Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs

Neuro pharmacokinetics: the secret life of - old and novel - psychopharmacological drugs Miroslav Savić Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia In the 21st century, the pace of development of new pharmacological treatments for general medical and psychiatric disorders is remarkably different. While successes for the former are frequent, new drugs for mental, behavioral and neurodevelopmental disorders are sporadic. Many factors contribute to this discrepancy. Probably the most important is the complexity of etiology and manifestations of mood, psychotic, anxiety, neurocognitive and other disorders that are commonly treated with psycho pharmacological drugs. Although this factor cannot be directly addressed in drug development, optimization of drug exposure in brain tissue can certainly help to balance the efficacy and safety of both widely used and novel psycho pharmacological drugs. While drug exposure of various organs and tissues can be easily assessed from free (unbound) blood concentrations, the central nervous system (CNS) has a number of barriers, most notably the blood-brain barrier (BBB) that separates nervous tissue from the periphery. Optimised CNS exposure of a drug to its target site over a desired time period is critical to triggering its therapeutic effect. The presence of the BBB readily leads to an asymmetry of drug (unbound) exposure in the brain and in the systemic circulation, which prohibits the use of unbound drug concentration in plasma as a surrogate for unbound drug concentration in the brain. Comprehensive pharmacokinetic/pharmacodynamic studies of marketed CNS drugs have shown that the concentration of unbound drug in brain interstitial fluid is an appropriate measure of CNS exposure in the context of cell membrane targets of action. The more recent concept of brain-plasma partition coefficient, Kp,uu, as a parameter describing the relationship between the concentration of unbound drug in brain interstitial fluid and the concentration of unbound drug in plasma, is assumed to be the most important means of assessing brain exposure. Experimental assessment of Kp,uu requires either measurement of the brain unbound drug concentration in the interstitial fluid by microdialysis in vivo or estimation of the fraction of unbound drug in the whole brain homogenate (fu,brain) by equilibrium dialysis in vitro. Kp,uu can be calculated by dividing either the area under the curve (AUC) of the profile of the concentration of unbound drug in brain and plasma after a single administration or the steady-state unbound concentrations of drug in brain interstitial fluid and plasma. Although many marketed psychotropic drugs have Kp,uu values as low as 0.1-0.2, it is theorized that the most successful small molecule CNS drugs should have Kp,uu values near 1. The neuropharmacokinetic behavior of benzodiazepine compounds, both widely used and those in preclinical and clinical development, is presented as a showcase. Given the variety of receptor subpopulations at which these drugs act as positive allosteric modulators of GABAA receptors, the complexity of linking brain exposure data to the corresponding pharmacodynamic effect is explained

Prekliničko predviđanje neželjenih efekata lekova na nervni sistem

The adverse effects of pharmaceuticals on the central or peripheral nervous systems are poorly predicted by the current in vitro and in vivo preclinical studies performed during research and development process. Increasing the predictivity of the preclinical toolbox is a clear need, and would benefit to human volunteers/patients (safer drugs) and pharmaceutical industry (reduced attrition). The NeuroDeRisk Consortium consists of 18 academic, pharmaceutical industry and small and medium enterprise partners within the Innovative Medicines Initiative project (2019-2022). University of Belgrade – Faculty of Pharmacy is the partner that leads the work package devoted to preclinical prediction of mood and cognitive adverse effects. The other two groups of challenging adverse effects tackled by the project are seizures and peripheral neuropathies. By employing a plethora of experimental techniques and numerous pharmaceuticals previously connected with each of major adverse effects examined, the project looks for innovative tools, assays and protocols, which cover in silico, in vitro, in vivo and ex vivo approaches. Besides widening the knowledge on many widely used pharmaceuticals, the major goal of the project is to develop an integrated platform for better risk-assessment in exploratory and regulatory studies in the future.Postojeće in vitro i in vivo prekliničke studije koje se sprovode tokom procesa istraživanja i razvoja teško mogu predvideti neželjene efekte farmaceutika na centralni i periferni nervni sistem. Postoji jasna potreba za povećanjem prediktivnosti prekliničkih oruđa, što bi bilo korisno za humane volontere/pacijente (bezbedniji lekovi) i farmaceutsku industriju (smanjena stopa neuspeha). NeuroDeRisk konzorcijum se sastoji od 18 akademskih institucija, kompanija farmaceutske industrije i malih i srednjih preduzeća u okviru projekta Inicijative za inovativne lekove (2019-2022). Univerzitet u Beogradu – Farmaceutski fakultet jeste partner koji predvodi radni parket posvećen prekliničkom predviđanju neželjenih efekata na raspoloženje i kogniciju. Druge dve grupe izazovnih neželjenih efekata koje projekat obrađuje jesu konvulzivni napadi i periferne neuropatije. Korišćenjem mnoštva eksperimentalnih tehnika i brojnih farmaceutika koji su prethodno povezani sa svakim od ispitivanih velikih neželjenih efekata, projekat traga za inovativnim oruđima, esejima i protokolima, koji pokrivaju in silico, in vitro, in vivo i ex vivo pristupe. Mimo širenja znanja o brojnim široko korišćenim farmaceuticima, glavni cilj projekta jeste razvoj integrisane platforme za bolju procenu rizika u budućim eksploratornim i regulatornim studijama.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Bezbednost primene antibakterijskih lekova

