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Kim HI, Jung DH, Lee SJ, Kim N, Kim SH, Ji YJ, Byon HJ, Shin SK. Determining ED90 of Flumazenil for Selective Respiratory Distress Improvement Using Remimazolam During Endoscopic Submucosal Dissection of Gastric Neoplasms: A Prospective Study. Cancers (Basel) 2025; 17:321. [PMID: 39858103 PMCID: PMC11763922 DOI: 10.3390/cancers17020321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/12/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Patients undergoing endoscopic submucosal dissection under monitored anesthesia care (MAC) with remimazolam may develop respiratory distress during the procedure. In these cases, low doses of flumazenil improved respiratory distress without completely reversing sedation, which is a novel phenomenon. This study aimed to explore the ED90 of flumazenil to selectively improve respiratory distress in patients with MAC treated with remimazolam. METHODS Flumazenil dose determination followed a biased-coin up-and-down design. Starting with a dose of 5 mcg, if respiratory distress improved, the biased-coin method was used to give the same dose in the next patient with a probability of 8/9, and a decreased dose of 5 mcg in the next patient with a probability of 1/9. Any improvement in respiratory distress within 30 s of flumazenil administration was recorded. After the procedure, patients were asked whether they had any memory recall during the procedure. Centered isotonic regression was used to determine the ED90 of flumazenil. RESULTS Sixty patients were included in the study. The estimated ED90 was 76.72 mcg (95% CI: 68.07-102.62). Memory recall occurred in two of thirteen patients (15%) near the ED90 dose range (75 mcg and 80 mcg). None of the patients developed major postoperative complications (bleeding, perforation, or aspiration) within the 2-day postoperative period. CONCLUSIONS This study determined that the ED90 of flumazenil for effectively alleviating respiratory distress in patients undergoing MAC with remimazolam was 76.7 mcg, without reversing consciousness. These findings provide valuable guidance for the care of patients undergoing sedation.
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Affiliation(s)
- Hyun Il Kim
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Da Hyun Jung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea;
| | - Sung Jin Lee
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Namo Kim
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Seung Hyun Kim
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Yu Jun Ji
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Hyo-Jin Byon
- Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea; (H.I.K.); (S.J.L.); (N.K.); (S.H.K.); (Y.J.J.)
| | - Sung Kwan Shin
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea;
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Norouzi M, Nazeri MT, Shaabani A, Notash B. Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions. Beilstein J Org Chem 2024; 20:2870-2882. [PMID: 39559445 PMCID: PMC11571948 DOI: 10.3762/bjoc.20.241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/22/2024] [Indexed: 11/20/2024] Open
Abstract
An efficient and facile synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives was developed through the isocyanide-based multicomponent reaction of isocyanides, gem-diactivated olefins, and cyclic imines such as dibenzoxazepine, dibenzothiazepine, and triazolobenzodiazepine under solvent- and catalyst-free conditions. Purposefully, this approach produced various bioactive scaffolds using environmentally friendly, mild, and simple conditions. Due to their bioactive moieties, these compounds with exclusive fluorescence properties may attract great attention in biomedical applications, clinical diagnostics, and conjugate materials.
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Affiliation(s)
- Marzieh Norouzi
- Department of Organic Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran, 1983969411, Iran
| | - Mohammad Taghi Nazeri
- Department of Organic Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran, 1983969411, Iran
| | - Ahmad Shaabani
- Department of Organic Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran, 1983969411, Iran
| | - Behrouz Notash
- Department of Inorganic Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran, 1983969411, Iran
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3
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Getachew B, Csoka AB, Copeland RL, Manaye KF, Tizabi Y. Dihydromyricetin Protects Against Salsolinol-Induced Toxicity in Dopaminergic Cell Line: Implication for Parkinson's Disease. Neurotox Res 2023; 41:141-148. [PMID: 36585544 DOI: 10.1007/s12640-022-00631-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/01/2023]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease associated with loss of dopaminergic neurons in the substantia nigra pars compacta. Although aging is the primary cause, environmental and genetic factors have also been implicated in its etiology. In fact, the sporadic nature of PD (i.e., unknown etiology) renders the uncovering of the exact pathogenic mechanism(s) or development of effective pharmacotherapies challenging. In search of novel neuroprotectants, we showed that butyrate (BUT), a short-chain fatty acid, protects against salsolinol (SALS)-induced toxicity in human neuroblastoma-derived SH-SY5Y cells, which are considered an in-vitro model of PD. Dihydromyricetin (DHM), a flavonoid derived from Asian medicinal plant, has also shown effectiveness against oxidative damage and neuroinflammation, hallmarks of neurodegenerative diseases. Here we show that pretreatment of SH-SY5Y cells with DHM concentration-dependently prevented SALS-induced toxicity and that a combination of DHM and BUT resulted in a synergistic protection. The effects of both DHM and BUT in turn could be completely blocked by flumazenil (FLU), a GABAA antagonist acting at benzodiazepine receptor site, and by bicuculline (BIC), a GABAA antagonist acting at orthosteric site. Beta-hydroxybutyrate (BHB), a free fatty acid 3 (FA3) receptor antagonist, also fully blocked the protective effect of DHM. BHB was shown previously to only partially block the protective effect of BUT. Thus, there are some overlaps and some distinct differences in protective mechanisms of DHM and BUT against SALS-induced toxicity. It is suggested that a combination of DHM and BUT may have therapeutic potential in PD. However, further in-vivo verifications are necessary.
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Affiliation(s)
- Bruk Getachew
- Department of Pharmacology, Howard University College of Medicine, 520 W Street, Washington, NWDC, 20059, USA
| | - Antonei B Csoka
- Department of Anatomy, Howard University College of Medicine, Washington, DC, USA
| | - Robert L Copeland
- Department of Pharmacology, Howard University College of Medicine, 520 W Street, Washington, NWDC, 20059, USA
| | - Kebreten F Manaye
- Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
| | - Yousef Tizabi
- Department of Pharmacology, Howard University College of Medicine, 520 W Street, Washington, NWDC, 20059, USA.
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Postoperative Heart Failure with Preserved Ejection Fraction Induced by Flumazenil Administered for Remimazolam Antagonism. Case Rep Anesthesiol 2022; 2022:8923008. [DOI: 10.1155/2022/8923008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022] Open
Abstract
Remimazolam is an ultrashort-acting benzodiazepine intravenous anesthetic characterized by rapid awakening after anesthesia. However, the method for administering remimazolam in clinical practice remains unclear. Here, we report a case of postoperative heart failure with preserved ejection fraction (HFpEF) after antagonizing remimazolam with flumazenil. An 82-year-old woman was scheduled to undergo lumbar laminectomy for lumbar spinal canal stenosis. Preoperative echocardiography revealed normal left ventricular systolic function, left atrial enlargement, and impaired left ventricular diastolic function. General anesthesia was induced with 10 mg/kg/h remimazolam and maintained with 0.8 mg/kg/h remimazolam intraoperatively. Before extubation, a total of 1.0 mg of flumazenil was administered. After extubation, the patient developed pulmonary edema due to HFpEF. When remimazolam is administered in elderly patients with cardiac dysfunction, the maintenance dose should be customized according to the patient’s general condition to minimize the dosage of flumazenil.
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ORUCH R, HUNEIF MA, PRYME IF, FASMER OB, LUND A. Drug treatment of insomnia: impact of zopiclone. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2022. [DOI: 10.23736/s0393-3660.22.04792-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Whoriskey S, Pearson LE, Harris HS, Whitmer ER, Liwanag HEM, Brodie E, Johnson S. Using a combination of midazolam and butorphanol is a safe and effective reversible field sedation protocol for Weddell seal (Leptonychotes weddellii) pups. Vet Rec 2022; 191:e2238. [PMID: 36251215 DOI: 10.1002/vetr.2238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/31/2022] [Accepted: 09/02/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Weddell seals (Leptonychotes weddellii) are a well-studied species of phocid with an apparent sensitivity to immobilising agents. Mortality as high as 31% has been reported during field immobilisation. This study investigated the use of a benzodiazepine in combination with an opioid agonist/antagonist for sedation in Weddell seal pups as part of a physiological study. METHODS During the 2017 and 2019 Antarctic pupping seasons, 18 Weddell seal pups were sedated by intramuscular administration of a combination of midazolam and butorphanol or intravenous midazolam alone. Individuals were sedated at 1, 3, 5 and 7 weeks of age. Naltrexone and flumazenil were used to reverse sedation. The combination was 100% effective in providing appropriate sedation for the intended procedures. RESULTS Analyses were performed to investigate relationships between dose administered, age, individual reactions, adverse effects and changes in dive physiology. Transient apnoea (10-60 seconds) was the most frequently observed adverse effect. No sedation-associated morbidity or mortality occurred. LIMITATIONS The sample size is small and there is no pharmacokinetic information for either sedative or reversal in phocid species. CONCLUSIONS The combination of midazolam (0.2-0.3 mg/kg) and butorphanol (0.1-0.2 mg/kg) provided safe and effective sedation, with reversible effects, in Weddell seal pups.
