MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia.

In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.

Inflammation and oxidative stress induced by cigarette smoke in Lewis rat brains.

Exposure to cigarette smoke has been associated with an increased risk of neurological diseases such as stroke, Alzheimer's disease and multiple sclerosis. In these studies, serum and brain sections from Lewis rats or those exposed to cigarette smoke and control rats were examined for evidence of increased inflammation and oxidative stress. Immunocytochemical staining of brain sections from CS-exposed rats showed increased expression of class II MHC and, in ELISA, levels of IFN-gamma and TNF-α were higher than for non-exposed rats. In polymerase chain reaction assays there was increased interferon-gamma, TNF-α, IL-1α, IL-1ß, IL-23, IL-6, IL-23, IL-17, IL-10, TGF-ß, T-bet and FoxP3 gene expression with CS exposure. There was also markedly elevated MIP-1α/CCL3, less prominent MCP-1/CCL2 and no elevation of SDF-1α gene expression. Analysis of samples from CS-exposed and control rats for anti-oxidant expression showed no significant difference in serum levels of glutathione and, in brain, similar levels of superoxide dismutase and decreased thioredoxin gene expression. In contrast, there was increased brain gene expression for the pro-oxidants iNOS and the NADPH components NOX4, dual oxidase 1 and p22(phox). Nrf2 expression, which is typically triggered as a secondary response to oxidative stress, was also increased in brains from CS-exposed rats with nuclear translocation of this protein from cytoplasm demonstrated in astrocytes in association with increased expression of the aryl hydrocarbon receptor gene, an Nrf2 target. These studies, therefore, demonstrate that CS exposure in these animals can trigger multiple immune and oxidative responses that may have important roles in the pathogenesis of CNS inflammatory neurological diseases.

Retinoids and drugs of abuse: implications for neurological disease risk in human immunodeficiency virus type 1 infection.

Among injection drug users, human immunodeficiency virus (HIV) type 1 infection may be associated with an increased risk of nervous system disease. For HIV-infected drug users with vitamin A deficiency, the overall risk of HIV-related morbidity and mortality may also be higher. In previous studies, levels of retinol, retinol-binding protein, and transthyretin in samples from such individuals were examined and found to be lower than such levels in seronegative control subjects. Also, in studies using an activated mononuclear cell line, all-trans retinoic acid and 9-cis retinoic acid suppressed production of the tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. However, simultaneous exposure of the cells to morphine at a concentration similar to that to which drug users are exposed resulted in increased production of these cytokines. Therefore, morphine may alter the immunomodulatory effects of retinoids, thereby potentially affecting the clinical outcome of studies involving retinoid administration to HIV-infected drug users and increasing the risk for the development of HIV-related complications, including neurological disease.

Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) affects about 1 in 20 individuals with the acquired immunodeficiency syndrome (AIDS) and has been associated with poor survival. This report describes the results of a phase II clinical trial using the drug topotecan, a semisynthetic analogue of camptothecan, administered to a cohort of subjects with AIDS-related PML. Data were evaluated on 11 of 12 subjects enrolled in the study. Three responded to therapy. Additionally, one patient was treated off-protocol and showed a response to treatment. Progression occurred after the first course; however, a partial response was noted after five courses. One study patient died from accidental overdose of topotecan. Overall, responders had higher pretreatment Karnofsky and lower Kurtzke expanded disability status scale scores than nonresponders. The most frequent toxicities were hematologic (anemia, neutropenia, and thrombocytopenia). Five patients had dose delays; all delays were due to hematologic adverse events. This study demonstrates that topotecan treatment may be associated with decreased lesion size and prolonged survival from the infection. Because of the small number of subjects in the study, further studies are required to evaluate the efficacy of topotecan in treating this disease.

Retinol measurements and retinoid receptor gene expression in patients with multiple sclerosis.