Selective mechanisms of action, based on the biochemical differences between bacteria and host cells, assure the positive benefit-risk ratios for all antibacterial drugs in current use. On the whole, the adverse effects of these drugs are usually mild and reversible on treatment termination. Nonetheless, some of the cornerstone safety issues of drug use were triggered by cases related to this class of drugs. First of all, it was not before the reports of chloramphenicol-associated aplastic anemia in 1950s that adverse drug reaction reporting began to be legally required from drug manufacturers. The sulphonamide and -lactam classes of antibiotics exemplify the variety of allergic and pseudoallergic reactions to drug. Similarly, the aminoglycosides became the academic exemplars for explaining the drug-induced ototoxicity and nephrotoxicity. Discovery of tetracycline accumulation in teeth and bones of children was one of the first established concerns with drug use in pregnancy, lactation and early childhood. Finally, while previous issues were far from specific to antibacterial drugs, these precious agents are also uniquely responsible for selecting and spreading of multiresistant microorganisms worldwide.Selektivni mehanizmi dejstva, zasnovani na biohemijskim razlikama između bakterija i ćelija domaćina, obezbeđuju pozitivne odnose korist-rizik za sve antibakterijske lekove u savremenoj upotrebi. U celini, neželjena dejstva ovih lekova su obično blaga i reverzibilna po okončanju terapije. Ipak, neka od temeljnih pitanja bezbednosti primene lekova pokrenuta su slučajevima vezanim za ovu terapijsku klasu. Pre svega, izveštaji iz 1950-ih o aplastičnoj anemiji povezanoj sa hloramfenikolom su bili povod za postavljanje zakonskog zahteva pred proizvođače da izveštavaju neželjene reakcije na lekove. Sulfonamidska i -laktamska klasa antibiotika predstavljaju primer raznovrsnosti alergijskih i pseudoalergijskih reakcija na lekove. Slično, aminoglikozidi su postali akademski uzor za objašnjavanje lekom-izazvane ototoksičnosti i nefrotoksičnosti. Otkriće akumulacije tetraciklina u zubima i kostima dece je značilo jednu od prvih zabrinutosti vezanih za primenu lekova u trudnoći, laktaciji i ranom detinjstvu. Konačno, dok prethodni primeri svakako nisu specifični za antibiotike, ovi dragoceni lekovi su takođe jedinstveno odgovorni za selektovanje i širenje multirezistentnih mikroorganizama u čitavom svetu

