piperidines and Ascites

We herein report a case of idiopathic refractory ascites following allogeneic hematopoietic cell transplantation that was successfully treated with ibrutinib. A 39-year-old man presented with massive transudative ascites. Despite a high portal venous pressure, the liver histology showed traces of alloreactivity inconsistent with veno-occlusive disease/sinusoidal obstructive syndrome. Ibrutinib was administered for ascites possibly secondary to portal hypertension associated with the alloreactivity. The ascites dramatically improved, and the portal venous pressure was reduced. This case may help clarify the mechanism through which refractory ascites develops after allogeneic hematopoietic cell transplantation and establish appropriate treatment protocols.

Topics: Adult; Ascites; Hematopoietic Stem Cell Transplantation; Humans; Liver; Male; Piperidines

Emerging findings suggested the efficacy of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in several pathological conditions included tumours. In this study we investigated in vitro the effects of SR141716 on viability and the molecular pathways of methylcholanthrene-induced fibrosarcoma (Meth-A) cells and in vivo its anti-tumour properties in Meth-A-bearing mice. We evaluated in vitro the effect of SR141716 on Meth-A cell viability by trypan blue staining assay. Cell cycle progression and apoptosis were assessed by flow cytometry. Protein expression was investigated by Western blot. The anti-tumour efficacy of SR141716 was evaluated in vivo monitoring weight increase and survival of Meth-A injected mice. SR141716 affects Meth-A cell viability inducing apoptosis and controls cell cycle progression by modulation of the levels of the cell cycle inhibitor p21waf, cyclins E, D1 and NF-kB molecules. Importantly, SR141716 affects AKT/pFoxO1 pathway which promotes cell survival and regulates the cell cycle. The molecular effects observed are accompanied by reduced COX2 expression and induction of the CB1 receptor expression. Finally, SR141716 was able to reduce the tumour size and prolong animal survival, when administered in vivo during tumour growth. Our findings shed light on a novel molecular pathway associated with control of tumour growth by SR141716 and confirm the anti-cancer and anti-inflammatory properties of this drug suggesting its potential applications in the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Ascites; Cell Cycle; Cell Line, Tumor; Cell Survival; Female; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sarcoma

Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats.. Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed.. A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P < .05). Liver fibrosis was reduced in group 2 by 30% (P < .05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score.. Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.

Topics: Animals; Ascites; Blood Pressure; Carbon Tetrachloride; Cardiac Output; Diuresis; Dose-Response Relationship, Drug; Kidney; Liver Cirrhosis, Experimental; Male; Natriuresis; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Rimonabant; Sodium; Sodium, Dietary; Time Factors; Vascular Resistance

TIPS is a percutaneous procedure which diverts blood from the portal to the systemic circulation preventing rebleeding from varices and stopping or reducing the formation of ascites. The choice of the anaesthetic technique is still a matter of debate. Since January 2003, 150 consecutive TIPS were performed using total intravenous anesthesia (TIVA), (propofol/fentanyl or remifentanil), endotracheal intubation and mechanical ventilation. Sixty-one patients were classified as ASA 2, 73 ASA 3, and 16 ASA 4. According to CHILD classification, 96 patients were in Class A, 48 in Class B, 6 in Class C. Mean duration f the procedure was 100+/-62 min. After TIPS placement Portal vein pressure decreased from 30+/-10 to 14+/-4 mmHg while RAP increased from 8+/-4 to 12+/-6 mmHg. Intraoperative fluid management included mainly crystalloids (750+/-200 ml, 5.4+/-1.5 ml/kg/h). Fresh frozen plasma (median 2 units, range 1-3) was given in 20 patients (13%) if PT INR was >2. Packed red cells (median 2 units, range 1-5) were transfused in 35 patients (23%) to keep haematocrit >25%; platelets were administered before the procedure if platelet count was <50,000x10(-9) (20 patients, 13%). Urine output was kept above 4 ml/kg/h with loops diuretics (mean diuresis 700+/-200 ml, 5+/-1.5 ml/kg/h). Ten patients (6.6%) required ICU after the procedure, because of intraoperative hemodynamic instability. Three patients (2%) died in the early postoperative period because of multiple organ failure associated with the acute deterioration of an already marginal hepatic function.

Topics: Adult; Anesthesia, Intravenous; Ascites; Budd-Chiari Syndrome; Diuresis; Female; Fentanyl; Hematocrit; Humans; Intubation, Intratracheal; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Portasystemic Shunt, Transjugular Intrahepatic; Propofol; Remifentanil; Respiration, Artificial; Retrospective Studies

We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.. Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.. The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD50 of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD50 in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.. Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.

Topics: Antineoplastic Agents; Ascites; Blotting, Western; Carboplatin; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; Doxorubicin; Flavonoids; Humans; Neoplasms; Paclitaxel; Piperidines; Pleural Effusion, Malignant; Proto-Oncogene Proteins c-bcl-2; Time Factors; Tumor Cells, Cultured

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Ascites; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Drug Resistance; Leukemia L1210; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Piperazines; Piperidines; Transplantation, Homologous