Apoptotic mimicry: phosphatidylserine liposomes reduce inflammation through activation of peroxisome proliferator-activated receptors (PPARs) in vivo.

BACKGROUND AND PURPOSE: Recently, there has been much attention paid to understanding the molecular mechanisms underlying apoptosis and the functional consequences of apoptotic body clearance by phagocytes. In an attempt to investigate this latter aspect, the present study evaluated the anti-inflammatory effects of in vivo administration of phosphatidylserine (PS) liposomes, a well-characterised membrane component expressed during apoptosis. The participation of peroxisome proliferator-activated receptors (PPARs) in PS-mediated effects was also investigated. EXPERIMENTAL APPROACH: The anti-inflammatory effect of PS liposomes on the delayed phase of carrageenan mouse paw oedema was studied. PS liposomes were injected at different doses and times, after carrageenan. Hind paws were collected for evaluation of interleukin-1beta (IL-1beta) levels, myeloperoxidase (MPO) and N-acetyl-glucosaminidase (NAG) activities and Evans blue dye leakage. Participation of PPAR pathways was explored by using PPAR antagonists (BADGE and GW9662). KEY RESULTS: Administration of PS, but not phosphatidylcholine (PC), liposomes (20-200 mg kg(-1), i.p., 8 h after carrageenan) reduced the paw oedema in a dose-dependent manner. PS liposomes were effective even when administered 24 and 48 h after carrageenan, a time at which indomethacin (1 mg kg(-1), i.p.) had no significant effects. Carrageenan-induced Evans blue leakage and IL-1beta production was decreased in PS-treated paws. The PPAR antagonists (BADGE and GW9662) partially prevented the anti-inflammatory effects of PS administration. CONCLUSIONS AND IMPLICATIONS: PS liposomes have anti-inflammatory effects in vivo that are at least partly dependent on PPAR activation. Therapeutic strategies mimicking apoptosis may be useful for the treatment of inflammatory disorders.

Continuous infusion versus bolus injection of loop diuretics in congestive heart failure.

BACKGROUND: Loop diuretics, when given as intermittent bolus injections in acutely decompensated heart failure, may cause fluctuations in intravascular volume, increased toxicity and development of tolerance. Continuous infusion has been proposed to avoid these complications and result in greater diuresis, hopefully leading to faster symptom resolution, decrease in morbidity and possibly, mortality. OBJECTIVES: To compare the effects and adverse effects of continuous intravenous infusion of loop diuretics with those of bolus intravenous administration among patients with congestive heart failure Class III-IV. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003) and the HERDIN database. We also contacted pharmaceutical companies . SELECTION CRITERIA: Randomized controlled trials comparing the efficacy of continuous intravenous infusion versus bolus intravenous administration of loop diuretics in congestive heart failure were included DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study eligibility, methodological quality and did data extraction. Included studies were assessed for validity. Authors were contacted when feasible. Adverse effects information was collected from the trials. MAIN RESULTS: Eight trials involving 254 patients were included. In seven studies which reported on urine output, the output (as measured in cc/24 hours) was noted to be greater in patients given continuous infusion with a weighted mean difference (WMD) of 271 cc/24 hour (95%CI 93.1 to 449; p<0.01). Electrolyte disturbances (hypokalemia, hypomagnesemia) were not significantly different in the two treatment groups with a relative risk (RR) of 1.47 (95%CI 0.52 to 4.15; p=0.5). Less adverse effects (tinnitus and hearing loss) were noted when continuous infusion was given, RR 0.06 (95%CI 0.01 to 0.44; p=0.005). Based on a single study, the duration of hospital stay was significantly shortened by 3.1days with continuous infusion WMD -3.1 (95%CI -4.06 to -2.20; p<0.0001) while cardiac mortality was significantly different in the two treatment groups, RR 0.47 (95% CI 0.33 to 0.69; p<0.0001). Based on two studies, all cause mortality was significantly different in the two treatment groups, RR 0.52 (95%CI 0.38 to 0.71; p<0.0001). AUTHORS' CONCLUSIONS: Currently available data are insufficient to confidently assess the merits of the two methods of giving intravenous diuretics. Based on small and relatively heterogenous studies, this review showed greater diuresis and a better safety profile when loop diuretics were given as continuous infusion. The existing data still does not allow definitive recommendations for clinical practice and larger studies should be done to more adequately settle this issue.

