Albumin synthesis in very low birth weight infants is enhanced by early parenteral lipid and high-dose amino acid administration.

BACKGROUND & AIMS: Albumin is one of the most important plasma proteins and plays a key role in many physiologic processes, such as preserving colloid osmotic pressure, scavenging radicals, and binding and transporting bilirubin, hormones, and drugs. However, albumin concentrations are often low in preterm infants during the first days of life. We hypothesized that early parenteral lipid and high-dose amino acid (AA) administration to very low birth weight (VLBW) infants from birth onwards increases hepatic albumin synthesis rates. METHODS: Inborn VLBW infants were randomized to receive from birth onwards either 2.4 g amino acids/(kg(·)d) (control group), 2.4 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (AA + lipid group), or 3.6 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (high AA + lipid group). On postnatal day 2, infants received a primed continuous infusion of [U-(13)C6,(15)N]leucine. Mass spectrometry was used to determine the fractional and absolute albumin synthesis rates (FSR and ASR, respectively). RESULTS: In total, 28 infants (median gestational age 27 weeks (IQR 25-28), median birth weight 810 g (IQR 679-998) were studied. The median FSR was 6.5%/d in the control group, 10.6%/d in the AA group, and 12.3%/d in the high AA + lipid group, while the median was 84 mg/(kg(·)d) in the control group, 138 mg/(kg(·)d) in the AA group, and 160 mg/(kg(·)d) in the high AA + lipid group. CONCLUSION: A group of VLBW infants given parenteral nutrition containing lipids and high-dose amino acids showed a higher rate of albumin synthesis compared to infants receiving no lipids and standard amounts of amino acids during the first two days of life.

Phenylalanine requirements of enterally fed term and preterm neonates.

BACKGROUND: Phenylalanine, which is an essential aromatic amino acid, is either used for protein synthesis or irreversibly hydroxylated to tyrosine. The provision of optimal amounts of dietary phenylalanine is not only important for growth and development but might also influence catecholamine synthesis and release rates. The current recommended aromatic amino acid requirement for infants aged 0-6 mo is based on the amino acid content of human milk. OBJECTIVE: We quantified the requirements for phenylalanine in the presence of excess tyrosine (166 or 177 mg/kg per day for term and preterm infants, respectively) for term and preterm neonates by using the indicator amino acid oxidation method with l-[1-(13)C]lysine 2HCl as an indicator. Hence, we determined the minimum obligatory phenylalanine requirement. DESIGN: Fully enterally fed term and preterm infants received randomly graded amounts of phenylalanine (5-177 mg/kg per day) as part of an elemental formula. Data are expressed as means ± SDs. RESULTS: Twenty term (birth weight: 3.19 ± 0.34 kg; gestational age: 38.9 ± 1 wk) and 16 preterm (birth weight: 1.75 ± 0.17 kg; gestational age: 32.5 ± 0.6 wk) Asian infants participated at a postnatal age of 17 ± 8 d. In total, 44 studies were performed. The minimum obligatory phenylalanine requirement was 58 mg/kg per day (95% CI: 38-78 mg/kg per day) and 80 mg/kg per day (95% CI: 40-119 mg/kg per day) for term and preterm infants, respectively. CONCLUSION: The determined mean phenylalanine-requirement estimates are lower than the contents of term and preterm formulas currently on the market. This trial was registered at www.trialregister.nl as NTR1610.

Threonine Requirement of the Enterally Fed Term Infant in the First Month of Life.

OBJECTIVE: Threonine is one of the essential amino acids. Its major fate is incorporation into intestinal mucosal proteins and synthesis of secretory glycoproteins. Therefore, it has an important function in the neonatal gut barrier integrity. The objective was to quantify the threonine requirement in fully enterally fed term neonates by means of the indicator amino acid oxidation (IAAO) method, using L-[1-C]phenylalanine as indicator. METHODS: After a 24-hour test diet adaptation, containing randomly assigned amounts of threonine (range 5-182 mg · kg · day), the participating neonates received a primed continuous infusion of [C]bicarbonate and L-[1-C]phenylalanine. At baseline and during the plateau phase of both infusions, breath samples were obtained for CO2. The fractional L-[1-C]phenylalanine oxidation (FCO2) was estimated and plotted against the threonine intakes. Biphasic linear regression crossover analysis was used to calculate the breakpoint of the FCO2, representing the mean threonine requirement. Data are presented as mean ±â€ŠSD. RESULTS: Thirty-two term neonates (gestational age 39 ±â€Š1 weeks, birth weight 3.3 ±â€Š0.3 kg, mean postnatal age 10 ±â€Š4 days) were studied. The mean threonine requirement was estimated to be 68 mg · kg · day with an upper and lower 95% confidence interval of 104 and 32 mg · kg · day, respectively (r = 0.37). CONCLUSIONS: The determined threonine requirement is extremely close to the existing requirement recommendations (∼90% of the present World Health Organization requirement guidelines). Infant formula preparations presently on the market, however, contain up to twice as much threonine as recommended. The threonine intake in formula-fed infants may therefore be reduced considerably.

