Direct acting inhibitors of ammoniagenesis: a role in post-TIPS encephalopathy?

A limited number of medications are typically considered for the management of hepatic encephalopathy occurring as a complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. Multiple alternative compounds aimed at disrupting ammoniagenesis are or will soon be available, though their use tends to be limited by a lack of large data sets and of clinical awareness. In this review, we provide a targeted overview of the mechanisms and availability of five anti-ammoniagenic compounds (sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate, L-ornithine L-aspartate, and ornithine phenylacetate) identified as possibly useful alternative therapeutic agents for cirrhotic encephalopathy. Three of these medications have been FDA approved for use in congenital urea cycle disorders only, while two are under active investigation for use in cirrhotic patients. In spite of limitations posed by cost and comorbidities, familiarity with these options may prove beneficial in cases refractory to conventional management.

Unusual cause of general malaise: a young woman with ornithine transcarbamylase deficiency.

A young woman presented with general malaise in relation to the metabolic condition ornithine transcarbamylase deficiency. Her ammonia level had risen to 229 µmol/L (normal range 0-59 µmol/L). She was treated using her emergency pack of intravenous medicines and made a complete response. We briefly discuss the need to make an urgent diagnosis, the 'mechanism' for checking serum ammonia levels and therapies.

Effects of indobufen and pentoxifylline on walking capacity and hemostasis in patients with intermittent claudication: results of six months of treatment.

Seventy-one patients with peripheral arterial occlusive disease (PAOD) were randomized into two groups of different treatment modalities. The diagnosis of PAOD was established by history of intermittent claudication, clinical examination, and by Doppler pressure assessment or lower extremity arteriography. After a three-month washout period, 35 patients (Group 1) started treatment with indobufen (400 mg per day) and 36 patients (Group 2) with pentoxifylline (600 mg per day). Twenty-nine patients from each group completed six months of treatment. Both of the drugs significantly improved maximal and pain-free walking distances, but the effect of indobufen was more pronounced than that of pentoxifylline. Patients with PAOD exhibited signs of hypercoagulation. Fibrinogen, D-dimer, and b-thromboglobulin concentrations did not change significantly following treatment in both of the groups. The authors observed a decrease of platelet aggregation after treatment with indobufen and a decrease of F1 + 2 fragment and PAI-1 antigen after treatment with pentoxifylline.

Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients.

A long-standing arteriovenous (A-V) fistula may develop thrombotic complications. In 20 patients on intermittent peritoneal dialysis (IPD) arteriovenous fistula was made surgically. We evaluated the efficacy of three antiplatelet drugs: Ibustrin (Group A), sulphinpyrazone (Group B) and alpha-tocopherol (Group C) in preventing thrombotic occlusion of A-V fistulas. Results of the trial indicate that the three drugs significantly reduce spontaneous platelet aggregation and ADP induced aggregation. The heparin neutralizing activity was significantly increased during treatment. Significant prolongation of bleeding time was observed only in Groups B and C. In patients receiving antiplatelet drugs no occlusion of A-V fistulas was observed. In the control group such complications occurred in 3 of the 20 patients. Our results indicate that antiplatelet drugs by inhibiting the platelet function may prevent thrombotic occlusions of A-V fistulas in IPD patients.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

BACKGROUND: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. METHODS: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. RESULTS: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. CONCLUSIONS: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

[Italian Study on Atrial Fibrillation (SIFA): status report]. / Studio Italiano Fibrillazione Atriale (SIFA): stato della ricerca.

Non-valvular atrial fibrillation increases the risk of stroke by a factor of 5 and is present in about 15% of patients with acute stroke. Its prevalence in the general population increases from 0.5% at 50-59 years to > 10% at 80-99 years. In patients with non-valvular atrial fibrillation the risk of stroke increases with age, blood pressure and other evidence of cardiac disease. In addition, non-valvular atrial fibrillation is associated with a greater early mortality and a greater risk of recurrent stroke. The anticoagulant therapy to prevent early recurrent embolism is likewise controversial. Anticoagulant therapy appears to reduce this risk, but there is the danger of accentuating hemorrhagic infarction, especially in patients with large strokes. The effectiveness of antiplatelet drugs in patients with cardioembolic stroke is also not defined. The Studio Italiano Fibrillazione Atriale (SIFA) is a multicentric, randomized trial to assess the efficacy and safety of anticoagulant, warfarin, versus antiplatelet treatment, indobufen, a reversible inhibitor of platelet cyclo-oxygenase, in the prevention of recurrent cerebral ischemia and other systemic embolisms in non-valvular atrial fibrillation patients. Patients of both sexes, aged > 30 years with non-valvular atrial fibrillation, who have presented in the last 2 weeks an ischemic cerebral event (transitory ischemic attack or non-disabling stroke) and who have given their informed consent, were eligible. Patients with hemorrhagical diseases or contraindications to anticoagulant therapy were excluded. Patients were randomly given either indobufen (400 mg/die) or oral warfarin to an international normalized ratio of 2.0-3.5. The primary end-points were: recurrence of cerebral ischemia, systemic embolisms, intracranial or fatal hemorrhage, acute myocardial infarction, vascular death.(ABSTRACT TRUNCATED AT 250 WORDS)

Thromboembolic complications and pharmacological prophylaxis in orthopaedic surgery.

