Phosphodiesterase III inhibitors (VIVUS)

Fat embolism syndrome (FES) occurs when fat droplets from bone marrow or adipose tissue enter the circulation due to bone fractures or surgical interventions. It typically develops 12 to 72 hours after injury. However, fulminant FES, characterized by its rapid onset, is rare and can rapidly progress to a life-threatening condition. In this case report, a 90-year-old woman underwent osteosynthesis on the fourth day after admission (day 4) following a femoral diaphyseal fracture. During the insertion of an intramedullary nail into the femur, rapid deterioration of oxygenation was observed, followed by shock and severe right heart failure. Emergency veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated. Suspecting thromboembolism, contrast-enhanced CT was performed, but no massive thrombus was found in the pulmonary artery. Based on the clinical course, we diagnosed fulminant FES. The patient received respiratory and circulatory support with VA-ECMO, along with reduction of the right heart afterload using inhaled nitric oxide (iNO) and phosphodiesterase III inhibitors. The patient was successfully weaned off ECMO on day 7, iNO was discontinued on day 10, and the ventilator was removed on day 11. The patient was subsequently transferred to the general ward on day 13, where she exhibited no significant neurological deficits. Although fat embolism syndrome can only be managed symptomatically, the patient's outcome was favorable because of the prompt initiation of ECMO in response to the fulminant presentation.

Zacopride (4-amino-5-chloro-2-methoxy-N-(quinuclidin-3-yl)-benzamide) is a potent agonist in human 5-HT4 serotonin receptors in vitro and in the gastrointestinal tract. Zacopride was studied as an antiemetic drug and was intended to treat gastric diseases. Zacopride has been speculated to be useful as an antiarrhythmic agent in the human ventricle by inhibiting cardiac potassium channels. It is unknown whether zacopride is an agonist in human cardiac 5-HT4 serotonin receptors. We tested the hypothesis that zacopride stimulates human cardiac atrial 5-HT4 serotonin receptors. Zacopride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac-specific overexpression of human 5-HT4 serotonin receptors (5-HT4-TG). However, it was inactive in wild-type mouse hearts (WT). Zacopride was as effective as serotonin in raising the force of contraction and beating rate in atrial preparations of 5-HT4-TG. Zacopride raised the force of contraction in human right atrial preparations (HAP) in the absence and presence of the phosphodiesterase III inhibitor cilostamide (1 µM). The positive inotropic effect of zacopride in HAP was attenuated by either 10 µM tropisetron or 1 µM GR125487, both of which are antagonists at 5-HT4 serotonin receptors. These data suggest that zacopride is also an agonist at 5-HT4 serotonin receptors in the human atrium.