Aaron Burstein - Academia.edu (original) (raw)

Papers by Aaron Burstein

BMC Neurology, Jan 15, 2014

Background: TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evalua... more Background: TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). A previous report describes decreased decline in ADAS-cog (delta = 3.1, p = 0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis. Methods: 399 patients were randomized to one of two oral TTP488 doses (60 mg for 6 days followed by 20 mg/ day; 15 mg for 6 days followed by 5 mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL.

The Nurse practitioner, Nov 1, 1999

PubMed, 1996

The objectives of this study were to describe the serum concentration time profile for midazolam ... more The objectives of this study were to describe the serum concentration time profile for midazolam following intranasal administration to adult dental surgery patients and to ascertain the effect of midazolam on anxiety. Six female patients received a single 20 mg (0.32 to 0.53 mg/kg) dose of midazolam. Blood samples were collected at 5, 10, 20, 30, 45, and 60 min following dose administration. Midazolam plasma concentrations were determined by gas chromatography. Anxiety was evaluated using a 100-mm visual analogue scale. The maximum concentration of midazolam was reached 25.8 min (range 18 to 35 min) following dose administration. Maximum concentrations were variable. However, there was no relationship between the weight-adjusted dose and maximal concentration. Patients experiencing baseline anxiety exhibited a trend toward reduction in their measured anxiety score (P = 0.06). Plasma concentrations above the hypothesized minimum effective concentration for sedative effects were attained when midazolam was administered intranasally to adult dental patients.

Annals of Pharmacotherapy, Dec 1, 1996

Status epilepticus (SE) is a condition characterized by continuous seizure activity for longer th... more Status epilepticus (SE) is a condition characterized by continuous seizure activity for longer than 30 minutes, or two or more seizures occurring without recovery of consciousness between episodes.' While any seizure type (tonic--clonic, absence, simple partial, complex partial) may occur in the context of SE, they will share the common characteristic of continuous epileptiform activity as seen on electroencephalogram (EEG). Additionally, nonconvulsive SE may occur in which, despite epileptiform activity on EEG, no clinical seizure activity is evident. Generalized convulsive SE represents the most common and dangerous of SE subtypes; guidelines have been previously published regarding optimal treatment. I Nonconvulsive SE, although not as dangerous, nevertheless requires aggressive treatment as well if neurologic damage is to be minimized. Benzodiazepines are considered by many to be the drug of choice to acutely terminate SE.' The utility of this class of compounds relates to their ability to enhance both preand postsynaptic inhibition mediated by gamma-aminobutyric acid, the endogenous inhibitory neurotransmitter.2 It may be inferred that agents within the benzodiazepine class, including midazolam, would be effective in controlling SE. As no evidence supporting superior efficacy of one agent over another is available, the decision regarding which benzodiazepine to use is often based on duration of effect. Despite the lack of comparative efficacy data, lorazepam has supplanted diazepam as the preferred agent due to its pharmacokinetic properties resulting in a prolonged duration of action. The majority of the 50000-60000 Americans affected annually by SE respond to conventional first-line therapy consisting of benzodiazepines (Iorazepam or diazepam) followed by a short infusion of phenytoin. However, it has been estimated that 2000-6000 of these cases will be refractory to the conventional therapies including adequate doses of benzodiazepines, phenytoin, and possibly phenobarbital.3Traditionally, these refractory ca~es have been managed with continuous infusion phenobarbitaJ,3 pentobarbita),3 diazepam,4 lorazepam,s Iidocaine,3 or inhalation anesthetics.3Due to concerns regarding the potential for hemodynamic instability while receiving pentobarbital infusions, midazolam has been used as an alternative in the management of RSE.6.12

Critical Care Medicine, May 1, 2003

To evaluate the relationship between the acute inflammatory response after surgical trauma and ch... more To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. Design: Prospective, open-label study with each patient serving as his or her own control. Setting: University-affiliated, acute care, general hospital. Patients: A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n ‫؍‬ 5), complete or partial colectomy (n ‫؍‬ 6), or peripheral vascular surgery with graft (n ‫؍‬ 5). Interventions: Cytochrome P450 3A4 activity was estimated using the carbon-14 [ 14 C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1␤, and tumor necrosis factor-␣. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. Measurements and Main Results: ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p ‫؍‬ .06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r s ‫؍‬ ؊.541, p ‫؍‬ .03) and log interleukin-6 area under the curve from 0 to 72 hrs (r s ‫؍‬ ؊.597, p ‫؍‬ .014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% ؎ 5.2% vs. 74.7% ؎ 5.1%, p < .001). Conclusions: Acute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.

