Biomedical subjects
Publications and source records attributed to S Ripa.
A series of derivatives of 2,2'-bipyridyl-6-carboxamidoxime which combine structural features of antitumor compounds and of the antifungal antibiotic caerulomycin have been synthesized and evaluated for antitumor, antibacterial and antifungal activities. Many of the studied compounds displayed significant antifungal activity.
The pharmacokinetics of cefoperazone was determined following single and multiple intravenous and intramuscular administrations in man. Ten subjects at each dose level were given eleven successive doses, at 12 h intervals of 500 and 1000 mg i.m. and i.v.. Serum concentrations and urinary excretion were determined in all subjects after the first, fifth and eleventh doses. The first i.m. doses yielded mean peak serum levels of 37 micrograms/ml and 76 micrograms/ml at 1.0 h after injection. The first i.v. doses yielded mean serum levels of 93 and 180 micrograms/ml at 5 min after the injection. No tendency toward drug accumulation was observed on multiple dosage. The pharmacokinetics could be described by a linear, open, two-compartment model of drug distribution. The terminal serum half-life (2.1-2.4 h after i.v. doses and 2.6-2.8 h after i.m. doses) remained essentially constant over the period of the study by dose levels. The no-significant differences of areas under the curve between the two routes, at two doses, show the absolute bioavailability of cefoperazone was about 95% following i.m. administration. The high binding to serum proteins (90%) influences favourably the pharmacokinetic parameters of cefoperazone. It yielded high and prolonged serum concentrations and has very useful distribution properties. These favourable properties, together with its good antibacterial activity, suggest that cefoperazone will be effective in treating bacterial infections in human beings.
Levels of cefatrizine, a new oral cephalosporin, were determined in blood and in tonsils, paranasal sinus secretions and middle ear exudates from 18 patients with acute infections at these sites. Three and six hours after administration of 500 mg cefatrizine satisfactory levels of the antibiotic were found at all the sites examined. Levels in the tonsils and middle ear were higher than those in blood, while lower levels were recorded in nasal secretions.
366 human staphylococci were tested for the production of coagulase and thermonuclease and were subdivided into lyogroups. 98% of the isolates showed uniformly positive or uniformly negative results for the production of two enzymes. All uniformly positive strains belonged to the species Staphylococcus aureus, whereas coagulase-thermonuclease negative strains were easily subdivided into five lyogroups. Seven strains produced only one of two enzymes and were identified by analysis of their bacteriolytic activity. Two of these strains were identified as Staphylococcus aureus, one was coagulase negative and the other thermonuclease negative.
The oral bioavailability of cefatrizine was studied in four groups, each of ten healthy young male volunteers. Capsules and suspension formulations were each administered at doses of 250 and 500 mg. Both the capsules and suspensions had mean peak plasma levels at 1.6 h at both dose levels. Mean peak plasma levels were 4.1 and 4.3 micrograms/ml for the 250 mg capsule and suspension doses respectively and 7.1 and 7.5 micrograms/ml for the 500 mg capsules and suspension doses respectively. The overall mean half-life was 1.7 h. For both types of formulations and at both dose levels 63-65% of the doses were excreted in the urine as intact cefatrizine, 85% of this amount within 8 h. The overall mean renal clearance was 157 ml/min. The cefatrizine capsule and suspension formulations were completely bioequivalent in regard to both rate and extent of bioavailability. Plasma concentrations and urinary recoveries of cefatrizine were higher than those previously reported, due to precautions taken in sample collection and storage.
Fructose-1, 6-diphosphate hydrated sodium salt (FDP), intravenously injected, remarkably stimulates the production of serum lysozyme in man, rabbit, and mouse with a different kinetics in each of them: Man and rabbit show, in the first hour, a concentration peak followed by a slow decrease, whereas in mouse the concentration is less variable with time.
The antibacterial activity of cefamandole was evaluated against 120 methicillin-susceptible and methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococcal strains, using both large (10(8) CFU per ml) and small (10(4) CFU per ml) inocula. Cefamandole appeared superior to cephalothin against methicillin-resistant strains, displaying at 10 micrograms/ml a bacteriostatic and for some strains a bactericidal action against a large inoculum of bacteria.
