Bill Massey - Academia.edu (original) (raw)
Papers by Bill Massey
Frontiers in Microbiology
Pharmacy & Pharmacology International Journal
It also identifies the prescribing physician as an important locus for identification and interve... more It also identifies the prescribing physician as an important locus for identification and intervention of opiate addiction. Coordination and cooperation between prescribing physicians and opiate abuse treatment providers is a necessary tool in stemming this crisis.
Pharmacy & Pharmacology International Journal
Psychopharmacology, 2015
Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, ... more Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, is impaired in rodents by subchronic (sc) treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), a widely studied model of cognitive impairment in schizophrenia (CIS). The principal objective of this study was to determine the ability of serotonin (5-HT)1A partial agonism and 5-HT7 receptor antagonism to improve RL in scPCP-treated mice. Male C57BL/6J mice were trained on an operant RL (ORL) task, then received PCP, 10 mg/kg, or saline, bid, for 7 days, followed by a 7-day washout period. scPCP significantly diminished the percent correct responding, increased total incorrect trials, and total incorrect responses, in the reversal phase performance of the ORL task. Pre-treatment with the selective 5-HT1A partial agonist, tandospirone, or the selective 5-HT7 antagonist, SB269970, but not the 5-HT7 agonist, AS 19, reversed the scPCP-induced deficit in RL. Pre-treatment with atypical antipsychotic drug lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, as well as a 5-HT2A and dopamine (D)2 antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit. These results indicate that 5-HT7 antagonism and 5-HT1A partial agonism contribute to restoration of RL in scPCP-treated mice. It is suggested that these two mechanisms are effective in restoring RL by decreasing excessive GABAergic inhibition of cortical pyramidal neurons following withdrawal of scPCP treatment.
= 1.0 at P < 0.0001 ) when 8 validation sample... more = 1.0 at P < 0.0001 ) when 8 validation samples are included in the correlation. - Predictions of antipsychotic activity, agranulocytosis risk, and hERG risk are correlated with % confidence of yes and the accuracy of the decisions. All yes/no models ( Figure 2 ) are tested with leave 10% out cross-validation and the agranulocytosis risk model ( Figure
The Primary Care Companion For CNS Disorders, 2012
To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predicto... more To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation of schizophrenia for patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis of schizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio for SULT4A1-1(-) versus SULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated, SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). The SULT4A1-1 haplotype may be an important predictor of risk of hospitalization. SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine.
Current Pharmaceutical Design, 2014
Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodi... more Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.
Schizophrenia Research, 2013
Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. B... more Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. Based on both biological rationale and prior evidence of an impact on Parkinson's disease, we conducted an association study for 106 SNPs in the synaptic vesicle protein 2C (SV2C) gene using genetic and treatment response data from the Clinical Trial of Antipsychotic Intervention Effectiveness (CATIE). We examined response to the atypical antipsychotics for Caucasian subjects in the blinded phases, Phases 1A, 1B, and 2, of CATIE with sample sizes as follows: olanzapine (N = 134), quetiapine (N = 124), risperidone (N = 134), and ziprasidone (N = 74). Response was defined as change in the Positive and Negative Syndrome Scale (PANSS) score using a mixed model repeat measures approach. Subjects homozygous for the T allele of rs11960832 displayed significantly worse response to olanzapine treatment, the only finding with study-wide significance (p = 2.94 × 10 −5 ; false discovery rate = 2.18 × 10 −2). These subjects also displayed worse response to quetiapine with nominal significance (p = 4.56 × 10 −2). While no other SNP achieved study-wide significance, one SNP (rs10214163) influencing Parkinson's disease displayed nominally significant association with olanzapine and quetiapine response, while the second such SNP (rs30196) showed a statistical trend toward correlating with olanzapine and quetiapine response. Furthermore, both coding SNPs examined (rs31244 and rs2270927) displayed nominally significant correlations with treatment response: one for olanzapine (rs227092), and one for quetiapine (rs31244). The fact that multiple SNPs in SV2C may impact response to atypical antipsychotics suggests that further evaluation of SNPs in this gene as PGx predictors of antipsychotic response is warranted.
