The Maillard reaction in the human body. The main discoveries and factors that affect glycation

Ever since the discovery of the Maillard reaction in 1912 and the discovery of the interaction between advanced glycation end-products and cellular receptors, impressive progress has been made in the knowledge of nonenzymatic browning of proteins in vivo. This reaction which leads to the accumulation of random damage in extracellular proteins is known to have deleterious effects on biological function, and is associated with aging and complication in chronic diseases. Despite a controlled membrane permeability and a protective regulation of the cells, intracellular proteins are also altered by the Maillard reaction. Two main factors, protein turnover and the concentration of carbonyls, are involved in the rate of formation of the Maillard products. This paper reviews the key milestones of the discovery of the Maillard reaction in vivo, better known as glycation, and the factors which are likely to affect it.     

Pharmacodynamic assessment of clarithromycin in a murine model of pneumococcal pneumonia

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10(8)-CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r(2) = 0.72 to 0.82), median survival (r(2) = 0.93 to 0.94), and total percent survival (r(2) = 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC(0-24)/MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >or=4 microg/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 microg/ml.     

Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations

Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.     

Blood plasma fluoride in haemodialysed patients

Blood plasma fluoride was determined in 15 chronic haemodialysed patients (60.2 +/- 7.2 yr old) before and after a 4-h dialysis using dialysates with very low fluoride level, and in two control groups, the first of 20 healthy younger subjects (45.9 +/- 3.4 yr old), the second of 8 healthy older subjects (69.1 +/- 6.8 y old). Before haemodialysis the fluoride concentration (1.31 +/- 0.31 mumol/l; 24.8 +/- 5.9 micrograms/l), was higher than in both control groups (0.35 +/- 0.16 mumol/l; 6.6 +/- 3.1 micrograms/l and 0.44 +/- 0.16 mumol/l 8.4 +/- 3.0 micrograms/l, respectively). During dialysis, the mean fluoride concentration fell to 0.94 +/- 0.26 mumol/l, remaining however, significantly higher than in control subjects. The use of fluoride-free dialysates seems to partially compensate the effect of renal impairment since plasma fluoride is only moderately increased in these patients.     

Inhibitory effects of heterotopic noxious counter‐stimulation on perception and brain activity related to Aβ‐fibre activation

Heterotopic noxious counter‐stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non‐nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter‐balanced sessions, including non‐nociceptive (selective Aβ‐fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20‐min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0–100 scale, where 0 is no pain and 100 the worst pain imaginable). Non‐nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII‐reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non‐nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak‐to‐peak amplitude at Cz was significantly decreased by HNCS for non‐nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aβ‐fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide‐dynamic‐range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.