Skin Deep - Clinical & Cosmetic Dermatology Blog

Skin Deep is a blog for dermatologists and skin care professionals with focus on theoretical, cosmetic and aesthetic dermatology. This blog is associated with ‘Dermatologists Sans Borders’ one of the largest curated groups of skin care professionals on facebook. If you are looking for non-technical information, please visit http://skinhelpdesk.com


Adolescent Argireline

Read the full series here.
Hope you enjoyed the peptide story so far. Now we will explore the charming Acetyl hexapeptide-3 (Argireline), the botulinum toxin in a bottle. Acetyl hexapeptide-3 has the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 patterned from the N-terminal end of the protein SNAP-25. Before going into the details, let me ask my readers few questions about cosmeceuticals?
Lily Allen. A cropped version of Image:Lily 1.jpg
Lily Allen. A cropped version of Image:Lily 1.jpg (Photo credit: Wikipedia)

How new is new?
How recent is recent?
How similar is similar?

Acetyl hexapeptide-3 is still considered a ‘new’ technological innovation in cosmetic industry. Wikipedia still gives the benefit of doubt to Acetyl hexapeptide-3 for not having long-term safety related data because ‘it has been developed relatively recently’. ( http://en.wikipedia.org/wiki/Acetyl_hexapeptide-3 ). But the earliest pubmed published article [1] on Acetyl hexapeptide-3 dates back to 2002 ( http://www.ncbi.nlm.nih.gov/pubmed/18498523 ) and the actual discovery of the peptide to 1983. Acetyl hexapeptide-3 is not an infant as we think, but an adolescent.

Though it is not fair to criticise the initial perception about a technology, I can’t help but quote few lines from this initial article:

“Botulinum neurotoxins (BoNTs) represent a revolution in cosmetic science because of their remarkable and long-lasting antiwrinkle activity. (fair enough) However, their high neurotoxicity seriously limits their use. ” (really!)

“BoNT A is the most potent toxin known to humankind and therefore BOTO@” treatment has to be under strict medical control”

May God save those admitted with severe neurotoxicity after BOTO@ and medical fraternity, please have a strict control over the BOTO@ party next door.

Please take a note of the word ‘potent’ above. See another statement the authors have made in the abstract of the same article:

“Analysis of the mechanism of action showed that Acetyl hexapeptide-3 significantly inhibited neurotransmitter release with a potency similar to that of BoNT A, although as expected, it displayed much lower efficacy than the neurotoxin.”

Was clinical research so advanced a decade back so that potency and efficacy could be assessed by analysis of the mechanism of action? 
English: Chemical structure of Argireline (Ace...
English: Chemical structure of Argireline (Acetyl hexapeptide-3) (Photo credit: Wikipedia)

If you scroll down to the “Results and Discussion” you will see a section on rational design of Acetyl hexapeptide-3 that is irrational. More about this in my informatics blog.

Will be back soon with more stories on the adolescent Acetyl hexapeptide-3 and the similarity of its potency with BoNT A.

In spite of the limitations in this decade old initial studies, Acetyl hexapeptide-3 should still be considered a conceptual innovation even now.

Read the full series here.
Reference:
1. Blanes‐Mira, C et al. "A synthetic hexapeptide (Argireline) with antiwrinkle activity." International journal of cosmetic science 24.5 (2002): 303-310.


Disclaimer: Argireline is a registered trademark. All information presented here is given in good faith but without warranty or guarantee of any kind whatsoever, whether implied or expressed. 
Read the full series here.

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Dark Circles, Omalizumab, PRP, Metformin and Dermal Fillers


Here is a quick review of few interesting articles before I go into peptides again.