Two thousand, three hundred and three patients who had undergone major orthopaedic surgery were statistically analysed for the incidence of complications comparing three regimens of prophylaxis and coexisting diseases; 2090 patients did not present postoperative complications. PTE occurred in 0.65% (one fatal). The mortality rate was 0.34% and the incidence of haemorrhage (haematoma and one gastric haemorrhage) was 3.8%. Patients treated with indobufen had a shorter hospital stay and the need for homologous blood transfusions was lower than for patients treated with calcium heparin. The rate of PTE was notably different in the three groups, being lower in the group treated with enoxaparin, although this result was not found to be statistically significant.

[The effect of indobufen on aortocoronary bypass patency after 1 week and after 1 year]. / Vliv indobufenu na pruchodnost aortokoronárních bypassu po týdnu a po jednom roce.

A randomized clinical study was conducted to compare the effect of "conventional" antiaggregation therapy (ASA plus dipyridamole) versus indobufen in patients after aortocoronary bypass (ACB) surgery. The patency of venous ACB using coronary DSA one week and one year after surgery was evaluated in 52 patients divided into two groups. The study included only ACB's with intraoperative blood flow rates < or = 40 ml/min as it is just these ACB's which are at the highest risk of early and late occlusions. While, in the ASA plus dipyridamole-treated group, occlusions were found in 11 of the 39 reconstructions (28.2%), the proportion was nine out of 37 procedures (24.3%) in the indobufen group. One year after surgery, occlusion was found in 14 out of 32 ACB's (43.7%) in the ASA plus dipyridamole group compared to 14 occlusions in 31 ACB's (45.2%) in the indobufen group. The difference in the number of occlusions between the two groups was not statistically significant. Because of some benefits of indobufen compared to ASA (shorter time of effect, superior tolerance in patients with ulceration), the former drug can be recommended for use in some indicated cases.

Long-term treatment of girls with ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase is an X-linked mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine. A deficiency of this enzyme leads to hyperammonemia and hyperglutaminemia. In boys the disease is often fatal when its onset occurs during the neonatal period, but it is milder when onset occurs later in childhood. Heterozygous girls may be normal or may have episodes of hyperammonemic encephalopathy and decline in cognitive function. We report here on the long-term outcome in girls with ornithine transcarbamylase deficiency enrolled in studies of treatments designed to activate new pathways of waste-nitrogen excretion. METHODS: We studied 32 girls (age, 1 to 17 years) with ornithine transcarbamylase deficiency who had had at least one episode of encephalopathy. The patients were assigned to treatment that consisted of sodium benzoate, alone or in combination with sodium phenylacetate or sodium phenylbutyrate, or sodium phenylbutyrate alone. Collaborating physicians provided clinical, metabolic, and developmental data at specified intervals. RESULTS: Patients treated according to these protocols had greater than 90 percent survival at five years and maintained appropriate weight for height. The frequency of hyperammonemic episodes decreased with increasing age and with sodium phenylacetate or sodium phenylbutyrate treatment. Although the mean IQ before treatment was in the low average range, 19 of the 23 girls in whom intelligence was tested longitudinally had stable test scores. CONCLUSIONS: Girls with symptomatic ornithine transcarbamylase deficiency who are treated with drugs that activate new pathways of waste-nitrogen excretion have fewer hyperammonemic episodes and a reduced risk of further cognitive decline.

[Assessment of complications of major orthopedic surgery: comparison of indobufen, calcium heparin, and low molecular heparin]. / Valutazione delle complicanze in chirurgia ortopedica maggiore: confronto tra indobufene, eparina calcica ed eparina a basso peso molecolare.

OBJECTIVE: Evaluation of incidence of postoperative thrombotic and haemorrhagic complications in autotrasfused patients undergoing blood predepositing, hemodilution, intra and postoperative blood saving and treated with indobufen, heparin calcine and low molecular weight heparin (enoxeparin). EXPERIMENTAL DESIGN: Comparative study. Length of follow up: 6 months. SETTING: Three division of Orthopaedic Surgery related to 1st Anaesthesiology and Intensive Care Unit of Rizzoli Orthopaedic Institute. PATIENTS: 980 consecutive patients admitted to hospital from 1-1-1992 to 30-6-1994 (321 males and 159 females), aged between 20 and 90 years (mean 62 +/- 11 years), with basal hemoglobin at 13.4 +/- 1.4 g/dI (range 6.7-17.9), who had undergone antithromboembolic prophylaxis with indobufen (Indo, 668), heparin calcine (CaHe, 200) and low molecular weight heparin (LMWH). INTERVENTIONS: Total hip (714) and knee (121) arthroprosthesis and hip replacements (cup 33, stem 10, cup and stem 102). MEASUREMENTS: The incidence of death, thromboembolic complications (pulmonary embolism, deep vein thrombosis), hemorrhage (hematoma and homologous transfusions), cardiac ischaemia. ANOVA and contingency tables (CT) were used for statistical. RESULTS: The absence of complications was significantly greater in patients treated with indobufen (Indo 94.3% vs CaHe 83.5% vs LMWH 85.7%, CT: p = 0.0001); the incidence of thromboembolic complications was significantly higher in patients treated with heparin calcine and low molecular weight heparin; in patients treated with heparin calcine the incidence of haemorrhagic complications was significantly higher. Due to bleeding brought about by the use of heparin calcine, one patient with coronary heart disease suffered from anemia and severe hypotensions by myocardiac infarction and cardiogenous shock which led to the patient's death. The use of homologous transfusions was significantly higher in patients treated with heparin calcine (Indo 4.2% vs CaHe 14.5% vs LMWH 4.5%, CT: p = 0.0001). CONCLUSIONS: In patients undergoing autotransfusion and hemodilution, indobufen has a lower of haemorrhagic complications compared to heparine calcine and low molecular weight heparin and it is more effective in the prevention of thrombotic complications at clinical evidence.