Amoxicillin was administered at doses of 500 mg and 1000 mg, intravenously and intramuscularly to normal volunteers in a parallel study. Intramuscular amoxicillin was 100% bioavailable at both dose levels. Mean peak serum levels observed for the 500 mg and 1000 mg doses, respectively, were: i.v. (5 min after dosing) 46 and 74 micrograms/ml; i.m. (30 min after dosing) 14 and 21 micrograms/ml. Six hour trough levels ranged between 0.5 and 0.9 micrograms/ml. Between 50% and 60% of the doses were excreted in urine as intact amoxicillin in the 24 h after dosing. Almost 90% of this excretion occurred in the first 3 h after dosing. There was a statistically significant increase in mean clearance, after i.v. dosing, from the 500 mg level (14.8 l/h) to the 1000 mg level (20.7 l/h) implying that amoxicillin pharmacokinetics are non-linear over this range. Since there was very little difference between mean renal clearances at these dose levels (9.2 and 11.7 l/h, respectively) this clearance change might be due to enhancement of non-renal clearance. It would not be expected that this non-linearity would have any therapeutic influence.
The human oral pharmacokinetics of cefadroxil were studied in parallel at doses of 250, 500, and 1,000 mg in three groups of 10 healthy young male volunteers. Renal excretion of intact cefadroxil, accounted for 82, 79, and 77% of the above doses. Mean peak serum levels were dose linear: 9, 18, and 35 microgram/ml at 250, 500, and 1,000 mg, respectively. However, overall pharmacokinetics were linear only in the 250- to 500-mg dose range; apparent serum clearances were 10 liters/h, and true renal clearances were 9 and 8 liters/h at 250 and 500 mg. At 1,000 mg, apparent serum clearance dropped to about 7 liters/h, true renal clearance, dropped to 6 liters/h, and the area under the curve increased disproportionately. At 250 and 500 mg, mean half-life was about 1.2 h; at 1,000 mg, however, it was 1.6h. The nonlinear decrease in clearance could be related to saturation of active renal tubular secretion of cefadroxil between the 500- and 1,000-mg doses. Previous results indicating that cefadroxil has greater persistence than other oral cephalosporins such as cephalexin, cephradine, cefaclor were confirmed.
The pharmacokinetic of ceforanide, a new parenteral cephalosporin antibiotic, were examined at intravenous and intramuscular doses of 250, 500, and 1,000 mg in healthy male volunteers. Over the above dosing range, ceforanide pharmacokinetics were essentially linear, with plasma clearances varying from 2.2 to 2.5 liters/h. The best present overall estimate of the drug's half-life was 2.9 h. Intramuscular ceforanide was 100% bioavailable, Peak intravenous serum levels were 39, 71, and 135 micrograms/ml at the end of 30-min infusions of 250, 500, and 1,000 mg; after intramuscular injections of 250, 500, and 1,000 mg, the respective peak serum levels were 21, 38, and 69 micrograms/ml. From 80 to 85% of the above doses were eliminated as unchanged.
Single doses of 250 and 500 mg of BL-S 578 (cefadroxil), a new semisynthetic cephalosporin, were orally administered to 13 normal, healthy volunteers and serum levels determined at timed intervals for 7 h. Peak concentration was obtained at 1 1/2 h after administration of 250 mg (8.981 micrograms/ml) or 500 mg (17.861 micrograms/ml). Urniary excretion levels within 24 h after ingestion of single doses of 250 and 500 mg of cefadroxil were 89.92 and 86.34%, respectively.
BL-S 578 (Cefadroxil) is a new orally active semisynthetic cephalosporin antibiotic with broad-spectrum antibacterial activity. The new compound was evaluated in vitro in comparison with cephalexin. Some properties studies such as, antibacterial activity, binding with serum proteins and stability in acid and neutral solution at 37 degrees C for both cephalosporins were similar. In experimental infections of mice, the protective action of BL-S 578 was more effective than cephalexin against Staphylococcus aureus and Streptococcus pneumoniae. BL-S 578 was more resistant than cephalexin to the beta-lactamases produced by Klebsiella pneumoniae and Escherichia coli.
The loop method permits determining of bacteriuria without the necessity for serial dilution, and with a precision greater than that of the dip inoculum test. Results indicate that the method allows us to establish the level of bacteria present in infected urine (approximately 10(5) germs/ml) quite precisely, and furnishes reliable evaluation of high levels. Due to the small quantity removed by the loop, the possible presence of strong concentrations of chemobiotics does not influence the results, as subinhibiting concentrations easily occur with diffusion.
