From Therapeutic Drug Monitoring to Model-Informed Precision Dosing for Antibiotics.

Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.

Successful Treatment of Methicillin Susceptible Staphylococcus aureus Osteomyelitis with Oritavancin.

Staphylococcus aureus remains the most common causative pathogen in osteomyelitis. New or alternative therapies are often needed to treat S. aureus infections adequately in patients with drug allergies, treatment failures, or drug interactions. Oritavancin is a novel long-acting lipoglycopeptide approved by the U.S. Food and Drug Administration in 2014 for the treatment of acute bacterial skin and skin structure infections. With a terminal half-life of 8-10 days, oritavancin dosing regimens with infrequent parenteral administration now exist to treat infectious diseases such as osteomyelitis that would otherwise require daily dosing of intravenous antimicrobials for weeks; however, clinical experience is lacking. In this article, the first case of S. aureus osteomyelitis resulting from traumatic injury, successfully treated with oritavancin, is presented. Removal of the nail used for a comminuted tibial shaft fracture repair followed by a 6-week treatment course with oritavancin resulted in clinical response.

Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus.

Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The phase 3 studies SOLO I and SOLO II demonstrated comparable efficacy and safety of a single dose of oritavancin compared with 7-10 days of twice-daily vancomycin in adults with acute bacterial skin and skin-structure infections (ABSSSIs). The present analysis assessed clinical responses by pathogen at 48-72 h and at study days 14-24 in SOLO patients within the pooled data set. Of the 1959 patients in the pooled SOLO studies, 1067 had at least one baseline Gram-positive pathogen and 405 had MRSA. Clinical response rates were similar for oritavancin- and vancomycin-treated patients by pathogen, including Staphylococcus aureus with or without the Panton-Valentine leukocidin (pvl) gene and from different clonal complexes, and were similar for pathogens within each treatment group. Oritavancin exhibited potent in vitro activity against all baseline pathogens, with MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) of 0.12 µg/mL for Staphylococcus aureus, 0.25 µg/mL for Streptococcus pyogenes and 0.06 µg/mL for Enterococcus faecalis. Whereas both oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus, oritavancin provides a single-dose alternative to 7-10 days of twice-daily vancomycin to treat ABSSSIs.

The antimicrobial peptide sublancin ameliorates necrotic enteritis induced by Clostridium perfringens in broilers.

Sublancin is an antimicrobial peptide produced by 168 containing 37 amino acids. The objective of this study was to investigate its inhibitory efficacy against both in vitro and in vivo. In the in vitro study, we determined that sublancin had a minimum inhibitory concentration of 8 µM against , which was much higher than the antibiotic lincomycin (0.281 µM). Scanning electron microscopy showed that sublancin damaged the morphology of . The in vivo study was conducted on broilers for a 28-d period using a completely randomized design. A total of 252 chickens at 1 d of age were randomly assigned to 1 of 6 treatments including an uninfected control; an infected control; 3 infected groups supplemented with sublancin at 2.88, 5.76, or 11.52 mg activity/L of water; and an infected group supplemented with lincomycin at 75 mg activity/L of water (positive control). Necrotic enteritis was induced in the broilers by oral inoculation of on d 15 through 21. Thereafter, the sublancin or lincomycin were administered fresh daily for a period of 7 days. The challenge resulted in a significant decrease in ADG ( < 0.05) and a remarkable deterioration in G:F ( < 0.05) during d 15 to 21 of the experiment. There was a sharp increase of numbers in the cecum ( < 0.05). The addition of sublancin or lincomycin reduced caecal counts ( < 0.05). The counts had a tendency to decrease in the lincomycin treatment ( = 0.051) but were the highest in the sublancin treatment (5.76 mg activity/L of water). A higher villus height to crypt depth ratio in the duodenum and jejunum as well as a higher villus height in the duodenum were observed in broilers treated with sublancin or lincomycin ( < 0.05) compared with infected control broilers. It was observed that sublancin and lincomycin decreased IL-1ß, IL-6, and tumor necrosis factor-α levels ( < 0.05) in the ileum compared with the infected control. In conclusion, although sublancin's minimum inhibitory concentration is much higher than lincomycin in vitro, less sublancin is needed to control necrotic enteritis induced by in vivo than lincomycin. These novel findings indicate that sublancin could be used as a potential antimicrobial agent to control necrotic enteritis.

Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram-Positive Infections.

Health care-associated infections, especially those caused by multidrug-resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are a growing public health threat. In 2014, the U.S. Food and Drug Administration approved two new lipoglycopeptides, oritavancin and dalbavancin, for the treatment of acute bacterial skin and skin structure infections. The rationale for the development of these antimicrobials was partly to aid in the battle against vancomycin resistance in both Staphylococcus and Enterococcus. Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d-alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails. This addition allows for these agents to have prolonged half-lives, giving them unique dosing profiles. In addition, by concentrating at the site of action, they have increased potency against MRSA compared with vancomycin, the current mainstay of therapy. In this review, we focus on comparing and contrasting these two new agents with regard to their pharmacology, mechanisms of action, spectrum of activity, safety profiles, dosage and administration, and drug and laboratory interactions, and we review the clinical trials evaluating their use.

What's new in the treatment of serious MRSA infection?

PURPOSE OF REVIEW: Vancomycin has been the cornerstone of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infections. This review describes new MRSA-active antibiotics that have recently been introduced and highlights emerging resistance. RECENT FINDINGS: Elevations in the vancomycin minimum inhibitory concentration within the susceptible range are associated with treatment failure and mortality in the treatment of MRSA infections. Ceftaroline and ceftobiprole are anti-MRSA cephalosporins and are noninferior to comparator agents in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and pneumonia. Tedizolid is more potent than linezolid, has improved pharmacokinetics and reduced toxicity and is active against cfr-containing S. aureus. Telavancin now has approval for treatment of hospital-acquired pneumonia, and recent phase 2 trial data showed similar cure rates in S. aureus bacteremia. Dalbavancin and oritavancin are administered once weekly and are noninferior to comparators for acute bacterial skin and skin structure infections. Resistance has emerged against many new anti-MRSA antimicrobials including ceftaroline. Combination therapy of ß-lactams with vancomycin or daptomycin is increasing. SUMMARY: Several new MRSA-active agents are now approved for use, although much of the data is derived from treatment of acute bacterial skin and skin structure infections or pneumonia. Further studies are required for more invasive infections, such as bacteremia and endocarditis.

[Detection of the first strain of glycopeptide intermediary Staphylococcus aureus in Tunis Rabta hospital]. / Détection de la première souche de Staphylococcus aureus de sensibilité diminuée aux glycopeptides à l'hôpital la Rabta de Tunis.

Since the advent of the first glycopeptide intermediately susceptible Staphylococcus aureus (GISA) and its heterogeneous variant hGISA in 1997, debate still ensues as their clinical significance. We report here the first case of GISA in Rabta hospital of Tunisia. Antimicrobial resistance was determined by the disk diffusion method in accordance with CA-SFM (Comity of Antibiogramm of French society of Microbiology). The MIC of vancomycin and teicoplanin was determined by E-test. The detection of mec A gene, virulence factors genes and agr groups (1-4) was performed by multiplex PCR. spa types were determined with the assistance of Ridom of Staph Type software (Ridom GmbH, Wurburg, Germany). The allelic profiles of MRSA were assigned on the basis of their MLST type using the eBURST program. A MRSA bacteraemia patient was treated with teicoplanin for 14 days. S. aureus isolated from patient's blood culture was identified as MRSA and GISA with teicoplanin MIC of 16 mg/l. The molecular study of this strain showed that it belongs to the clonal complex CC8 and is attached to the iberian clone (agr1, enterotoxin A, ST 247, spa type t052). Clinicians and laboratories alike are increasingly aware that patients on long-term vancomycin therapy may signal the presence and potential spread of hGISA/GISA strains. hGISA/GISA strains emerged from lineages with agr types I and II. The multiresitance of the Iberian clone ST247 could be explained by the presence of several resistance genes.

Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids.

