Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trial

Autism spectrum disorders are a neurodevelopmental disorders with reduced cortical functional connectivity relating to social cognition. Polyunsaturated fatty acids arachidonic acid (ARA) and docosahexaenoic acid (DHA) may have key role in brain network maturation. In particularly, ARA is important in signal transduction related to neuronal maturation. Supplementation with larger ARA doses added to DHA may therefore mitigate social impairment. In a 16-week, double-blind, randomized, placebo-controlled trial, we evaluated the efficacy of supplementation with large doses of ARA added to DHA (n = 7) or placebo (n = 6) in 13 participants (mean age, 14.6 [SD, 5.9] years). To examine underlying mechanisms underlying the effect of our supplementation regimen, we examined plasma levels of antioxidants transferrin and superoxide dismutase, which are useful markers of signal transduction. The outcome measures were the Social Responsiveness Scale and the Aberrant Behavior Checklist-Community. Repeated-measures analysis of variance revealed that our supplementation regimen significantly improved Aberrant Behavior Checklist-Community-measured social withdrawal and Social Responsiveness Scale-measured communication. Treatment effect sizes were more favorable for the treatment group compared with the placebo group (communication: treatment groups, 0.87 vs, placebo, 0.44; social withdrawal: treatment groups, 0.88, vs placebo, 0.54). There was a significant difference in the change in plasma transferrin levels and a trend toward a significant difference in the change in plasma superoxide dismutase levels between the 2 groups. This preliminary study suggests that supplementation with larger ARA doses added to DHA improves impaired social interaction in individuals with autism spectrum disorder by up-regulating signal transduction.     

Pharmacology in health foods: effects of arachidonic acid and docosahexaenoic acid on the age-related decline in brain and cardiovascular system function

Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are major constituents of cell membranes and play important roles in preserving physiological and psychological function. Recently, data from several studies have indicated that impairments in long-term potentiation (LTP), the process underlying plasticity in synaptic connections, are associated with a decrease in membrane ARA and DHA in aged rats; and treatment of aged rats with either of these polyunsaturated fatty acids (PUFAs) reverses age-related decrease in LTP and the decrease in membrane fatty acid concentration. This review focuses on our recent findings concerning the effects of ARA and DHA on the age-related decline in the function of the brain and cardiovascular system. ARA supplementation decreased P300 latency and increased P300 amplitude of event-related potentials in healthy elderly men. Cognitive impairments in patients with mild cognitive impairment (MCI) and patients with organic brain lesions were significantly improved with ARA and DHA supplementation. ARA and DHA supplementation also increased coronary flow velocity reserve in elderly individuals; this suggests beneficial effects of PUFAs on coronary microcirculation. In conclusion, ARA and DHA may be beneficial in preventing and/or improving age-related declines in brain and cardiovascular system function.     

Subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonate-enriched triglyceride oil (SUNTGA40S) in rats.

Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) are natural constituents found in human milk, fish oil or egg yolk. Until recently, infant formulas, though providing the essential fatty acid precursors for these PUFAs, did not contain preformed ARA or DHA. In this study the safety of SUNTGA40S as source of ARA, not only for use in infant formulas but also for nutritional products or food supplements, was evaluated in a subchronic study in Wistar rats, preceded by a 4-week pretreatment period of parental (F(0)) rats and exposure of the F(0) dams throughout mating, gestation and lactation. SUNTGA40S was administered at dietary levels of 0.5%, 1.5% and 5% (wt/wt) adjusted with corn oil to 5.76% added fat. An additional group received 3.65% (wt/wt) SUNTGA40S in conjunction with 2.11% (wt/wt) high DHA Tuna oil, providing an ARA:DHA ratio of 2.7:1. High-fat and low-fat controls received basal diet with or without 5.76% corn-oil supplement. The content, stability and homogeneous distribution of the test substances in the diet were confirmed under study conditions. The administration of SUNTGA40S, with or without DHA oil, did not affect health, growth, fertility or reproductive performance of the parental rats, nor pup characteristics (condition, weight gain, viability, number per litter or sex ratio). In the subchronic study with the offspring (F(1)) rats, no significant differences were found in condition, neurobehavioural observations, ophthalmoscopy, growth, urinalysis or macroscopic and microscopic findings between the test groups and the low-fat or the high-fat controls. In males of the 5% SUNTGA40S and the SUNTGA40S/DHA group, red blood cell counts, haemoglobin concentration and packed cell volume were lower and reticulocytes were slightly higher than in the high-fat and low-fat control groups. Cholesterol, triglycerides and phospholipids in plasma were lower than in the high-fat controls in both sexes in the 5% SUNTGA40S and the SUNTGA40S/DHA group and (for triglycerides only) in the 1.5% SUNTGA group. Due to the administration of extra dietary fat, food intake and prothrombin time (males only) were lower and alkaline phosphatase activity was higher in all the high-fat groups, including the corn-oil controls, as compared to the low-fat controls. The weight of the spleen was higher in males of the 5% SUNTGA40S and the SUNTGA40S/DHA group compared to both the low-fat and the high-fat controls. The effects noted in this study at high dose levels of SUNTGA40S are consistent with previously reported physiological responses to dietary intake of high PUFA containing oils. The present results provide evidence that SUNTGA40S is a safe source of arachidonic acid. Except during lactation when the intake in dams doubled, 5% Suntga40S in the diet was equivalent to an overall intake of approximately 3g/kg body weight/day in F(0) and F(1) animals.     

Evaluation of bioequivalency and toxicological effects of three sources of arachidonic acid (ARA) in domestic piglets

Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are routinely added to infant formula to support growth and development. We evaluated the bioequivalence and safety of three ARA-rich oils for potential use in infant formula using the neonatal pig model. The primary outcome for bioequivalence was brain accretion of ARA and DHA. Days 3-22 of age, domestic pigs were fed one of three formulas, each containing ARA at ∼0.64% and DHA at ∼0.34% total fatty acids (FA). Control diet ARA was provided by ARASCO® and all diets had DHA from DHASCO® (Martek Biosciences Corp., Columbia, MD). The experimental diets a1 and a2 provided ARA from Refined Arachidonic acid-rich Oil (RAO; Cargill, Inc., Wuhan, China) and SUNTGA40S (Nissui, Nippon Suisan Kaisha, Ltd., Tokyo, Japan), respectively. Formula intake and growth were similar across all diets, and ARA was bioequivalent across treatments in the brain, retina, heart, liver and day 21 RBC. DHA levels in the brain, retina and heart were unaffected by diet. Liver sections, clinical chemistry, and hematological parameters were normal. We conclude that RAO and SUNTGA40S, when added to formula to supply ∼0.64% ARA are safe and nutritionally bioequivalent to ARASCO in domestic piglets.     

A 3-week dietary bioequivalence study in preweaning farm piglets of two sources of docosahexaenoic acid produced from two different organisms

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are components of human breast milk and commonly added to infant formula. The first DHA-containing algal oil for infant formulas was DHASCO® produced from the microalgae Crypthecodinium cohnii. Recently, new DHA-rich oil was obtained from the microalgae Schizochytrium sp., herein named DHASCO-B. The objectives of this study were to evaluate the bioequivalence of DHASCO-B to DHASCO when administered in a blend with ARA oil and the potential effects after 3 weeks’ administration in milk replacer formula to preweaning farm piglets. DHASCO-B and DHASCO were added to formula at concentrations 0.32% and 0.96% DHA (% of total fatty acids). There were no test article-related effects of any diet on piglet growth and development (clinical observations, body weight, food consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). DHA content in plasma, RBC, heart, liver and brain showed dose-related accumulation and confirmed no differences between corresponding DHASCO-B and DHASCO groups. Therefore, dietary exposure to DHASCO-B and DHASCO was well tolerated by the preweaning piglets during the 3-week dosing period right after birth and DHASCO-B and DHASCO were bioequivalent.     

Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats.

Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm, 15,000 ppm and 75,000 ppm. An additional high-dose group received 75,000 ppm ARA-oil in combination with 55,000 ppm fish oil containing docosahexaenoic acid (DHA), at a ratio of ARA to DHA, comparable to the ratio in mother's milk of 2:1. The total levels of fat in each diet were kept constant by adding the appropriate amounts of corn oil. A concurrent control group received 130,000 ppm corn oil in the diet. An additional carrier control group was fed unsupplemented rodent diet. Administration of the test substances from 4 weeks prior to mating, throughout mating, gestation, lactation of parental (F(0)) animals and weaning of the F(1) pups did not affect fertility or reproductive performance, nor the general condition of pups, viability, sex ratio or number of pups. Pup weight gain in the ARA/DHA-oil group was lower than the controls administered equal amounts of corn oil. In the subsequent subchronic study survival, clinical signs, body weight gain and food consumption were not adversely affected by the test substances. Ophthalmoscopic examination did not reveal any treatment-related changes. There were no treatment-related effects observed up to dietary test substance concentrations of 15,000 ppm. The following statistically significant differences were found in the ARA high-dose group and /or in the ARA/DHA group compared to the corn oil control group: decreased alkaline phosphatase activity, decreases in cholesterol, triglycerides and phospholipids concentrations, increased creatinine and urea concentrations. Furthermore, these groups showed increased adrenal, spleen and liver weights. The incidence of hepatocellular vacuolation was increased in females of the ARA high-dose group and the ARA/DHA group. Oil droplets were observed in the mesenteric lymph nodes and in the intestinal villi in the ARA high-dose group and the ARA/DHA group. In addition, lipogranulomas were observed in the mesenteric lymph nodes in these groups. The observed changes in the high-dose groups may be effects of the high intake of high-fat levels, rather than specific effects of the ARA-oil. The no-observed-effect level in this study was placed at 15,000 ppm ARA-oil. This level is equivalent to approximately 970mg ARA-oil/kg body weight/day.     

Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial.

Patients with depression have been extensively reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs), including significantly low eicosapentaenoic acid and docosahexaenoic acid in cell tissue contents (red blood cell membrane, plasma, etc.) and dietary intake. However, more evidence is needed to support its relation. In this study, we conducted an 8-week, double-blind, placebo-controlled trial, comparing omega-3 PUFAs (6.6 g/day) [corrected] with placebo, on the top of the usual treatment, in 28 patients with major depressive disorder. Patients in the omega-3 PUFA group had a significantly decreased score on the 21-item Hamilton Rating Scale for Depression than those in the placebo group (P < 0.001). From the preliminary findings in this study, omega-3 PUFAs could improve the short-term course of illness and were well tolerated in patients with major depressive disorder.     

Safety evaluation of sources of docosahexaenoic acid and arachidonic acid for use in infant formulas in newborn piglets.

Human milk provides small quantities of preformed docosahexaenoic acid (DHA) and arachidonic acid (ARA), usually less than 1% of total fatty acids. Vegetable oil blends commonly used in infant formulas have, until recently, provided the essential fatty acid precursors for these long-chain polyunsaturated fatty acids (LCPUFA), but no preformed DHA and ARA. This study evaluated the safety of ingredient sources of DHA and ARA for use in infant formulas in a neonatal piglet model. Newborn piglets were allowed to suckle for 3 days and then divided into 4 feeding groups of 6 males and 6 females. Piglets were bottle-fed at frequent feeding intervals until 19 days of age. The composition of the piglet formulas was modeled after standard milk-based formulas for human infants while meeting nutritional requirements for piglets. Formulas were a control formula (no added DHA or ARA), a DHA formula providing 55 mg DHA/100 Cal, an ARA formula providing 96 mg/100 Cal ARA, and a DHA+ARA formula providing 34 mg DHA and 62 mg ARA/100 Cal. All formulas were equal in fat content and provided approximately 1000 Cal/l. The ARA-rich oil was from a fermentation product of Mortierella alpina (40 wt.% fatty acids as ARA) and DHA was from high DHA tuna oil (25 wt.% fatty acids as DHA). There were no test article related effects of DHA and/or ARA indicative of an adverse health consequence to the animals seen in the clinical signs, body weights, food consumption, clinical chemistry, hematology, organ weights or gross or histopathology. The findings in this neonatal animal study support the safety of these ingredient oil sources of DHA and ARA for use in infant formulas.     

Safety of efalizumab therapy in patients with moderate to severe psoriasis: an open-label extension of a phase IIIb trial.