A novel 6-mercaptopurine oral liquid formulation for pediatric acute lymphoblastic leukemia patients - results of a randomized clinical trial.

OBJECTIVE: Pediatric patients with acute lymphoblastic leukemia (ALL) are treated with oral 6-mercaptopurine (6MP) for nearly 2 years, but no pediatric formulation has been available. In this study, an oral 6MP liquid suitable for pediatric use was developed and tested in the target population. METHOD: A randomized cross-over study was performed in 20 pediatric ALL patients (age 1.9 - 14.6 years), comparing pharmacokinetics and pharmacodynamics of a newly developed 6MP liquid formulation to 6MP capsules, both taken orally for 4 weeks. RESULTS: Based upon trough levels of the principal active metabolite,6-thioguanine nucleotides (6-TGN),a relative bioavailability of the liquid vs. capsules of 1.01 was found (90% CI 0.86 - 1.20), demonstrating bioequivalence. This was supported by the similarly observed 6MP dosages needed for leucocyte depletion, for both formulations (35 mg/day (range 10 - 115 mg)). 75% of the parents/patients (p = 0.005) preferred the oral liquid over the capsules because of the ease of administration. CONCLUSION: We conclude that the novel 6MP liquid is a promising treatment for ALL.

Adaptive regulation of amino acid metabolism on early parenteral lipid and high-dose amino acid administration in VLBW infants - a randomized, controlled trial.

BACKGROUND & AIMS: An anabolic state can be achieved upon intravenous amino acid administration during the immediate postnatal phase despite a low energy intake. The optimal dosing of amino acid and energy intake has yet to be established. The aim was to quantify the efficacy of early initiation of parenteral lipids and increased amounts of amino acids on metabolism and protein accretion in very low birth weight infants. METHODS: 28 very low birth weight infants were randomized to receive parenteral nutrition with glucose and either 2.4 g amino acids/(kg·d) (control group), 2.4 g amino acids/(kg·d) plus 2-3 g lipid/(kg·d) (AA + lipid group), or 3.6 g amino acids/(kg·d) plus 2-3 g lipid/(kg·d) (high AA + lipid group) from birth onward. On postnatal day 2, we performed a stable isotope study with [1-(13)C]phenylalanine, [ring-D4]tyrosine, [U-(13)C6,(15)N]leucine, and [methyl-D3]α-ketoisocaproic acid to quantify intermediate amino acid metabolism. RESULTS: The addition of lipids only had no effect on phenylalanine metabolism, whereas the addition of both lipids and additional amino acids increased the amount of phenylalanine used for protein synthesis. In addition, high amino acid intake significantly increased the rate of hydroxylation of phenylalanine to tyrosine, increasing the availability of tyrosine for protein synthesis. However, it also increased urea concentrations. Increasing energy intake from 40 to 60 kcal/(kg·d) did not increase protein efficiency as measured by phenylalanine kinetics. The leucine data were difficult to interpret due to the wide range of results and inconsistency in the data between the phenylalanine and leucine models. CONCLUSIONS: High amino acid and energy intakes from birth onwards result in a more anabolic state in very low birth weight infants, but at the expense of higher urea concentrations, which reflects a higher amino acid oxidation. Long-term outcome data should reveal whether this policy deserves routine implementation. This trial was registered at www.trialregister.nl, trial number NTR1445, name Nutritional Intervention for Preterm Infants-2.

Branched-chain amino acid requirements for enterally fed term neonates in the first month of life.

BACKGROUND: Knowledge of essential amino acid requirements in infants is important because excessive intake of protein can lead to increased long-term morbidity such as obesity. A deficient intake may lead to suboptimal growth and impaired neurodevelopment. The current recommended branched-chain amino acid requirements in infants aged 0-1 mo are based on the amino acid content of human milk. OBJECTIVE: We quantified the requirements for isoleucine, leucine, and valine for term neonates by using the indicator amino acid oxidation method with [1-(13)C]phenylalanine as the indicator. DESIGN: Fully enterally fed term infants received randomly graded amounts of isoleucine (5-216 mg · kg(-1) · d(-1)), leucine (5-370 mg · kg(-1) · d(-1)), or valine (5-236 mg · kg(-1) · d(-1)) as part of an elemental formula. Data are expressed as means ± SDs. RESULTS: Eighty-three Asian, term neonates (mean ± SD birth weight: 3.3 ± 0.4 kg; gestational age: 39.4 ± 1.3 wk) were studied at a postnatal age of 13 ± 5 d. Mean requirements for isoleucine, leucine, and valine (measured in boys only) were 105 mg · kg(-1) · d(-1) (r(2) = 0.61, P < 0.001), 140 mg · kg(-1) · d(-1) (r(2) = 0.26, P < 0.01), and 110 mg · kg(-1) · d(-1) (r(2) = 0.35, P = 0.001), respectively. CONCLUSIONS: Current human milk-based recommendations for isoleucine and valine in term infants aged 0-1 mo are correct. However, the current recommendation for leucine (166 mg · kg(-1) · d(-1)) is higher than the mean requirement of 140 mg · kg(-1) · d(-1) that we determined in this study. This trial was registered at www.trialregister.nl as NTR1610.

Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants.

OBJECTIVE: To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. STUDY DESIGN: VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg(-1) · d(-1) (control group), or 2.4 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (AA + lipid group), or 3.6 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. RESULTS: The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. CONCLUSIONS: In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.

Methionine requirement of the enterally fed term infant in the first month of life in the presence of cysteine.

BACKGROUND: The essential amino acid methionine can be used for protein synthesis but also serves as a precursor for homocysteine and cysteine. OBJECTIVE: The objective of this study was to determine the minimal obligatory methionine requirement of infants in the presence of excess cysteine (91 mg ⋅ kg(-1) ⋅ d(-1)) by using the indicator amino acid oxidation (IAAO) method with l-[1-(13)C]phenylalanine as the indicator. DESIGN: Fully enterally fed term infants <1 mo of age were randomly assigned to methionine intakes that ranged from 3 to 59 mg ⋅ kg(-1) ⋅ d(-1) as part of an elemental formula. After 1 d of adaptation to the test diet, [(13)C]bicarbonate and l-[1-(13)C]phenylalanine tracers were given enterally. Breath samples were collected at baseline and during isotopic plateaus. The mean methionine requirement was determined by using biphasic linear regression crossover analysis on the fraction of (13)CO(2) recovery from l-[1-(13)C]phenylalanine oxidation (F(13)CO(2)). Data are presented as means ± SDs. RESULTS: Thirty-three neonates (gestational age: 39 ± 1 wk) were studied at 13 ± 6 d. With increasing methionine intakes, F(13)CO(2) decreased until a methionine intake of 38 mg ⋅ kg(-1) ⋅ d(-1); additional increases in methionine intake did not affect F(13)CO(2). The mean methionine requirement was determined at 38 mg ⋅ kg(-1) ⋅ d(-1), and the upper and lower CIs were 48 and 27 mg ⋅ kg(-1) ⋅ d(-11), respectively (P < 0.0001, r(2) = 0.59). CONCLUSIONS: Although the current recommended methionine intake of 28 mg ⋅ kg(-1) ⋅ d(-1) is within the CIs of our study, the estimated mean requirement is substantially higher. However, most of the infant formulas provide a methionine intake of 49-80 mg ⋅ kg(-1) ⋅ d(-1), which is above the upper CI of our study. This trial was registered at www.trialregister.nl as NTR1610.

Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics.

Human fetal metabolism is largely unexplored. Understanding how a healthy fetus achieves its fast growth rates could eventually play a pivotal role in improving future nutritional strategies for premature infants. To quantify specific fetal amino acid kinetics, eight healthy pregnant women received before elective cesarean section at term, continuous stable isotope infusions of the essential amino acids [1-13C,15N]leucine, [U-13C5]valine, and [1-13C]methionine. Umbilical blood was collected after birth and analyzed for enrichments and concentrations using mass spectrometry techniques. Fetuses showed considerable leucine, valine, and methionine uptake and high turnover rates. α-Ketoisocaproate, but not α-ketoisovalerate (the leucine and valine ketoacids, respectively), was transported at net rate from the fetus to the placenta. Especially, leucine and valine data suggested high oxidation rates, up to half of net uptake. This was supported by relatively low α-ketoisocaproate reamination rates to leucine. Our data suggest high protein breakdown and synthesis rates, comparable with, or even slightly higher than in premature infants. The relatively large uptakes of total leucine and valine carbon also suggest high fetal oxidation rates of these essential branched chain amino acids.

