Topical clofibrate (0.25%w/w) is available through Dr. Fukaya’s web shop.

 Topical clofibrate is a non-steroidal ointment but can suppress mild eczema without rebound phenomenon. The anti-inflammatory effect is weaker than topical steroids.  It can be used individually or simultaneously with the Dr Fukaya’s skin repair lotion (hyaluronan lotion of 100,000 dalton ). As the hyaluronan lotion only prevents skin atropy due to steroids or helps to recover from it and doesn’t work as an anti-inflammatory agent, combination therapy of the lotion and topical clofibrate is recommended for better results to eczema-sufferers.

 Topical clofibrate is an ointment easy to be prepared by any physician or pharmacist. The materials needed are clofibrate capsules which is widely available, cheap and old medication for hyperlipidemia and white petrolatum as a base ointment. The base ointment is not limited to white petrolatum. You can mix clofibrate to anything you prefer or whatever your skin can tolerate. Even water can be used as a base (oil in water emulsion).

 The above photo shows aspiration of clofibrate by a medical syringe and needles from the capsule. Clofibrate is oily transparent liquid and the specific gravity is 1.14. One capsule contains 250mg (0.21ml).

 By aspiration from about 7 capsules, one can collect about 1.1ml of clofibrate. It weighs 1.25grams and is just the amount for 0.25%w/w in 500 gram base.

 White petrolatum is a solid material at the room temperature.

  The melting point of white petrolatum is about 38-60℃. So it becomes liquid completely at the temperature of 70℃. One can add the clofibrate to the white petrolatum liquid and mix them to make uniform.

  After cooling, it returns to solid ointment again and the clofibrate ointment (0.25%w/w) is prepared.

 What is the mechanism of clofibrate as an anti-inflammatory agent? How does it work? It is a little complicated. Clofibrate is one of PPAR alpha ligands. PPAR alpha activates NFkappaB which stimulates to produce TSLP in keratinocytes. The below figure shows the vicious cycle in atopic dermatitis which was elucidated by Matsuoka et al in 2012 (J Clin Invest. 2012 Jul 2;122(7):2590-600). The PPAR alpha ligand such as clofibrate works at the point of red arrow and terminates the vicious cycle.

  There is an interesting report about topical PPAR ligands. Hatano et al reported that a kind of topical PPAR alpha ligand, which had been revealed to suppress mild eczema but have not enough power to suppress severe eczema, can suppress experimental rebound phenomenon after continuous topical steroid use in mice. In the experiment, mice were treated to express eczema by some allergen artificially on the skin, followed by topical steroids application and then continued to be applied topical steroids in one group and replaced to topical PPAR alpha ligands in the other group. The former group developed rebound while the latter didn’t (J Invest Dermatol. 2011 Sep;131(9):1845-52).  

The figure is referred from Hatano’s article above mentioned.

 So if topical steroids therapy is changed to topical PPAR alpha ligand therapy on the way the eczema subsides, sufferers are estimated to have less risk to develop rebound phenomenon. Moreover, as topical PPAR alpha ligands themselves have weak anti-inflammatory effect, eczema sufferers may try to use them as the first choice before using steroids.

 The most recommended usage of my hyaluronan lotion and topical clofibrate for prevention of rebound by topical steroids is summarized as the followings.

1 When you apply topical steroids, add my hyaluronan lotion to the area for the purpose of prevention of epidermal atrophy.

2 After the eczema subsided from severe into mild by topical steroids, change them to topical clofibrate.

3 If the eczema is enough mild, topical clofibrate can suppress the eczema without using any topical steroids.

4 For aged eczema sufferers especially over 60 years old at age, the combination therapy of my hyaluronan lotion and topical clofibrate is highly recommended because the aged atrophy of epidermis contributes to the eczema itself more or less.