BACKGROUND: Psoriasis is a chronic autoimmune disease characterized by infiltration of the dermis and epidermis by activated T cells and the hyperproliferation and abnormal differentiation of keratinocytes. It is a life-long disease with alternating periods of remission and recurrence. Efalizumab is a humanized, recombinant, T-cell targeting monoclonal antibody, approved for use in adults with chronic moderate to severe plaque psoriasis. OBJECTIVE: To assess the safety of continued or newly initiated treatment with efalizumab for up to 48 weeks in patients with psoriasis who were treated previously with efalizumab or placebo. METHODS: This study was an open-label, 48-week extension of a previously published 12-week, randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase IIIb study, carried out in the US and Canada between 24 October 2002 and 2 July 2004. Patients were followed and treated at the study clinic in an outpatient setting and also were trained to self-administer the drug at home. Patients comprising individuals with chronic moderate to severe plaque psoriasis who had completed the 12-week, placebo-controlled segment of the study were eligible for enrolment in the extension phase. Of the 686 patients enrolled in the study, 636 (92.7%) enrolled in the open-label extension of the study, 418 of whom had received 12 weeks of efalizumab therapy and 218 of whom had received 12 weeks of placebo. All patients entering the open-label phase of the study received efalizumab 1 mg/kg/wk for an additional 48 weeks, for a maximum exposure of up to 60 weeks. Safety was evaluated by an assessment of adverse events, including infections and serious adverse events. RESULTS: The rate of withdrawal due to adverse events remained low throughout the trial, ranging from 1.2% to 6.6% during the 12-week segments of the open-label extension phase of the trial. The incidence of adverse events decreased with increased exposure to efalizumab; the incidence during the initial 12 weeks of exposure to efalizumab was 79.0% compared with 72.9% for patients exposed to placebo. Patients treated with efalizumab for 13-24 weeks, 25-36 weeks, 37-48 weeks and 49-60 weeks experienced adverse events at an incidence of 66.8%, 54.3%, 49.6% and 48.5%, respectively. The incidence of serious adverse events ranged from 1.6% to 3.5% during the 12-week segments of efalizumab therapy, compared with an incidence of 3.4% for placebo-treated patients. The incidence of infection ranged from 9.9% to 14.7% during the 12-week segments of efalizumab therapy, compared with an incidence of 19.1% for placebo-treated patients. Malignancies were reported with an incidence of 相似文献   

The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis - a pilot study

Aliment Pharmacol Ther 2012; 35: 255–265

Summary

Background Primary sclerosing cholangitis (PSC) is characterised by progressive inflammatory and fibrotic destruction of the biliary ducts. There are no effective medical therapies and presently high dose ursodeoxycholic acid is no longer recommended due to significant adverse events in a recent clinical trial. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is associated with PSC in both children and adults. Since CFTR dysfunction leads to altered fatty acid metabolism, specifically reduced docosahexaenoic acid (DHA), we hypothesised that DHA supplementation might be an effective therapy for patients with PSC. Aim To determine the safety and efficacy of oral DHA supplementation for the treatment of PSC. Methods We conducted a 12 month open‐label pilot study to evaluate safety of oral DHA and its effects on serum alkaline phosphatase as a primary outcome measure in 23 patients with PSC. DHA was administered orally at 800 mg twice per day. Secondary outcomes included changes in other liver function tests and fibrosis biomarkers. Results A 1.7‐fold increase in serum DHA levels was observed with supplementation. The mean alkaline phosphatase level (±S.E.) at baseline was 357.8 ± 37.1 IU compared to 297.1 ± 23.7 IU (P < 0.05) after 12 months of treatment. There were no changes in other liver function tests and fibrosis biomarkers. No adverse events were reported. Conclusions Oral DHA supplementation is associated with an increase in serum DHA levels and a significant decline in alkaline phosphatase levels in patients with PSC. These data support the need for a rigorous trial of DHA therapy in PSC.     

Evaluation of single-cell sources of docosahexaenoic acid and arachidonic acid: 3-month rat oral safety study with an in utero phase.

