ANTIMALARIAL EFFECTS OF RIBOFLAVIN DEFICIENCY

1040 TABLE

II-MEFLOQUINE AND

PYRIMETHAMINE SERUM LEVELS

24

(DAY

HOURS 1) AND 7 DAYS AFTER TREATMENT IN TWO PATIENTS WITH RESISTANT AND FIVE PATIENTS WITH SENSITIVE PLASMODIUM FALCIPARUM INFECTIONS

Hypothesis ANTIMALARIAL EFFECTS OF RIBOFLAVIN DEFICIENCY PURABI DUTTA JOHN PINTO RICHARD RIVLIN

Results

mean±SD.

pmol mefloquine/lx378=pg mefloquine/1 and mol pyrimethamine/1x 249 =pg pyrimethamine/l. "3 *None of the 7 patients had detectable levels of SP or mefloquine in their sera before

as

INTRODUCTION

treatment.

tPatients whose smears were negative on days 6 and 7.

Discussion The finding that 2 of 36 P falciparum infections exhibited RII or RIII resistance to the combination of mefloquine and sulfadoxine-pyrimethamine (MSP) in an area where there was very little resistance to SP and where mefloquine had never been used was unexpected. 24% of 31 isolates tested during the same time period produced schizonts in the presence of 16 pmol (3-2mol/1) of mefloquine and were considered resistant to mefloquine in vitro. The in-vivo resistance to MSP may be a reflection of simultaneous parasite resistance to mefloquine and SP. The mefloquine resistance could represent cross-resistance to quinine, a related 4-quinolinemethanol that has been used in Irian Jaya for many years. It is also possible, however, that there may have been antagonism between M and SP. The RII-resistant isolate from patient M-6 was sensitive to mefloquine in vitro, there was no more resistance to SP alone than to MSP, and subsequent studies have not detected any RII or RIII resistance and have revealed only slight RI resistance to SP in Jayapura (unpublished). In-vitro studies indicate some degree of antagonism between mefloquine and SP in some isolates.12 The possibility of a disadvantage of MSP compared with SP or mefloquine alone deserves careful study before MSP is more widely introduced for the treatment and prevention of malaria. We thank Purnomo, Sofyan Masbar, Margreet Djuanda, Azalia Sinto, Maman Supnatman, Iwa Wiady, Melchias Mendosir, and Silas Nari for technical support; Dr Soesilo Soerjosembodo and the Irian Jaya Health Services; Dr T. H. Oey and the staff of the Provincial Hospital of Irian Jaya; Dr B. Sanjaya and the staff of the Provincial Laboratory of Irian Jaya for support; and Dr Carlos C. Campbell and Dr Jeff Chulay for reviewing the paper. We thank Dr Keith Arnold and the Hoffman-La Roche Foundation for providing antimalarials and technical support

Supported through funds provided by US Naval Medical Research and Development Command, Navy Department, for work unit 3M16l102BSlO.AF428 and by Indonesian Ministry of Health. Correspondence to S. L. H., Malaria Branch, Stop 20, Naval Medical Research Institute, Bethesda, Maryland 20814-5055, USA; reprint requests to Publications Office, US Naval Medical Research Unit No 2, APO San Francisco, California 96528, USA. REFERENCES

B, Richle R, Peters W. The inhibitory effect of a drug combination

of mefloquine resistance Parasitol 1980; 74: 1-9.

development

in

Plasmodium

berghei.

IN most circumstances the prevalence and of A infection is made worse by malnutrition. notable exception to this is the relation between riboflavin deficiency and susceptibility to malarial infection. Numerous studies in both animals and human beings have shown that riboflavin deficiency inhibits the growth of Plasmodium. As early as 1944 Seeler and Ou1 reported that riboflavin deficiency in chicks inhibited the multiplication of Plasmodium lophurae. Siddiqui and colleagues,2 in an in-vitro study, found no effect on the growth of P knowlesi after one day of riboflavin deficiency. Thurnham and co-workers3 reexamined the effect of riboflavin deficiency on the growth of Plasmodium both in rats and in human beings. They showed that chronic riboflavin deficiency reduces parasitaemia in animals infected experimentally with P berghei and found an inverse relation between riboflavin nutritional status and malarial parasitaemia in infants.4 Thus, except for one very short-term study, there is strong evidence that riboflavindeficiency provides protection against Plasmodium infection.

severity

The isolate from patient M-6 with RII in-vivo resistance to MSP did not produce schizonts in the presence of 4-0 pmol (0-8 mol/1) mefloquine and was considered sensitive to mefloquine in vitro.