Clinical Infectious Diseases, Jan 15, 2002

Herbal therapies are widely used, but there are few data on their interactions with conventional ... more Herbal therapies are widely used, but there are few data on their interactions with conventional medications. This study evaluated the effect of garlic supplements on the pharmacokinetics of saquinavir. Ten healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25, and 36-39, and they received a total of 41 doses of garlic caplets taken 2 times daily on study days 5-25. Blood samples were obtained on study days 4, 25, and 39 for determination of saquinavir plasma pharmacokinetic parameters. In the presence of garlic, the mean saquinavir area under the curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels at 8 h after dosing decreased by 49%, and the mean maximum concentrations (C max) decreased by 54%. After the 10-day washout period, the AUC, trough, and C max values returned to 60%-70% of their values at baseline. Patients should use caution when combining garlic supplements with saquinavir when it is used as a sole protease inhibitor.

The Journal of Clinical Pharmacology, Apr 1, 2011

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerabili... more This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Alzheimers & Dementia, Jul 1, 2010

Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the t... more Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the treatment of Alzheimer’s disease (AD). The pharmacokinetics and pharmacodynamics of ponezumab were evaluated in two phase 1 studies in patients with mild-to-moderate AD, and the results compared. Methods: Placebo or ponezumab at 0.1 (n 1⁄4 6), 0.3 (n 1⁄4 6), 1 (n 1⁄4 6), 3 (n 1⁄4 8), or 10 mg/kg (n 1⁄4 11) were administered via 2-hour infusion to 37 patients with AD in a randomized, double-blind, placebo-controlled, dose-escalation study (A9951001). A second study (A9951008) was designed as an open-label, parallel-group, dose-escalation trial with ponezumab administered at 1 (n 1⁄4 3), 3 (n 1⁄4 3), 5 (n 1⁄4 4), or 10 (n 1⁄4 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid b (Ab), and CSF ponezumab, Ab, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. Results: Pharmacokinetics and pharmacodynamics were similar between the two studies. Plasma ponezumab reached maximum concentration (Cmax) shortly after infusion, followed by a biphasic decline. Cmax and area under the concentration-time curve increased in a dose-proportional manner. The pharmacokinetics of ponezumab were linear with a mean terminal half-life of 35-52 days. Ponezumab CSF concentrations at Day 29 post-dose (A9951001) were quantifiable in 2 of 8 patients administered a 10 mg/kg dose (?0.5% of plasma values). In both studies, plasma Ab concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Ab concentrations were around 500 in the 10 mg/kg group compared with 1 in the placebo group. At the 10 mg/kg dose (A9951001), mean CSF Ab percentage change from baseline at Day 29 increased 38% (p < 0.05), 29% (p > 0.05), and 15% (p < 0.05) for Ab1-x, Ab1-40, and Ab1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. Conclusions: The pharmacokinetics of ponezumab were similar between the two studies linear, with central penetration seen following the highest dose in some patients. Increases in plasma Ab biomarker response and Tmax were dose dependent. CSF Ab concentrations increased from baseline at Day 29 for the 10 mg/ kg dose. No ADAs were detected.

Alzheimers & Dementia, Jul 1, 2012

Neurology, 2004

1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in... more 1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in essential tremor (ET) animal models at a much lower dose than ethyl alcohol. The authors conducted a randomized, placebocontrolled pilot trial of a single oral dose of 1 mg/kg of 1-octanol in 12 patients with ET. No significant side effects or signs of intoxication were observed. 1-Octanol significantly decreased tremor amplitude for up to 90 minutes. The results suggest 1-octanol as a well-tolerated and safe potential treatment for ET. Further trials are warranted.

Alzheimers & Dementia, Jul 1, 2012

ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, pla... more ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a “Go-No-Go” decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

Annals of Pharmacotherapy, 1993

To report and describe the apparent first case of acute oculogyric crisis following administratio... more To report and describe the apparent first case of acute oculogyric crisis following administration of pentazocine, and to discuss the possible mechanism for this reaction. Patient case and relevant review of literature. The patient, a 39-year-old woman, developed acute oculogyric crisis following administration of Talacen (pentazocine and acetaminophen) for pain relief. The crisis resolved after discontinuation of the medication and administration of intravenous diphenhydramine 50 mg. Based on the temporal relationship of drug administration to occurrence of the event, pentazocine is implicated as the cause of this acute oculogyric crisis. A plausible mechanism for precipitation of this crisis is the agonism of pentazocine on sigma opiate receptors, with postulated subsequent modulation of dopamine receptors.

Alzheimer's & Dementia, 2016

The Journal Of Prevention of Alzheimer's Disease, 2018

Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) i... more Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer’s disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and ...

Alzheimer's & Dementia, 2017

Alzheimer's & Dementia, 2020

Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was eva... more Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was evaluated in an 18‐month Phase 3 study as a treatment for patients with mild Alzheimer’s disease (AD) (the STEADFAST Study). Post‐hoc analyses in a T2D subgroup (HbA1c ≥ 6.5%) found that azeliragon‐treated patients exhibited less cognitive decline (ADAS‐cog11), less whole brain atrophy, less hippocampal atrophy, less ventricular enlargement, and reduced plasma inflammatory cytokine concentrations compared to patients treated with placebo. The current retrospective exploratory analysis was performed to evaluate ADAS‐cog and CDR symptom domains and individual test items to ascertain which were sensitive to treatment effects.

Alzheimer's & Dementia, 2019

Pre-diabetes HbA1c 5.7-6.5% N= 60mg/day x 6d → 20 mg/day x 6 months Placebo (PBO) x 6 months 110 ... more Pre-diabetes HbA1c 5.7-6.5% N= 60mg/day x 6d → 20 mg/day x 6 months Placebo (PBO) x 6 months 110 subjects with Type 2 diabetes and persistent albuminuria Primary Endpoint: UACR Subjects with diabetes Secondary Endpoints: eGFR, serum creatinine, markers of RAGE inhibition Key-secondary: none 20 mg/day completed 6 months No increase in AEs of confusion and falls Questions following Phase 2 Studies: ▪ Is the effect on cognition/function dependent on glucose levels? ▪ Does RAGE antagonism affect glucose metabolism? 60mg/day x 6d → 20 mg/day x 18 months 15 mg/day x 6d → 5 mg/day x 18 months Placebo (PBO) x 18 months 399 subjects with probable mild-moderate AD MMSE 14-26 Stable background AcheI's or memantine Primary Endpoint: ADAS-cog11 Subjects with diabetes were excluded

The Journal of Clinical Pharmacology, 2006

Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under... more Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.

Alzheimer's & Dementia, 2012

being relatively safe and inexpensive. Methods: We are clinically exploring a target dose of 25 m... more being relatively safe and inexpensive. Methods: We are clinically exploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a "Go-No-Go" decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

Alzheimer's & Dementia, 2012

BMC Neurology, Jan 15, 2014

Background: TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evalua... more Background: TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). A previous report describes decreased decline in ADAS-cog (delta = 3.1, p = 0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis. Methods: 399 patients were randomized to one of two oral TTP488 doses (60 mg for 6 days followed by 20 mg/ day; 15 mg for 6 days followed by 5 mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL.

The Nurse practitioner, Nov 1, 1999

PubMed, 1996

The objectives of this study were to describe the serum concentration time profile for midazolam ... more The objectives of this study were to describe the serum concentration time profile for midazolam following intranasal administration to adult dental surgery patients and to ascertain the effect of midazolam on anxiety. Six female patients received a single 20 mg (0.32 to 0.53 mg/kg) dose of midazolam. Blood samples were collected at 5, 10, 20, 30, 45, and 60 min following dose administration. Midazolam plasma concentrations were determined by gas chromatography. Anxiety was evaluated using a 100-mm visual analogue scale. The maximum concentration of midazolam was reached 25.8 min (range 18 to 35 min) following dose administration. Maximum concentrations were variable. However, there was no relationship between the weight-adjusted dose and maximal concentration. Patients experiencing baseline anxiety exhibited a trend toward reduction in their measured anxiety score (P = 0.06). Plasma concentrations above the hypothesized minimum effective concentration for sedative effects were attained when midazolam was administered intranasally to adult dental patients.

