Hydrolyzed milk-serum peptides reduce body weight and fat content of dietary obese rats ameliorating their antioxidant status and liver functions.

AIM: Recent studies suggested that weight reduction under energy restriction required protein supplementation. Moreover, a significant decrease in serum cholesterol and triglycerides was observed when milk-serum proteins and, in particular, their hydrolyzed peptides were compared to milk casein. METHODS: Six Sprague-Dawley rats were fed with the standard diet for 8 weeks. Eighteen rats were fed with the obesity- producing diet for 4 weeks. After this period and for the remaining 4 weeks, these rats were divided into 3 groups, the 1st was fed with the obesity-diet, the 2nd and the 3rd were fed with the casein--and with the hydrolyzed milk-serum peptides--restricted diet, respectively. RESULTS: Treatment with the obesity-diet, compared to standard-diet, induced an increase in the body weight and fat content, with a decrease in protein mass and dehydration state. There was also an increase in blood levels of cholesterol, triglycerides and glucose. The lipoperoxides content in the plasma, heart, brain and liver had also increased, while the content of glutathione and ATP and the membrane fluidity in the liver had significantly decreased. The administration of the restricted caloric diet, in particular the one containing the hydrolyzed peptides were capable of an improvement of all these parameters. CONCLUSIONS: The metabolic modifications induced by the hydrolyzed peptides-restricted diet contribute to control better the over-weight thus reducing the risk of the onset of the dismetabolic pathologies correlated to it.

Study of the effect of lactobacillus GG supplementation in combination with and without arginine aspartate on lipoproteins and liver peroxidation in cholesterol-fed rats.

The effect of diet integration with lactobacillus GG and arginine aspartate administered singly or together to rats submitted to a cholesterol-enriched diet have been evaluated by measuring both the changes in the levels of cholesterol and triglycerides and the variations of the most indicative parameters of peroxidation in plasma lipoproteins and livers. The administration of lactobacillus GG alone is able to induce a significant hypocholesterolaemic effect while the arginine aspartate singly or together with the lactobacillus does not seem to promote any significant hypocholesterolaemic effect. The cholesterol levels (expressed as mg x dL-1) are in fact: 45.5 for the control diet; 185.4 for the cholesterol-enriched diet; 131.1 for the cholesterol-enriched diet + lactobacillus; 178.2 for the cholesterol enriched diet + arginine aspartate and 122.4 for the cholesterol-enriched diet + lactobacillus + arginine aspartate. On the contrary, the co-administration of lactobacillus and arginine aspartate gives rise to a very high preventive activity against the cholesterol-induced peroxidation damages both in the plasma lipoproteins and in the liver. Such preventive activity is higher by far than that obtainable when lactobacillus or arginine aspartate are administered singly to the rats.

Synthesis and antimicrobial properties of cephalosporin derivatives substituted on the C(7) nitrogen with arylmethyloxyimino or arylmethyloxyamino alkanoyl groups.

Some 7-aminocephalosporanic acid (7-ACA) derivatives substituted on the C(7) nitrogen with 2-(arylmethyloxyimino)propionyl (3a-f), 2-(arylmethyloxyamino)propionyl (4a-d) and (arylmethyloxyamino)acetyl (2a-d) moieties were synthesized by reaction of the appropriate acylating agents with 7-ACA protected as a t-butyl ester, followed by removal of the t-butyl protecting group. The new compounds, tested in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria, proved to possess a modest activity directed only against Gram-positive microorganisms.

Penetration of vancomycin into human lung tissue.

Vancomycin penetration into lung tissue was evaluated in thirty patients following the administration of 1 g of vancomycin as a 1 h i.v. infusion. Mean concentrations (range) of vancomycin in lung tissue were 9.6 (6.3-12.1) mg/kg at 1h, 5.7 (4.7-7.4) mg/kg at 2 h, 4.2 (0.8-6.5) mg/kg at 3-4 h, 2.4 (1.4-4.7) mg/kg at 6 h, and 2.8 (0.9-7.8) mg/kg at 12 h after the end of infusion. Ratios of lung tissue to serum concentration ranged 0.24 to 0.41 at 1 and 12 h, respectively. One of six patients observed at 6 h, and 3 of 7 patients at 12 h did not have detectable levels of vancomycin in lung tissue. A 1 h iv infusion of a 1 g dose of vancomycin does not achieve sustained lung concentrations above the MIC for susceptible staphylococci over a dosing interval of 12 h. Therefore, a more appropriate modality of administration, such as continuous infusion, should be considered.

