For each compound, four to six male, 12 week old F344 rats were exposed to a low dose, mid dose(s) and a high dose of the toxicant and sacrificed at 6, 24 and 48 hr later (Table 1).
On day 1, only the mid dose (3/5) and high doses (1/5) were affected, whilst by day 3 the incidence had risen to 3/5 at 50 ppm, 5/5 at 500 ppm and 1000 ppm.
Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis.
Discontinuation rates due to adverse events were 9%, 12%, and 18% for placebo, low- and mid-dose, and high-dose phentermine/topiramate ER, respectively.
The incidence of neurocognitive adverse effects was 2.0% for low-dose, 5.6% for mid-dose, and 7.8% for full-dose phentermine/topiramate ER compared to 1.7% for placebo.
Two plasma samples were obtained per patient (mid-dose and trough), after administration of at least three doses, to ensure steady-state.
27 Phentermine/topiramate ER was associated with significantly greater weight loss (−1.4 kg for placebo, −8.1 kg for mid-dose, and −10.2 kg for high-dose therapy), as well as greater maintenance of weight loss.
In comparison with placebo, depression-related adverse events were more frequent with full-dose PHEN/TPM, but not with the mid-dose PHEN/TPM; anxiety-related adverse events had a higher frequency with the mid-dose and full-dose.
In addition, 79.3% of participants in the high-dose and 75.2% in the mid-dose phentermine/topiramate ER groups achieved a ≥5% reduction in mean body weight from baseline, compared to 30% in the placebo group, while 53.9% of participants in the mid-dose and 50.3% in the high-dose phentermine/topiramate ER groups achieved ≥10% weight loss.
The doses to be used were set according to the results in the pilot study, so that the high dose, intermediate dose (mid-dose), and low dose each represent the 10, 5, and 2.5percentt of the LD50 for each compound in the mixture, respectively (Table 2, where the high dose corresponds to the doses used in the pilot study).
× 3 times along with TCDD one time with the mid dose of harmine and harmaline.
