214 research outputs found
Neuropharmacokinetics: the secret life of - old and novel - psychopharmacological drugs
Neuro pharmacokinetics: the secret life of - old and novel - psychopharmacological drugs
Miroslav SaviÄ
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
PrekliniÄko predviÄanje 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 ā 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.PostojeÄe in vitro i in vivo prekliniÄke studije koje se sprovode tokom procesa
istraživanja i razvoja teŔko mogu predvideti neželjene efekte farmaceutika na centralni i
periferni nervni sistem. Postoji jasna potreba za poveÄanjem prediktivnosti prekliniÄkih
oruÄa, Å”to 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 preduzeÄa u
okviru projekta Inicijative za inovativne lekove (2019-2022). Univerzitet u Beogradu ā
Farmaceutski fakultet jeste partner koji predvodi radni parket posveÄen prekliniÄkom
predviÄanju neželjenih efekata na raspoloženje i kogniciju. Druge dve grupe izazovnih
neželjenih efekata koje projekat obraÄuje jesu konvulzivni napadi i periferne neuropatije.
KoriÅ”Äenjem mnoÅ”tva eksperimentalnih tehnika i brojnih farmaceutika koji su prethodno
povezani sa svakim od ispitivanih velikih neželjenih efekata, projekat traga za inovativnim
oruÄima, esejima i protokolima, koji pokrivaju in silico, in vitro, in vivo i ex vivo pristupe.
Mimo Å”irenja znanja o brojnim Å”iroko koriÅ”Äenim farmaceuticima, glavni cilj projekta jeste
razvoj integrisane platforme za bolju procenu rizika u buduÄim eksploratornim i
regulatornim studijama.VIII Kongres farmaceuta Srbije sa meÄunarodnim uÄeÅ”Äem, 12-15.10.2022. Beogra
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.RazliÄiti fiziÄki, fizioloÅ”ki i psiholoÅ”ki faktori, poznati kao stresori, utiÄu na homeostazu organizma. Stresni sistem, smeÅ”ten u centralnom nervnom sistemu kao i u perifernim organima, posreduje zaÅ”titni 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, veÄ zavisi od prirode stresora. Analiza podataka iz eksperimenata sa ljudima i životinjama pokazala je mnogo bližu korelaciju izmeÄu adrenalina u plazmi i promena ACTH (kao mere aktivnosti hipotalamo-hipofizno-adrenokortikalnog sistema), nego izmeÄu odgovora adrenalina i noradrenalina. Dok je odbrana od stresora od životnog znaÄaja, 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 poremeÄaja mogli biti bolje tretirani sa oÄekivanom novom generacijom lekova koji centralnim mehanizmom modifikuju stres, kao Å”to su antagonisti kortikotropin (ACTH) oslobaÄajuÄeg hormona (CRH) hipotalamusa
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 epidemioloÅ”kih istraživanja ukazuje na Å”iroke moguÄnosti primene vitamina i minerala u primarnoj i sekundarnoj prevenciji bolesti. Ovaj koncept brige o zdravlju, podržavan medijski i marketinÅ”ki, postao je Å”iroko prihvaÄen u opÅ”toj populaciji. Randomizovana kontrolisana dvostruko slepa ispitivanja imaju najveÄu 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, najÄeÅ”Äe, neutralne rezultate. Dobijanje afirmativnih rezultata preventivnih efekata unoÅ”enja vitamina i minerala, u uslovima kada ne postoji jasna deficijencija, predstavlja izuzetak koji treba otkriti, a ne pravilo koje treba potvrditi. Posebnu pažnju pobuÄuju rezultati meta-analiza koji pokazuju da bi primena odreÄenih antioksidativnih vitamina (vitamin A, beta-karoten, vitamin E) mogla biti povezana sa poveÄanjem mortaliteta u odnosu na kontrolnu grupu
PoremeÄaji 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 prilagoÄavanju, i nastale promene su uglavnom veÄ stabilizovane sa ulaskom u starije životno doba. Uporedo, raste i uÄestalost veÄine poremeÄaja spavanja, dok drugi, vezani za sporotalasno spavanje koje se skraÄuje, poÄinju da izostaju. U poremeÄaje na koje treba obratiti posebnu pažnju kod starijih osoba spadaju insomnija, narkolepsija, poremeÄaj ponaÅ”anja u REM spavanju, opstruktivna apneja u snu i poremeÄaji pokreta vezani za spavanje (sindrom nemirnih nogu i periodiÄni pokreti nogu). Za kontrolu insomnije, koriste se mere higijene spavanja i, u periodu od najduže Äetiri nedelje, hipnotici koji deluju kao pozitivni alosterni modulatori na benzodiazepinskom mestu vezivanja GABAA receptora. Izbor meÄu hipnoticima treba zasnovati na razlikama u dužini njihovog dejstva, a ne na relativnoj receptorskoj selektivnosti koju pokazuju pojedini predstavnici. Relativni znaÄaj novijih hipnotika, koji deluju preko receptora za melatonin, za sada nije jasan. U druge lekove koji se koriste kod poremeÄaja spavanja spadaju centralni stimulansi modafinil i metilfenidat, kao i natrijum oksibat kod narkolepsije, odnosno levodopa-karbidopa i agonisti receptora za dopamin kod poremeÄaja ponaÅ”anja u REM spavanju i poremeÄaja pokreta vezanih za spavanje. Za kontrolu opstruktivne apneje u snu najefikasnija je primena kontinuiranog pozitivnog pritiska vazduha