1. Merkli

Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, USA

Ann

on

the

Trop Med

Interference, Activity

with

Riboflavin

Metabolism and Antimalarial

Several studies have shown biochemical similarities between riboflavin deficiency and hypothyroidism5,6 In

2. Peters

W, Robinson BL. The chemotherapy of rodent malaria XXXV Further studies

the retardation of drug resistance by the use of a triple combination of mefloquine, pyrimethamine and sulfadoxine in mice infected with P berghei and "P on

berghei NS". Ann Trop Med Parasitol 1984; 78: 459-66. Development of mefloquine as an antimalarial drug. Bull WHO 1983;

3. Anon.

61:

169-78. 4. Hoffman

SL, Campbell JR, Marwoto HA, et al. Prolonged incubation improves the micro-scale in-vitro test for drug sensitivity of Plasmodium falciparum. Lancet 1984; i: 7-9. 5 Heizmann P, Geschke R. Determination of the antimalarial mefloquine in human plasma by gas chromatography with electron-capture detection. J Chromatogr 1984, 311: 411-17. 6. Timm U, Weidekamm E. Determination of pyrimethamine in human plasma after administration of Fansidar or Fansidar-mefloquine by means of high-performance liquid chromatography with fluorescence detection. J Chromatogr 1982; 230: 107-14. 7. Chemotherapy of malaria and resistance to anti-malarials: Report of aWHO Scientific Group. Tech Rep Ser WHO 1973; no 529: 30-35 8. Lepes T, Molineaux L, Wernsdorfer WH Monitoring of drug sensitivity in Plasmodium falciparum. Geneva: WHO/MAP, 1980: 80.2. 9. Reickmann KH, Campbell GH, Sax LJ, Mrema JE. Drug sensitivity of Plasmodium fasciparum. An in-vitro microtechnique. Lancet 1978; i: 22-23. 10. Smrkovski LL, Buck RL, Alcantara AK, Rodriguez CS, Uylangco CV. In-vitro mefloquine-resistant Plasmodium falciparum from the Philippines. Lancet 1982;ii: 322. 11. Grab B, Wernsdorfer WH Evaluation of in vitro tests for drug sensitivity in Plasmodium falciparum: Probit analysis of logdose/response test from 3-8 points assay. Geneva: WHO/MAL, 1983 83.990. 12. Milhous WK, Weatherly NF, Bowdre JH, Desjardins RE Interaction of mefloquine and a fixed combination of sulfadoxine and pyrimethamine (Fansidar) against Plasmodium falciparum in vitro Presented at Joint meeting of American Society of Tropical Medicine and Hygiene and American Society of Parasitologists (San Antonio, Texas, Dec 4-8, 1983). 13. Bruce-Chwatt LJ, ed. Chemotherapy of malaria. Geneva: World Health Organisation, 1981: 223.