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The in vitro inhibitory and bactericidal activities of the investigational fluoroquinolone trovafloxacin were studied and compared with those of five other fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin, rufloxacin and sparfloxacin) against a wide range of clinical isolates from Italian hospitals. Against gram-positive bacteria, trovafloxacin was overall more active than the other antibiotics tested, including sparfloxacin, another gram-positive-oriented fluoroquinolone, and was active against all ciprofloxacin-resistant streptococci, enterococci, and listeriae, all ciprofloxacin-resistant Staphylococcus aureus isolates and most ciprofloxacin-resistant coagulase-negative staphylococci. Its antistaphylococcal activity was not affected by oxacillin resistance or susceptibility of the isolates, nor was its antipneumococcal activity affected by whether isolates were susceptible or resistant to penicillin. Against gram-negative bacteria, trovafloxacin retained a high potency mostly comparable with that of ciprofloxacin. Rufloxacin and pefloxacin were less active than the other fluoroquinolones against most test strains of both gram-positive and gram-negative organisms. Trovafloxacin minimal bactericidal concentrations usually equalled or exceeded by 2-4 times the minimal inhibitory concentration values, indicating that the compound is overall highly bactericidal.
The pharmacokinetic profile of azithromycin, after oral ingestion of 500 mg, was determined in 10 healthy volunteers. Statistical and biochemical reason seemed to indicate a zero-order absorption of the drug. The disposition of azithromycin was described by a two-compartment model (plasma compartment and extravascular compartment) with elimination from the plasma compartment. The absorption process ends abruptly after a time T = 2.3 +/- 0.49 h, from the administration. The transfer rate constant from the plasma compartment to the extravascular compartment (k12 = 0.12 +/- 0.04 h-1) and the mean residence time of the drug in the extravascular compartment (MRT2 = 43.53 +/- 13.80 h) indicate a rapid and extensive distribution of azithromycin from the serum into the extravascular fluids. The results confirmed the efficacy of a single daily dose of 500 mg per os for clinical use.
This pivotal, multicentre, double-blind, parallel-group study evaluated the efficacy and safety of cerivastatin 0.8 mg. Patients with primary hypercholesterolaemia were randomized, after 10 weeks' dietary stabilization on an American Heart Association (AHA) Step I diet, to treatment with cerivastatin 0.8 mg (n = 776), cerivastatin 0.4 mg (n = 195) or placebo (n = 199) once daily for 8 weeks. Cerivastatin 0.8 mg reduced mean low density lipoprotein-cholesterol (LDL-C) by 41.8% compared with cerivastatin 0.4 mg (-35.6%, P < 0.0001) or placebo. In 90% of patients receiving cerivastatin 0.8 mg LDL-C was reduced by 23.9 -58.4% (6th - 95th percentile). Overall attainment of the National Cholesterol Education Program (NCEP) goal was achieved by 84% of patients receiving cerivastatin 0.8 mg and by 59% of those with coronary heart disease (CHD). In the sub-population meeting the NCEP criteria for pharmacological therapy for LDL-C reduction, 74.6% of patients, including the 59% with CHD, reached the goal with cerivastatin 0.8 mg. Cerivastatin 0.8 mg also reduced mean total cholesterol by 29.9%, apolipoprotein B by 33.2% and median triglycerides by 22.9% (all P < 0.0001). Mean high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 were elevated 8.7% (P < 0.0001) and 4.5% (P < 0.0001), respectively, by cerivastatin 0.8 mg. Reductions of triglyceride and elevation in HDL-C were dependent upon triglyceride baseline levels; in patients having baseline triglyceride levels 250 - 400 mg/dl, cerivastatin 0.8 mg reduced median triglycerides by 29.5% and elevated HDL-C by 13.2%. Cerivastatin 0.8 mg was well tolerated. The most commonly reported adverse events included headache, pharyngitis and rhinitis (4 - 6%). Symptomatic creatine kinase elevations > 10 times upper limit of normal occurred in 0%, 1% and 0.9% of patients receiving placebo, cerivastatin 0.4 mg or cerivastatin 0.8 mg, respectively. Cerivastatin 0.8 mg is an effective and safe treatment for patients with primary hypercholesterolaemia who need aggressive LDL-C lowering in order to achieve NCEP-recommended levels.