• Biomolecules & Therapeutics
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• v.6 no.1
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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.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.234-234
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• 1996

DA-5018은 여러 opiate수용체 실험에서 morphine 또는 naloxone 보다 10-100배 정도 낮은 친화력을 나타내었다. 기니픽 회장표본과 랫드 수정관표본의 전기자극 실험에서는 DA-5018의 의해 유도된 수축반응이 naloxone의 영향을 받지 앉았고, 랫드에서의 진통효과도 naloxone 전처치에 의해 차단되지 않았으므로, DA-5018은 opiate 수용체를 경유하지 앉는 것으로 생각된다. 또한, OA-5018 120$\mu$M에서 cyclooxygenase 생성을 50% 증가시켰고 mM 농도에서 5-lipooxygenase 합성을 약간 억제하였으므로, NSAID계 유사약물이 아님을 확인하였다. DA-5018은 기니픽 기관 표본에 대해 capsaicin과 동일하게 수축반응을 나타내었고, 이것은 capsazepine 전처리에 의해 억제되었다. 척수에서의 substance P 유리활성은 capsaicin보다 약 9배 강한 것으로 나타났다. 또한 랫드에 DA-5018 진통유효용량인 1mg/kg을 피하주사한 후 분리한 척수에서 capsaicin에 의한 substance P의 유리활성은 15분 후에 감소하였고 120분 후에는 회복되었다. 따라서 OA-5018의 진통작용에도 substance P의 고갈이 관여하는 것으로 생각된다. 이상의 결과로부터, DA-5018의 진통작용은 capsaicin수용체를 매개하는 것으로 사료된다.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.133-149
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• 1997

4-week repeated dose toxicity of DA-5018, a new capsaicin analogue analgesic agent, was examined in 5D rats at dosage levels of 0,0.4,2, 10 and 50 mg/kg/day. DA-5018 was administered orally to 17 males and 17 females per group at doses of 0, 10 and 50 mg/kg and to 12 males and 12 females per group at doses of 0.4 and 2 mg/kg. After the administration period, 5 males and 5 females at the 0, 10 and 50 mg/kg were placed on withdrawal for 2 weeks. Treatment-related clinical signs were observed at 10 and 50 mg/kg. Clinical signs observed immediately after the administration of DA-5018 were grooming, sedation or depression, lacrimation, atacia, reddening of extremities and ears, ventral or lateral recumvincy, respiratory distress, cyanosis and convulsion. Delayed-type clinical signs including focal scabbing and depilation around nose were also observed 1 or 2 weeks after the start of administration of DA-5018. Only at the 50 mg/kg group, corneal opacities, reduced body weight gain (male) and death (male 6/17, female 3/17) were noted. In blood biochemical analysis, serum levels of glucose and triglyceride decreased at 10 and 50 mg/kg. In hematological examination, there were increases in the number of red blood cell, hemoglobin content and percent of hematocrit at 10 and 50 mg/kg. Pulmonary enlargement and hemorrhagic spot, focal scabbing and depilation around nose and corneal opacities were seen at the necropsy of the animals died during the dosing of DA-5018 50 mg/kg. Focal scabbing and depilation around nose were observed in the animals terminally necropsied at doses of 10 and 50 mg/kg. Histopathological examination revealed pulmonary hemorrhage, focal necrosis in the scabbed area, corneal necrosis, fibrosis and neovasculization in the stroma. At 0.4 and 2 mg/kg, there were no significant toxic changes attributable to the administration of DA-5018. In conclusion, target organs following to 4-week repeated dose of DA-5018 in the rat were determined to be lung, skin and eyes. Definite toxic dose and no-observed-adverse-effect-level (NOAEL) were estimated to be 50 and 2 mg/kg/day, respectively.

• Biomolecules & Therapeutics
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• v.5 no.2
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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.

• Journal of Pharmaceutical Investigation
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• v.27 no.1
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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.

• Proceedings of the PSK Conference
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• 2000.04a
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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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• v.4 no.4
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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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• v.4 no.3
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• pp.232-238
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• 1996

The physical dependence potency of DA-5018, a non-narcotic analgesic agent, was tested in mice dosed with 0.5 and 4 mg/kg/day for 2 months and daily increasing doses of 1, 2, 4, 6, 8 and 10 mg/kg over 10 days. Physical dependence was assessed taking natural withdrawal induced morphine-type abstinence (jumping, falling, biting or backward locomotion, rearing etc.) as well as barbiturates-type abstinence (body weight reduction, convulsion, ataxia etc.) into consideration. The results were compared with those after the same daily increasing doses of morphine. DA-5018 did not show evidence of physical dependence liability or abuse potential as measured by morphine-type or barbiturate-type abstinence signs following daily increasing or 2-month repeated administration. On the other hand, daily increasing doses of morphine produced physical dependence and the dependent state disappeared about 6 hours after the start of withdrawal signs. In the single dose suppression test, a single dose of morphine completely suppressed natural withdrawal signs that appeared in morphine-dependent animals. Therefore, these results indicate that DA-5018 does not have abuse potential and physical dependence liability.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.235-235
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• 1996

1. 초산 writhing법에서 DA-5018, morphine, capsaicin 및 acetaminophen의 E $D_{50}$ 은 각각 0.1, 0.3, 1.4 및 45.4 mg/kg이었으며, formalin법에서 DA-5018과 morphine의 E $D_{50}$은 0.17과 4.3 mg/kg이었다. Randall-Selitto법에서 DA-5018, morphine, capsaicin 및 acetaminophen의 E $D_{50}$은 0.66, 3.9, 4.2 및 643 mg/kg이었다. Tail flick법에서 DA-5018, morphine 및 capsaicin의 E $D_{50}$ 은 2.0, 2.6 및 14.2 mg/kg이었고 hot plate법에서 DA-5018과 capsaicin의 E $D_{50}$은 1.7 및 26.5mg/kg이었다. 그러나 열자극에 의한 동통모델에서 acetaminophen은 진통효과가 없었다. 2. Streptozotocin유발 당뇨랫드에 DA-5018 0.2, 0.5 및 1.0mg/kg 또는 capsaicin 10 mg/kg 투여시 1, 3, 7 일째에서 각각 유의성있는 동통역치의 증가를 나타내었으나 ketoprofen(10 mg/kg) 및 desipramin(10 mg/kg) 투여시는 동통역치의 유의성있는 증가가 나타내지 않았다. 관절염 동통모델에서 DA-5018, ketoprofen 및 capsaicin을 투여한 후 7일째에 동통역치를 2배 증가시키는 용량은 각각 0.66, 3.76 및 17.38 mg/kg이었다. 3. 이상의 결과로부터 DA-5018은 morphine 및 capsaicin에 비해 동등 이상의 효력을 갖고 있으며, 비스테로이드성 진통제보다 효능이 우수함을 확인하였다.

• Archives of Pharmacal Research
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• v.22 no.6
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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.