The novelty is different
Expert: the way of pharmaceuticals is to improve existing medicines
It seemed that humanity was on the verge of creating fundamentally new and very effective drugs for cancer, HIV infection, cardiovascular and other socially significant diseases, and soon, thanks to the achievements of pharmacology, people will remain cheerful until old age. But the expected pharmaceutical breakthrough never happened.
Is it possible to wait for it in the foreseeable future? What are the current trends in obtaining new medicines? Our expert is Nina Borisovna Melnikova, Head of the Department of Pharmaceutical Chemistry and Pharmacognosy of Nizhny Novgorod State Medical University, Professor, Doctor of Chemical Sciences.
The novelty is differentElena Shitova: Every year new medicines appear on the pharmaceutical market, not only generics, but also original drugs.
When will quantity turn into quality?
Nina Melnikova: Among the new drugs entering the market, there are actually very few that are actually new. Synthesis (chemical, biotechnological, microbiological) of fundamentally new medicinal substances is a rare phenomenon. Moreover, practically no new pharmaceutical substances are being created. In the vast majority of cases, new drugs are the result of improvement of previously known ones by modification, improvement of the quality of purification, a new combination of substances, etc. One of the most important trends of recent times is the development of new dosage forms of medicines: transdermal, inhalation and others. Particular attention is paid to the selective administration of the drug, targeted delivery to the site of exposure.
– But pharmaceutical manufacturers claim that their drugs are new. Or does novelty not always mean efficiency?
– In the pharmaceutical market, many drugs are positioned as new, whereas in fact their novelty is far from indisputable. According to the French review for 2011-2012, published in the journal PRESCRIRE INTERNATIONAL (April 2012/volume 21 No. 126), out of 37 new trademarks, only 11 are such. In particular, the advantage over known drugs such as orifolitropin alpha, recombinant FSH for ovarian stimulation, C1‑esterase inhibitor for the treatment of attacks of hereditary Quincke's edema has not been confirmed. 4 old medicines have been identified:
- fampiridine, intended for the treatment of motor functions in adults with multiple sclerosis;
- amifampridine used to treat Lambert-Eaton myasthenic syndrome;
- quetiapine is a neuroleptic;
- prukaloprid is a stimulator of gastrointestinal motility.
Three drugs are repetitions (me-toos, "me too"): antidepressants eslicarbazepine and oxoazbazepine (repeat one previously known substance), the prostate cancer drug histrelin and velaglucerase alpha for the treatment of Gaucher's disease.
– Is there really nothing fundamentally new and effective?
– There is, but very little. According to the materials of the same review, only three out of 92 were recognized as the most successful drugs with a high degree of novelty. Examples include boceprevir and telaprevir for the treatment of viral hepatitis. Antiviral drugs tamiflu (oseltamivir) and ingavirin have proven themselves well in Russia in recent years.
The balance of efficiency and safety– Why are there so few really new drugs?
Has pharmaceutical science reached a dead end?
– In order for a new drug to become in demand, good statistical material must be accumulated, full-fledged preclinical and clinical studies are needed. It is extremely important to identify the maximum number of side effects, to study the interaction of the drug with other medicinal substances. It is not enough to achieve the desired pharmacotherapeutic effect, it is also necessary to comply with the safety requirements of the drug, which are in the foreground. All recent international standards in this area are aimed at strengthening safety, including GMP standards.
– Any drug has a side effect. Is there a chance that the priority of safety will become an insurmountable obstacle to the creation of new medicines?
– You always have to balance between the effectiveness and safety of the drug. In order to minimize the possible negative consequences of the application, it is necessary to study them very carefully. A good level of research is when the list of contraindications is greater than the indications. If there are a lot of "white spots" in the instructions for the drug, that is, indications that certain factors have not been studied, this should be alarming.
– Isn't it necessary for the manufacturer to conduct a full study of the drug in order to bring it to the market?
– There is a clear regulation of which documents need to be drawn up, how many and what kind of studies to conduct, which patent confirmations to provide, etc. But even such a complex procedure is not a guarantee of the absolute safety of the drug. For example, clinical trials are always conducted in a certain area, among a limited number of subjects. Who can guarantee that in other conditions the drug will have exactly the same effect? There are many factors that cannot be fully taken into account. In addition, drugs are usually studied for no more than ten years, and long-term consequences may occur much later. There are difficulties with preclinical studies. If earlier tests on cats and dogs were widely carried out, now animal advocates around the world have achieved restrictions on such experiments.