Treatment with interferon (IFN)-beta1a has been associated with decreased disease activity in patients with multiple sclerosis (MS). In several biological systems, type 1 IFNs and retinoids have been demonstrated to have synergistic effects. In these studies, we measured blood and cerebrospinal fluid (CSF) retinol levels and naïve and memory T-helper cell subset percentages in samples from a group of patients with MS. We also examined retinol receptor expression in peripheral blood cells from MS patients with or without a history of prior treatment with IFN-beta1a. The mean plasma retinol level for untreated relapsing-remitting (RR) MS patients was lower than for patients with noninflammatory neurological disease. Among IFN-beta1a-treated RR patients, mean levels were slightly higher than for RR patients not on treatment Lower plasma retinol levels among the MS patents studied were associated with higher CSF retinol index measurements--a measure that was calculated to correct for nonspecific leakage of retinol from blood into CSF. Far the MS samples examined, there was a borderline statstically significant direct correlation between CSF retinol index measurements and CSF memory T-helper cell percentages. Examination of peripheral blood from untreated RR patents for retinoid receptor mRNA expression revealed the expression of the retinoic add receptor (RAR)-alpha, RAR-gamma, and retinoic X receptor (RXR)-alpha receptor subtypes. For RR patients on IFN-beta1a therapy, expression of the some RAR subtypes was noted as well as expression of RXR-beta and RXR-gamma. These studies suggest an association between plasma retinol levels and clincal disease activity in patents with MS and that treatment with IFN-beta1a may be associated with activation of specific retnoid receptor subtypes.

The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS.

To explore the respective roles of highly active antiretroviral therapy (HAART) and alpha-interferon in improving survival of patients with AIDS-related PML, we retrospectively analyzed all patients with AIDS and PML who were referred to Johns Hopkins University HIV Neurology Program from 1985 to 2000. For 97 evaluable patients, we compared survival of those who were on HAART (three or more antiretroviral drugs) to those who were not on HAART. The effect of alpha-interferon was also studied. Multivariate analysis showed no difference in survival among patients on none, one, or two forms of antiretrovirals; however, survival was significantly greater for those on HAART. Whereas alpha-interferon use was shown to be associated with longer survival (P < 0.057), this effect was not independent of the effects of HAART. HAART significantly increases survival for patients with PML and AIDS; however, alpha-interferon does not appear to provide additional benefit.

Neurologic disease in injection drug users: therapeutic issues.

Illicit drug use may cause nervous system impairment as a result of direct and indirect effects on the integrity and function of nervous system tissue and, potentially, through immune effects. HIV-1 infection poses an additional risk of impairment, and this risk may be decreased as a result of antiretroviral drug treatment. Obviously, the goal of such therapy is to improve the potential clinical course of infection. However, interactions between antiretroviral drugs, abused drugs, and hepatic metabolic enzyme systems may result in impaired or more efficient drug clearance and, consequently, antiretroviral or substance abuse treatment failure. The clinical outcome of this interaction may potentially include drug-related neurotoxicity or neurologic disease induced by HIV infection. The actual impact of these interactions on the occurrence of neurologic impairment and disease are unknown at this time, and, therefore, require study.

Progressive multifocal leukoencephalopathy demonstrating contrast enhancement on MRI and uptake of thallium-201: a case report.

We describe a patient with AIDS who presented with focal neurological symptoms, and who had contrast-enhancing brain lesions on MRI which demonstrated increased thallium-201 uptake on SPECT. These findings were consistent with lymphoma; however, brain biopsy established a diagnosis of progressive multifocal leukoencephalopathy (PML). To our knowledge, this is the first reported case of PML with increased thallium-201 uptake on brain SPECT.

Expression of adhesion molecules and CD28 on T lymphocytes during human immunodeficiency virus infection.

Adhesion molecules, which play a major role in lymphocyte circulation, have not been well characterized in human immunodeficiency virus (HIV) infection. T-lymphocyte populations, including CD3, CD4, CD28, and adhesion molecules (L selectin, LFA-1, VLA-4, and ICAM-1) were measured by flow cytometry in a cross-sectional study of 100 HIV-infected and 49 HIV-seronegative adults. HIV-infected adults had lower numbers of CD3+ lymphocytes expressing L selectin (P < 0.0001) and VLA-4 (P < 0.01) and higher numbers of CD3+ lymphocytes expressing LFA-1bright (P < 0.002) than did HIV-negative adults. By CD4+-lymphocyte count category (>500, 200 to 500, or <200 cells/microl), HIV-infected adults with more advanced disease had lower percentages of CD3+ lymphocytes expressing L selectin and VLA-4 and higher percentages of CD3+ lymphocytes expressing LFA-1. The percentages of CD3+ CD28+ lymphocytes and of CD3+ L selectin+ lymphocytes were positively correlated (Spearman coefficient = 0.86; P < 0.0001), and the percentage of CD3+ CD28+ lymphocytes and the CD3+ LFA-1bright lymphocyte/CD3+ LFA-1dim lymphocyte ratio were negatively correlated (Spearman coefficient = -0.92; P < 0.00001). The results of this study suggest that HIV infection is associated with altered expression of adhesion molecules.

Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study.

UNLABELLED: A retrospective chart review was conducted to determine the effect of alpha-Interferon (alpha-IFN) on disease progression, symptom palliation, and survival in HIV-associated Progressive Multifocal Leukoencephalopathy (PML). METHODS: Subjects were HIV seropositive patients diagnosed with PML at the Johns Hopkins Hospital between 1985 and July of 1986. Diagnostic criteria for PML included both clinical symptomatology and histologic or radiographic confirmation. All patients with concomitant CNS infections were excluded. Patients receiving a minimum treatment of 3 weeks of 3 million units of alpha-IFN daily were compared to untreated historical controls. From 104 PML cases reviewed, 77 met the defined criteria for PML. Twenty-one patients had received open-label alpha-IFN treatment in a non-randomized manner for at least 3 weeks, and 32 met criteria for inclusion in the untreated group as historical controls. Deceased treated patients were comparable to deceased untreated patients with respect to age, gender, race, HIV risk factors, AIDS-defining illnesses, and CD4+ counts. CD4+ counts and use of anti-retroviral medications within 6 months of PML onset were higher among those who were living at the time of the study. RESULTS: Among deceased patients, median survival of treated patients was 127.5 days longer than that of untreated patients (Chi-square=4.21, P=0.04). When living and deceased treated patients were combined, the median survival was 325 days (range 35 - 1634) versus 121 days (range 46 - 176) in untreated patients (Chi-square=13.47, P < 0.001). When survival times in untreated patients were left-censored to account for possible survivorship bias in treated patients, survival in treated patients remained significantly prolonged (325 days versus 175.5 days, Chi-square=4.65, P=0.03). In addition, use of alpha-IFN was associated with a significant delay in the onset of memory loss (Chi-square=8.59, P < 0.01). Seven alpha-IFN treated patients showed sustained remissions of several months to over a year, with documented improvements in mental status, aphasia, dysarthria, dysphagia, paresis, and dyscoordination. Moreover, four IFN-treated patients had evidence of MRI lesion regression, although this was not always correlated with clinical remission. Four of 32 untreated patients also reported transient symptomatic improvements. CONCLUSION: This open-label study suggests that alpha-IFN may delay progression, palliate symptoms, and significantly prolong survival in HIV-associated PML, and we therefore suggest that a controlled clinical trial is warranted.

Variable progression of HIV-associated dementia.

A consecutive series of 71 patients diagnosed with HIV-associated dementia (HAD) (1984-1994) were studied to characterize the clinical course of HAD, and to identify predictive markers of rapid neurologic progression. Neurologic progression rate was determined from the change in the Memorial Sloan Kettering (MSK) dementia severity score from diagnosis to death. Those with the most rapid progression in neurologic disability were compared with those with slow or no progression. Autopsy material was immunostained for macrophage activation markers and gp41 in 30 individuals. Median survival was 3.3 months and 6.1 months for rapid-progression and no-progression patients, respectively. Rapid progression was associated with injection drug use but not with race, gender, or age. CD4+ cell counts were lower at diagnosis among rapid-progression than no-progression patients but no differences in AIDS-defining illnesses or patterns of antiretroviral therapy were found. At presentation, rapid-progression patients had more prominent symptoms of mental slowing than those with no progression; however, no other clinical features, CSF, or imaging features distinguished the groups. Less abundant macrophage activation in both basal ganglia and midfrontal gyrus regions, as judged by HAM56 immunostaining, was noted in 9 no-progression patients, compared with 12 rapid-progression patients. Neurologic progression and survival with HAD is highly variable. A significant proportion of individuals with dementia have prolonged survival of more than 12 months and remain cognitively stable. A history of injection drug use and presentation with prominent psychomotor slowing is associated with more rapid neurologic progression, and these patients tend to show more abundant macrophage activation within the CNS.

T cell subsets and cytomegalovirus retinitis in human immunodeficiency virus-infected patients.

