PD-116948

Cyclophosphamide (CPX)-induced prostatic toxicity remains a clinically relevant concern, with limited strategies available to mitigate its adverse effects. This study investigates the potential protective effects of lacosamide (LCS), an FDA-approved anticonvulsant with antioxidant, anti-inflammatory, and anti-apoptotic properties, against CPX-induced prostate injury in rats. We examined LCS's effects on the Notch-1 signaling pathway and its potential interaction with nuclear factor kappa B (NF-κB). Male Wistar albino rats were divided into five groups: normal control, LCS control (40 mg/kg/day), CPX control (200 mg/kg), and two LCS treatment groups (10 and 40 mg/kg/day) co-administered with CPX. CPX exposure significantly increased oxidative stress markers (elevated malondialdehyde; reduced glutathione, superoxide dismutase, glutathione peroxidase, and catalase), upregulated proinflammatory markers (phosphorylated NF-κB p65, interleukin-6, interleukin-1β, tumor necrosis factor-α), and increased apoptotic markers (downregulation of B-cell lymphoma 2; upregulation of Bcl-2 associated X protein and cleaved caspase-3). Additionally, CPX enhanced Notch-1 receptor and Notch-1 intracellular domain expression, decreased serum testosterone levels, altered prostate-specific antigen levels, and suppressed androgen receptor expression. LCS co-administration, particularly at the higher dose, improved these parameters, suggesting modulation of oxidative stress, inflammation, and apoptotic pathways. These findings indicate that LCS treatment may provide protective effects against CPX-induced prostatic alterations and suggest its potential consideration as an adjuvant agent during CPX-based therapy.

Venetoclax has been combined with intensive chemotherapy regimens in the treatment of acute myeloid leukemia (AML). We aimed to investigate the safety and efficacy of venetoclax combined with full‐dose CPX‐351 (CPX + VEN) in newly diagnosed (ND) AML. Seventeen patients with a median age of 59 years (range, 43–69) were treated; 71% had secondary AML, 47% had prior hypomethylating agent (HMA) exposure, 59% had myelodysplastic syndrome (MDS)‐related (MR) mutations, 47% had complex karyotype, and 29% were TP53 mutated. The overall response rate (ORR) was 82% (95% CI, 57–96) with a composite complete remission rate (CRc) of 71% (95% CI, 50–93). Patients with MR mutations had an ORR of 100% (95% CI, 69–100), including a CRc of 90% (95% CI, 55–100). Patients with prior HMA exposure had a CRc of 63% (95% CI, 24–91). With a median follow‐up time of 11.8 months, the median overall survival (OS) was 12.8 months (95% CI, 5–NE) with a 2‐year OS of 34% (95% CI, 10–61). Patients with MR mutations had a median OS of 17.9 months versus 5.1 months in patients without MR mutations (P = 0.039). Twelve (86%) of 14 responding patients proceeded to stem cell transplant (SCT); the median recurrence‐free survival and OS landmarked from date of SCT were 14.7 months (95% CI, 1–32) and 14.7 months (95% CI, 4–25), respectively. The 4‐week mortality was 0% and the 8‐week mortality was 17%. The most common adverse events were related to myelosuppression. CPX + VEN resulted in high remission rates and enabled progression to allogenic SCT for the majority of a highly adverse group of ND AML patients.