LitCovid-sentences  

PMC:7463108 / 96888-111927 JSONTXT 10 Projects

Annnotations TAB TSV DIC JSON TextAE Lectin_function

Id Subject Object Predicate Lexical cue
T1234 0-39 Sentence denotes Questions Remaining – Future Directions
T1235 41-96 Sentence denotes Modeling the Pharmacology of Opioid Self-Administration
T1236 97-319 Sentence denotes Opiate self-administration as seen with addiction can have different CNS consequences than “steady-state” (e.g., continuous via a pump or time-release drug implant) exposure to the same drug (Kreek 1987, 2001; Kreek et al.
T1237 320-435 Sentence denotes 2002), and we predict the pharmacokinetic differences in opiate exposure will markedly impact neuroHIV progression.
T1238 436-691 Sentence denotes Differential effects based on “on-off” and “steady-state” drug administration schedules have been reported for the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, the endogenous opioid system, and the dopamine system (Kreek 1973; Kreek et al.
T1239 692-711 Sentence denotes 2002; George et al.
T1240 712-718 Sentence denotes 2012).
T1241 719-913 Sentence denotes Acute opiate exposure typically activates the HPA axis, corticotropin releasing factor, and peripheral steroidogenesis in a species-dependent manner (Koob and Kreek 2007; Cleck and Blendy 2008).
T1242 914-1040 Sentence denotes Alternatively, chronic self-administration of short-acting opiates suppresses diurnal cortisol rhythmicity (Facchinetti et al.
T1243 1041-1059 Sentence denotes 1984; Vuong et al.
T1244 1060-1181 Sentence denotes 2010), while opiate withdrawal typically evokes HPA activation (Culpepper-Morgan and Kreek 1997; Kreek 2007; Paris et al.
T1245 1182-1188 Sentence denotes 2020).
T1246 1189-1379 Sentence denotes The daily, repeated bouts of relative withdrawal seen with opiate addiction cause sustained HPA activation, stress (Koob and Kreek 2007; Koob 2020), and immune suppression (Eisenstein 2019).
T1247 1380-1531 Sentence denotes Importantly, maintenance therapy with the long-acting drug methadone achieves steady-dose opiate levels and normalization of the HPA axis (Kreek 1973).
T1248 1532-1664 Sentence denotes Further, it is known that HIV infection significantly alters the HPA axis, due to CNS toxicity and cytokine production (Costa et al.
T1249 1665-1723 Sentence denotes 2000; George and Bhangoo 2013; Chrousos and Zapanti 2014).
T1250 1724-1905 Sentence denotes Additionally, the nature of opiate exposure in the context of neuroHIV needs to be considered as it may induce different outcomes on neurotransmitter metabolism and gene expression.
T1251 1906-2049 Sentence denotes Specifically, the NAc shell demonstrates molecular and structural changes associated with intravenous heroin self-administration (Jacobs et al.
T1252 2050-2056 Sentence denotes 2005).
T1253 2057-2364 Sentence denotes Moreover, earlier studies have reported differential alterations in the turnover rates of various neurotransmitters for active versus passive morphine administration, including dopamine, serotonin, γ-aminobutyric acid (GABA), acetylcholine, aspartate, and glutamate during exposure to morphine (Smith et al.
T1254 2365-2377 Sentence denotes 1982, 1984).
T1255 2378-2656 Sentence denotes The disruptions were noticed specifically in brain regions involved in reinforcement processes, including the NAc, frontal cortex, and striatum, and encompassed increased dopamine and norepinephrine levels and turnover, which are central in opiate reward processes (Smith et al.
T1256 2657-2663 Sentence denotes 1982).
T1257 2664-2905 Sentence denotes Heroin abuse is known to downregulate dopaminergic activity in the NAc and may reflect a compensatory reduction in of dopamine biosynthesis in response to excessive dopaminergic stimulation resulting from chronic opiate exposure (Kish et al.
T1258 2906-2912 Sentence denotes 2001).
T1259 2913-2997 Sentence denotes Additionally, HIV is known to interfere with dopamine neurotransmission (Nath et al.
T1260 2998-3019 Sentence denotes 2000b; Gaskill et al.
