The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Victor B. Fenik - One of the best experts on this subject based on the ideXlab platform.

  • catecholamiNergic a1 c1 NeuroNs coNtribute to the maiNteNaNce of upper airway muscle toNe but may Not participate iN Nrem sleep related depressioN of these muscles
    Respiratory Physiology & Neurobiology, 2017
    Co-Authors: Irma Rukhadze, Atul Malhotra, Nancy J Carballo, Sathyajit S Bandaru, Patrick M Fuller, Victor B. Fenik
    Abstract:

    Neural mechaNisms of obstructive sleep apNea, a commoN sleep-related breathiNg disorder, are iNcompletely uNderstood. Hypoglossal motoNeuroNs, which provide toNic aNd iNspiratory activatioN of geNioglossus (GG) muscle (a major upper airway dilator), receive catecholamiNergic iNput from medullary A1/C1 NeuroNs. We aimed to determiNe the coNtributioN of A1/C1 NeuroNs iN coNtrol of GG muscle duriNg sleep aNd wakefulNess. To do so, we placed iNjectioNs of a viral vector iNto DBH-cre mice to selectively express the hMD4i iNhibitory chemoreceptors iN A1/C1 NeuroNs. AdmiNistratioN of the hM4Di ligaNd, ClozapiNe-N-Oxide (CNO), iN these mice decreased GG muscle activity duriNg NREM sleep (F1,1,3=17.1, p<0.05); a similar NoN-sigNificaNt decrease was observed duriNg wakefulNess. CNO admiNistratioN had No effect oN Neck muscle activity, respiratory parameters or state duratioNs. IN additioN, CNO-iNduced iNhibitioN of A1/C1 NeuroNs did Not alter the magNitude of the Naturally occurriNg depressioN of GG activity duriNg traNsitioNs from wakefulNess to NREM sleep. These fiNdiNgs suggest that A1/C1 NeuroNs have a Net excitatory effect oN GG activity that is most likely mediated by hypoglossal motoNeuroNs. However, the activity of A1/C1 NeuroNs does Not appear to coNtribute to NREM sleep-related iNhibitioN of GG muscle activity, suggestiNg that A1/C1 NeuroNs regulate upper airway pateNcy iN a state-iNdepeNdeNt maNNer.

James G. Flood - One of the best experts on this subject based on the ideXlab platform.

  • DetermiNatioN of ClozapiNe, NorClozapiNe, aNd ClozapiNe-N-Oxide iN serum by liquid chromatography.
    Clinical Chemistry, 1993
    Co-Authors: Sheila A. Volpicelli, Frances R Frankenburg, Franca Centorrino, P R Puopolo, Judith C. Kando, Ross J. Baldessarini, James G. Flood
    Abstract:

    We report a New assay to measure the serum coNceNtratioNs of the atypical aNtipsychotic drug ClozapiNe aNd two major metabolites, NorClozapiNe aNd ClozapiNe-N-Oxide. The aNalytes aNd aN iNterNal staNdard (triprolidiNe) were extracted from alkaliNized samples iNto ethyl acetate aNd back-extracted iNto 0.1 mol/L HCl. The acid extracts were chromatographed oN a reversed-phase liquid chromatographic columN with photodiode array detectioN (210-340 Nm). With the 254-Nm sigNal, betweeN-ruN imprecisioN (CV) was < 2% for ClozapiNe aNd NorClozapiNe at 400 micrograms/L, aNd 4.1% for ClozapiNe-N-Oxide at 100 micrograms/L. Absolute recovery exceeded 65%, aNd the detectioN limit was approximately 3-4 micrograms/L. IN 25 patieNts at steady state at a meaN daily ClozapiNe dosage of 269 mg (3.09 mg/kg), ClozapiNe averaged 231 +/- 144 micrograms/L (meaN +/- SD); NorClozapiNe aNd ClozapiNe-N-Oxide coNceNtratioNs averaged 84% aNd 23% that of ClozapiNe. ANalyte coNceNtratioNs were sigNificaNtly correlated with daily dose. The method's ability to quaNtify ClozapiNe aNd two major metabolites simultaNeously with precisioN aNd seNsitivity makes it useful iN pharmacokiNetic studies aNd therapeutic moNitoriNg.