Caution does not hurt– It's no secret that marketing strategies play a huge role in the promotion of any product, including medicines.
If a new drug is presented as a panacea, then patients, doctors, and pharmacists begin to believe in it. Do these expectations always come true in practice?
– The international pharmaceutical and medical community calls for caution when prescribing new drugs due to insufficient evidence base (often there are no clinical trials) and reliable statistical data. As an example, denosumab is a microbiological drug based on human IgG2 monoclonal antibodies intended for the treatment of osteoporosis. At one time it was very widely promoted, it even claimed the status of the "gold standard", but later it was recognized that there was too little evidence for side effects for this drug.
Drugs with weak evidence and unreliable statistics include a cytotoxic drug of plant origin from the group of taxanes – docetaxel, as well as an abatacept offered for the treatment of rheumatoid arthritis, bendamustine (Treakisym®, Ribomustine®) for the treatment of sarcoma and chronic lymphocytic leukemia.
– For which types of drugs is caution in prescribing especially important?
– Any new medicine requires a balanced approach, drugs obtained using biotechnological and microbiological methods deserve special attention. By the way, nanomedicine, which is popular today, also needs increased attention in terms of studying side effects.
How to improve the "gold standard"
– If new drugs are always fraught with potential danger, and the old ones do not solve existing problems in the treatment of diseases, then what can doctors and patients hope for?
– I think that the most promising way at this stage of development is to improve existing drugs. It can go in several directions, one of which is the modification of known medicinal substances to active metabolites, as well as to derivatives with better biological availability, digestibility and less toxic effects. The advantage of this way is that medicinal substances are used that are recognized as the "gold standard" of treatment, which are not only well researched, but also tested by many years of experience in use.
– How is this done in practice?
– The simplest modification of well–known, well-proven medicinal substances is the formation of esters, amides and salts. An example is the improvement of the effectiveness of common hormonal drugs. Hydrocortisone, which is a free alcohol, is very slightly soluble in water. This is associated with a very limited range of its use, mainly in the form of ointments and as part of aerosols. But if you convert alcohol into salt, then the solubility index and the range of applications change. Thus, hydrocortisone acetate can be used not only in the form of ointment, but also in the form of eye drops and suspensions for intramuscular and intra-articular injections, and hydrocortisone hemisuccinate, due to its high solubility, is used intramuscularly and intravenously.
A successful technique is the modification of known medicinal substances to metabolites that exhibit higher pharmacological activity, which makes it possible to reduce their dose and expand the range of medical applications. Examples of such drugs are derivatives and metabolites of vitamins D2 and D3 (ergocalciferol and cholecalciferol). These drugs, which are essentially "siblings", have different indications for use (from psoriasis to renal osteodystrophy), and dosage forms – from ointments and gels to tablets and injections.
– Can the modification not only increase the effectiveness of the medicinal substance, but also reduce its toxicity?
– Such developments are especially relevant for antitumor drugs. For example, the well‑known 5-fluorouracil has a highly toxic effect not only on tumor cells, but also on the entire body as a whole. The study of the biotransformation of this substance led to the creation of less toxic drugs Tegafur and Xeloda (the active substance is capecitabine). Capecitabine is a prodrug that, as a result of biotransformation in the liver, is converted into 5‑fluorouracil, which is a true medicine. Thus, cytotoxic 5‑fluorouracil is formed directly in the damaged tissue, without having a significant negative effect on the entire body. In general, the concept of creating prodrugs that are converted into an active substance at the point of application is of interest to researchers all over the world.
About the form and content– How relevant is the creation of drugs by creating new dosage forms of known substances?
– This strategy of obtaining new medicines is most in demand at the moment and shows the best results. The global trend is such that, first of all, those forms that allow avoiding the injectable route of drug administration are welcome. In particular, receiving insulin in transdermal form allows to relieve diabetics from the need for frequent injections. In some cases, it is important to refuse oral medication.
Often, new dosage forms allow not only to increase the convenience of use, but also to increase efficiency and reduce toxicity. A striking example is the use of the well-known antitumor cytostatic doxorubicin in a new liposomal form. In this case, the drug is injected directly into the tumor tissue of the liver, which allows to increase the effectiveness many times.
– What other methods allow you to deliver the drug directly to the place of action?
– Recently, such a direction as the use of the delivery vector has become very popular. This can be done with the help of various pharmaceutical and medical technologies. In general, the use of medical technologies and methods of treatment plays a very significant role in increasing the pharmacotherapeutic effectiveness of medicines. The dosage, combination of drugs and even the sequence of their use is of great importance. The same drug can show completely different effectiveness depending on the chosen treatment method.
