April 2nd 2018
Researchers might have finally found the trigger for autoimmune diseases. Given that rosacea has most likely (although not yet proven) an auto-immune element to it, this could be interesting for rosacea patients too. Scientists have identified a chain reaction that explains why our own bodies can turn against our own healthy cells. The reaction, discovered in 2017 after four years of research in mice, has been described as a "runaway train" where one error leads the body to develop a very efficient way of attacking itself. The study focused on B cells gone rogue. Normally these cells produce antibodies and program our bodies' immune cells to attack unwanted invaders (or foreign substances; think of viruses or bacteria). An autoimmune disease is a chronic inflammatory condition caused by a person’s own immune cells, which mistakenly believes the body is under threat and so responds by attacking the bodies' own healthy cells and tissues.
Scientists found an 'override switch' in mouse B cells that messed up this behaviour and caused autoimmune attacks. "Once your body's tolerance for its own tissues is lost, the chain reaction is like a runaway train," said one of the team, Michael Carroll from Boston Children's Hospital and Harvard Medical School. "The immune response against your own body's proteins, or antigens, looks exactly like it's responding to a foreign pathogen." These B-cells-gone-awry could in turn explain the biological phenomenon known as epitope spreading, where our bodies start to hunt down different antigens that shouldn't be on the immune system's 'kill list'. Epitope spreading has long been observed in the lab but scientists have been in the dark about how it happens, and why autoimmune diseases evolve over time to target more and more healthy organs and tissues. In this case the research looked at a mouse model of the lupus autoimmune disease, considered an archetypal or 'classic' type of autoimmune disease that many others are based on. Lupus is known as 'the great imitator' because the disease can have so many symptoms resembling other common conditions and because it affects many organs. When B cells sense a foreign body – or something healthy that appears to be a foreign body – they swing into action in clusters called germinal centres. Those centres are why your lymph nodes become swollen when you've got a cold coming on, for example. B cell clones actually battle each other inside these centres so the body can determine which antibody is best suited to fight the threat, and in the case of this study that meant one colour of protein winning out against the others. The problem comes when the body incorrectly identifies a normal protein as a threat. When that happens, the B cell selection process produces what are known as autoantibodies that prove very effective at harming our own bodies. Over time, the B cells that initially produce the 'winning' autoantibodies begin to recruit other B cells to produce additional damaging autoantibodies – just as ripples spreading out when a single pebble is dropped into water. This has only been examined in mice so far, but the researchers now want to use this confetti model to look at how B cell production of autoantibodies is regulated and gets sped up. Autoreactive B cells are competing inside germinal centres to design an autoantibody, but the immune response then broadens to attack other tissues in the body, leading to epitope spreading at the speed of wildfire. Hence, why people with one auto immune disease so often develop more and different ones over time. Eventually, blocking the germinal centres in some way could put a break on the vicious cycle that autoimmune diseases create. It would effectively block the immune system's short term memory. Unfortunately, as always, that kind of treatment is still a long way off.
And there is more new research on auto immune diseases: a team of researchers from Yale University has linked autoimmune reactions to a bacteria in the gut called Enterococcus gallinarum. An autoimmune response, they say, can be triggered when the bacterium spontaneously migrates from the gut to other organs in the body, such as the spleen, liver, and lymph nodes. During the study, the researchers genetically engineered mice to be susceptible to autoimmune diseases. They then analyzed the gut bacteria to identify those that caused inflammation or were involved in the production of antibodies known to promote autoimmune responses. The culprit was Enterococcus gallinarum. The results were confirmed when they compared cultured liver cells of healthy people versus those of people with an autoimmune disease and found traces of Enterococcus gallinarum in the latter group. The researchers weren’t just able to identify the source, they also developed effective ways to reduce autoimmune symptoms. By using antibiotics or a vaccine, the researchers dulled symptoms by suppressing the growth of Enterococcus gallinarum. The vaccine was delivered through injection in muscle to avoid targeting other bacteria that reside in the gut. It is hoped that this research can be developed into successful treatment options with an antibiotic and other approaches such as vaccination for certain autoimmune diseases, including autoimmune liver disease and systemic lupus.
April 1st 2018
I read that after the information revolution, we are now heading towards the revolution of genetic engineering. Scientists are experimenting with CRISPR; programming plant- and human- and animal cells and doing DNA surgery. CRISPR allows scientists today already to cut and paste in DNA strands. Like a programmable scissor, that can recognize a certain spot on the genome of an organisms, and modify the genome at will. The technology is based on Dutch research about little parts of DNA in bacteria, called CRISPR. Bacteria suffer from viruses too, like us. When a virus hits them , it releases DNA into the bacteria, in order to create more viruses. But bacteria have their own defense system, CRISPR/cas, which allows them to recognize the DNA from viruses and to find it and then cut to pieces.
Emmanuella Charpentier came up with a similar system to cut and paste DNA from organisms (CRISPR cas9). DNA consists of 4 substances, given the letters C, G, A and T. The order of these substances dictates the genetic code of a cell. CRISPR can accurately read this info and change it. It allows DNA reprogramming through cutting and pasting in any cell, not just in virus DNA. She and her colleague Jennifer Doudna are up for a Nobel prize apparently, and won a lot of other prizes already for this discovery. They studied evolution, to change evolution. Rewriting our own genetical make-up. Reprogramming viruses, like an app would do; viruses are software anyway, like a memory stick, loaded with specific information, and once it attaches to a physical structure, that allows the virus to load its program onto the cell. That program is nowadays: print more viruses. But viruses could also be loaded with a different message, one that we as humans find interesting to program into the cell. For instance; make this protein, because it is a good drug for us, or load the program into a cancer cell and program it to die. Viruses can be reprogrammed and are like software; like an app. And viruses today are designed, from scratch, in order to make biological programs with new applications possible. All cancers have different DNA, but some people are already working on viruses that are adjusted to very specific tumour genetics. Special DNA printers can then print that DNA and put it in viruses. Every cancer patient can this way get a personalized cancer drug. Digital synthetic virus designs and it's already tested on dogs with cancer. An epi-pen for all of us, uploaded by the doctor and auto-inject. Personalized medicine. It's going to happen eventually. A medical netflix subscription with which you keep your body healthy. Soon we can print medication and change ourselves genetically (I can't wait for that, hopefully before my old age they can cut out my genetic illnesses, ruthlessly!). People are trying to write programs now that eradicate cancer cells. Science students could soon have opportunities that today only pharmaceutical companies have.