BACKGROUND: Phenylketonuria (PKU) requires a lifelong low-phenylalanine diet that provides the majority of protein from a phenylalanine-free amino acid (AA) formula. Glycomacropeptide (GMP), an intact protein formed during cheese production, contains minimal phenylalanine. OBJECTIVE: The objective was to investigate the effects of substituting GMP food products for the AA formula on acceptability, safety, plasma AA concentrations, and measures of protein utilization in subjects with PKU. DESIGN: Eleven subjects participated in an inpatient metabolic study with two 4-d treatments: a current AA diet (AA diet) followed by a diet that replaced the AA formula with GMP (GMP diet) supplemented with limiting AAs. Plasma concentrations of AAs, blood chemistries, and insulin were measured and compared in AA (day 4) and GMP diets (day 8). RESULTS: The GMP diet was preferred to the AA diet in 10 of 11 subjects with PKU, and there were no adverse reactions to GMP. There was no significant difference in phenylalanine concentration in postprandial plasma with the GMP diet compared with the AA diet. When comparing fasting with postprandial plasma, plasma phenalyalanine concentration increased significantly with the AA but not with the GMP diet. Blood urea nitrogen was significantly lower, which suggests decreased ureagenesis, and plasma insulin was higher with the GMP diet than with the AA diet. CONCLUSIONS: GMP, when supplemented with limiting AAs, is a safe and highly acceptable alternative to synthetic AAs as the primary protein source in the nutritional management of PKU. As an intact protein source, GMP improves protein retention and phenylalanine utilization compared with AAs.

[Pharmacodynamic and pharmacokinetic of antibiotics for treatment of skin and soft tissue infections]. / Farmacologia degli antibiotici nelle infezioni della cute e dei tessuti molli.

The pharmacodynamic and pharmacokinetic characteristics of antimicrobial agents are the two fundamental pharmacological components which provide a rational for the choice of therapy for skin and skin structure infections, and especially serious infections. The most important PK-PD parameters are well known which can potentiate therapeutic efficacy. Antimicrobial agents ca be subdivided into categories based on whether their activity is dependent on concentration or exposure time. Therefore, a correct dosing regimen for the time-dependent molecules (i.e. beta-lactams, linezolid, tigecycline) should prolong the maximum exposure time to maintain serum levels over the minimum inhibitory concentration (MIC). The concentration-dependent molecules, on the other hand, which include aminoglycosides and fluoroquinolones, should be given in order to reach maximum concentrations, since they are bactericidal in direct proportion to their concentrations and possess a prolonged post-antibiotic effect.

Efficacy of oritavancin in a murine model of Bacillus anthracis spore inhalation anthrax.

The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of care for inhalational anthrax postexposure prophylaxis is ciprofloxacin therapy twice daily for 60 days. The potent in vitro activity of oritavancin, a semisynthetic lipoglycopeptide, against B. anthracis (MIC against Ames strain, 0.015 microg/ml) prompted us to test its efficacy in a mouse aerosol-anthrax model. In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15, or 50 mg/kg 24 h after a challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge, whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity post symptom development; a single i.v. dose of 50 mg/kg administered 42 h after challenge provided 56% proportional survival at 30 days. In a preexposure prophylaxis study, a single i.v. oritavancin dose of 50 mg/kg administered 1, 7, 14, or 28 days before lethal challenge protected 90, 100, 100, and 20% of mice at 30 days; mice treated with ciprofloxacin 24 h or 24 and 12 h before challenge all died within 5 days. Efficacy in pre- and postexposure models of inhalation anthrax, together with a demonstrated low propensity to engender resistance, promotes further study of oritavancin pharmacokinetics and efficacy in nonhuman primate models.

Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria.

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of phenylalanine hydroxylase (PAH) that requires life-long adherence to a low-phenylalanine (Phe) diet. Glycomacropeptide (GMP) is uniquely suited to the nutritional management of PKU, because pure GMP contains no Phe. Our aim was to assess how ingestion of diets containing GMP support growth and affect the concentrations of amino acids in plasma and brains of mice with a deficiency of PAH, the Pah(enu2) mouse (PKU mouse). Experiments were conducted in 4- to 6-wk-old wild-type (WT) (C57Bl/6) and PKU mice fed diets containing 20% protein from casein, amino acids, or GMP supplemented with limiting indispensable amino acids (IAA). PKU mice fed the GMP diet showed gains in body weight, feed efficiency, and a protein efficiency ratio that did not differ from the amino acid diet. The concentrations of isoleucine and threonine in plasma showed a significant 2- to 3-fold increase for WT and PKU mice fed GMP compared with casein or amino acid diets, respectively. PKU mice fed the GMP diet had decreased concentrations of Phe in plasma (11% decrease) and in 5 regions of the brain (20% decrease) compared with the amino acid diet. The concentration of Phe in the brain was inversely correlated with the concentrations of isoleucine, threonine, and valine in plasma (R2 = 0.74; P < 0.0001), suggesting competitive inhibition of Phe transport into the brain. In summary, PKU mice fed GMP showed comparable growth and reduced concentrations of Phe in plasma and the brain compared with an amino acid diet. These data support the use of GMP supplemented with IAA as an alternative source of dietary protein for individuals with PKU.

[Effects of LbGp on the intracellular free calcium concentration of cardiomyocytes induced by hypoxia and KCl].

OBJECTIVE: Hypoxia/KCl injury model in the cultured neonatal rat cardiomyocytes (CMs) was established to investigate the protective effect of Lycium barbanun Glycopeptide (LbGp) on calcium overload. METHOD: Cultured neonatal rat CMs were divided into three groups, namely normal control, hypoxia groups and LbGp-treated group. CMs in LbGp-treated group and hypxia group were cultured in an incubator ventilated with 95% N2 and 5% CO2 with or without LbGP. CMs viability under hypoxia was measured by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide colorimetry (MTT). The intracellular free calcium concentration in cardiomyocytes was measured by laser confocal microscope with Fura-3/AM as a calcium indicator. The protective effects of LbGp on the CMs treated by KCl (60 mmol x L(-1)) was observed. RESULT: As compared with normal controls, the degree of MTT metabolism was significantly reduced (P < 0.01) in hypoxic group and slightly reduced in LbGp (P < 0.05). Hypoxia-induced enhancement of intracellular calcium ([Ca2+]i) was attenuated by LbGp significantly (P < 0.01). Moreover, KCl-induced enhancement of [Ca2+]i was also reduced by LbGp at the doses of 25, 50, 100 microg x mL(-1) in a concentration-dependent manner. CONCLUSION: The result suggested that LbGp is able to increase the survival ratio and inhibit the enhancement of the intracellular free calcium concentration in cardiomyocytes induced by hypoxia and high potassium. One of the mechanisms is that LbGp acts on L-type calcium channels.

Dalbavancin: an investigational glycopeptide.

Glycopeptide antimicrobials have been a component of our therapeutic armamentarium for nearly 50 years. Although vancomycin, and more recently teicoplanin, have performed yeoman service over the years, the specter of bacterial resistance among Gram-positive aerobes has created doubts concerning how long they will continue to be useful antimicrobial agents. In an attempt to prolong the utility of the glycopeptides, efforts are underway to create new derivatives with improved pharmacologic and pharmacokinetic properties. One example of an improved glycopeptide from the pharmacokinetic perspective is dalbavancin (BI397)--a teicoplanin analog currently undergoing human testing. Elimination of this compound from the body occurs extremely slowly, with terminal disposition half-lifes of up to 200 h in healthy volunteers, thus allowing once-weekly dosing. Although not generally considered to be a potential alternative for the treatment of infections due to glycopeptide-resistant Gram-positive pathogens, dalbavancin may still be considered an advance on existing agents based on its patient-convenient once-weekly dosing regimen.

Protection against muscle damage in competitive sports players: the effect of the immunomodulator AM3.

