<p>Raloksifen je predstavnik selektivnih modulatora estrogenih receptora koji se koristi u terapiji osteoporoze i invazivnog oblika raka dojke u postmenopauzi. Raloksifen se relativno dobro resorbuje iz gastrointestinalnog trakta, ali pri prvom prolasku kroz jetru podleže biotransformaciji u značajnom procentu, &scaron;to je uzrok njegove niske biolo&scaron;ke raspoloživosti. Bioraspoloživost kod ljudi iznosi 2%, a kod Wistar pacova 39%. Različite supstance se koriste da bi se pobolj&scaron;ala bioraspoloživost lekova. Žučne kiseline, kao &scaron;to je deoksiholna kiselina, omogućavaju bolji prolazak kroz biolo&scaron;ke membrane drugim supstancama, te mogu povećati bioraspoloživost lekova. Apigenin je &scaron;iroko rasprostranjeni flavonoid koji inhibi&scaron;e različite metaboličke puteve i na taj način može usporiti metabolizam i eliminaciju i povećati koncentraciju lekova u krvi. Ciljevi ovog istraživanja su bili da se ispita da li apigenin i natrijum-deoksiholat mogu povećati bioraspoloživost raloksifena, njihov uticaj na biohemijske parametre i parametre hemostaze, kao i da se ispita antioksidativni potencijal apigenina. Ispitan je i uticaj apigenina na akutno o&scaron;tećenje jetre usled primene toksične doze paracetamola. U istraživanju su kori&scaron;ćeni zdravi, beli pacovi mu&scaron;kog roda, soja Wistar. U ogledu su ukupno kori&scaron;ćene 84 eksperimentalne životinje. Sva ispitivanja na životinjama je odobrila Etička komisija Univerziteta u Novom Sadu. Raloksifen je primenjen intravenski i per os, dok su natrijum-deoksiholat i apigenin aplikovani peroralno. Uzorci krvi, urina i fecesa su kori&scaron;ćeni za određivanje farmakokinetskih parametara, dok su za određivanje biohemijskih, hemostatskih i parametara oksidativnog stresa kori&scaron;ćeni serum i uzorci jetre laboratorijskih životinja. Pretretman natrijum-deoksiholatom je doveo do smanjenja koncentracije raloksifena u krvi zbog olak&scaron;anog i brzog prodora raloksifena u periferne kompartmane. Time je značajno produženo poluvreme eliminacije i srednje vreme zadržavanja raloksifena i značajno je povećan volumen distribucije raloksifena. Apigenin je doveo do manjeg pada koncentracije raloksifena u prvim satima nakon intravenske primene raloksifena, dok su koncentracije raloksifena bile značajno vi&scaron;e nakon osmog časa od primene leka. Uticaj raloksifena na biohemijske parametre je bio značajno veći nakon intravenske nego nakon peroralne primene. Nakon intravenske primene raloksifena je značajno povećana aktivnost enzima jetre, ALP, ALT, AST i GGT, dok su pokazatelji funkcije bubrega, urea, mokraćna kiselina i kreatinin bili sniženi. U grupama koje su pretretirane natrijum-deoksiholatom i apigeninom vrednosti ovih parametara bile su niže u odnosu na grupu tretiranu samo raloksifenom. Statistički najznačajniji uticaj je imala primena trojne kombinacije, raloksifena, natrijum-deosiholata i apigenina, koja je dovela do značajnog pada aktivnosti enzima jetre, i u odnosu na grupu tretiranu raloksifenom i u odnosu na kontrolnu grupu. Kod životinja tretiranih kombinacijom apigenina i paracetamola pokazatelji toksičnosti su bili značajno niži, naročito vrednosti ALT i ALP, u odnosu na grupu koja je dobijala samo paracetamol. Hepatotoksičnost izazvana toksičnom dozom paracetamola je potvrđena i histopatolo&scaron;kim promenama na jetri, koje nisu primećene u grupi životinja tretiranih kombinacijom apigenina i paracetamola. Ispitivanjem je utvrđeno da apigenin može da spreči paracetamolom indukovano povećanje nivoa MDA, &scaron;to ukazuje da apigenin pozitivno utiče na očuvanje integriteta ćelije. Aktivnost enzima CAT i GR u homogenatima jetre je bila značajno povećana nakon primene toksične doze paracetamola u odnosu na kontrolnu grupu. Aktivnost enzima CAT i GR u grupi tretiranoj kombinacijom apigenina i paracetamola je bila približna vrednostima u kontrolnoj grupi. Na osnovu rezultata istraživanja može se zaključiti da natrijum-deoksiholat i apigenin značajno utiču na farmakokinetiku raloksifena. Primena natrijum-deoksiholata dovela je do pada koncentracije raloksifena u krvi, značajnog prelaska raloksifena iz krvi u