1041 CAUSES OF RIBOFLAVIN DEFICIENCY AND THEIR ANTIMALARIAI. both disorders, there is a reduction of the intracellular ACTIVITIES flavin mononucleotide concentrations of the coenzymes well as a dinucleotide as (FAD), (FMN) and flavin adenine depression of the activities of several flavoenzymes-eg, glutathione reductase, aminoacid oxidases, xanthine oxidase, succinic dehydrogenase, and a-glycerophosphate dehydrogenase.6,7 These characteristics in hypothyroidism appear to affect enzyme activities by impairment of the rate of incorporation of riboflavin into FMN and FAD. Lee and McCormick6 confirmed these findings by showing that in hypothyroidism the reduction in hepatic levels of FMN and FAD is the result of reduced activities of the flavin coenzymesynthesising enzymes, flavokinase and FAD synthetase. Metabolic similarities between riboflavin deficiency and hypothyroidism extend to other aspects of intermediary +=has been shown to occur. metabolism. There are several reports of similar changes in both disorders in the relative concentration of polyunsaturated fatty acids in membranes, with a fall in the given serious consideration in the search for fresh approaches ratio of arachidonic acid to linoleic acid.8,9 Furthermore, to antimalarial therapy in view of widespread emergence of thyroxine, reverse triiodothyronine (T3), and riboflavin each chloroquine-resistant strains. In support of this they provide have antioxidative properties and may protect unsaturated evidence that t-butyl hydroperoxide inhibits growth of fatty acids against peroxidation. 10, II Hypothyroidism has P vinckci in vivo and P falciparum in vitro.2O Several other been shown to have antimalarial effects in experimental agents which generate activated oxygen-eg, primaquine,21 animals,12,13 and this supports our hypothesis that in an phenylhydrazine,2z hydrogen peroxide,23 and alloxan23 have endocrine disorder which impairs riboflavin metabolism the antimalarial properties. The generation of free radicals in survival of the rodent malaria parasite is reduced. vivo is also observed during riboflavin deficiency, a disorder riboflavin in that induce experimental which is associated with increased production of lipid Drugs deficiency animals also show antimalarial properties (see figure). The peroxides.2’ Conversely riboflavin and its derivatives are phenothiazine derivative, chlorpromazine, which accelerates suppressants of peroxide formation and inhibit oxygen the urinary excretion of riboflavin and impairs FAD uptake in the process of peroxidation.ll formation,14,15 inhibits malarial parasitaemia. At a Other investigators25have suggested that new antimalarial concentration of 10 pmol/1 it reduces the growth of P drugs could be developed by means of selective inhibition of falciparum by 40%, and at 50 p.molllsgrowth of the parasite is erythrocyte superoxide dismutase, which is sequestered by reduced by 100%.16 Plasmodium for its defence against oxidative stress. Since In studies of Lactobacillus casei an organism which requires malarial parasites do not synthesise their own superoxide dismutase but depend upon that synthesised by the host, the exogenous riboflavin, addition of riboflavin to the culture medium antagonises the, growth-inhibitory action of several inhibition of host superoxide dismutase should make the antimalarial compounds.17 parasites particularly vulnerable to activated oxygen. Other drugs which have inhibitory effects on riboflavin Doxorubicin is known to interfere with FAD biosynthesis IS metabolism resembling those of chlorpromazine include the and is catabolised by microsomal enzymes which produce 5 reactive oxygen species,19 and it is predicted that this tricyclic antidepressants, imipramine and amitriptyline, 15 and the anthracycline derivative, doxorubicin.’8 Like compound should also have antimalarial properties. chlorpromazine, each of these drugs is similar in structure to Although the high cytotoxity of doxorubicin would render it riboflavin and its coenzyme derivatives. The antimalarial an unlikely choice for clinical application, these relations are effects of these drugs in man should be studied. Doxorubicin, important theoretically. in addition to its interference with FAD formation in tissue, is HYPOTHESIS catabolised by microsomal enzymes which produce free We propose that not only dietary riboflavin deficiency, but radicals of oxygen. 19 Clark and colleagues20 have proposed also drugs and hormonal disorders which interfere with that agents which generate free radicals of oxygen should be riboflavin metabolism, should also provide protection against malaria. We also hypothesise that the therapeutic effects of antimalarial agents which have structural similarities to riboflavin may be related to or mediated by the inhibition of riboflavin metabolism. Such inhibition is manifested as diminished synthesis of flavin nucleotides. In preliminary studies with quinacrine, an antimalarial drug which is similar in structure to riboflavin (see figure), we have shown that it inhibits conversion of(4C) riboflavin into FMN and FAD in various tissues of the rat.26 Other known antimalarial drugs are being tested in our laboratory to determine their effectiveness as riboflavin antagonists. The causes of riboflavin deficiency and their antimalarial activities are Structural formulae of riboflavin (vitamin B2), chlorpromazine (a given in the table. Wecannot predict with certainty that all antimalarial drugs psychotropic agent), and quinacrine (an antimalarial drug). will inhibit flavin biosynthesis. The question of whether Both chlorpromazme and quinacrine mhibit the incorporation of nboflavin into FAD. antimalarial drugs which do not resemble riboflavin

