Docosahexaenoic acid supplementation in lactating women increases breast milk and plasma docosahexaenoic acid concentrations and alters infant omega 6:3 fatty acid ratio.

This study investigated the effects of docosahexaenoic acid (DHA) supplementation on the fatty acid composition of breast milk and plasma concentrations in lactating women and their infants. Eighty-nine lactating women 4-6 weeks post-partum received placebo, 200 mg or 400 mg DHA for 6 weeks with usual diets. Breast milk fatty acids and maternal plasma fatty acids were measured at the beginning and end of the study and infant plasma at the end of the study. Breast milk and maternal plasma DHA were significantly greater with 200 mg and 400 mg DHA compared with placebo (50% and 123% breast milk p<0.05; 71% and 101% plasma, p<0.0001), respectively. Infant plasma omega 6:3 and arachidonic acid (AA):DHA were significantly greater in the placebo group compared to both supplement groups (67% and 106%; 71% and 116%, respectively, p<0.05). DHA supplementation impacts infant fatty acids important for brain development and breast milk fatty acid composition.

A dose-ranging study of ranitidine and its effect on intragastric and intra-oesophageal acidity in subjects with gastro-oesophageal reflux disease.

METHODS: This randomized, double-blind, single-centre, crossover study was designed to assess the effects of three regimens of ranitidine (150 mg b.d., 300 mg b.d. and 300 mg q.d.s.) and placebo on intra-oesophageal and intragastric pH in subjects with gastro-oesophageal reflux disease (GERD). Twenty-six subjects were screened, and 9 were evaluable by the admission criteria. These 9 subjects received each of the regimens for 72 h, and a wash-out period of at least 48 h followed each dosing period. Standard meals and beverages were provided. RESULTS: With increasing doses of ranitidine, 24-h intragastric mean H+ and integrated H+ fell, and the percentage of the time the pH was equal to or greater than 4 (% time pH > or = 4) rose: the minimum effective dose for these effects was ranitidine 300 mg daily. With increasing doses of ranitidine there was also a progressive decline in mean 24-h intra-oesophageal H+ and integrated H+, and increasing % time pH > or = 4. The minimal effective dose was 300 mg daily for intra-oesophageal mean H+ and integrated H+, and 600 mg for % time pH > or = 4. The minimal effective dose to decrease the number of reflex episodes was 1200 mg ranitidine. For the daytime upright position, a dose effect of increasing ranitidine was also seen, with minimal effective ranitidine doses of 300 mg for a decrease in mean H+, and 1200 mg for % time pH > or = 4. CONCLUSION: If these higher doses of ranitidine are confirmed to be more effective than the standard 150 mg b.d. regimen for the treatment of patients with gastro-oesophageal reflux disease, then the mechanism of this action probably relates to the lower exposure of the oesophageal mucosa to acid.

A single night-time dose of famotidine is equivalent to ranitidine in decreasing 24-hour gastric acidity in asymptomatic duodenal ulcer subjects.

Six asymptomatic, non-smoking men with endoscopically proven duodenal ulcer disease received single nocturnal doses of placebo, 40 mg famotidine and 300 mg ranitidine each for 1 week prior to serial measurement of pH, peptic activity and serum gastrin concentrations over 24 h and of acid output. The intragastric pH fluctuated between 1.53 and 5.07 when subjects were given placebo but within 2 h of taking famotidine or ranitidine it rose to 5.57 or higher; the effect lasted for 12 h from midnight. Peptic activity fell during famotidine and ranitidine treatment and the decline was somewhat greater 8-15 h after using famotidine. Serum gastrin levels did not change materially with any treatment. The study shows the equivalent effect of standard bed-time doses of famotidine and ranitidine on intragastric pH, acid output and serum gastrin concentrations in asymptomatic men with duodenal ulcer disease.

Diurnal variation in the pharmacokinetics of nizatidine in healthy volunteers and in patients with peptic ulcer disease.

Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross-over fashion. Steady-state serum nizatidine concentrations and gastric pH were measured over a 24-hour period. No significant differences in the pharmacokinetic indices were observed between the healthy volunteers and patients with duodenal ulcer disease. In patients with duodenal ulcers, significantly lower peak serum concentrations, longer half-life (t1/2) and larger volume of distribution (Vd) were observed after the night doses compared with the daytime doses. The diurnal variation in drug kinetics between the nighttime and daytime doses in the twice daily regimen may be caused by a slower absorption rate, paralleled with a higher extent of distribution. Despite lower serum nizatidine concentrations, gastric pH was higher in the evening than in the daytime; it is speculated that this was due to a time-dependent enhanced distribution of the H2-receptor blocker into the site of action.