A case-control study was done to investigate the relationship between T cell subsets and cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected subjects with or without CMV retinitis and CD4+ cell counts of <0.050 x 10(9)/L. Cell surface markers on peripheral blood lymphocytes were evaluated using flow cytometry. Patients with CMV retinitis had significantly lower levels of CD8+ cells (median: 0.152 x 10(9)/L) compared with levels for controls (median: 0.296 x 10(9)/L, P < .001). Significant down-regulation of costimulatory molecule CD28+ and lymphocyte function-associated antigen-1 (LFA-1) expression was observed in patients versus controls (CD28+: 0.048 x 10(9)/L vs. 0.143 x 10(9)/L, P < .001; LFA-1: 0.238 x 10(9)/L vs. 0.400 x 10(9)/L, P < .001), but no significant differences were noted for NK cells. We propose that progressive loss of the CD3+ CD8+ cell subset and down-regulation of CD28 and LFA-1 accessory molecules are associated with an increased risk of CMV retinitis in HIV-infected patients.

Comparison of neuropsychological performance between AIDS-free injecting drug users and homosexual men.

We performed a cross-sectional comparison of the baseline neuropsychologic performance of 107 injecting drug users and 230 homosexual men participating in two longitudinal studies. Cognitive tests measured attention, memory and psychomotor speed. Using multiple regression modelling, the analysis adjusted for age, IQ score, race, six-month history of alcohol, cocaine, opiates and marijuana use, HIV serostatus and CD4+ lymphocyte count. Injecting drug users showed significantly poorer scores in all neuropsychologic tests in the univariate analysis. However, once adjusted for age, IQ score and race, only Rey Complex Figure tests were significantly worse among injecting drug users. These data indicate that age and IQ score rather than risk group account primarily for the differences in the cognitive performance, regardless of serostatus and CD4+ count.

HIV infection and cognition in intravenous drug users: long-term follow-up.

A cohort of 185 HIV-infected injection drug users (IDUs) and seronegative controls was followed with semiannual neuropsychological assessments for up to 4.5 years. Changes in cognitive performance over time were evaluated, and results of seronegative controls were used to adjust for level of education and practice effects. The effects of duration of follow-up, decline in CD4+ count, development of clinical symptoms, antiretroviral use, and diagnosis of AIDS on changes in neuropsychological performance over time were assessed with regression models using the generalized estimating equation approach. Improvement in performance over time, consistent with practice effects, was observed for all measures. The only subtest for which the magnitude of the practice effects was mildly attenuated relative to the seronegative controls was Grooved Pegboard, dominant hand. After adjusting for disease progression and antiretroviral therapy use, none of the time trends for the neuropsychological test scores were significant, suggesting no decline in performance of the seropositive patients relative to the seronegative controls. With development of clinical symptoms, there was a trend in the direction of declining performance. For subjects reporting two or more symptoms but not using antiretroviral therapy, the trend was not significant, whereas having two or more symptoms and using antiretroviral therapy was associated with significantly worse performance on tests of psychomotor speed and memory. With development of AIDS, a significant decline in performance was observed on measures of motor and psychomotor speed as well as memory. There is thus no evidence to suggest that HIV infection in the context of chronic drug and alcohol use significantly alters the frequency or rate of progression of cognitive symptoms. These findings suggest that the natural history of cognitive changes secondary to HIV infection is similar among HIV-infected IDUs and other risk groups such as homosexual/bisexual men.

Cognitive sequelae of repeated head injury in a population of intravenous drug users.

The relationship between closed head injury and performance on neuropsychological (NP) tests was investigated in a group of intravenous drug users (IVDUs). Subjects with repeated head traumas involving loss of consciousness (LOC) performed worse than both a control group without LOC and reference group with only a single episode of LOC. There were no significant differences between the last two groups. Performance on tests of memory, attention, and motor performance was significantly worse in the group with repeated head injury. The average time since the last episode of LOC was more than 11 years. We conclude from these findings that a single episode of LOC does not result in significant cognitive impairment in this population. Two or more episodes, however, are more likely to produce chronic cognitive impairment.

Normative data for a brief neuropsychologic test battery in a cohort of injecting drug users.