periferne kompartmane i povećanja njegovog volumena distribucije, dok je apigenin značajno usporio metabolizam i eliminaciju raloksifena i doveo do njegovog produženog zadržavanja u krvi. Natrijum-deoksiholat i apigenin su pokazali pozitivan uticaj na biohemijske parametre, parametre hemostaze i smanjenje nivoa oksidativnog stresa. Kombinacija natrijum-deoksiholata i apigenina je pokazala sinergistički uticaj na navedene parametre, odnosno dovela je do značajnih promena u odnosu na pojedinačnu primenu ovih supstanci. Rezultati ispitivanja ukazuju na to da apigenin smanjuje stepen lipidne peroksidacije i da dovodi do značajnog povećanja enzimskih antioksidantnih mehanizama odbrane kod pacova kod kojih je hepatotoksičnost indukovana paracetamolom.</p> / <p>Raloxifene is selective estrogen receptor modulator used in treatment of osteoporosis and invasive breast cancer in postmenopausal women. Raloxifene is well absorbed from the gastrointestinal tract, but undergoes extensive first-pass metabolism, which results in very low bioavailability of raloxifene, 2% in humans, and 39% in Wistar rats. Various supstances are used for increasing bioavailability of other drugs. Bile acids, such as deoxycholic acid, promote transport of other supstances through biological membranes, and consequently, may increase their bioavailability. Apigenin is a widespread flavonoid, which inhibits different metabolic pathways. Thus, apigenin can slow down metabolism and elimination of drugs, and raise drug concentration in blood. Aims of this study were to investigate if apigenin and sodium deoxycholate could increase bioavailability of raloxifene, their influence on biochemical and hemostasis parameters, and to investigate antioxidative potential of apigenin. Furthermore, influence of apigenin on acute liver damage after toxic dose of paracetamol was examined. In vivo experiments were performed on 84 laboratory healthy male Wistar rats. All experiments were approved by Ethics Committee of University of Novi Sad. Raloxifene was applied intravenously and per os, while sodium deoxycholate and apigenin were given perorally. Blood, urine and feces samples were used for pharmacokinetic parameters measurement, whereas serum and liver samples were used for evaluation of biochemical, hemostasis and oxidative stress parameters. Pretreatment of sodium deoxycholate led to raloxifene blood concentration decrease due to easier penetration of raloxifene in peripher compartments. As a result, raloxifene half-life and mean residence time were significantly longer and volume of distribution was increased. Apigenin caused lower decrease in raloxifene concentration in first few hours after raloxifene intravenous application, while raloxifene concentrations after apigenin pretreatment were significantlny higher 8 hours after raloxifene application. Influence of raloxifene on biochemical parameters was more significant after intravenous than after per os application. Intravenous application of raloxifene led to increased activity of liver enzymes, ALP, ALT, AST and GGT, while parameters of kidney function, urea, uric acid and creatinine were decreased in comparison to the control group. In experimental groups pretreated with sodium deoxycholate and apigenin these parameters were lower than in the group treated only with raloxifene. Statistically the most significant effects were in the group treated with combination of raloxifene, sodium deoxycholate and apigenin, which caused significant decrease in activity of liver enzymes compared both with raloxifene and control group of animals. In experimental animals treated with combination of apigenin and paracetamol bioindicators of paracetamol toxicity were significantly lower, especially activity of ALT and ALP, in comparison to the group treated only with paracetamol. Hepatotoxicity induced by toxic dose of paracetamol was also confirmed by histopathological alterations in liver, which were not observed in the experimental group treated with combination of apigenin and paracetamol. In this study it was confirmed that apigenin could prevent paracetamol-induced MDA level increase, which