Hypothalamic norepinephrine synthesis rate in overfed, underfed and fasted mice.

Hypothalamic norepinephrine (NE) synthesis rate during acute (1-day and 3-day) and chronic (11-day) overfeeding (14 kcal/day) and underfeeding (7 kcal/day) and 24 hr food deprivation was determined in four-week-old female mice. Mice were fed ad lib quantity or 51% of ad lib in a meal-feeding paradigm, a 60% fat diet providing constant protein intake across groups. NE synthesis rate, during the thermic effect of a meal, was calculated from the rate of NE accumulation after monoamine oxidase inhibition by pargyline and clorgyline. Acute and chronic underfeeding versus overfeeding had no effect on NE synthesis rate in the hypothalamus or in the rest of brain, or chronically in hypothalamic nuclei. In mice deprived of food for 24 hr, NE synthesis rate in the paraventricular nucleus only was five-fold higher than in fed mice. Thus, NE synthesis rate within the hypothalamus appears to be more related to short-term food intake regulation than to the thermic effect of eating or body fat content.

Pharmacokinetics of ampicillin during parenteral nutrition.

Seven healthy volunteers (four males, 20-28 years) were studied to determine the effect of parenteral nutrition (PN) on ampicillin clearance. Each volunteer received intravenous infusions of 1 liter of PN (3.75% amino acid and 10% dextrose) alternating with 1 liter of 10% dextrose (containing all additives as PN except for calcium and phosphorus); and a meal containing similar fluid volume, caloric, protein, and sodium content as the PN solution. Ampicillin (250 mg) was given intravenously 2 hr after commencement of each intravenous solution and 4 hr after the meal. During PN infusion, the mean (+/- SE) glomerular filtration rate (GFR) as indicated by creatinine clearance was 125 +/- 18 ml/min; ampicillin pharmacokinetic data included area under the serum ampicillin concentration-time curve of 899 +/- 118 micrograms min/ml, terminal elimination half life of 37 +/- 4.3 min, volume of distribution at steady state of 11.9 +/- 1.6 liter, total body clearance of 4.7 +/- 0.6 ml/min/kg, renal clearance of 3.8 +/- 0.5 ml/min/kg, and 82 +/- 6.7% of the ampicillin administered was excreted in urine over 10 hr. The results were not significantly altered by different nutrient regimens or the order of infusion of intravenous solutions. We conclude that the use of PN is unlikely to affect the pharmacokinetics of ampicillin provided the renal functions including GFR, remain unchanged.

Trace element contamination of total parenteral nutrition. 2. Effect of storage duration and temperature.

BACKGROUND: Patients who receive home total parenteral nutrition (TPN) frequently are supplied with solutions up to 30 days in advance of anticipated use. The purpose of this study was to determine the stability of trace elements relative to time and temperature conditions, in a typical adult TPN solution stored in a usual home environment by examining variations in delivery of intended trace elements and inadvertent trace element contamination. METHODS: Trace element concentrations were determined using inductively coupled plasma-mass spectrometry technology. The effect of the delivery apparatus, storage duration (36 hours or 30 days) after compounding, and storage temperature (4 degrees C or 20 degrees C) were examined. RESULTS: The delivery apparatus contaminated the delivered TPN solution with cobalt but did not alter trace elements formulated into the TPN solution. Storage duration and temperature significantly decreased three (Zn, Cu, and Mn) of the six trace elements formulated into the TPN solution. Higher temperatures and longer duration of storage accelerated this decrease. Boron, Al, V, Ti, Ba, Sr, and CO were the trace elements that appeared as contaminants during storage. Boron, Al, V, and Ti contamination decreased with higher temperatures and longer duration of storage. CONCLUSIONS: Longer storage duration and higher storage temperature progressively reduced the deliverable concentrations of trace elements specifically formulated into the TPN solution and also of those trace elements that were not formulated into the TPN solution but that appeared as contaminants.

Trace element contamination of total parenteral nutrition. 1. Contribution of component solutions.