Psychopharmacology, 1996
ABSTRACT
Pharmacology Biochemistry and Behavior, 1990
Six rats were Irained to respond under a multiple fixed-ratio 30, fixed-interval 3-rain schedule ... more Six rats were Irained to respond under a multiple fixed-ratio 30, fixed-interval 3-rain schedule for food presentation. Acute administration of phencyclidine (0.1-3.2 mg/kg, IP) produced decreases in fixed-ratio response rates at doses above 0.3 mg/kg, but fixed-interval response rates were only decreased at the highest dose. However, the pattern of fixed-interval responding (as evidenced by quarter-life values) was affected at doses above 0.3 mg/kg. Osmotic minipumps were implanted, SC, which infused saline (2 rats) or phencyclidine (4 rats, 10.0 mg/kg/day) for 10 days, and then removed. Dally behavioral sessions were conducted during infusions and for 10 days afterwards. The effects of phencyclidine infusions on fixed-ratio responding were variable. Fixed-interval response rate and quarter-life values were only modestly affected during drug infusion. All three parameters were markedly affected upon cessation of chronic phencyclidine dosing, but there did not appear to be differential effects between the schedule components. No effects on responding were observed during or after saline infusions.
Life Sciences, 1990
Rats were chronically infused with phencyclidine (PCP, 13.3 mg PCP.HCl/kg/day) or saline, s.c., f... more Rats were chronically infused with phencyclidine (PCP, 13.3 mg PCP.HCl/kg/day) or saline, s.c., for 10 days using osmotic minipumps (n = 5 for each group). Twenty-four hours after the cessation of dosing, the rats were sacrificed, and brains were removed for analysis of PCP receptor binding. Saturation studies of the binding of [3H]-TCP to brain homogenates revealed statistically significant increases in the maximum binding capacity (Bmax) and decreases in the affinity for [3H]-TCP in the PCP-treated group.
Journal of the Experimental Analysis of Behavior, 1987
Using a color-tracking procedure with responses reinforced under a second-order schedule, the dis... more Using a color-tracking procedure with responses reinforced under a second-order schedule, the discriminative-stimulus properties of phencyclidine were studied in pigeons maintained at 70%, 80%, or 90% of their free-feeding weights. The generalization curves for phencyclidine were similar at all three body weights. Generalization curves for pentobarbital, d-amphetamine, and saline were also unrelated to body weight. These data suggest that food deprivation may not influence the discriminative-stimulus properties of drugs in the way that it influences the reinforcing-stimulus properties of drugs. The reason may be that during discrimination training interoceptive stimuli resulting from food deprivation do not become conditioned to the stimulus properties of the drug, because the fooddeprivation stimuli are paired equally often with the presence and absence of drug stimuli.
European Journal of Pharmacology, 2009
Intravenous amiodarone (Amiodarone IV) is widely used to treat cardiac arrhythmias. The most freq... more Intravenous amiodarone (Amiodarone IV) is widely used to treat cardiac arrhythmias. The most frequent clinical adverse event associated with Amiodarone IV administration is systemic hypotension which has been attributed to the cosolvents used in the formulation, polysorbate 80 and benzyl alcohol. To minimize hypotension Amiodarone IV is diluted in 5% dextrose in water prior to administration and slowly infused. PM101 is a novel intravenous formulation that uses sulfobutylether-7-beta-cyclodextrin to solubilize amiodarone, and thus should be devoid of the untoward hemodynamic effects associated with polysorbate 80 and benzyl alcohol. Beagle dogs (n = 7/group) were anesthetized with morphine and α-chloralose and instrumented to assess aortic blood pressure, cardiac output, cardiac contractility, and heart rate. Animals were treated with the U.S. approved human-equivalent loading dose (2.14 mg/kg) of Amiodarone IV, PM101, and their respective vehicle controls. Administration of Amiodarone IV rapidly and significantly decreased mean aortic pressure, cardiac output, and cardiac contractility. A significant increase in heart rate was also observed as was a transient, but not significant, decrease in systemic vascular resistance. A similar pattern of rapid and significant hemodynamic changes was produced by the Amiodarone IV Vehicle (polysorbate 80/ benzyl alcohol) alone. In marked contrast, PM101 and its vehicle produced no significant hemodynamic effects. This study provides a useful model for the continued search for a safe and effective intravenous amiodarone formulation devoid of the hypotensive risk associated with the current commercial formulation.
