Chapter 29 Research to Suppress Rebound - 3
Inhibitory Activity of CX-659S, a Novel Diaminouracil Derivative, against the Rebound Phenomenon following Withdrawal of Corticosteroid Therapy for Chronic Contact Hypersensitivity Responses.
By Y Inoue, M Isobe, T Shiohara, H Hayashi published in the Int Arch Allergy Immunol 2003;131:143-152
Tetsuo Shiohara (Kyorin University) is involved in this paper, which studied the effects of CX-659S when topically used.
----- Excerpt -----
Although topical corticosteroids have been widely utilized in steroid responsive dermatoses such as AD, their chronic use may be associated with significant side effects. In addition, a rebound phenomenon often occurs after discontinuation of prolonged use of topical corticosteroids, with enhanced production of IgE and Th2 cell cytokines.
----- End of excerpt -----
They were quick to admit the existence of the rebound phenomenon. Yoshifumi Inoue, one of the authors, is a researcher of Japan Energy Corporation and an actual study seems to have been conducted there. I do not know other papers that refer to the rebound phenomenon associated with topical corticosteroids in such a straight forward manner and also include as an author a professor of the dermatological department of a Japanese university. In that sense, I’d like to pay my respects to Dr. Shiohara.
The paper includes the experiment using mice. Murine ears, while picryl chloride is topically applied repeatedly, develop inflammation. (This is almost the same experimental animal model as that used in the review of ALLELOCK.) This inflammation, which is initially the usual rash called delayed-type hypersensitivity reaction, is known to change into immediate-type response followed by a late-type reaction through repetitive stimulation. It comes to look more like AD flare with IgE level increased. Besides, this model exhibits the addiction and rebound phenomena where strong inflammation is observed when topical corticosteroid application is stopped after a certain duration of use compared to the case where topical corticosteroids were no used, and is a very optimum model for studying the clinical condition of AD.
Inhibitory Activity of CX-659S, a Novel Diaminouracil Derivative, against the Rebound Phenomenon following Withdrawal of Corticosteroid Therapy for Chronic Contact Hypersensitivity Responses.
By Y Inoue, M Isobe, T Shiohara, H Hayashi published in the Int Arch Allergy Immunol 2003;131:143-152
Tetsuo Shiohara (Kyorin University) is involved in this paper, which studied the effects of CX-659S when topically used.
----- Excerpt -----
Although topical corticosteroids have been widely utilized in steroid responsive dermatoses such as AD, their chronic use may be associated with significant side effects. In addition, a rebound phenomenon often occurs after discontinuation of prolonged use of topical corticosteroids, with enhanced production of IgE and Th2 cell cytokines.
----- End of excerpt -----
They were quick to admit the existence of the rebound phenomenon. Yoshifumi Inoue, one of the authors, is a researcher of Japan Energy Corporation and an actual study seems to have been conducted there. I do not know other papers that refer to the rebound phenomenon associated with topical corticosteroids in such a straight forward manner and also include as an author a professor of the dermatological department of a Japanese university. In that sense, I’d like to pay my respects to Dr. Shiohara.
The paper includes the experiment using mice. Murine ears, while picryl chloride is topically applied repeatedly, develop inflammation. (This is almost the same experimental animal model as that used in the review of ALLELOCK.) This inflammation, which is initially the usual rash called delayed-type hypersensitivity reaction, is known to change into immediate-type response followed by a late-type reaction through repetitive stimulation. It comes to look more like AD flare with IgE level increased. Besides, this model exhibits the addiction and rebound phenomena where strong inflammation is observed when topical corticosteroid application is stopped after a certain duration of use compared to the case where topical corticosteroids were no used, and is a very optimum model for studying the clinical condition of AD.
As indicated in the above figure, mice were sensitized one week prior to the experiment, and then PC was topically applied every 2 days during the experiment.
In the above graph, the Y-axis value indicates the ear thickness (severity of inflammation) of mice, the ○ mark represents the untreated subjects, the ▲ mark stands for the subjects treated with topical steroid between Day 0 and Day 24, and the ● mark represents the subjects for which CX-659S was topically applied during the same period. On Day 34 and thereafter, the ▲-line goes beyond the ○-line, which indicates that the rebound has occurred. In contrast, in the ● group, rebound has not occurred after discontinuation.
These are pictures of experimental murine ears. Picture “a” shows a normal ear, b corresponds to the ○ subject, c to the ● subject and d to the ▲ subject. In Picture b, the ear is swollen due to inflammation. The symptom of the ear in Picture c is milder than that in Picture b. Picture d shows the swollen ear due to rebound.