Owing to the presence of the polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) and arachidonic acid (ARA) in human milk and their important biological function, several authorities recommend that they be added to infant formulas. This study assessed the safety of an algal oil rich in DHA and a fungal oil rich in ARA, blended to provide a DHA to ARA ratio similar to human milk. The oil blend was incorporated into diets and fed to rats such that they received 3, 11 and 22 times the anticipated infant exposure to DHA and ARA. Low-fat and high-fat control groups received canola oil. Rats received experimental diets over a premating interval and throughout mating, gestation and lactation. Pups born during this period (F1) consumed treatment diets from weaning for 3 months. Physical observations, ophthalmoscopic examinations, body weight, food intake, clinical chemistry, neurobehavioural evaluations and postmortem histopathology of selected tissues were performed. No statistically significant, dose-dependent adverse effects were seen in reproductive performance or fertility, nor in the neonates from birth to weaning. Mid- and high-dose treated F1 animals exhibited increased white cell count, neutrophil count and blood urea nitrogen; increased liver and spleen weights (absolute and relative to body weight) also were observed. There were no corresponding microscopic findings. The clinical pathology and organ weight differences at these treatment levels represent physiological or metabolic responses to the test substance rather than adverse responses. These single-cell oils produced no adverse effects in rats when administered in utero and for 90 days at dietary levels resulting in exposures up to 22 or 66 times higher than those expected in infant formulas when extrapolated on the basis of diet composition (g/100 Cal) or intake (g/kg body weight), respectively.     

Amitriptyline in the treatment of anorexia nervosa: a double-blind, placebo-controlled study

The tricyclic antidepressant drug amitriptyline was evaluated as a short-term treatment of anorexia nervosa patients. In a 5-week double-blind, placebo-controlled study 11 patients were given amitriptyline and 14 received placebo. In addition, 18 patients who refused to participate in the drug trial and received only psychosocial treatment were used as an additional comparison group. Overall, patients in the three groups showed little improvement. No statistically significant differences favoring amitriptyline were found in any of the outcome variables. Plasma levels varied widely among patients receiving similar doses. No association was found between plasma levels and improvement in either psychiatric symptomatology or weight. Amitriptyline patients did not manifest any tendency for a reduction of depressive symptomatology. In addition, amitriptyline treatment was associated with substantial discomfort and adverse affects.     

Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity

Propranolol may reduce symptoms of autonomic arousal associated with early cocaine abstinence and improve treatment outcome. This trial was an 8-week, double-blind, placebo-controlled trial of propranolol in 108 cocaine dependent subjects. The primary outcome measure was quantitative urinary benzoylecgonine levels. Secondary outcome measures included treatment retention, addiction severity index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events. Propranolol treated subjects had lower cocaine withdrawal symptom severity but otherwise did not differ from placebo treated subjects in any outcome measure. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol in comparison to placebo. In these subjects, propranolol treatment was associated with better treatment retention and lower urinary benzoylecgonine levels as compared with the placebo treatment. Propranolol may be useful only for the treatment of cocaine dependent patients with severe cocaine withdrawal symptoms.     

Pimozide Augmentation of Clozapine Inpatients with Schizophrenia and Schizoaffective Disorder Unresponsive to Clozapine Monotherapy

Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.     

Omega-3 fatty acid monotherapy for pediatric bipolar disorder: a prospective open-label trial.

BACKGROUND: To test the effectiveness and safety of omega-3 fatty acids (Omegabrite(R) brand) in the treatment of pediatric bipolar disorder (BPD). METHOD: Subjects (N=20) were outpatients of both sexes, 6 to 17 years of age, with a DSM-IV diagnosis of BPD and Young Mania Rating Scale (YMRS) score of >15 treated over an 8-week period in open-label trial with omega-3 fatty acids 1290 mg-4300 mg combined EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). RESULTS: Subjects experienced a statistically significant but modest 8.9+/-2.9 point reduction in the YMRS scores (baseline YMRS=28.9+/-10.1; endpoint YMRS=19.1+/-2.6, p<0.001). Adverse events were few and mild. Red blood cell membrane levels of EPA and DHA increased in treated subjects. CONCLUSIONS: As only 35% of these subjects had a response by the usual accepted criteria of >50% decrease on the YMRS, omega-3 fatty acids treatment was associated with a very modest improvement in manic symptoms in children with BPD.     

