Preclinical Drug Evaluation for Combination Therapy in Acute Stroke Using Systematic Review, Meta-Analysis, and Subsequent Experimental Testing

Abstract

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.

Superiority of Preventive Antibiotic Treatment Compared with Standard Treatment of Poststroke Pneumonia in Experimental Stroke: A Bed to Bench Approach

“…For example, neuroprotective effects have been shown for the antibiotics ceftriaxone 35 and minocycline, notwithstanding that the latter failed to prove efficacy in a recent elaborate preclinical study. 36 However, in a previous study, treatment with a gyrase inhibitor had no further neuroprotective effect when infections were prevented by restoring immune function via adoptive cell transfer. 14 Thus, neuroprotection by antibiotics may be mediated rather indirectly by preventing or mitigating the infection-induced systemic inflammatory response.…”

The Role of Neuroplasticity and the Immune System in Recovery from Strokes and Other Forms of Brain Trauma

“…Studies in animals of the effect of ischemic strokes have found minocycline to have beneficial effect on post-stroke deficits [12]. Minocycline is a broad-spectrum antibiotic of the tetracycline class that has Immuno suppressing effects, to also have a neuroprotective effect and it can reduce inflammatory reactions to decaying cells and reduce the size of the infarct by as much as 40%.…”

A Discussion of the Role of Complex Evolved Systems in the Development of Invasive Cardiovascular Interventions as Illustrated by the Blalock- Taussig Shunt and Intra-Arterial Stents

“…Both the law and funding priorities must change, as it is unethical to fund projects with such a small probability of success [67,[401][402][403][404][405][406][407][408][409][410][411][412][413][414][415][416][417]. Moreover, society accepts the moral cost of animal experimentation only when it leads to safer drugs as a matter of routine, and even then many do not accept animal experimentation at all.…”