Example of dark circles
Example of dark circles (Photo credit: Wikipedia)
(1) Dark circles is a common and difficult to treat cosmetic concern. Many factors are incriminated including transparency of periorbital skin and microcirculatory disturbance. It may also be just shadows being thrown by your own features. Filling of periorbital hollow with dermal fillers and a variety of other materials claim to improve dark circles. But clinical proof of efficacy is absent in most cases. This article describes a collagenase digested fat cell grafts that minimised visible lumps post procedure. However only 60% of those treated got improvement. Safety of collagenase in this anatomically thin area also needs to be evaluated.

English: Uriticaria
English: Uriticaria (Photo credit: Wikipedia)
(2) The monoclonal anti IgE drug omalizumab has reached phase III trials in Chronic Idiopathic Urticaria. At present it is licensed for the treatment of asthma. The referenced writeup in medpage today depicts it as a serendipitous discovery. Chronic Idiopathic Urticaria should be a natural target for a monoclonal IgE antibody useful in asthma.

(3) As I concluded after my series on PRP, Platelet rich plasma is a mixture of growth factors with diametrically opposite effects.  This study shows that excessively high concentrations of platelets actually have an inhibitory effect on the wound healing processes and are, therefore, counterproductive.
Metformin
Metformin (Photo credit: Wikipedia)

(4)Metformin reduces hepatic glucose output and has anti-platelet and anti-oxidant effects. It has many non-diabetic cutaneous indications as well. This article reviews its beneficial effect on hirsutism, acne, hidradenitis suppurativa, acanthosis nigricans, psoriasis and skin cancer.

(5) The dermal filler manufacturers control the consistency and longevity of their products by altering the chain length and cross linking. Hyaluronic acid stabilized by carboxyl - hydroxyl inner esterification may have the additional benefit of pro-proliferative activity of cutaneous fibroblasts and keratinocytes.

References:

1. Youn, S. "Correction of Infraorbital Dark Circles Using Collagenase-Digested ..." 2013. http://www.ncbi.nlm.nih.gov/pubmed/23437990

2. "Asthma Drug Curbs Chronic Hives." 2013. 25 Mar. 2013 http://www.medpagetoday.com/MeetingCoverage/AAAAI/37508

3. Giusti, Ilaria et al. "The effects of platelet gel–released supernatant on human fibroblasts." Wound Repair and Regeneration (2013).

4. Badr, D, M Kurban, and O Abbas. "Metformin in dermatology: an overview." Journal of the European Academy of Dermatology and Venereology (2013).

5. Wohlrab, Johannes, David Wohlrab, and Reinhard HH Neubert. "Comparison of noncross‐linked and cross‐linked hyaluronic acid with regard to efficacy of the proliferative activity of cutaneous fibroblasts and keratinocytes in vitro." Journal of cosmetic dermatology 12.1 (2013): 36-40.


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The peptide avengers - Part 4


Read the full series here.

Matrixyl 3000 was a double-headed serpent (a mixture of Palmitoyl Oligopeptide & Palmitoyl Tetrapeptide-7). He had a weapon that others did not have: an anti-inflammatory sword. When Matrixyl’s son Tetrapeptide 21 was born, there was a voice from the heavens. “He who is born by immaculate bioinformatics shall rule the world of peptides. He shall win the heart of the elusive hyaluronic acid”.  If you want to read the transcript of the voice from heaven it is here. Please don’t forget to read the story of his bioinformatics birth and his effect on hyaluronic acid on page 2.

Here is my take on Tetrapeptide 21’s bioinformatics birth:
Please be warned that it is going to be a shameless self promotion without actually giving away much information. My plan is to get noticed by the top 100 cosmetic manufacturers.

The war still rages within....

English: Gene expression pattern of the HAS1 gene.
English: Gene expression pattern of the HAS1 gene. (Photo credit: Wikipedia)
Epilogue: Tetrapeptide 21 could not marry Hyaluronic Acid. He marries her slave HAS1 instead. Matrixyl 3000 marries copper and has a complex son. Read the story below.

[http://www.nature.com/jid/journal/v110/n2/abs/5600157a.html  Has1 and Has2 genes are regulated independently and synthesized hyaluronan may have a different function in epidermis and dermis.]

