Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity.

Elderly patients with acute myeloid leukemia (AML) have a poor prognosis. The authors examined the in vitro and clinical activity of the histone deacetylase inhibitor valproic acid (VA) combined with cytosine arabinoside (AraC) in elderly patients with AML unsuited to intensive therapy. For the in vitro studies, primary AML cells from 11 patients were treated with AraC and VA and analyzed for apoptosis, cytostatic effects, differentiation and acetyl histone H3 induction. VA (alone and with AraC) enhanced apoptosis and induced acetyl histone H3. VA inhibited cell proliferation. For the clinical trial, 15 patients were treated with VA and subcutaneous AraC and assessed for toxicity and response. No complete or partial remissions were achieved. In conclusion, VA has in vitro activity against AML and has additional activity with AraC. However, in this study, this combination demonstrated limited clinical activity in elderly patients with AML.

Noninvasive cardiovascular markers of acoustically induced arousal from non-rapid-eye-movement sleep.

STUDY OBJECTIVES: Changes in cardiovascular measures such as heart rate (HR) and pulse transit time (PTT) have been advocated as sensitive markers of autonomic arousal from sleep. In animal studies, alerting stimuli produce particularly marked skin vascular responses. We hypothesized that changes in skin vascular conductance would provide more sensitive markers of autonomic arousal during sleep compared to central cardiovascular response measures such as HR and PTT. DESIGN: Cardiovascular responses to auditory-induced arousals were recorded during overnight sleep studies. SETTING: Sleep disorders unit in a 270-bed teaching hospital. PARTICIPANTS: Eleven young healthy male subjects. INTERVENTIONS: Throughout ovemight sleep studies, auditory tones (5-second duration, 54-90 decibels, 22-56 per subject) were presented during non-rapid-eye-movement sleep. Beat-by-beat HR, PTT, laser-Doppler fingertip skin blood flow (SBF) and finger and ear photoplethysmogram pulse wave amplitudes (PWA) were measured in the 20 seconds preceding and 30 seconds following each tone and compared to control measurements obtained during 50-second periods of recording with no stimulus (no tone, 6-22 per subject). Electroencephalographic (EEG) arousals were scored according to standard criteria (American Sleep Disorders Association) into no discemible, 3- to 10-second duration, or 10- to 15-second duration arousals. Poststimulus cardiovascular measurements were expressed as a percentage of the prestimulus mean and response magnitudes quantified from peak responses and the area under the poststimulus response curve. The ability of each cardiovascular response measure to discriminate EEG arousals (EEG changes lasting more than 3 seconds) was assessed from the area under the receiver operating characteristic (ROC) curve. MEASUREMENTS AND RESULTS: There were no significant changes in any cardiovascular parameter during control recordings. In contrast to all other parameters, finger PWA and SBF decreased following tones that produced no discernible EEG arousal (P < 0.05). A significant HR rise and decreases in all cardiovascular measures occurred with greater than 3-second arousals, with longer duration arousals generally exhibiting larger responses. Conventional EEG arousals (greater than 3 seconds) were relatively poorly detected from HR responses (ROC area HR rise 0.80 +/- 0.04) compared to changes in SBF (0.85 +/- 0.02), PTT (0.85 +/- 0.03) and finger PWA (0.90 +/- 0.01). CONCLUSIONS: Decreases in skin vascular conductance (finger PWA and SBF) provide sensitive markers of autonomic arousal during sleep. They are at least as sensitive as PTT for detecting conventionally scored EEG arousals and may be more sensitive in detecting "subcortical" arousals.