From Sjogren's to Leaky Gut to Menière's to Labyrinthitis - a proposed theory

I have come across a few published articles that cover the high incidence of systemic autoimmune diseases in patient's with Menière's Disease, for example [1, 2], but I always wondered if the other way around could also be a possibility. I mean, one of the health disturbing aspects I have seen reported in Sjogren's patients has to do with events of labyrinthitis (inflammation of part of the inner ear) or pressure put in the inner ear by a very inflamed parotid gland that can trigger vestibular disturbance (i.e., related to the inner ear and sense of balance). However, since Sjogren's is so intrinsically related to metabolism and diet, I have also learned of the nefarious effects caused by certain foods and beverages in a patient's balance, vestibular 'equilibrium' and an impaired digestive tract.

It is easy to establish a chain of consequences that is potentially triggered at any point of the affected physiological system, one that in a healthy person can be counteracted and re-established to normality, but that in an autoimmune one will have to be compensated with potential biological actions that can, on their own, eventually initiate particular imbalances elsewhere in the system. 

However, autoimmunity (where Sjogren's sits as a syndrome) appears to be quite associated with Menière's disease (a pathophysiology marked by vertigo, tinnitus, high pressure felt at the inner ear, and in grave cases even resulting in hearing impairment) [1]. Menière's can play episodically through events usually marked by inflammation at an associated contiguous point, even resulting in potential bilateral vestibular hypofunction (in the worst scenarios). But just as Sjogren's syndrome, also Menière's disease is a chronic condition, hence persistent and recurrent, where the associated vertigo episodes can last from a only a few minutes to excruciating long hours. Now imagine the impact on the performing of regular activities such as driving, operating machinery, walking, etc.

Where some doctors might immediately resort to prescribing prochlorperazine maleate or any other typical phenothiazine indicated for severe nausea, from a personal perspective a patient must also learn how to identify the triggers that typically promote the onset of such vestibular disturbance. In different examples to me presented, I had the chance to read that this can be very closely associated to dietary options alongside the typical promoters, such as stress, anxiety, opportunistic viral infections that take advantage of structurally-compromised tissues, and the consumption of desiccants (such as alcohol, spicy foods, etc.).

Add to all this the still quite abstract concept of leaky gut, a disorder that has not yet been fully clinically accepted and medically characterised, but one that it is thought to involve cracks in the intestinal tissue that will allow the passage of unexpected macromolecules to the blood stream... molecules that due to their size, composition and complexity were not supposed to be allowed in the circulatory system, and that will, therefore, promote physiological disturbance. It is extremely difficult to find literature to support the idea of a leaky gut, but the same people who have been blaming gluten for several metabolic and physiological ailments have now turned (no personal judgement here at all!) to the idea of a leaky gut - as the portal to disarray. From within a list of supposed complications one can identify the multifactorial Menière's disease [3]. And considering what the authors also debate, i.e., "that patients often complain of aspecific gastrointestinal symptoms associated with autonomic dysregulation, frequently outweighed by the otological manifestations", a recurrent cycle of afflictions is theoretically hereby established.

In a way, and as suggested in the image that I have edited and enclosed in the post, the metabolic dietary stressors will trigger a reinforced imbalanced immune response, that is already appanage of an autoimmune disease patient. However, in association with a debilitated gastrointestinal mucosa, be it in the stomach (as it occurs typically with reflux or H. pylori infections, for example) or at the intestinal tissue, the molecules unexpectedly absorbed into the bloodstream will add to the inflammatory dynamics and  this will potentially increase the implications of ongoing inflammation at the vestibular domain. Ergo, making the vestibular tissues even more vulnerable to opportunistic viral infections, and affecting the profile of the naturally-occurring crystals in the inner ear's liquids (the endolymph and perilymph), consequently affecting the audiovestibular moiety, adding to the incidence and seriousness of the reported "dizziness, generalised, imbalance, ataxia, motion intolerance, positional vertigo, oscillopsia, and episodic vertigo" [2].

In that sense, it is my personal belief that dietary changes need to account for the supposed 'leakiness' of the gut, and might be able to help reduce (not cure!!!) the episodic occurrence of inflammation that affects equilibrium in an autoimmune patient. What do you have to say about it? Does it sound feasible?

[1] Gazquez, I., Soto-Varela, A., Aran, I. et al (2011). "High Prevalence of Systemic Autoimmune Diseases in Patients with Menière's Disease". PLoS One, 6(10): e26759.

