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James K Rowlett - One of the best experts on this subject based on the ideXlab platform.
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tolerance and dependence following chronic Alprazolam treatment in rhesus monkeys role of gabaa receptor subtypes
Drug and Alcohol Dependence, 2021Co-Authors: Angela N Duke, V Phani Babu V N Tiruveedhula, Dishary Sharmin, Daniel E Knutson, James M Cook, Donna M Platt, James K RowlettAbstract:Abstract Background To assess GABAA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce “cross-tolerance”) or precipitate withdrawal during chronic Alprazolam treatment. Methods Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered Alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic Alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, Alprazolam, followed by quantitative behavioral observations. The ligands included Alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for α1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABAA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABAA receptors). Results Acutely, Alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as “rest/sleep posture” at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic Alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic Alprazolam. Administration of βCCT, but not HZ-166, resulted in significant withdrawal signs. Conclusions These results are consistent with a role for α1-containing GABAA receptor subtypes in tolerance and dependence observed with chronic Alprazolam, although other receptors may be involved in the withdrawal syndrome.
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tolerance and dependence following chronic Alprazolam treatment quantitative observation studies in female rhesus monkeys
Psychopharmacology, 2020Co-Authors: Angela N Duke, Donna M Platt, James K RowlettAbstract:In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required. This research evaluated the ability of chronic treatment with a commonly prescribed benzodiazepine, Alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys. Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. Alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for Alprazolam and withdrawal signs were assessed for 7 days. Maximal sedation (“deep sedation”) was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, “rest/sleep posture,” emerged by day 3 and did not decline over 38 days. Cessation of Alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg). Chronic Alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABAA receptor subtypes.
Angela N Duke - One of the best experts on this subject based on the ideXlab platform.
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tolerance and dependence following chronic Alprazolam treatment in rhesus monkeys role of gabaa receptor subtypes
Drug and Alcohol Dependence, 2021Co-Authors: Angela N Duke, V Phani Babu V N Tiruveedhula, Dishary Sharmin, Daniel E Knutson, James M Cook, Donna M Platt, James K RowlettAbstract:Abstract Background To assess GABAA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce “cross-tolerance”) or precipitate withdrawal during chronic Alprazolam treatment. Methods Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered Alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic Alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, Alprazolam, followed by quantitative behavioral observations. The ligands included Alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for α1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABAA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABAA receptors). Results Acutely, Alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as “rest/sleep posture” at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic Alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic Alprazolam. Administration of βCCT, but not HZ-166, resulted in significant withdrawal signs. Conclusions These results are consistent with a role for α1-containing GABAA receptor subtypes in tolerance and dependence observed with chronic Alprazolam, although other receptors may be involved in the withdrawal syndrome.
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tolerance and dependence following chronic Alprazolam treatment quantitative observation studies in female rhesus monkeys
Psychopharmacology, 2020Co-Authors: Angela N Duke, Donna M Platt, James K RowlettAbstract:In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required. This research evaluated the ability of chronic treatment with a commonly prescribed benzodiazepine, Alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys. Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. Alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for Alprazolam and withdrawal signs were assessed for 7 days. Maximal sedation (“deep sedation”) was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, “rest/sleep posture,” emerged by day 3 and did not decline over 38 days. Cessation of Alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg). Chronic Alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABAA receptor subtypes.
Donna M Platt - One of the best experts on this subject based on the ideXlab platform.
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tolerance and dependence following chronic Alprazolam treatment in rhesus monkeys role of gabaa receptor subtypes
Drug and Alcohol Dependence, 2021Co-Authors: Angela N Duke, V Phani Babu V N Tiruveedhula, Dishary Sharmin, Daniel E Knutson, James M Cook, Donna M Platt, James K RowlettAbstract:Abstract Background To assess GABAA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce “cross-tolerance”) or precipitate withdrawal during chronic Alprazolam treatment. Methods Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered Alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic Alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, Alprazolam, followed by quantitative behavioral observations. The ligands included Alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for α1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABAA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABAA receptors). Results Acutely, Alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as “rest/sleep posture” at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic Alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic Alprazolam. Administration of βCCT, but not HZ-166, resulted in significant withdrawal signs. Conclusions These results are consistent with a role for α1-containing GABAA receptor subtypes in tolerance and dependence observed with chronic Alprazolam, although other receptors may be involved in the withdrawal syndrome.
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tolerance and dependence following chronic Alprazolam treatment quantitative observation studies in female rhesus monkeys
Psychopharmacology, 2020Co-Authors: Angela N Duke, Donna M Platt, James K RowlettAbstract:In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required. This research evaluated the ability of chronic treatment with a commonly prescribed benzodiazepine, Alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys. Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. Alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for Alprazolam and withdrawal signs were assessed for 7 days. Maximal sedation (“deep sedation”) was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, “rest/sleep posture,” emerged by day 3 and did not decline over 38 days. Cessation of Alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg). Chronic Alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABAA receptor subtypes.
Edward M Sellers - One of the best experts on this subject based on the ideXlab platform.