Kortikosteroidi - mehanizmi dejstva i farmakoloŔki 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 11Ī²-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 fizioloÅ”ki i farmakoloÅ”ki efekti kortikosteroida pripisuju se genomskim i ne-genomskim mehanizmima. Genomski mehanizmi ukljuÄuju 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 razliÄitim prateÄim proteinima, Å”to dovodi do ushodne ili nishodne regulacije ekspresije osetljivih gena. Brzi ne-genomski efekti se takoÄe pokreÄu citosolnim receptorima, ali dodatno i receptorima vezanim za membrane i moguÄim direktnim interakcijama sa Äelijskim membranama. Lokalni metabolizam pod dejstvom 11Ī²-hidroksisteroid dehidrogenaznih enzima je odgovoran za selektivni pristup kortizola glukokortikoidnim ili mineralokortikoidnim receptorima u razliÄitim tkivima. Efekti kortikosteroida su brojni, i ukljuÄuju promene u metabolizmu ugljenih hidrata, proteina i masti, zatim održavanje ravnoteže vode i elektrolita, kao i oÄuvanje normalne funkcije kardiovaskularnog sistema, imunskog sistema, bubrega, skeletnih miÅ”iÄa, endokrinog sistema i nervnog sistema. Ovi hormoni su od suÅ”tinskog znaÄaja za oÄuvanje života, i omoguÄuju organizmu da se izbori sa fiziÄkim i emocionalnim stresom
Lekovi za dermatoloŔku 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 dermatoloÅ”kih bolesti mogu da se primenjuju topikalno (lokalno) ili sistemski, Å”to omoguÄuje razliÄite modifikacije u terapiji. MeÄutim, kožne promene su raznovrsne i vrlo Äeste u opÅ”toj populaciji. Mnoge od njih je teÅ”ko kontrolisati na zadovoljavajuÄi naÄin sa postojeÄim 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 Äetiri poteÅ”koÄe koje je potrebno prevaziÄi: izostanak velikog ekonomskog potencijala ovih lekova, teÅ”koÄe u proceni odnosa koristi i rizika, ograniÄenja usled neadekvatnosti surogatnih parametara procena i nekompletnost poznavanja patofizioloÅ”kog supstrata kožnih bolesti. PostojeÄi lekovi imaju razliÄite i Äesto samo parcijalno upoznate mehanizme dejstva. UobiÄajena je situacija da za pojedina stanja nema zvaniÄno indikovanih lekova, Å”to dovodi do Å”iroke primene lekova van i bez upotrebne licence. Brojne su neispunjene terapijske potrebe i jedan od skoraÅ”njih pomaka u oblasti odnosio se na uvoÄenje bioloÅ”kih lekova, koji su prvobitno razvijani prvenstveno za leÄenje bolesti unutraÅ”njih organa
Psihofarmaci - juÄe, danas, sutra
There is no doubt that the inventors of chlorpromazine in 1952 were not able to anticipate the permanent consequences of their enterprise. Besides triggering discoveries of the vast number of further psychotropic drugs, this landmark ushered in the new era of development of neuroscience on the whole. The current use of psychotropic drugs is huge, and accounts for about 20% of all prescriptions. However, the drug development in the past few decades did not add much to the clinical efficacy or safety of the originally introduced antipsychotics, antidepressants or anxiolytics, and some serious suspicions on the overall role of this class of drugs have appeared in the meantime. The future investigations should answer these questions, and also make it possible to clinically separate wanted from unwanted effects of psychotropic drugs.Nesumnjivo, istraživaÄi koji su 1952. uveli hlorpromazin u kliniÄku primenu nisu mogli da pretpostave kakav trajan uticaj Äe imati njihov poduhvat. Pored podstreka za otkriÄe velikog broja drugih psihofarmaka, ovaj dogaÄaj je bio prekretnica koja je neuronauku u celini uvela u novu eru razvoja. SadaÅ”nja primena psihofarmaka je velika, i obuhvata oko 20% svih lekova izdatih na recept. Ipak, razvoj lekova u toku prethodnih nekoliko decenija nije doneo mnogo sa aspekta efikasnosti ili bezbednosti antipsihotika, antidepresiva ili anksiolitika, a u meÄuvremenu su se javile odreÄene ozbiljne sumnje vezane za ukupnu ulogu ove klase lekova. Dalja istraživanja treba da odgovore na ta pitanja, ali i da uÄine ostvarljivim kliniÄko razdvajanje željenih od neželjenih efekata psihofarmaka
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