Drug and Alcohol Dependence, 1994
Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pen... more Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pentobarbital (PB: IO m&/kg. i.g., 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s ITI, FRI). Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with PB and ethanol (EtOH), alone or in combination. Administration of PB alone resulted in a dose-related increase (O-100%) in the percentage of responses emitted on the drug-appropriate lever. The mean ED?,, for PB was 7.0 mgikg (95% C.L. = 6.3-7.7 mgikg). When administered 60 min pre-session, EtOH engendered a dose-related increase in PB appropriate trials and substituted completely for PB at 3.0 g/kg in two monkeys. In the third monkey, EtOH engendered a maximum of 65% PBappropriate responding at 1.7 g/kg given 30 min pre-session and predominantly saline-appropriate respondmg at other pretreatment times. The group ED,, for EtOH at the time of maximum effect was 1.9 g/kg (95% C.L. = 1.4-2.5 g/kg). Administration of 0.3 g/kg EtOH in combination with PB had little or no effect on the PB dose effect function (PB ED,, = 6.7 mgkg) while I .(.I g/kg EtOH shifted the PB dose-effect function to the left in all monkeys, an average of approximately 3-fold (PB ED,,, = 2. I mgikg). lsobolographic analysis of the effects of the combination revealed that EtOH and PB were dose additive.
Frontiers in Microbiology
Pharmacy & Pharmacology International Journal
It also identifies the prescribing physician as an important locus for identification and interve... more It also identifies the prescribing physician as an important locus for identification and intervention of opiate addiction. Coordination and cooperation between prescribing physicians and opiate abuse treatment providers is a necessary tool in stemming this crisis.
Pharmacy & Pharmacology International Journal
Psychopharmacology, 2015
Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, ... more Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, is impaired in rodents by subchronic (sc) treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), a widely studied model of cognitive impairment in schizophrenia (CIS). The principal objective of this study was to determine the ability of serotonin (5-HT)1A partial agonism and 5-HT7 receptor antagonism to improve RL in scPCP-treated mice. Male C57BL/6J mice were trained on an operant RL (ORL) task, then received PCP, 10 mg/kg, or saline, bid, for 7 days, followed by a 7-day washout period. scPCP significantly diminished the percent correct responding, increased total incorrect trials, and total incorrect responses, in the reversal phase performance of the ORL task. Pre-treatment with the selective 5-HT1A partial agonist, tandospirone, or the selective 5-HT7 antagonist, SB269970, but not the 5-HT7 agonist, AS 19, reversed the scPCP-induced deficit in RL. Pre-treatment with atypical antipsychotic drug lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, as well as a 5-HT2A and dopamine (D)2 antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit. These results indicate that 5-HT7 antagonism and 5-HT1A partial agonism contribute to restoration of RL in scPCP-treated mice. It is suggested that these two mechanisms are effective in restoring RL by decreasing excessive GABAergic inhibition of cortical pyramidal neurons following withdrawal of scPCP treatment.