1042

structurally

do

not

inhibit riboflavin metabolism should be

studied. Possible Mechanisms

of the Antimalarial Action of Riboflavin

Deficiency Three mechanisms can be considered as potential causes of antimalarial effects of riboflavin deficiency: (1) riboflavin deficiency may render erythrocytes more susceptible to haemolysis and therefore not permit intracellular proliferation of Plasmodium; (2) riboflavin deficiency may inhibit the production of reticulocytes, the preferred site of Plasmodium invasion; and (3) riboflavin deficiency may cause a fall in the level of intraerythrocyte reduced glutathione, an essential metabolite produced by the cell and needed for survival of Plasmodium. However, our recent observations27 do not support the notion that riboflavin deficiency makes erythrocytes more fragile, as monitored by the haemolytic response to ferriprotoporphyrin IX, a product of oxidative degradation of haemoglobin. In addition, neither the reticulocyte count nor the concentration of reduced glutathione in erythrocytes is reduced in riboflavin deficiency in

rats.27

The antimalarial effects of riboflavin deficiency may be achieved by other mechanisms, such as a change in the structural and/or functional integrity of red-blood-,cell membranes. Riboflavin deficiency reduces the level of polyunsaturated fatty acids in membrane phospholipids, and this would be expected to influence fluidity, permeability, and binding properties not only in membranes of host cells, but also in membranes of plasmodia. We have shown that diverse membrane-active agents, including a number of antimalarial drugs-eg, chloroquine, mefloquine, and quinine-stimulate the haemolytic response of the cell membrane to ferriprotoporphyrin IX.28 Such an effect may be mediated by interaction with phospholipids.2$ Tricyclic antidepressants affect phospholipid metabolism in a similar way to the antimalarial drug chloroquine.29 Furthermore, the phenothiazine derivative, chlorpromazine,

stimulates

ferriprotoporphyrin-IX-induced haemolysis, possibly through interaction with membrane phospholipids.16 It is therefore likely that the conditions which cause riboflavin deficiency have a common biochemical mechanism for their antimalarial activity-namely, they compromise the composition and integrity of membrane phospholipids. Alternatively, the common mechanism in antimalarial actions of drugs which inhibit riboflavin metabolism may be the formation of a disproportion of certain essential metabolite(s)-eg, adenosine triphosphate or reduced glutathione, the balance of which critically affects parasite viability. Flavin coenzymes are essential for energy transduction and metabolism, and it is recognised that at least antimalarial drugs, chloroquine and primaquine, deplete the tissue concentrations of A TP. 30 Other studies have shown that the activity of glutathione reductase is two to three times higher in erythrocytes infected with P berghei than in non-infected cells.31 The finding of relatively high activity of glutathione reductase in the parasitised red cell suggests that this enzyme may have an essential role in the metabolism of the parasite. That function is probably the maintenance of reduced glutathione, which is elevated by two to three times in the parasitised erythrocyte, compared with that in non-infected red blood cells." This elevated concentration of reduced glutathione may be necessary for the parasite to cope with oxidative stress, since two

the plasma membrane of the parasite is known to be more vulnerable to oxidative injury than that of the host.32 Therefore, it is conceivable that riboflavin deficiency may selectively affect glutathione metabolism in the parasitised red blood cells, since glutathione reductase is an FADrequiring enzyme. Our preliminary studies indicate that the level of reduced glutathione in non-infected erythrocytes isolated from riboflavin-deficient rats is not lowered.227 Another consideration is that parasites may have a requirement for riboflavin or its nucleotide derivatives greater than that of the host erythrocyte, and therefore the former may be relatively more dependent than the latter upon riboflavin for antioxidant metabolism. The problem of resistance to antimalarial drugs worldwide is alarming.33 New therapeutic approaches with metabolic inhibitors of riboflavin metabolism should be investigated for their therapeutic potential as antimalarial agents. This study was supported by the Clinical Nutrition Research Unit Grant5 PO CA 29502, Research Trammg Grant 5 T 32 HL 07379, and Cancer Core Grant CA 08748 from the National Institutes of Health, and by grants from the American Federation for Aging Research, The Stella and Charles Guttman Foundation, the William H. Donner Foundation, Inc, and The General Foods Fund. The research was carried out in the Sperry Corporation Nutrition Research Laboratory ofSloan-Kettenng Institute. John Pinto is the recipient of Future Leaders Award of the Nutrition Foundation.

