Preventing the Progression of Intestinal Failure-Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid.

BACKGROUND: To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL). STUDY DESIGN: Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin. RESULTS: Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment ( P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups. CONCLUSIONS: Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.

From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction.

Pharmacologic agents for CNS disorders are often inhibitors that occupy receptors, with frequent unavoidable side effects likely due to continuous binding. This review summarizes development of a novel aldehyde dehydrogenase 2 (ALDH2) inhibitor that specifically targets unique drug related episodic surges in dopamine (DA), a pathophysiologic mechanism that appears to underlie much of drug-seeking behavior. We have synthesized highly selective novel ALDH2 inhibitors (ALDH2i) that block alcohol- and cocaine cue-induced surges in nucleus accumbens (NAc) DA and prevent reinstatement of alcohol heavy drinking, cocaine self-administration and reinstatement of cocaine relapse-like behavior. The mechanism of action of ALDH2i depends on inhibiting dopamine aldehyde (DOPAL) clearance by ALDH2, enabling unmetabolized DOPAL to condense with DA to generate tetrahydropapaveroline (THP). THP selectively inhibits the activated (phosphorylated) tyrosine hydroxylase (TH) to suppress DA synthesis. Selective inhibition of ALDH2 appears to have therapeutic potential for treating cue-induced drug relapse, a major unmet need for treating addicted subjects.

Expert beliefs regarding novel lipid-based approaches to pediatric intestinal failure-associated liver disease.

OBJECTIVE: To determine expert beliefs regarding the probability of intestinal failure-associated liver disease (IFALD) with novel lipid-based approaches (lipid minimization/ω-3 lipids) in managing IFALD to facilitate Bayesian analyses of clinical trials of these therapies. STUDY DESIGN: Structured interviews were conducted using a validated approach to belief elicitation with 60 intestinal failure (IF) experts from across North America. Participants were asked to estimate, in an average population of infants referred for management of IF with early IFALD, the probability of advanced IFALD at 3 months following referral in each of 3 scenarios: (1) conventional lipid, (2) ω-3 lipids, and (3) lipid minimization. Probability distributions of the risk of advanced IFALD with each strategy were developed. Distributions of the elicited treatment effect for the novel approaches, relative to conventional lipid, were calculated. RESULTS: Median duration of experience of participants managing patients with IF was 8.5 (range, 2-35) years. The median probability of advanced IFALD using conventional lipid was 32.5%; ω-3 lipids, 17.5%; and lipid minimization, 13%. The median of the elicited treatment effects relative to conventional lipid was a relative risk of 0.53 for the ω-3 lipid and 0.45 for lipid minimization. CONCLUSIONS: There was consistent expert opinion that the novel lipid-based approaches are superior to conventional therapy, with similar estimates of treatment efficacy for the 2 approaches. The distributions of the elicited treatment effects can be used as prior distributions in Bayesian analyses of clinical trials of these novel strategies.

Novel lipid-based approaches to pediatric intestinal failure-associated liver disease.

Historically, intestinal failure-associated liver disease (IFALD) has been the greatest contributor to the morbidity experienced by children with intestinal failure. Although the cause of IFALD is multifactorial, recently much attention has been devoted to the critical role that intravenous lipid emulsions play in the development of IFALD. This attention has prompted an interest in alternate approaches to the provision of intravenous lipid in children with IFALD. The 2 approaches that have been advanced are that of lipid minimization and alternate intravenous lipid emulsions, including those containing ω-3 fatty acids. This article examines the rationale and current evidence for these approaches in children with intestinal failure. Our overall finding is that although these alternate approaches show significant promise, they have primarily been studied in uncontrolled settings, mainly in children with advanced IFALD. As such, we believe that there remains a lack of definitive evidence for their efficacy. Furthermore, important safety parameters remain to be evaluated, including the effect of these therapies on growth and development. Therefore, there is currently insufficient evidence to support the use of these novel therapies as standard of care in children with no or early IFALD with the goal of preventing the progression of liver disease.

Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

Is the use of parenteral omega-3 lipid emulsions justified in surgical neonates with mild parenteral nutrition-associated liver dysfunction?

PURPOSE: Although evidence suggests that parenteral omega-3 lipid emulsions (O-3LEs) may be beneficial in treating advanced parenteral nutrition (PN)-associated liver disease, our objective was to determine if O-3LEs are justified in those with early liver disease. METHODS: This is a retrospective analysis of prospectively collected data on all surgical neonates, who received more than 1 day of PN postoperatively between 2001 and 2004 with observation through 2005 (era before O-3LE introduction). We examined the proportion of those who developed mild and advanced liver dysfunction. RESULTS: Of the 292 infants in the cohort, 104 (36%) developed mild liver dysfunction (conjugated bilirubin, 34 micromol/L [cBili34]) after a mean of 22 days. Thirty-one (30%) of the cBili34 patients reached a serum conjugated bilirubin of 100 micromol/L, and 13 (13%) developed liver failure. Of these, 4 underwent transplantation, and 5 died of hepatic disease. Overall, 86 of the cBili34 patients (83%) were weaned off PN. CONCLUSION: With more than 80% of cBili34 patients being weaned from PN without adverse hepatic sequelae, it is difficult, in the absence of definitive evidence of efficacy and safety for O-3LEs together with increased costs, to justify the routine use of O-3LEs in this low-risk population outside formal research protocols.

Ranolazine attenuates behavioral signs of neuropathic pain.

Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain.

Omega-3 lipids for intestinal failure associated liver disease.

Intestinal failure associated liver disease (IFALD) is one of the most common and devastating complications in infants with intestinal failure. Although multifactorial, its pathophysiology is clearly related to the administration of parenteral nutrition (PN), with a recent focus on the role of PN lipid emulsions. This paper will review the evidence for the use of omega-3 fatty acid PN lipid emulsions, which are proposed to have efficacy in the treatment of IFALD. Mechanisms explaining their effects will be considered as will future research directions.

Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.

BACKGROUND: Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH-2 inhibitor might affect other metabolic factors involved in regulating drinking. METHODS: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co-crystal structure of ALDH-2 and daidzin. We tested the efficacy of a highly selective reversible ALDH-2 inhibitor, CVT-10216, in models of moderate and high alcohol drinking rats. We studied 2-bottle choice and deprivation-induced drinking paradigms in Fawn Hooded (FH) rats, operant self-administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue-induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. RESULTS: CVT-10216 increases acetaldehyde after alcohol gavage and inhibits 2-bottle choice alcohol intake in heavy drinking rodents, including deprivation-induced drinking. Moreover, CVT-10216 also prevents operant self-administration and eliminates cue-induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT-10216 prevents alcohol-induced increases in NAc DA without changing basal levels. CVT-10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. CONCLUSION: Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.

Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome.

BACKGROUND: Parenteral omega-3 fatty acids, such as Omegaven, may benefit patients with pediatric short bowel syndrome (SBS) who develop parenteral nutrition-associated liver disease (PNALD). PATIENTS AND METHODS: Retrospective cohort describing the outcome of all 12 children with SBS and advanced PNALD who were treated with Omegaven (target omega-6 to omega-3 fatty acid ratio = 1:1 to 2:1). RESULTS: The median age was 7.5 (range 3.6-46) months, and median parenteral nutrition duration before starting Omegaven was 28.4 (range 15.3-55.3) weeks. Median initial serum conjugated bilirubin was 137 (range 54-203) micromol/L (8.06 [3.18-11.94] mg/dL). Of the 12 patients, 9 had complete and sustained resolution of hyperbilirubinemia within a median of 24 (range 7-37) weeks, and all are no longer being considered for liver transplantation. Improvements in markers of hepatic inflammation as well as nutritional status also were noted in these patients. Three patients received a liver-intestine transplant while taking Omegaven. There were no complications attributable to Omegaven. CONCLUSIONS: Omegaven is associated with restoration of liver function in patients with SBS and advanced liver disease. Parenteral omega-3 fatty acids, such as Omegaven, have the potential to fundamentally alter the paradigm of neonatal SBS from one of early death or transplantation from liver failure to a more chronic disease. More children with SBS should achieve full enteral tolerance and those who do not have the capacity for intestinal adaptation should be able to survive and receive an intestinal graft when older.

The rationale for the use of parenteral omega-3 lipids in children with short bowel syndrome and liver disease.

