HSP ensitivity of young monkeys to fludarabine when coadministered with busulfan was not previously known, and there are no published measurements of fludarabine pharmacokinetics in rhesusmonkeys, particularly in this age group. Therefore, to avoid possible adverse effects, the initial dosage was at the lower end of the clinical fludarabine dosing range. For the first series of animals, six monkeys were administered busulfan and three of these monkeys were also administered fludarabine. There was no discernible additive effect from berberine fludarabine coadministration on the clinical outcomes. Most relevant, there was no induction of lymphopenia, which is the hallmark of fludarabine activity when used in humans at therapeutic dosages.23 Based on these findings, the next group of three monkeys was administered higher dosages of fludarabine at the upper end of the typical clinical range. There was no additional clinical toxicity, lymphopenia, or other hematological toxicities, compared to the recipients receiving busulfan only. In the final group, fludarabine dosages were increased successively, such that one each received fludarabine at 75 mg/m2 3 days, 87.5 mg/m2 3 days, or 100 mg/m2 3 days.
There were no clinical or hematological effects disufenton sodium beyond those of the busulfan alone with this additional treatment regimen. For the last three recipients, fludarabine plasma levels were serially measured following the first dose and used to compute the peak concentrations, the clearance, and total exposure. Despite dose escalation of fludarabine from 75 to 87.5 to 100 mg/m2, the fludarabine AUC were very similar. The fludarabine clearance in the monkey infants was markedly more rapid than that observed in human studies where the circulating half life ranges from 8 to 20 hours.22,24 Although a drug drug interaction between busulfan and fludarabine is possible, the concentrations of busulfan were not altered with the addition of fludarabine. Hematological effects of the conditioning regimens Transient neutropenia and thrombocytopenia occurred in all recipients. In the first two groups dabigatran of animals, there were no discernible differences in the degree or time course of myelosuppression that developed in recipients of busulfan alone compared to those receiving both busulfan and fludarabine.
In the third group of animals, recipients of higher dosages of fludarabine with busulfan displayed earlier onsets of neutropenia than did the recipients of busulfan only, suggesting that the fludarabine did have some suppressive effect ongranulocytopoiesis in the time period immediately post treatment. The nadir neutrophil and platelet counts were correlated inversely with the busulfan levels achieved. In contrast, there was no dosage related effect of busulfan on total lymphocyte counts. Addition of fludarabine to the busulfan did not alter either the busulfan AUC achieved or the nadir ANC levels reached compared to treatment with busulfan alone without fludarabine. Lentiviral vector transduction of CD34 cells For all transplants, the autologous CD34 cells isolated from bone marrow were divided into two equal portions, with one fraction transduced with the SIV NoN marker vector and the other fraction transduced with the SIV GFP vector. These cells were re admixed and infused i.v.