Back to nature!– It turns out that in order to create modern effective and safe medicines, it is absolutely not necessary to synthesize fundamentally new substances?
– Synthesis of new substances is fine, but that's not all. Optimal forms, dosages, combinations, methods and much more should be determined for each medicinal substance. One of the most important ways to increase the effectiveness and safety of drugs is to increase the purity of medicinal substances, dietary supplements and the widespread use of natural compounds with a high degree of purification. It should be borne in mind that even a tiny fraction of some impurities can distort the effect of the medicinal substance.
– You mentioned not only medicines, but also dietary supplements, to which the medical community has a very ambiguous attitude.
– Throughout the civilized world, dietary supplements are part of the culture of maintaining a healthy lifestyle. In the American pharmacopoeia there is a separate volume on dietary supplements, and they are analyzed according to the same program as medicinal substances, including identification of authenticity and comprehensive determination of all components. Unfortunately, this is not the case with us. Many manufacturers and sellers of dietary supplements are beginning to cheat, deviate from the requirements. As a result, incomprehensible products with unpredictable effects are sometimes sold under the guise of dietary supplements. But this is not a question of dietary supplements, but about legality, culture and basic self-respect.
– What did you mean by natural compounds?
– It often happens that the new is the well–forgotten old. Substances that have long been used in folk medicine can now be studied and applied at a higher, modern level. As an example, pumpkin oil, well-known in folk medicine, can be cited. It is considered that its main advantage is the high content of polyunsaturated fatty acids. Now it has been found out that it still contains phytosterols – plant hormones that have a mild effect and are capable of biotransformation.
The situation is similar with carotenoids – precursors of vitamin A contained in many vegetable oils. Thirty years ago, 70 carotenoids were described, and in 2014 there were publications that 700 of them are already known. Previously, they could not be isolated, only modern methods allowed this to be done. Carotenoids are the strongest and at the same time non–toxic antioxidants for the body.
The tokols contained in the oils are also of great interest. It was believed that alpha-tocopherol has the main effect as vitamin E and an antioxidant, whereas currently the main attention is paid to gamma-tocopherol – the predominant tocol in vegetable oils, which has a preventive effect against many types of neoplasms, vasodilating and anti-inflammatory effects.
In addition, oils contain a large amount of tocotrienols that regulate redox processes in the body. In short, as they began to purify and investigate vegetable oils, a new page of their medical application began to open. This is a very promising direction in the creation of medicines.
The path to active longevity– There is a lot of talk about the need to increase life expectancy.
What role does the use of modern medicines play in this process?
– All over the world, serious attention is paid to the problems of gerontology and "diseases of old age", for example, Alzheimer's disease, diabetes mellitus, oncological diseases. However, many studies show that in the absence of social assistance and human participation, medicines are ineffective. In particular, these factors led to a decrease in the rating of such drugs for the treatment of Alzheimer's disease as donepezil, galantomine, rivastigmine and memantine. The duration and quality of life of elderly people largely depends on socially significant conditions.
– How do you feel about the calculations of American Professor Frank Lichtenberg, who believes that life expectancy in Russia may increase by more than two years with an increase in the consumption of modern drugs?
– In the research of a respected scientist, a statement of facts is given that, in his opinion, reduce life expectancy. Indeed, 63 years for men is catastrophically little. But there is no in-depth analysis of the reasons for this situation. We cannot say that there are no modern drugs in our country. Another issue is that they are not always available due to the high cost. In addition, insufficiently researched new drugs are entering our market, the use of which is unlikely to have a positive impact on the duration and quality of life. And most importantly, there is a different way of life in our country, other social factors that need to be taken into account.
– What is the place of medicines in improving the quality of life and increasing its duration?
– I really like the approach to prolonging active longevity used in Japan. It is based on a combination of mild drug support and the creation of optimal social conditions under which a person would be in demand and show both physical and intellectual activity. Elderly people need to read and write, and not on a computer, but by hand, they need to engage in physical culture, be able to take care of others. For example, joint classes of elderly people and children with developmental problems give excellent results. At the same time, the state of health improves both in the elderly and in sick children.
Of course, medications are important, but they are not the main factor in prolonging life and improving its quality. To save a person, he must be loved and respected. Without this, even the most miraculous means will be ineffective.
Portal "Eternal youth" http://vechnayamolodost.ru29.04.2014