[2] Girasoli, L., Cazzador, D., Padoan, R et al. (2018). "Autoimmunity and Otolaryngology Diseases - Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment".  Journal of Immunology Research, pp. 1-16.

[3] Berardino, F., Zanetti, D., Ciusani, E. et al (2018). "Intestinal permeability and Ménière's disease". Am J Otolaryngol, 39(2), pp. 153-156.

Original post photo by Omid Armin on Unsplash

Why is there a “delayed onset” of antipsychotic action?

As a medical information specialist I am confronted with a variety of questions related to the trending therapeutic areas out there: immunoncology, cardiovascular, central nervous system, virology, orphan diseases, immunology, and so on and so forth. Every day I learn something new, from medical nomenclature to the mode of action of a certain drug, a wide range of topics pass through my eyes and I savour the opportunity to be well informed. Often, I myself, try to understand certain disease area aspects that are not so well explicit to the public or still remain a huge question mark for most of the healthcare professionals, clinicians and researchers out there. 

Recently, I have asked myself 'Why is there a “delayed onset” of antipsychotic action when changing between products?' as this is a recurrent situation to which I was never offered a clear response. Why is it so typical of treatments with antipsychotics that the patients deriving from product A to product B will quite often experience an adaptation phase? I can immediately relate to, for example, some research work I did back in the days when I graduated and my final year research project covered Cushing's syndrome. The case study I prepared did partially look through the desensitisation experienced by the patient's organism after a certain period of exposure to the very same drug. Different active substances would perform differently in terms of the body responses to the drug (pharmacokinetics) and the effects of such drugs in the different human sub-systems (pharmacodynamics). But when you consider the same basic active agents however in different products, it's very unlikely (if not almost impossible) that the aggregating/stabilising salt where these molecules 'sit' would impact that much on the efficacy of the product.

I decided to investigate a bit further, and here's what I found on the delayed onset of antipsychotic action, especially when changing between products?

Effect timings

Apparently, when considering the findings of the review article by Agid et al (2006) [1] there isn't a delayed onset, and actually the antipsychotic effect is within the first day, however the strongest more 'visible' antipsychotic effects are produced in the first two weeks after administration. Still according to this review, the most improvement is obtained in the very first month of treatment against any other period of treatment or follow up.

Even though it does not immediately respond to the question, as there is no switch between products in the previous paragraph, it already offers some nice pointers to understanding this issue. Could all this be a myth? Let's continue investigating.

A myth or a theory?

Psychotherapy is full of acquired myths as it is the norm for any therapeutic area with considerable difficulty in scientifically measuring improvement. But according to [1] it was in the 70s when this idea appeared stating that the onset of antipsychotic action is delayed in about 2 to 3 weeks. This led to investigations on what would be the underlying causes prompting such delay; and some authors arrived to a possible theory known as 'The Depolarisation Block Theory'. As per the authors two studies suggest that the explanation for a delayed onset of action is based on preclinical studies (on paralysed anaesthetised mice) involving recordings of dopamine neuron firing proposing that the effect on dopaminergic neurons in the brain after repeated administration of an antidopaminergic drug (commonly known as antipsychotic) is the inactivation of firing that usually occurs only after ~3 weeks of continuous treatment with said drug - ergo, a delay onset. Consequently, clinicians and investigators thought that this reported delay explained the delay in the therapeutic effect of the administered drugs [2] [3] [4].

The fact is that this theory was so strongly believed as factual that researchers started looking for biomarkers to actually support it. If found, no one would dare question its prevalence and thus the theory would be validated into something more clinically and scientifically accepted. The idea of its consubstantiation was to basically grow the theory into a postulate, to then grow it into an axiom.

After many different attempts this theory was 'officially' refuted as so well discussed by Agid et al (2003) [5]. The authors quite well mention that for understanding the mechanism of action of antipsychotics it is crucial to have a clear understanding of the time course over which effects take place. [5] put to test the delayed-onset hypothesis by subjecting it to a meta-analytic study, meaning by subjecting 'a large amount of data from a multitude of studies' to a statistical combinatorial arrangement that in the end informs on whether effects in different studies are equal or vary to the next one. And sometimes, it is even possible to obtain from a meta-analysis study, the underlying reason why effects were different/same. Clever, isn't it? One got to love this STATS geniuses!