BACKGROUND: Trace elements have been shown to contaminate total parenteral nutrition (TPN) solutions. METHODS: This study used the multi-elemental technology of inductively coupled plasma-mass spectrometry to demonstrate the extent to which trace elements were present in amounts above (ie, as contaminants) or below expected levels in eight TPN component solutions. RESULTS: Of the 66 trace elements scanned, there were 12 trace element contaminants in amounts >1 microg/L (zinc, copper, manganese, chromium, selenium, boron, aluminum, titanium, barium, vanadium, arsenic, and strontium) in the eight component solutions studied. Trace element contaminants were present in all solutions, and different trace elements contaminated the solutions at various concentrations. Component solutions of amino acid, potassium chloride, calcium gluconate, and sodium chloride contained the greatest numbers of trace element contaminants, whereas the lowest numbers were present in sterile water and magnesium sulfate. Interlot and intermanufacturer variations were apparent. Measured concentrations of trace elements in the multi-trace element additive solution also were higher than the labeled values. A comparison of the amounts of contaminated trace elements delivered by a typical TPN mixture relative to the amounts typically absorbed by the gastrointestinal tract indicates that the inadvertent delivery of trace elements from contaminated TPN solutions may be substantial. CONCLUSIONS: All eight components tested were contaminated with trace elements not intended to be present in the product, and similarly, the multi-trace element component contained trace elements either above or below that which the label claimed.

Extent of trace-element contamination from simulated compounding of total parenteral nutrient solutions.

The extent and sources of trace-element contamination during simulated manual and automated compounding of total parenteral nutrient (TPN) solutions were studied. Four experimental groups were prepared: (1) sterile water for injection as received from the manufacturer, (2) TPN bags manually filled with sterile water for injection, (3) TPN bags automatically filled with sterile water for injection, and (4) sterile water for injection manually added directly to sample vials (i.e., bypassing the TPN bag). After the bags had been stored for 16 hours at 4 degrees C, samples were analyzed for 66 trace elements by inductively coupled plasma-mass spectrometry. Of the 66 trace elements analyzed for, 3 (zinc, boron, and aluminum) were present as contaminants in each of the experimental groups. Very low background concentrations of zinc, boron, and aluminum were found to contaminate the sterile water as received from the manufacturer. Simulated compounding (manual or automated) in TPN bags did not contribute additional boron or aluminum but did result in a mean total zinc concentration of 35.4 micrograms/L; of this, 12.4 micrograms/L came from the compounding equipment, 9.1 micrograms/L from the TPN bag, and 13.9 micrograms/L from the sterile water for injection. Although the amount of zinc contributed by compounding was significantly higher than the background level, the amount was inconsequential compared with that needed to satisfy physiological requirements. Simulated compounding of TPN solutions either manually or with an automated system contributed minimal trace-element contamination.

Effect of nizatidine and ranitidine on 24 hour intragastric pH, pepsin, prostaglandin E2 and serum gastrin concentrations in healthy volunteers.

In order to achieve possible greater therapeutic efficacy, ranitidine 300 mg bid (R2) may be given rather than 300 mg qhs (R1), or nizatidine 300 mg bid (N2) may be given rather than 300 mg qhs (N1). A randomized placebo-controlled crossover study was performed in six healthy volunteers (four males, two females) who ranged in age from 23 to 43 years, comparing R1, R2, N1 and N2 versus placebo (P), measuring 24 h intragastric pH by the aspiration technique, gastric juice pepsin and prostaglandin E2 (PGE2) concentrations, as well as serum gastrin concentrations. In all treatment groups, 24-h intragastric pH was higher than with P; the 24 h and daytime (0800-2200 h) pH was higher with N2 than with N1, but not with R2 versus R1. The percentage pH > or = 3 was greater with N2 than with N1 during the daytime. Night-time (2200-0800 h) and 24 h pepsin concentrations were higher in R2 than in R1, were similar in N1 and N2, and were lower in these treatment groups than in P. The gastric juice PGE2 concentration at night-time, but not at daytime, was increased in the four treatment groups compared with P. Despite the higher pH values at night-time in the treatment groups, the night-time concentrations of serum gastrin were unchanged, and yet during the daytime the higher values of pH were associated with increased gastrin concentrations when R2 or N2 were given, but not with R1 and N1. There was a negative correlation between intragastric juice pH and pepsin concentration during the daytime, and a positive correlation between pH and PGE2 concentration during the night-time. The slopes and y-axis intercepts between pH and pepsin or PGE2 concentrations differed between the placebo and the treatment groups, suggesting that these H2-receptor antagonists may have an effect on lowering pepsin and raising PGE2 concentrations in addition to their effects on pH. As the percentage of time over the 24 h period and night-time periods when the pH was greater than 3 was not different between ranitidine and nizatidine, the two regimens will likely have similar clinical efficacy.