T1261 3020-3130 Sentence denotes 2017) causing reductions in presynaptic dopamine terminals and dopamine transport in the striatum (Wang et al.
T1262 3131-3149 Sentence denotes 2004; Chang et al.
T1263 3150-3168 Sentence denotes 2008; Midde et al.
T1264 3169-3181 Sentence denotes 2012, 2015).
T1265 3182-3344 Sentence denotes The decline in dopamine function may exacerbate opioid abuse tendencies and drug-seeking behaviors as the rewarding effects of opioids are discounted by neuroHIV.
T1266 3346-3441 Sentence denotes Opioid Substitution Therapies and the Role of Selective/Biased Agonism in neuroHIV Pathogenesis
T1267 3442-3743 Sentence denotes Although morphine, methadone, and buprenorphine all activate MOR, each can impart different signals through MOR, related to the nature and timing of their coupling to Gα, Gβγ, β-arrestin and/or regulators of G protein signaling (RGS), since each downstream effector couples into unique cell functions.
T1268 3744-3885 Sentence denotes Functional selectivity occurs at each opioid receptor type, and for most endogenous opioid peptides at all three receptor types (Gomes et al.
T1269 3886-3892 Sentence denotes 2020).
T1270 3893-4117 Sentence denotes Moreover, opioid receptors can be expressed on a subset of virtually every cell type in the CNS—with second messenger coupling to each opioid receptor type potentially being unique, cell-type specific, and context dependent.
T1271 4118-4207 Sentence denotes Thus, the “pluridimensional” (Galandrin and Bouvier 2006; Kenakin 2011; Costa-Neto et al.
T1272 4208-4442 Sentence denotes 2016) actions of any opiate at MOR are sufficiently complicated that it is not possible to predict whether, e.g., morphine, methadone or buprenorphine, would similarly effect any aspect of neuroHIV pathology without empirical testing.
T1273 4443-4684 Sentence denotes Despite their significant use as medication-assisted therapies for treating opioid addiction, few studies have directly compared commonly used opiate substitution therapies (Bell and Strang 2020), especially in relation to HIV (Khalsa et al.
T1274 4685-4702 Sentence denotes 2006; Choi et al.
T1275 4703-4709 Sentence denotes 2020).
T1276 4710-4839 Sentence denotes Opioid substitution therapies significantly reduce the frequency of injection drug use (Kwiatkowski and Booth 2001; Pettes et al.
T1277 4840-4895 Sentence denotes 2010), decrease HIV transmission risk (MacArthur et al.
T1278 4896-4914 Sentence denotes 2012; Platt et al.
T1279 4915-4971 Sentence denotes 2016), and reduce drug-related mortality (Mathers et al.
T1280 4972-5024 Sentence denotes 2013) and the risk of opioid overdose (Volkow et al.
T1281 5025-5031 Sentence denotes 2014).
T1282 5032-5232 Sentence denotes Further, improved ARV outcomes among PWH have been reported with opioid substitution therapies, including the uptake and retention on ARV, medication adherence rates, and viral suppression (Low et al.
T1283 5233-5257 Sentence denotes 2016; Mukandavire et al.
T1284 5258-5264 Sentence denotes 2017).
T1285 5265-5460 Sentence denotes The two main medications used for opioid substitution therapy include methadone, a MOR full agonist, and buprenorphine, a MOR partial agonist and partial antagonist of KOR (Noble and Marie 2018).
T1286 5461-5741 Sentence denotes In comparison to methadone, buprenorphine has been shown to have fewer pharmacodynamic interactions with ARVs and causes less opioid withdrawal symptoms potentially due to its partial agonism on MOR, but also due to its high affinity and long duration of MOR binding (Walsh et al.
T1287 5742-5791 Sentence denotes 1994; McCance-Katz 2005; Whelan and Remski 2012).
T1288 5792-5913 Sentence denotes Further, differential proinflammatory and neurotoxic effects have been noted for various opioid treatments (Boland et al.
T1289 5914-5934 Sentence denotes 2014; Fitting et al.
T1290 5935-5957 Sentence denotes 2014b; Carvallo et al.
