William Z. Potter

Cerebrospinal Fluid Biomarker Signature in Alzheimer’s Disease Neuroimaging Initiative Subjects

Develop a cerebrospinal fluid biomarker signature for mild Alzheimers disease (AD) in Alzheimers Disease Neuroimaging Initiative (ADNI) subjects.

Acetaminophen-Induced Hepatic Necrosis

The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low dos

Acetaminophen‐induced hepatic injury: Protective role of glutathione in man and rationale for therapy

Recent studies of acetaminophen‐induced liver damage in animals indicate that acetaminophen is converted in the liver to a chemically reactive arylating agent that normally is detoxified by conjugation with glutathione. When the dose of acetaminophen is large enough to deplete hepatic glutathione, however, there is extensive arylation of hepatic macromolecules and cell death. This paper presents evidence that administration of glutathione‐like nucleophiles, such as cysteamine, protects mice from arylation of hepatic macromolecules, hepatic necrosis, and death caused by the reactive acetaminophen metabolite. Additional studies indicate that glutathione may serve a similar protective function in man as in other animals. Thus, logical treatment of patients overdosed with acetaminophen might be based on cysteamine or other nucleophiles.

The Alzheimer’s Disease Neuroimaging Initiative: Progress report and future plans

The Alzheimers Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6‐year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimers disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)/blood biomarkers as predictors and outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C‐11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid β (Aβ) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C‐11 Pittsburgh compound B PET, and CSF measurements of Aβ and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI‐like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD.

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia

OBJECTIVE There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia. METHOD In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia. RESULTS Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function. CONCLUSIONS These results support further investigation of xanomeline as a novel approach to treating schizophrenia.

Acetaminophen-Induced Hepatic Necrosis V. Correlation of Hepatic Necrosis, Covalent Binding and Glutathione Depletion in Hamsters

We previously postulated that acetaminophen-induced hepatic necrosis in mice results from the formation of a reactive metabolite that arylates vital cellular macro-molecules. While studying species di

Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen

Abstract Acetaminophen, a widely prescribed analgesic that causes fulminant hepatic necrosis in overdosed humans, produced varying degrees of hepatotoxixity in mice, rats, hamsters, guinea pigs and rabbits. The severity of hepatic injury paralleled the rate of activation of acetaminophen by hepatic microsomal enzymes to a potent arylating agent. The severity of hepatic damage in various species also correlated directly with the rate of hepatic glutathione depletion after acetaminophen. These findings support the hypothesis that the electrophilic arylating agent formed from acetaminophen in vibo is preferentially detoxified by conjugation with glutathione and that arylation of hepatic macromolecules occurs only when glutathione availability is exceeded. Since N-hydroxylation of another N-acetylarylamine (2-acetylaminofluorene) occurs to a much greater extent in the species that are susceptible to acetaminophen-induced hepatic necrosis, the data also are consistent with the hypothesis that the toxic metabolite of acetaminophen results from N-hydroxylation.

Update on the biomarker core of the Alzheimer's Disease Neuroimaging Initiative subjects

Here, we review progress by the Penn Biomarker Core in the Alzheimers Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimers disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control subjects to AD. The Penn Biomarker Core also collaborated with other ADNI Cores to integrate data across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that serve as mileposts and predictors of the conversion of normal control to MCI as well as MCI to AD, and the progression of AD. Initial CSF studies by the ADNI Biomarker Core revealed a pathological CSF biomarker signature of AD defined by the combination of Aβ1‐42 and total tau (T‐tau) that effectively delineates mild AD in the large multisite prospective clinical investigation conducted in ADNI. This signature appears to predict conversion from MCI to AD. Data fusion efforts across ADNI Cores generated a model for the temporal ordering of AD biomarkers which suggests that Aβ amyloid biomarkers become abnormal first, followed by changes in neurodegenerative biomarkers (CSF tau, F‐18 fluorodeoxyglucose‐positron emission tomography, magnetic resonance imaging) with the onset of clinical symptoms. The timing of these changes varies in individual patients due to genetic and environmental factors that increase or decrease an individuals resilience in response to progressive accumulations of AD pathologies. Further studies in ADNI will refine this model and render the biomarkers studied in ADNI more applicable to routine diagnosis and to clinical trials of disease modifying therapies.

Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Examination of isoniazid metabolites revealed that rapid acetylators hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.

LY354740, an mGlu2/3 Receptor Agonist as a Novel Approach to Treat Anxiety/Stress

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO 2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.