Effect of intravenous and oral omeprazole on 24-hour intragastric acidity in duodenal ulcer patients.

Nine patients with duodenal ulcer were on separate occasions given omeprazole, 20 mg orally, 10 mg intravenously (IV), and 40 mg IV once daily for 5 days. On day 1, the median reduction of 24-hour intragastric acidity was 42.2% for the 20-mg oral dose and 54.8% and 88.4% for the two IV doses, respectively, but the between-patient variability was considerable for all three doses. On day 5, the degree of reduction had increased for all three doses to a median value of 99.9% for the 20-mg oral dose and 95.7% and 99.9% for the two IV doses, respectively. Plasma omeprazole concentrations increased significantly from day 1 to day 5 only for the 20-mg oral and 40-mg IV doses. Thus, the increased pharmacological effect of omeprazole during repeated once daily administration can only partly be explained by increased plasma concentrations, suggesting that some additional factor(s) must influence the degree of reduction of 24-hour intragastric acidity. Thus, when determining the optimal dose of omeprazole for acid inhibition, the route and duration of administration must be taken into consideration; after 5 days of once-daily administration of doses as low as 10 mg IV and 20 mg orally are effective and dependable in reducing 24-hour intragastric acidity in patients with duodenal ulcer. However, a daily dose of 40 mg IV omeprazole is not sufficient to keep intragastric pH above 4 in all patients during the first day of treatment.

Twice daily nizatidine or ranitidine is superior to once daily dosing in elevating 24 h intragastric pH in patients with duodenal ulcer disease.

The present study was performed in six asymptomatic patients with a history of resistant duodenal ulcers in whom 24 h intragastric pH, gastric juice pepsin and PGE2 concentrations, as well as serum gastrin concentrations, were measured. We wanted to compare the effects on these parameters of a single night time (q.h.s.) dose of nizatidine 300 mg (N1), nizatidine 300 mg b.i.d. (N2), ranitidine 300 mg q.h.s. (R1) or ranitidine 300 mg b.i.d. (R2) compared with placebo (P). During the night (22.00-08.00 h), all treatments gave a higher mean pH than P, but during the day (08.00-22.00 h) the mean pH was higher than P only for patients administered R2 and N2. Doubling the dose of nizatidine (N2 vs N1) or ranitidine (R2 vs R1) increased the mean daytime pH, but had no effect on night time pH. The daytime pepsin concentration was unaffected by H2-receptor antagonists, while night time pepsin was lower with R1 and R2, but not with N1 or N2. The night time gastrin concentration was unaffected by H2-receptor antagonists; doubling the dose of the H2-receptor antagonist (R2 vs R1 and N2 vs N1) increased daytime gastrin concentration. During the night, each treatment increased PGE2 concentration by at least six-fold compared with P. Thus, where it is therapeutically indicated to achieve greater suppression of acid secretion, doubling the total daily dose by dosing with twice daily versus once daily night time nizatidine or ranitidine is efficacious.

Isolated sulfite oxidase deficiency: review of two cases in one family.