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Affiliation(s)
| | - Linnea E Pearson
- California Polytechnic State University, San Luis Obispo, California, USA
| | - Heather S Harris
- The Marine Mammal Center, Sausalito, California, USA.,California Polytechnic State University, San Luis Obispo, California, USA
| | | | | | - Erin Brodie
- The Marine Mammal Center, Sausalito, California, USA
| | - Shawn Johnson
- The Marine Mammal Center, Sausalito, California, USA.,Sea Change Health, Sunnyvale, California, USA
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Getachew B, Csoka AB, Tizabi Y. Dihydromyricetin Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line: Role of GABA A Receptor. Neurotox Res 2022; 40:892-899. [PMID: 35386023 DOI: 10.1007/s12640-022-00503-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/07/2022] [Accepted: 03/29/2022] [Indexed: 11/26/2022]
Abstract
Toxicity induced by binge alcohol drinking, particularly in adolescent and young adults, is of major medical and social consequence. Recently, we reported that butyrate, a short chain fatty acid, can protect against ethanol (ETOH)-induced toxicity in an in vitro model. In this study, we sought to evaluate the potential effectiveness of dihydromyricetin (DHM), a natural bioactive flavonoid, alone or in combination with butyrate in the same model. Exposure of SH-SY5Y cells for 24 h to 500 mM ETOH resulted in approximately 40% reduction in cell viability, which was completely prevented by 0.1 μM DHM. Combinations of DHM and butyrate provided synergistic protection against alcohol toxicity. Whereas butyrate effect was shown to be mediated primarily through fatty acid receptor 3 activation, DHM protection appears to be mediated primarily via benzodiazepine receptor site of GABAA receptor. This is based on the finding that DHM's effect could be completely prevented by pretreatment with flumazenil, a selective antagonist at this site, but not by bicuculline, a selective antagonist at the actual GABAA receptor binding site. These findings suggest potential utility of DHM alone or in combination with butyrate against ETOH-induced toxicity.
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Affiliation(s)
- Bruk Getachew
- Department of Pharmacology, Howard University College of Medicine, 520 W Street NW, Washington, DC, USA
| | - Antonei B Csoka
- Department of Anatomy, Howard University College of Medicine, 520 W Street NW, Washington, DC, USA
| | - Yousef Tizabi
- Department of Pharmacology, Howard University College of Medicine, 520 W Street NW, Washington, DC, USA.
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Jin EH, Song JH, Lee J, Bae JH, Chung SJ. Midazolam dose is associated with recurrence of paradoxical reactions during endoscopy. World J Clin Cases 2021; 9:8763-8772. [PMID: 34734054 PMCID: PMC8546803 DOI: 10.12998/wjcc.v9.i29.8763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/06/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Midazolam is commonly used for sedation during gastrointestinal procedures. However, some patients experience paradoxical reactions characterized by excessive movement or excitement.
AIM To investigate the rate of recurrence of paradoxical reactions to midazolam during an upper endoscopy.
METHODS We retrospectively reviewed 122152 sedative endoscopies among a total of 58553 patients at the Seoul National University Hospital, Healthcare System Gangnam Center, from July 2013 to December 2018. Among them, 361 patients with a history of paradoxical reaction during sedative upper endoscopy were enrolled. The characteristics of patients in the recurrent and non-recurrent groups were compared via multivariable analysis using logistic regression.
RESULTS Paradoxical reactions occurred in 0.86% (1054/122152) of endoscopies, and in 1.51% (888/58553) of patients. Among the 361 subjects with previous paradoxical reactions in sedative endoscopies, 111 (30.7%) experienced further paradoxical reactions. Univariable analysis revealed that the total midazolam dose used was higher in the recurrent group (6.74 ± 2.58 mg) than in the non-recurrent group (5.49 ± 2.04 mg; P < 0.0001). Patients were administered a lower dose of midazolam than previous doses: 1 mg less in the recurrent group and 2 mg less in the non-recurrent group. Multivariable analysis showed that the midazolam dose difference was an independent risk factor for recurrent paradoxical reaction (odds ratio: 1.213, 95%CI: 1.099-1.338, P = 0.0001).
CONCLUSION The rate of recurrence of paradoxical reactions is significantly associated with midazolam dosage. The dose of midazolam administered to patients with previous paradoxical reactions should be less than that previously used.
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Affiliation(s)
- Eun Hyo Jin
- Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 06236, South Korea
| | - Ji Hyun Song
- Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 06236, South Korea
| | - Jooyoung Lee
- Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 06236, South Korea
| | - Jung Ho Bae
- Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 06236, South Korea
| | - Su Jin Chung
- Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 06236, South Korea
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Jahanbani R, Bahramnejad E, Rahimi N, Shafaroodi H, Sheibani N, Moosavi-Movahedi AA, Dehpour AR, Vahdati K. Anti-seizure effects of walnut peptides in mouse models of induced seizure: The involvement of GABA and nitric oxide pathways. Epilepsy Res 2021; 176:106727. [PMID: 34333374 DOI: 10.1016/j.eplepsyres.2021.106727] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 11/17/2022]
Abstract
Epilepsy is one of the foremost medical disorders. Oxidative stress is a well-known mechanism in epileptogenesis, and many studies suggest that oxidative stress affects the onset and evolution of epilepsy. Here we evaluated the walnut peptide extracts' anti-seizure property in three different mouse seizure models including pentylenetetrazole-induced clonic seizure, chemical kindling, and maximal electroshock. Walnut peptides (20 mg/Kg) were administered by intraperitoneal (IP) injection of mice 60 min before seizure induction in the three models. To delineate the mechanisms of walnut peptides anti-seizure activity, we evaluated the impact of diazepam, flumazenil, and a NOS inhibitor on this activity. Intraperitoneal administration of walnut peptides significantly increased the seizure threshold. Our results also demonstrated that walnut peptides exert their anti-seizure properties through the modulation of benzodiazepine receptors. Thus, walnut peptides may be considered as a new anti-convulsion agent, which can reduce seizure occurrence and slow down seizure progression.
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Affiliation(s)
- Raheleh Jahanbani
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Bahramnejad
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Rahimi
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Shafaroodi
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nader Sheibani
- Departments of Ophthalmology and Visual Sciences, Cell and Regenerative Biology, and Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Ali Akbar Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Kourosh Vahdati
- Department of Horticulture, College of Aburaihan, University of Tehran, Tehran, Iran.
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Hossain R, Al-Khafaji K, Khan RA, Sarkar C, Islam MS, Dey D, Jain D, Faria F, Akbor R, Atolani O, Oliveira SMR, Siyadatpanah A, Pereira MDL, Islam MT. Quercetin and/or Ascorbic Acid Modulatory Effect on Phenobarbital-Induced Sleeping Mice Possibly through GABA A and GABA B Receptor Interaction Pathway. Pharmaceuticals (Basel) 2021; 14:ph14080721. [PMID: 34451819 PMCID: PMC8398796 DOI: 10.3390/ph14080721] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/28/2022] Open
Abstract
Depressive disorder is a recurrent illness that affects large numbers of the general population worldwide. In recent years, the goal of depression treatment has moved from symptomatic response to that of full remission. However, treatment-resistant depression is a major challenge in the treatment of depression or depression-related disorders. Consensus opinion, therefore, suggests that effective combined aggressive initial treatment is the most appropriate strategy. This study aimed to evaluate the effects of quercetin (QUR) and/or ascorbic acid (AA) on Phenobarbital-induced sleeping mice. QUR (50 mg/kg) and/or AA (25 mg/kg) with or without intraperitoneally pre-treated with GABA receptor agonist (diazepam: 2 mg/kg, i.p.) or antagonist (Flumazenil: 2.5 mg/kg, i.p.) to underscore the effects, as well as the possible involvement of the GABA receptor in the modulatory action of QUR and AA in sleeping mice. Additionally, an in silico study was undertaken to predict the involvement of GABA receptors in the sleep mechanism. Findings suggest that the pretreatment of QUR and AA modulated the onset and duration of action of the standard drugs in experimental animals. The acute administration of QUR and/or AA significantly (p < 0.05) reversed the DZP-mediated onset of action and slightly reversed the duration of sleep time in comparison to the vehicle (control) group. A further combination of QUR or AA with the FLU resulted in an enhancement of the onset of action while reducing the duration of action, suggesting a FLU-like effect on the test animals. In in silico studies, AA and QUR showed good to moderate binding affinities with GABAA and GABAB receptors. Both QUR and AA produced a stimulatory-like effect on mice, possibly through the GABAA and GABAB receptor interaction pathways. Further studies are necessary to verify this activity and clarify the exact mechanism of action(s) involved.