Correspondence should be addressed to John Thomas Pinto, Assistant Member, Memorial Sloan-Kettenng Cancer Center, 1275 York Avenue, Box 140, New York, New York 10021.1. REFERENCES 1 Seeler 2

AO, Ott WH Effect of riboflavin deficiency

on

the

course

of Plasmodium

lophurae infection in chicks. J Infect Dis 1944, 75: 175-78 Siddiqui WA, Schnell JV, Geiman QM. Nutritional requirements for in vitro cultivation ofa Simian malarial parasite, Plasmodium knowlesi. Military Med 1969;

134: 929-38 3. Kaikai P, Thurnham DI. The influence of riboflavin deficiency on Plasmodium berghei infection in rats. Trans R Soc Trop Med Hyg 1983; 77: 680-86. 4. Thurnham DI, Oppenheimer SJ, Bull R Riboflavin status and malaria in infants in Papua New Guinea Trans R Soc Trop Med Hyg 1983; 77: 423-24. 5. Rivlin R Regulation of flavoprotein enzymes in hypothyroidism and riboflavin deficiency. Adv Enzyme Regul 1970; 8: 239-50. 6 Lee SS, McCormick DB. Thyroid hormone regulation of flavoenzyme biosynthesis. Arch Biochem Biophys 1985; 237: 197-201. 7 Menendez CE, Hacker P, Sonnenfeld M, McConnell R, Rivlin RS. Thyroid hormone control of glutathione reductase activity in rat erythrocytes and liver Am J Physiol 1974, 226: 1480-83. 8. Taniguchi M, Yamamota T, Nakamura M Effects of riboflavin deficiency on the lipids of rat liver mitochondria and microsomes J Nutr Sci Vitaminol 1978; 243: 363-81 9 Faas FH, Carter WJ. Fatty acid desaturation and microsomal lipid fatty acid composition in experimental hypothyroidism. Biochem J 1982, 207: 29-35. 10. Tseng YCL, Latham KR. Iodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation. Lipids 1984; 19: 96-102. 11. Tahara K, Matsuoka S, Ohama H. Effects of riboflavin and riboflavin 2’, 3’, 4’, 5’, tetrabutyrate on rat liver microsomal lipid peroxidation. J Nutr Sci Vitaminol 1974; 20: 81-88. 12. Shoemaker JP. Plasmodium berghei: possible role of thyroxine in growth and metabolism. Exp Parasitol 1974; 36: 261-64. 13 Shoemaker JP, McAllister RG, Selby JB, Hoffman RV. Effect of hypothyroidism on parasitemia and survival in rodent malaria. Am J Med Sci 1974; 268: 281-85 14. Pinto J, Wolinsky M, Rivlin RS Chlorpromazine antagonism of thyroxine induced flavin formation. Biochem Pharmacol 1979; 28: 597-600. 15 Pinto J, Huang YP, Rivlin RS. Inhibition of riboflavin metabolism in rat tissues by chlorpromazine, imipramine and amitryptaline J Clin Invest 1981, 67: 1500-06. 16. Panijpan B, Kanitakanit N. Chlorpromazine enhances hemolysis induced by hemin. J Pharm Pharmacol 1983; 35: 473-75. 17. Madinaveitia J. The antagonism of some antimalarial drugs by riboflavin. Biochem J 1946; 40: 373-75. 18 Pinto J, Huang YP, Pelliccione N, Rivlin RS. Adriamycin inhibits flavin synthesis in heart: possible relation to cardiotoxicity of anthracyclines. Clin Res 1983; 31: 467A 19. Doroshow JH. Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. Cancer Res 1983, 43: 4543-51 20. Clark IA, Coden WB, Butcher GA. Free oxygen radical generators as antimalarial drugs Lancet 1983, i: 234 21 Kelman SN, Sullivan SG, Stern A. Primaquine-mediated oxidative metabolism in the human red cell Biochem Pharmacol 1982, 31: 2409-14. 22 Clark IA, Hunt NH. Evidence for reactive oxygen intermediates causing hemolysis and parasite death in malaria. Infect Immum 1983; 39: 1-6. 23. Dockrell HM, Playfair JHL. Killing of blood-stage murine malaria parasites by hydrogen peroxide. Infect Immun 1983; 39: 456-59

