HUMAN PSYCHOPHARMACOLOGY, VOL. 10, 243-250 (1995)

BOOK REVIEWS

Book Reviews

Anxiolytic Beta-Carbolines: From Molecular Biology to the Clinic. Edited by Springer-Verlag, Berlin, 1994. pp.151. DM.148. ISBN 3-540-5714&2.

The first benzodiazepines were discovered in the 1950’s and shown to have anxiolytic, sedative, anticonvulsant and muscle relaxant properties. The plethora of benzo- diazepines discovered since that time are remarkably similar in their clinical and pharmacological actions, dif- fering mainly with respect to their potency, duration of action and presence of active metabolites.

Since the sensational research of Squires and Braes- trupp, and Moehler and Okada in 1977, it is now known that benzodiazepines with similar pharmacological properties ail act as full agonists on the benzodiazepine- GABA-A receptor complex. The complexity of the ben- zodiazepine-GABA-A complex only became apparent fairly recently with the discovery that the IxnzodiazCpine receptor can respond in various directions depending on the nature of the ligand. Thus full inverse agonists have the opposite effect of full agonists in that they cause anxiety, are proconvulsant and cause muscle spasm. The importance of this discovery has now led to the design of drugs with selective affinity for the various subtypes of benzodiazepine receptors thereby enabling the ben- eficial effects (e.g. the anxiolytic action) to be maintained without the sedative effects. Abercarnil is an example of a benzodiazepine ligand with a beta carboline struc- ture which in preliminary studies appears to be anxiolytic without the adverse effects usually associated with full agonists.

The present monograph is devoted to an examination of the properties of the beta carbolines with particular emphasis on abercarnil. Although the first beta carbo-

lines to be discovered were inverse agonists of the benzo- diazepine receptor, it soon became apparent that differ- ent types of beta carbolines have full agonist effect. The diverse pharmacological properties of these compounds are described in this important monograph by Schmie- chen and colleagues.

Lueddens and Turner in their chapters describe the subtypes of GABA-A receptor that have been discovered following the application of molecular biological tech- niques while Pribilla and co-workers shows how abercar- nil is unique in exhibiting full agonist properties for some benzodiazepine receptor subtypes but only partial ago- nist properties for others. These properties may be important in explaining the anxiolytic effects (full ago- nist) with only weak muscle relaxant, sedative and ataxic effects (partial agonist). These aspects are ably covered by Biggio et al. and Stephens et al.

Later chapters convincingly show that, in monkeys and dogs, abercarnil does not cause tolerance or depen- dence despite their being experimental evidence that it can prevent withdrawal effects when conventional benzo- diazepines are abruptly withdrawn after chronic treat- ment of rats.

Despite the fascinating experimental findings that are reported in this monograph, it still remains to be shown that abercarnil has selective anxiolytic action in man without any of the adverse effects often associated with the benzodiazepine. The final chapter of the monograph by Duka and colleagues is cautiously optimistic but only the outcome of properly developed clinical trails will tell.

B. E. LEONARD GaIway. Ireland

Cerebral Ischemia arid Basic Mechanisms. Edited by A. HARTMAN, F. YATSU and W. KUSCHINSKY, Springer- Verlag, Berlin, 1994, pp.443. 298 DM. ISBN 3-540-56573-6.

The high incidence of cerebrovascular diseases and the lack of successful treatment for stroke and related dis- eases has led to a large growth in research into the exact mechanisms of ischaemic cell death. The advances in technology have made it possible to measure the exact

changes that occur following an ischaemic incident. The present volume is a series of monographs that outlines the proceedings of an international conference on cerebral ischaemia and basic mechanisms held in Bad Scha- chedlake Constance, Germany in June 1992.

The book is outlined in 44 sections under seven main headings (energy metabolism, acidosis, intracellular messengers, excitatoiy amino acids and excitotoxicity, free radicalslprotein synthesis, gene expression and leuko- cytes, microcirculation and the coagulation system). All

0 1995 by John Wiley & Sons, L,td.

244 BOOK REVIEWS

the relevant sections dealing with each event that occurs in an ischaemic situation are grouped together.