 I was very much interested in Hatano’s paper and made up my mind to confirm the utility of topical clofibrate by myself two years ago. So I announced my idea through internet in Japanese and collected 20 patients who would participate in my study. They were divided into two groups double-blindly and the effects were compared between the topical clofibrate applied group and placebo group. The efficacy of objective and subjective symptoms was confirmed significantly and TARC in the clofibrate group also decreased significantly while placebo group not. The whole results of the study was made up to an article and published in the Journal of Drugs in Dermatology. 2014 Mar;13(3).

http://jddonline.com/articles/dermatology/S1545961614P0259X/1

From my experience of 20 patients, I should add some impression about topical clofibrate. They are as follows:

1 There exist topical clofibrate responder and non-responder. It doesn’t correlate with whether the patient is addicted to topical steroids or not.

2 Even in topical clofibrate responders, abrupt aggravation due to exposure to some factor (allergen etc.) can occur. Patients who chose non- steroidal way and expected much in topical clofibrate are liable to be disappointed in case of such aggravation. Patients with steroid-phobia might even misunderstand the aggravation as the rebound to topical clofibrate.

 So I suggest to topical clofibrate users (especially steroid-phobic patients) as the followings:

1 Try topical clofibrate anyway for about two weeks to one month.

2 If you feel effective, continue to apply it instead of your moisturizer. It seems to have no addicted tendency judging from my observation of several topical clofibrate responders for about one year.

3 If the eczema becomes worsened abruptly, don’t be too much depressed. Remember any abrupt aggravation means a hint for you to find out the aggravating factor in your own case. You may use steroids temporarily or may just endure the severe period until recovery. Even if you use topical steroids, you can change them to topical clofibrate after the eczema subsides and avoid topical steroids addiction.

 As I have already mentioned, manufacturing of topical clofibrate is very easy for physicians or pharmacists. However, if you can’t find such cooperative medical professionals, you can purchase it through Dr. Fukaya’s web shop from me. The price is JPN 3,000 at the amount of 500 grams.

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Is Gloria Sam really a victim of topical steroid phobia?

 In 2009 in Australia, a couple of parents were judged guilty over their daughter’s death.Their daughter suffered from atopic dermatitis and the direct cause of death was infection. The parents were accused of medical neglect.You can find the media article in the following URL

 

http://www.smh.com.au/national/parents-guilty-of-manslaughter-over-daughters-eczema-death-20090605-bxvx.html

 

In 2013, a medical article was published about the case.

https://www.mja.com.au/journal/2013/199/7/treatment-failure-atopic-dermatitis-result-parental-health-belief

In that article, authors summarized that topical steroid phobia was the largest mistake of the parents.
I don’t agree with the authors. The patient died from infection (sepsis) and not from disuse of topical steroids. Topical steroids never prevent infection or sepsis in eczema sufferers. There is no such medical evidence.

People （including non-special medical doctors） are liable to think that the skin treated by topical steroids is apparently clean and such skin must be strong against infection. However, it is an illusion. Topical steroids suppress the immune system and damage the epidermis. After all, the skin of eczema sufferers is easy to cause infection regardless of use or disuse of topical steroids.

Malnutrition is a factor of susceptibility. The daughter of Indian parents had fallen into malnutrition. The cause of malnutrition is therapeutic failure of atopic dermatitis. If the patient was treated by topical steroids, malnutrition might be avoided. In that meaning, topical steroids could be one tool for preventing the tragedy. However, were topical steroids absolutely necessary in this kind of case? I don’t think so. I have already written an article about it.
http://mototsugufukaya.blogspot.jp/2013/06/for-parents-of-atopic-children-some-of.html

Experienced food allergy specialists (mostly pediatricians) can treat atopic children successfully without using topical steroids. They never only restrict food items but look for what is eatable for the baby. They never forget to check the patient’s weight and draw the growth-curve.

The common method of such pediatricians starts from stopping breastfed. Totally controlled artificial milk is their tool. They add various food items one by one carefully observing the child’s eczema. They balance the weight increase and eczema status.