Strenuous physical exercise of the limb muscles commonly results in damage, especially when that exercise is intense, prolonged and includes eccentric contractions. Many factors contribute to exercise-induced muscle injury and the mechanism is likely to differ with the type of exercise. Competitive sports players are highly susceptible to this type of injury. AM3 is an orally administered immunomodulator that reduces the synthesis of proinflammatory cytokines and normalizes defective cellular immune fractions. The ability of AM3 to prevent chronic muscle injury following strenuous exercise characterized by eccentric muscle contraction was evaluated in a double-blind and randomized pilot study. Fourteen professional male volleyball players from the First Division of the Spanish Volleyball League volunteered to take part. The participants were randomized to receive either placebo (n=7) or AM3 (n=7). The physical characteristics (mean+/-s) of the placebo group were as follows: age 25.7+/-2.1 years, body mass 87.2+/-4.1 kg, height 1.89+/-0.07 m, maximal oxygen uptake 65.3+/-4.2 ml.kg(-1).min(-1). Those of the AM3 group were as follows: age 26.1+/-1.9 years, body mass 85.8+/-6.1 kg, height 1.91+/-0.07 m, maximal oxygen uptake 64.6+/-4.5 ml.kg(-1).min(-1). All participants were evaluated for biochemical indices of muscle damage, including concentrations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatine kinase (CK) and its MB fraction (CK-MB), myoglobin, lactate dehydrogenase, urea, creatinine and gamma-glutamyltranspeptidase, both before and 30 days after treatment (over the peak of the competitive season). In the placebo group, competitive exercise (i.e. volleyball) was accompanied by significant increases in creatine kinase (494+/-51 to 560+/-53 IU.l(-1), P < 0.05) and myoglobin (76.8+/-2.9 to 83.9+/-3.1 microg.l(-1), P < 0.05); aspartate aminotransferase (30.8+/-3.0 to 31.1+/-2.9 IU.l(-1)) and lactate dehydrogenase (380+/-31 to 376+/-29 IU.l(-1)) were relatively unchanged after the 30 days maximum effort. AM3 not only inhibited these changes, it led to a decrease from baseline serum concentrations of creatine kinase (503+/-49 to 316+/-37 IU.l(-1), P < 0.05) and myoglobin (80.1+/-3.2 to 44.1+/-2.6 IU.l(-1), P < 0.05), as well as aspartate aminotransferase (31.1+/-3.3 to 26.1+/-2.7 IU.l(-1), P < 0.05) and lactate dehydrogenase (368+/-34 to 310+/-3 IU.l(-1), P < 0.05). The concentration of CK-MB was also significantly decreased from baseline with AM3 treatment (11.6+/-1.2 to 5.0+/-0.7 IU.l(-1), P < 0.05), but not with placebo (11.4+/-1.1 to 10.8+/-1.4 IU.l(-1)). In conclusion, the use of immunomodulators, such as AM3, by elite sportspersons during competition significantly reduces serum concentrations of proteins associated with muscle damage.

A two-stage continuous culture system to study the effect of supplemental alpha-lactalbumin and glycomacropeptide on mixed cultures of human gut bacteria challenged with enteropathogenic Escherichia coli and Salmonella serotype Typhimurium.

AIMS: Certain milk factors may promote the growth of a gastrointestinal microflora predominated by bifidobacteria and may aid in overcoming enteric infections. This may explain why breast-fed infants experience fewer intestinal infections than their formula-fed counterparts. The effect of formula supplementation with two such factors was investigated in this study. METHODS AND RESULTS: Infant faecal specimens were used to ferment formulae supplemented with glycomacropeptide (GMP) and alpha-lactalbumin (alpha-la) in a two-stage compound continuous culture model. At steady state, all fermenter vessels were inoculated with 5 ml of 0.1 m phosphate-buffered saline (pH 7.2) containing 108 CFU ml-1 of either enteropathogenic Escherichia coli 2348/69 (O127:H6) or Salmonella serotype Typhimurium (DSMZ 5569). Bacteriology was determined by independent fluorescence in situ hybridization. Vessels that contained breast milk (BM), as well as alpha-la and GMP supplemented formula had stable total counts of bifidobacteria while lactobacilli increased significantly only in vessels with breast milk. Bacteroides, clostridia and E. coli decreased significantly in all three groups prior to pathogen addition. Escherichia coli counts decreased in vessels containing BM and alpha-la while Salmonella decreased significantly in all vessels containing BM, alpha-la and GMP. Acetate was the predominant acid. SIGNIFICANCE AND IMPACT OF THE STUDY: Supplementation of infant formulae with appropriate milk proteins may be useful in mimicking the beneficial bacteriological effects of breast milk.

Use of gamma-inulin/liposomes/Vitamin E adjuvant combination in contraceptive vaccines.

The adjuvanticity of two gamma inulin/liposomes/Vitamin E combinations was evaluated in the mouse, in contraceptive vaccines with sperm protein extracts or a synthetic HE2 peptide ("Human Epididymis gene product"; residues 15-28) as antigen. The HE2 peptide was not conjugated to a protein carrier, to ensure that the antibodies elicited were specific against the HE2 peptide. The adjuvant combinations were designed to increase adjuvanticity, as their components have complementary mechanisms, and their performance was compared to Freund's adjuvant. Antibody production against native sperm structures was determined in sera by ELISA immunoassay and immunohistology. Toxicity of adjuvants was determined by histopathological study and treated mice were monitored for signs of pain or distress. Our results show that the gamma inulin (1-2 microm particle size)/liposomes/Vitamin E combination, with sperm protein extracts, is better than Freund's adjuvant because it elicits good antibody titres without any toxicity. When the synthetic HE2 peptide is used as antigen, the gamma inulin (1-2 microm particle size)/liposomes/Vitamin E combination is less effective than Freund's adjuvant; nevertheless, the anti-HE2 antibodies elicited are highly specific and recognize native structures in sperm.

