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...

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15-min period and 500 mg paracetamol given orally. Mean +/- SD total AUC (microgram/ml.h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 +/- 4.27 vs 21.04 +/- 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 +/- 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15-min infusion and as a 2-min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2-min bolus injection, the 15-min infusion was well tolerated without any complaints reported.

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.

Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.