Counterfeiting and faking

Ethical prostitution rules in all areas of society and thus does not bypass phytotherapy. Magic erection pills, fascinatingly effective creams for atopic dermatitis, sedatives that somehow calm down too much, weight loss preparations that keeps us awake at night; a whole branch of phytotherapy “salted” with chemistry was created. And more than that, they justify themselves: “we only put a little”. The only question I ask is: why do fellow pharmacists repeatedly honour such manufacturers? Are we so beneath morals? If prostitution rules the internet, does it have to be in a profession that fights for status and meaning in medicine?

Why counterfeiting and faking?

Had the human mind been so creative in other activities as in scams, they would have long ago ruled half the galaxy. Joking aside, there are two main causes of counterfeiting and faking.

  1. Counterfeiting drugs with cheaper substitutes or falsifying the declared dose. It is fully motivated by earnings. More expensive drugs like ginseng or ginkgo are being replaced by other cheaper extracts, of which there are many documented cases. Sometimes the contents are falsified, so a smaller dose is used instead of the declared dose.
  2. Counterfeiting with synthetic drugs is motivated in a completely different way. Namely, herbal remedies can sometimes work quickly, but in some diseases, it is simply not a quick process. In order to “speed up” this process, not only drugs are added to the herbal preparation, but completely untested substances in order to make the effect “spectacular” and thus, of course, the sale is good. Of course, these substances are not declared, but are simply mixed into plant extracts. We have encountered this in Croatia as well, and it has become very common in the USA, Canada and the EU. We have not encountered this kind of crime in thousands of years of phytotherapy history. The most common cases described are preparations for erectile dysfunction, weight loss and sedation, and cosmetics to which corticosteroids and retinoids are added.

Case 1: ginkgo without ginkgo

prijevare In 2008 The Croatian Institute of Public Health conducted an analysis of dietary supplements based on ginkgo. Satisfactory content of active substances was not obtained in 75% of the preparations. In other words, 75% of ginkgo was not ginkgo in the true sense of the word.

Unfortunately, only the story related to general percentages remained, no products were listed by name, and all manufacturers were quicker to point the finger at others instead of being ethical and apologizing to their consumers for the scam and promising clear corrective action. Everyone knew very well what extracts they were procuring. Fortunately, the fraudulent management is still infantilely afraid of such public results, despite the apparent arrogance, so a year later, 75% of ginkgo products were satisfactory regarding quality. Interestingly, in 2008, the independent organization Consumerlab in the US announced that five out of seven ginkgo products did not meet quality expectations.

It is very difficult to know in the field of dietary supplements whether the said product contains declared amounts of active substance. It is not uncommon for food manufacturers in the US to be subject to the same rules of good manufacturing practice and inspection as drug manufacturers. This would not even be required in the US had it not been for the sheer cases of fraud. The situation is also improving in the EU.

Such ways of managing production and the regulations themselves cost a lot. In the end, it is the customer who pays the high price of a system that tries to curb immorality.

Case 2: potency preparations

The most famous case in Croatia and in the world is the addition of synthetic substances to “herbal” potency preparations. Namely, very few plants show an “instant effect” as shown by today’s drugs, most often inhibitors of the enzyme phosphodiesterase 5 (PDE5). One of the few natural substances that show such an effect is an extract of the bark of the yohimbe plant (Pausinystalia yohimbe) rich in the alkaloid yohimbine and c orynanthine. Other classic herbs used in erectile dysfunction, such as tribulus (Tribulus terrestris), maca (Lepidium meyeni) and large flowered barrenwort (Epimedium grandiflorum, show effects only after continuous and regular intake. As we live in an age when people don’t think much about more durable solutions but want a solution right away, ingenious fraudsters have created products that will hide synthetic substances that are phosphodiesterase 5 inhibitors under the guise of a “plant product”. They achieve the desired “instant effect” so we wonder if we have reason to be worried about that, when drugs of the same composition are sold anyway? There are reasons for that.

First, such products are advertised as herbal preparations and thus registered, and there is a complete lack of quality control of the final product. Potential contaminants in synthesis, the exact content of the dose in the capsule or tablet, stability during storage time, quality control by national regulatory agencies – all these are points that are completely lacking in such products. Such products mock both the plant world and phytotherapy, but also the pharmaceutical industry, which invests millions not only in quality control and quality assurance but also spends large fees on national regulatory agencies that also care about product safety for patients. Aside from the fact that it is a scam, because it does not declare an ingredient that can have severe side effects and can only be prescribed by a doctor and the patient should have regular contact with a doctor, but an even bigger problem is the quality. Does the capsule really always contain the same dose of hidden medicine? What if it contains twice the amount?

viagraOther, even bigger problem, is that such products end up with compounds that have not been clinically tested at all nor are they in clinical use. Namely, since the regulatory agencies of the EU, USA and Canada started “combing” such products and looking for three standard drugs for erectile dysfunction in them (sildenafil citrate, tadalafil, vardenafil), manufacturers began to find ways to avoid the detection of such substances in the analysis.