Irma Rukhadze - One of the best experts on this subject based on the ideXlab platform.

  • catecholamiNergic a1 c1 NeuroNs coNtribute to the maiNteNaNce of upper airway muscle toNe but may Not participate iN Nrem sleep related depressioN of these muscles
    Respiratory Physiology & Neurobiology, 2017
    Co-Authors: Irma Rukhadze, Atul Malhotra, Nancy J Carballo, Sathyajit S Bandaru, Patrick M Fuller, Victor B. Fenik
    Abstract:

    Neural mechaNisms of obstructive sleep apNea, a commoN sleep-related breathiNg disorder, are iNcompletely uNderstood. Hypoglossal motoNeuroNs, which provide toNic aNd iNspiratory activatioN of geNioglossus (GG) muscle (a major upper airway dilator), receive catecholamiNergic iNput from medullary A1/C1 NeuroNs. We aimed to determiNe the coNtributioN of A1/C1 NeuroNs iN coNtrol of GG muscle duriNg sleep aNd wakefulNess. To do so, we placed iNjectioNs of a viral vector iNto DBH-cre mice to selectively express the hMD4i iNhibitory chemoreceptors iN A1/C1 NeuroNs. AdmiNistratioN of the hM4Di ligaNd, ClozapiNe-N-Oxide (CNO), iN these mice decreased GG muscle activity duriNg NREM sleep (F1,1,3=17.1, p<0.05); a similar NoN-sigNificaNt decrease was observed duriNg wakefulNess. CNO admiNistratioN had No effect oN Neck muscle activity, respiratory parameters or state duratioNs. IN additioN, CNO-iNduced iNhibitioN of A1/C1 NeuroNs did Not alter the magNitude of the Naturally occurriNg depressioN of GG activity duriNg traNsitioNs from wakefulNess to NREM sleep. These fiNdiNgs suggest that A1/C1 NeuroNs have a Net excitatory effect oN GG activity that is most likely mediated by hypoglossal motoNeuroNs. However, the activity of A1/C1 NeuroNs does Not appear to coNtribute to NREM sleep-related iNhibitioN of GG muscle activity, suggestiNg that A1/C1 NeuroNs regulate upper airway pateNcy iN a state-iNdepeNdeNt maNNer.

David Weinshenker - One of the best experts on this subject based on the ideXlab platform.

  • The DREADD agoNist ClozapiNe N-Oxide (CNO) is reverse-metabolized to ClozapiNe aNd produces ClozapiNe-like iNteroceptive stimulus effects iN rats aNd mice.
    Scientific Reports, 2018
    Co-Authors: Daniel F Manvich, Joseph H Porter, Kevin A Webster, Stephanie L Foster, Martilias S Farrell, James C. Ritchie, David Weinshenker
    Abstract:

    ClozapiNe-N-Oxide (CNO) has loNg beeN the ligaNd of choice for selectively activatiNg DesigNer Receptors Exclusively Activated by DesigNer Drugs (DREADDs). However, receNt studies have challeNged the loNg-held assertioN that CNO is otherwise pharmacologically iNert. The preseNt study aimed to 1) determiNe whether CNO is reverse-metabolized to its pareNt compouNd ClozapiNe iN mice (as has receNtly beeN reported iN rats), aNd 2) determiNe whether CNO exerts ClozapiNe-like iNteroceptive stimulus effects iN rats aNd/or mice. FollowiNg admiNistratioN of 10.0 mg/kg CNO, pharmacokiNetic aNalyses replicated receNt reports of back-coNversioN to ClozapiNe iN rats aNd revealed that this pheNomeNoN also occurs iN mice. IN rats aNd mice traiNed to discrimiNate 1.25 mg/kg ClozapiNe from vehicle, CNO (1.0–20.0 mg/kg) produced partial substitutioN for the ClozapiNe stimulus oN average, with full substitutioN beiNg detected iN some iNdividual aNimals of both species at doses frequeNtly used to activate DREADDs. The preseNt demoNstratioN that CNO is coNverted to ClozapiNe aNd exerts ClozapiNe-like behavioral effects iN both mice aNd rats further emphasizes the Need for appropriate coNtrol groups iN studies employiNg DREADDs, aNd highlights the utility of the drug discrimiNatioN procedure as a tool with which to screeN the off-target effects of Novel DREADD agoNists.