Synthesis and antimicrobial activity of 7 beta-(S)- and 7 beta-[(R)-3-(methyleneaminoxy)-2-methylpropionamido]substituted cephalosporanic acid derivatives.

Some 7-amino cephalosporanic acid derivatives substituted on the C(7) nitrogen with (S)-and (R)-3-(methyleneaminoxy)-2-methylpropionyl groups were synthesised and tested in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria. Some of the new compounds showed a modest activity directed only against Gram-positive microorganisms.

Synthesis and antimicrobial activity of benzo[a]dihydrocarbazole and benzotetrahydrocyclohept[1,2-b]indole derivatives.

A certain number of benzodihydrocarbazoles and benzotetrahydrocycloheptindoles were synthesized and tested for their antimicrobial activity. Compounds substituted on the nitrogen of the tetracyclic systems with a dimethylaminopropyl chain showed an antibacterial activity directed almost exclusively towards Gram-positive bacteria, while their N-unsubstituted analogs were completely inactive.

Synthesis and antimicrobial activity of 7 beta-[N-(arylmethyloxyimino) acetamido]cephalosporanic acid derivatives.

Some cephalosporanic acid derivatives substituted on the C(7) amino nitrogen with (arylmethyloxyimino)acetyl moieties were synthesized and tested in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria. The new compounds showed a modest activity directed only against Gram positive microorganisms.

Effects of magnesium-aluminum hydroxide antacid on absorption of rufloxacin.

The present study was designed to determine the effects of an antacid suspension containing magnesium hydroxide and aluminum hydroxide (30 ml of Maalox) on the oral bioavailability of rufloxacin (400 mg). Rufloxacin was administered orally to 12 healthy volunteers according to a randomized, balanced, crossover design. Three treatments were administered to each subject, with a 10-day washout period between treatments; the treatments included rufloxacin alone, rufloxacin taken 5 min after antacid, and rufloxacin taken 4 h before antacid. Administration of antacid within 5 min before the administration of rufloxacin resulted in a substantial decrease in rufloxacin absorption, with a mean percent relative bioavailability compared with control values of 64% (range, 42 to 77%). Administration of antacid 4 h after the administration of rufloxacin slightly affected the absorption of the quinolone (mean relative bioavailability, 87%; range, 51 to 110%). Antacids that contain magnesium and aluminum salts reduce the absorption of rufloxacin. The extent of this interaction depends on the time that elapses between administration of the two drugs.

A new HPLC method for pidotimod plasma levels determination.

This paper describes a HPLC method for the determination of Pidotimod (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid; PGT/1A), a new biological response modifier, in plasma. The column was an Aminex Ion Exclusion HPX 874 with a PRP precolumn, the mobile phase was 0.05% sulfuric acid-acetonitrile (88:12, v/v), the flow rate was 0.6 ml/min, the detection wavelength was 210 nm. Plasma (1 ml) was added with internal standard (Oxiracetam, concentration 400 micrograms/ml) (50 microliters) and 35% perchloric acid (100 microliters). The supernatant (0.5 ml) was added with mobile phase (0.5 ml) and, after centrifugation, injected into the column. The retention times of Pidotimod and Oxiracetam were 16.5 and 13.8 min. respectively. The method was validated for recovery, accuracy and reproducibility. The results after oral administration of 800 mg of Pidotimod in male volunteers were also given. This method is better than that previously described because it utilizes an internal standard and reaches a lower detection limit.

Pharmacokinetics of oxatomide given percutaneously to healthy volunteers.

The percutaneous absorption of oxatomide gel at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25.7 +/- 0.8 years (mean +/- SEM) weighing 64.4 +/- 4.5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0.2 ng ml-1 in plasma and 1.0 ng ml-1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5.03 +/- 0.79 ng ml-1 following application of the gel for 7 days and 10.08 +/- 1.29 ng ml-1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1.42 +/- 0.39 micrograms and 3.93 +/- 0.92 micrograms.

Determination of vincamine in human plasma by high-performance liquid chromatography with ultraviolet detection.