Kateholamini, adrenalni hormoni i stres

Different physical, physiological and psychological factors, known as stressors, affect the homeostasis of an organism. The stress system, located in the central nervous system as well as in peripheral organs, mediates the protective stress response. The three principal effector parts of the stress system are hypothalamic-pituitaryadrenocortical, adrenomedullary hormonal system and sympathetic nervous system. Their main respective mediators are cortisol, adrenaline and noradrenaline. The stress response is not the stereotyped one, but depends on the nature of the stressor. The analysis of data from human and animal experiments has shown much closer correlation between the plasma adrenaline and ACTH changes (as a measure of activity of the hypothalamic-pituitary-adrenocortical system) than between adrenaline and noradrenaline responses. While the defense against stressors is of vital importance, inappropriate stress responses, in the direction of deficiency or excess, have been related to a significant number of psychiatric and somatic complaints. It is hoped that at least some of these disorders may be better treated with the anticipated new generation of stress-modifying medications with a central mode of action, such are antagonists of corticotropin (ACTH) releasing hormone (CRH) from hypothalamus.Različiti fizički, fiziološki i psihološki faktori, poznati kao stresori, utiču na homeostazu organizma. Stresni sistem, smešten u centralnom nervnom sistemu kao i u perifernim organima, posreduje zaštitni stresni odgovor. U tri osnovna efektorna elementa stresnog sistema spadaju hipotalamo-hipofizno-adrenokortikalni, adrenomedularni hormonski i simpatikusni nervni sistem. Glavni medijatori ova tri sistema su, redom, kortizol, adrenalin i noradrenalin. Stresni odgovor nije stereotipan, već zavisi od prirode stresora. Analiza podataka iz eksperimenata sa ljudima i životinjama pokazala je mnogo bližu korelaciju između adrenalina u plazmi i promena ACTH (kao mere aktivnosti hipotalamo-hipofizno-adrenokortikalnog sistema), nego između odgovora adrenalina i noradrenalina. Dok je odbrana od stresora od životnog značaja, neadekvatni stresni odgovori, bilo u smeru nedovoljnosti bilo prekomernosti, povezivani su sa znatnim brojem psihijatrijskih i somatskih tegoba. Postoji nada da bi makar neki od ovih poremećaja mogli biti bolje tretirani sa očekivanom novom generacijom lekova koji centralnim mehanizmom modifikuju stres, kao što su antagonisti kortikotropin (ACTH) oslobađajućeg hormona (CRH) hipotalamusa

Lekovi koji utiču na aktivnost sistema renin-angiotenzin-aldosteron i ishemijska bolest srca

The renin-angiotensin-aldosterone (RAAS) system is a multilayered cascade of mediators involved in regulation of arterial pressure, tissue perfusion and extracellular volume, and hence the cardiovascular and renal homeostasis. Classicaly, the system has been seen as consisting of angiotensinogen substrate and two enzymes, renin and angiotensin-converting enzyme, which sequentially convert it to angiotensin I and II. Angiotensin II, the main effector of the cascade, acts through two subtypes of angiotensin receptors, and gives rise to rapid and slow pressor response and vascular and cardiac hypertrophy and remodeling. Additionally, it regulates release of mineralocorticoid hormone aldosterone from adrenal cortex. The expanded view of RAAS system covers a number of other angiotensins (III, IV, 1-7), as well as newlycharacterized enzymes and receptors. Five classes of drugs directly affect the activity of this cascade: antagonists of β adrenergic receptors, renin inhibitors, angiotensinconverting enzyme inhibitors, antagonists of angiotensin receptor subtype 1 and antagonists of mineralocorticoid receptors. It was shown that angiotensin-converting enzyme inhibitors, but not antagonists of angiotensin receptor, can be beneficial in primary and secondary prevention of myocardial infarction, and this class of drugs should be used as a first -line treatment in patients with ischemic heart disease requiring suppression of RAAS axis.Sistem renin-angiotenzin-aldosteron (RAAS) predstavlja višeslojnu kaskadu medijatora uključenih u regulaciju arterijskog pritiska, perfuzije tkiva i ekstracelularnog volumena, i time homeostazu kardiovaskularnog sistema i bubrega. Klasično viđenje je da se RAAS sistem sastoji od supstrata angiotenzina i dva enzima, renina i angiotenzinkonvertujućeg enzima, koji sekvencijalno prevode supstrat u angiotenzin I i II. Angiotenzin II, glavni efektor kaskade, deluje preko dva podtipa receptora za angiotenzin i dovodi do brze i spore komponente porasta krvnog pritiska, hipertrofije i remodelovanja srca i krvnih sudova. Dodatno, angiotenzin II reguliše i oslobađanje mineralokortikoidnog hormona aldosterona iz kore nadbubrežnih žlezda. Prošireno viđenje RAAS sistema obuhvata i jedan broj drugih angiotenzina (III, IV, 1-7), kao i novo-karakterisane enzime i receptore. Pet klasa lekova direktno utiče na aktivnost ove kaskade: antagonisti β adrenergičkih receptora, inhibitori renina, inhibitori angiotenzinkonvertujućeg enzima, antagonisti receptora za angiotenzin, podtip 1, i antagonisti mineralokortikoidnih receptora. Pokazano je da inhibitori angiotenzin-konvertujućeg enzima, ali ne i antagonisti angiotenzinskih receptora, mogu da budu korisni u primarnoj i sekundarnoj prevenciji infarkta miokarda, i ovu klasu lekova treba koristiti kao terapiju prvog izbora kod pacijenata sa ishemijskom bolešću srca kod kojih je indikovana supresija RAAS osovine