This is only possible if they take a completely different molecule of similar action. How is that possible? During the pharmaceutical research, a whole range of molecules are discovered that act on the desired molecule, in this case inhibiting PDE5. But of the dozens, even hundreds of such molecules, only one develops due to various properties (cheaper synthetic pathway, less toxicity, better pharmacokinetic properties…). Other molecules are very often described in the scientific literature and patents, but never experience a clinical trial or become a drug. Then the hidden chemical industry enters the scene, most often in Chinese illegal laboratories. Published and clinically unexamined molecules are synthesized and can be obtained through hidden channels over the Internet. Not only that, they are very easily available and even procured in Croatia, and the substances themselves are “smuggled” by ordinary postal packages, mostly falsely declared as, for example, “plant powders”. The laboratories that synthesize them do not have the classical quality control. Therefore, their safety is often questionable, and the main problem is that such molecules have not been clinically tested and we do not know their exact profile of side effects nor do we know what they do to the body through continuous use.

This concept is called the designer drug concept and is known primarily from the world of illegal drugs. Namely, when regulatory agencies or the police find a hidden drug, such as sildenafil, the manufacturer changes the name of the product and adds a different substance, such as homosildenafil. It is only a slightly modified basic molecule, but regulatory agencies initially “miss” such a molecule because it is detected quite differently analytically. To make matters more complicated, herbal substances are added to the capsules that contain hundreds of different compounds and create a real “noise” of signals in laboratory analyses. When the regulatory agency detects such a new compound, the manufacturer puts a third molecule in the new product with a new name, already quite modified, such as acetyldenafile. And so the game of cat and mouse continues. If it weren’t for such a case in our country, such a detective story with dangerous consequences would have gone unnoticed in our country. Investigative journalism also deals with this abroad, and it was published in several reportages, and National Geographic has dedicated an entire documentary to it. And all this in order to warn the public about this growing problem. The FDA has a complete list of such warning letters, which you can search by year here.

The following figure shows such sildenafil derivatives that are detected in plant products, and the modifications in the molecule that do not reduce the effect of the new molecule on PDE5 are marked in red, and serve to “hide” the detection by regulatory authorities. This problem has been going on for a long time, so the first summary papers were published about ten years ago, such as the work of Blok-Tip et al.

derivati sildenafila

The problem in these “small” modifications is that they can completely change the toxicological profile of such molecules. This is also a call to analysts in the laboratories of regulatory agencies not to “look for” only classical drugs for potency in such preparations, but also other molecules, some of which have not yet been used.

There are no other words than that it is a mafia in the true sense of the word, which does stoop to endanger the health of thousands of people for the sake of profit. It is a great responsibility of healthcare professionals to take care of this, and not just watch the daily revenue. It is a big responsibility on the pharmacist. Two years before the detection by HALMED (Agency for Medicinal Products and Medicinal Devices of Croatia), people in Croatia complained about the side effects of such preparations, from two-day and three-day long-lasting painful erections, hypotension, tachycardia, which rarely can be caused by any herbal preparation of “classic” potency composition. If morality is worth less than a few thousand kunas in earnings, then all health professionals who think so did not even deserve their diplomas, because they violated the oath. But even this text will not resonate until the consequences with a fatal outcome occur. It is enough to pay a fine that is ridiculous in relation to the profit made, so that the business goes on. If Dante Alighieri were alive today, I wonder where in the Divine Comedy such cases would end up.

Case 3: weight loss products

If you look at the list of FDpreparati za mršavljenjeA warning letters, you can see that in addition to “potency” products, “weight loss” are the most popular type of product to which illegally (without declaring and registering as a drug) drugs are added.

The field of obesity drugs is already quite “thin” after the withdrawal of Reductil (sibutramine) and Acomplia (rimonabant) from the market, and the ban on ephedra (Ephedra sinica) in herbal preparations. However, after Abbott withdrew sibutramine from the market in 2010 due to serious side effects, manufacturers continued the practice of illegally adding such a drug consciously knowing that they were putting patients’ health at risk, all in the name of profit. Moreover, as early as 2006, synthetic analogues of sibutramine were detected in dietary supplements, primarily N-di-desmethylsibutramine, similar to the designer drug concept in sildenafil. In 2013 alone, the FDA issued a warning for as many as five such products.

Consequences? We also had a case in Croatia a few years ago that people bought various shakes. Several people complained of palpitations and insomnia, primarily because such preparations, in addition to sibutramine and its derivatives, also contained very high doses of caffeine, and this combination is especially bad for health – it should not be forgotten that sibutramine was withdrawn precisely because of health risks to the vascular system. Unfortunately, weight loss is a type of human activity that does not ask for a price for your own body, so you can usually “ignore” such side effects without big questions.

