The in vitro activity of teicoplanin, a new antibiotic related to vancomycin, was determined against 456 gram-positive cocci. The activity of teicoplanin in comparison with that of vancomycin was similar against staphylococci but 4 to 40 times higher against enterococci and I8-hemolytic and viridans streptococci. The single-dose pharmacokinetics of teicoplanin were studied in six healthy volunteers after administration of 3 and 6 mg/kg intravenously and of 3 mg/kg intramuscularly. The kinetic parameters after both intravenous doses were very similar. The curves for concentration in plasma for the 3-and 6-mg/kg intravenous doses showed a triexponential decline with elimination half-lives of 47.3 and 44.1 h, respectively. The percentages of the doses recovered in urine (0 to 102 h) were 43.2 and 44.1%, respectively. The areas under the plasma curves were dose related: 256.5 and 520.9 ,tg/h per ml, respectively. The bioavailability of teicoplanin after injection of 3 mg/kg intramuscularly was 90%, and the peak level was 7.1 ,ug/ml. The mean levels in plasma 24 h after the 3-mg/kg doses were 2.1 and 2.3 ,ug/ml, respectively, and the mean level in plasma 24 h after the 6-mg/kg intravenous dose was 4.2 ,ug/ml.Teicoplanin is a glycopeptide antibiotic related to vancomycin and ristocetin. It has formerly been described as teichomycin A2, one of the major components of a complex of antibiotics produced by Actinoplanes teichomyceticus nov. sp. ATCC 31121 (1, 16). Teicoplanin is active in vitro and in vivo against gram-positive microorganisms (2,5,7,8,11,12,14,15,18 with inocula of 105 to 106 CFU per spot delivered by a multipoint inoculator. Growth of the streptococci (except for Streptococcus faecalis) was supported with 5% lysed horse blood added to the medium. The antibiotics were tested in twofold serial dilutions at concentrations ranging from 0.004 to 128 ,ug/ml. The plates were incubated overnight at 36°C, except those containing oxacillin and inoculated with staphylococci, which were incubated at 30°C for 24 h. The MIC was read as the lowest concentration of antibiotic which allowed no visible growth.Pharmacokinetic study design. Six healthy male volunteers participated in this study after providing informed consent. They ranged in age from 22 to 23 years and averaged 74.3 ± 6.4 kg (mean ± standard deviation) in weight and 1.93 ± 0.10 m2in surface area; mean creatinine clearance was 108.4 + 14.9 ml/min. They were considered to be normal on the basis of medical history, renal and liver function tests, comnplete blood count, and urinalysis. A history of hypersensitivity to drugs was not present in any of the study subjects.Teicoplanin was administered in a triple-crossover design at the following intravenous and intramuscular doses (strictly adjusted per kilogram of body weight): 3 and 6 mg/kg (in 20 ml of physiological saline) intravenously (i.v.) through a forearm vein as a slow (5-min) bolus injection, and 3 mg/kg (as 100 mg/ml saline solution) intramuscularly (i.m.), deep in the lateral gluteal region. The dif...
A s bstract. Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p < 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol.The hypothesis that short-term regulation of HMGCoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dosedependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant
The phannacokinetics of piperacillin were studied in a total of 26 Caucasian normal male volunteers. Single intramuscular doses of 0.5, 1.0, and 2.0 g were given to three groups, each containing eight volunteers. Mean peak serum concentrations of 4.9, 13.3, and 30.2 jig/ml were assayed at 30 to 50 min, and measurable levels were present up to 4, 6, and 8 h, respectively, after dosing. Single intravenous bolus doses of 1.0, 2.0, 4.0, and 6.0 g were given to four groups of five subjects, and mean serum concentrations of 70.7, 199.5, 330.7, and 451.8 ,jg/ml were measured at the end of the injections. The antibiotic had a mean terminal serum half-life of 60 to 80 min after the intramuscular doses and 36 to 63 min after intravenous administrations, depending on the dose. The apparent distribution volume was 20 to 24 liters/1.73 m2, and distribution volume at steady state was 16 to 19 liters/1.73 M2. Mean urinary recovery in 24 h was 74 to 89% for the intravenous doses and 57 to 59% for the intramuscular doses. The piperacillincreatinine clearance ratios indicated that the proportion of renal excretion of piperacillin through tubular secretion was 56 to 73%, and this was confirmed by the renal clearance data from eight volunteers receiving probenecid treatment before the piperacillin dose. Probenecid (1 g given orally before administration of piperacillin) increased peak serum concentration by 30%, terminal serum half-life by 30%, and the area under the plasma concentration curve by 60%, and it decreased the apparent distribution volume by 20% and the renal clearance of the intramuscularly administered (1 g) antibiotic by 40%. Injections of piperacillin by both parenteral routes were well tolerated.Piperacillin (T-1220) is the generic name for sodium 6-[D(-)-a (4-ethyl-2,3-dioxo-1-piperazinylcarbonyl-amino)-a-phenylacetamido] penicillinate, a new semisynthetic aminobenzyl penicillin derivative with an unusually wide spectrum of activity (2,7,9). In vitro testing showed piperacillin to be active against all members of the Enterobacteriaceae, including Klebsiella (of which 58% were inhibited by 8 ,ig/ml), and also against Pseudomonas aeruginosa. The activity of piperacillin was at least equivalent, but generally superior to, that of ampicillin and carbenicillin, especially against Enterobacter species, Klebsiella species, Serratia marcescens, all Proteus species, including the indole-positive species, and Providencia species. Most striking was its activity on P. aeruginosa, of which 50% were inhibited by 2 ,ug/ml and 83% were inhibited by 4 jig/ml (9).Klebsiella pneumoniae, Escherichia coli, P. aeruginosa, Enterobacter species, and, increasingly, S. marcescens are, the major organisms causing life-threatening infections in debilitated patients. The activity of ampicillin is virtually limited to E. coli; that of carbenicillin is extended to Enterobacter species, S. marcescens, and P. aeruginosa, but the majority of the latter species are only inhibited by carbenicillin at concentrations of 32 jug/ml or above. The subs...
The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.
1 Ranitidine single dose pharmacokinetics and absolute bioavailability have been studied in five healthy male volunteers. Following an overnight fast, 150 mg was given intravenously as a bolus injection or orally as a tablet formulation to each subject on separate occasions. 2 Following intravenous administration, plasma levels declined biexponentially. The mean (+ s.d.) distribution half-life (t2¼a) was 6.6 + 1.6 min; plasma half-life (t,12/3) was 1.7 + 0.2 h; the volume of distribution (V) was 96 + 9 1; total body clearance (CL) was 647 + 94 ml/min and renal clearance (CLR) 520 + 123 ml/min. 3 Following oral administration plasma levels showed a bimodal pattern with a first peak at 1.1 + 0.4 h and a second peak at 3 + 0 h. The absolute availability was 60 + 17%. The plasma half-life (t/2) of 2.3 + 0.4 h was significantly longer (P < 0.05) after oral than after i.v. administration. 4 Renal excretion of unchanged ranitidine accounted for 79 + 9% of the dose after i.v. administration and for 27 + 7% after oral administration. 5 Our results suggest a more extensive biotransformation of ranitidine and biliary excretion of metabolites after oral administration while i.v. administered ranitidine is preferentially excreted unchanged in the urine.
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