So by scrutinising 42 published studies, 7450 patients 119 independent treatment response and time curves, the investigators recognised that actually an 'early onset effect' was present even beating the timeline of the estimated effect of the placebo treatment!!! In conclusion, the analysis fully rejects the 'delayed onset' theory, reinforces the idea that effects initiates at first week and grows in strength over the proceeding weeks, and that the most 'readable/visible' signs of effect are observed two weeks after treatment has initiated [5].

Big names of the neuroscience field throughout the middle of the 20th century helped propagate this idea of 'delayed onset' of antipsychotics. This helped propagate yet another theory that resulted as the possible physiological explanation, the aforementioned 'depolarisation block hypothesis'. But because the precise time course of improvement observed after administration of antipsychotics in a patient-treatment has never been solidly scientifically established, this hypothesis cannot be assumed as having enough scientific backing to support its reliability.

As extremely well presented and discussed in [5], the crucial detail in this debate is to accept and differentiate 'delayed onset' from 'delayed realisation of full improvement' as suggested by the authors. OK, many people can say - 'Well, but the idea is to know when you feel better; it doesn't really matter if it's working or not in the body if in fact one can't feel the physical effects and improve'.

I give' em that. Makes perfect sense!!! ... But then, that is what happens in all medical areas, with specific differences concerning the class of pharmaceuticals used> Nonetheless, all pharmaceuticals will take their time to act upon the subject. What really makes an incredible difference in all of this debate is, in my opinion, four very important things:

1) The level of affliction - a patient who is feeling quite poorly will urge the healthcare professionals for an immediate effect of the administered treatment (drug or drugs) on the physical system; if compliance, quality of drug or prescribed treatment as a whole is not adequate, it is possible that the patient will turn on the drugs' supposed 'delayed onset' as the one factor undermining improvement to his/her health. Add to that a multitude of disease experts making noise about the same and there you go, you have built your much wanted axiom. But one can never forget that wrongly or incompletely postulated ideas are not scientific validations, and ... a headache is a headache, a psychosis is a psychosis.

2) The seriousness of the disease - The more complex a disease the harder it is for a single pharmaceutical to respond to improvement expectancy, especially when there is concomitant medication involved. That and to an extent, considering their different biochemical natures, will affect the perceiving of efficacy of the drug under scrutiny.

3) The drug's mode of action - drugs are not all acting the same way or via the same pathways. Physiological resistances are present as they would normally be in a hyper-dynamic responsive organism as the human body is.  Where the effects might take different times to be 'concretely felt' by the patient, some drugs will operate differently or through different mechanisms even when the overall goal is the same. This will immediately impact on how rapidly their effects are observed, not only concerning its pharmacodynamics, but actual also in the sense of improvement felt by the patient.


[1] Agid, O., Seaman, P., Kapur, S. (2006). "The “delayed onset” of antipsychotic action — an idea whose time has come and gone". J Psychiatry Neurosci, 31(2), pp. 93–100.

[2] Bunney, B S., Grace, A. A. (1978). "Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity". Life Sci., 23(16), pp. 1715-27.

[3] Grace, A. A., Bunney, B. S. (1986). "Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording". J Pharmacol Exp Ther, 38(3), pp. 1092-100.

[4] Bunney, B. S.,  (1984). "Antipsychotic drug effects on the electrical activity of dopaminergic neurons". Trends in Neurosciences, 7(6), pp. 212-215.

[5] Agid, O, Shitij, K., Tamara, A. et al (2003). "Delayed-Onset Hypothesis of Antipsychotic Action: A Hypothesis Tested and Rejected". Arch Gen Psychiatry. 60(12), pp.1228-1235. 

Post image by Laurynas Mereckas on Unsplash.

How to know if a pharmaceutical product is authentic (in the EU)?

It is typical for the Big Pharma to undergo certain regulatory updates aiming the betterment of the pharmacovigilance and quality processes. It's all for the sake of respecting and protecting the end-user. Serialisation is a big part of the whole grand scheme of things and is to know further developments this coming 9th of February 2019. This is the day the European Union will put into place two levels of requirements that will help verify the authenticity of a product, by 1) demanding all marketed pharmaceuticals to contain a unique identifier, thus enabling the verification of its authenticity and the authenticity of its associated parts; 2)  demanding an anti-tampering physical system to make sure the product has never been compromised.