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Affiliation(s)
- Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Khattab Al-Khafaji
- Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, 27310 Gaziantep, Turkey;
| | - Rasel Ahmed Khan
- Pharmacy Discipline, Life Science School, Khulna University, Khulna 9280, Bangladesh;
| | - Chandan Sarkar
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Md. Shahazul Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj 8100, Bangladesh;
| | - Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Vanasthali 304022, Rajasthan, India;
| | - Farhana Faria
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Rukaya Akbor
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
| | - Olubunmi Atolani
- Department of Chemistry, University of Ilorin, Ilorin P.M.B. 1515, Nigeria;
| | - Sónia M. R. Oliveira
- CICECO-Aveiro Institute of Materials & Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
- Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
| | - Abolghasem Siyadatpanah
- Ferdows School of Paramedical and Health, Birjand University of Medical Sciences, Birjand 9717853577, Iran;
| | - Maria de Lourdes Pereira
- CICECO-Aveiro Institute of Materials & Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal;
- Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Correspondence: (M.d.L.P.); (M.T.I.)
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; (R.H.); (C.S.); (M.S.I.); (F.F.); (R.A.)
- Correspondence: (M.d.L.P.); (M.T.I.)
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11
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Farhid H, Khodkari V, Nazeri MT, Javanbakht S, Shaabani A. Multicomponent reactions as a potent tool for the synthesis of benzodiazepines. Org Biomol Chem 2021; 19:3318-3358. [PMID: 33899847 DOI: 10.1039/d0ob02600j] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Benzodiazepines (BZDs), a diverse class of benzofused seven-membered N-heterocycles, display essential pharmacological properties and play vital roles in some biochemical processes. They have mainly been prescribed as potential therapeutic agents, which interestingly represent various biological activities such as anticancer, anxiolytic, antipsychotic, anticonvulsant, antituberculosis, muscle relaxant, and antimicrobial activities. The extensive biological activities of BZDs in various fields have encouraged medicinal chemists to discover and design novel BZD-based scaffolds as potential therapeutic candidates with the favorite biological activity through an efficient protocol. Although certainly valuable and important, conventional synthetic routes to these bicyclic benzene compounds contain methodologies often requiring multistep procedures, which suffer from waste materials generation and lack of sustainability. By contrast, multicomponent reactions (MCRs) have recently advanced as a green synthetic strategy for synthesizing BZDs with the desired scope. In this regard, MCRs, especially Ugi and Ugi-type reactions, efficiently and conveniently supply various complex synthons, which can easily be converted to the BZDs via suitable post-transformations. Also, MCRs, especially Mannich-type reactions, provide speedy and economic approaches for the one-pot and one-step synthesis of BZDs. As a result, various functionalized-BZDs have been achieved by developing mild, efficient, and high-yielding MCR protocols. This review covers all aspects of the synthesis of BZDs with a particular focus on the MCRs as well as the mechanism chemistry of synthetic protocols. The present manuscript opens a new avenue for organic, medicinal, and industrial chemists to design safe, environmentally benign, and economical methods for the synthesis of new and known BZDs.
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Affiliation(s)
- Hassan Farhid
- Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran.
| | - Vida Khodkari
- Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran.
| | - Mohammad Taghi Nazeri
- Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran.
| | - Siamak Javanbakht
- Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran.
| | - Ahmad Shaabani
- Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran. and Peoples' Friendship University of Russia (RUDN University), 6, Miklukho-Maklaya Street, Moscow, 117198, Russian Federation
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12
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Kalogirou AS, Kourtellaris A, Koutentis PA. Synthesis and Chemistry of Benzo[ e][1,2,6]thiadiazino[3,4- b][1,4]diazepin-10(11 H)-ones and Related Ring Transformations. J Org Chem 2021; 86:5702-5713. [PMID: 33818096 DOI: 10.1021/acs.joc.1c00206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
2-[(3,5-Dichloro-4H-1,2,6-thiadiazin-4-ylidene)amino]benzamides are cyclized to benzo[e][1,2,6]thiadiazino[3,4-b][1,4]diazepin-10(11H)-ones via (i) treatment with NaH and via (ii) Pd-catalyzed C-N coupling. The behavior of the latter toward nucleophiles and thermal, oxidative, and reductive conditions revealed unexpected transformations to 3,5-dioxo-4,5-dihydro-3H-benzo[e][1,4]diazepine-2-carbonitrile and 2-(4-substituted-1,2,5-thiadiazol-3-yl)quinazolin-4(3H)-ones.
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Affiliation(s)
- Andreas S Kalogirou
- Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P.O. Box 22006, 1516 Nicosia, Cyprus
| | - Andreas Kourtellaris
- Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
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13
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A high-resolution in vivo atlas of the human brain's benzodiazepine binding site of GABA A receptors. Neuroimage 2021; 232:117878. [PMID: 33610745 PMCID: PMC8256681 DOI: 10.1016/j.neuroimage.2021.117878] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 12/15/2020] [Accepted: 02/12/2021] [Indexed: 12/29/2022] Open
Abstract
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system. Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABAA receptors (GABAA Rs), generated on the basis of in vivo [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABAA R, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAA R and the BZR density at each location in the brain.
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14
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Benini A, Gottardo R, Chiamulera C, Bertoldi A, Zamboni L, Lugoboni F. Continuous Infusion of Flumazenil in the Management of Benzodiazepines Detoxification. Front Psychiatry 2021; 12:646038. [PMID: 33815177 PMCID: PMC8012511 DOI: 10.3389/fpsyt.2021.646038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/15/2021] [Indexed: 11/24/2022] Open
Abstract
An effective approach in the treatment of benzodiazepine (BZD) overdosing and detoxification is flumazenil (FLU). Studies in chronic users who discontinued BZD in a clinical setting suggested that multiple slow bolus infusions of FLU reduce BZD withdrawal symptoms. The aim of this study was to confirm FLU efficacy for reducing BZD withdrawal syndrome by means of continuous elastomeric infusion, correlated to drugs plasma level and patients' compliance. Methods: Seven-day FLU 1 mg/day subcutaneously injected through an elastomeric pump and BZDs lormetazepam, clonazepam, and lorazepam were assessed by HPLC-MS/MS in serum of patients before and after 4 and 7 days of FLU continuous infusion treatment. Changes in withdrawal severity were assessed by using the BZD Withdrawal Scale (BWS). Results: Fourteen patients (mean age ± SD 42.5 ± 8.0 years, 5 male and 9 female), admitted to the hospital for high-dose BZD detoxification, were enrolled in the study. Serum FLU concentrations significantly decreased from 0.54 ± 0.33 ng/ml (mean ± SD) after 4 days of treatment to 0.1 ± 0.2 ng/ml at the end of infusion. Lormetazepam concentrations were 502.5 ± 610.0 ng/ml at hospital admission, 26.2 ± 26.8 ng/ml after 4 days, and 0 at the end of treatment. BWS values decreased during FLU treatment temporal period. FLU was well-tolerated by patients. Conclusions: Elastomeric FLU infusion for BZD detoxification is a feasible administration device to maintain adequate, constant, and tolerated FLU concentrations for reducing BZD withdrawal symptoms.
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Affiliation(s)
- Anna Benini
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Rossella Gottardo
- Forensic Toxicology Laboratory, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Cristiano Chiamulera
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Anna Bertoldi
- Department of Internal Medicine, Addiction Unit, Verona University Hospital, Verona, Italy
| | - Lorenzo Zamboni
- Department of Internal Medicine, Addiction Unit, Verona University Hospital, Verona, Italy
| | - Fabio Lugoboni
- Department of Internal Medicine, Addiction Unit, Verona University Hospital, Verona, Italy
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15
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Horowski R. Dependence liability of lormetazepam: are all benzodiazepines equal? The case of the new i.v. lormetazepam for anesthetic procedures. J Neural Transm (Vienna) 2020; 127:1107-1115. [PMID: 32468272 PMCID: PMC8823007 DOI: 10.1007/s00702-020-02209-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 05/11/2020] [Indexed: 01/21/2023]
Abstract
There are contradictory publications and reports regarding the dependence liability of the 3-hydroxy-benzo-1,4-diazepine derivative lormetazepam, one of the most often prescribed hypnotic benzodiazepines which is now also available as an intravenous (i.v.) product for anesthetists. The author was involved in the preclinical and subsequently in the clinical development and post-marketing surveillance of lormetazepam. Here, he reviews the published and unpublished data about lormetazepam dependence and proposes explanations for contradictory views from other authors. On this basis and in contrast to class labeling from regulatory bodies and WHO, the author comes to the conclusion that use of lormetazepam definitely carries a lower risk of inducing dependence and causing abuse than most other benzodiazepines. This applies as well to Sedalam®, the new i.v. application form of lormetazepam, which is much better tolerated than propofol. Because of its pharmacokinetic properties and because all its effects can be fully antagonized with the benzodiazepine antagonist flumazenil, this innovative intravenous application form of lormetazepam provides an excellent method for premedication, symptomatic treatment of excitation and anxiety in the context of surgical or diagnostic procedures including outpatient interventions and for basic sedation during anesthesia.
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16
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Woo J, Lee CJ. Sleep-enhancing Effects of Phytoncide Via Behavioral, Electrophysiological, and Molecular Modeling Approaches. Exp Neurobiol 2020; 29:120-129. [PMID: 32408402 PMCID: PMC7237266 DOI: 10.5607/en20013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/16/2022] Open
Abstract
Sleep is indispensable for living animals to live and maintain a normal life. Due to the growing number of people suffering from sleep disorders such as insomnia, there have been increasing interests in environmentally friendly therapeutic approaches for sleep disorders to avoid any side effects of pharmacological treatment using synthetic hypnotics. It has been widely accepted that the various beneficial effects of forest, such as relieving stress and anxiety and enhancing immune system function, are caused by plant-derived products, also known as phytoncide. Recently, it has been reported that the sleep-enhancing effects of phytoncide are derived from pine trees such as (-)-α-pinene and 3-carene. These are the major constituents of pine tree that potentiate the inhibitory synaptic responses by acting as a positive modulator for GABAA-BZD receptor. In this review, we discuss the effects of phytoncide on sleep and review the latest approaches of sleep-related behavioral assay, electrophysiological recording, and molecular modeling technique.
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Affiliation(s)
- Junsung Woo
- Center for Cell and Gene Th erapy, Baylor College of Medicine, Houston, TX 77030, USA
| | - C Justin Lee
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea
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17
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Bjerring PN, Morgan MY, Vilstrup H, Nielsen SM, Christensen R, Gluud LL. Medical interventions for prevention and treatment of hepatic encephalopathy in adults with cirrhosis: a network meta‐analysis. Cochrane Database Syst Rev 2018; 2018:CD013241. [PMCID: PMC6517127 DOI: 10.1002/14651858.cd013241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the beneficial and harmful effects of medical interventions for prevention and treatment of hepatic encephalopathy in adults with cirrhosis.
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Affiliation(s)
- Peter N Bjerring
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionHvidovreDenmark
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Hendrik Vilstrup
- Aarhus University HospitalDepartment of Hepatology and GastroenterologyNørrebrogade 44AarhusDenmark
| | - Sabrina M Nielsen
- The Parker Institute, Bispebjerg and Frederiksberg HospitalMusculoskeletal Statistics UnitCopenhagenDenmark2000 F
| | - Robin Christensen
- Bispebjerg and Frederiksberg HospitalMusculoskeletal Statistics Unit, The Parker InstituteCopenhagenDenmark
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionHvidovreDenmark
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18
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Appiani FJ, Castro GS. Catatonia is not schizophrenia and it is treatable. Schizophr Res 2018; 200:112-116. [PMID: 28610803 DOI: 10.1016/j.schres.2017.05.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 05/20/2017] [Accepted: 05/25/2017] [Indexed: 01/25/2023]
Abstract
Catatonia is a cluster of motor features that appears in many recognized psychiatric illnesses, that according to the DSM-5 it is not linked as a subtype to schizophrenia anymore. The classic signs are mutism, a rigid posture, fixed staring, stereotypic movements, and stupor, which are all part of a broad psychopathology that may be found in affective, thought, neurological, toxic, metabolic and immunological disorders. Despite the many etiologies, catatonia may be a life-threatening condition with a specific treatment. Benzodiazepines are the first line therapeutic option for catatonia, being lorazepam the first-choice drug. Eighty percent of the patients are relieved by the use of barbiturates or benzodiazepines, while in those who fail, an improvement is achieved by electroconvulsive therapy (ECT). With more than 60years of use in catatonic patients, ECT has proven to be an effective and safe tool for the treatment of this frequent and sometimes forgotten syndrome.
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Affiliation(s)
- Francisco J Appiani
- Program of Pharmacology, Direction of Teaching and Research, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Gonzalo S Castro
- Fellowship in abnormal movements, Program of Abnormal Movements and Parkinson disease, Neurology Division, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina
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19
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Yu X, Franks NP, Wisden W. Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems. Front Neural Circuits 2018; 12:4. [PMID: 29434539 PMCID: PMC5790777 DOI: 10.3389/fncir.2018.00004] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 01/11/2018] [Indexed: 01/07/2023] Open
Abstract
Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABAA receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure—it is used for long term sedation in hospital intensive care units—under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.
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Affiliation(s)
- Xiao Yu
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Nicholas P Franks
- Department of Life Sciences, Imperial College London, London, United Kingdom.,Centre for Neurotechnology, Imperial College London, London, United Kingdom.,UK Dementia Research Institute, Imperial College London, London, United Kingdom
| | - William Wisden
- Department of Life Sciences, Imperial College London, London, United Kingdom.,Centre for Neurotechnology, Imperial College London, London, United Kingdom.,UK Dementia Research Institute, Imperial College London, London, United Kingdom
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20
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Abstract
Fatal familial insomnia (FFI) and sporadic fatal insomnia (sFI), or thalamic form of sporadic Creutzfeldt-Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene (PRNP) at chromosome 20. sFI is a phenocopy of FFI and likely its sporadic form. Both diseases are primarily characterized by progressive sleep impairment, disturbances of autonomic nervous system, and motor signs associated with severe loss of nerve cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of 19 kDa identified as resPrPTSE type 2. To date at least 70 kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is thought to cause FFI by destabilizing the mutated prion protein and facilitating its conversion to PrPTSE. The thalamus is the brain region first affected. A similar mechanism triggered spontaneously may underlie sFI.
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21
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Practice Guidelines for Intravenous Conscious Sedation in Dentistry (Second Edition, 2017). Anesth Prog 2018; 65:e1-e18. [PMID: 30702348 PMCID: PMC6318731 DOI: 10.2344/anpr-65-04-15w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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22
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Goh ET, Andersen ML, Morgan MY, Gluud LL, Cochrane Hepato‐Biliary Group. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev 2017; 8:CD002798. [PMID: 28796283 PMCID: PMC6483298 DOI: 10.1002/14651858.cd002798.pub4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. OBJECTIVES To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. SELECTION CRITERIA We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. DATA COLLECTION AND ANALYSIS Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. MAIN RESULTS We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. AUTHORS' CONCLUSIONS We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
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Affiliation(s)
- Ee Teng Goh
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Mette L Andersen
- RigshospitaletDepartment of HepatologyBlegdamsvej 9Dept. 2121CopenhagenDenmark2100
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
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23
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Manchester KR, Lomas EC, Waters L, Dempsey FC, Maskell PD. The emergence of new psychoactive substance (NPS) benzodiazepines: A review. Drug Test Anal 2017; 10:37-53. [DOI: 10.1002/dta.2211] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/11/2017] [Accepted: 04/26/2017] [Indexed: 01/17/2023]
Affiliation(s)
- Kieran R. Manchester
- School of Applied Sciences, Queensgate Campus; University of Huddersfield; Huddersfield UK
| | - Emma C. Lomas
- School of Applied Sciences, Queensgate Campus; University of Huddersfield; Huddersfield UK
| | - Laura Waters
- School of Applied Sciences, Queensgate Campus; University of Huddersfield; Huddersfield UK
| | - Fiona C. Dempsey
- MedAnnex Ltd, 1 Summerhall Place; Techcube 3.5; Edinburgh EH9 1PL UK
| | - Peter D. Maskell
- School of Science, Engineering and Technology; Abertay University; Dundee UK
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24
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Goh ET, Andersen ML, Morgan MY, Gluud LL. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev 2017; 7:CD002798. [PMID: 28745801 PMCID: PMC6483159 DOI: 10.1002/14651858.cd002798.pub3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. OBJECTIVES To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. SELECTION CRITERIA We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. DATA COLLECTION AND ANALYSIS Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. MAIN RESULTS We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from 2 randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; 9 randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. AUTHORS' CONCLUSIONS We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.
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Affiliation(s)
- Ee Teng Goh
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Mette L Andersen
- RigshospitaletDepartment of HepatologyBlegdamsvej 9Dept. 2121CopenhagenDenmark2100
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards AlleHvidovreDenmark2650
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25
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de Biase S, Nilo A, Gigli GL, Valente M. Investigational therapies for the treatment of narcolepsy. Expert Opin Investig Drugs 2017; 26:953-963. [PMID: 28726523 DOI: 10.1080/13543784.2017.1356819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.