Hopefully the technology can repair genetic diseases, now that so many illnesses have been mapped DNA-wise in the past decade. But between a discovery in the lab, and using that discovery to develop a new technology and usable medication, there are usually around 20 years... It is also very expensive, so scientists are told to only go after the largest diseases and disease groups. But hopefully soon all the DNA errors that switches on genetic diseases can be identified and put into switch blocks and be eradicated or changed. And to build new biological constructions with them. Some people are already making and selling CRISPR-kits, for geeks to use at home; bio hackers (instead of computer hackers). Genetic engineering, in order to experiment, for instance with trying to make muscle mass grow. Changing your skin- or hair colour, growing more or less hair. Or attempting to have humans grow wings. Ultimately all the knowledge should be shared and people should be able to create the same stuff as pharmaceutical companies, but at a much better price. There is already genetic experimenting done on human embryo's now.. At a very early age when they are just a couple of cells. The worry is that technology will be used to make designer babies. Of course you could wait for the moment that there are fights erupting about the patenting of (parts of) this CRISPR technology, which is going on right now. And many companies have started working on the technique and on the treatment of certain diseases, but out of fear that someone will steal their inventions or know-how, they do not share any of with with other companies or scientists. Which holds back the entire development pace. Not just a few companies (Editas, Caribou and Crispr therapeutics), but also especially big universities in the USA can gather enough money (hundreds of millions of dollars with each round) to have teams of hundreds of the best people around working on this technique now. Editas, Caribou and Crispr therapeutics can become the new Google and Apple of the future if the CRISPR technology turns out to be effective and profitable.
April 1st 2018
Researchers under guidance of Richard Gallo from the University of California, San Diego, might have figured out why bacteria only causes acne in some people, and how to stop it. Pretty much all of our skin is covered in bacteria always, as a skin defense system against germs. Usually there is a balance and symbioses going on, and we don't get acne from it, but some people are more prone to such infections. Gallo and his colleagues showed that a usually harmless bacterium that lives on our skin starts triggering inflammation and breakouts when it finds itself trapped in airless, oily conditions, such as hair follicles. Everyone has hair follicles in their skin, but not all hair follicles are the same and created equal. Dr. Gallo and researchers now suspect that some people might have hair follicles that are more "suffocating" than others. The researchers specifically looked at a type of bacterium known as Propionibacterium acnes, which can cause acne breakouts.
"Most of us have P. acnes on our face all the time, but it doesn't always cause breakouts. So the team tested the bacteria under a range of conditions on the skin of mice to try and figure out what was going on. They showed that when trapped in airless environments alongside hair and skin cells, P. acnes turned sebum - the oil found on our skin - into fatty acids that activate inflammation in nearby skin cells. Usually this inflammation is switched off by enzymes called histone deacetylases, but the fatty acids produced by the bacteria deactivated that brake, so inflammation continued unchecked - going on to cause red, itchy breakouts. So far, the research has only been done on mice, but the team is now looking to replicate their results in humans, and they're hopeful that the inflammation pathway involved will be the same."
"For the first time, it shows how fatty acids derived from P. acnes act on skin cells to induce inflammation," Holger Brüggemann, an expert on skin bacterium from Aarhus University in Denmark, explained. New findings could also explain why teenagers are so prone to breakouts, because their sex hormones during puberty put their sebum production into overdrive, giving P. acnes more fuel. The bad news is that cleaning your face regularly isn't the answer, because the team showed that the bacteria clump together to form structures called biofilms, which effectively locks them onto your skin. And, when this type of bacterium isn't causing havoc inside suffocating hair follicles, P. acnes is actually beneficial to skin health, which explains why antibiotic treatments don't work for many people - and in some cases, can actually make things worse. But now that the team understands the root cause of the inflammation, they're confident they'll be able to come up with new treatments for acne. "We can either inhibit these fatty acids, or block their impact on the skin," Gallo told New Scientist. "We're working on how to do this ... If we get lucky, it could lead to new medications in two to five years."
March 15th 2018
New class of menopause drugs reduces severity of hot flushes in three days
A new class of experimental drugs reduces hot flushes in menopausal women by almost three-quarters in just three days. The treatment, tested by scientists at Imperial College London, also reduces the severity of hot flushes by over a third within three days of taking it. The research, funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR), is a new in-depth analysis of data collected from a clinical trial initially published last year. This class of new drugs may provide women with a much-needed alternative to HRT, but it could also be an interesting new treatment on the horizon for people with vascular rosacea and facial flushing. Other medication aimed at reducing the severity of hot flashes (for instance clonidine, mirtazapine, other SSRI-antidepressants and certain beta blockers) all are prescribed by various dermatologists to try to curb facial flushing, a difficult to treat rosacea symptom. The original drug trial, which was a randomised, double-blind, placebo-controlled trial, involved 37 menopausal women aged between 40 and 62 years old – and who experienced seven or more hot flushes a day. Participants were randomly chosen to first receive either an 80mg daily dose of the drug, called MLE4901 (which was previously developed as a drug for schizophrenia) or a placebo over the course of a four-week period. They then switched to receive the other tablet for an additional four weeks. This ensured the women acted as their own controls during the study, and the effects of the drug were clear. The researchers found that the compound MLE4901 significantly reduced the average total number of flushes during the four-week treatment period, as well as their severity, compared to when the patients received the placebo for four weeks.