Vitamini i minerali u prevenciji bolesti - dokazi

A huge number of experimental results and the observations of epidemiological studies have opened wide possibilities of the use of vitamins and minerals in primary and secondary prevention of disease. This kind of health care concept, backed by media and marketing campaign, has been thoroughly established in general population. The randomized controlled double-blind trials possess the highest value in hierarchy of evidence for claims on the efficacy and safety of a treatment. Such investigations of the use of vitamins and minerals in disease prevention (cancer, cardiovascular diseases, respiratory infections, fractures, dementia, neonatal morbidity) have mostly produced, up to date, the null results. The obtaining of the affirmative results of preventive effects of vitamins and minerals, in the settings of the lack of clear deficiency, appears to be an exception needed to be revealed, but not a rule ready to be confirmed. Furthermore, the results of meta-analyses which show that the use of certain antioxidant vitamins (vitamin A, beta-carotene and vitamin E) may be associated with an increase in mortality in comparison with the control group ask for an additional attention.Veliki broj eksperimentalnih nalaza i rezultata epidemioloških istraživanja ukazuje na široke mogućnosti primene vitamina i minerala u primarnoj i sekundarnoj prevenciji bolesti. Ovaj koncept brige o zdravlju, podržavan medijski i marketinški, postao je široko prihvaćen u opštoj populaciji. Randomizovana kontrolisana dvostruko slepa ispitivanja imaju najveću vrednost u hijerarhiji dokaza za tvrdnje o efikasnosti i bezbednosti primene nekog tretmana. Ovakva ispitivanja primene minerala i vitamina u prevenciji bolesti (kancer, kardiovaskularne bolesti, respiratorne infekcije, frakture, demencija, neonatalni morbiditet) dala su, za sada, najčešće, neutralne rezultate. Dobijanje afirmativnih rezultata preventivnih efekata unošenja vitamina i minerala, u uslovima kada ne postoji jasna deficijencija, predstavlja izuzetak koji treba otkriti, a ne pravilo koje treba potvrditi. Posebnu pažnju pobuđuju rezultati meta-analiza koji pokazuju da bi primena određenih antioksidativnih vitamina (vitamin A, beta-karoten, vitamin E) mogla biti povezana sa povećanjem mortaliteta u odnosu na kontrolnu grupu

Neuro pharmacokinetics: the secret life of - old and novel - psychopharmacological drugs

In the 21st century, the pace of development of new pharmacological treatments for general medical and psychiatric disorders is remarkably different. While successes for the former are frequent, new drugs for mental, behavioral and neurodevelopmental disorders are sporadic. Many factors contribute to this discrepancy. Probably the most important is the complexity of etiology and manifestations of mood, psychotic, anxiety, neurocognitive and other disorders that are commonly treated with psycho pharmacological drugs. Although this factor cannot be directly addressed in drug development, optimization of drug exposure in brain tissue can certainly help to balance the efficacy and safety of both widely used and novel psycho pharmacological drugs. While drug exposure of various organs and tissues can be easily assessed from free (unbound) blood concentrations, the central nervous system (CNS) has a number of barriers, most notably the blood-brain barrier (BBB) that separates nervous tissue from the periphery. Optimised CNS exposure of a drug to its target site over a desired time period is critical to triggering its therapeutic effect. The presence of the BBB readily leads to an asymmetry of drug (unbound) exposure in the brain and in the systemic circulation, which prohibits the use of unbound drug concentration in plasma as a surrogate for unbound drug concentration in the brain. Comprehensive pharmacokinetic/pharmacodynamic studies of marketed CNS drugs have shown that the concentration of unbound drug in brain interstitial fluid is an appropriate measure of CNS exposure in the context of cell membrane targets of action. The more recent concept of brain-plasma partition coefficient, Kp,uu, as a parameter describing the relationship between the concentration of unbound drug in brain interstitial fluid and the concentration of unbound drug in plasma, is assumed to be the most important means of assessing brain exposure. Experimental assessment of Kp,uu requires either measurement of the brain unbound drug concentration in the interstitial fluid by microdialysis in vivo or estimation of the fraction of unbound drug in the whole brain homogenate (fu,brain) by equilibrium dialysis in vitro. Kp,uu can be calculated by dividing either the area under the curve (AUC) of the profile of the concentration of unbound drug in brain and plasma after a single administration or the steady-state unbound concentrations of drug in brain interstitial fluid and plasma. Although many marketed psychotropic drugs have Kp,uu values as low as 0.1-0.2, it is theorized that the most successful small molecule CNS drugs should have Kp,uu values near 1. The neuropharmacokinetic behavior of benzodiazepine compounds, both widely used and those in preclinical and clinical development, is presented as a showcase. Given the variety of receptor subpopulations at which these drugs act as positive allosteric modulators of GABAA receptors, the complexity of linking brain exposure data to the corresponding pharmacodynamic effect is explained.10th IAPC Meeting, Book of Abstract