But what is this Serialisation everyone is talking about these days? Serialisation is a sort of tracking system to assure pharmaceutical companies, healthcare professionals and patients that the products in their hands can be trusted. For that matter a series of unique identifiers (almost like a person's national citizen card) are produced, recorded and tracked so authenticity can always be checked and verified. Serialisation protects not only the end-customer, but also the profile of the pharmaceutical company as it shows that the company is in control of the different stages of the manufacturing and distribution processes, authenticity-wise.

How does serialisation work? In very simplistic terms, all pharmaceutical products contain a coding that work as their identification details. The product code is an assigned number that identifies a specific strength, dosage form, and formulation for a particular product/company. These codes are made of unique identifiers (code numbers) that can be found affixed on the saleable unit of any pharmaceutical product, and also at any underlying levels of packaging (cases, pallets, pouches, etc). The numbers and the way they are displayed can differ slightly from place to place (geographically speaking) due to different regulations. However, for some areas there is standardised referencing, e.g., the Global Trade Item Number (GTIN) standard. The GTIN standard, when properly assigned, is globally unique and assigned to a product at the stock keeping unit level, meaning NO OTHER PRODUCT ANYWHERE IN THE WORLD CAN EVER BE ASSIGNED THAT SAME GTIN. 

Is serialisation coding always the same? Some companies have chosen additional nomenclatures or reference numbers. For example, some use what is known as National Trade Item Number (NTIN). In addition, the National Healthcare Reimbursement Number (NHRN or NN for short) is used in a number  of countries to facilitate the reimbursement process. In the packaging and in the subsequent levels of product, any displayed Serial Number (SN) must relate to the particular unit (GTIN/NTIN) and also to a particular lot. In that sense, the serial number is a very specific identifier, related to all four components that make of serialisation a very useful scheme for one to be always sure that the product is reliable in its authenticity.

In summary, typically, units can have the human readable serialised code, the 2D bar code and an anti-tampering tape to ensure the product is fully controlled. The requirements now for the EU market is that hospitals, pharmacies and other medicines dispensers are responsible for scanning the data matrix on the pack and waiting for a confirmation of its authenticity before releasing the product to a patient. So pharmaceutical companies must check the components mentioned above and if they don't match up this will trigger what is known as a Level 5 alert, also known as Potential Falsification Alert. In case a compromised and/or non-authentic product is discovered, the information must be transferred to the National Competent Authorities for a serious investigation to be carried on, and the product must be immediately quarantined.

Let me know if this post was clear in helping you understand what serialisation is and how it does help protect you as a patient/end-user.

Cheers

Image 1 kindly taken from CrestSolutions, [http://www.crestsolutions.ie/serialisation-pharma-turkey].

Image 2 kindly taken from The Pharmaceutical Journal, [https://www.pharmaceutical-journal.com/news-and-analysis/news/mhra-says-falsified-medicines-directive-could-cost-500m-over-ten-years/20205213.article?firstPass=false]. 

The real survival rates to cancer - Part 2 of 3

Following on the first part (see here) where the origins of chemotherapy were briefly discussed, I am here today to present the numbers available on the web and that concern survival rates to cancer. This topic is far from being of a simplistic nature; the disease itself is complicated, multifaceted and generates eruptive emotions. But times have been changing with developments made known that bring new pharmaceuticals to hospitals, better knowledge on disease development and more sensitive predictive technology. Available literature on the matter of survival to cancer is not scarce at all, having said that it is difficult to summarise the enormous lists of sources, references and cited researches that populate the Internet these days.

To better present data in a simplified manner, I decided to generate a summary table where you can find the different categories and the sources used to populate it. Bear in mind that, as expected, this is not an exhaustive compilation of data, but a rough approach to some of the most relevant articles I was able to find with the very limited time I have available these days. I hope that this table can, at least, lead you to the very fine research that is being developed by some important research groups worldwide. Apologies if most of these results are retrospective, but as one can imagine the time it takes for these groups to compile genuine data and make sense of the gathered numbers, discuss these and reproduce meaningful information in the shape of reliable publications, is on its own self-explanatory.

Finally, it would be simpler to just copy-paste incredibly well-put information obtained from websites such as the Cancer Research UK (access here) where a comprehensive and extraordinarily well structured summary of cancer survival rates (for most common cancers) is presented concerning the regions of England and Wales. However, this pool of information comes with many limitations, the first one being the fact that not all countries are represented, and the disease specificity as well as the medical techniques involved are not so well described.