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Affiliation(s)
- Stefano de Biase
- a Neurology Unit, Department of Experimental and Clinical Medical Sciences , University of Udine Medical School , Udine , Italy
| | - Annacarmen Nilo
- a Neurology Unit, Department of Experimental and Clinical Medical Sciences , University of Udine Medical School , Udine , Italy
| | - Gian Luigi Gigli
- a Neurology Unit, Department of Experimental and Clinical Medical Sciences , University of Udine Medical School , Udine , Italy.,b Department of Neurosciences , "S. Maria della Misericordia" University Hospital Udine , Udine , Italy
| | - Mariarosaria Valente
- a Neurology Unit, Department of Experimental and Clinical Medical Sciences , University of Udine Medical School , Udine , Italy.,b Department of Neurosciences , "S. Maria della Misericordia" University Hospital Udine , Udine , Italy
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Jo CW, Park CH, Lee JH, Kim JH. Managing the behavior of a patient with autism by sedation via submucosal route during dental treatment. J Dent Anesth Pain Med 2017; 17:157-161. [PMID: 28879345 PMCID: PMC5564151 DOI: 10.17245/jdapm.2017.17.2.157] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 06/07/2017] [Accepted: 06/10/2017] [Indexed: 11/15/2022] Open
Abstract
In sedation via the submucosal route, the drug is administered through the maxillary buccal submucosa. It is time saving, effective, and safe. Patients with autism, a mental disorder, often find it hard to make relationships with other people. These patients display a strong resistance to dental treatment and sedation. This study reports a successful case of behavioral management during dental treatment, using sedation via the submucosal route. The patient was strongly resistant to sedation via the oral, intramuscular, and intravenous routes. The drug used was 9 mg (0.1 mg/kg) of midazolam. Through this case report, we reaffirm the significance of sedation via the submucosal route, and expect that it will be used more frequently for patients with autism, who display behaviors that are difficult to manage, patients with other disabilities, and children.
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Affiliation(s)
- Chan-Woo Jo
- Department of Pediatric Dentistry, Wonju Severance Christian Hospital, Yonsei University, Wonju, Korea
| | - Chan-Hee Park
- Department of Pediatric Dentistry, Wonju Severance Christian Hospital, Yonsei University, Wonju, Korea
| | - Jong-Hyug Lee
- Department of Pediatric Dentistry, Wonju Severance Christian Hospital, Yonsei University, Wonju, Korea
| | - Ji-Hun Kim
- Department of Dentistry, Wonju College of Medicine, Yonsei University, Wonju, Korea
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Moody OA, Talwar S, Jenkins MA, Freeman AA, Trotti LM, García PS, Bliwise D, Lynch JW, Cherson B, Hernandez EM, Feldman N, Saini P, Rye DB, Jenkins A. Rigor, reproducibility, and in vitro cerebrospinal fluid assays: The devil in the details. Ann Neurol 2017; 81:904-907. [PMID: 28440033 DOI: 10.1002/ana.24940] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/15/2017] [Accepted: 02/17/2017] [Indexed: 11/09/2022]
Affiliation(s)
- Olivia A Moody
- Program in Neuroscience, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA
| | - Sahil Talwar
- Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
| | | | - Amanda A Freeman
- Center for the Study of Human Health, Emory College, Atlanta, GA
| | - Lynn Marie Trotti
- Department of Neurology and Emory Program in Sleep, Emory University School of Medicine, Atlanta, GA
| | - Paul S García
- Program in Neuroscience, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA.,Anesthesiology and Research Divisions, Atlanta VA Medical Center, Atlanta, GA.,Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA
| | - Donald Bliwise
- Department of Neurology and Emory Program in Sleep, Emory University School of Medicine, Atlanta, GA
| | - Joseph W Lynch
- Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.,School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
| | | | | | - Neil Feldman
- St Petersburg Sleep Disorders Center, St Petersburg, FL
| | - Prabhjyot Saini
- Department of Neurology and Emory Program in Sleep, Emory University School of Medicine, Atlanta, GA
| | - David B Rye
- Program in Neuroscience, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA.,Department of Neurology and Emory Program in Sleep, Emory University School of Medicine, Atlanta, GA
| | - Andrew Jenkins
- Program in Neuroscience, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA.,Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA.,Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
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28
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Scott PJH, Shao X, Desmond TJ, Hockley BG, Sherman P, Quesada CA, Frey KA, Koeppe RA, Kilbourn MR, Bohnen NI. Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET. ACS Med Chem Lett 2016; 7:746-50. [PMID: 27563397 DOI: 10.1021/acsmedchemlett.5b00435] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 06/01/2016] [Indexed: 11/28/2022] Open
Abstract
Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.
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Affiliation(s)
- Peter J. H. Scott
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
- The Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Xia Shao
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Timothy J. Desmond
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Brian G. Hockley
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Phillip Sherman
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Carole A. Quesada
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Kirk A. Frey
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Department
of Neurology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Robert A. Koeppe
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Michael R. Kilbourn
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Nicolaas I. Bohnen
- Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Department
of Neurology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Neurology Service and Geriatrics Research,
Education, and Clinical Center, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan United States
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Betten DP, Vohra RB, Cook MD, Matteucci MJ, Clark RF. Antidote Use in the Critically Ill Poisoned Patient. J Intensive Care Med 2016; 21:255-77. [PMID: 16946442 DOI: 10.1177/0885066606290386] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The proper use of antidotes in the intensive care setting when combined with appropriate general supportive care may reduce the morbidity and mortality associated with severe poisonings. The more commonly used antidotes that may be encountered in the intensive care unit ( N-acetylcysteine, ethanol, fomepizole, physostigmine, naloxone, flumazenil, sodium bicarbonate, octreotide, pyridoxine, cyanide antidote kit, pralidoxime, atropine, digoxin immune Fab, glucagon, calcium gluconate and chloride, deferoxamine, phytonadione, botulism antitoxin, methylene blue, and Crotaline snake antivenom) are reviewed. Proper indications for their use and knowledge of the possible adverse effects accompanying antidotal therapy will allow the physician to appropriately manage the severely poisoned patient.
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Affiliation(s)
- David P Betten
- Department of Emergency Medicine, Sparrow Health System, Michigan State University College of Human Medicine, Lansing, Michigan 48912-1811, USA.
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The Effects of Flumazenil After Midazolam Sedation on Cerebral Blood Flow and Dynamic Cerebral Autoregulation in Healthy Young Males. J Neurosurg Anesthesiol 2016; 27:275-81. [PMID: 25602623 DOI: 10.1097/ana.0000000000000156] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND It is unknown whether flumazenil antagonizes the decrease in cerebral blood flow or the alteration in dynamic cerebral autoregulation induced by midazolam. We, therefore, investigated the effects on cerebral circulation of flumazenil administered after midazolam, to test our hypothesis that, along with complete reversal of sedation, flumazenil antagonizes the alterations in cerebral circulation induced by midazolam. METHODS Sixteen healthy young male subjects received midazolam followed by flumazenil. The modified Observer's Assessment of Alertness/Sedation (OAA/S) scale and bispectral index (BIS) were used to assess levels of sedation/awareness. For evaluation of cerebral circulation, steady-state mean cerebral blood flow velocity (MCBFV) was measured by transcranial Doppler ultrasonography. In addition, dynamic cerebral autoregulation was assessed by spectral and transfer function analysis between mean arterial pressure (MAP) variability and MCBFV variability. RESULTS During midazolam sedation, defined by an OAA/S score of 3 (responds only after name is called loudly and/or repeatedly), BIS, steady-state MAP, steady-state CBFV, and transfer function gain decreased significantly compared with baseline. After flumazenil administration, an OAA/S score of 5 (responds readily to name spoken in a normal tone) was confirmed. Then, BIS and MAP returned to the same level as baseline. However, steady-state MCBFV showed a further significant decrease compared with that under midazolam sedation, and the decreased transfer function gain persisted. CONCLUSIONS Contrary to our hypothesis, the present results suggest that despite complete antagonism of the sedative effects of midazolam, flumazenil would not reverse the alterations in cerebral circulation induced by midazolam.
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Abstract
Dental anxiety is common and frequently poses a barrier to necessary dental treatment. The increasing availability of conscious sedation in dental practice has made treatment much more accessible for anxious patients. At present, benzodiazepines are the most commonly used drugs in sedation practice and provide a pleasant experience for most, but not all, patients. An understanding of the mechanism of action of benzodiazepines should inform our practice and deepen our understanding of why and how sedation may fail. CPD/CLINICAL RELEVANCE: As an increasing number of dentists provide sedation for their patients an update on benzodiazepines is timely.