The war divides the country into chronological and photo ageing. The retinoids, fractional lasers for skin rejuvenation and dermarollers still rule the rest of the world.

Will be back with the story of Argireline.

Disclaimer: Matrixyl and Argireline are registered trademarks. All information presented here is given in good faith but without warranty or guarantee of any kind whatsoever, whether implied or expressed. 
Read the full series here.

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Hyaluronic Acid and the hidden beauty. Peptides Part 3

English: Peptide bond formation. Français : Fo...
Peptide bond formation. (Photo credit: Wikipedia)

Read the full series here.

KTTKS was the son of alpha-pro-collagen I, the most influential dermal fibrous protein. He was in the bad company of water because of his polar nature. Mr Pro-collagen I called KTTKS one day and told him a little secret. The secret to increase his power 5 times. In a hidden vault in their house KTTKS found it, a lethal weapon called the palmitoyl, a fatty acid derivative. It increased his penetration 5 times. Palmitoyl-KTTKS became the king of all cosmetics and adopted the name Matrixyl.

Matrixyl, the king of all cosmetics was relatively stable in his base formulation, penetrated reasonably well. In spite of his weakness inside the cell, he was a good king. But, one fine day Matrixyl fell in love with the beautiful Hyaluronic acid, a polysaccharide. Matrixyl being a peptide could influence most other proteins since they all had the same amino acid core. But HA was beyond his reach since she had no amino acid in her. Besides she was in love with the ubiquitous villain UVB.

What followed was the epic war that lasted for 1000 years. Matrixyl was brutally murdered in the war. But all was not over. Matrixyl’s brother, Matrixyl 3000 and his son Tetrapeptide-21 vowed to avenge the death of Matrixyl.

To be continued.... But during the break, why not read the stories below:

http://www.ncbi.nlm.nih.gov/pubmed/21454612 [Collagen fragments inhibit hyaluronan synthesis in skin fibroblasts in response to ultraviolet B (UVB): new insights into mechanisms of matrix remodeling.]

http://www.ncbi.nlm.nih.gov/pubmed/11085364 [This article describes a method for measuring the true flux of peptides across skin in vitro and a kinetic model which simply describes the skin penetration of peptides.]

Want to know more about the Matrixyl clan? Read thisRead the full series here.

Disclaimer: Matrixyl is a registered trademark. All information presented here is given in good faith but without warranty or guarantee of any kind whatsoever, whether implied or expressed. 

Read the full series here.

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3 villains in the peptide story - Part 2


Prologue: The dermis has fibrillar components called Collagen and Elastin embedded in an Extracellular matrix composed of Glicosamino glycans (GAG), hyaluronic acid being the most important (and popular). There are synthetic and degradation pathways for collagen like most other proteins in the body. The synthetic pathway leads to the fountain of youth. 

Julian Voss-Andreae's sculpture Unravelling Co...
Julian Voss-Andreae's sculpture Unravelling Collagen (2005), stainless steel, height 11 ft 3 in (3.40 m). (Photo credit: Wikipedia)
So here is the story: Peptides similar in composition to collagen resemble collagen degradation fragments. When these peptides are introduced into the skin, they trick the body into believing that the degradation pathway is active. To compensate, the synthetic pathway is activated by the body and Voila, you are young again!

Penetration
Penetration (Photo credit: Man Alive!)
There are 3 villains in this story. The first one is Mr Stability. The peptides are not very stable in their base formula. Mr Penetration makes the passing of these peptides across the stratum corneum difficult. The third and the most lethal one Mr Destroyer, dismantles these peptides into amino acids as soon as they penetrate. So reaching the bounty of youth is not so easy as it seems.

The hero is bound to have strong and muscular brothers in Hindi cinema, who will come together in the end because they share the same tattoo or sing the same song. Likewise if you set out to find Tetra or Pentapeptides similar to collagen, you have millions of them. So how does the director find the hero from a million possible heros?

