The dose-finding step was designed as an open-label, single sequence dose escalation, single-dosing study to determine the lowest oseltamivir dose detectable in plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and showing dose-linearity with two higher oseltamivir doses.
To this aim, we injected subretinally in Large White pigs AAV2/8 dual AAV hybrid ABCA4 vectors (of which the 5′-half vector included or not the CL1 sequence, dose of each vector/eye: 1 × 10 GC).
Among taxane schedules, the taxane combination (TAC) was overall associated with the highest incidence of hematologic toxicity, and the dose-dense paclitaxel part of the sequence dose-dense schedule with the lowest incidence (Table 3).
The relatively low incidence of hematologic toxicity, with the exception of low-grade anemia, with the sequence dose-dense schedule is notable and may reflect the sequential dosing schedule and the obligatory use of granulocyte-colony stimulating factor therapy.
Overall among taxane schedules, the incidences of dose delays (13.8%) and of hospitalization (25%) were markedly higher with the sequence dose-dense schedule (dose-dense epirubicin/dose-dense paclitaxel regimen) versus other taxane schedules.
No patients receiving the sequence schedule, the combination dose-dense schedule or the sequence dose-dense schedule received primary anti-infective prophylaxis – while among those patients who received the combination taxane schedule, 44% received no prophylaxis and 56% received ciprofloxacin on days 5 to 14.
This study has several limitations that are inherent to fixed-sequence dose escalation studies.
Randomly sequenced doses of hawthorn extract (1000 mg, 1500 mg, and 2500 mg) and placebo were assigned to each participant.
Whatever schedule chosen, with (arm B) or without (arm A) an extra 2-week interval between both sequences, dose-dense chemotherapy yielded an unacceptable high rate of grade 3 4 skin toxicity (32.4% and 18.9% in arm A and B, respectively).
In the last two decades, antihypertensive effects of some of these peptides have been evaluated in spontaneously hypertensive rats (SHR) and hypertensive humans, and the peptide sequences, doses, and maximum decreases of systolic blood pressure (SBP) have been summarized in several reviews [ 23– 25].
Thereafter, a descending sequence of dose levels was selected at 2-folded intervals (500 and 250 mg/kg/day) with a view to demonstrating any dose related response and no-observed-adverse effects at the lowest dose level (NOAEL).
