA-5018 was significantly increased by repeated topical administration. After topical application of unlabelled DA-5018, 0.1% and 0.3% cream to rabbits, the plasma and urine concentrations were under the detection limit. Above data indicated that the skin permeation of DA-5018 was lower and the metabolism of DA-5018 was higher in rabbits than that in rats.

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.70-81
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• 2000

DA-5018 is a synthetic capsaicin derivative under development as a non-narcotic a analgesic ag$\varepsilon$nt. DA-50 18 showed a potent analgesic activity against acute and chronic pain m model(Tablel, 2.), but it had a narrow margin of safety. DA-5018 did not bind to opioid(${\kappa}, {\delta}, {\mu}$), NKl, CGRP receptors in vitro and its analgesic effect was not antagonized by naloxone, a and it did not develop analgesic tolerance. In addition DA-5018 had no inhibitory effects against c cyclooxygenase and 5-lipooxygenase activities. DA-5018 significantly increased the relcase of substance P from the slices of the rat spinal cord. These results suggest that DA-50 18 is not a narcotic nor aspirin-like analgesic and the release of substance P is one of analgesic mechanism of action of DA-5018. We found that DA-5018 was almost ten times more potent and was at l least IOO-times less irritable compared to capsaicin. Accordingly development of topical formula was adopted. Topical formula was desiged and screened by flux test of DA-5018 using hairless mouse skin and several formulas were selected. With these topical formulas we a assessed the analgesic efficacy and carried out the toxicity, skin irritation and pharmacokinetic studies. In streptozotocin-induced hyperalgesic rat and 50 % galactose-fed hyperalgesic rat as diabetic pain models, DA-5018 cream increased the pain thresh이ds up to 77.0% and 24.4% respectively, while Zostrix-HP(capsaicin cream) incr$\varepsilon$as cd by 65.9% and 21.0%. DA-5018 c cream showed a good analgesic effect as welI in FCA-induced arthritic rat. DA-5018 cream did not show any toxicological signs in acute and chronic toxicity test and had little skin irritation in car swclIing and scratching t$\varepsilon$st. Pharmacokinetics of DA-50 18 were studied after topical application of ${14}^C$-Iabelled or unlabelIed DA-5018 cream. Plasma and skin concentrations c except applied skin wcre below the dctection limit and after 7-day cummulative application, plasma concentrations were also below detection limit DA-50 18 may have an advantag$\varepsilon$ ov$\varepsilon$r c capsaicin and is now being developed as a topical agent for the treatment of pains. DA-50 18 cream was approved for Korean IND and is now under a Phase II clinical study for arthritic pain a after finising Phase I study. DA-50 18 was also liscensed out to Stiefel Company in America in

• Biomolecules & Therapeutics
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• 제5권2호
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• pp.117-124
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• 1997

The analgesic effects of DA-5018, a new caosaucin derivative, were evaluated in various experimental pain models. Drugs were administered subcutaneously or topically. When drugs were administered subcutaneously, 1) the $ED_{50}$ of DA-5018, morphine . HCI, capsaicin and acetaminophen were 0.091-2.0, 0.3-4.3, 1.4-26.5 and 45.4-643 mg/kg, respectively in various pain or inflammatory models including acetic acid writhing, formalin, tail flick, Randall-Selitto, hot plate and crouton oil-induced ear edema test, 2) the AD2 values (the dose for doubling of pain threshold of vehicle control) of DA-5018, capsaicin and ketoprpgin were 1.07 $\pm$ 0. 18, 23.47$\pm$4.46 and 2.97$\pm$0.43 mg/kg in Freund's complete adjuvant (FCA)-induced arthritic pain model. And by topical application, 1) neither DA-5018 0.3% cream nor Zostrix-HP (capsaicin 0.075%) were effective in formalin test, 2) although DA-5018 0.3% cream significantly inhibited the croton oil-induced ear edema being better than Zostrix-HP and Kenofen (ketoprofen 3%). 3) In FCA model, DA-5018 0.3% cream reversed the decreased pain threshold of arthritic rat from 136.4 g (day 0) to 289.0 g (day 5) and 250.1 g (day 10), which was similar to Zostrix-HP. These results suggest that DA-5018 administered subcutaneously has a potent and broad analgesic spectrum than nonsteroidal antiinflammatory drugs against acute and chronic pain, and by topical application it exerts comparable analgesic and antiinglammaatory effects to capsaicin cream.