The new experimental compounds are thought to work by blocking the action of a brain chemical called neurokinin B (NKB). Previous animal and human trials have shown increased levels of NKB may trigger hot flushes. The drug compound is thought to prevent NKB activating temperature control areas within the brain – which appears to halt hot flushes. The new data also revealed that the drug was as effective at improving daytime flush symptoms as it was at improving night time symptoms. Furthermore, the women reported a 82 percent decrease in the amount their hot flushes interrupted their sleep, and a 77 percent reduction in interruption to their concentration. Dr Julia Prague, first author of the study, explained: “As NKB has many targets of action within the brain the potential for this drug class to really improve many of the symptoms of the menopause, such as hot flushes, difficulty sleeping, weight gain, and poor concentration, is huge. To see the lives of our participants change so dramatically and so quickly was so exciting, and suggests great promise for the future of this new type of treatment.” The new analysis shows the compound has a significant
effect within just three days explains Professor
Waljit Dhillo, an NIHR Research Professor from the Department of Medicine at Imperial: “We already knew this compound could be a game-changer for menopausal women, and get rid of three-quarters of their hot flushes in four weeks. But this new analysis confirms the beneficial effect is obtained very quickly – within just three days.” Professor Dhillo explains this specific compound will not be taken further in trials, due to side effects that may affect liver function. However, two very similar drugs, which also block NKB but do not appear to carry these side effects have entered larger patient trials, with one such trial launched in the US last year. The research was funded by the Medical Research Council and the National Institute for Health Research. The study was supported by the Imperial NIHR/Wellcome Trust Clinical Research Facility.
Update: due to side effects the research of this anti hot flash drug seems to have currently stalled, sadly enough... https://en.wikipedia.org/wiki/Pavinetant
March 12th 2018
In this good research paper, scientists summarized the treatment options for neurogenic rosacea; rosacea subtype 1 with skin redness (erythema), skin burning and flushing.
It states that this rosacea subtype requires a unique approach of management. In the paper, typical symptoms and triggers are mentioned for people with this type of rosacea, based on 14 test persons:
"Prominent symptoms included burning or stinging pain (100% [14 of 14]), erythema (skin redness) (100% [14 of 14]), and flushing (93% [13 of 14]), sometimes accompanied by facial edema (skin swelling) (50% [7 of 14]), telangiectasias (visible blood vessels in the skin) (50% [7 of 14]), pruritus (43% [6 of 14]), and papules (36% [5 of 14]).
Important symptom triggers included heat (93% [13 of 14]), sunlight (93%[13 of 14]), hot showers (79% [11 of 14]), stress (71% [10 of 14]), exercise (64% [9 of 14]), and alcohol consumption (57% [8 of 14]). Use of makeup (50% [7 of 14]), eating spicy foods (43% [6 of 14]), touching skin (36% [5 of 14]), drinking hot beverages (29% [4 of 14]), cold weather (21% [3 of 13]), and humidity (14% [2 of 13]) were less reliable triggers. Notably, 71% of patients experienced relief from cooling via fans or cold compresses or ice applied to the face or held in the mouth (10 of 14).
|Facial erythema is seen in most patients at baseline and uniformly during flares. Inflammatory papules and pustules and rhinophymatous change are unusual in this subset of patients.|
In the paper it is written that of the examined patients with neurogenic rosacea, a high percentage had neurologic (43% [6 of 14]) or neuropsychiatric (50% [7 of 14]) conditions, including complex regional pain syndrome, essential tremor, depression, and obsessive-compulsive disorder. Neurovascular disorders, including headaches (71% [10 of 14]) and Raynaud phenomenon (29% [4 of 14]), as well as rheumatologic disorders (36% [5 of 14]), including lupus, rheumatoid arthritis, fibromyalgia, mixed connective tissue disease, and psoriatic arthritis, were also common. Many patients had tried the following treatments with limited success:*Topical metronidazole (0 of 12 were helped)
*Topical steroids (1 of 8)
*Oral antibiotics, usually tetracyclines (4 of 8).
Most patients benefited from treatments that tried to calm the burning pain down, for instance gabapentin (5 out of 11), duloxetine (4 of 6), pregabalin (1 of 4), tricyclic antidepressants (2 of 3), and memantine (2 of 2). Topically creams were only occasionally effective, for instance doxepin, glycopyrrolate, amitriptyline, capsaicin, and ketamine.
*Hydroxychloroquine (Plaquenil) (3 of 5)
The researchers also added that this group of patients with strikingly prominent neurologic (nerve pain) symptoms, are an underrecognized subgroup of rosacea. By highlighting and formally naming this subgroup, they hope to increase awareness and recognition of these patients and aid the practicing dermatologist in their therapeutic management. The cause of rosacea is complex, poorly understood, and likely multiple causes and factors, including bad functioning blood vessels in the facial skin and with most likely an auto-immune aspect to it. Also the nerves in the skin are no longer functioning as they should with this rosacea type. There is an element of abnormal response to heat and an increase of inflammation in the skin. And the injury of the nerves in the skin of rosacea patients with this subtype 1, also leads to dysesthesias: an abnormal sensation in the skin, of pain, skin burning, wetness, itching, electric shock, and pins and needles. It is sometimes described as feeling like acid under the skin.
"Patients with prominent vasomotor symptoms, defined clinically by flushing and telangiectasias, may respond to vasoactive medications, including β-blockers, alpha-1 adrenergic blockers, and calcium channel blockers. In addition, laser- and light-based therapies seem to be more effective in this subset of patients.
Patients with inflammatory features such as papules, pustules, or edema may respond, if symptoms are mild, to traditional topical therapies such as metronidazole, azelaic acid, or sulfur. Systemic antibiotics and antimalarial agents used for their anti-inflammatory effect may be useful for nonresponders.
Finally, patients with dysesthesia out of proportion to flushing or inflammation can be difficult to treat and require a unique approach first used to treat disorders such as complex regional pain syndrome and neuropathic itch. In our experience, neuroleptic agents (eg, gab-apentin, pregabalin), tricyclic antidepressants, and pain-modifying antidepressants (eg, duloxetine) are the most effective. N-methyl-D-aspartic acid receptor antagonists (eg, memantine), systemic antibiotics, and other topically formulated medications (eg, ketamine, glycopyr-rolate, capsaicin) may be helpful in certain cases. Because of the associated heightened sensitivity to heat and sunlight, laser- and light-based interventions should be used with caution.
Because our understanding of this enigmatic subclass of rosacea is extremely limited, further research is clearly needed to better describe the underlying patho-physiologic characteristics and to identify additional effective treatment methods."
September 12th 2017clinical trials for Secukinumab, used to treat rosacea. It is an open label study to assess the effect of Secukinumab in moderate to severe papulopustular rosacea. However hopes are that it will also address rosacea redness and inflammation. Test participants receive injections of secukinumab. First impressions from one rosacea patient who is undergoing these tests were: "Redness was almost completely gone by Saturday afternoon. [one day post injection]. The doctor says full results are shown anywhere from 12 to 16 weeks."
Update from this rosacea patient, September 29th 2017: "Secukinumab update:
So this thing has really worked immensely. My redness is gone and I'm going back to Stanford medical center to get my 5th dosage. I'd recommend everyone in this group if you can get there, to do so. So you can finally rid yourself of this disease."
Secukinumab is a "human IgG1κ monoclonal antibody" that binds to the protein interleukin (IL)-17A. It is injected once weekly for four weeks (or around 5 booster shots) and then once a month for 5 months. It works a bit like methotrexate; suppressing the immune response and inflammation. Secukinumab lowers the bodies immune response and is used to treat auto immune diseases like psoriasis and related inflammation in the joints (artritis psoriatica). In psoriasis the bodies immune system goes in overdrive, and multiplies the skin cells too quickly, causing plaques of skin, inflammation and scaling and ultimately a lot of skin cell shedding. By lowering the immune system response, the skin symptoms can be calmed down too. Rosacea does not have an issue usually with increased skin cell formation, but some scientists do think that rosacea can be an auto immune disease as well, having the bodies own immune system attacking normal tissue and as such creating inflammation and redness. I know of some severe rosacea sufferers who were given methotrexate and who had their skin issues (redness, flushing) calm down significantly. Side effects can be significant
however, increased risk of infections (viral infections, nose and throat infections, sinus infections and other infections) and it even raises the risk of certain cancers. That is generally the downside of methotrexate. Luckily Secukinumab does not seem to come with an increased risk of cancer. Several studies show that secukinumab demonstrates "a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer."
2016 study also showed that secukinumab seems to be effective in the treatment of multiple sclerosis. I am a bit hopeful for this new trial! I know that my dermatologist treated some very severe rosacea patients with methotrexate for a little while, and their skin really cleared up (also through suppressed immune response and inflammation), but that the increased risk of infections was too tricky. Since secukinumab does not have that side effect profile as much, it seems a great alternative.
Open Label Study to Assess the Effect of Secukinumab in Moderate to Severe
Anti-CGRP migraine drugs for rosacea treatment
From Science magazine: "Four pharmaceutical companies are racing to complete advanced clinical trials of antibodies that either neutralize CGRP by binding to it, or block its receptor. So far, the data suggest the drugs work faster, for longer, and better than anything currently available. Most striking, is a subset of “superresponders,” whose attacks appear to cease entirely for 6 months after a single injection of a CGRP-blocking antibody."
CGRP is a 37–amino acid (neuro)peptide that is released by the nervous system and is a very potent blood vessel dilator. When released from the trigeminovascular nerves, CGRP is a powerful vasodilator of the blood vessels of the brain. Medication that was designed to block CGRP’s receptor turned out to have too many side effects. Then researchers focused on antibodies to block CGRP, because they can last a long time in the body and can be exceptionally specific, reducing the frequency with which people need injections. many colleagues didn't think it was worth a shot, because antibodies are generally too large to pass through the blood-brain barrier, and it was thought to be necessary for migraine meds to target migraines actually in the brain. However, to their surprise, the CGRP peptide-blocking antibody "TEV-48125" managed to just do this; treating migraines from outside the brain, by blocking CGRP only in the peripheral nervous system. Trials show significant reductions in number of headache days over placebo, even for the most severe cases. This type of drug also lowers the risk of the side effects often provoked by drugs that act in the brain. Although there are still worries too, because of CGRP’s natural role in dilating arteries and maintaining blood supply to the heart and brain. “Theoretically, if you block CGRP you could translate a minor stroke or cardiac ischemia … into a full blown stroke or heart attack.” So far, the companies say they haven’t seen that or other significant side effects in the several thousand people who have completed phase I and II trials, but the drugs have only been administered for up to 6 months—not long enough to judge long-term effects. CGRP-blocking drugs are also tested now for fibromyalgia, a condition that is
somewhat overlapping in some symptoms with rosacea. And scientists have also discovered that CGRP plays a role in rosacea flushing and skin redness. Interestingly, migraine medication has so far been helping some people with rosacea. Drugs like propranolol, imitrex/sumatriptan and even botox have all been helpful for rosacea. Someone on the Rosacea Forum is successfully using the migraine med Maxalt/Rizatriptan for her severe type 1 rosacea/erythromelalgia.
Stress, rosacea flares and CGRP
CGRP is also part of the puzzle as to why stress can make rosacea flare so badly. Apart from stress raising blood pressure and inflammatory substances, experiments in rats now showed that corticotropin-releasing hormone, which the body releases in response to stress, also increases neuronal production of CGRP. More CGRP means much more blood vessel dilation, which causes our rosacea flares (for those with burning, flushing and redness). Strikingly, many migraine medications also boost CGRP in animal models, possibly explaining why people who use drugs like triptans too frequently end up with more severe migraines.
CGRP antagonistic treatment options for Rosacea
A patent is created for a special cream for rosacea patients to do just that. 'Therapeutic/cosmetic compositions comprising CGRP antagonists for treating skin redness/rosacea/discreet erythema.' But they are not just focusing on a CGRP blocker: "Skin redness, rosacea and/or discreet erythema afflicting a mammalian, notably human patient, are therapeutically treated by administrating to such patient a therapeutically/cosmetically effective amount of at least one CGRP antagonist, advantageously in combinatory immixture with at least one antagonist of a neuropeptide other than CGRP, e.g., a substance P antagonist, and/or at least one inflammation mediator antagonist."
So this patent for a new cream will focus on three different things;
*blocking CGRP (and thus blocking one factor that leads to blood vessel dilation in our faces)
*blocking P antagonist
*blocking an inflammation mediator in the skin
CGRP is a polypeptide chemical species that is produced and released by nerve endings. CGRP dilates blood vessels and is involved in lung issues and inflammatory diseases, in allergic diseases and in certain skin diseases such as eczema and prurigo. It is a new concept to treat skin redness with a CGRP antagonist. But developers now think that CGRP blocking substances can not only treat skin redness, but also prevent it from occurring. Blocking CGRP in the skin of our faces, through a cream, should help combat skin redness and flushing. This will be tested on test persons with rosacea, by first inducing a flush (with a substance called capsaicin), and then applying the cream and seeing if the redness can be toned down by it. They will test if the levels of CGRP that is released (and that cause blood vessel dilation), will be reduced upon measuring. Secondly, P antagonist will have to be another type of antagonist of a neuropeptide used, reinforcing the CGRP antagonist. A third ingredient will have to reduce inflammation in the skin (and they will select it from a group consisting of histamine antagonists, interleukin 1 antagonists, and tumor necrosis factor alpha antagonists, and the inflammation mediator antagonist is supposed to be a diethylenediamine, aminopropane or phenothiazine compound, selected from a group consisting of cinnarizine, cyclizine, dexchlorpheniramine, triprolidine, alimemazine, promethazine, auranofin, lisophyline, A802715, sulfasalazine, cetirizine hydrochloride, loratidine, esbatine, and setastine hydrochloride).
The patent described rosacea as follows:
"Rosacea is a skin affliction characterized by erythema (redness) of the face, predominantly on the cheeks, the forehead and the nose, hyperseborrhoea (thickened skin) of the face on the forehead, the nose and the cheeks, and an infectious component manifesting acneiform pustules (skin outbreaks and bumps). Moreover, these indications are associated with a neurogenic component, namely, a cutaneous hyperreactivity of the skin of the face and of the neck (nerve burning), characterized by the appearance of redness and subjective sensations of the itching or pruritus type (skin itching), sensations of burning or of heating, sensations of stinging, tingling, discomfort, tightness, etc.
These signs of hyperreactivity may be triggered by very varied factors such as the intake of food or of hot or alcoholic drinks, by rapid temperature variations, by heat and in particular exposure to ultraviolet or to infrared irradiation, by a low relative humidity (dry air), by exposure of the skin to strong winds or to currents of air (conditioned air, fans and blowing machines), by the application of surfactants (soaps, washing detergents), irritant dermatological topical agents (retinoids, benzoyl peroxide, alpha-hydroxy acids, etc.), or the use of certain cosmetics, even when these are themselves not recognized as being particularly irritating.
Hitherto, the mechanism for triggering these indications was very poorly understood and rosacea was treated with active agents such as anti-seborrhoeic agents and anti-infection agents, for example benzoyl peroxide, retinoic acid, metronidazole or cyclins, which act on infection and hyperseborrhoea but do not permit the neurogenic component of this affliction, and in particular hyperreactivity of the skin and redness, to be treated. Similarly, hitherto no treatment existed for the redness which develops in discreet erythema. This latter affliction occurs at times of emotion and is characterized by redness of the face and neckline, which possibly may be accompanied by pruritus (itching). This condition is very irritating for individuals suffering therefrom, and to date it could only be treated by beta-blockers, powerful drugs used for treating hypertension and exhibiting many contraindications.
Thus, serious need continues to exist in this art for an effective treatment of skin redness and of the state of hyperreactivity of skin affected by rosacea or discreet erythema." The patent acknowledges that their invention does not necessarily have to be applied through a cream on top of the skin: it is also possible to inject the CGRP antagonist into the skin, or even to take pills to achieve the same effect. They aim for a acceptable cream carrier, but the problem with most creams is that they contain alcohols (they help the active ingredient to penetrate deeper into the skin) and preservatives (parabens for instance, which are skin irritants). And some companies even put propylene glycol and plastic elements into their creams, which make them pretty much unusable for those with hyper reactive, intolerant rosacea skin. In the examples for cream ingredients that are mentioned in the patent itself, the list seems fairly OK to be honest, the only ingredients I wouldn't tolerate myself (but my skin is sickly reactive) are sunflower oil (12%), stearic acid, fragrance (if they are smart they leave that one out!) and preservatives.
CGRP and Rosacea
suggested to be controlled by two vasodilatory mechanisms including humoral substances and neuronal stimuli (Wilkin, 1988), but the exact mechanism of action is unknown. Although scientists learn increasingly more over time about how sensory nerve endings are activated to release vasoactive neuropeptides during flushing, which also triggers the inflammatory process in different stages of rosacea. Specific TRP Channels are involved in this.