T1291 5958-5984 Sentence denotes 2015; Dutta and Roy 2015).
T1292 5985-6089 Sentence denotes In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al.
T1293 6090-6111 Sentence denotes 2000; Belcheva et al.
T1294 6112-6133 Sentence denotes 2003; McLennan et al.
T1295 6134-6151 Sentence denotes 2008; Hahn et al.
T1296 6152-6306 Sentence denotes 2010), and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca2+]i alone or following Tat co-exposure (Fitting et al.
T1297 6307-6314 Sentence denotes 2014b).
T1298 6315-6417 Sentence denotes Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al.
T1299 6418-6450 Sentence denotes 2008a; Dave 2012; El-Hage et al.
T1300 6451-6616 Sentence denotes 2014), while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al.
T1301 6617-6638 Sentence denotes 2014; Carvallo et al.
T1302 6639-6671 Sentence denotes 2015; Jaureguiberry-Bravo et al.
T1303 6672-6693 Sentence denotes 2016; Chilunda et al.
T1304 6694-6700 Sentence denotes 2019).
T1305 6701-7003 Sentence denotes As most opiate drugs preferentially act via MOR, a potential explanation for differential interactive effects of opioids in the context of neuroHIV is the phenomenon of selective or “biased agonism”, such that different agonists can trigger distinct signaling events at the same receptor (Hauser et al.
T1306 7004-7010 Sentence denotes 2012).
T1307 7011-7152 Sentence denotes For example, coupling of MOR to Gα, Gβγ, and/or β-arrestin have been noted to differ depending on the MOR agonists involved (McPherson et al.
T1308 7153-7174 Sentence denotes 2010; Thompson et al.
T1309 7175-7196 Sentence denotes 2015; Burgueno et al.
T1310 7197-7203 Sentence denotes 2017).
T1311 7204-7406 Sentence denotes Physiologic outcomes of MOR activation in any cell type are determined by a bias for specific signaling pathways, the initial step of which is activation of G proteins and/or β-arrestin (Williams et al.
T1312 7407-7427 Sentence denotes 2013b; Violin et al.
T1313 7428-7451 Sentence denotes 2014; Suomivuori et al.
T1314 7452-7458 Sentence denotes 2020).
T1315 7459-7628 Sentence denotes The subcellular organization of GPCR signaling transduced by heterotrimeric G proteins and β-arrestin has been recently reviewed in detail (Eichel and von Zastrow 2018).
T1316 7629-7827 Sentence denotes In the context of HIV, it has been shown that selective MOR agonists such as endomorphin-1, but not DAMGO or morphine, significantly increase HIV-1 replication in infected microglia (Peterson et al.
T1317 7828-7834 Sentence denotes 1999).
T1318 7835-8052 Sentence denotes This effect might be due to an apparent bias of endomorphin-1 towards arrestin recruitment and receptor phosphorylation, which was significantly correlated with agonist-induced internalization of MOR (McPherson et al.
T1319 8053-8059 Sentence denotes 2010).
T1320 8060-8300 Sentence denotes It is suggested that ligands that display bias towards G protein-mediated pathways and away from β-arrestin 2 recruitment may have improved therapeutic profiles against the development of tolerance and dependence/addiction (McPherson et al.
T1321 8301-8307 Sentence denotes 2010).
T1322 8309-8380 Sentence denotes Opioid Effects on Antiretroviral Efficacy within the CNS and Vice Versa
T1323 8381-8454 Sentence denotes Opioid misuse has been linked to poor adherence to cART (Jeevanjee et al.
T1324 8455-8461 Sentence denotes 2014).
T1325 8462-8566 Sentence denotes However, adherence to ARV therapy improves after initiation of opioid substitution therapy (Nosyk et al.
T1326 8567-8583 Sentence denotes 2015; Low et al.
T1327 8584-8602 Sentence denotes 2016; Adams et al.
T1328 8603-8609 Sentence denotes 2020).
T1329 8610-8824 Sentence denotes Although better adherence can improve therapeutic outcomes in PWH, little information is currently available on the interaction between opioids or opioid substitution therapies and cART specifically within the CNS.
