Preclinical drug evaluation for combination therapy in acute stroke using systematic review, meta-analysis, and subsequent experimental testing.
There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more 'realistic' model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes; nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective.
Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia. ocollins@unimelb.edu.au
Victoria E
VE
O'Collins
Malcolm R
MR
Macleod
Susan F
SF
Cox
Leena
L
Van Raay
Elena
E
Aleksoska
Geoffrey A
GA
Donnan
David W
DW
Howells
D000367:Age Factors; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D008278:Magnesium Sulfate / Q000627:therapeutic use*; D008550:Melatonin / Q000627:therapeutic use*; D008911:Minocycline / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D012720:Severity of Illness Index; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D008278:Magnesium Sulfate; D008911:Minocycline; D008550:Melatonin