A simple and rapid high-performance liquid chromatographic method was developed for the determination of vincamine in human plasma. Plasma samples were buffered at pH 9 and after extraction with tert.-butyl methyl ether back-extracted into 0.017 M orthophosphoric acid. Propranolol was used as the internal standard. An aliquot was injected on to a high-performance liquid chromatographic system using a C18 reversed-phase column and an acetonitrile-phosphate buffer containing triethylamine (30:70) as mobile phase. Detection was performed with an ultraviolet detector at 273 nm. The method had good accuracy and precision and the detection limit (0.3 ng/ml with a signal-to-noise ratio of 3:1) allowed the assessment of vincamine concentrations in plasma in pharmacokinetic studies on healthy human volunteers.

Effect of single doses of rufloxacin on the disposition of theophylline and caffeine after single administration.

Several reports indicate that quinolone antibiotics affect the pharmacokinetics of theophylline and caffeine. This study investigated the effects of one single oral dose of rufloxacin, a new quinolone antibacterial, on the pharmacokinetics of theophylline and caffeine, given as single oral doses. Twelve healthy male volunteers were randomly given one of the following treatments: treatment T: 300 mg theophylline; treatment T + R: 300 mg theophylline followed by 400 mg rufloxacin after 30 min; treatment C: 200 mg caffeine; treatment C + R: 200 mg caffeine followed by 400 mg rufloxacin after 30 min. Blood samples for determination of xanthine plasma levels were taken immediately before and 1, 2, 4, 6, 8, 10, 12, 24 and 48 hours after xanthine administration. Urine were collected before treatment and at 0-6, 6-12, 12-24 and 24-48 h intervals. There were no significant differences in the pharmacokinetic parameters or in urinary excretion after administration of either theophylline or caffeine when combined with rufloxacin. Sleep disturbances were reported by two subjects after both treatment T + R and C + R, and by four subjects after treatment T + R. The results of this study indicate that there is no significant pharmacokinetic interaction between a single oral dose of rufloxacin and single doses of theophylline and caffeine.

Inter- and intrasubject variabilities in the pharmacokinetics of rufloxacin after single oral administration to healthy volunteers.

Rufloxacin is a new long-acting, once-daily quinolone antibacterial agent. We evaluated inter- and intrasubject variations in pharmacokinetics of rufloxacin following oral administration of 400 mg (two capsules) under controlled conditions, at an interval of 2 weeks (periods I and II), to 12 healthy male subjects. Plasma and urine samples were collected up to 48 h after drug administration. Plasma drug levels determined by bioassay were higher than those measured by high-performance liquid chromatography, indicating that one or more active metabolites were formed. Individual high-performance liquid chromatography plasma rufloxacin concentrations were fitted with a one-compartment open model with first-order input. There were considerable variations in the plasma concentration-time profiles among subjects; for example, the elimination half-life in plasma varied from 14.6 to 95.5 h. However, pharmacokinetic parameters calculated for the two periods did not differ significantly. These results suggest that the intrasubject variation in the pharmacokinetics of rufloxacin is usually small in spite of the considerable intersubject variation.

Pharmacokinetics of fluocinolone acetonide in patch versus cream formulations.

The pharmacokinetics of the fluocinolone acetonide patch containing 8 mcg/cm2 and a 0.025% cream were studied in a cross-over trial in 12 healthy volunteers 6 male and 6 female mean age 24.9 years. Each subject was treated with 0.8 mg of both fluocinolone acetonide formulations for 12 h on non-consecutive days. The high performance liquid chromatography method was used to determine the plasma and urine levels of the drug. Minor fluctuations in the plasma profile after patch application were observed, even if no significant difference was found between the two formulations with regard to peak plasma concentration, time to reach peak levels, area under the concentration curve and half-life.

Synthesis and antimicrobial properties of substituted 3-aminoxypropionyl and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams.

The substituted 3-aminoxyproprionyl (VII) and 3-aminoxy-(E)-2-methoxyiminopropionyl monobactams (VIII) which possess the monocyclic beta-lactam nucleus of aztreonam (IX) were synthesized by reaction of triethylammonium (3S, 4S)-3-amino-4-methyl-2-oxo-1-azetidinsulfonate with the aminoxy acids X and XI, respectively. Compounds VII and VIII were assayed in vitro for their antimicrobial properties against Gram-positive and Gram-negative bacteria, whether producers of beta-lactamases or otherwise. Both types of compounds (VII and VIII) exhibited a poor antibacterial activity towards Gram-positive bacteria, comparable to that of aztreonam. On the contrary VII and VIII proved to be practically inactive against Gram-negative microorganisms, towards which aztreonam exhibits a high degree of activity.