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Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication - A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol 2015; 118:37-44. [DOI: 10.1111/bcpt.12434] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 06/15/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Elisabeth I Penninga
- Department of Medicines Licensing and Availability; Danish Health and Medicines Authority; Copenhagen Denmark
- Danish Poison Information Centre; Bispebjerg University Hospital; Copenhagen Denmark
| | - Niels Graudal
- Department of Rheumatology; Rigshospitalet; Copenhagen University Hospital; Copenhagen Denmark
| | - Morten Baekbo Ladekarl
- Danish Poison Information Centre; Bispebjerg University Hospital; Copenhagen Denmark
- Department of Radiology; Roskilde University Hospital; Roskilde Denmark
| | - Gesche Jürgens
- Danish Poison Information Centre; Bispebjerg University Hospital; Copenhagen Denmark
- Unit of Clinical Pharmacology; Roskilde University Hospital; Roskilde Denmark
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Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, Freeman A, Garcia PS, Owens MJ, Ritchie JC, Jenkins A. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med 2013; 4:161ra151. [PMID: 23175709 DOI: 10.1126/scitranslmed.3004685] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The biology underlying excessive daytime sleepiness (hypersomnolence) is incompletely understood. After excluding known causes of sleepiness in 32 hypersomnolent patients, we showed that, in the presence of 10 μM γ-aminobutyric acid (GABA), cerebrospinal fluid (CSF) from these subjects stimulated GABA(A) receptor function in vitro by 84.0 ± 40.7% (SD) relative to the 35.8 ± 7.5% (SD) stimulation obtained with CSF from control subjects (Student's t test, t = 6.47, P < 0.0001); CSF alone had no effect on GABA(A) signaling. The bioactive CSF component had a mass of 500 to 3000 daltons and was neutralized by trypsin. Enhancement was greater for α2 subunit- versus α1 subunit-containing GABA(A) receptors and negligible for α4 subunit-containing ones. CSF samples from hypersomnolent patients also modestly enhanced benzodiazepine (BZD)-insensitive GABA(A) receptors and did not competitively displace BZDs from human brain tissue. Flumazenil--a drug that is generally believed to antagonize the sedative-hypnotic actions of BZDs only at the classical BZD-binding domain in GABA(A) receptors and to lack intrinsic activity--nevertheless reversed enhancement of GABA(A) signaling by hypersomnolent CSF in vitro. Furthermore, flumazenil normalized vigilance in seven hypersomnolent patients. We conclude that a naturally occurring substance in CSF augments inhibitory GABA signaling, thus revealing a new pathophysiology associated with excessive daytime sleepiness.
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Affiliation(s)
- David B Rye
- Department of Neurology, Program in Sleep, Emory University School of Medicine, Atlanta, GA 30322, USA.
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Vuilleumier PH, Besson M, Desmeules J, Arendt-Nielsen L, Curatolo M. Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study. PLoS One 2013; 8:e43896. [PMID: 23554851 PMCID: PMC3598812 DOI: 10.1371/journal.pone.0043896] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 11/12/2012] [Indexed: 11/18/2022] Open
Abstract
Background and Aims Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. Methods In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. Results For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. Conclusions Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. Trial Registration ClinicalTrials.gov NCT01011036
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Affiliation(s)
- Pascal H. Vuilleumier
- University Department of Anesthesiology and Pain Therapy, Bern University Hospital, Inselspital, Bern, Switzerland
| | - Marie Besson
- Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Center, University Hospital, Geneva, Switzerland
| | - Jules Desmeules
- Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Center, University Hospital, Geneva, Switzerland
| | - Lars Arendt-Nielsen
- Center for Sensory–Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Michele Curatolo
- University Department of Anesthesiology and Pain Therapy, Bern University Hospital, Inselspital, Bern, Switzerland
- Center for Sensory–Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
- * E-mail:
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Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABA A-related mechanistic probes. Psychopharmacology (Berl) 2008; 197:523-34. [PMID: 18236028 DOI: 10.1007/s00213-007-1066-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Accepted: 12/20/2007] [Indexed: 10/22/2022]
Abstract
RATIONALE A disordered regulation of neuroactive steroids release in response to acute stress could induce GABAergic dysfunctions underlying anxiety disorders. OBJECTIVES First, we conducted studies indicating that a short immobilization stress in anxious Balb/cByJ mice produced an anticonvulsive effect. Second, the effects of different positive allosteric modulators (etifoxine, progesterone, clonazepam, and allopregnanolone) of GABA A receptors were compared in a mouse model mimicking the disruption of the acute stress-induced neuroactive steroids release with finasteride (types I and II 5alpha-reductase inhibitor). RESULTS The acute stress-induced anticonvulsive effect, expressed by the threshold dose of t-butylbicyclophosphorothionate-producing clonic seizures, was time-dependent. The extent of the enhancement of acute stress-induced anticonvulsive effect was lowered in the presence of finasteride. The same effect was observed with PK11195, which behaves as an antagonist of the peripheral benzodiazepine receptor in the dose range used in this study. Picrotoxin reduced the acute stress anticonvulsive effect, proving that this effect operates through the GABA A receptor. Contrary to progesterone (up to 30 mg/kg), etifoxine (50 mg/kg), allopregnanolone (10 mg/kg), and clonazepam (10 microg/kg) inhibited the finasteride effect in stressed animals. The effect of etifoxine was blocked in the presence of finasteride and picrotoxin combined in stressed animals. CONCLUSIONS These findings support the hypothesis suggesting an involvement of neuroactive steroids in the anticonvulsive effect of restraint stress. The dual and complementary mechanisms of action of etifoxine (directly on the GABA A receptor and indirectly via the neuroactive steroids) may represent a therapeutic benefit in the treatment of various anxiety disorders with abnormal production of neuroactive steroids.
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Li J, Fish RL, Cook SM, Tattersall FD, Atack JR. Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors. Neuropharmacology 2006; 51:168-72. [PMID: 16697018 DOI: 10.1016/j.neuropharm.2006.03.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2005] [Revised: 03/03/2006] [Accepted: 03/15/2006] [Indexed: 11/21/2022]
Abstract
In the present study, the occupancy of flumazenil (Ro 15-1788; 1-30mg/kg p.o.) at the benzodiazepine site of rat brain GABA(A) receptors was compared using in vivo and ex vivo binding methodologies with [(3)H]flumazenil as the radioligand. Animals either received tracer quantities of [(3)H]flumazenil 3min before being killed for the in vivo binding, or were killed and brain homogenates incubated with 1.8nM [(3)H]flumazenil. The flumazenil dose required to inhibit in vivo binding of [(3)H]flumazenil by 50% (ID(50)) was 2.0mg/kg, which represents the most accurate measure of benzodiazepine site occupancy by flumazenil in vivo. Occupancy measured in crude brain homogenates using the ex vivo method was time dependent with a 3mg/kg dose giving occupancies of 77% and 12% using 0.5 or 60min ex vivo incubations times, respectively, presumably due to dissociation from the binding site during the ex vivo incubation. When incubation time was minimised (0.5min), and despite being under non-equilibrium conditions, the ex vivo method gave an ID(50) of 1.5mg/kg which was not too dissimilar from that observed using in vivo binding (2.0mg/kg). As expected, ex vivo binding can give an underestimation of receptor occupancy but this can be minimised by careful attention to the kinetics of unlabelled drug and radioligand.
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Affiliation(s)
- Jennifer Li
- Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
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Mathiasen L, Mirza NR. A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test. Psychopharmacology (Berl) 2005; 182:475-84. [PMID: 16133136 DOI: 10.1007/s00213-005-0119-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2005] [Accepted: 06/30/2005] [Indexed: 10/25/2022]
Abstract
RATIONALE GABAA receptors containing an alpha2 subunit are proposed to mediate the anxiolytic effect of benzodiazepines (BZ) based on studies in transgenic mice using unconditioned models of anxiety. Conditioned models of anxiety were not assessed and are rarely encountered in phenotyping of genetically modified animals. The novel benzodiazepine site ligand L838,417 is a partial agonist at GABAA receptors containing an alpha2, alpha3 or alpha5 subunit and an antagonist at alpha1 receptors, giving an anxiolytic profile devoid of sedation. However, this compound has not previously been assessed in mice. OBJECTIVES (1) Establish the Vogel conflict test (VCT) in C57BL/6J mice and validate it with a range of pharmacological tools and (2) compare the full and partial GABAA receptor positive modulators chlordiazepoxide (CDP) and bretazenil (BRZ), respectively, with the subtype selective ligands zolpidem (ZOL; alpha1 selective) and L838,417. RESULTS (1) enhanced thirst (water deprivation or isoproterenol administration), analgesia (lamotrigine) or cognitive impairment (MK-801) did not generate false positives in the VCT; (2) CDP and BRZ engendered linear dose-related anti-conflict effects and also increased unpunished drinking; (3) L838,417 engendered a bell-shaped anti-conflict effect and did not increase unpunished drinking; (4) the anti-conflict effect of CDP and L838,417 were antagonised by flumazenil, whereas BRZ's effect was insensitive to this antagonist; and (5) ZOL induced motoric deficits and no anti-conflict effect. CONCLUSION We have established the VCT in C57BL/6J mice and validated this test behaviourally, physiologically and pharmacologically. The novel GABAA receptor ligand L838,417 was anxiolytic in this mouse model, and unlike the non-selective compounds, had no effect on unpunished drinking.
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Affiliation(s)
- L Mathiasen
- Department of in-vivo Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, 2750, Ballerup, Denmark.
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Girdler NM, Fairbrother KJ, Lyne JP, Neave N, Scholey A, Hargaden N, Wesnes KA, Engler J, Rotherham NA. A randomised crossover trial of post-operative cognitive and psychomotor recovery from benzodiazepine sedation: effects of reversal with flumazenil over a prolonged recovery period. Br Dent J 2004; 192:335-9; discussion 331. [PMID: 15552071 DOI: 10.1038/sj.bdj.4801369] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To study the post-operative cognitive and psychomotor recovery from midazolam conscious sedation, after reversal with the benzodiazepine antagonist flumazenil over a prolonged recovery period. DESIGN A prospective, double-blind, randomised, crossover trial. SETTING Out-patient Sedation Department, Newcastle Dental Hospital and School METHOD Eighteen patients, ASA I or II, received midazolam on two separate occasions to undergo equivalent dental treatment. Following treatment patients were reversed with intravenous flumazenil or saline (placebo) at alternate appointments. Assessment of mood and cognitive function was undertaken using a highly sensitive and specific computerised battery of cognitive tests administered by telephone. Cognitive and psychomotor tests were administered prior to sedation and every hour for 6 hours post reversal. RESULTS Results indicated no significant effect of flumazenil on simple reaction time and choice reaction time but did show a trend of reversing the effects of midazolam on numeric working memory and word recognition. CONCLUSION The cognitive and psychomotor effects of the sedation were not fully reversed by flumazenil. Cognitive impairments were still present up to 6 hours post-reversal, despite patients appearing clinically more alert. This has important implications for treatment protocols and discharge instructions.
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Affiliation(s)
- N M Girdler
- University of Newcastle Dental School and Hospital, University of Newcastle, Newcastle upon Tyne.
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Mancuso CE, Tanzi MG, Gabay M. Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options. Pharmacotherapy 2004; 24:1177-85. [PMID: 15460178 DOI: 10.1592/phco.24.13.1177.38089] [Citation(s) in RCA: 156] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Benzodiazepines frequently are administered to patients to induce sedation. Paradoxical reactions to benzodiazepines, characterized by increased talkativeness, emotional release, excitement, and excessive movement, are relatively uncommon and occur in less than 1% of patients. The exact mechanism of paradoxical reactions remains unclear. Most cases are idiosyncratic; however, some evidence suggests that these reactions may occur secondary to a genetic link, history of alcohol abuse, or psychological disturbances. This review evaluates the numerous cases of paradoxical reactions to benzodiazepines in adult and pediatric patients that have been reported in the biomedical literature. It also explores the advantages and disadvantages of the various available treatment options.
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Affiliation(s)
- Carissa E Mancuso
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois, Chicago, Illinois 60612-7230, USA
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Suzuki M, Nishina M, Nakamura S, Maruyama K. Benzodiazepine-sensitive GABA(A) receptors in the commissural subnucleus of the NTS are involved in the carotid chemoreceptor reflex in rats. Auton Neurosci 2004; 110:108-13. [PMID: 15046734 DOI: 10.1016/j.autneu.2003.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2003] [Revised: 12/17/2003] [Accepted: 12/22/2003] [Indexed: 12/28/2022]
Abstract
We studied the role of benzodiazepine (BDZ) receptors in the commissural subnucleus of the nucleus tractus solitarius (commNTS) in chemoreceptor reflex in urethane-anesthetized, pancronium-immobilized, artificially ventilated and bilaterally vagotomized rats. A BDZ agonist, diazepam (1-4 micromol/kg), administered intravenously reduced resting phrenic nerve activity (PNA) and blood pressure (BP). Stimulation of carotid chemoreceptors induced an increase in PNA and an increase in BP. Diazepam inhibited this chemoreceptor reflex. The effects of intravenous injection of diazepam (4 micromol/kg) on the chemoreceptor reflex were antagonized by microinjection of the BDZ antagonist flumazenil (100 pmol) into the commNTS. Microinjection of flumazenil (100 pmol) alone had no effect on the basal PNA and BP, and the chemoreceptor reflex. These results suggest that BDZ receptors are present in the carotid chemoreceptor reflex pathway in the commNTS and potentiate GABA(A) transmission.
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Affiliation(s)
- Masahiko Suzuki
- Department of Pharmacology, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan.
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Abstract
BACKGROUND Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy. SEARCH STRATEGY Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies. SELECTION CRITERIA Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I(2). Potential sources of heterogeneity were explored through subgroup analyses. MAIN RESULTS Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous. REVIEWERS' CONCLUSIONS Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.
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Affiliation(s)
- B Als-Nielsen
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Department 7102, H:S Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
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42
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Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C. Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Addict Biol 2002; 7:385-95. [PMID: 14578014 DOI: 10.1080/1355621021000005973] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Flumazenil (FLU), a benzodiazepine (BZD) partial agonist with a weak intrinsic activity, was previously found unable to precipitate withdrawal in tolerant subjects submitted to long-lasting BZD treatment. The potential use of FLU to treat BZD withdrawal symptoms has also been evaluated tentatively in clinical studies. In the present experiment, FLU (treatment A) was compared with oxazepam tapering (treatment B) and placebo (treatment C) in the control of BZD withdrawal symptoms in three groups of BZD dependent patients. Group A patients (20) received FLU 1 mg twice a day for 8 days, and oxazepam 30 mg in two divided doses (15 mg + 15 mg) during the first night, oxazepam 15 mg during the second night and oxazepam 7.5 mg during the third night. FLU was injected i.v. in saline for 4 hours in the morning and 4 hours in the afternoon, in association with placebo tablets. Group B patients (20) were treated by tapering of oxazepam dosage (from 120 mg) and with saline solution (as placebo) instead of FLU for 8 days. Group C patients (10) received saline instead of FLU and placebo tablets instead of oxazepam for 8 days. FLU immediately reversed BZD effects on balance task and significantly reduced withdrawal symptoms in comparison with oxazepam and placebo on both self-reported and observer-rated withdrawal scales. The partial agonist also reduced craving scores during the detoxification procedure. In addition, during oxazepam tapering, group B patients experienced paradoxical symptoms that were not apparent in FLU patients. Patients treated with FLU showed a significantly lower relapse rates on days 15, 23 and 30 after the detoxification week. Our data provide further evidence of FLUs ability to counteract BZD effects, control BZD withdrawal and normalize BZD receptor function. The effectiveness of FLU may reflect its capacity to upregulate BZD receptors and to reverse the uncoupling between the recognition sites of BZD and GABA, on the GABA(A) macromolecular complex, that has been reported in tolerant subjects.
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Affiliation(s)
- G Gerra
- Addiction Research Center, Ser. T., AUSL, Via Spalato 2, 43100 Parma, Italy.
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43
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Abstract
The effects of BZ drugs result from interaction at the GABAA receptor within the CNS, producing anxiolysis, hypnosis, and amnesia in a dose-dependent fashion. These sedative effects are best titrated to reproducible clinical endpoints, using scoring systems such as the Ramsay scale. All BZs exhibit similar pharmacologic effects, but the important differences in pharmacokinetics and pharmacodynamics should be recognized to use these drugs safely and effectively within the ICU. Diazepam is the classic anxiolytic, amnestic, and sedative agent, but the presence of long-acting active metabolites that depend on the kidneys for elimination limits its use in many ICU patients. Lorazepam is the most potent BZ used in the ICU; it has stable pharmacokinetics and relatively low cost. This drug is best reserved for situations in which rapid onset is not essential and long-term sedation is anticipated. Midazolam has the shortest t1/2 of the commonly used BZs, generates few active metabolites, and is water soluble at physiologic pH. Thus, it is well suited for continuous infusion in the ICU, and the recent introduction of generic formulations of midazolam has decreased the drug-acquisition cost for many hospitals. Optimal sedation for ICU patients often requires BZ and concomitant therapy with drugs such as haloperidol, dexmedetomidine, opioids, and so forth, to reduce untoward side effects and, perhaps, overall drug costs. Flumazenil, a specific BZ antagonist, can be used for diagnostic or therapeutic reversal of BZ agonists when appropriate. Most experienced intensivists recommend an individualized approach to sedation and titration of anxiolysis to maximize efficacy, minimize side effects, and optimize cost effectiveness in the ICU. New CNS monitors of the EEG, such as the BIS or entropy EEG monitors, may refine titration algorithms further in the near future.
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Affiliation(s)
- C C Young
- Duke University Medical Center, Durham, North Carolina, USA
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Zedkova L, Rauw GA, Baker GB, Coupland NJ. A rapid high-pressure liquid chromatographic procedure for determination of flumazenil in plasma. J Pharmacol Toxicol Methods 2001; 46:57-60. [PMID: 12164261 DOI: 10.1016/s1056-8719(01)00162-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Flumazenil antagonizes the effects of benzodiazepines at gamma-aminobutyric acid (GABA) type A receptors in the central nervous system. Flumazenil has been reported to provoke panic attacks in patients with panic disorder (PD) but not in healthy controls. A rapid high-pressure liquid chromatographic (HPLC) method was developed for determination of flumazenil in plasma samples from PD patients receiving flumazenil and the results obtained with that assay are reported here. METHODS Samples from 37 PD subjects receiving 2 mg of flumazenil intravenously were analyzed. Extraction under basic conditions was followed by an HPLC assay with UV detection (250 nm). Lamotrigine was used as intermal standard and a standard curve was constructed for each assay run. Flumazenil concentrations were measured in all the subjects in samples collected at 2 and 4 min after the drug administration and in some subjects, measurements were also done in samples collected at 7.5, 15, 30, 45, and 60 min. RESULTS The procedure was reproducible and linear (from 2.5 to 1000 ng/ml). At 2 and 4 min after flumazenil administration, the concentrations did not differ significantly between panicking and nonpanicking subjects, indicating that the pharmacokinetics of the drug is not the major determinant of the responses. There was a steep decline in the plasma concentration-time profile during the first 4 min, reflecting an extensive and rapid distribution after which the decline was slower. DISCUSSION The method described here is rapid, replicable, and convenient for the determination of flumazenil in plasma.
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Affiliation(s)
- L Zedkova
- Department of Psychiatry, Psychopharmacology Research Unit and Neurochemical Research Unit, University of Alberta, Edmonton, AB, Canada.
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Zhao YH, Le J, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Butina D, Beck G, Sherborne B, Cooper I, Platts JA, Boutina D. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 2001; 90:749-84. [PMID: 11357178 DOI: 10.1002/jps.1031] [Citation(s) in RCA: 357] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The human intestinal absorption of 241 drugs was evaluated. Three main methods were used to determine the human intestinal absorption: bioavailability, percentage of urinary excretion of drug-related material following oral administration, and the ratio of cumulative urinary excretion of drug-related material following oral and intravenous administration. The general solvation equation developed by Abraham's group was used to model the human intestinal absorption data of 169 drugs we considered to have reliable data. The model contains five Abraham descriptors calculated by the ABSOLV program. The results show that Abraham descriptors can successfully predict human intestinal absorption if the human absorption data is carefully classified based on solubility and administration dose to humans.
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Affiliation(s)
- Y H Zhao
- Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
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Butterfield K, Bennett JD. Reversal Agents. Oral Maxillofac Surg Clin North Am 2001. [DOI: 10.1016/s1042-3699(20)30162-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Als-Nielsen B, Kjaergard LL, Gluud C. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy. Cochrane Database Syst Rev 2001:CD002798. [PMID: 11687160 DOI: 10.1002/14651858.cd002798] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor antagonists for hepatic encephalopathy, but the results are conflicting. OBJECTIVES To evaluate the efficacy and safety of benzodiazepine receptor antagonists for patients with acute or chronic hepatic encephalopathy. SEARCH STRATEGY Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of relevant articles, authors of trials, and the pharmaceutical company known to produce benzodiazepine receptor antagonists. SELECTION CRITERIA Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy were included, regardless of language or publication status. DATA COLLECTION AND ANALYSIS Trial inclusion and data extraction were made independently by two contributors. Depending on the presence or absence of significant heterogeneity (P<0.1) a random or fixed effect model was used. Potential causes for heterogeneity were explored by sensitivity analyses. MAIN RESULTS Twelve randomised trials with 765 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (341/370 (92%) survived in the flumazenil group versus 325/356 (91%) in the placebo group). Flumazenil had no significant effect on full recovery (two trials), survival (nine trials), or on the occurrence of adverse events (five trials). However, flumazenil was associated with a significant effect on improvement of hepatic encephalopathy compared to placebo at the end of treatment (103/346 (30%) versus 23/332 (7 %), risk difference 0.23, 95% confidence interval 0.18 to 0.28, five trials). REVIEWER'S CONCLUSIONS Flumazenil had no significant effect on recovery or survival from hepatic encephalopathy. However, flumazenil had a significant effect on short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.
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Affiliation(s)
- B Als-Nielsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshospitalet, Dep. 7701, Blegdamsvej 9, Copenhagen, Denmark, DK-2100.
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Wille RT, Chaffee BW, Ryan ML, Elta GH, Walter V, Barnett JL. Pharmacoeconomic evaluation of flumazenil for routine outpatient EGD. Gastrointest Endosc 2000; 51:282-7. [PMID: 10699772 DOI: 10.1016/s0016-5107(00)70356-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Flumazenil is a benzodiazepine antagonist indicated for reversal of the sedative effects of benzodiazepines. Previous studies suggest that flumazenil may shorten recovery time after endoscopy, but there are few data on actual recovery room times and charges. METHODS Fifty patients undergoing routine upper endoscopy were sedated with midazolam alone in the usual titrated manner. Patients were randomized in a double-blind fashion to receive either flumazenil or saline immediately after procedure. Assessments of responsiveness, speech, facial expression, and ptosis (Observer's Assessment of Alertness/Sedation [OAA/S] scale) were made before procedure, immediately after procedure and every 15 minutes thereafter. The patient was discharged from the recovery room when vital signs and OAA/S scale reached preprocedure levels. Recovery room times and charges were recorded. RESULTS The flumazenil group demonstrated shorter recovery room times and recovery room charges than the placebo group (p < 0.001). The difference in recovery room charges was not statistically different when flumazenil charges were included (p = 0.09). CONCLUSIONS The routine use of flumazenil after midazolam sedation for upper endoscopy significantly shortened recovery time and charges but did not statistically reduce overall charges.
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Affiliation(s)
- R T Wille
- University of Michigan Hospitals, Ann Arbor, Michigan, USA
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Zeegers A, van Wilgenburg H, Leeuwin RS. Cardiac effects of benzodiazepine receptor agonists and antagonists in the isolated rat heart: a comparative study. Life Sci 1999; 63:1439-56. [PMID: 9952290 DOI: 10.1016/s0024-3205(98)00411-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Effects of PK 11195 and flumazenil on cardiac responses to diazepam, clonazepam and zolpidem were compared. Coronary flow rate was increased at relatively low doses of diazepam and decreased at higher doses. Clonazepam induced a dose-dependent increase, and zolpidem a decrease of coronary flow rate. PK 11195 reduced the diazepam-induced increase of coronary flow rate, and flumazenil was ineffective. Neither antagonist evoked substantial changes in the decrease of coronary flow rate. PK 11195, and less so flumazenil, antagonized the clonazepam-induced increase. PK 11195 and flumazenil only in their highest doses suppressed and respectively potentiated the zolpidem-induced decrease. Inotropy showed a biphasic response in the presence of diazepam, i.e. an initial transient decrease, followed by a dose-dependent increase in two steps. Clonazepam induced a similar response. Zolpidem increased the inotropy. The negative inotropic response induced by diazepam did not change significantly in the presence of PK 11195 or flumazenil. The positive inotropic response was suppressed by PK 11195, and less so by flumazenil. The negative response to clonazepam was antagonized by both PK 11195 and flumazenil; the positive response was not significantly changed. In the presence of lower doses of PK 11195, the zolpidem-induced response was potentiated, whereas higher doses produced reversal; flumazenil potentiated the response. In conclusion, the results support earlier suggestions, involving receptor mechanisms with cardiac effects of benzodiazepines. Both agonists and antagonists (inter)act in a different manner, suggesting that rather ambiguous receptor mechanisms are involved in benzodiazepine effects in the heart.
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Affiliation(s)
- A Zeegers
- Department of Pharmacology, University of Amsterdam, Academic Medical Center, The Netherlands
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Bernik MA, Gorenstein C, Vieira Filho AH. Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users. J Psychopharmacol 1998; 12:146-50. [PMID: 9694026 DOI: 10.1177/026988119801200205] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The acute effects of flumazenil, a benzodiazepine (BZD) receptor antagonist in long-term BZD users were used as a possible test to detect physiological dependence. Thirty-four subjects (20 females, 14 males) aged 26-48 years (mean + SD, 42.4+/-8.5 years), all chronic users of low doses of diazepam (5-20 mg/day, 14.2+/-4.8 mg/day) for 5 to 28 years (10.5+/-6 years), received a single 1-mg i.v. flumazenil dose or saline, infused slowly under double-blind conditions. Physiological dependence was suggested as all patients receiving flumazenil developed an anxiety reaction while the placebo group did not. Flumazenil triggered a qualitatively different reaction amounting to a panic attack during infusion in nine out of 15 patients. These patients had a diagnosis of panic disorder or a history of panic attacks. Caution should be exercised when giving flumazenil to panic patients who are taking BZDs as maintenance treatment.
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Affiliation(s)
- M A Bernik
- Ambulatório de Ansiedade, Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil.
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