Next, it was checked if CX-659S could suppress the rebound after topical steroid discontinuation. The ○ represents the group for which only PC was applied with no treatment, the △ represents the group for which topical steroid was applied and then discontinued (to induce rebound), the ▲ represents the group for which vehicle was applied after steroid discontinuation, the □ represents the group for which 0.75% CX-659S was applied and the ■ represents the group for which 2.5% CX-659S was applied after steroid discontinuation. The rebound phenomenon is seen as to the △ and ▲ groups, whereas it is somewhat suppressed as to the □ and ■ groups.
Then serum IgE level was examined on the 17th, 28th and 52nd days. Though the IgE levels in the control (△) and the vehicle (▲) groups were higher than that of the non-treatment (○) group, the CX-659 administered groups (□,■) had decreased values (statistically significant results were gained for the 2.0% CX-659 administered group only).
Then inflamed ear skin cytokines were examined by measuring mRNA level. 1, 2, 3, 4 and 5 indicate non-treatment, control, vehicle, 0.75% and 2.0%CX-659S groups respectively. The above results reveal that Th2 cytokines (IL-4, IL-10) synthesis was suppressed by CX-659S.
At the end of the experiment concerning CX-659S, interesting data is shown. In the above graph, the ○ represents the group in which only PC was applied, the ▲ represents the group for which CX-659S was used to alleviate the rebound phenomenon after topical steroid discontinuation, and the ■ represents the group for which ibuprofen piconol (non-steroidal anti-inflammatory agent, Steaderm) was used instead of CX-659S. Comparing this data with the second experimetal graph, it is found that rebound severity is enhanced. This is considered“hypersensitivity after steroid withdrawal,”which is frequently observed in clinical events supporting the withdrawal.
Having retrieved on the Internet, I could not find later reports on CX-659 other than the one in 2003. Japan Energy Corporation seems to exist but it might have given up developing it as a new drug. Differing from checking the already developed drugs such as ALLELOCK for additional effects, it will be difficult to develop a new drug for addiction or rebound from scratch.
But it sure is research that Japanese dermatologists should push forward in cooperation with companies. In Japan, where all people were put under the National Health Insurance System, topical corticosteroids were available at the cheapest price and most abundantly in the world from 1960s to early 1990s. This contributed, sorry to say, to a large number of steroid addicts, and we should have more enthusiastically studied this and developed new drugs for treatment. How I could feel a sense of pride if Japanese dermatologists had been able to overcome the topical steroid problems and released the useful information to the world.
There’s no progress as long as the Japanese Dermatological Association Guideline is controlled by the authoritative dermatologists who insist that topical corticosteroids are safe drugs and studying on steroid withdrawal and rebound only gives excuses for the atopic business and provides patients with unnecessary fear and hardship.
Reference
I’d like to show an example of hypersensitivity after topical corticosteroid withdrawal. A patient who fairly recovered from rebound flare after topical corticosteroid discontinuation applied an adhesive plaster due to folliculitis or other reasons, and developed inflammation as shown in the left picture. When the same plaster was put on the forearm one year later, inflammation did not develop (right picture) .
Having retrieved on the Internet, I could not find later reports on CX-659 other than the one in 2003. Japan Energy Corporation seems to exist but it might have given up developing it as a new drug. Differing from checking the already developed drugs such as ALLELOCK for additional effects, it will be difficult to develop a new drug for addiction or rebound from scratch.
But it sure is research that Japanese dermatologists should push forward in cooperation with companies. In Japan, where all people were put under the National Health Insurance System, topical corticosteroids were available at the cheapest price and most abundantly in the world from 1960s to early 1990s. This contributed, sorry to say, to a large number of steroid addicts, and we should have more enthusiastically studied this and developed new drugs for treatment. How I could feel a sense of pride if Japanese dermatologists had been able to overcome the topical steroid problems and released the useful information to the world.
There’s no progress as long as the Japanese Dermatological Association Guideline is controlled by the authoritative dermatologists who insist that topical corticosteroids are safe drugs and studying on steroid withdrawal and rebound only gives excuses for the atopic business and provides patients with unnecessary fear and hardship.
Reference
I’d like to show an example of hypersensitivity after topical corticosteroid withdrawal. A patient who fairly recovered from rebound flare after topical corticosteroid discontinuation applied an adhesive plaster due to folliculitis or other reasons, and developed inflammation as shown in the left picture. When the same plaster was put on the forearm one year later, inflammation did not develop (right picture) .