Annals of Pharmacotherapy, Dec 1, 1996

Status epilepticus (SE) is a condition characterized by continuous seizure activity for longer th... more Status epilepticus (SE) is a condition characterized by continuous seizure activity for longer than 30 minutes, or two or more seizures occurring without recovery of consciousness between episodes.' While any seizure type (tonic--clonic, absence, simple partial, complex partial) may occur in the context of SE, they will share the common characteristic of continuous epileptiform activity as seen on electroencephalogram (EEG). Additionally, nonconvulsive SE may occur in which, despite epileptiform activity on EEG, no clinical seizure activity is evident. Generalized convulsive SE represents the most common and dangerous of SE subtypes; guidelines have been previously published regarding optimal treatment. I Nonconvulsive SE, although not as dangerous, nevertheless requires aggressive treatment as well if neurologic damage is to be minimized. Benzodiazepines are considered by many to be the drug of choice to acutely terminate SE.' The utility of this class of compounds relates to their ability to enhance both preand postsynaptic inhibition mediated by gamma-aminobutyric acid, the endogenous inhibitory neurotransmitter.2 It may be inferred that agents within the benzodiazepine class, including midazolam, would be effective in controlling SE. As no evidence supporting superior efficacy of one agent over another is available, the decision regarding which benzodiazepine to use is often based on duration of effect. Despite the lack of comparative efficacy data, lorazepam has supplanted diazepam as the preferred agent due to its pharmacokinetic properties resulting in a prolonged duration of action. The majority of the 50000-60000 Americans affected annually by SE respond to conventional first-line therapy consisting of benzodiazepines (Iorazepam or diazepam) followed by a short infusion of phenytoin. However, it has been estimated that 2000-6000 of these cases will be refractory to the conventional therapies including adequate doses of benzodiazepines, phenytoin, and possibly phenobarbital.3Traditionally, these refractory ca~es have been managed with continuous infusion phenobarbitaJ,3 pentobarbita),3 diazepam,4 lorazepam,s Iidocaine,3 or inhalation anesthetics.3Due to concerns regarding the potential for hemodynamic instability while receiving pentobarbital infusions, midazolam has been used as an alternative in the management of RSE.6.12

Critical Care Medicine, May 1, 2003

To evaluate the relationship between the acute inflammatory response after surgical trauma and ch... more To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. Design: Prospective, open-label study with each patient serving as his or her own control. Setting: University-affiliated, acute care, general hospital. Patients: A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n ‫؍‬ 5), complete or partial colectomy (n ‫؍‬ 6), or peripheral vascular surgery with graft (n ‫؍‬ 5). Interventions: Cytochrome P450 3A4 activity was estimated using the carbon-14 [ 14 C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1␤, and tumor necrosis factor-␣. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. Measurements and Main Results: ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p ‫؍‬ .06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r s ‫؍‬ ؊.541, p ‫؍‬ .03) and log interleukin-6 area under the curve from 0 to 72 hrs (r s ‫؍‬ ؊.597, p ‫؍‬ .014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% ؎ 5.2% vs. 74.7% ؎ 5.1%, p < .001). Conclusions: Acute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.

Clinical Infectious Diseases, Jan 15, 2002

Herbal therapies are widely used, but there are few data on their interactions with conventional ... more Herbal therapies are widely used, but there are few data on their interactions with conventional medications. This study evaluated the effect of garlic supplements on the pharmacokinetics of saquinavir. Ten healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25, and 36-39, and they received a total of 41 doses of garlic caplets taken 2 times daily on study days 5-25. Blood samples were obtained on study days 4, 25, and 39 for determination of saquinavir plasma pharmacokinetic parameters. In the presence of garlic, the mean saquinavir area under the curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels at 8 h after dosing decreased by 49%, and the mean maximum concentrations (C max) decreased by 54%. After the 10-day washout period, the AUC, trough, and C max values returned to 60%-70% of their values at baseline. Patients should use caution when combining garlic supplements with saquinavir when it is used as a sole protease inhibitor.

The Journal of Clinical Pharmacology, Apr 1, 2011

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerabili... more This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Alzheimers & Dementia, Jul 1, 2010

Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the t... more Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the treatment of Alzheimer’s disease (AD). The pharmacokinetics and pharmacodynamics of ponezumab were evaluated in two phase 1 studies in patients with mild-to-moderate AD, and the results compared. Methods: Placebo or ponezumab at 0.1 (n 1⁄4 6), 0.3 (n 1⁄4 6), 1 (n 1⁄4 6), 3 (n 1⁄4 8), or 10 mg/kg (n 1⁄4 11) were administered via 2-hour infusion to 37 patients with AD in a randomized, double-blind, placebo-controlled, dose-escalation study (A9951001). A second study (A9951008) was designed as an open-label, parallel-group, dose-escalation trial with ponezumab administered at 1 (n 1⁄4 3), 3 (n 1⁄4 3), 5 (n 1⁄4 4), or 10 (n 1⁄4 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid b (Ab), and CSF ponezumab, Ab, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. Results: Pharmacokinetics and pharmacodynamics were similar between the two studies. Plasma ponezumab reached maximum concentration (Cmax) shortly after infusion, followed by a biphasic decline. Cmax and area under the concentration-time curve increased in a dose-proportional manner. The pharmacokinetics of ponezumab were linear with a mean terminal half-life of 35-52 days. Ponezumab CSF concentrations at Day 29 post-dose (A9951001) were quantifiable in 2 of 8 patients administered a 10 mg/kg dose (?0.5% of plasma values). In both studies, plasma Ab concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Ab concentrations were around 500 in the 10 mg/kg group compared with 1 in the placebo group. At the 10 mg/kg dose (A9951001), mean CSF Ab percentage change from baseline at Day 29 increased 38% (p < 0.05), 29% (p > 0.05), and 15% (p < 0.05) for Ab1-x, Ab1-40, and Ab1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. Conclusions: The pharmacokinetics of ponezumab were similar between the two studies linear, with central penetration seen following the highest dose in some patients. Increases in plasma Ab biomarker response and Tmax were dose dependent. CSF Ab concentrations increased from baseline at Day 29 for the 10 mg/ kg dose. No ADAs were detected.