This newly discovered TRP channel receptor family is currently composed of 28 channels with seven subfamilies. They sit on neuronal and non-neuronal tissues all over the body. One in particular is interesting for rosacea, as it is singe handedly capable to cause a lot of blood vessel dilation. It is called vanilloid 1 (TRPV1), also known as the “capsaicin receptor”. It has many functions, including as a censor in cells, signalling pain sensations and inflammation. This receptor responds to a lot of triggers, including heat, cold temperatures, touch and changes in the cell membrane.
TRP Channels as Thermosensors in Rosacea?
Both TRPA1 and TRPV1 channels are triggered by heat and temperature increase. It is no surprise probably that 53% of rosacea patients stated in polls that hot and cold weather are triggers for their rosacea. Very cold temperatures can also directly activate TRPA1 channels. Perhaps TRPA1 is a “cold sensor” channel. Another TRP channel (melastin) TRPM8 is also activated at temperatures below ∼23 °C. So when you are hypersensitive for the cold, it is most likely this TRPA1 channel deep in your body cells, that is responsible! (Just so you know how to blame haha). Anyway, the cold can also cause inflammation in rosacea skin.
But heat is just as much a trigger for rosacea. Heat, sun, hot baths; they all dilate out blood vessels as our body temperature rises. And rosacea skin already is a little bit warmer than 'normal' skin temperature. When the temperature rises quickly, even in healthy people, our cells produce TRPV1. Therefore TRPV1 channels have an essential role in temperature hypersensitivity when it comes to inflammation. And on top of all this, rosacea facial skin has shown to have a significantly lower heat pain threshold compared to the rest of our skin. Our faces notice heat quicker and develop painful skin much quicker (tingling, burning, prickling, blushing, pain) when we are in a warm surrounding than the rest of our bodies skin. I think everyone had detected that for him or herself already anyway :) And again, our little friend TRPV1 seems to be involved in this. The same goes for flushing after eating spices TRPV1 is dubbed the "capsaicin receptor", because it is directly activated when someone eats capsaicin, which is the chemical that makes chilli peppers so hot. The same happened in trials with mice; capsaicin also stimulates an increase in mouse skin blood flow, which shows that this blood flow increase is triggered ultimately by TRPA1 stimulation. TRPA1 is triggered by cinnamaldehyde, the main ingredient of cinnamon, which also leads to intense and acute painful burning sensation. This is even the case by those who do not have rosacea, and the burning they can feel from this is probably similar to that observed in rosacea. These findings highlight that TRPA1 and TRPV1 may be activated by the triggers of rosacea, such as cold or hot temperatures and spices, to mediate flushing or burning sensation episodes of rosacea.
Another aspect that makes rosacea skin burn and flush, is blood flow. Flushing longer than 10 minutes is indicative for rosacea (and therefore 'not normal' for normal skin). The smallest systems of blood vessels in our body are dilated in rosacea patients. TRPA1 is also here a factor. It sits in the basal layer of the epidermis, in the dermis, and in the epithelium of the hair follicle, so basically all throughout our skin. And when this TRPA1 is activated (for instance through heat, cold, stress, spices), a substance called "proinflammatory cytokine IL-1" is released, which is a key contributor to skin inflammation. Our skin actually recovers from such a TRPA1 triggered rosacea attack, by exposing our skin to cold air. Apart from more blood flow in the skin, rosacea patients in studies also showed heightened sympathetic nerve activity compared to those without rosacea. The sympathetic nervous system is a part of the body’s autonomic nervous system that controls involuntary functions such as heart rate, digestion, breathing and perspiration. This portion of the autonomic nervous system functions largely below the level of consciousness and has been shown to respond to emotion.
Substance P and CGRP in Rosacea
So, studies have shown that activation of TRPV1 (by capsaicin) and TRPA1 (by mustard oil) caused the release of neuropeptides. Normal human skin that was rubbed in with a cream containing capsaicin, showed a big red flare. But, this flare could then controlled again by a specific TRPV1 antagonist, SB705498. And there is also a new oral CGRP antagonist,
telcagepant, which also managed to bring down a capsaicin-induced flushed skin reaction.
Ultimately, what makes our skin flare, is not TRPV1, but another chemical, that is triggered by TRPV1: called CGRP. CGRP is one of the strongest blood vessel dilators in the skin. And to make matters worse, it makes sure that your skin also has increased inflammatory substances as a result of all this extra blood flow going around. The neuropeptide SP is elevated in rosacea skin. They linger around the dilated blood vessels. Research showed that laser treatment reduced facial sensitivity, sensory nerve marker, and SP-positive nerve fibers in the skin of 31 rosacea patients. And there is also evidence that SP can also induce skin redness. When rosacea patients have an inflammatory flare, and biopsies are taken from their skin, scientists tend to find widely dilated blood vessels in the skin. SP might play a role in all this, as SP can stimulate mast cells to release histamine and 5-hydroxytryptamine. These mediators bind to histamine H1 receptors and serotonin 5-hydroxytryptamine-1 receptors, and as such they cause blood vessel dilation through the nerves of the skin. CGRP can make matters worse then, by forming skin redness. It is therefore a whole cluster of substances that work together to fire up a flare for us: CGRP creates blood vessel dilation and SP triggers skin redness, histamine release and inflammation, and they even strengthen each others powers by blocking degradation of each other by the body.
Proteases in Rosacea
It is also known that protease activity is higher in the facial skin of rosacea patients, and that antibiotics such as tetracyclines can indirectly inhibit (control) these proteases. Proteases also degrade elastin and collagen, which means your skin becomes less firm and strong and is not beneficial for the lymphatic system in your skin. They also indirectly increase inflammation in the skin, by stimulating the release of SP and CGRP. And in the last place, there is Reactive Oxygen
Species (ROS), which also seems to play a role in rosacea. Substance P can cause their release. There is evidence in the literature suggesting that inflammation in the early stage of rosacea may be linked with ROS such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, which are released by inflammatory cells such as neutrophils. The level of ROS was significantly higher in the facial skin of patients with rosacea compared with healthy control subjects, OR of the same rosacea patients after being treated with the antibiotic azithromycin. ROS is involved in microbicidal activity.