OBJECTIVE: The authors describe two cases of isolated sulfite oxidase deficiency found in one family. This is a rare autosomal-recessive disorder presenting at birth with seizures, severe neurologic disease, and ectopia lentis. It can be easily missed with metabolic screening; however, the finding of lens subluxation stresses the importance of ophthalmic assessment in making the diagnosis. DESIGN: Two observational case reports. INTERVENTION/METHODS: Ophthalmic assessment, biochemical assay for specific urinary and plasma metabolites, magnetic resonance imaging, and gene sequencing were used to make the diagnosis of the disease in the proband. The diagnosis was subsequently recognized in a previously affected sibling after the postmortem neuropathology was reviewed. Mutation analysis was performed on cultured fibroblasts from the proband to identify and categorize the specific mutation responsible for the disease in the family. From this, future prenatal detection of sulfite oxidase deficiency is possible. MAIN OUTCOME MEASURES: The diagnosis of sulfite oxidase deficiency was established in this family, enabling appropriate genetic counseling and recurrence risk estimation. RESULTS: Point mutations were found in both alleles of the sulfite oxidase gene in the proband. The first is a 623C-->A mutation, which predicts an A208D substitution, and the second is a 1109C-->A, which predicts an S370Y substitution. Both residues A208D and S370Y are critical for sulfite oxidase activity. CONCLUSIONS: Isolated sulfite oxidase deficiency is a rare heritable disease for which mutation analysis can allow accurate prenatal screening. It often is difficult to diagnose by clinical presentation alone, but the critical finding of lens subluxation accompanying seizures and diffuse neurologic disease in an infant should alert the physician to the diagnosis.

Protein status of infants with phenylketonuria undergoing nutrition management.

OBJECTIVES: The objectives of this study were to determine if Phenex-1, amino-acid modified medical food with iron maintained normal indices of protein status in infants with phenylketonuria (PKU) and to investigate factors that influence plasma amino acid concentrations. METHODS: A study was conducted for six months in 35 infants with classical PKU diagnosed in the neonatal period. Diet diaries and plasma amino acid concentrations were obtained monthly. Blood for analysis of plasma albumin, blood urea nitrogen (BUN), retinol binding protein (RBP) and transthyretin was obtained at one, three and six months of study. RESULTS: Mean (+/-SEM) total daily intake of medical food and nutrients was 79+/-4 g; 17.3+/-0.6 g protein, 660+/-18 kcal, 255+/-10 mg phenylalanine (Phe), and 1423+/-56 mg tyrosine (Tyr). Mean concentrations of plasma amino acids, except cystine (during entire study), glycine (first month) and Phe were in the normal range. Mean concentrations of plasma Phe were in the treatment range (120 to 360 micromol/L). Plasma concentrations of arginine, methionine, Phe, tryptophan, Tyr, and valine were positively correlated with intakes at various months of study. Concentrations of aspartic and glutamic acids, Phe, and Tyr were positively correlated and 17 amino acids were negatively correlated with the interval between feeding and blood draw. At six months of study, concentration of plasma albumin was 4.1+/-0.1 g/dL, RBP was 3.74+/-0.2 mg/dL, transthyretin was 17.9+/-0.9 mg/dL, and urea nitrogen was 11.9+/-0.5 mg/dL. CONCLUSION: During study, all mean plasma indices of protein status were in normal reference ranges. Phenex-1 supports normal mean plasma amino acid, albumin, RBP, transthyretin, and BUN concentrations when fed in adequate amounts.

Nutrient intake and growth of infants with phenylketonuria undergoing therapy.

BACKGROUND: Because of reports of poor growth, a study was conducted for 6 months in 35 infants with classic phenylketonuria diagnosed during the neonatal period who were fed Phenex-1 Amino Acid Modified Medical Food With Iron (Ross Products Division, Columbus, OH, U.S.A.).as their primary protein source. METHODS: Diet diaries and anthropometric measures were obtained monthly as part of a larger study in which nutrition status was evaluated. RESULTS: In 6-month-old infants, mean percentiles for crown-heel length (59.14+/-4.31 SEM), head circumference (63.88+/-4.50) and weight (71.51+/-4.25) were normal. Mean (+/- SEM) daily intake of medical food was 79+/-4 g; protein and energy intakes were 17.3+/-0.6 g and 2772+/-75.6 kJ (660+/-18 kcal). Mean daily phenylalanine and tyrosine intakes per kilogram of body weight were 40+/-1 mg and 219+/-9 mg. Intakes of protein, energy, and tyrosine were positively correlated with crown-heel length, head circumference, and weight at 3 months of study. Overall plasma phenylalanine and tyrosine concentrations during the 6-month study were 297+/-41 micromol/l and 58+/-5 micromol/l, respectively. Neither plasma phenylalanine nor tyrosine concentration was correlated with growth. CONCLUSION: Phenex-1 supports normal growth when fed in adequate amounts. These data support those of the Medical Research Council Working Party on Phenylketonuria for 3 g/kg per day of amino acids from medical food.