High-dose cysteine administration does not increase synthesis of the antioxidant glutathione preterm infants.

OBJECTIVE: Our aim was to evaluate whether administration of additional cysteine is safe and stimulates glutathione synthesis in preterm infants in early life. METHODS: We conducted a prospective, randomized, clinical trial with infants with birth weights of <1500 g (N = 20). The infants were assigned randomly to receive either a standard dose (45 mg/kg per day) or a high dose (81 mg/kg per day) of cysteine. Intakes of other amino acids were similar, providing a total protein intake of 2.4 g/kg per day in both groups. We recorded base requirements in the first 6 days of life. On postnatal day 2, we conducted a stable isotope study to determine glutathione concentrations and synthesis rates in erythrocytes. RESULTS: Base requirements were higher in the high-dose cysteine group on days 3, 4, and 5. Despite an 80% increase in cysteine intake, plasma cystine concentrations did not increase. Glutathione concentrations and synthesis rates did not increase with additional cysteine administration. CONCLUSIONS: Administration of a high dose of cysteine (81 mg/kg per day) to preterm infants seems clinically safe but does not stimulate glutathione synthesis, compared with a lower dose (45 mg/kg per day). Further research is required to determine whether there is significant benefit associated with cysteine supplementation.

Human fetal amino acid metabolism at term gestation.

BACKGROUND: Knowledge on human fetal amino acid (AA) metabolism, largely lacking thus far, is pivotal in improving nutritional strategies for prematurely born infants. Phenylalanine kinetics is of special interest as is debate as to whether neonates will adequately hydroxylate phenylalanine to the semiessential AA tyrosine. OBJECTIVE: Our aim was to quantify human fetal phenylalanine and tyrosine metabolism. DESIGN: Eight fasted, healthy, pregnant women undergoing elective cesarean delivery at term received primed continuous stable-isotope infusions of [1-(13)C]phenylalanine and [ring-D(4)]tyrosine starting before surgery. Umbilical blood flow was measured by ultrasound. Maternal and umbilical cord blood was collected and analyzed by gas chromatography-mass spectrometry for phenylalanine and tyrosine enrichments and concentrations. Data are expressed as medians (25th-75th percentile). RESULTS: Women were in a catabolic state for which net fetal AA uptake was responsible for > or = 25%. Maternal and fetal hydroxylation rates were 2.6 (2.2-2.9) and 7.5 (6.2-15.5) micromol phenylalanine/(kg . h), respectively. Fetal protein synthesis rates were higher than breakdown rates: 92 (84-116) and 73 (68-87) micromol phenylalanine/(kg . h), respectively, which indicated an anabolic state. The median metabolized fraction of available phenylalanine and tyrosine in the fetus was <20% for both AAs. CONCLUSIONS: At term gestation, fetuses still show considerable net AA uptake and AA accretion [converted to tissue approximately 12 g/(kg . d)]. The low metabolic uptake (AA usage) implies a very large nutritional reserve capacity of nutrients delivered through the umbilical cord. Fetuses at term are quite capable of hydroxylating phenylalanine to tyrosine.

Human fetal albumin synthesis rates during different periods of gestation.

BACKGROUND: Despite nutritional intervention, albumin concentrations are often low in critically ill premature neonates. OBJECTIVE: Our aim was to quantify albumin synthesis rates during early life under physiologic circumstances. Human fetuses thereby reflect the developmentally related optimal condition. DESIGN: Pregnant women undergoing elective cesarean delivery received 3 different labeled amino acid infusions starting at different times before surgery. With the use of mass spectrometry techniques, this novel model enabled us to quantify fetal albumin synthesis from a single blood sample taken from the umbilical cord after cesarean delivery. The fractional synthesis rate reflects the fraction of the albumin pool that is daily renewed. The absolute synthesis rate is the absolute amount of albumin that is daily synthesized. Results are expressed as medians (25th-75th percentile). RESULTS: We studied 8 fetuses at 29.9 (28.4-35.4) weeks of gestation and 8 fetuses around term. Fractional synthesis rates in premature fetuses [17.5 (12.1-24.4) %/d] were higher (P = 0.02) than in mature fetuses [10.4 (9.1-13.7) %/d]. Absolute synthesis rates were also higher (P = 0.02) in premature than in mature fetuses: 280 (227-365) versus 205 (184-238) mg . kg(-1) . d(-1). CONCLUSIONS: On a weight basis, albumin synthesis rates in premature fetuses were higher than in fetuses at term and were higher than the rates previously found in neonates after preterm birth. Considering that the premature fetal liver can synthesize albumin at a high rate, the observed hypoalbuminemia in premature infants therefore seems to suggest that current (nutritional) therapies fail to meet requirements necessary to sustain optimum albumin synthesis rates.