[A]

So to overcome this over generalisation that can be informative to a certain extent, but may lack on a certain identity, I decided to approach this article with a live-table. This table is not amorphous or rigid but a 'tool' that I will be updating whenever I find specific articles that due to their inherent quality and development of a particular treatment analysis represent, in my humble opinion, a good retrospective-or-present indicator of the survival rates associated to a certain population/technique/cancer type/methodology. In addition, this is a nicer method to assess how survival rates have changed through time with the improvements on methodology and technology. And click on the images for better resolution!!!

Please consider this article in constant progression: 

[1] Young, J, L., Ries, L. G., Silverberg, E. et al (1986). "Cancer Incidence, Survival and Mortality for Children Younger than Age 15 Years old". Cancer, 58, pp. 598-602.

[2] Lai, E. C., Tompkins, R. K., Mann, L. L., Roslyn, J. J. (1987). "Proximal Bile Duct Cancer. Quality of Survival". Annals of Surgery, 205(2), pp. 111-118.

[3] Folkesson, J., Birgisson, H., Pahlman, L. et al (2005). "Swedish Rectal Cancer Trial: Long lasting benefits from radiotherapy on survival and local recurrence rate". Journal of Clinical Oncology, 23(24), pp. 5644-5650.

[A] Images kindly taken from Cancer Research UK, Cancer survival for common cancers, [http://www.cancerresearchuk.org/health-professional/cancer-statistics/survival/common-cancers-compared#heading-Two], last visited on the 6th of June 2018, last update unknown.

The real survival rates to cancer - Part 1 of 3

It is very difficult for anyone detached from the reality of clinical trials and the research developed by the biggest pharmaceutical companies to have access to secretive data pharmaceutical companies hold on their pipeline products (even when they become fully marketed ones).  We don't necessarily have to initiate or feed any kind of global conspiracy theory. There is huge investment in researching a pharmaceutical product destined to battle diseases as serious as cancer is. Such investment must be claimed back when the product reaches the market and becomes fully or partly available to hospitals, patients, for compassionate use, etc. Not always the different governments support pharmaceutical research to the same extent as governments claim taxation on these companies or impose price cuts/subsidiary support when the products are given market authorisation. 

It is not my job to analyse the soul of said companies as it is not my job to scrutinise the role of governments in the market authorisation and governmental participation process. But for such a global, relevant and recurrent disease that is ever so present in our day-to-day lives (every single one of us has to some extent come across a friend/relative/acquaintance affected by its ramifications) the BIG C is an obscure scenario. Whenever we are forced to bereave upon such frailty, our human side becomes a lot more mechanical, I suppose; a lot more statistical. The positive ones will hold onto the minimum numbers and foresee survival, the negative ones will probably see the opposite side of the mirror. I'm not here to judge, but I tend to be a positive one, and I would want everybody to be positive on their experience with such terrifying disease.

Hence, the idea of "celebrating" about 75 years of the first use of chemotherapy agents in a cancer patient [1] made perfect sense to me. A celebration based on survival, on the numbers that we are to increase but still attribute hope, regardless of how small they can be. 

We are then obliged to mention JD, as he was known back at the Yale Medical Center in 1941 when he was diagnosed with lymphosarcoma (a cancer of lymphocites). The expected treatment would be a combination of radiation and surgical resection. A fast-spreading disease branched through JD's body and the cervical tumours he had been screened for suddenly were unresponsive to radiation and spread to his armpit. His fate was about to be drawn if it wasn't for WWI's nitrogen mustard gas and its associated leukopenia (reduction of white blood cells - leukocytes - in the blood) inducing a low count on those exposed to it.

Well cancer, in very basic terms, isn't but a fast and abnormal multiplication of cells. Therefore, any substance that could attack those sub-systems prone to quick cellular production (hair, immune system, etc) could represent a potential pharmaceutical agent if shown to have reduced toxicity against humans. That wasn't the case for mustard gas, but at least the motto for what would become a very interesting research phase was given the go-ahead flag. And nowadays the common plebeian response to cancer is an immediate word -  chemotherapy. However, statistics are still quite hidden beneath the veil of frailty and business approach that both people (affected by their dramas) and pharmaceutical companies (profiting from the human drama) tend to either ignore, restrict, keep or cherry-pick.

***

I decided that for this post I'd refer only 1 article, the one by Panos Christakis (see below). The reason being the fact that it is a great article that can do wonders for your need for historical feed on how chemotherapy emerged from the shadows of Word War I. How life typically emerges from death and vice-versa, in a strange synergy of an uninterrupted circle. As if life and death weren't; and all we have is a continuum. The referred article deserves your uttermost attention as I believe it to be a great piece of work that instruct us on the chronological process of bringing a clinical and pharmacological product/procedure to life from the unexpected.