Recent epidemiologic studies of the cognitive performance of injecting drug users have demonstrated the need to establish appropriate test norms for this population. This report provides normative data from a group of 150 injecting drug users on a battery of standardized tests of cognitive performance stratified by age group (range 20 to 49 years) and educational level (mean 11.6, standard deviation 2.0). The analysis also includes estimation of partial correlations between neuropsychologic test scores and age and education. The analysis demonstrates that age and education are important determinants of performance for several of these tests, and provides norms that may be of use as a reference for clinical evaluation and research in drug user populations.

Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) p24 antigen levels in HIV-1-related dementia.

Human immunodeficiency virus type 1 (HIV-1) p24 antigen, a putative marker of virus load, was assayed in 79 blood and 83 cerebrospinal fluid (CSF) samples from 90 HIV-1-seropositive individuals with or without dementia. Twenty-eight subjects had no evidence of neuropsychological impairment, 17 had mild impairment without objective evidence of dementia, and 45 were demented. HIV-1 p24 antigen was detected more frequently in CSF samples from demented (19/40) than normal (1/26) or mildly impaired (1/17) subjects and in 67% of individuals with significant dementia (MSK stages 2-4). p24 Antigen was detected less frequently in CSF from demented subjects on antiretroviral drugs than untreated demented individuals. Overall, the sensitivity of the antigen capture assay in CSF among demented individuals was 47.5%; the specificity, 95.0%; positive predictive value, 90.4%; negative predictive value, 66.1%; and the efficiency, 72.2%. A direct relationship was also noted between the degree of cognitive impairment and blood p24 antigen detection frequency and antigen concentration. CD4+ blood lymphocyte counts were lower for demented individuals, and HIV-1 p24 antigen was detected more frequently and p24 antigen concentration was higher in blood and CSF from individuals with low CD4+ blood lymphocyte counts. beta 2-Microglobulin levels were higher in CSF from demented subjects and correlated directly with CSF p24 antigen concentration. However, in contrast to CD4+ blood lymphocyte counts and beta 2-microglobulin levels, only p24 antigen concentration correlated with dementia severity. Therefore, p24 antigen can be a useful marker for dementia related to HIV-1 infection.

Effect of chronic substance abuse on the neuropsychological performance of intravenous drug users with a high prevalence of HIV-1 seropositivity.

Limited data are available on cognitive performance in populations of intravenous drug users during the early, asymptomatic stages of human immunodeficiency virus type 1 (HIV-1) infection. Between 1988 and 1990, 151 participants from the AIDS Link to Intravenous Experience (ALIVE) Study in Baltimore, Maryland, were evaluated neuropsychologically on a semiannual basis. This analysis focused on whether history of substance abuse influenced neuropsychological test performance. At baseline, 102 participants were HIV-1-seropositives who were free of acquired immunodeficiency syndrome and 49 participants were seronegative. Multivariate analyses, adjusting for correlation of repeated outcome measures, were conducted to determine predictors of neuropsychological functioning. Effects of the frequency of reported past use of marijuana, heroin, cocaine, barbiturates, and alcohol were not statistically associated with performance on the tests. Age and education were the most important predictors of test performance, and a significant practice effect was observed for most measures. After adjustment for age, education, the practice effect, and frequency of drug use, neuropsychological performance over time did not vary by HIV-1 serostatus. Overall, after acutely intoxicated individuals were excluded, neither frequency of drug and alcohol use nor HIV-1 seropositivity significantly influenced neuropsychological test performance over a 1-year period.

HIV-1 infection and intravenous drug use: longitudinal neuropsychological evaluation of asymptomatic subjects.

A previous baseline cross-sectional comparison of cognitive performance of a group of AIDS-free, HIV-seropositive intravenous drug users with seronegative control intravenous drug users revealed no significant differences attributable to HIV. We now present longitudinal follow-up results from the same cohort of 160 intravenous drug users. There were no differences in performance by serostatus group at either 6- or 12-month follow-up visits, although differences by age and education were observed. Improvement in performance secondary to practice effects was comparable in both serostatus groups. These findings confirm that chronic intravenous drug use may be associated with a wide range of neuropsychological deficits, but there is no evidence that such preexisting deficits interact with HIV infection to produce additional cognitive impairment in otherwise asymptomatic intravenous drug users. Together with results from other high-risk groups such as homosexual/bisexual men and hemophiliacs, these results confirm that neurocognitive abnormalities during the presymptomatic stages of HIV infection are rare, regardless of the route of acquisition of the virus.