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The Measurement of Transport in Vivo Using Radiotracers
Published in Lelio G. Colombetti, Biological Transport of Radiotracers, 2020
Thus, the extraction E at time t is equal to the difference between the uC-chlorprom-azine content at time t, [RT(0] minus the 113mIn-transferrin content, [R*(t)]. Graphically, the counting data in a normal subject is shown in Figure 7. Lung activity increases rapidly as the bolus enters the lung field. The washout of 11C-chlorpromazine was much slower than that of the vascular indicator, transferrin. Using this technique, it was shown that the mean initial extraction of chlorpromazine was ∿90% in normal patients vs. ∿64% in patients with chronic obstructive pulmonary disease (p < 0.001). This difference was attributed to possible differences in the qualitative or quantitative alterations of lung disease. The significance of these preliminary studies is that a quantitative and noninvasive technique is now available to assess the significance of the pulmonary extraction of suitably labeled compounds in both normal and disease states in humans. Such studies should permit a better understanding of the role of the lungs in regulating various endogenous and xenobiotic compounds.
Clinical Pharmacogenomics Of Human Cyp2d6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Tetrabenazine, a drug for the treatment of Huntington’s disease chorea, is metabolized primarily by CYP2D6 (Fasano and Bentivoglio 2009; Frank 2014; Guay 2010). It is subject to important drug–drug interactions with inhibitors and inducers of CYP2D6, reserpine, and lithium. The effect of CYP2D6 inhibition by paroxetine on the pharmacokinetics of tetraben-azine and its metabolites is studied in 25 healthy subjects after a single 50-mg dose of tetrabenazine given after 10 days of administration of paroxetine 20 mg daily (Guay 2010). There is an approximately 30% increase in Cmax and an approximately threefold increase in AUC for α-hydroxytetrabenazine in subjects given paroxetine before tetrabenazine compared to tetrabenazine given alone. For β-hydroxy-tetrabenazine, the Cmax and AUC are increased 2.4- and 9-fold, respectively, in subjects given paroxetine before tetrabenazine given alone. In a recent study, it is found that CYP2D6 UM patients need a longer titration (8 vs. 3.3, 4.4, and 3 weeks, respectively; P < 0.01) to achieve optimal benefit and require a higher average daily dose than the other patients, but this difference does not reach statistical significance (Mehanna et al. 2013). The treatment response is less robust in the IMs when compared with the EM patients (P = 0.013), but there are no statistically significant differences between the various phenotype groups with regard to adverse effects (Mehanna et al. 2013).
CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
Naloxazone is a monomeric hydrazone derivative of naloxone, and naloxonazine is a dimeric azine derivative of naloxone. The ability of naloxazone to undergo spontaneous transformation to naloxonazine suggests that naloxonazine may be the active form of naloxazone (Hahn and Pasternak, 1982; Hahn et al., 1982). The ability of these naloxone derivatives to react covalently with opioid receptors cannot be readily demonstrated and is inferred by the inability of repeated washing to remove the ligand. Even if a covalent linkage is produced, it is unclear how stable it would be under in vivo or in vitro conditions. These considerations are important since it has been shown that unreacted (free) naloxonazine binds to μ opioid receptors (μ2 using Pasternak’s terminology) in the GPI (Gintzler and Pasternak, 1983). Crucizni et al. (1987) investigated the effect of naloxonazine treatment combined with extensive washing to remove unreacted ligand on opioid receptor binding and failed to observe a noncompetitive (i.e., irreversible) loss of high affinity binding sites. Instead, they observed that the naloxonazine treatment produced a reduction of the apparent binding affinity of the ligands tested (labeled and unlabeled DADLE and DAMGO) at all sites labeled with no significant change in the measured binding capacity. This is characteristic of reversible competitive interactions.
Multi-targeted drug design strategies for the treatment of schizophrenia
Published in Expert Opinion on Drug Discovery, 2021
Piotr Stępnicki, Magda Kondej, Oliwia Koszła, Justyna Żuk, Agnieszka A. Kaczor
Zajdel and coworkers synthesized novel isoquinoline-, arylpiperazinyl-alkyl quinolone- and naphthalene-sulfonamides with flexible and semi-rigid alkylene spacer and tested their activity for serotonin and dopamine receptors. Compounds with a semi-rigid alkylene spacer turned to be very promising [97]. The same research group in 2013 confirmed the results received earlier by obtaining new quinoline- and isoquinoline-sulfonamide derivatives of aripiprazole. They investigated the influence of the ether/amide group replacement with sulfonamide, and the position of a sulfonamide moiety in the azine scaffold. Two identified molecules turned out to be 5-HT1A agonists, D2 partial agonists or 5-HT2A, 5-HT7 antagonists. Additionally, compound (7) (Figure 3) displayed a comparable multi-receptor binding and functional profile and also exhibited considerable antipsychotic activity in behavioral studies [98]. In another research project the same team developed novel azine sulfonamides of alicyclic amine derivatives with arylpiperazine/piperidine rings. Structure-activity relationship studies exploration allowed to conclude that the 1,2-benzothiazol-3-yl and benzothiophen-4-yl-piperazine as well as (isoquinolin-4-ylsulfonyl)-(S)-pyrrolidinyl moieties increased binding to serotonin receptors (5-HT1A, 5-HT2A, 5-HT6, 5-HT7,) and dopamine (D2, D3) receptors. Moreover, it was found that the interactions of new compounds with serotonin 5-HT6 receptor was conditioned by the stereochemistry of the alicyclic amine. Of all received compounds, compound (8) (Figure 3) exhibited the most beneficial properties [99].
Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Hend Kothayer, Samar Rezq, Ahmed S. Abdelkhalek, Damian G. Romero, Samar S. Elbaramawi
The common pharmacophoric structural features of the previously reported dual COX-2/15-LOX inhibitors include three regions: nitrogen-containing bicyclic ring, a central five or six-membered nitrogen-containing heterocycle (azole or azine), and a hydrophobic terminal usually containing an aromatic ring. Replacement of the central azole or azine with an open ring analogue has also been reported as observed in compounds (J–M)16.
Protective effect of rutin and β-cyclodextrin against hepatotoxicity and nephrotoxicity induced by lambda-cyhalothrin in Wistar rats: biochemical, pathological indices and molecular analysis
Published in Biomarkers, 2022
Walaa A. Ali, Walaa A. Moselhy, Marwa A. Ibrahim, Maha M. Amin, Shaimaa Kamel, Ehab B. Eldomany
The level of urea was estimated based on the Fenton reaction with the di azine chromogen using the urease-colorimetric method (absorbance measured at 540 nm) according to the procedure suggested by (Patton and Crouch 1977). Analytical measurements were performed as per the manufacturer’s instructions.