  • behavioral aNd pharmacokiNetic properties of the putatively iNert dreadd ligaNd ClozapiNe N Oxide cNo iN rats aNd mice
    The FASEB Journal, 2017
    Co-Authors: Joseph H Porter, Daniel F Manvich, Kevin A Webster, Stephanie L Foster, Martilias S Farrell, David Weinshenker
    Abstract:

    ClozapiNe-N-Oxide (CNO) is a major metabolite of the aNtipsychotic drug ClozapiNe that has beeN utilized iN maNy studies as aN “iNert” molecule to activate DREADDs (DesigNer Receptors Exclusively A...

Michael W. Jann - One of the best experts on this subject based on the ideXlab platform.

  • fluvoxamiNe reduces the ClozapiNe dosage Needed iN refractory schizophreNic patieNts
    The Journal of Clinical Psychiatry, 2000
    Co-Authors: Hsien-yuan Lane, Michael W. Jann, Kunpo Chen, Wen-ho Chang
    Abstract:

    BackgrouNd CoNcomitaNt fluvoxamiNe use caN poteNtially reduce the dosage of ClozapiNe Needed iN treatmeNt-refractory patieNts with schizophreNia. Previous reports have showN that fluvoxamiNe caN iNcrease plasma ClozapiNe coNceNtratioNs by iNhibitioN of cytochrome P450 (CYP) 1A2. We evaluated the safety aNd efficacy of fluvoxamiNe, 50 mg/day, coadmiNistratioN with ClozapiNe, 100 mg/day, iN refractory schizophreNic patieNts. Method IN this prospective study, 18 treatmeNt-refractory patieNts with DSM-IV schizophreNia (10 NoNsmokers aNd 8 smokers) were treated with ClozapiNe at a target dose of 100 mg h.s. After steady-state coNditioNs of ClozapiNe had beeN reached, 50 mg/day of fluvoxamiNe was theN added. Plasma levels of ClozapiNe, NorClozapiNe, aNd ClozapiNe N-Oxide were measured prior to fluvoxamiNe additioN aNd oN days 14 aNd 28 duriNg combiNed treatmeNt. Side effects aNd efficacy were moNitored with staNdardized ratiNg iNstrumeNts. Results After 14 days of combiNed treatmeNt, the meaN +/- SD plasma ClozapiNe level iNcreased 2.3-fold to 432.4+/-190.9 Ng/mL without further elevatioN oN day 28. All patieNts completed the study without sigNificaNt adverse side effects. Twelve of the 18 patieNts achieved plasma ClozapiNe coNceNtratioNs of at least 350 Ng/mL. While plasma NorClozapiNe levels also rose (but to a smaller exteNt), plasma ClozapiNe N-Oxide levels remaiNed uNchaNged after the add-oN therapy. PatieNts who smoked had 34% lower plasma ClozapiNe coNceNtratioNs thaN NoNsmokers (NS). Three of the 4 patieNts who did Not reach ClozapiNe plasma levels of at least 300 Ng/mL were smokers. Plasma NorClozapiNe/ClozapiNe ratios, especially iN smokers, decliNed sigNificaNtly with fluvoxamiNe additioN. CoNclusioN The additioN of fluvoxamiNe, 50 mg/day, to low-dose ClozapiNe, 100 mg/day, caN raise plasma ClozapiNe levels to at least 300 Ng/mL iN most patieNts. ONly slight dosage adjustmeNts with ClozapiNe may be Needed after fluvoxamiNe coadmiNistratioN iN some patieNts who smoke. Plasma ClozapiNe levels remaiNed stable after 14 days of fluvoxamiNe additioN. The combiNed treatmeNt was well tolerated, aNd cliNical improvemeNt was observed iN our patieNts. Further loNg-term studies with this drug combiNatioN are Needed to determiNe its ecoNomic impact.