T1330 8825-8933 Sentence denotes There are several known drug-drug interactions between opioids and ARVs that affect systemic concentrations.
T1331 8934-9039 Sentence denotes The partial opioid agonist, buprenorphine, is metabolized primarily by cytochrome P450 (CYP) 3A4 and 2C8.
T1332 9040-9190 Sentence denotes Both buprenorphine and its active metabolite, norbuprenorphine, are glucuronidated by UDP-glucuronosyltransferase (UGT) 1A1 and then excreted in bile.
T1333 9191-9247 Sentence denotes Several ARVs inhibit or induce these metabolic pathways.
T1334 9248-9302 Sentence denotes However, not all interactions are clinically relevant.
T1335 9303-9604 Sentence denotes The boosted protease inhibitor combination, atazanavir/ritonavir, inhibits CYP 3A4 and UGT 1A1, leading to increases in overall systemic exposure of buprenorphine and norbuprenorphine and also results in symptoms of opioid excess, such as increased sedation and impaired cognition (McCance-Katz et al.
T1336 9605-9611 Sentence denotes 2007).
T1337 9612-9737 Sentence denotes Dose adjustments of buprenorphine are recommended when initiating therapy with atazanavir to avoid symptoms of opioid excess.
T1338 9738-9852 Sentence denotes Methadone is a full opioid substrate with multiple metabolic pathways, including CYP 3A4, 2B6, 2C19, 2C9, and 2D6.
T1339 9853-9945 Sentence denotes Several pharmacokinetic interactions are reported between methadone and protease inhibitors.
T1340 9946-10050 Sentence denotes However, withdrawal symptoms are rare, and therefore, dose adjustments are not recommended (Bruce et al.
T1341 10051-10071 Sentence denotes 2006; Meemken et al.
T1342 10072-10078 Sentence denotes 2015).
T1343 10079-10243 Sentence denotes In contrast, efavirenz and nevirapine induce CYP 3A4, resulting in decreased systemic concentrations of methadone and the development of opioid withdrawal symptoms.
T1344 10244-10388 Sentence denotes To avoid opioid withdrawal, increased methadone dosing is recommended when either efavirenz or nevirapine therapy is initiated (Marzolini et al.
T1345 10389-10408 Sentence denotes 2000; Clarke et al.
T1346 10409-10429 Sentence denotes 2001; Meemken et al.
T1347 10430-10436 Sentence denotes 2015).
T1348 10437-10589 Sentence denotes Oxycodone metabolism is inhibited by lopinavir/ritonavir, increasing oxycodone concentrations as well as the self-reported drug effects (Nieminen et al.
T1349 10590-10607 Sentence denotes 2010; Feng et al.
T1350 10608-10614 Sentence denotes 2017).
T1351 10615-10695 Sentence denotes The pharmacokinetic studies above focused on overall systemic exposure of drugs.
T1352 10696-10782 Sentence denotes Plasma concentrations, however, are not always accurate indicators of tissue exposure.
T1353 10783-10875 Sentence denotes Similarly, CNS drug exposure is often estimated based on drug concentrations within the CSF.
T1354 10876-10949 Sentence denotes However, CSF drug levels may not accurately predict brain concentrations.
T1355 10950-11086 Sentence denotes For many drugs with high efflux activities (e.g., substrates of P-gp), CSF tends to over-predict brain tissue concentrations (Liu et al.
T1356 11087-11106 Sentence denotes 2006; Friden et al.
T1357 11107-11127 Sentence denotes 2009; Kodaira et al.
T1358 11128-11140 Sentence denotes 2011, 2014).
T1359 11141-11245 Sentence denotes This could be due, in part, to differential expression of transporters at the blood-CSF barrier vs. BBB.
T1360 11246-11466 Sentence denotes In a study of the ARV drug amprenavir, concentrations of [14C]-amprenavir in CSF versus brain were 23.3 ± 11.2 and 3.33 ± 0.6 nCi/g, respectively, demonstrating overprediction of brain concentrations by CSF (Polli et al.
T1361 11467-11473 Sentence denotes 1999).
T1362 11474-11600 Sentence denotes These studies illustrate the high likelihood of misinterpreting drug brain penetration when using CSF as the surrogate marker.