Hey, don’t ask questions now. You shall know the entire plot of the story towards the end.

To cut a long story short our hero is called Pal-KTTKS known as Matrixyl to 'aam janta'. He is in love with the beautiful GAG Hyaluronic Acid (HA). But tragedy strikes!  HA belongs to a different religion! Unlike other GAGs, HA is not even a peptidoglycan. She is just a polysaccharide with no peptide in her!

I have to take a commercial break here. Will be back again soon.

Read the full series here.

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The Peptide Era - Part 1

Pharmacy Rx symbol
Pharmacy Rx symbol (Photo credit: Wikipedia)
Recently I reviewed two peptides for hair loss and canitis. Here I shall attempt a holistic overview of peptides in general with an emphasis on anti-ageing peptides.

Retinoids are the gold standard prescription product for anti-ageing. Retinoids go right inside the cells and bind to the RAR and RXR neuclear receptors and directly promote collagen synthesis at the transcription level. Since retinoids are prescription products, these effects are well documented and demonstrable by in vivo studies. However like most prescription products, they are not without side effects. The non-prescription Vitamin A derivatives are less irritating, but they are less effective also.

Peptides are the cosmetic industry's answer to retinoids. As the thin line between clinical and cosmetic dermatology is becoming more and more hazy, these peptides are finding a niche in the dermatologists prescriptions as well. But do they actually work?

Peptides are short chain amino acid sequences not long enough to be a protein, that promise more but deliver less, a limitation commonly seen with many novel biotechnology innovations. (How long have you been hearing about personalised medicine?) But that is a different topic worth a consideration in my informatics blog. The storyline is quite fascinating in most cases.

In my next post I shall discuss the story of peptides that can trick the body into producing more collagen and peptides that simulate Botulinum Neurotoxin along with the 'other side of the story'.

Read the full series here.

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Threadbare facelifts

After elevation of the flap,the healed excess ...
After elevation of the flap,the healed excess soft tissue and cartilage has been sculpted. (Photo credit: Wikipedia)

Thread implant is a semi-invasive ‘face-lifting’ procedure that has extricated from plastic surgeons grasp into the dermatologists office in the form of an office facelift. I recently saw two designs. One made of Polydioxanone is incorporated into a needle and the placing is as simple as giving a subcutaneous injection! The second made of Poly Lactic Acid (PLA) had bidirectional cones separated by knots for stability. The resorption starts after 2 to 6 weeks in both cases. I believe threads should have enough mechanical stability for lifting and durability for stimulation of collagen production. So in my opinion the first one can lift only the mind (but sometimes body may follow!). The second one may reposition the soft tissue in a superficial plane without addressing excess skin. I have also noticed a growing craze for gold not just in threads, but in various products as well. We shall explore the properties of gold soon.

Do you think gold has a role in cosmetic dermatology? 

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Interferon Gamma Release Assay

Recently Dr Vijay George asked about Interferon gamma release assay in the Dermatologists facebook group. I just googled a bit to learn more about the investigation, as I had absolutely no idea about this. I have put down few interesting things I found:

According to CDC guidelines an interferon gamma release assay may be used in place of (but not in addition to) a tuberculin skin test in all situations in which CDC recommends tuberculin skin test.

Interferon gamma release assays which measure the Th1-mediated immune response may pose a challenge even in clinical scenarios, such as pregnancy, in which Th1 immunity is altered. In cutaneous TB, this could be a problem as some of the cutaneous TB types show less immune response. So the sensitivity is unlikely to be more than Mantoux in Cutaneous TB. (My opinion)

The Mantoux skin test consists of an intraderm...
The Mantoux skin test consists of an intradermal injection of exactly one tenth of a milliliter (mL) of PPD tuberculin. (Photo credit: Wikipedia)
It does not cross react with BCG, Mycobacterium bovis, or Mycobacterium avium. But it cannot distinguish MTB from Mycobacterium marinum, Mycobacterium kansasii, and Mycobacterium szulgai. So it is more specific than the skin test.