suggests that apigenin have positive effects on cell integrity. Activity of CAT and GR in liver homogenates was significantly increased after toxic dose of paracetamol in comparison to the control group, while activity of these enzymes in the group treated with apigenin and paracetamol was similar to values in the control group. Results of this study showed that sodium deoxycholate and apigenin can significantly change pharmacokinetic parameters of raloxifene. Sodium deoxycholate caused signicant decrease in raloxifene blood concentration, extensive distribution from blood to peripheral compartments and increase of raloxifene volume of distribution. Apigenin inhibited metabolism and elimination of raloxifene and thus prolonged half-life and mean residence time of raloxifene. Sodium deoxycholate and apigenin showed positive effects on biochemical and hemostasis parameters and decreased the level oxidative stress. Combination of sodium deoxycholate and apigenin showed synergistic effects on these parameters in comparison to effects of separate application of sodium deoxycholate and apigenin. The result of our study indicates that apigenin inhibits the level of lipid peroxidation and significantly increase the enzyme antioxidant defence mehanisms in paracetamol induced hepatotoxicity in rats.</p>

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<p dir="ltr">People suffering from COPD are also known to suffer from other musculoskeletal issues like fracture risk, back pain, etc. Intervertebral disc degeneration (IVD) is a prominent cause of back pain and inflammation, influenced by factors such as aging, sudden loading, and genetics. <i>SERPINA1</i>, a common genetic variant in individuals with chronic obstructive pulmonary disease (COPD), encodes the alpha-antitrypsin protein (AAT). AAT deficiency is also associated with IVD degeneration, bone loss, and gait impairment. Currently, AAT-deficient individuals receive costly and short-lived weekly AAT injections, with no established guidelines for managing IVD degeneration and osteoporosis. Our primary research objective was to examine the effects of <i>serpinA1a/c</i> using a mouse model with global knockout (KO) of <i>serpinA1a/c</i>, generated through CRISPR technology, on intervertebral discs (IVD) and bone. We found that global deletion of <i>serpinA1a/c</i> was found to cause IVD elastin degradation, leading to a loss of mechanical properties. Moreover, <i>serpinA1</i> was associated with increased bone-resorbing cells (osteoclasts) and a reduction in bone-forming cells (osteoblasts). Notably, sexual dimorphism was observed, with female IVDs exhibiting less degeneration than male counterparts, and <i>serpinA1a/c</i> KO mice were protected from mechanically-induced tail compression. Even in human IVDs, males expressed more AAT-1 compared to female IVDs. There are no FDA-approved drugs currently existing for IVD degeneration. Since IVD degeneration frequently occurs in individuals with osteoporosis, it shows a probable cross-talk happening between IVD and bone. In our study, we found the association of <i>serpinA1 </i>with estrogen receptor alpha and osteoclasts. Hence, we investigated the potential of raloxifene, an FDA-approved selective estrogen receptor modulator (SERM) typically prescribed to post-menopausal women for osteoporosis treatment, in averting IVD degeneration and improving mechanical characteristics in IVD. Our findings suggest that raloxifene injection may retard IVD degeneration induced by AAT deficiency, particularly in male mice. Furthermore, the latter study touched upon a conditional <i>serpinA1a</i> mouse model crossed with aggrecan-cre, specifically targeting <i>serpinA1a</i>-expressing cells in the IVD while sparing bone. Conditional <i>serpinA1a</i> deletion induced mild IVD degeneration without affecting bone loss. In summary, this study serves as a foundation for testing potential treatments for AAT patients with IVD degeneration and osteoporosis. It also provides compelling evidence for considering raloxifene as a treatment option for IVD degeneration in AAT-deficient patients experiencing IVD-related pain.</p>