Poremećaji spavanja i starenje

After early adulthood, sleep architecture is being subjected to continuous modifications, and the changes produced are mainly consolidated before moving into an older age group. In parallel, there is an increase in incidence of the majority of sleep disorders, while the others, related to the slow-wave sleep which is becoming more and more short-term, are starting to disappear. Insomnia, narcolepsy, REM-sleep behavior disorder, obstructive sleep apnea, sleep-related movement disorders (restless leg syndrome and periodic leg-movements) are among the disorders requiring an especial attention in older people. For insomnia management, one can use the general principles of sleep hygiene and, for a period no longer than 4 weeks, the hypnotics acting as positive allosteric modulators at the benzodiazepine binding site on GABAA receptors. The choice among hypnotics should be based on the differences in the length of their actions, and not on the relative receptor selectivity exerted by some of them. The relative role of newer hypnotics, acting through the melatonin receptors, is not clear yet. Among the other drugs which can be used in sleep disorders, there should be mentioned modafinil and methylphenidate as central stimulants, as well as sodium oxybate in narcolepsy, and levodopa-carbidopa and dopamine receptor agonists in REM-sleep behavior disorder and sleep-related movement disorders. The use of continuous positive airway pressure is the most effective treatment for obstructive sleep apnea.Po odrastanju, arhitektura sna podleže kontinuiranom prilagođavanju, i nastale promene su uglavnom već stabilizovane sa ulaskom u starije životno doba. Uporedo, raste i učestalost većine poremećaja spavanja, dok drugi, vezani za sporotalasno spavanje koje se skraćuje, počinju da izostaju. U poremećaje na koje treba obratiti posebnu pažnju kod starijih osoba spadaju insomnija, narkolepsija, poremećaj ponašanja u REM spavanju, opstruktivna apneja u snu i poremećaji pokreta vezani za spavanje (sindrom nemirnih nogu i periodični pokreti nogu). Za kontrolu insomnije, koriste se mere higijene spavanja i, u periodu od najduže četiri nedelje, hipnotici koji deluju kao pozitivni alosterni modulatori na benzodiazepinskom mestu vezivanja GABAA receptora. Izbor među hipnoticima treba zasnovati na razlikama u dužini njihovog dejstva, a ne na relativnoj receptorskoj selektivnosti koju pokazuju pojedini predstavnici. Relativni značaj novijih hipnotika, koji deluju preko receptora za melatonin, za sada nije jasan. U druge lekove koji se koriste kod poremećaja spavanja spadaju centralni stimulansi modafinil i metilfenidat, kao i natrijum oksibat kod narkolepsije, odnosno levodopa-karbidopa i agonisti receptora za dopamin kod poremećaja ponašanja u REM spavanju i poremećaja pokreta vezanih za spavanje. Za kontrolu opstruktivne apneje u snu najefikasnija je primena kontinuiranog pozitivnog pritiska vazduha