When the patient is suspected severe infection (sepsis), such pediatrician also might use topical steroids temporarily. Topical steroids certainly improve eczema and lessen protein loss from the skin. It benefits for  improvemrnt of malnutrition. It is a method of short-cut for emergency.

However, daily routine use of topical steroids is not necessary for care of atopic children from the viewpoint of prevention of malnutrition. Some pediatrician even prefers disuse of topical steroids because it can clarify the causal food more obviously.

The tragedy of the Indian family originated from that they couldn’t believe the modern medicine. If the main reason of their distrust lies in steroid-phobia, the problem exists in the side of our modern medicine. If we could accept and treat the daughter without using topical steroids, the parents might have believed our medicine. If the parents could find any doctor who would treat the baby without using topical steroids, the tragedy might not have occurred.

It is enough possible medically in fact. The problem is that such method of topical steroids disuse is far more troublesome than simple prescription of topical steroids. Disuse of topical steroids is not medically wrong but inconvenient or unfavorable for dermatologists. That’s all.

In Japan, we have experienced almost the similar case. A baby with atopic dermatitis died from malnutrition and sepsis several years ago. Their parents were believers of newly-arisen religion. They didn’t take the baby to see any doctor and tried to treat the baby’s eczema by their religion but only to fail. They were judged guilty by Japanese coart.

After media news was presented, many dermatologists referred to the case and blamed disuse of topical steroids by atopic patients. But the baby didn’t die from disuse of topical steroids. The baby died because the parents didn’t take him to hospitals. Why didn’t the parents take the baby to hospitals? It is because they couldn’t find any doctor who would see the baby without steroids. Why are most dermatologists reluctant to see such patients who prefer disuse of topical steroids? It is because either they are not used to such a way or they think it is too troublesome and not to pay.

I am not so proud about this problem because I am also not seeing patients with atopic dermatitis now. What I think I am proud is that I am honest. Most dermatologists (or pediatricians also) seem to try to conceal the truth and seem to try to lay the blame on topical steroid phobia.
Why do patients with atopic dermatitis feel topical steroid fear? Why do only patients with atopic dermatitis fear while asthmatic patients feel far less fear to inhaled steroids? It is just because there exists the phenomenon of topical steroid addiction in the skin organ. The skin can be damaged by the long term use of topical steroids and the eczema becomes hard to cure.
Many patients notice that phenomenon worldwide and that is the origin of steroid-phobia.

The blame by dermatologists to disuse of topical steroids in case like Gloria Sam will never solve the problem. Patients with steroid phobia will become more reluctant to visit hospitals if they are blamed and the tragedy might even increase. It ends only as a self-satisfaction of dermatologists in the small society of dermatology at all.
What is the most needed is the warning of malnutrition and sepsis to parents of eczema babies and recommendation of immediate hospital visit apart from the discussion of steroids if they noticed such symptoms. It is not the essence of the case of poor Sam family whether we should use topical steroids in patients with atopic dermatitis or not.

I never blame any dermatologist for not seeing patients with atopic dermatitis without using topical steroids. It is really troublesome and not to pay. I also am not seeing them now.
However, we dermatologists should be honest in front of patients at least as human beings. We should not make an awkward story of poor Gloria Sam as a victim of topical steroid phobia just because it is convenient for dermatologists. It is a shame in Japanese feeling and a sin in European sense.
There are still very few dermatologists or pediatricians who eagerly see such patients without profit-and-loss arithmetic just as me over ten years ago. They are a real property for both patients and doctors. We should not disturb them by the stupid debate like this.

PS : May the soul of little Gloria Sam be peaceful in heaven and her parents become happy again in the future. They must have suffered and struggled enough.

Related my article about infection in atopic dermatitis is also in the following URL.
http://topicalsteroidaddiction.weebly.com/chapter-2212288hostile-criticism.html

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Ophthalmological complications

“You don’t need to visit any dermatologist including me, but you should visit an ophthalmologist periodically.” That was my habitual saying to patients with atopic dermatitis.