Studies have shown that cathelicidin, a potent inflammatory peptide, is upregulated in rosacea.
Cathelicidin can stimulate ROS, which plays a role in inflammation. And ROS is in turn again linked to TRPV1 receptor activation, which dilates our blood vessels and increases blood flow in the skin. It is a rosacea avalanche, in other words, when all working and activating each other together. And this is another reason why rosacea should be treated as soon as possible and controlled.
So in summary, TRPV1 and TRPA1 may contribute to the development of rosacea. The high skin reactivity of rosacea skin can be blamed on TRPA1 and TRPV1 receptors. When they are activated, they create blood vessel dilating substances such as CGRP and SP, as well as inflammation, which may further aggravate the symptoms of rosacea. They work together and strengthen each others actions. All the more reason to be very excited about this new treatment option; blocking of the neuropeptide-driven inflammatory processes resulting from activation of TRPV1 and TRPA1 receptors. This could become a completely new therapeutic approach to treating rosacea.
0,5% ketamine with 1% amitriptyline in a cream base..You use it topically and it apparently pales the skin. It also helps (more officially) with erythromelalgia, a health condition that also involves a deep red flushing and burned red skin of the legs, arms, chest etc. The cream has to be made by a compounding pharmacist. My doctor is looking for one right now, willing to make it, as it's not a commercial cream yet. Here is some more information on this cream:
-Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
Deansm wrote on December 2nd, 2016: "Cleared up my type 1 Rosacea (flushing red nose).
I have had flushing and swelling (caused by the flushing) on my nose for around 7 years (no pustules or pastules). Tried antibiotics, Soolantra, metrogel etc, nothing worked, every treatment has had absolutely zero effect. Two months ago the GP I am seeing prescribed me an ointment containing Ketamine 0.5% and Amitriptyline 1%. Withing 3 days of using it twice a day the flushing disappeared and my skin is white, the same as it was before Rosacea. It has been the same ever since for the last two months. I can eat, exercise, go out in the sun and nothing will bring on a flush. If anyone has this subtype and nothing has worked have a look into this, I have no side affects(the GP said it is very safe as the amount of active ingredients is too low and it's not absorbed systemically). I am not sure which or if both of the ingredients are working. I have since learned that topical Ketamine behaves as an anti-inflammatory by acting on Toll-like receptor (TLRs), which leads to down regulation of pro-inflammatory gene expression." [..] "The packaging has no branding, it was made in a compounding pharmacy. He said he has found it helpful going back years for patients with Erythromelalgia and it was worth trying for my Rosacea as nothing else worked."
Hg24 wrote on December 3rd, 2016: "This is really interesting, Dean. I googled and found reference to a study about this topical for erythromelalgia. The ointment seems to be for the pain (versus redness). I have type 1 rosacea, too. Flushing and permanent redness. Dean, you mentioned that your skin color is back to normal (pre-rosacea). So did you also have permanent redness? Or just the redness that comes on temporarily when you flushed? I guess I'm wondering if the ointment returned your vessels to normal - constricted them back. I wonder if the ingredients work because they address nerve pain. Nerves can stimulate our flushing. Eg, nerves release acetylcholine, a chemical that tells our vessels to dialate."
Deansm wrote on December 3rd, 2016: "I'm from Wales, I don't see any reason why it could not be prescribed in the other UK countries (The only problem I can think of is Scotland/Wales/England having separate devolved NHS bodies and rules etc). It probably is completely up to the GP, how many treatments you have already tried etc. He told me the ointment reduced redness and flushing on patients with Erythromelalgia(no idea what this was). I never expected this to work as every other treatment he presvribed (Soolantra, Antibiotics, Metrogel) has either done nothing or even made my Rosacea worse. [..] My Rosacea started (I was 24) as a sudden huge flareup (huge flushing episode) on my nose when I went to bed one night. I had never blushed or flushed on my nose before that first flareup. Ever since every night without fail I would have a flareup when I went to bed. Through the day I had one or two flareups and my nose was sensitive to flushing but not as bad as in the night. After each flare up it would take around 2-3 hours for my skin to return normalish in colour but there was always a slight pink hue on my nose. The worse symptom of all is the nose swelling for around 7 hours when I sleep and waking up every morning with a swollen nose. The flushing has stopped now and that stopped the swelling. My nose still looks a bit swollen but it's slowly going down now(2 months so far)."
Fiugs wrote on December 4th, 2016: "There is a topical with the brand name Epicept, although I think the compund's percentages are different than you describe, Deansm.
https://www3.rcsb.org/ligand/NP1. Did your GP indicate if s/he thought this would be a short or long term solution? Just wondering because I got the impression that some topical analgesics lose their effectiveness after a while.... I say that only based on what my local pharmacist told me in relation to a lidocaine based gel I was inquiring about; he said it would stop working after a while. I will certainly ask my GP about this! Thanks Deansm and all the best. I also found this article, referring to a compound using the same percentages as Deansm has been given http://jamanetwork.com/journals/jamadermatology/fullarticle/403191
Deansm wrote on December 4th, 2016: "From looking at the link EpiCept Cream is much stronger (2% ketamine / 4% amitriptyline), The cream I am on is 1%ami and 0.5%ket and it stops the flushing (the lower dose it works the better). Since my doctor said he had success with the ointement on patients with Erythromelalgia I have been reading a lot on Erythromelalgia forums about the safety of this cream (it seems very safe at low dose). I am not sure which ingredient (or a combination of both) is stopping the flushing, but this is something I found about topical ketamine.
https://www.practicalpainmanagement.com/treatments/pharmacological/non-opioids/topical-ketamine-ready-prime-time. Also from reading various Erythromelalgia forum posts, the vasodilation, flushing, redness are very similar to Rosacea, only it happens on the feet and hands and sometimes the face in Erythromelalgia. The only real difference over type 1 Rosacea as far as symptoms is the addition of more pain, stinging. It is interesting hearing about the other treatments they use on those forums to stop flushing that might also work for flushing on people with Rosacea."