Glycomacropeptide and alpha-lactalbumin supplementation of infant formula affects growth and nutritional status in infant rhesus monkeys.

BACKGROUND: Advances in dairy technology make it possible to enrich infant formula with specific bovine milk components that may enhance nutrient status. Glycomacropeptide, a carbohydrate-rich casein peptide, may increase absorption of calcium, iron, or zinc. alpha-Lactalbumin, a major breast-milk protein, may contribute to a balanced amino acid pattern and increase calcium and zinc absorption. OBJECTIVE: We determined the effects of glycomacropeptide- and alpha-lactalbumin-supplemented infant formula on growth; trace mineral status; iron, zinc, and calcium absorption; and plasma amino acid, blood urea nitrogen, and plasma insulin concentrations. DESIGN: Infant rhesus monkeys (n = 5 infants per group) were breastfed or fed control or alpha-lactalbumin- or glycomacropeptide-supplemented formula from birth to 4 mo of age. Hematologic measures and growth were assessed monthly. Mineral absorption was measured with radioisotopes and whole body counting. RESULTS: Infants fed glycomacropeptide had higher food intake than did other formula-fed infants. Infants fed glycomacropeptide or control formula had higher hematocrit values than did infants that were breastfed or fed alpha-lactalbumin. Infants fed glycomacropeptide or control formula had higher plasma zinc and zinc absorption than did breastfed infants. Where differences were observed, breastfed infants and infants fed alpha-lactalbumin had similar plasma essential amino acid and insulin profiles, which were different from those of infants fed glycomacropeptide or control formula. CONCLUSIONS: Glycomacropeptide- or alpha-lactalbumin-supplemented formula has no adverse effects on nutritional status in infant monkeys. Glycomacropeptide supplementation increases zinc absorption, which may permit the reduction of formula zinc concentrations, and alpha-lactalbumin supplementation promotes a plasma amino acid pattern similar to that of breastfed infant monkeys.

AM3 (Inmunoferón) as an adjuvant to hepatitis B vaccination in hemodialysis patients.

BACKGROUND: Patients with end-stage renal disease (ESRD) undergoing hemodialysis have severe alterations in cell-mediated immunity (CMI) that increases their risk of contracting chronic hepatitis B virus (HBV) infection and decreases their protective responses to HBV vaccine. In an effort to improve the humoral response to an accelerated HBV vaccine protocol in these patients, the ability of an immunomodulator, AM3, to improve seroconversion was investigated. METHODS: A total of 269 patients were enrolled in a multicenter trial. All patients received a DNA recombinant vaccine (40 microg HBsAg/dose/day) on days 0, 10, 21, and 90. AM3 or placebo (3 g/day) was given orally for 30 consecutive days beginning 15 days prior to the first vaccine dose. Anti-HBsAg titers were measured on days 120 and 270 after the beginning of the trial. RESULTS: After one month, 207 patients could be evaluated and 132 patients after six months. The placebo and AM3-treated groups had comparable seroconversion and protective response rates one month after the final vaccine dose. The AM3 treatment group, but not the placebo group, maintained these protective titers up to six months after the final vaccine dose. At this time, the percentage of high responders (anti-HBsAg>100 IU/L) and mean anti-HBsAg titers in the AM3 group was significantly higher than in the placebo group. CONCLUSIONS: AM3 is a safe and easily tolerated oral agent that potentiates long-term serological immunity to hepatitis B in hemodialysis patients after vaccination.

Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis.

Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP(-/-) knockout and NEP(+/+) wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP(-/-) animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP(-/-) mice, the acute inhibition of NEP in NEP(+/+) animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP(-/-) compared with NEP(+/+) animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

Study of the immunostimulating effect of glycophosphopeptical (AM3) in mice.

The results of this study show that glycophosphopeptical (AM-3) has a marked immunostimulant effect in mice, in terms of an increase in the number of haemolytic plaque-forming B lymphocytes producing antibodies against sheep erythrocytes as compared with saline-treated controls. The results also demonstrate the activity of this drug when administered intraperitoneally.