 There are several ophthalmological complications in atopic dermatitis. Well, I will make a question about it.

 You should clear the exam before treating your atopic dermatitis by yourself. Never feel easy about ophthalmological complications only because you are seeing some dermatologist. They see only your skin and never see your eyes.

 Which is the ophthalmological complication in atopic dermatitis?

a.cataract  b.retinal detachment  c.conjunctivitis d.keratoconus e.glaucoma

1.a  2.a,b  3.a,b,c,d  4.all 5.none

  Atopic cataract occurs suddenly. Though steroids can induce cataract, atopic cataract occurs regardless of steroid therapy. There were patients with atopic cataract several decades ago when steroids were not yet invented.

 Cataract has a tendency to develop a while after severe dermatitis has subsided. Some dermatologists criticize TSW insisting that TSW is the cause of cataract. But it is a ridiculous theory because the cause of TSW (A) is topical steroids. Bad dermatologists neglect their duty to give information about ophthalmological complication before the patients develop cataract and blame their TSW after the development of cataract. 

 When cataract is developed, the patient’s pupil becomes cloudy. It occurs one day and progresses in a few days. It is just like you have a drip of milk in your eye. Fortunately, cataract can be treated by operation. You can recover eyesight. Ophthalmologists might use eye drops of topical steroids for the purpose of conditioning the situations around the operation. You should not be so nervous but you can request of the ophthalmologist to refrain from using it if you never like to use it. Usually ophthalmologists are not so stubborn about topical steroids and accept your request.

 Anyway, your cataract should be operated not only because you could recover eyesight but also because it will help an early identification of retinal detachment.

 Retinal detachment in atopic dermatitis starts in the peripheral parts of the retina. It is the part of difficulty in examination. If there were untreated cataract, ophthalmologists couldn’t check the part.

 If the retinal detachment is identified early when it is small, laser therapy can stop the progression. So it is very important to find out as early as possible.

 Retinal detachment is considered to be caused by the repeated or frequent banging to the skin around the eyes. Mechanical vibration is an inducement. So we dermatologists often warn patients not to bang around the eyes but the stress of the patients become increased by the warning itself and they bang or spank more and more. Nobody seems to be able to stop it. So I recommend patients to visit an ophthalmologist at least. The damage would become the least by examining the retina periodically.

 Conjunctivitis is a symptom of allergy. Sometimes the cornea is also damaged mechanically because of the mucosal roughness of the eyelid side of the conjunctiva. Keratoconus is completely a complication of atopic dermatitis itself. The eyesight of the patient with keratoconus can be corrected by the contact lens.

 Glaucoma is the side effect of steroids or antihistamines if the ocular tension decreases by stopping those drugs. Glaucoma is never a complication of atopic dermatitis. So the answer of the above question is 3.

 I used to introduce all patients with atopic dermatitis to the ophthalmological department first of all before I myself see the patients. I am now retired but if I had continued to see TSA/W patients after resigning the national hospital, I would have studied ophthalmology and equipped with the instruments of funduscopy and slit lamps in my clinic. It is so important a problem.

 If the patient is an infant or a child, you need not become so nervous. But even a child also can develop cataract if the dermatitis is severe. Keep being careful.

 Now I will refrain my usual almost habitual saying again. You, patients with atopic dermatitis don’t need to come to dermatologists including me but you should visit to an ophthalmologist periodically. They will not prescribe any medicine but examine your eyes. It is very important.
 

PS:　In Japan, patients can see an ophthalmologist (eye doctor) for the purpose of only examinations under the public health insurance at the cost of about 30 USD. Patients usually don’t need to make any reservation or appointment. I don’t know how much it costs or how hard it is to make a reservation overseas. If you have any experience of seeing an ophthalmologist, please leave a comment for the exchange of information.

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A report about a biological product for patients with atopic dermatitis.