Continuous infusion versus bolus injection of loop diuretics in congestive heart failure.

BACKGROUND: Loop diuretics, when given as intermittent bolus injections in acutely decompensated heart failure, may cause fluctuations in intravascular volume, increased toxicity and development of tolerance. Continuous infusion has been proposed to avoid these complications and result in greater diuresis, hopefully leading to faster symptom resolution, decrease in morbidity and possibly, mortality. OBJECTIVES: To compare the effects and adverse effects of continuous intravenous infusion of loop diuretics with those of bolus intravenous administration among patients with congestive heart failure Class III-IV. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003) and the HERDIN database. We also contacted pharmaceutical companies. SELECTION CRITERIA: Randomized controlled trials comparing the efficacy of continuous intravenous infusion versus bolus intravenous administration of loop diuretics in congestive heart failure were included DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study eligibility, methodological quality and did data extraction. Included studies were assessed for validity. Authors were contacted when feasible. Adverse effects information was collected from the trials. MAIN RESULTS: Eight trials involving 254 patients were included. In seven studies which reported on urine output, the output (as measured in cc/24 hours) was noted to be greater in patients given continuous infusion with a weighted mean difference (WMD) of 271 cc/24 hour (95%CI 93.1 to 449; p<0.01). Electrolyte disturbances (hypokalemia, hypomagnesemia) were not significantly different in the two treatment groups with a relative risk (RR) of 1.47 (95%CI 0.52 to 4.15; p=0.5). Less adverse effects (tinnitus and hearing loss) were noted when continuous infusion was given, RR 0.06 (95%CI 0.01 to 0.44; p=0.005). Based on a single study, the duration of hospital stay was significantly shortened by 3.1days with continuous infusion WMD -3.1 (95%CI -4.06 to -2.20; p<0.0001) while cardiac mortality was not significantly different in the two treatment groups, RR 0.47 (95% CI 0.33 to 0.69; p<0.0001). Based on two studies, all cause mortality was not significantly different in the two treatment groups, RR 0.52 (95%CI 0.38 to 0.71; p<0.0001). REVIEWER'S CONCLUSIONS: Currently available data are insufficient to confidently assess the merits of the two methods of giving intravenous diuretics. Based on small and relatively heterogenous studies, this review showed greater diuresis and a better safety profile when loop diuretics were given as continuous infusion. The existing data still does not allow definitive recommendations for clinical practice and larger studies should be done to more adequately settle this issue.

[Vegetable protein diets with or without non-absorbable antibiotics for the treatment of chronic portal systemic encephalopathy]. / Son necesarios los antibioticos inabsorbibles en pacientes con encefalopatía hepática manejados con dieta de proteínas vegetales?

Five patients with mild chronic portal systemic encephalopathy (PSE) were studied. The study was designed in a double cross over fashion in which each patient received during period I a 40 g vegetable protein diet as single treatment. During period II three g/day of oral kanamycin were added and then new periods of single vegetable protein diet (period III) and vegetable protein diet plus kanamycin (period IV) were introduced (identical to periods I and II respectively). Each period lasted two weeks. Several biweekly assessements-tests were determined including: mental state, asterixis grade, electroencephalograms, number connection tests, figure connection tests, blood ammonia levels and stool counts of total aerobes/anaerobes per g/feces were done. During the study none of the patients developed acute encephalopathy. In any case it was detected a significant improvement of the PSE parameters assessed with the addition of oral kanamycin. Fecal counts were very similar during the various periods of the study. We conclude that in mild portal systemic encephalopathy controlled with vegetable protein diet, the addition of non absorbable antibiotics is not mandatory for the management of these patients and may represent a potential risk of serious side effects. At the beginning of treatment vegetable protein diet should be administered and only in case of failure, antibiotics are to be indicated.