Outpatient-based therapy of oral fludarabine and subcutaneous alemtuzumab for asian patients with relapsed/refractory chronic lymphocytic leukemia.

Background. Intravenous alemtuzumab and fludarabine are effective in combination for the treatment of chronic lymphocytic leukemia (CLL), but require hospital visits for intravenous injection. We performed a pilot study to assess the safety and efficacy of outpatient-based oral fludarabine with subcutaneous alemtuzumab (OFSA) for the treatment of relapsed/refractory CLL. Results. Depending on their response, patients were given two to six 28-day cycles of subcutaneous alemtuzumab 30 mg on days 1,3, and 5 and oral fludarabine 40 mg/m(2)/day for 5 days. Median patient age was 74. The lymphocyte counts of all five patients fell after the 1st cycle of treatment and reached normal/low levels on completion of 2 to 6 cycles of therapy. Platelet counts and hemoglobin were unaffected. All five patients achieved complete hematological remission, while two attained minimal residual disease negativity on 4-color flow cytometry. Conclusions. Our OFSA regimen was effective in elderly Asian patients with relapsed/refractory CLL, and it should be investigated further.

Tonic firing of rat nucleus accumbens neurons: changes during the first 2 weeks of daily cocaine self-administration sessions.

Activity of single neurons in the nucleus accumbens (NAcc) of rats was recorded extracellularly on the 2nd and 15th days of intravenous cocaine self-administration. Each of the two electrophysiological recording sessions consisted of three successive phases: a pre-drug baseline recording period, a cocaine self-administration session, and a post-drug recording period. Firing of individual neurons was typically inhibited during the self-administration session, relative to the pre-drug period. The inhibition was greater on the 15th day relative to the 2nd day. Additionally, firing rates during the pre-drug period and the self-administration session were typically lower on the 15th day as compared to the 2nd day. The present data are consistent with previous acute electrophysiological findings and are in line with the hypothesis that repeated drug self-administration engenders changes in the mesoaccumbens pathway that contribute to drug addiction.

Phasic firing time locked to cocaine self-infusion and locomotion: dissociable firing patterns of single nucleus accumbens neurons in the rat.

The activity of single nucleus accumbens (NAcc) neurons of rats was extracellularly recorded during intravenous cocaine self-administration sessions (0.7 mg/kg per infusion, fixed ratio 1). We reported previously that NAcc neurons showed a change, usually a decrease, in firing rate during the first 1 min after the cocaine-reinforced lever press. This postpress change was followed by a progressive reversal of that change, which began within the first 2 min after the press and was not complete until the last 1 min before the next lever press (termed the change + progressive reversal firing pattern). In the present study we documented a regular pattern of locomotion that occurred in parallel with the change + progressive reversal firing pattern. This observation suggested that discharges time locked to locomotion may determine the change + progressive reversal firing pattern. However, 55% of the neurons failed to show firing time locked to locomotion that could have contributed to the change + progressive reversal firing pattern. Moreover, for all neurons, the change + progressive reversal firing pattern was apparent even if the calculation of firing rate excluded all periods of locomotion. The present data showed that the change + progressive reversal firing pattern is not solely attributable to phasic changes in firing time locked to the execution of locomotion. The change + progressive reversal firing pattern closely mirrors changes in drug level and dopamine overflow observed by previous researchers and may thus be a component of the neurophysiological mechanism by which drug level regulates drug-taking behavior during an ongoing self-administration session.

Operant behavior during sessions of intravenous cocaine infusion is necessary and sufficient for phasic firing of single nucleus accumbens neurons.

The activity of individual accumbens neurons in rats was recorded in relation to intravenous cocaine infusions that were either response (i.e., lever press) contingent or response non-contingent. Neural firing was additionally recorded in relation to non-reinforced lever presses. Comparisons of firing under the three conditions showed that operant behavior was necessary and sufficient for preinfusion firing to occur. Surprisingly, the same was true, in many cases, for firing that occurred during the infusion. For other neurons, firing during the infusion was unrelated to operant behavior and possibly related to infusion stimuli. The relationship to operant behavior exhibited by the majority of NAcc neurons is consistent with previous studies that demonstrated a necessary relationship between NAcc neurons and cocaine reinforced operant behavior.