 Have you heard of the medicine called a biological product? It is a practical application of the monoclonal antibody.
 There are various biological products available nowadays. Among them Xolair (Omalizumab) is the most promising for atopic dermatitis at present.

 Xolair was studied as a medicine for asthma. Patients with asthma often suffer from atopic dermatitis also. Some patients with asthma to whom Xolair was administered also improved their eczema. So doctors started to study the efficacy of the medicine for atopic dermatitis. Some reported Xolair was useful while the others reported not effective. There was no double blinded case-control study. The below report is the first double blinded case-control study about Xolair for atopic dermatitis though the population is small.

Immunologic Effects of Omalizumab in Children with Severe Refractory Atopic Dermatitis: A Randomized, Placebo-Controlled Clinical Trial. Iyengar SR,et al. Int Arch Allergy Immunol. 2013 Jun 27;162(1):89-93　　

 The number of patients was 8 at the age of 4-22. They were divided to two groups of placebo and Omalizumab administration.
 They were all refractory patients (“All patients had severe AD that had failed standard therapy.”）. Whole the treatment was discontinued one week before the first administration of the placebo or Omalizumab. The agent was administered by subcutaneous injection and the dosage of Omalizumab was 150-375mg every time. The frequency was every 2-4 weeks and the duration of treatment was 22 weeks.

 Total IgE, Free IgE, TARC and SCORAD values are picked up from the results of the article as the following table. How do you read the numerals?

 Omalizumab is an antibody to IgE. It binds to the patient’s IgE and inactivates it. The free IgE decreaseed and Th2 system also became inactivated.
 However, about the SCORAD which indicate the clinical severity of atopic dermatitis, the values decreased in both the placebo and Omalizumab groups. How should we understand the result?

 I consider there is a possibility that the placebo patients improved  by topical steroid withdrawal(TSW) for 22 weeks.

 In the article, the authors didn’t mention the result of the statistical analysis. So I did the matched Student’s t test to their results. The P value were as the following.
 

  At the 0.05% of the significance level, the placebo group improved while Omalizumab group didn’t improve.

 The author’s comment is as the following.
“The high rate of response to placebo has been well documented in these types of studies and, had any of the above published studies examining the clinical effects of anti-IgE included a placebo arm, a similar rate of response may have been seen.”

 Wait for a while. The phrase is likely to be skipped just carelessly but you ( the author) mentioned the patients were all refractory to the usual standard therapy, weren’t they? You admit such patients improved by the placebo treatment for 22 weeks and it is often the case with that kind of studies?

 Yes, atopic dermatitis has a tendency of natural healing. But the enrolled patients were “All patients had severe AD that had failed standard therapy.” I suppose you should not have forecasted their natural improvement before the study.

 The price of Xolair is about USD 350 per 75mg. It costs about USD 4200-21000 for 22 week treatment.
 Here I should clarify my stance about this therapy. I dare say I will buy Xolair and administer to my child if he or she suffers from the refractory atopic dermatitis. If I were a sufferer, I definitely buy the treatment. The problem about the above article is only the SCORAD result of the placebo group. The results of blood examination are clear and convincing. The significance of SCORAD is over 0.05 but I believe it will decrease if the population becomes larger.
 The cost is really high. But fortunately I can afford it. I will pay for the medicine even though there is a small risk of anaphylaxis or carcinogenicity due to immunosuppression. I take the merit heedless to the risk of this medicine.

 But I know well all the patients can’t try the treatment because of the financial problem. Don’t worry. You could also become improved only by discontinuance of the whole treatment for 22 weeks just like the patients of placebo group.

 Yes, it is the essence of the TSW. Patients feel strong anxiety to the situation of “nothing to do”. Placebo patients in the above article might have worsened temporarily but they could stand it because they thought they were through a treatment. Doctors could also stand the stressful situations because they thought they were scientifically right. Do consider. If the placebo patients remain worsened, the best scientific outcome could be obtained. Otherwise the doctors couldn’t stand seeing worsening patients without any treatment and must have recommended to resume topical corticosteroids.