T1363 11601-11795 Sentence denotes Therefore, direct measurement of brain tissue concentrations in animal models are likely to be more predictive of the interactive effects of ARVs and opioids on ARV and/or opioid brain exposure.
T1364 11796-11913 Sentence denotes A few studies have investigated the impact of opioids and ARV administration on drug concentrations within the brain.
T1365 11914-12195 Sentence denotes One study investigated the impact of 5 d continuous exposure to morphine on ARV brain concentrations (dolutegravir, lamivudine and abacavir) and demonstrated that morphine exposure resulted in regionally specific decreases in the concentrations of select ARV drugs (Leibrand et al.
T1366 12196-12384 Sentence denotes 2019) and, furthermore, that the decreases in ARV concentrations (dolutegravir and abacavir) were likely due to increased efflux by the drug efflux transport protein, P-gp (Leibrand et al.
T1367 12385-12391 Sentence denotes 2019).
T1368 12392-12496 Sentence denotes Morphine alterations in P-gp within the brain could have wide reaching impact on other CNS active drugs.
T1369 12497-12667 Sentence denotes HIV preferentially infects microglia and perivascular macrophages within the brain, although BMECs, astrocytes, and pericytes can also be infected (Kramer-Hammerle et al.
T1370 12668-12674 Sentence denotes 2005).
T1371 12675-12766 Sentence denotes Achieving optimal intracellular ARV concentrations are essential to suppress the infection.
T1372 12767-12926 Sentence denotes Few studies have examined whether ARV drugs differentially accumulate within different neural cell types and especially within cells of the neurovascular unit.
T1373 12927-13245 Sentence denotes Although nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are efficacious in inhibiting viral replication within monocyte-derived macrophages, only a few drugs within each ARV class can effectively inhibit viral replication within astrocytes (Gray et al.
T1374 13246-13330 Sentence denotes 2013), which could be a result of poor intracellular accumulation within astrocytes.
T1375 13331-13525 Sentence denotes In vitro studies have demonstrated darunavir and raltegravir intracellular concentrations to be approximately 100-fold lower (with higher EC50 values) in microglia than in PBMCs (Asahchop et al.
T1376 13526-13532 Sentence denotes 2017).
T1377 13533-13703 Sentence denotes Another study measured intracellular concentrations of dolutegravir, tenofovir and emtricitabine in primary human astrocytes, microglia, pericytes and BMECs (Patel et al.
T1378 13704-13710 Sentence denotes 2019).
T1379 13711-13824 Sentence denotes Intracellular ARV concentrations were typically significantly higher in BMECs than in the other brain cell types.
T1380 13825-13959 Sentence denotes Dolutegravir achieved the highest relative concentrations within each cell type, whereas tenofovir accumulated the least (Patel et al.
T1381 13960-13966 Sentence denotes 2019).
T1382 13967-14116 Sentence denotes Furthermore, 24 h treatment with morphine significantly decreased intracellular accumulation of composite ARV concentrations, but only in astrocytes.
T1383 14117-14236 Sentence denotes In contrast, morphine exposure significantly increased the net accumulation of drugs within BMECs compared to controls.
T1384 14237-14306 Sentence denotes BMECs may sequester ARV drugs as a protective mechanism (Patel et al.
T1385 14307-14313 Sentence denotes 2019).
T1386 14314-14592 Sentence denotes Using experimental data from SIV-infected, morphine-addicted macaques, mathematical modeling suggests that morphine exposure increases the proportion of cells with high susceptibility to SIV infection, at least in part, because of increased co-receptor expression (Vaidya et al.
T1387 14593-14599 Sentence denotes 2016).
T1388 14600-14866 Sentence denotes In addition to promoting a higher steady state viral loads and larger CD4 count declines, the model also predicts that morphine exposure results in the need for more efficacious ARV treatment than would be necessary for animals not exposed to morphine (Vaidya et al.
T1389 14867-14873 Sentence denotes 2016).
T1390 14874-15039 Sentence denotes Although the direct impact of morphine on ARV concentrations was not investigated, the study provides evidence supporting morphine’s negative impact on ARV efficacy.