Up in Smoke? A Preliminary Open-Label Trial of Nicotine Replacement Therapy and Cognitive Behavioral Motivational Enhancement for Smoking Cessation Among Youth in Los Angeles

In 2008–2009, we conducted a 6-week, open-label trial of transdermal nicotine replacement therapy and practical counseling for 34 adolescents seeking smoking cessation in Los Angeles. Dependent outcomes were study retention, use of the patch, and 7-day quit status at the end-of-study and at follow-up visits. Predictors of outcomes included cigarette dependence, withdrawal symptoms, demographic and psychiatric measures, and other substance use. Variables significant in bivariate analysis (p < .10) were retained in a multivariate model. Subjects had significant pre-to-post reductions in quit rates, dependence, and withdrawal symptoms. Subjects also reported a high number of comorbidities. Implications for clinicians are discussed.     

A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome

A 6-week placebo-controlled trial evaluated the efficacy of trazodone hydrochloride for the relief of chronic low back pain. Forty-two subjects (22 trazodone, 20 placebo) with a 20.3-year average history of back pain were titrated to an average dose of trazodone 201 mg or placebo 238 mg and evaluated daily on a Visual Analogue Scale of pain intensity, at 2-week intervals on an observer rating of pain behavior while walking, and before and after the trial on the Beck Depression Inventory, the Sickness Impact Profile, and a solid state microcomputer (Vitalog) that measured physical activity. Trazodone blood levels and urine toxicology screens were also obtained. There were no significant differences between groups in treatment effect. The results of this study require confirmation by longer trials with larger, less chronic, more homogeneous samples at higher doses with follow-up assessments.     

Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence

BACKGROUND: Slow-release oral morphine (SROM) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. However, the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population. METHODS: In 14 methadone maintenance patients reporting adequate (holders, n=7) or inadequate (non-holders, n=7) withdrawal suppression between doses, plasma drug concentrations and indices of opioid effect (withdrawal severity, pupil diameter, and respiratory rate) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM (once-daily Kapanol) using an open-label, crossover design. RESULTS: Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations, which peaked later for morphine compared to (R)-methadone (6.5 +/- 2.3 h vs. 2.5 +/- 1.4 h, P<0.001). For methadone non-holders, the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone (3.4 +/- 2.6 vs. 9.0 +/- 3.2, P<0.01); for holders it was approximately equal (4.4 +/- 3.0 vs. 4.0 +/- 3.7, P<0.76). Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication. Twelve of the 14 subjects preferred SROM to methadone (P=0.01). CONCLUSIONS: The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence, particularly for patients responding poorly to methadone maintenance treatment.     

Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized,placebo-controlled trial

Short-chain fatty acids (SCFAs) are products of microbial fermentation of dietary fiber in the colon and may mediate microbiota-gut-brain communication. However, their role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is not mechanistically studied in humans. In this triple-blind, randomized, placebo-controlled intervention trial, we examine in a parallel group design the effects of 1-week colonic SCFA-mixture delivery in doses equivalent to fermentation of 10 g or 20 g of arabinoxylan oligosaccharides on responses to psychosocial stress and fear tasks in 66 healthy men. We demonstrate that low and high doses of SCFAs significantly attenuate the cortisol response to psychosocial stress compared to placebo. Both doses of SCFAs increase serum SCFA levels and this increase in circulating SCFAs co-varies significantly with the attenuation of the cortisol response to psychosocial stress. Colonic SCFA delivery does not modulate fecal SCFA concentrations, serum brain-derived neurotrophic factor, cortisol awakening response, fear learning and extinction, or subjective mood ratings. These results demonstrate that colon-delivered SCFAs modulate hypothalamic-pituitary-adrenal axis reactivity to psychosocial stress, thereby supporting their hypothesized role in microbiota-gut-brain communication.Subject terms: Human behaviour, Emotion, Fear conditioning, Stress and resilience, Translational research     

Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study

OBJECTIVE: The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated. METHODS: In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography. RESULTS: FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet. CONCLUSION: This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.