Stroke Therapy: Basic, Preclinical, and Clinical Directions.

Until recently, stroke books could generally be categorized as descriptions of either neurological deficits or rehabilitative approaches, reflecting a widespread nihilism about the prospects for altering the acute pathophysiology in a clinically useful way. That it is now possible to note that a book devoted to developments in drug treatment for acute stroke enters a field crowded with rivals is an indication of how radically our thinking has been changed by the explosion of scientific and clinical activity catalysed by the first demonstration of neuroprotection in the late 1980s. Stroke Therapy contains little that can be dated back beyond 1988. The preface states the intention of presenting a `bench to bedside' overview of stroke therapy, appealing both to clinicians and to basic scientists, and with the emphasis on fostering understanding of the drug development process. The target audience is very much clinician scientists in the US academic mould, rather than the British clinician, with a further very clear aim towards those in the pharmaceutical industry wishing to gain a quick overview of particular therapeutic areas. The competition in this field is already quite intense. Several all-encompassing tomes of US or European parentage have been published in the last 12 months, providing comprehensive coverage of both basic and clinical aspects of stroke, but more clearly aimed at the clinical audience. The much bigger, glossier and less expensive single volume Primer on Cerebrovascular Diseases consists of brief reviews on a huge range of subjects, including basic pharmacology and pathophysiology, but extending to all manner of clinical topics, and is aimed at clinicians entering stroke research. A number of smaller texts target niche areas, including books covering neuroprotective agents and the clinical pharmacology of cerebral ischaemia. Does Stroke Therapy bring anything to tempt stroke physicians or researchers to add to their already-groaning shelves? The book is organized into 16 chapters, the first 12 of which are preclinical and the last four clinical, each one a review that can stand alone. The authors are a mixture of basic scientists, many employed in the pharmaceutical industry, and clinicians, only one of whom practises outside North America. The distribution of chapters reflects accurately the focus of the book, which is firmly in the field of the basic pharmacology and preclinical study of cerebral ischaemia in animal models. Moreover, the agenda follows very closely that of the pharmaceutical industry, with all the therapeutic approaches discussed being drug-based and overwhelmingly geared towards the concept of neuroprotection, which sadly remains an area of wholly preclinical relevance after repeated failures to translate findings in animals to man. After an introductory overview, and a review of animal models of cerebral ischaemia, individual chapters discuss the preclinical pharmacology, pathophysiology and areas of potential intervention, for glutamate, GABA, adenosine, sodium and calcium channels, nitric oxide, apoptosis, intracellular processes mediating ischaemic injury, inflammation, free radicals and brain repair processes. The four clinical chapters then present reviews of clinical trial methodology, thrombolysis, perioperative stroke, and a summary of recent clinical trials. There are some excellent contributions that provide the reader with an objective overview of their topics. My personal preference was for those chapters in which the authors had adopted a critical approach to their field and led the discussion from the basic chemistry and pharmacology through to clinical applications, emphasising at every stage the evidence for and against importance to human stroke therapeutics. Those who assumed the relevance of their topics without feeling the onus to prove it I found least convincing. This feeling stems largely from a fact reflected in the sheer range of subjects covered here: although 12 years ago nothing was known to be neuroprotective, it now seems that everything is. In the absence of clinical data to support the primacy of any single mechanism, it is important for all involved in stroke therapeutics to be able to form as objective a view as possible of the areas most likely to give rise to useful treatments. My own nagging feeling that apoptosis is of peripheral importance to stroke, but has been pushed to the front by virtue of having a large number of pathways amenable to measurement using commercially available assays, has not been dispelled by the contribution here, for instance. Chapters that are highly recommended in their entirety are Ed Hall's review of free radical pathophysiology, a nicely objective view of inflammatory responses by Leonardo Pantoni and the late Julio Garcia, and Colin Campbell and Jackie Hunter's critique of animal models (although this last would benefit from some illustrations). The chapter on intracellular events associated with ischaemia establishes a framework for assessing the potential of associations being causally important. On a more clinical note, Greg del Zoppo provides a characteristically excellent review of thrombolysis, and Seth Finklestein and Steven Cramer argue convincingly for the therapeutic potential of enhancing CNS plasticity in stroke recovery. Elsewhere, reviews of glutamate, GABA and ion channels are strong and comprehensive on basic pharmacology, but stray into commentary on clinical results that is often patchy superficial and out of date. These