Synthesis and antimicrobial properties of substituted beta-aminoxypropionyl penicillins and cephalosporins.

Some beta-aminoxypropionyl penicillins (3) and cephalosporins (4 and 5), planned on the basis of the hypothesis that the (methyleneaminoxy)methyl group (greater than C = NOCH2) could be a "bioisoster" of either aryls or other aromatic groups, were synthesized and assayed for their antimicrobial properties. Compounds 3-5, tested on Gram-positive and Gram-negative bacteria, both sensitive to enzyme inactivation and otherwise, exhibited an activity trend that was not substantially different from that of the corresponding phenylacetamido derivatives taken as terms of comparison.

Pharmacokinetics of cefonicid in serum and its penetration into lung tissue, bronchial mucosa and pleura.

Cefonicid pharmacokinetics in serum and tissue penetration into the lung parenchyma, bronchial mucosa and pleura were studied in 39 patients undergoing lung excision for malignancy. Cefonicid concentrations in serum and tissues samples were assayed at different times after a single 1 g intramuscular administration. The concentrations observed were much higher than the reported minimal inhibitory concentrations for the microorganisms commonly responsible for bronchial and pulmonary infections and therapeutic concentrations were still detectable in the tissues 24 h after dosing. Kinetic findings demonstrated a similar half-life for cefonicid in tissues and in serum. These data provided a further kinetic explanation for the observed clinical efficacy of cefonicid with a single daily dose.

Semisynthetic beta-lactam antibiotics. VI. Synthesis and antimicrobial activity of alpha-hydrazonobenzylcephalosporins.

Using as a model cephalosporins with an alpha-hydroxyimino moiety in the side chain, some new (E)-alpha-hydrazono and alpha-methylhydrazono benzyl cephalosporins were prepared. While the synthesis of methylhydrazono-derivatives (I a-d) involved direct condensation of the methylhydrazionacid (II a-b) with a protected 7-aminocephalosporanic derivative, the N-unsubstituted compounds (I e-f) had to be prepared from the N-acyl protected hydrazono acids (III a-d). The cephalosporin (I f) was also obtained as Z-isomer by condensation of the corresponding alpha-oxo compound with 4-nitrobenzyloxycarbonylhydrazine, chromatographic separation of the obtained E-Z mixture, and hydrogenolysis of the Z form. The in vitro antibacterial evaluation showed that N-methyl substitution is favorable among the E compounds, whereas among the N-unsubstituted hydrazono derivatives, the compound Z-(I f), although less stable, is much more potent than the corresponding E-isomer.

Pharmacokinetics of norfloxacin in chronic renal failure.

Norfloxacin is an antibacterial drug chiefly eliminated by the kidney and therefore useful in the treatment of urinary tract infections. To study its pharmacokinetics in chronic renal failure, we administered a single oral dose of 400 mg to 14 patients and 6 controls with normal renal function. Patients were divided into three groups according to the severity of renal failure. Norfloxacin was measured in serum and urine by bioassay. Serum half-life in controls was 3.87 hours and prolonged to 5.85 hours in group I (creatinine clearance 80-45 ml/min), 7.25 hours (p less than 0.05) in group II (creatinine clearance 44-20 ml/min) and 8.34 hours (p less than 0.01) in group III patients (creatinine clearance less than 20 ml/min). A good linear correlation between the elimination rate constant and creatinine clearance (r = 0.79, p less than 0.01) has been found. Total urinary excretion in the 72 hour period after administration achieves 40.4% in controls, falls to 23.5% (p less than 0.05), 15.6% (p less than 0.01) and 8.2% (p less than 0.01) of administered dose in groups I, II and III, respectively. Similarly, urinary concentrations decrease in all patient groups with respect to controls. Our data show that effective urinary antibacterial concentrations of norfloxacin after 400 mg single oral dose were obtained even in patients with severe renal failure. In these patients systemic accumulation after repeated dose administration is a probable event. Therefore, dosage adjustment is advisable in patients with creatinine clearance less than 20 ml/min, although it will inevitably cause lower urinary concentrations.