Parenteral nutrition associated liver disease (PNALD) is the major source of morbidity and mortality in children with short bowel syndrome (SBS). There is emerging evidence that omega-6 fatty acids (omega6FA) within the parenteral solution play a major role in PNALD and their effects may be reversed or ameliorated by substitution with omega-3 fatty acids (omega3FA). This paper reviews the mechanisms whereby omega3FAs may influence PNALD by improving bile flow, inhibiting steatosis, and having immunomodulatory effects. The early clinical experience with omega3FAs in SBS and PNALD is briefly reviewed and the implications of such, and future directions are considered.

The contrast enema for Hirschsprung disease: predictors of a false-positive result.

PURPOSE: To examine predictors of a false-positive (FP) result on contrast enema (CE) for the diagnosis of Hirschsprung disease (HD). METHODS: Retrospective analysis, over a 5-year period (1999-2004), of infants (<6 months of age) with suspected HD undergoing rectal biopsy following abnormalities identified on CE (transition zone [TZ], abnormal rectosigmoid ratio, microcolon, retained contrast, or mucosal irregularity). RESULTS: One hundred twenty-nine patients underwent rectal biopsy following an abnormal CE. The FP rate was 48.5% (66 with HD). Age below 30 days (OR, 3.4; 95% CI, 1.1-10.3), female sex (OR, 3.4; 95% CI, 1.6-7.3), and absence of TZ (OR, 6.3; 95% CI, 2.6-15.3) were independently associated with an increased risk for FP on multiple variable logistic regression. A history of bilious emesis decreased the probability of FP (OR, 0.2; 95% CI, 0.06-0.5). CONCLUSIONS: Transition zone, sex, age, and bilious emesis are important predictors of FP in those with suspected HD and CE abnormalities. With 100% incidence of FP, infants younger than 30 days with neither bilious emesis nor a TZ and female infants younger than 30 days with these features may represent a subpopulation in whom rectal biopsy can be avoided.

Fundoplication and gastrostomy versus image-guided gastrojejunal tube for enteral feeding in neurologically impaired children with gastroesophageal reflux.

BACKGROUND: Neurologically impaired children with gastroesophageal reflux (GER) usually are treated with a fundoplication and gastrostomy (FG); however, this approach is associated with a high rate of complications and morbidity. The authors evaluated the image-guided gastrojejunal tube (GJ) as an alternative approach for this group of patients. METHODS: A retrospective review of 111 neurologically impaired patients with gastroesophageal reflux was performed. Patients underwent either FG (n = 63) or GJ (n = 48). All FGs were performed using an open technique by a pediatric surgeon, and all GJ tubes were placed by an interventional radiologist. RESULTS: The 2 groups were similar with respect to diagnosis, age, sex and indication for feeding tube. Patients in the GJ group were followed up for an average of 3.11 years, and those in the FG group for 5.71 years. The groups did not differ statistically with respect to most complications (bleeding, peritonitis, aspiration pneumonia, recurrent gastroesophageal reflux [GER], wound infection, failure to thrive, and death), subsequent GER related admissions, or cost. Children in the GJ group were more likely to continue taking antireflux medication after the procedure (P <.05). Also, there was a trend for GJ patients to have an increased incidence of bowel obstruction or intussusception (20.8% v 7.9%). Of the FG patients 36.5% experienced retching, and 12.7% experienced dysphagia. Eighty-five percent of patients in the GJ group experienced GJ tube-specific complications (breakage, blockage, dislodgment), and GJ tube manipulations were required an average of 1.68 times per year follow-up. Nine patients (14.3%) in the FG group had wrap failure, with 7 (11.1%) of these children requiring repeat fundoplication. In the GJ group, 8.3% of patients went on to require a fundoplication for persistent problems. A total of 14.5% of GJ patients had their tube removed by the end of the follow-up period because they no longer needed the tube for feeding. CONCLUSIONS: Image-guided gastrojejunal tubes are a reasonable alternative to fundoplication and gastrostomy for neurologically impaired children with GER. The majority can be inserted without general anesthesia. This technique failed in only 8.3% patients, and they subsequently required fundoplication. A total of 14.5% of GJ patients showed some spontaneous improvement and had their feeding tube removed. Each approach, however, still is associated with a significant complication rate. A randomized prospective study comparing these 2 approaches is needed.