1043

Reviews of Books Screening for Cancer Edited by Anthony B. Miller, University of Toronto. Orlando, Florida: Academic Press. 1985. Pp 458.$65. L65.

A wide range of evidence

on cancer

screening is surveyed in this

volume-from results of controlled trials of effectiveness to the need control and evaluation in existing screening The list of eminent contributors from various counprogrammes. tries reflects the editor’s role with the UICC (International Agency Against Cancer). Screening for cancer of the cervix, breast, lung, large bowel, stomach, bladder, and mouth is covered in some depth. There are three sections. The first covers the conceptual framework that must be assimilated in order to understand why, for example, the detection of early-stage cancer by a screening test does not prove its effectiveness. This and many other thorny issues for the uninitiated are lucidly explained in two initial chapters which render the subject accessible, if not easy. By way of contrast, cancer screening is set in a socioeconomic context in a chapter on economic benefit best described as "challenging" in style. The second section takes each screening test in turn (eg, mammography, pulmonary cytology, faecal occult blood testing) and not only describes the technique but also addresses issues of validity and quality control. This series of fairly technical reviews is of considerable interest, mainly because of the difficulty of extracting such information from the literature without knowledge of the field and for

quality

access to

specialist journals.

The third section reviews the evidence for effectiveness of screening for individual cancer sites and the practical difficulties experienced in implementing cancer screening programmes. It would in fact be better if the non-epidemiological reader turned the book upside down and began at the back. The chapters on screening for cervix, breast (both by the editor), and lung cancer are excellent reviews which demonstrate why the conceptual framework presented in the first section is so necessary. For the interested community physician, the epidemiologist, or even the health service manager this is cancer screening on a plate, albeit with North American relish. A state of the art book, yet "art" is something of an over-statement in the context of the disarray of the cervical screening programme in the UK. Although the important issue of continuing programme evaluation and management is addressed here, the reader will have to look beyond the information presented in order to find practical solutions for our

present problems. Department of Community Medicine General Practice, University of Oxford

and

DAVID MANT

Sarcoidosis

which has increased its size in the course of 18 years from 542 pages to 704. This means that although some new views have been included, a lot of the old material remains. Why this 30% increase in size? Possibly because the junior co-author, taken on board for this edition, has been too tender or lenient with his revision, and also possibly because of the numerous case histories dotted throughout. Many of these case histories were published by other authors, including, believe it or not, those of patients reported in 1917 by Schaumann. Thus the original text, which became a classic of its kind in 1967, has now become a 1985 thesaurus or treasure-trove of information. Dip into it for all aspects of sarcoidosis, except, sadly, the cause of this fascinating disorder. We are no nearer a solution than we were in 1967 when this book was first published. We have more plausible immunological conjecture, far more global epidemiology, better understanding of the abnormal calcium metabolism, and improved therapeutic regimens to prevent blindness. But the aetiology continues to elude us and this means that we, including the authors, must intensify our efforts for a third edition. The first international conference on sarcoidosis was held in 1958 in London. The participants, from many parts of the world, must have enjoyed the contact with each other because it led to a series of worldwide congresses every three years. The tenth world congress was held in 1984 at the Johns Hopkins Hospital, Baltimore. This sarcoidosis movement has been the spur accelerating increased knowledge on sarcoidosis worldwide. What a pity that this movement was ignored in the preface to the first edition and only referred to perfunctorily now. The proceedings of these congresses provide a continuing update on the subject, and any textbook is out-of-date unless it draws largely from the latest of these transactions. Ciba-Geigy have been avuncular godfathers to this edition by paying for illustrations, so they deserve a creditable mention. What a pity that the captions use the term sarcoid as a noun. Much confusion arises from this misuse of the term. Sarcoid is always an adjective never a noun; the relevant noun is sarcoidosis. But this is minor criticism compared with their generous support in publishing sixteen colour photographs. ’