The first four sections outline the role that changes in energy metabolism play in ischaemia and contributors include W. D. Heiss, R. S. J. Frackoivick, G. M. Teasdale and J. McCulloch. These sections focus on the new ad- vances in CT and PET scanning that have allowed the exact areas of energy failure to be mapped in vivo after an ischaemic incident.

The next six sections discuss the role of acidosis in ischaemic brain injury. In the second of these Strong and Monteiro used acidosis (potassium imaging, regional pH, etc.) as markers for the penumbra and a target for treat- ment. In the following sections the role of astrocytes and the use of in vivo NMR to assess ischaemic damage are examined in depth.

There follows a large portion (eight sections) on in- tracellular messengers. The first of these discusses the use of calcium channel blockers and monosialoganglioside GM1 as neuroprotective agents. De Graba and Girotta examine the threshold of calcium influx after global and focal ischaemia and ask if this has implications for the window of therapeutic opportunity. As many calcium dependent enzymes such as protein kinase C, calmodulin (CaM), kinases, calpain I and phospholipase A, are be- lieved to be activated during ischaemia and may play a major role in neuronal death, these investigators used an immunohistological method to stain for CaM in global and focal models of ischaemia. Their results indicate that this technique may provide valuable information into the development of ischaemia and the best time for inter- vention. This section is concluded by an evaluation of intracellular messenger receptors following 4 VO in the rat by the Japanese group of Onodera and coworkers. They examined the density of protein kinase C ([3H] phorbal 12, 13-dibutyrate), inositol 1,4,5-triphosphate, GTP and L-type calcium channel receptors 1,3,6,12 h, 1,

27 and 100 days after surgery and found large losses in these receptors in the CA1 hippocampal region 7 and 100 days post-occlusion.

The role of excitatory amino acids is discussed in the following four sections of the book and contains an excel- lent chapter by Waxman et al. on in vitro ischaemia in the hippocampal slice. There follows a small section on free radicals focusing on the role of NO synthase inhibitors as neuroprotective agents and examining the function of protein synthesis and gene expression in ischaemia. This leads nicely into five sections on gene expression in ischae- mia. In the first of these Suga and Nowark (Jr) examined the expression of hsp 70 following global ischaemia in the gerbil. In the subsequent sections the expression of c-fos and c-jun are examined. It is clear that this research will provide valuable insight into cell defence mechanisms and these genes can also be used as markers of ischaemic damage. These genes may also help elucidate some of the possible causes of ischaemia and as described by Yatsu this may have possible clinical relevance.

The final portion of the book contains 11 sections on the microcirculation and coagulation systems. This sec- tion of the book contains some excellent photographs on the microcirculation and detailed examination of the role of leukocytes and neutrophils in ischaemia.

In conclusion, this volume is a valuable addition to anyone interested in the areas of cerebral ischaemia, neu- rodegeneration and cerebrovascular disorders. There are more than 150 contributions from experts in all areas of ischaemia. The mix of research from both research scien- tists and clinicians and the detailed investigations into the exact mechanisms of cell death pave the way for the development of anti-ischaemic agents.

MICHAEL O’NEILL Galway, Ireland

Alzheimer’s Disease: Optimizing Drug Development Strat- egies. By NEAL R. CUTLER, JOHN J. SRAMEK and AMY E. VEROFF. John Wiley & Sons, Chichester, UK, 1994. ISBN 0-471-951455.

The authors, from California Clinical Trials, are to be congratulated in producing a relatively short monograph that summarizes many of the practical details which re- searchers wish to know in designing a drug trial in Alz- heimer’s disease. Nine chapters cover the most important areas of research starting with a short overview of the pathology of the disease followed by chapters on diag- nosis, and on the difficulties found by researchers in

developing a relevant animal model of Alzheimer’s dis- ease. The importance of imaging techniques, and the value of a computerized neuropsychological test battery to assist in assessment and diagnosis form the basis of two further chapters. The problems involved in developing a simple biochemical test of cholinergic function in humans is also critically discussed and evidence presented to dem- onstrate the limited value of measuring red blood cell cholinesterase, or salivary amylase, activity.

The concluding three chapters, (on subject selection and sample size, on methods for determining the correct dose of a potentially useful drug and of the need to take into account the effect of age on measuring response) are