Before I leave you today with the premise to what is to be expected with the upcoming two additional posts - namely, the numbers on cancer survival rates (scientifically published), I'd like to share with you an additional motto for me to produce this trilogy of posts. It has to do with my past experience as an interpreter working in the NHS when I came across a cancer patient for the first time. No personal details will obviously be mentioned, but on the next post I will open with this extremely intense experience I lived and how it affected me tremendously... emotionally... and spiritually.

[1] Christakis, P. (2011). "The Birth of Chemotherapy at Yale". Yale Journal of Biology and Medicine, 84(2), pp. 169-172.

1st image kindly taken from The Irish Times [https://www.irishtimes.com/life-and-style/health-family/happy-birthday-75-years-of-chemotherapy-is-worth-celebrating-1.3200991].

2nd image kindly taken from Haiku Deck [https://www.haikudeck.com/history-of-wwi-uncategorized-presentation-546htuF1RC].

Russian Crocodile (the zombie drug that eats junkies)

I have been postponing this article for a long time because I couldn't find enough information on this serious topic. It appears that there is a flesh-eating drug, becoming ever so "famous" in Russia, named Krokodil (Crocodile). But what is in fact Krokodil, its components, its origin, side-effects, short/long term effects. This post is the informational fix you've been longing for. And now that I noticed the drug has entered the United States it is time to blow the alarm. Be ready because this is no fun at all, this is serious stuff as you will be able to judge right after I go through the answers for most of the questions we have on the matter. I hope that after these you can be aware that this new mixture can really "zombify" the bodies of people close to you.

What is Krokodil?

Krokodil is an opioid derivative of codeine named Krokodil in the streets, but its real name for pharmacists would be Desomorphine, plus a lot of other noxious ingredients mixed by street dealers. Among these hazardous compounds one can find gasoline, paint thinner, hydrochloric acid, iodine, red phosphorous [1, 2]. Let me very briefly explain a few concepts to you: opioids are medications that relieve pain and codeine is a medicine used to treat mild to moderate pain. This drug can be produced just like illicit metamphetamine is "cooked". The name Krokodil clearly derives from the green, dark, dead and moribund aspect the flesh gains as if one was turning into a crocodile (see image).

Where did it come from?
Apparently, it was first formulated in 1932 as a derivative of morphine; it is patented in Switzerland under the brand name Permonid [3]. Permonid is known to be 8 to 10 times stronger than morphine, and because people are always looking for incredibly stupid ways of destroying their lives, it became a recreational drug for hardcore junkies. Later in 2002 this drug jumped frontiers and "landed" in cold rural Russia, turning into a customary drug due to the easiness of manufacturing protocols [1]. It was actually an Afghan fungal crop disease that reduced opium production by 48%, back in 2010, that made people move from heroin to injectable over-the-counter codeine (easily found in compositions for common colds and cough) [2].

What are the effects of using Krokodil?
It has sedative and analgesic effects, but let me tell you of the most visible and shocking ones. The compounds within cause blood poisoning and the acids cause vessels to burst, and then corrosion of the tissues occurs all the way to the bone. Open ulcers, infections, gangrene, limb amputations. Liver and kidney damage. The typical rotting gums and tooth loss [2]. Etc Etc Etc to the classical HIV.

Is Krokodil addictive?
Tremendously! Especially considering that it costs a third of the common street heroin. There are now over a million people in Russia ghastly dying on Krokodil, but it has also been reported in other places like Germany, Georgia, Ukraine, Norway and Kazakhstan [2].

How do I know my friend is on Krokodil?
Oh you'll know, and that will not be Shawn of the Dead fun.

[1] Why are millions addicted to a drug that eats  the flesh of their bones?, Forbes, [http://www.forbes.com/sites/daviddisalvo/2013/12/10/why-are-millions-addicted-to-a-drug-that-eats-the-flesh-off-their-bones/], last visited on the 5th of December, 2015; last update on the 12th of October, 2013.

2] Krokodil (Desomorphine), [http://www.drugs.com/illicit/krokodil.html], last visited on the 5th of December 2015, last updated on the 21st of October, 2014.

[3] Permonid - PubChem, [http://pubchem.ncbi.nlm.nih.gov/compound/5362456#section=Top', last visited on the 5th of December 2015, last update unknown.