ABSTRACT
UK-74505, a novel 1,4-dihydropyridine PAF antagonist, exhibited highly selective, time-dependent inhibition of PAF-induced aggregation of rabbit washed platelets (IC50 = 26.3 +/- 0.88 and 1.12 +/- 0.04 nM after 0.25 and 60 min preincubation, respectively), which became irreversible within 15 min, whereas inhibition by WEB-2086 was both independent of preincubation time (IC50 = 145.7 +/- 24.7 nM) and competitive (KI = 27.5 +/- 7.7 nM; Schild slope = 0.98 +/- 0.04). The selective inhibition of specific [3H]PAF binding by UK-74,505 exhibited a slower onset, the IC50 obtained without preincubation (14.7 +/- 2.6 nM) decreasing 2-fold at 45 min. UK-74,505 was 450-fold weaker as an antagonist of [3H]nitrendipine binding to bovine brain membranes and KCl-induced contraction of rat aorta. UK-74,505 was 10-30-fold more potent than WEB-2086 in vivo as an inhibitor of PAF-induced hypotension in rats (ED50 = 35 +/- 5.8 micrograms/kg, i.v.), cutaneous vascular permeability in guinea pigs (ED50 = 0.37 +/- 0.08 mg/kg, p.o.) and lethality in mice, with oral ED50 values of 0.26 +/- 0.03 and 1.33 +/- 0.19 mg/kg at 2 and 8 h, respectively. These data demonstrate that UK-74,505 is a potent, selective, long-acting irreversible PAF antagonist.
Subject(s)
Dihydropyridines/pharmacology , Imidazoles/pharmacology , Platelet Activating Factor/antagonists & inhibitors , Platelet Aggregation Inhibitors/pharmacology , Administration, Oral , Animals , Aorta/drug effects , Aorta/physiology , Azepines/pharmacology , Blood Platelets/drug effects , Blood Platelets/metabolism , Brain/metabolism , Brain/ultrastructure , Calcium Channels, L-Type , Capillary Permeability/drug effects , Cattle , Diltiazem/metabolism , Gallopamil/metabolism , Guinea Pigs , Hypotension/chemically induced , Hypotension/prevention & control , In Vitro Techniques , Kinetics , Male , Membranes/metabolism , Mice , Mice, Inbred Strains , Muscle Contraction/drug effects , Muscle Proteins/metabolism , Nitrendipine/metabolism , Platelet Activating Factor/metabolism , Platelet Aggregation/drug effects , Potassium Chloride/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Skin/blood supply , Triazoles/pharmacology , TritiumABSTRACT
UK-18,892, a new semisynthetic aminoglycoside, was active against bacteria possessing aminoglycoside-inactivating enzymes, with the exception of some known to possess AAC(6') or AAD(4') enzymes. This activity has been rationalized by using cell-free extracts of bacteria containing known inactivating enzymes, where it was shown that UK-18,892 was not a substrate for the APH(3'), AAD(2''), AAC(3), and AAC(2') enzymes. It was also demonstrated that UK-18,892 protected mice against lethal infections caused by organisms possessing aminoglycoside-inactivating enzymes.
Subject(s)
Bacteria/enzymology , Kanamycin/analogs & derivatives , Bacteria/drug effects , Enzyme Repression , Gentamicins/pharmacology , Kanamycin/pharmacology , Lethal Dose 50ABSTRACT
The antibacterial activity of UK-18,892, a new semisynthetic aminoglycoside, was examined against aminoglycoside-susceptible and aminoglycoside-resistant clinical isolates of gram-negative bacilli and Staphylococcus aureus. UK-18,892 had a similar degree of activity to those of amikacin and kanamycin A against aminoglycoside-susceptible bacteria but was less potent than gentamicin against all isolates except Providencia spp. UK-18,892 was highly active against aminoglycoside-resistant bacteria, inhibiting 93% of the 268 isolates examined at 12.5 mug/ml. Amikacin was similarly active, whereas gentamicin inhibited only 14% of these isolates at 12.5 mug/ml.
