Pharmacokinetics of a valpromide isomer,valnoctamide, in healthy subjects

Summary The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a prodrug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.     

Oral administration of taurolidine ameliorates chronic DSS colitis in mice.

Taurolidine (TRD) has antimicrobial and anti-inflammatory properties. However, the anti-inflammatory effects of TRD in inflammatory bowel diseases (IBD) have not been investigated. Here, we have analyzed the toxicity of TRD after oral long-term application in mice and examined the impact of oral TRD in a dextran sulfate sodium (DSS) model of experimental colitis. Female C57/BL6 mice received TRD in various concentrations (0.1% to 0.4%) for 60 days. Toxicity was evaluated by use of a disease activity index (DAI) and histological examination of major metabolic organs. Furthermore, the impact of 0.2% TRD on a chronic DSS colitis was examined by daily DAI, histological crypt damage score (CDS), bacterial translocation into mesenteric lymph nodes (MLN), and colonic expression of tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, interleukin (IL)-1beta, IL-6, cytochrome oxidase (COX)-2, and monocyte chemotactic protein (MCP)-1 by real-time polymerase chain reaction (PCR). Oral TRD administration for 60 days was well tolerated by the animals and did not show any toxic effects in terms of DAI and histological changes. TRD treatment of DSS colitis led to increased survival of 100%, compared to 33% in the untreated colitis group (p < or = .005). Clinical amelioration was mirrored by significantly reduced DAI and CDS in the TRD treated colitis. Colonic cytokine expression and bacterial translocation into MLN showed no differences between both groups. We thus report for the first time that oral application of TRD results in amelioration of an experimental IBD model. We hypothesize direct intraluminal antimicrobial effects of TRD as well as anti-inflammatory effects during the acute phase of DSS colitis.     

Treatment of type B aortic dissection: endoluminal repair or conventional medical therapy?

OBJECTIVE: To evaluate the mid-term results of endovascular stent-grafting for type B aortic dissection, in comparison with those of standard medical therapy in uncomplicated cases. METHODS: Between January 1999 and 2004, among 56 patients (mean age 59.5+/-11.5 years) with type B aortic dissection, hypotensive medical therapy was the only treatment in 28 uncomplicated cases, (group A), while stent-graft implantation was performed in 28 patients with uncontrolled hypertension, persistent pain or evidence of dissection progression or complication (group B). In 14 cases (50%) the procedure was performed in an acute setting. Stent-grafting procedures were monitored with intraoperative trans-esophageal echocardiography and cine-angiography. CT scan and trans-esophageal echocardiography were performed before hospital discharge, at 6 and 12 months and then yearly. RESULTS: Follow-up (range 1-61 months, average 18.1+/-16.9 months) was 100% complete. In-hospital mortality was 10.7% (three patients, all belonging to Group B; P=0.24). No spinal cord injuries were observed. Early endoleak occurred in one patient (3.5%). Mid-term mortality was lower in Group B, although the difference was not significant (10.7 versus 14.3% in Group A, P=0.71). Follow-up CT scans evidenced complete thrombosis of the false lumen in 75% cases in Group B, 10.7% in Group A (P=0.0001), and an aneurismal dilatation of the descending aorta in 3.5% cases in Group B, 28.5% in Group A (P=0.02). CONCLUSIONS: Although with still considerable early mortality, endovascular stent-graft implantation is an effective option for the treatment of complicated type B aortic dissection. Endovascular treatment achieved a better mid-term fate of the descending thoracic aorta than medical therapy alone, even in patients with worse preoperative conditions.     

Pulmonary Sequestration In A Child With Acute Myelold Leukemia

The article describes a relatively rare congenital anomaly that was difficult to diagnose in a 10-year-old child with acute nonlymphoblastic leukemia. Just at diagnosis of leukemia, the patient showed a pathologic chest radiograph because of a parenchymal thickening at the right lung apex. The presence of bronchopneumonia was suspected, and broad-spectrum antibiotic therapy was started with subsequent antifungal treatment for persistent fever and concurrent chemotherapy-induced marrow aplasia, which did not favor pulmonary infiltrate recovery. Continuous culture tests, including bronchial swab, proved negative for Koch-Weeks bacillus, fungal organisms, and other pathogens. Computed tomography, however, was suggestive of Aspergillus lung involvement, and apical sepmentectomy was performed. The anatomic pathologist suggested the diagnosis of intralobar sequestration. In summary, when pulmonary pathology with an excavation is found in a leukemic child, one must consider the possibility of pulmonary sequestration complicated by an infectious disease.     

Inhibition by erythromycin of the conversion of carbamazepine to its active 10,11-epoxide metabolite.

The serum levels of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were determined in seven subjects after a single dose of CBZ (400 mg) in the control state and during co-administration of erythromycin (500 mg three times daily for 10 days). Erythromycin treatment was associated with a decrease in CBZ clearance and a prolongation of CBZ half-life, while CBZ-E levels were markedly reduced. These data provide evidence that erythromycin inhibits the conversion of CBZ to its epoxide metabolite.