Glutathione synthesis rates after amino acid administration directly after birth in preterm infants.

BACKGROUND: The availability of glutathione, the main intracellular antioxidant, is compromised in preterm neonates. A possible explanation is the low availability of substrate for synthesis, because many neonatologists are reluctant to administer amino acids in the direct postnatal period for fear of intolerance. OBJECTIVE: The objective of the study was to determine the effects of amino acid administration directly after birth on glutathione synthesis rates and markers of oxidative stress. DESIGN: Premature infants (<1500 g) received from birth onward either dextrose (control group; n = 10) or dextrose plus 2.4 g amino acids . kg (- 1) . d(-1) (intervention group; n = 10). On postnatal day 2, [1-(13)C]glycine was administered to determine glutathione fractional synthesis rates (FSR(GSH)) and absolute synthesis rates (ASR(GSH)) in erythrocytes. In plasma, advanced oxidized protein products and dityrosine, both markers of oxidative stress, were measured. The results are expressed as means +/- SDs. RESULTS: The FSR(GSH) was not different between groups: 44 +/- 6 and 48 +/- 9%/d in the control and intervention groups, respectively (P = 0.28). The concentration of erythrocyte glutathione was higher (P < 0.001) in the intervention group (2.28 +/- 0.35 mmol/L) than in the control group (1.73 +/- 0.37 mmol/L). ASR(GSH) values were 6.5 +/- 1.5 and 11.3 +/- 1.9 mg . kg(-1) . d(-1) in the control and intervention groups, respectively (P < 0.001). Advanced oxidized protein products and dityrosine concentrations were not significantly different between groups. CONCLUSIONS: Amino acid administration directly after birth increases ASR(GSH) in preterm infants. Our data are consistent, however, with higher glutathione concentrations rather than a higher FSR(GSH). Greater availability of glutathione, nevertheless, did not decrease markers of oxidative stress.

The gut takes nearly all: threonine kinetics in infants.

BACKGROUND: Threonine is an essential amino acid that is abundantly present in intestinally produced glycoproteins. Animal studies show that intestinal first-pass threonine metabolism is high, particularly during a restricted enteral protein intake. OBJECTIVE: The objective of the study was to quantify intestinal first-pass threonine metabolism in preterm infants during full enteral feeding and during restricted enteral intake. DESIGN: Eight preterm infants (x +/- SD birth weight: 1.1 +/- 0.1 kg; gestational age: 29 +/- 2 wk) were studied during 2 periods. During period A, 40% of total intake was administered enterally and 60% was administered parenterally. Total threonine intake was 58 +/- 6 micromol kg(-1) h(-1). During period B, the infants received full enteral feeding, and the total threonine intake was 63 +/- 6 micromol kg(-1) h(-1). Dual stable-isotope tracer techniques were used to assess splanchnic and whole-body threonine kinetics. RESULTS: The fractional first-pass threonine uptake by the intestine was remarkably high in both periods: 82 +/- 6% during partial enteral feeding and 70 +/- 6% during full enteral feeding. Net threonine retention was not affected by the route of feeding. CONCLUSION: In preterm infants, the splanchnic tissues extract a very large amount of the dietary threonine intake, which indicates a high obligatory visceral need for threonine, presumably for the purposes of synthesis.

Effects of early amino acid administration on leucine and glucose kinetics in premature infants.

We previously showed that, in prematurely born infants, an anabolic state without metabolic acidosis can be achieved upon intravenous amino acid (AA) administration in the immediate postnatal phase, despite a low energy intake. We hypothesized that the anabolic state resulted from an increased protein synthesis and not a decreased proteolysis. Furthermore, we hypothesized that the energy needed for the higher protein synthesis rate would be derived from an increased glucose oxidation. To test our hypotheses, 32 ventilated premature infants (<1500 g) received intravenously either solely glucose or glucose and 2.4 g AA/kg/d immediately postnatally. On postnatal d 2, each group received primed continuous infusions of either [1-13C]leucine or [U-13C6]glucose. 13CO2 enrichments in expiratory air and plasma [1-13C]alpha-KICA (as an intracellular leucine precursor) and [U-13C6]glucose enrichments were measured by mass spectrometry techniques. The AA administration resulted in an increased incorporation of leucine into body protein and a higher leucine oxidation rate, whereas leucine release from proteolysis was not affected. Glucose oxidation rate did not increase upon AA administration. In conclusion, the anabolic state resulting from AA administration in the immediate postnatal period resulted from increased protein synthesis and not decreased proteolysis. The energy needed for the additional protein synthesis was not derived from an increased glucose oxidation.