I think, It will be helpful only to confirm MTB in a Mantoux Positive case with clinical suspicion. But only 1 visit is needed and the inter-observer interpretation variability is less.

I found out from the lab that it costs about US$ 230/-.

BTW, one of the first articles I read was about the use of IGRA in pregnancy. Their conclusion started like this:
Comparing the tuberculin skin test and interferon gamma release assay results in pregnancy.
That would be a very risky comparison indeed! :-)

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Beauty of Dark Hair

chemical structure of melanotan-I
chemical structure of melanotan-I (Photo credit: Wikipedia)
This is part 2 of the theoretical exploration of a biomimetic alpha-MSH agonist that can reverse graying of hair. The product will be called 'The Bang'. Please read Part 1 here.

I was basically trying to find answers to few pertinent questions from their promotional material.

1. How do they make a biomimetic MC1R ligand follicle specific? MC1R is not confined to follicles after all!

2. Do they have clinical evidence to actually prove the claims?

3. How does this not-so-short peptide molecule penetrate the skin and bind to follicular melanocytes?

4. Do they make any 'cosmetic-company-like' claims? It is very common for cosmetic companies to make claims without any connection with their story-line for the proposed mechanism of action.

Here is what I think..

1. I don't know. They don't provide any information in the promotion material. Theoretically it is possible by exploiting the structural differences between alpha-keratins in the hair and the keratins in the keratinocytes.

2. No. They don't, at least not at this stage. All the studies they mention in their brochure are ex-vivo studies. Ex-vivo studies cannot assess the effect of cutaneous penetration and systemic toxicity. Attempt to use surrogate markers like cAMP in the evaluation of a cosmetic, needs to be viewed with suspicion. Besides demonstration of efficacy is not an FDA requirement for a cosmeceutical.

LTQ Mass Spectrometer for Peptides
LTQ Mass Spectrometer for Peptides (Photo credit: EMSL)
3. Penetration is a big challenge for peptides like this. But formulation optimization by adjusting the lipophilicity and charge may do the trick. May be they are using penetration enhancers as well. In any case mechanical penetration enhances like dermarollers may be useful too.

4. Yes, They do! According to the brochure the biomimetic peptide extends the life of hair colorant and gives hair protection, two important consumer needs. A natural color enhancer talking about extending the life of hair colorant is a cause for concern!

Dr Ranju asked a very interesting question in the Dermatologists facebook group? Can this be used before laser hair reduction to improve the outcome? It depends on the answer to question 1. If it is follicle specific, that is a really good idea.

Here is what I shall do next....

I  will explore the structure of 'The Bang' with my informatics friends on my informatics blog here, to find answers to the following questions:

1. How similar is it to Afamelanotide?

2. Does the structure of 'The Bang' favour follicular binding? Can we improve it further? (This should answer Dr Ranju's question)

3. Is the structure optimised for cutaneous penetration?

Here is what You can do.... :)

1. Please comment, if you have practical experience with the bang.

2. Please share this with 'The Bang' guys! :)

3. Join the Pigment Map Project (PMP) [click here]

We shall share this with the Pigmentary Disorders Society for their comments. BTW they are organising the first Pigmentarycon. Details here.

GulfDoctor.net peel rating
My Rating: 3 peels
What is peel score?

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About Me

As a Dermatologist and Informatician my research mainly involves application of bioinformatics techniques and tools in dermatological conditions. However my research interests are varied and I have publications in areas ranging from artificial intelligence, sequence analysis, systems biology, ontology development, microarray analysis, immunology, computational biology and clinical dermatology. I am also interested in eHealth, Health Informatics and Health Policy.

Address

Bell Raj Eapen
Hamilton, ON
Canada