= 1.0 at P < 0.0001 ) when 8 validation sample... more = 1.0 at P < 0.0001 ) when 8 validation samples are included in the correlation. - Predictions of antipsychotic activity, agranulocytosis risk, and hERG risk are correlated with % confidence of yes and the accuracy of the decisions. All yes/no models ( Figure 2 ) are tested with leave 10% out cross-validation and the agranulocytosis risk model ( Figure
The Primary Care Companion For CNS Disorders, 2012
To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predicto... more To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation of schizophrenia for patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis of schizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio for SULT4A1-1(-) versus SULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated, SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). The SULT4A1-1 haplotype may be an important predictor of risk of hospitalization. SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine.
Current Pharmaceutical Design, 2014
Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodi... more Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.
Schizophrenia Research, 2013
Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. B... more Pharmacogenetic (PGx) predictors of response would improve outcomes in antipsychotic treatment. Based on both biological rationale and prior evidence of an impact on Parkinson's disease, we conducted an association study for 106 SNPs in the synaptic vesicle protein 2C (SV2C) gene using genetic and treatment response data from the Clinical Trial of Antipsychotic Intervention Effectiveness (CATIE). We examined response to the atypical antipsychotics for Caucasian subjects in the blinded phases, Phases 1A, 1B, and 2, of CATIE with sample sizes as follows: olanzapine (N = 134), quetiapine (N = 124), risperidone (N = 134), and ziprasidone (N = 74). Response was defined as change in the Positive and Negative Syndrome Scale (PANSS) score using a mixed model repeat measures approach. Subjects homozygous for the T allele of rs11960832 displayed significantly worse response to olanzapine treatment, the only finding with study-wide significance (p = 2.94 × 10 −5 ; false discovery rate = 2.18 × 10 −2). These subjects also displayed worse response to quetiapine with nominal significance (p = 4.56 × 10 −2). While no other SNP achieved study-wide significance, one SNP (rs10214163) influencing Parkinson's disease displayed nominally significant association with olanzapine and quetiapine response, while the second such SNP (rs30196) showed a statistical trend toward correlating with olanzapine and quetiapine response. Furthermore, both coding SNPs examined (rs31244 and rs2270927) displayed nominally significant correlations with treatment response: one for olanzapine (rs227092), and one for quetiapine (rs31244). The fact that multiple SNPs in SV2C may impact response to atypical antipsychotics suggests that further evaluation of SNPs in this gene as PGx predictors of antipsychotic response is warranted.
Psychopharmacology, 1996
ABSTRACT
Pharmacology Biochemistry and Behavior, 1990
Six rats were Irained to respond under a multiple fixed-ratio 30, fixed-interval 3-rain schedule ... more Six rats were Irained to respond under a multiple fixed-ratio 30, fixed-interval 3-rain schedule for food presentation. Acute administration of phencyclidine (0.1-3.2 mg/kg, IP) produced decreases in fixed-ratio response rates at doses above 0.3 mg/kg, but fixed-interval response rates were only decreased at the highest dose. However, the pattern of fixed-interval responding (as evidenced by quarter-life values) was affected at doses above 0.3 mg/kg. Osmotic minipumps were implanted, SC, which infused saline (2 rats) or phencyclidine (4 rats, 10.0 mg/kg/day) for 10 days, and then removed. Dally behavioral sessions were conducted during infusions and for 10 days afterwards. The effects of phencyclidine infusions on fixed-ratio responding were variable. Fixed-interval response rate and quarter-life values were only modestly affected during drug infusion. All three parameters were markedly affected upon cessation of chronic phencyclidine dosing, but there did not appear to be differential effects between the schedule components. No effects on responding were observed during or after saline infusions.
Life Sciences, 1990
Rats were chronically infused with phencyclidine (PCP, 13.3 mg PCP.HCl/kg/day) or saline, s.c., f... more Rats were chronically infused with phencyclidine (PCP, 13.3 mg PCP.HCl/kg/day) or saline, s.c., for 10 days using osmotic minipumps (n = 5 for each group). Twenty-four hours after the cessation of dosing, the rats were sacrificed, and brains were removed for analysis of PCP receptor binding. Saturation studies of the binding of [3H]-TCP to brain homogenates revealed statistically significant increases in the maximum binding capacity (Bmax) and decreases in the affinity for [3H]-TCP in the PCP-treated group.
