AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0-to 2.1-fold) in an E max model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.
Limited data suggest that the cerebrospinal fluid Treponema pallidum particle agglutination assay (CSF-TPPA) is sensitive and a CSF Treponema pallidum hemagglutination assay (CSF-TPHA) titer of Ն1:640 is specific for neurosyphilis diagnosis. CSF-TPPA reactivity and titer were determined for a convenience sample of 191 CSF samples from individuals enrolled in a study of CSF abnormalities in syphilis (training data set). The sensitivity of a reactive test and the specificity for reactivity at serial higher CSF dilutions were determined. Subsequently, CSF-TPPA reactivity at a 1:640 dilution was determined for all available samples from study participants enrolled after the last training sample was collected (validation data set, n ϭ 380). Neurosyphilis was defined as (i) a reactive CSF Venereal Disease Research Laboratory test (CSF-VDRL), (ii) detection of T. pallidum in CSF by reverse transcriptase PCR, or (iii) new vision loss or hearing loss. In the training data set, the diagnostic sensitivities of a reactive CSF fluorescent treponemal antibody absorption test (CSF-FTA-ABS) and a reactive CSF-TPPA did not differ significantly (67 to 98% versus 76 to 95%). The specificity of a CSF-TPPA titer of Ն1:640 was significantly higher than that of lower dilutions and was not significantly different from that of CSF-VDRL. In the validation data set, the diagnostic specificity of a CSF-TPPA titer of Ն1:640 was high and did not differ significantly from that of CSF-VDRL (93 to 94% versus 90 to 91%). Ten CSF samples with a nonreactive CSF-VDRL had a CSF-TPPA titer of Ն1:640. If a CSF-TPPA titer of Ն1:640 was used in addition to a reactive CSF-VDRL, the number of neurosyphilis diagnoses would have increased from 47 to 57 (21.3%). A CSF-TPPA titer cutoff of Ն1:640 may be useful in identifying patients with neurosyphilis when CSF-VDRL is nonreactive.KEYWORDS TPPA, diagnosis, human immunodeficiency virus, neurosyphilis, syphilis T here is no single sensitive and specific test for the diagnosis of neurosyphilis. The cerebrospinal fluid Venereal Disease Research Laboratory test (CSF-VDRL) is considered the "gold standard" test. While CSF-VDRL is specific, its sensitivity is 30 to 70% (1, 2). Conversely, CSF treponemal tests, in particular, the CSF fluorescent treponemal antibody absorption test (CSF-FTA-ABS), are more sensitive than CSF-VDRL, but they lack specificity (3). The sensitivities of CSF treponemal tests are greater than 90% when neurosyphilis is defined as a reactive CSF-VDRL and are lower when the diagnosis of neurosyphilis is based on clinical findings (3). Limited data on the use of the CSF Treponema pallidum particle agglutination assay (CSF-TPPA) for neurosyphilis diagnosis suggest that, like CSF-FTA-ABS, it may be diagnostically sensitive (4, 5). The Treponema pallidum hemagglutination assay (TPHA) is similar to TPPA, and two studies have suggested that a CSF-TPHA titer of Ն1:640 is specific for neurosyphilis diagnosis (6, 7). CSF-FTA-ABS requires a fluorescence microscope, while TPHA and TPPA are simpler...
Selegiline was safe and well tolerated by HIV-infected individuals with cognitive impairment and mild to moderate immune suppression; however, no cognitive or functional improvement was observed in this phase II study.
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