 However,what a happy ending of the study! All patients became improved in the above article and the efficacy of TSW was also confirmed. A toast to the authors!

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The bankrupt of the regulation of cortisol level in the skin tissue might be the essence of TSA.

Recently it has been revealed that epidermal cells produce cortisol (corticosteroid) by themselves. Topical steroid addiction (TSA) is considered to be related with the skin atrophy which causes the barrier dysfunction. The bankrupt of the regulation of cortisol concentration in the skin tissue might be its ground.

 The concentration of cortisol in the skin tissue is kept lower than in the blood.
 According to the following article about thermal injured patients, for example, plasma total cortisol took the value of 8.8μg/dl, free (protein unbound) cortisol 1.7μg/dl and tissue (skin) cortisol 0.74μg/dl.

 Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation.Cohen J et al, Crit Care. 2009;13(6):R189. Epub 2009 Nov 27.
   
 In healthy subjects as a control, the tissue cortisol was 0.20μg/dl. Only a fraction of the concentration in the blood is detected in the normal skin tissue outside the blood vessels and the value increases once inflammation such as burn occurs.

  By the way, epidermal cells, hair follicular cells and fibroblasts in the dermis can produce cortisol by themselves. What is more interesting is that the production of cortisol by those cells is amplified by the skin tissue cortisol. There is a positive feedback mechanism.

On the other hand, there is  also an enzyme that inactivates cortisol in the sweat gland. The concentration of cortisol in the skin tissue is controlled by those factors. The following figure is what is summarized.

11βHSD1 is an enzyme that converts cortisone (inactive steroid) to cortisol (active steroid) while 11βHSD2 is an enzyme that converts the latter to the former.
 What is the meaning of the positive feedback mechanism of cortisol production? It must be for the purpose of increasing the skin tissue concentration of cortisol rapidly in case of any inflammation such as burn occurs.

 If topical steroids are applied to the skin, epidermal cells or fibroblasts react to TS and produce cortisol. The increased cortisol effects to the cells themselves and suppress their own proliferation. In case of systemic steroids such as oral steroids, the effect to the skin tissue concentration is not so much because blood vessels regulate cortisol not to transfer too much to the skin tissue.

  Now you can understand how abnormal the situation of continuous use of topical steroids to the skin is. Physiologically the concentration of cortisol in the skin tissue is kept considerably low. Topical steroids violate the controlled situation.

 After stopping topical steroids, the epidermis becomes thicker than before TS application temporarily. It means the skin tissue lacks enough steroids temporarily.

 

1A:Before application of TS, 1B: thin epidermis after TS application, 1C 1D 1E: temporarily thickened epidermis after discontinuance of TS

（Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin. Zheng P, et al. J Invest Dermatol 82: 345-352, 1984）

 

 The fact that epidermis becomes thick means that the steroid deficiency has occurred. But what is the mechanism of the deficiency? There must have been too much steroids.

 

  One of the possible mechanism is as the following.

  11βHSD1/2 balance, which is 11βHSD1 dominant in the epidermal cells normally, changes to become11βHSD2 dominant after considerable dose of TS application.

 After discontinuance of TS, the skin tissue cortisol becomes low temporarily. Inactive form of steroid (cortisone ) is accumulated within the cell. After 11βHSD1 reactivation, skin tissue cortisol will be produced but from the accumulated cortisone. It never is a normal condition. The gene coding cortisol will not be up-regulated under such a condition and various proteins which are related to the gene will not  also be produced. So the skin remains fragile and the barrier dysfunction continues.

 It is only a hypothesis. However the temporarily deficiency of steroids after discontinuance must be explained in any way.  
 
 The below figure shows 11βHSD1/2 expression of the normal skin (brown means 11βHSD) . 11βHSD1 is expressed on the whole cells of epidermis while 11βHSD2 is expressed only on the outer layer. Obviously there is a regulated balance of 11βHSD1/2 in the normal conditions.