Brady Barrows wrote on December 4th, 2016: "What a wonderful find to substantiate this thread. Note what the article says: "Erythromelalgia is a clinical syndrome characterized by attacks in which the affected limbs become bright red, hot, and excruciatingly painful. The common trigger is heat exposure induced by exercise or increased ambient temperature. As the condition progresses, the limbs become permanently red, hot, and painful. The pain of erythromelalgia, commonly described as hot and burning in quality, is frequently disabling, and patients obtain relief by lowering skin temperature, for example, by applying cold objects to the affected area, exposing the affected extremities to cold surfaces, immersing the limb in ice water, or by elevating the affected extremity. Frequently, these measures damage the skin, further exacerbating the pain, and occasionally cause maceration. Pain associated with erythromelalgia may be difficult to treat. Because erythromelalgia is not a single disease but a syndrome, the response to various treatments may differ depending on the underlying condition and pathophysiology. Furthermore, treatment of the pain symptoms may have little if any effect on the other manifestations (ie, the redness and increased temperature of the affected limbs). According to various theories, erythromelalgia is a vascular disorder or neuropathic condition. In previous studies, we have shown that both systems are involved, but we do not know which one is affected first. It is plausible that the vascular and neuropathic components differ in each subject depending on the underlying cause." Hopefully in the future we will know more if this treatment for erythromelalgia will be a standard treatment for rosacea."
Arsenalista wrote on December 5th, 2016: "Looks like another guy has also great results with this stuff.. https://www.reddit.com/r/SkincareAddiction/comments/5ggpha/beforeafter_dealing_with_rosaceaerythromelalgia/ I was read about Erythromelalgia (first time hear about it) and it looks like something very similar to rosacea but more painful. One of my worst symptoms is a chronic burning feeling at all my face. Damn, have to get the prescription."
I wrote on December 6th, 2016: "A very interesting find! I'm very curious if more people with facial (rosacea) flushing and burning will find relief from this cream. It's also a big bonus if your pharmacist can just add the powdered medication to your regular moisturizer. It's a fascinating distinction between facial erythromelalgia and rosacea. I'm not completely sure how you can detect one from the other, (apart from EM typically at the least affecting the hands and feet - but people with rosacea can get Raynauds (me too), which mimic these symptoms a lot), as these cases mentioned here look and sound pretty much like rosacea.
"A 53-year-old man presented to an outside dermatologist with an erythematous
facial eruption of 4 years' duration. The eruption was associated with burning and swelling,
which the patient reported worsened with sun exposure. These symptoms were debilitating,
preventing the patient from working and maintaining daily activities. Initially, the eruption was
thought to be rosacea and actinic damage; however, it was unresponsive to standard therapies."
"Upon further questioning, the patient reported skin burning not only with sun exposure, but also
with heat exposure. Furthermore, he reported attempting cooling measures, such as the frequent
use of ice packs, to relieve his symptoms. With these additional details, a clinical diagnosis of facial
and auricular erythromelalgia was established. Further workup excluded potential causes of secondary erythromelalgia. Given that erythromelalgia is thought to involve both small fiber neuropathy as well as vasculopathy, we initiated therapy with aspirin, pentoxifylline, and
gabapentin.1 Subsequently, nifedipine was added to this treatment regimen. At 5 months' follow-
up, the patient reported 80% improvement (Fig 2, B) and was able to return to work and enjoy
normal daily activities
With a picture:
Curious if aspirin, pentoxifylline and gabapentin together could help some of us too. And this woman seems to have serious rosacea, and she wonders whether or not she has erythromelalgia or rosacea;
And people with FIBROMYALGIA also mention rosacea symtomps more often: http://www.fibromyalgia-symptoms.org/forums/fibromyalgia_support_groups/beside_having_fibromyalgia_who_here_has_rosacea_/
Someone with fybro emailed me that her rosacea disappeared once she started to take guaifenesin tablets (a decongestant). Anyway, shows how complex these skin conditions are, there might be a lot of overlap and different factors at play. So curious to hear who else here might have benefit from this cream that is suggested."
RaymondS wrote on April 18th, 2017: "Didn't harm me but didn't help either. And it was a hell of a process to get the stuff. Just proves what works for one doesn't always work for another.
I will keep it and just use in one area to make sure that over time it works or doesn't.
But unfortunately it did not cure me."
Fiugs replied on April 18th, 2017: "Sorry to hear it didn't work for you either. I gave up on mine quite some time ago as it really aggravated my skin. It seems that only one person on our forum - the original poster - got marked results with this. It's truly weird, isn't it, that our skins are all so different! Every day I grow more of the opinion that there is no such single condition as Rosacea, but rather it's a blanket term for a red, irritated and sensitive flushy face, that may or may not include P&Ps, the unique cure of which is probably only going to be determined by the cause(s)."
Vice wrote on February 23rd, 2017: "Nobody should be worried about ketmamine having an effect. I take ketamine in powedered form recreationally and in my eyes 'medicinally'. It has an anti depressant effect and is currently being reviewed and researched as a breakthrough anti depressant for treatment resistant patients. It's a wonder drug really. The hallucinations are more distortions and only occur with high doses. - I personally love them myself. I am also trying to get the cream ointment and am in the middle of the process to getting it in uk now but it's difficult. Obviously I know it won't have any effect on my mind but it's still crazy that a drug I used systemically to get high might also be a good treatment for Rosacea! Who'd have thought!"