Royal Northern Hospital,

D. GERAINT JAMES

London

Textbook of Anaesthesia G. Smith, University of Leicester School of Medicine, and A. R. Aitkenhead, Leicester Royal Infirmary. Edinburgh: Churchill Livingstone. 1985. Pp 586. ,EI9.50 (soft cover).

ONE of the difficulties facing the trainee anaesthetist has been the lack of a suitable introductory textbook, able to provide a good basic grounding yet uncluttered by extensive discussion or detail in both the theory and practice of anaesthesia. Professor Smith and Dr Aitkenhead have now set out to fill this gap. According to the preface, their intention was to produce a book that is "concise, readable ... (and) comprehensive". Overall, the editors have undoubtedly achieved this aim. In just under 600 pages, the 41 chapters cover topics ranging from fundamental anatomy, physiology, and pharmacology, through the practical conduct of anaesthesia for most surgical specialties, to intensive therapy and the work of the pain (relief) clinic. Postoperative care is covered in great detail, with separate chapters on the immediate recovery period, later sequelae of surgery and anaesthesia, and the management of pain following surgery. There is also a well chosen selection of appendices. In addition to normal ...

2nded. J. G. Scadding, formerly Brompton and Hammersmith Hospitals, London, and D. N. Mitchell, Brompton and Central Middlesex Hospitals, London. London: Chapman & Hall. 1985. Pp 704. L55.

THE first edition in 1967 was the Rolls-Royce on the subject and this second edition continues to purr just as gracefully in its twentyseven chapters on all aspects of the disorder. As a general rule, second editions of monographs are subjected to ruthless prunings by authors who, with greater experience, readily omit what they had felt obliged to include in a first edition. Not so with this textbook,

24

M. Effects of riboflavin deficiency on lipid peroxidation of rat liver J Nutr Sci Vitaminol 1980; 26: 401-13. 25 Fairfield AS, Meshnick SR, Eaton JW. Host superoxide dismutase incorporation by intraerythrocytic plasmodia In: Brewer G, Eaton JW, eds. Malaria and the red cell. New York. Alan R Liss, 1984: 13-23 26 Raiczyk GB, Dutta P, Pinto J Chlorpromazine and quinacrine inhibit flavin adenine dinucleotide biosynthesis in skeletal muscle Physiologist 1985; 28: 322 27 Dutta P, Pinto J, Rivlin R. Resistance to ferriprotoporphyrin-induced hemolysis in riboflavin deficiency. Clin Res 1985, 33: 703A. 28. Dutta P, Fitch CD Diverse membrane-active agents modify the hemolytic response to ferriprotoporphyrin IX J Pharmacol Exp Ther 1983; 225: 729-34.

Taniguchi

29 Grabner R, Meerbach W.

microsomes.

30 31

Imipramine and chloroquine induced alterations in phospholipid content of rat lung. Exp Path 1983; 24: 253-59. Kelman SY, Sullivan SG, Stern A. Stimulation of ATP hydrolysis by chloroquine and primaquine in human red blood cells. Biochem Med 1983; 29: 379-84. Eckman JR, Eaton JW. Dependence of Plasmodium glutathione metabolism of the host

cell Nature 1979; 278: 756-58 32 Stocker R, Hunt NH, Buffinton GD, Weidemann

MJ, Lewis-Hughes PH, Clark IA. Oxidative stress and protective mechanisms in erythrocytes in relation to Plasmodium vinckei load. Proc Natl Acad Sci USA 1985; 82: 548-51 33. Rollo IM Drugs used in the chemotherapy of malaria. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. New York: Macmillan Publishing Co, 1980 1038-60