 （Keratinocytes synthesize and activate cortisol.Cirillo et al.J Cell Biochem. 2011 Jun;112(6):1499-505)

 The concentration of cortisol in the skin tissue is kept low basically and the constituent cells produce or inactivate cortisol according to the inflammatory status. Topical steroids application violates its harmony and constituent cells become instable after TS application. I consider it might be the essence of TSA existing as the ground of the barrier dysfunction caused by TS.
 
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Do topical steroids prolong atopic dermatitis?

Apart from the problem of TSA/TSW, there exists another important problem which most of the patients are anxious about.
 
“If the population of patients with TSA is 10 or 20% as Dr. Fukaya mentions, why is the number of patients with atopic dermatitis increasing? Is there any possibility that TCS application prolongs AD and postpones the natural healing?”
 
 In fact, the number of patients with AD has been increasing after TCS was produced and came onto the market more than half a century ago . There is no other disease that a population of the patients increased after a medicine for the disease had been produced.
 
 One Japanese researcher presented an interesting article in 2010 about experiments using AD model mice. Mice treated with a kind of chemicals on the skin repeatedly develop AD like dermatitis. He compared the skin (ear) thickness and scratching behavior of TS treated group and non-treated group. The result revealed TS improve the skin thickness but argument the frequency of scratching behavior.The results were the same when he changed mice strain, chemicals or the kinds of TS.
 
Repeated topical application of glucocorticoids augments irritant chemical-triggered scratching in mice. Fujii Y et.al. Arch Dermatol Res. 2010 Nov;302(9):645-52.

 

The above figure is from Fujii’s article.　TPA is a kind of chemical which causes eczema.　The white bar is of mice not treated with TS and the black bar is of TS-treated. TS suppress the eczema (ear swelling) but increase scratching frequency.

 

Then, he measured the concentrations of the substanceP and NGF(nerve growth factor) of the skin lesion which are both associated with itch sensation of the skin.  Both were increased in the TS-treated lesion than non-treated lesion.

 
To explain instinctively for easy understanding, repeated stimulation by antigens causing eczema which subside apparently by application of TS, also cause decreased threshold of scratching. Inflammation that TS suppress is substantially a protection against extrinsic stimuli. After the suppression by TS, another mechanism of protection must start if the stimulus doesn't disappear. It is the mechanical protection by scratching behavior.

 
Some patients would agree in the result of experiments from their own experience. The itching just before the withdrawal when those patients felt ineffectiveness to TS seems to be very offensive and strange. The itching stays very inward and they often tell the itching after TSW is also itching but very different from that of before withdrawal. The latter is far better than the former.

 
The above mentioned Japanese researcher is Fujii in his name and he belongs to Astellas pharma Inc. which is the manufacturer and provider of Protopic ointment.

 
As I have already written, the history of Protopic (or Elidel in Europe) is dramatic. In around 2000, Protopic appeared like a savior of the TSA problem. We dermatologists all thought that TSA or rosacea-like dermatitis due to TS at least in the face would disappear in several years. But several cases were reported that Protopic also caused rosacea. All people concerned were shocked and thought “ What is the merit of Protopic if it also causes rosacea?” I imagine Fujii was also one of them. By the way,there was another preceding report by other researchers that Protopic was superior to TS in the suppression of scratching behavior.

 
 Inhibition of scratching behavior associated with allergic dermatitis in mice by tacrolimus, but not by dexamethasone.　Inagaki N et al. Eur J Pharmacol. 2006 Sep 28;546(1-3):189-96.

 
 Fujii might have been interested in it and retest it. The results were more than he expected. He has revealed not only the superiority of Protopic to TS but also the negative aspect of TS about the prolongation of the disease. Fujii concluded the end of the article like the following.

 
In summary, this study is the first to show the potential of topical glucocorticoids to augment itch sensation, not via the augmentation of inflammation. This phenomenon might result   from   the augmentation of   SP   and   NGF   production, along   with   nerve  fiber   extension,   at   the   application   site.
Given the profound impact of scratching on skin inflammation, these findings might explain the etiology of the exacerbation   of   atopic   dermatitis   and   other   dermatitises, which occurs after long-term or inappropriate use of topical glucocorticoids.

 
 What should Fujii or Astellas pharma inc. do next?  Can they promote Protopic successfully by introducing the above result of experiments to dermatologists who are prescribing TS everyday?
 TS are the main tool for most dermatologists and they can’t replace all to Protopic. Maybe dermatologists feel stressful and even emotional if Protopic were promoted in such a way.

 
From the viewpoint of patients, I am certain that Protopic should be promoted like that. Though I or my children are not eczema sufferers, I would prefer Protopic to TS if I must use definitely either of the two. Protopic has a risk of carcinogenesis. But I would take the risk of it rather than a risk of prolongation of healing by TS because the former seems to be much rarer than the latter instinctively (I only mean there is not such a statistics).

 
About the relation with my hyaluronic acid lotion, it certainly prevents the atrophy of the epidermis due to TS and development of TSA. I definitely recommend using it to TS users. But argumentation of scratching behavior due to TS would not be suppressed by it. So I recommend not to use TS for so long a time even if the patient applied my hyaluronic lotion. That is my thinking at present.

 
 PS; I uploaded my self-introduction video on Youtube because some of you might have intetest in what a guy I am. Please watch to enjoy it.http://www.youtube.com/watch?v=oh8uz7OObr8&feature=youtu.be

 

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About Strong Neo-Minophagen C（SNMC）

Note; This article is a supplementation to the comment in the following article.
[Paradoxical idea of systemic steroids use for withdrawal from topical steroids]
http://mototsugufukaya.blogspot.jp/2013/06/paradoxical-idea-of-systemic-steroids.html
 
Strong Neo-Minophagen C（SNMC）　is an old medicine made in Japan. It is administered only by intravenous injection.

The active ingredient is glycyrrhetinic acid, a constituent of liquorice.

The efficacy of Chinese herbs containing liquorice is thought to be due to glycyrrhetinic acid at least partially.

Some doctors in Japan prefer SNMC for suppressing rebound after TSW. The mechanism is considered as 11 beta-OHSD suppression.  11 beta-OHSD is an enzyme  which changes cortisol to cortisone: inactive form of cortisol.

The below graph is from Greaves’s article. The horizontal axis is the concentration of medicines and longitudinal axis is human skin branching due to topical steroids.

Beclomethasone dipropionate and hydrocortisone acetate are both TC and the former is stronger than the latter. The data tells the effect of hydorocortisone acetate is amplified by the addition of glycyrrhetinic acid.

Potentiation of hydrocortisone activity in skin by glycerrhetinic acid. Greaves MW. Lancet. 1990 Oct 6;336(8719):876.

Doctors using SNMC for the rebound seem to consider it is safe because it is not an administration of extrinsic steroids. However, it is very near to the weak systemic steroids injection in fact.

I also have experience of this method. It was rather weak and didn’t become popular among my patients. Systemic steroids injection is more recommendable than SNMC from my thinking but it is certain that SNMC is an alternative method anyway. I have never heard or read that SNMC caused rebound.

SNMC is provided by Minophagen pharmaceutical co. ltd.
http://www.minophagen.co.jp/English/index.html

The product is provided overseas to Asia area.

If any medical doctor who is reading my blog and interested in SNMC, don’t hesitate to contact me. I can export SNMC to your clinic. It is legal under Japanese law. The attached document of SNMC is here (just click).

Or I can export SNMC to any patient who prefer to use SNMC and could find a doctor who would inject it to you in your area. Please contact me by e-mail : fukaya*tclinic.jp (replace *to@).

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