Terapevtski potencial, varnost in potencial za zlorabo selektivnih modulatorjev androgenega receptorja

Stanković, Aleksandra (author), Peterlin Mašič, Lucija (mentor)

Selektivni modulatorji androgenega receptorja (ang. selective androgen receptor modulators – SARM) so novejša skupina kemično sintetiziranih spojin, ki se vežejo na androgeni receptor in izkazujejo tako agonistične kot antagonistične tkivno selektivne učinke. Razvili so jih z namenom zmanjševanja neželenih učinkov, ki jih imajo njihovi predhodniki, anabolni androgeni steroidi. Zadnje čase so deležni veliko pozornosti predvsem zaradi ugodnih anabolnih učinkov na mišice in kosti. Trenutno še noben selektivni modulator androgenega receptorja ni odobren za klinično uporabo, so pa številne učinkovine v različnih fazah kliničnega preskušanja kot potencialna terapija raka dojk, sarkopenije in kaheksije, ki je posledica raka ali kroničnih vnetnih bolezni, ter drugih bolezenskih stanj. Poleg obetavnega terapevtskega potenciala imajo selektivni modulatorji androgenega receptorja zaradi ugodnih anabolnih učinkov, tj. pozitivnega vpliva na povečanje mišične mase in posledično fizične moči, velik potencial za zlorabo s strani športnikov. V magistrski nalogi smo analizirali rezultate zaključenih kliničnih študij, ki preskušajo učinkovitost in varnost različnih selektivnih modulatorjev androgenega receptorja pri zdravljenju raka dojk in prostate, kaheksije, sarkopenije, erektilne disfunkcije ter stresne urinske inkontinence in na podlagi izsledkov ovrednotili njihov terapevtski potencial. S pregledom znanstvene literature smo ovrednotili tudi potencial za zlorabo teh snovi s strani profesionalnih in rekreativnih športnikov. Analizirali smo 9 študij ②. in ③. faze kliničnega preskušanja, ki so zaključene in katerih rezultati so dostopni. Nadalje smo pregledali znanstvene članke, ki so vsebovali izbrane ključne besede in so bili objavljeni v zadnjih petih letih. Ugotovili smo, da selektivni modulatorji androgenega receptorja izkazujejo določeno stopnjo učinkovitosti v terapiji kaheksije, ki je posledica raka ali kroničnih vnetnih bolezni, nezadostno učinkoviti pa so pri izboljševanju simptomov raka prostate, erektilne disfunkcije, stresne urinske inkontinence in sarkopenije. Naši rezultati kažejo, da ima izmed vseh predstavnikov te skupine učinkovin enobosarm največji terapevtski potencial, saj je že napredoval v ③. fazo kliničnega preskušanja za zdravljenje raka dojk. Veliko večji potencial pa imajo selektivni modulatorji androgenega receptorja za zlorabe. K temu največ pripomore njihova enostavna dostopnost preko spleta in promoviranje na družabnih omrežjih. Posledice zlorabe pa so lahko nevarne, saj lahko že po nekaj tednih njihove uporabe pride do poškodb jeter.

• Language: Slovenian
• Keywords: selektivni modulatorji androgenega receptorja, terapevtski potencial, varnost, zloraba
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-142758
• Publication date in RUL: 24.11.2022

Secondary language

• Language: English
• Title: Therapeutic potential, safety and abuse potential of selective androgen receptor modulators

Abstract

Selective androgen receptor modulators (SARMs) are a new group of chemically synthesised compounds that bind to the androgen receptor and have tissue-specific actions that include both agonistic and antagonistic effects. They were developed to minimise the off-target effects of anabolic androgenic steroids and have attracted a lot of attention recently, mainly because of their positive anabolic effects on muscle and bone tissue. Although not approved for therapeutic use, many of these compounds are being tested in clinical trials for the treatment of breast and prostate cancer, sarcopenia, cancer- or chronic disease-related cachexia and other conditions. In addition to their promising therapeutic potential selective androgen receptor modulators also have a high potential for abuse by athletes due to their beneficial anabolic effects on muscles and physical strength. In this Master's thesis, we analysed the results of the completed clinical trials, whose aim was to determine whether tested SARMs are safe and effective in the treatment of various conditions such as breast and prostate cancer, cancer- or chronic disease-related cachexia, erectile dysfunction, sarcopenia and stress urinary incontinence, and on this basis, we evaluated the therapeutic potential of SARMs. We also assessed the abuse potential of these substances by professional and recreational athletes based on the review of scientific articles. We analysed 9 phase 2 and 3 clinical trials that have been completed and whose results are available, and we also reviewed scientific articles containing the selected keywords and published in the last 5 years. We found that SARMs show some efficacy in the treatment of cachexia associated with cancer or chronic inflammatory diseases and are insufficiently effective in the management of prostate cancer, erectile dysfunction and stress urinary incontinence symptoms and treatment of sarcopenia. We also determined that enobosarm has the highest therapeutic potential among all SARMs tested, as it progressed to phase 3 clinical trials for the treatment of metastatic breast cancer. Selective androgen receptor modulators have a greater potential for abuse, primarily because they can be easily purchased on the internet and because of the impact of social media. In addition, the consequences of abuse can be dangerous, as they can cause liver damage after only a few weeks of use.

• Keywords: selective androgen receptor modulators, therapeutic potential, safety, abuse potential