Alzheimers & Dementia, Jul 1, 2012

Neurology, 2004

1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in... more 1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in essential tremor (ET) animal models at a much lower dose than ethyl alcohol. The authors conducted a randomized, placebocontrolled pilot trial of a single oral dose of 1 mg/kg of 1-octanol in 12 patients with ET. No significant side effects or signs of intoxication were observed. 1-Octanol significantly decreased tremor amplitude for up to 90 minutes. The results suggest 1-octanol as a well-tolerated and safe potential treatment for ET. Further trials are warranted.

Alzheimers & Dementia, Jul 1, 2012

ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, pla... more ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a “Go-No-Go” decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

Annals of Pharmacotherapy, 1993

To report and describe the apparent first case of acute oculogyric crisis following administratio... more To report and describe the apparent first case of acute oculogyric crisis following administration of pentazocine, and to discuss the possible mechanism for this reaction. Patient case and relevant review of literature. The patient, a 39-year-old woman, developed acute oculogyric crisis following administration of Talacen (pentazocine and acetaminophen) for pain relief. The crisis resolved after discontinuation of the medication and administration of intravenous diphenhydramine 50 mg. Based on the temporal relationship of drug administration to occurrence of the event, pentazocine is implicated as the cause of this acute oculogyric crisis. A plausible mechanism for precipitation of this crisis is the agonism of pentazocine on sigma opiate receptors, with postulated subsequent modulation of dopamine receptors.

Alzheimer's & Dementia, 2016

The Journal Of Prevention of Alzheimer's Disease, 2018

Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) i... more Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer’s disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and ...

Alzheimer's & Dementia, 2017

Alzheimer's & Dementia, 2020

Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was eva... more Azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), was evaluated in an 18‐month Phase 3 study as a treatment for patients with mild Alzheimer’s disease (AD) (the STEADFAST Study). Post‐hoc analyses in a T2D subgroup (HbA1c ≥ 6.5%) found that azeliragon‐treated patients exhibited less cognitive decline (ADAS‐cog11), less whole brain atrophy, less hippocampal atrophy, less ventricular enlargement, and reduced plasma inflammatory cytokine concentrations compared to patients treated with placebo. The current retrospective exploratory analysis was performed to evaluate ADAS‐cog and CDR symptom domains and individual test items to ascertain which were sensitive to treatment effects.

Alzheimer's & Dementia, 2019

Pre-diabetes HbA1c 5.7-6.5% N= 60mg/day x 6d → 20 mg/day x 6 months Placebo (PBO) x 6 months 110 ... more Pre-diabetes HbA1c 5.7-6.5% N= 60mg/day x 6d → 20 mg/day x 6 months Placebo (PBO) x 6 months 110 subjects with Type 2 diabetes and persistent albuminuria Primary Endpoint: UACR Subjects with diabetes Secondary Endpoints: eGFR, serum creatinine, markers of RAGE inhibition Key-secondary: none 20 mg/day completed 6 months No increase in AEs of confusion and falls Questions following Phase 2 Studies: ▪ Is the effect on cognition/function dependent on glucose levels? ▪ Does RAGE antagonism affect glucose metabolism? 60mg/day x 6d → 20 mg/day x 18 months 15 mg/day x 6d → 5 mg/day x 18 months Placebo (PBO) x 18 months 399 subjects with probable mild-moderate AD MMSE 14-26 Stable background AcheI's or memantine Primary Endpoint: ADAS-cog11 Subjects with diabetes were excluded

The Journal of Clinical Pharmacology, 2006

Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under... more Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.

Alzheimer's & Dementia, 2012

being relatively safe and inexpensive. Methods: We are clinically exploring a target dose of 25 m... more being relatively safe and inexpensive. Methods: We are clinically exploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a "Go-No-Go" decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

Alzheimer's & Dementia, 2012