Phosphodiesterase III inhibitors (VIVUS)

The dominant chemotherapeutic agent, cisplatin (CP), is widely used to manage various cancer types. Despite its effectiveness, CP use is associated with severe hepatotoxicity. Cilostazol (CSZ), a selective phosphodiesterase III inhibitor, has recently demonstrated remarkable anti-inflammatory and anti-apoptotic properties in different diseases. Additionally, it exhibits hepatoprotective effects against various forms of liver injury. Hence, this study aimed to assess the potential hepatoprotective and ameliorative effects of CSZ on CP-induced acute liver injury (ALI) and to elucidate the underlying molecular mechanisms. To achieve this, ALI was induced by a single injection of CP (20 mg/kg; i.p.) in male Wistar rats pretreated with CSZ (5 or 10 mg/kg) administered orally for one week. The findings revealed that CSZ effectively reversed CP-induced hepatic dysfunction, as evidenced by notable liver function tests and improvements in histological examination. Additionally, CSZ protected against CP-mediated liver oxidative stress by decreasing MDA levels while increasing GSH and GPx levels and enhancing SOD activity. Furthermore, CSZ exhibited a potent anti-inflammatory effect, reducing the expression of pro-inflammatory cytokines, including NF-κB, IL-1β, and TNF-α. Regarding hepatocyte apoptosis, CSZ suppressed Bax immunoexpression and caspase-3 and caspase-9 levels while enhancing Bcl-2 expression, thereby mitigating hepatic cell death. The hepatoprotective effects of CSZ could be attributed to the regulation of the miRNA-34a/AMPK/SIRT1/PGC-1α signaling pathway, leading to the activation of the Nrf2/HO-1-mediated antioxidative defense mechanism. In conclusion, CSZ could be a promising therapeutic agent for preventing CP-induced ALI, potentially improving the quality of life for cancer patients.

Enoximone, a phosphodiesterase III inhibitor, was approved in Germany in 1989 and initially proposed for heart failure and perioperative cardiac conditions. The research of Joachim Boldt and his supervisor Gunter Hempelmann came under scrutiny after investigations revealed systematic scientific misconduct leading to numerous retractions. Therefore, early enoximone studies by Boldt and Hempelmann from 1988 to 1991 were reviewed.

PubMed-listed publications and dissertations on enoximone from the Justus-Liebig-University of Giessen were analyzed for study design, participant demographics, methods, and outcomes. The data were screened for duplications and inconsistencies.

Of seven randomized controlled trial articles identified, two were retracted. Five of the non-retracted articles reported similarly designed studies and included similar patient cohorts. The analysis revealed overlap in patient demographics and reported outcomes and inconsistencies in cardiac index values between trials, suggesting data duplication and manipulation. Several other articles have been retracted. The analysis results of misconduct and co-authorship of retracted studies during Boldt’s late formative years indicate inadequate mentorship. The university’s slow response in supporting the retraction of publications involving scientific misconduct indicates systemic oversight problems.

All five publications analyzed remained active and warrant retraction to maintain the integrity of the scientific record. This analysis highlights the need for improved institutional supervision. The current guidelines of the Committee on Publication Ethics for retraction are inadequate for large-scale scientific misconduct. Comprehensive ethics training, regular audits, and transparent reporting are essential to ensure the credibility of published research.