The efficiency of multi-target drugs: the network approach might help drug design

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug design paradigm will depend not only on a new generation of computer models to identify the correct multiple hits and their multi-fitting, low-affinity drug candidates but also on more efficient in vivo testing.Comment: 6 pages, 2 figures, 1 box, 38 reference

Neostigmine antagonism of vecuronium paralysis during fentanyl, halothane, isoflurane, and enflurane anesthesia

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Failure of metronidazole to alter a vecuronium neuromuscular blockade in humans

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Evolution of vecuronium requirements for stable mechanical effect: Comparison with or without previous succinylcholine administration

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Clinical and pharmacological actions of a bolus injection of suxamethonium: Two phenomena of distinct duration

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cardiovascular and Neuromuscular Effects of Three Steroidal Neuromuscular Blocking Drugs in Dogs (ORG 9616, ORG 9426, ORG 9991)

Developmental research has been directed toward creating nondepolarizing muscle relaxants with an onset time and duration of actions shorter than that of vecuronium or atracurium. We determined the cardiovascular and neuromuscular effects of three new and promising nondepolarizing muscle relaxants in six dogs anesthetized with halothane. Each dog was anesthetized four times (each time separated from the others by at least 1 wk); one muscle relaxant was studied each time. Three doses (one, three, and five times the ED90) were given as intravenous bolus injections. ORG 9616 and ORG 9991 had shorter durations of action than ORG 9426. The duration of action of the doses that were five times the ED90 was 18 +/- 5.88 and 15.8 +/- 4.41 min (mean +/- SD) with ORG 9616 and ORG 9991, respectively, as compared with 39.7 +/- 17.15 min with ORG 9426 (P less than 0.05). ORG 9426 was virtually free of cardiovascular effects. The ED90 doses of ORG 9616 and ORG 9991 did not cause cardiovascular effects; the doses of three and five times the ED90 caused small decreases in mean arterial blood pressure and increases in heart rate. Mean arterial blood pressure decreased from 99 +/- 10.2 to 88 +/- 13.1 mm Hg and from 98 +/- 11.7 to 77 +/- 8.1 mm Hg with five times the ED90 dose of ORG 9616 and ORG 9991, respectively. The authors conclude that ORG 9426 has a duration of neuromuscular blockade that is probably similar to vecuronium, and one that is free of cardiovascular effects

The Neuromuscular Blocking Effects and Pharmacokinetics of ORG 9426 and ORG 9616 in the Cat

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P less than 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 +/- 5.7% (SD) and 6.0 +/- 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 +/- 9.2% and 52.4 +/- 9.2% of an injected dose of ORG 9426 and 35.7 +/- 12.2% and 46.8 +/- 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 +/- 6.5% and 33.5 +/- 15.6% of ORG 9426 and 14.0 +/- 3.2% and 18.1 +/- 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively

The Neuromuscular Blocking Effects and Pharmacokinetics of ORG 9426 and ORG 9616 in the Cat

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P less than 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 +/- 5.7% (SD) and 6.0 +/- 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 +/- 9.2% and 52.4 +/- 9.2% of an injected dose of ORG 9426 and 35.7 +/- 12.2% and 46.8 +/- 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 +/- 6.5% and 33.5 +/- 15.6% of ORG 9426 and 14.0 +/- 3.2% and 18.1 +/- 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively