Table 1.

Summary of the preclinical studies focused on toludesvenlafaxine.

Design	Results	Observations	Reference
Single and 13-week repeated-dose oral toxicity assessment and mutagenicity assays. Acute dose: 500 mg/kg, 1000 mg/kg, and 2000 mg/kg LPM570065 in SD rats. A 13-week toxicity study: 30 mg/kg, 100 mg/kg, or 300 mg/kg LPM570065 for 13 consecutive weeks + 4-week recovery period. N = 80 rats (40 males and 40 females).	In a single-dose acute study: 2 out of 20 rats died in the 1000 mg/kg group vs. seven out of 20 in the 2000 mg/kg group vs. none in the 500 mg/kg group. In the 13-week toxicity study: transitory salivation and minor body weight decrease was reported in the 300 mg/kg group in males. Serum PRL levels ↓ by 43% and 78% in male rats in 100 mg/kg and 300 mg/kg groups, respectively. Serum TST ↑ by 37% in the 30 mg/kg and 100 mg/kg males.	MTD = 500 mg/kg and lethal dose = 1000 mg/kg in the acute administration. In the long-term administration, no observed AE level was ≥300 mg/kg for rats; no mutagenic or clastogenic effects. MTD = 3000 mg/patient/day in clinical conditions. The effects of LPM570065 on sexual function are to be monitored.	Li C, Jiang W, Gao Y, et al. [77]
Acute phase: 30 mg/kg, 100 mg/kg, and 300 mg/kg LPM570065 vs. control. Female rats received 2 weeks of the investigational product + mating up to the 7th gestation day. Male rats received 4 weeks of investigational product + mating with treated female rats. Following this stage, all males were treated up to the ninth week and a new mating period was initiated with non-treated female rats. Mortality, toxicity symptoms, body weight, amount of food consumed, sexual cycle, mating behavior, pregnancy, sperm production, gross necropsy, and weight of organs. N = 264 rats were distributed in 4 groups (44 females and 22 males in each group).	Excessive salivation post-treatment in all females and males on 100 mg/kg and 300 mg/kg LPM570065 groups. BW gain ↓ in gravid rats with 300 mg/kg investigational product during gestation days 0–6. Decreased fertility rates were associated with a 300 mg/kg dose of investigational product in male rates. Sperm concentration and count were higher in all three groups treated with LPM570065 vs. controls. Duration of mating ↓ significantly to 37.5% after 9 weeks of treatment with 300 mg/kg.	The no observable AE level was established at 100 mg/kg (female rats) and 300 mg/kg (male rats). The no observable AE level for fertility and early embryonic development was established at 300 mg/kg (female rats) and 100 mg/kg (male rats).	Guo W, Gao Y, Jiang W, et al. [78]
Exploring extracellular 5HT, NE, and DA levels in the rat striatum after acute and chronic administration of LPM570065 vs. DSVLFX. The methods used were HPLC and microdialysis. N = 72 rats divided into 9 equal groups.	HPLC results showed that LPM570065 rapidly penetrates the striatum and converts into DSVLFX while presenting larger total exposure vs. DSVLFX. Long-term administration of LPM570065 (up to 14 days) via the oral route increased all three monoamine levels more than DSVLFX, and especially dopamine levels (detected by microdialysis). During the forced swim test, acute and chronic administration of LPM570065 ↓ the immobility time more than DSVLFX.	LPM570065 may possess an ↑ efficacy and/or a more rapid onset of antidepressant effect than DSVLFX. LPM570065 counterbalances the negative effects of DSVLFX on 5HT neurotransmission related to the 5HT1A autoreceptors.	Zhang R, Li X, Shi Y, et al. [79]
Adult male and female C57BL/6J mice, 5 groups, each group had 24 animals: control vs. single-stress vs. double-stress vs. LPM570065 vs. fluoxetine groups. Sucrose preference test, forced swimming test, and tail suspension test.	LPM570065 reduced susceptibility to depression-like behaviors in adult mice + maternal separation. LPM570065 protected against the reduced number of dendritic spines in the hippocampal CA1 of mice subjected to stress. LPM570065 regulated the expression of DNMTs in the mouse hippocampus.	LPM570065 may reduce depression vulnerability via epigenetic mechanisms involving the Oxtr expression.	Meng P, Li C, Duan S, et al. [80]
Male and female Wistar and Sprague–Dawley rats (total of 12/sex/group and 5/sex/group, respectively); affinity for monoamine transporters was determined by radioligand membrane binding assay; chronic unpredictable mild stress procedure; rat olfactory bulbectomized model, open field test, sucrose consumption test, serum corticosterone, and testosterone levels. Toludesvenlafaxine 10 μM.	The highest inhibition for serotonin transporters was reported in in vitro assays. The absorption was good after oral administration, and it was converted to O-desvenlafaxine due to the action of esterases in vivo, both reaching the hypothalamus in high concentration.	While desvenlafaxine does not increase the striatal level of dopamine, toludesvenlafaxine has this effect, which indicates supplementary benefits vs. the older drug.	Zhu H, Wang W, Sha C, et al. [81]

5HT = serotonin; AE = adverse effect; BW = body weight; DA = dopamine; DNMT = DNA methyltransferases; DSVLFX = desvenlafaxine; HPLC = high-performance liquid chromatography; MTD = maximum tolerated dose; NE = norepinephrine; Oxtr = oxytocin receptor; PRL = prolactine; SD = Sprague–Dawley; and TST = testosterone.