Case 4: Miracle creams

All dermatologists know how difficult it is to treat atopic dermatitis. We use corticosteroids, which very quickly improve the clinical picture, but we must not use these drugs for too long, and soon after stopping the therapy, the condition returns to normal. If we use dermocosmetics, it generally improves the condition a bit, although we can use it continuously.

And so the dark idea of illegally adding a corticosteroid to dermocosmetics was born. It has become a problem all over the world, and Croatia, let’s be ironic, has caught on such a trend. Apparently, we will have a “natural” cream with plant extracts, but it will have a spectacular effect due to corticosteroids. With one large but… Long-term, multi-month use without a doctor’s supervision leads to great health risks. I try to remember all the parents who told me that they had used such creams on children under the age of three for a year or more. Thin skin, problem of systemic action of corticosteroids through the skin, effects on the immune and hormonal system, metabolism: corticosteroids control over 1% of our genes, and if we keep in mind that we have about 30,000 genes, we just need to imagine how much consequences uncontrolled chronic use can have.

The Mafia benefits from the fact that in the case of corticosteroids, there is almost no need to reach for the designer drug concept. Namely, there are dozens of molecules on the market of this old class of drugs, which is a great challenge for analysts who detect illegally present drugs. Triamcinolone acetonide, betamethasone and its propionates and valerates, hydrocortisone, mometasone furoate, fluocinolone acetonide, desonide, budesonide…. this is only a small part of the list of corticosteroids on the market. There are commercially available corticosteroids that are not registered as drugs but are potent. And of course, the whole scam the consumer pays hundreds of kunas per small package, so there have been cases of parents of atopic children taking out loans to be able to buy sufficient quantities of such a cream. And all this in order to endanger the health of their child in the end.

And here common sense had to be involved and patients observed. Yarrow or calendula cannot cure atopic dermatitis or psoriasis in two days. Likewise, an extremely rapid return of disease symptoms after cessation of therapy, or even a rebound effect, worsening of the condition to a worse degree than the condition before therapy, are typical features of corticosteroids. But there was silence about all this. Indeed, fellow pharmacists also received a circular letter implicitly threatening lawsuits against those pharmacists who, using common sense, suspected that an illegal corticosteroid was hidden in the cream. Certificates of some external institutions that the cream is “corticosteroid-free” would be forged, and the certificate would say that “the corticosteroid has not been proven.” The accident of the Balkan mafia is that it perversely enjoys insulting reason and knowledge, because this is like writing “vitamin free” on a certificate. Which ones? Which exactly were these corticosteroids proven to have issued such a certificate?

The result? Punishment ridiculous compared to the earnings, thousands of children who are treated outside all the rules of pharmacology, all under the guise of words naturally. And of course, a lawsuit against a colleague by a patient to whom she sold such a cream. So: first there is a lawsuit if we refuse to issue such a cream, and then there is a lawsuit when we issue it.

And an even crazier result? Parents who, even after the published results of analyses and withdrawals from the market and public warnings, went to buy the same cream outside Croatia.

The latest achievement is a cream that is allegedly “made by nuns”. As nowadays people have lost trust in others, cunning corticosteroid strategists are left with an interesting weapon: it’s not possible that people who fear God would illegally add drugs to creams? I don’t think the nuns had anything to do with that cream, but nevertheless we named those “nuns” corticosteroid nuns who, obviously, serve a darker God. It is immediately suspicious when a supposedly traditional recipe smells like a synthetic strawberry scent. The illegal corticosteroid of “the nuns”, interestingly, comes from the “centuries-old hostile nation”, which only says that in the case of dishonourable affairs or the affairs of “the satan”, the “enemies” get along very well.

There is a lot to learn from these bitter stories. Patients and customers must finally stop blabbering on about express solutions. The poetic age of Dadaism was a hundred years ago. Both disease and treatment have their course. Furthermore, once upon a time, everyone who said they worked “naturally” immediately had the aura of good guys, unlike the evil pharmaceutical industry that is constantly trying to destroy those ultra-ethical naturalists. Still, people’s naivety is slowly diminishing, or so I hope. Healthcare professionals need to warn about what they come across in contact with patients. Young aggressive sales representatives of such products should pay attention to their arrogance, because their names will be remembered and the door will be closed to them in the future, even when they will work as representatives of good products. Those who come up with such ideas have nothing to learn from this story. They sold their souls a long time ago.

The pharmaceutical industry is often accused of playing dirty. Honestly, we cannot say that dirty games have not, unfortunately, become a modus vivendi from politicians down. There is corruption and pressure in the pharmaceutical industry and, in my opinion, really unnecessary phenomena such as bonuses for every ten drugs issued. But now judge for yourself how much better or worse the above three examples are than the conspiracy theories of the “evil” pharmaceutical industry.

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