Kortikosteroidi - mehanizmi dejstva i farmakološki efekti

The multiple physiologic and pharmacologic effects of corticosteroids are considered to be mediated by genomic and non-genomic mechanisms. Genomic mechanisms encompass direct DNA binding and regulation of transcription of responsive genes, as well as protein-protein interactions with other transcription factors. Both pathways include activation of cytosolic glucocorticoid or mineralocorticoid receptors by the ligand and interactions with different chaperone proteins, leading to up-regulation or down-regulation of responsive gene expression. The rapid nongenomic effects are also initiated by the cytosolic receptors, and additionally by membrane-bound receptors and possibly by the direct interactions with cellular membranes. Local metabolism by the 11β-hydroxysteroid dehydrogenase enzymes governs the selective access of cortisol to glucocorticoid and mineralocorticoid receptors in different tissues. The effects of corticosteroids are numerous, and include changes in metabolism of carbohydrates, proteins and fat, preservation of water and electrolytes balance, and contribution to normal functioning of cardiovascular system, immune system, kidneys, skeletal muscles, endocrine and nervous system. These hormones are essential to life, and enable the organism to cope with physical and emotional stress.Raznovrsni fiziološki i farmakološki efekti kortikosteroida pripisuju se genomskim i ne-genomskim mehanizmima. Genomski mehanizmi uključuju direktno vezivanje za DNK i regulaciju transkripcije osetljivih gena, kao i protein-protein interakcije sa drugim transkripcionim faktorima. Oba puta podrazumevaju aktivaciju citosolnih receptora za glukokortikoide ili mineralokortikoide i interakcije sa različitim pratećim proteinima, što dovodi do ushodne ili nishodne regulacije ekspresije osetljivih gena. Brzi ne-genomski efekti se takođe pokreću citosolnim receptorima, ali dodatno i receptorima vezanim za membrane i mogućim direktnim interakcijama sa ćelijskim membranama. Lokalni metabolizam pod dejstvom 11β-hidroksisteroid dehidrogenaznih enzima je odgovoran za selektivni pristup kortizola glukokortikoidnim ili mineralokortikoidnim receptorima u različitim tkivima. Efekti kortikosteroida su brojni, i uključuju promene u metabolizmu ugljenih hidrata, proteina i masti, zatim održavanje ravnoteže vode i elektrolita, kao i očuvanje normalne funkcije kardiovaskularnog sistema, imunskog sistema, bubrega, skeletnih mišića, endokrinog sistema i nervnog sistema. Ovi hormoni su od suštinskog značaja za očuvanje života, i omogućuju organizmu da se izbori sa fizičkim i emocionalnim stresom

Lekovi za dermatološku primenu - klasifikacija i mehanizmi dejstva

Medicinal products used to treat dermatology diseases can be applied topically or systemically, which offers the possibility of various therapeutic modifications. However, skin changes are numerous and also very common in the general population. Many of them are difficult to manage satisfactorily with the existing means, and there is a need to develop novel drugs. Nevertheless, few novel drugs indicated for diseases treated primarily by dermatologists were introduced in recent decades. There are four difficulties to be overcome: the lack of a huge economic potential of these drugs, their hard-to-assess benefit-to-risk relationship, limitations of inadequate surrogate end points as well as incompleteness of knowledge of the pathophysiological substrates of skin diseases. The current drugs have various and sometimes only partly understood mechanisms of action. It is a common situation that there are no officially indicated medicines for a disease, resulting in widespread unlicensed and off-label administration of drugs. There are many unmet therapeutic needs and one of recent breakthroughs in the field was related to the introduction of biologic drugs, otherwise originally developed mainly for internal diseases.Lekoviti proizvodi koji se koriste u tretmanu dermatoloških bolesti mogu da se primenjuju topikalno (lokalno) ili sistemski, što omogućuje različite modifikacije u terapiji. Međutim, kožne promene su raznovrsne i vrlo česte u opštoj populaciji. Mnoge od njih je teško kontrolisati na zadovoljavajući način sa postojećim sredstvima i postoji potreba za razvojem novih lekova. Uprkos potrebama, poslednjih decenija je uvedeno malo novih lekova primarno indikovanih za primenu od strane dermatologa. Postoje četiri poteškoće koje je potrebno prevazići: izostanak velikog ekonomskog potencijala ovih lekova, teškoće u proceni odnosa koristi i rizika, ograničenja usled neadekvatnosti surogatnih parametara procena i nekompletnost poznavanja patofiziološkog supstrata kožnih bolesti. Postojeći lekovi imaju različite i često samo parcijalno upoznate mehanizme dejstva. Uobičajena je situacija da za pojedina stanja nema zvanično indikovanih lekova, što dovodi do široke primene lekova van i bez upotrebne licence. Brojne su neispunjene terapijske potrebe i jedan od skorašnjih pomaka u oblasti odnosio se na uvođenje bioloških lekova, koji su prvobitno razvijani prvenstveno za lečenje bolesti unutrašnjih organa