Combination treatment for acute ischemic stroke: A ray of Hope?

Fagan, Susan C.; Bowes, Mark P.; Berri, Samir A.; Zivin, Justin A.

doi:10.1016/s1052-3057(99)80043-3

Cited by 10 publications

(4 citation statements)

References 54 publications

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“…There is a clear Janus face of defense mechanisms in the CNS, since each individual dysfunction has its own destructive and protective potential. The balance of these mechanisms in their magnitude and during the course of stroke by neuroprotective factors might offer the chance to exert influence on the stroke outcome (primary neurological endpoints such as infarct size and functional deficit) [20]. Besides tissue plasminogen activator, no successfully tested preclinical agent succeeded in acute stroke therapy in human, although most of them selectively target one of the above mechanisms or showed promising effects in animal models [21].…”

Section: Resultsmentioning

confidence: 99%

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia

Ulbrich

Zendedel

Habib

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Resultsmentioning

confidence: 99%

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia

Ulbrich

Zendedel

Habib

et al. 2012

The Journal of Steroid Biochemistry and Molecular Biology

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“…In the light of the multiple cell death mechanisms it may not be possible for a single neuroprotectant to have a long term protective effect. An alternative approach might be to intervene much further downstream, providing a cocktail of inhibitors against the separate death effector mechanisms (Culmsee et al, 2004;Fagan et al, 1999;Rogalewski et al, 2006). The combination of two different agents might allow the doses of the individual drugs to be diminished, leading to reduced side effects (Park et al, 2007;Wang et al, 2012).…”

Section: Development Of Neuroprotective Strategies In the Light Of Thmentioning

confidence: 99%

Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection

Puyal

Ginet²,

Clarke³

2013

Progress in Neurobiology

192

146

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There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death--apoptosis, autophagic cell death and necrosis--emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.

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“…Taking only one agent and one dose from each category, possible combination regimens number 128 (2 7 ). Head-to-head testing of all combinations of one agent/ dose from each category would require 8,128 trials and over 4 million patients.…”

Section: Alzheimer Diseasementioning

confidence: 99%

“…The most recent report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure lists 29 combination antihypertensive formulations currently marketed in the United States [2]. Combination therapies are also currently employed or in active development for conditions as diverse as rheumatoid arthritis [3], multiple sclerosis [4,5], acute myocardial infarction [6], acute ischemic stroke [7], male pattern hair loss [8], tobacco addiction [9], osteoporosis [10], HIV and other infections [11,12], gastritis [13], emesis [14], mood disorders [15], organ transplantation [16], atherosclerosis [17], and congestive heart failure [18], to offer only a few exemplars. Indeed it is hard to name a medical condition for which clinical researchers are not currently conducting or contemplating trials of combination medication regimens.…”

mentioning

confidence: 99%

Combination Therapies and the Theoretical Limits of Evidence-Based Medicine

Saver

Kalafut²

2001

Neuroepidemiology

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Background: Advances in molecular pharmacology and surgical, endovascular, and radiation techniques have yielded multiple effective or promising, and potentially complementary, classes of treatments for virtually every major medical disorder. Consequently, determining the optimum combination of therapies for a condition is a burgeoning challenge to clinical trialists and practicing physicians. Methods: General phase III trial strategies for testing combination regimens are described, and then applied to two illustrative conditions, Alzheimer disease and ischemic stroke. Results: Strategies for testing combination regimens include: head to head trials of all combinations, which lead to unwieldy trial numbers; very large multi-arm trials, which impractically delay interval information on regimen utility; and hierarchical, serial clinical trials. Systematic literature review revealed seven classes of agents already approved or in late phase III testing for preventing the development or slowing the progression of Alzheimer disease and five for ischemic stroke prevention. Possible combination regimens number 128 (2⁷) for Alzheimer disease and 32 (2⁵) for ischemic stroke. Hierarchical, serial clinical trials would permit identification of the optimum combination of these agent classes for Alzheimer disease through 127 trials, enrolling 63,500 patients, requiring 286 years; for ischemic stroke through 31 trials, enrolling 186,000 patients, requiring 155 years. Conclusions: Marked limitations in the ability of clinical trials to interrogate varied treatment combinations to determine the most effective ensemble exist, and their scope is widely underappreciated. Steps that may attenuate, though not eliminate, the challenge of a surfeit of combination treatment regimens include preclinical testing to identify the most promising regimens, use of surrogate outcome measures in exploratory clinical trials, and use of hierarchical, serial and factorial phase III trials.

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Combination treatment for acute ischemic stroke: A ray of Hope?

Cited by 10 publications

References 54 publications

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia

Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia

Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection

Combination Therapies and the Theoretical Limits of Evidence-Based Medicine

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