  • Reversible metabolism of ClozapiNe aNd ClozapiNe N-Oxide iN schizophreNic patieNts.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1998
    Co-Authors: Wen-ho Chang, Yw Francis Lam, Shih-ku Lin, Hsien-yuan Lane, Fu-chuan Wei, Michael W. Jann
    Abstract:

    1. To characterize the iNtercoNversioN process betweeN ClozapiNe aNd its metabolite ClozapiNe N-Oxide (CNO), eight healthy male schizophreNics were admiNistered a siNgle dose of ClozapiNe or CNO iN a raNdomized crossover maNNer. 2. UsiNg a geNeral pharmacokiNetic model for the iNtercoNversioN process, the meaN total clearaNces of ClozapiNe aNd CNO were 28.45 L/hr aNd 45.30 L/hr, respectively. These values were similar to the values obtaiNed by the usual model-iNdepeNdeNt method of pharmacokiNetic aNalysis. 3. WheN admiNistered ClozapiNe, meaN CNO plasma coNceNtratioNs of 17.7 +/- 16.4 Ng/ml were slightly lower thaN the other ClozapiNe metabolite-desmethylClozapiNe (DCLOZ) plasma levels of 24.4 +/- 8.6 Ng/ml at the 12 hour time poiNt. WheN CNO was admiNistered, plasma coNceNtratioNs at the 12 hour time poiNt of ClozapiNe were twice the amouNt of CNO (28.1 +/- 8.9 Ng/ml vs 14.4 +/- 8.8 Ng/ml). 4. DCLOZ plasma coNceNtratioNs were detected iN all patieNts upoN ClozapiNe admiNistratioN. UpoN CNO admiNistratioN, oNly oNe patieNt had detectable plasma DCLOZ levels. 5. The iNtercoNversioN process of ClozapiNe aNd CNO could partially accouNt for the wide iNterpatieNt variability reported for ClozapiNe plasma coNceNtratioNs iN schizophreNic patieNts.

  • Rapid formatioN of ClozapiNe iN guiNea-pigs aNd maN followiNg ClozapiNe-N-Oxide admiNistratioN.
    Archives internationales de pharmacodynamie et de therapie, 1994
    Co-Authors: Michael W. Jann, Yw Francis Lam, W. H. Chang
    Abstract:

    ClozapiNe aNd its metabolite ClozapiNe-N-Oxide (0.5 mg/kg) were admiNistered iNtraperitoNeally to guiNea-pigs. SigNificaNt amouNts of ClozapiNe were detected iN plasma, liver, froNtal cortex aNd caudate after ClozapiNe-N-Oxide admiNistratioN. The amouNt of ClozapiNe detected iN plasma two hours post-admiNistratioN of N-Oxide was approximately 40% of the amouNt of ClozapiNe after ClozapiNe iNjectioN. Tissue coNceNtratioNs of ClozapiNe iN liver, froNtal cortex aNd caudate were greater thaN plasma coNceNtratioNs. ClozapiNe coNceNtratioNs were almost equivaleNt iN the liver. ClozapiNe coNceNtratioNs after N-Oxide iNjectioN were approximately 40-50% lower compared to ClozapiNe coNceNtratioNs after ClozapiNe admiNistratioN iN the froNtal cortex aNd caudate. A siNgle dose of ClozapiNe-N-Oxide was giveN to a schizophreNic patieNt. ClozapiNe plasma coNceNtratioNs were detected after N-Oxide admiNistratioN. This study shows that ClozapiNe is formed from its N-Oxide metabolite aNd that a reversible metabolic pathway exists for ClozapiNe aNd ClozapiNe-N-Oxide.