Insufficient efficacy of intravenous ketanserin in severe early-onset pre-eclampsia.

OBJECTIVE: To analyze the efficacy of intravenous ketanserin in controlling blood pressure of severe early-onset pre-eclamptic patients. STUDY DESIGN: Pre-eclamptic patients (n=47) with a gestational age (GA) between 21 and 32 weeks were treated with intravenous ketanserin in a maximum dosage of 14 mg/h, to obtain a diastolic blood pressure of 90 mmHg or below. The number of patients reaching and maintaining target blood pressure was retrospectively assessed. Patient characteristics associated with an adequate or inadequate response to ketanserin treatment were identified. RESULTS: With a maximum intravenous dosage of ketanserin, target blood pressure was not achieved in 15 (32%) patients. A high systolic blood pressure at the start of treatment was significantly (p=0.02) associated with failure of ketanserin treatment. The median period of ketanserin treatment in the responding group was 3 days (range 1-10 days). In 26 (55%) of initially successfully treated patients, additional antihypertensive drugs had to be added to maintain adequate blood pressure control. CONCLUSION: Intravenous ketanserin lacks antihypertensive efficacy in a substantial proportion of severe pre-eclamptic patients, despite high dosages. In patients who initially respond well to ketanserin treatment, additional antihypertensive treatment is often necessary to maintain adequate blood pressure control.

Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors.

Adverse drug reactions are common; they are responsible for a number of debilitating side effects and are a significant cause of death following drug therapy. It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism, or excretion. HMG-CoA reductase inhibitors are generally very well tolerated and easy to administer with good patient acceptance. There are only two uncommon but potentially serious adverse effects related to HMG-CoA reductase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomyolysis in patients treated with cerivastatin has prompted concern on the part of physicians and patients regarding the tolerability of HMG-CoA reductase inhibitors. Apart from pravastatin and rosuvastatin, HMG-CoA reductase inhibitors are metabolized by the phase I cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The best-characterized pharmacogenetic polymorphisms are those within this enzyme family. One of these enzymes, CYP2D6, plays an important role in the metabolism of simvastatin. It has been shown that the cholesterol-lowering effect as well as the efficacy and tolerability of simvastatin is influenced by CYP2D6 genetic polymorphism. Because the different HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism by the different CYP enzymes, genotyping may help to select the appropriate HMG-CoA reductase inhibitor and the optimal dosage during the start of the treatment and will allow for more efficient individual therapy. A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance.

An in vitro study on the active conversion of flucytosine to fluorouracil by microorganisms in the human intestinal microflora.

BACKGROUND: Investigation of the rate of active conversion of flucytosine to fluorouracil by microorganisms in the intestinal microflora. METHODS: Active conversion of flucytosine was investigated using viable and nonviable Escherichia coli at different flucytosine concentrations. Additionally, flucytosine conversion was studied in fecal specimens from 3 neutropenic patients at the start of the antimicrobial/antifungal prophylaxis (C/A regimen) and 1 week later. RESULTS: Flucytosine levels decreased by an average of 72, 71 and 72% flucytosine after incubation for 48 h of 10(10) viable E. coli /ml suspension in broth containing 13, 130 and 1300 mg/l flucytosine, respectively. The decreasing flucytosine levels corresponded approximately to an identical increase in fluorouracil levels. Also, a 44% decrease of flucytosine levels occurred when nonviable E. coli were used, indicating that bacterial viability is not necessary for this conversion. When fecal specimens of 2 patients were investigated prior to the C/A regimen, significant flucytosine conversion occurred, whereas this conversion was not observed in the corresponding fecal specimens after 1 week of C/A regimen. CONCLUSION: These in vitro experiments showed that extensive flucytosine conversion can occur in the human intestinal microflora by E. coli. Consequently, fluorouracil exposure and fluorouracil-related toxicity may occur in the flucytosine-treated patient.