problems should have been ironed out by editing, which overall was one of the major weaknesses of the book. Other authors choose to ignore clinical trials in the field entirely, the enlimomab study for example being absent entirely from the chapter on inflammation. A few of the preclinical contributions I found less successful, and would suspect a fairly thorough basic knowledge of the topics to be necessary in order to place them in adequate context. The review of adenosine pharmacology quickly drowns the reader in such a deluge of acronyms and chemical structural information that I suspect only medicinal chemists would be left afloat. The nitric oxide review dismisses the large and confusing literature on its effects in cerebral ischaemia models in a few sentences and devotes most of its space to speculative studies on the interactions of NO with apoptosis, growth factors and metabotropic glutamate receptors, quoting exclusively from the sort of model that seems a great distance removed from anything of clinical relevance. The apoptosis section makes too many assumptions, and rather selectively concentrates on discussions of gene therapy while ignoring other anti-apoptotic strategies. Although probably an innocent assumption of the reader's level of basic knowledge, it also comes over as somewhat discourteous to omit reference to the original description of the process, a task left to the Introduction. The few clinical aspects that are covered are very much those that are of interest to those in the pharmaceutical industry, and have an air of a `need to know basis' about them. Sherman and Benavente's chapter on trial design reads like a shopping list for the pharmaceutical physician who has just been parachuted in to set up a stroke trial after a career in Alzheimer's. The review of perioperative stroke is interesting, but would have been better placed in the larger context of pre-emptive neuroprotection (where is subarachnoid haemorrhage, for example?). Justin Zivin and Leonard Miller finish off with a survey of clinical trials to date, and a singularly NINDS-centred view of the reasons for their failure. Stroke Therapy suffers as a book through lack of editing. Each chapter comes across as a wholly independent review. If read in its entirety, the internal inconsistencies and stylistic variations are irritating. To quote a few examples, the chapter on glutamate pharmacology states clinical trials of aptiganel and ACEA 1021 to be ongoing, while in a later chapter both are correctly identified as having been terminated for some time; models discussed heavily in relation to GABA and NO are not addressed in the chapter on animal models, making it difficult for the reader to place the results in context; a succession of preclinical chapters start with near-identical restatements of basic stroke epidemiology; the discussion of perioperative stroke relies on data for acadesine, an adenosine modulator that is not discussed in the adenosine chapter; and there are contradictory descriptions of clinical trial phases. The Introduction as a whole, and large parts of the GABA and adenosine chapters, would benefit from summarizing, rather than reporting experimental detail. The clinical coverage has a US bias notable from this side of the Atlantic. The routine failure to acknowledge the potential utility of the Oxfordshire Community Stroke Project classification system in trial design must impede the reader's understanding of why chlormethiazole remains in clinical development after a superficially `negative' phase III trial. The slightly self-congratulatory view of the NINDS alteplase programme that led to the licensing of rtPA would have benefited greatly from some alternative views. While important points are made about the inadequacy of too many pharmaceutical company approaches, the programme was not especially more rigorous than that of many other trials, and it could be argued that the NINDS trial simply had the luxury of time to recruit enough patients within a 3 hour time window without fear of share prices plummeting. The review of stroke trials omits all mention of magnesium, a subject admittedly close to my heart, but which had recruited more patients to phase II and III trials by mid-1998 than had a number of drugs prominently reviewed. The absence of in-depth discussion of clinical issues is to me the most disappointing aspect of Stroke Therapy. Finally, there are a number of apparently arbitrary but notable omissions, particularly the dismissal of heparins in a single (inaccurate) paragraph, but also the absence of antiplatelet agents, PAF antagonists, 5HT1A agonists, and any non-pharmacological approach to neuroprotection such as hypothermia. I suspect that Stroke Therapy will find a home amongst those in the pharmaceutical industry rather than with clinicians. The clinical coverage is too minimal and too specific to be of great value to clinicians, and most trainee neurologists embarking on a stroke research project will be likely to find insufficient depth on their specific field and too much on all the others to turn to this type of text. Overall, it provides a positive and upbeat approach to what has become a field littered with the debris of moribund clinical development programmes, and its lifespan ultimately will be dictated by future developments that are probably more about corporate risk analyses than about science or medicine. The existence of books such as Stroke Therapy is a testament to active and ongoing investigation in the field, and hopefully a marker of future benefits to our patients.