Journal of the Experimental Analysis of Behavior, 1987
Using a color-tracking procedure with responses reinforced under a second-order schedule, the dis... more Using a color-tracking procedure with responses reinforced under a second-order schedule, the discriminative-stimulus properties of phencyclidine were studied in pigeons maintained at 70%, 80%, or 90% of their free-feeding weights. The generalization curves for phencyclidine were similar at all three body weights. Generalization curves for pentobarbital, d-amphetamine, and saline were also unrelated to body weight. These data suggest that food deprivation may not influence the discriminative-stimulus properties of drugs in the way that it influences the reinforcing-stimulus properties of drugs. The reason may be that during discrimination training interoceptive stimuli resulting from food deprivation do not become conditioned to the stimulus properties of the drug, because the fooddeprivation stimuli are paired equally often with the presence and absence of drug stimuli.
European Journal of Pharmacology, 2009
Intravenous amiodarone (Amiodarone IV) is widely used to treat cardiac arrhythmias. The most freq... more Intravenous amiodarone (Amiodarone IV) is widely used to treat cardiac arrhythmias. The most frequent clinical adverse event associated with Amiodarone IV administration is systemic hypotension which has been attributed to the cosolvents used in the formulation, polysorbate 80 and benzyl alcohol. To minimize hypotension Amiodarone IV is diluted in 5% dextrose in water prior to administration and slowly infused. PM101 is a novel intravenous formulation that uses sulfobutylether-7-beta-cyclodextrin to solubilize amiodarone, and thus should be devoid of the untoward hemodynamic effects associated with polysorbate 80 and benzyl alcohol. Beagle dogs (n = 7/group) were anesthetized with morphine and α-chloralose and instrumented to assess aortic blood pressure, cardiac output, cardiac contractility, and heart rate. Animals were treated with the U.S. approved human-equivalent loading dose (2.14 mg/kg) of Amiodarone IV, PM101, and their respective vehicle controls. Administration of Amiodarone IV rapidly and significantly decreased mean aortic pressure, cardiac output, and cardiac contractility. A significant increase in heart rate was also observed as was a transient, but not significant, decrease in systemic vascular resistance. A similar pattern of rapid and significant hemodynamic changes was produced by the Amiodarone IV Vehicle (polysorbate 80/ benzyl alcohol) alone. In marked contrast, PM101 and its vehicle produced no significant hemodynamic effects. This study provides a useful model for the continued search for a safe and effective intravenous amiodarone formulation devoid of the hypotensive risk associated with the current commercial formulation.
Drug and Alcohol Dependence, 1994
Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pen... more Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pentobarbital (PB: IO m&/kg. i.g., 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s ITI, FRI). Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with PB and ethanol (EtOH), alone or in combination. Administration of PB alone resulted in a dose-related increase (O-100%) in the percentage of responses emitted on the drug-appropriate lever. The mean ED?,, for PB was 7.0 mgikg (95% C.L. = 6.3-7.7 mgikg). When administered 60 min pre-session, EtOH engendered a dose-related increase in PB appropriate trials and substituted completely for PB at 3.0 g/kg in two monkeys. In the third monkey, EtOH engendered a maximum of 65% PBappropriate responding at 1.7 g/kg given 30 min pre-session and predominantly saline-appropriate respondmg at other pretreatment times. The group ED,, for EtOH at the time of maximum effect was 1.9 g/kg (95% C.L. = 1.4-2.5 g/kg). Administration of 0.3 g/kg EtOH in combination with PB had little or no effect on the PB dose effect function (PB ED,, = 6.7 mgkg) while I .(.I g/kg EtOH shifted the PB dose-effect function to the left in all monkeys, an average of approximately 3-fold (PB ED,,, = 2. I mgikg). lsobolographic analysis of the effects of the combination revealed that EtOH and PB were dose additive.