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abuse potential of lasmiditan a phase 1 randomized placebo and Alprazolam controlled crossover study
The Journal of Clinical Pharmacology, 2020Co-Authors: Darren Wilbraham, Paul Berg, Max Tsai, Emily Liffick, Li Shen Loo, Erin G Doty, Edward M SellersAbstract:Lasmiditan is a centrally penetrant, highly selective 5-hydroxytryptamine (serotonin) receptor 1F (5HT1F ) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo- and positive-controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, Alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with Alprazolam and with placebo using the maximal effect score (Emax ) of the Drug-Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug-liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400-mg dose (upper 90% confidence limit on difference in least-squares [LS] means > 14 for all lasmiditan doses). Drug-liking scores for lasmiditan 400 mg were not significantly different from Alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug-liking scores at lower doses (100 and 200 mg) were significantly different from Alprazolam. During the treatment phase, the incidence of treatment-emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug-liking effects for lasmiditan versus placebo and versus Alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.
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randomized double blind placebo and active comparator controlled crossover study evaluating the abuse potential of the antiepileptic drug lacosamide in healthy recreational drug users
Journal of Clinical Psychopharmacology, 2017Co-Authors: Kerri A Schoedel, Jensotto Andreas, Pamela Doty, Klaus Eckhardt, Edward M SellersAbstract:PURPOSE This phase 1, randomized, double-blind, placebo- and active comparator-controlled crossover study assessed the abuse potential of the antiepileptic drug, lacosamide. METHODS After a qualification phase, 38 healthy, recreational central nervous system-depressant users were randomized to treatment sequences comprising single oral therapeutic (200 mg) and supratherapeutic (800 mg) doses of lacosamide, Alprazolam (1.5 and 3 mg), and placebo. Subjective effects were assessed for 24 hours following each dose using a range of scales, with a 5- to 9-day washout between treatments. FINDINGS Mean subjective effects for 200 mg lacosamide were statistically similar to placebo and significantly lower than with Alprazolam for most end points. Lacosamide 800 mg elicited transient, statistically significant positive effects compared with placebo, but also persistent Bad Drug Effects including statistically greater maximum effect (Emax) scores for Nausea and Dysphoria compared with other treatments (P < 0.0002). Consistent with this, the 800 mg lacosamide dose showed a significantly lower "at this moment" Drug Liking visual analog scale (VAS) Emax compared with 3 mg Alprazolam, but was not different from 1.5 mg Alprazolam (73.1/100, 85.4/100, and 78.9/100, respectively, where 50 is neutral). Overall Drug Liking VAS and Take Drug Again VAS Emax for 800 mg lacosamide were not significantly different from placebo and were lower than those for both Alprazolam doses (P < 0.0001). IMPLICATIONS These results suggest that in recreational central nervous system-depressant users, lacosamide has detectable abuse-related subjective effects, but a relatively low potential for abuse compared with Alprazolam. These findings contributed toward placement of lacosamide into Schedule V of the US Controlled Substances Act.
Koichi Otani - One of the best experts on this subject based on the ideXlab platform.
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no effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam
Therapeutic Drug Monitoring, 2002Co-Authors: Yohei Otsuji, Naoyuki Okuyama, Toshiaki Aoshima, Takashi Fukasawa, Kimiyasu Kato, Gisa Gerstenberg, Masatomo Miura, Tadashi Ohkubo, Kazunobu Sugawara, Koichi OtaniAbstract:To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of Alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200 mg/day or matched placebo orally for 6 days took an oral 0.8 mg dose of Alprazolam on day 4 of each treatment phase. Plasma concentration of Alprazolam was measured up to 48 h after Alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersogelser side effect rating scale. Itraconazole significantly (P < 0.01) increased the area under the concentration-time curves from 0 h to infinity (252 ± 47 versus 671 ± 205 ng h/ml), decreased the apparent oral clearance (0.89 ± 0.21 versus 0.35 ± 0.10 ml/min per kg) and prolonged the elimination half-life (15.7 ± 4.1 versus 40.3 ± 13.5 h) of Alprazolam. The test performed during itraconazole treatment showed significantly depressed psychomotor function. It is suggested that itraconazole, a potent CYP3A4 inhibitor, increases plasma concentration of Alprazolam via its inhibitory effects on Alprazolam metabolism. Thus, this study supports previous studies suggesting that CYP3A4 is the major enzyme catalyzing the metabolism of Alprazolam. Enhanced side effects of Alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes.
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a kinetic and dynamic study of oral Alprazolam with and without erythromycin in humans in vivo evidence for the involvement of cyp3a4 in Alprazolam metabolism
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Norio Yasui, Tadashi Ohkubo, Kazunobu Sugawara, Koichi Otani, Sunao Kaneko, Takako Osanai, Kan Chiba, Takashi IshizakiAbstract:Objective To assess the possible involvement of CYP3A4 in the metabolism of Alprazolam in vivo. Method Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of Alprazolam on the posttreatment day 8. Plasma concentration of Alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersogelser side effect rating scale. Results Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 ± 43 versus 322 ± 49 ng · hr/ml from 0 to 48 hours and 229 ± 52 versus 566 ± 161 ng · hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 ± 0.31 versus 0.41 ± 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 ± 4.5 versus 40.3 ± 14.4 hours) of Alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. Conclusion This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of Alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of Alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing. Clinical Pharmacology & Therapeutics (1996) 59, 514–519; doi: