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ERYTHROMYCIN IN THE TREATMENT OF CHLOROQUINE-RESISTANT FALCIPARUM MALARIA
805
INTRAVENOUS AMODIAQUINE AND ORAL
AMODIAQUINE/ERYTHROMYCIN
IN THE
TREATMENT OF CHLOROQUINE-RESISTANT FALCIPARUM MALARIA RODNEY E. PHILLIPS SORNCHAI LOOAREESUWAN NICHOLAS J. WHITE JUNTRA KARBWANG PANOSRI ATTANATH YUPIN BENJASURAT DAVID A. WARRELL
Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Nuffield Department of
University of Oxford; Liverpool School of Tropical Medicine; and Pra Pokklao Hospital, Chantaburi,
Clinical Medicine,
Thailand
Summary
In
eastern
Thailand,
14
adults with malaria were
falciparum amodiaquine dihydrochloride, loading dose 10 mg base/kg infused over 4 h followed by three further intravenous infusions of 5 mg base/kg at 24, 48, and 72 h. All patients were clinically cured—mean fever clearance time 37·8 h (range 24-60), mean parasite clearance time 64·9 h (18-164). There were no serious toxic effects. 33 patients aged over 5 years with uncomplicated falciparum malaria were given oral amodiaquine dihydrochloride (mean total dose 41 mg base/kg over 3 days) combined with erythromycin estolate (mean dose 48 mg base/kg daily for 5 days). 2 patients failed to respond. In the other 31 patients mean fever clearance time was 55·9 h (range 10-104) and mean parasite clearance time was 65·4 h (40-120). In both studies, more than half the patients followed-up had recurrent parasitaemia but reinfection could not be excluded. Parasites isolated from 18 patients were highly resistant to chloroquine in vitro. moderately
severe
treated with intravenous
were generally sensitive to in Africa and Thailand clinical trials In amodiaquine.4 more cleared parasitaemias than chloroquine.5-8 amodiaquine This difference between the two main 4-aminoquinolines could be exploited in several ways.
sensitivity
to
chloroquine
If the safety and efficacy of parenteral amodiaquine were confirmed it could be invaluable for the treatment of severe falciparum malaria. The WHO Scientific Group believes that chloroquine is too dangerous for parenteral use.9 They recommend quinine for all cases of severe malaria, although
life-threatening hypoglycaemia develops in some patients so treated.1O If amodiaquine retained schizontocidal activity against quinine-resistant falciparum malaria, a parenteral form could be life-saving againstan otherwise untreatable infection. In Africa and western Asia, where chloroquine resistance is emerging, the wider use of amodiaquine might improve radical cure rates of uncomplicated falciparum malaria. severe,
The combination of tetracycline and
amodiaquine had a chloroquine-resistant Erythromycin shows potentiating synergism when combined with chloroquine2 against chloroquine-resistant Plasmodium berghei in micel2 but, in falciparum malaria the effects of the combination were unimpressive.13 The combination of amodiaquine and erythromycin has not been tried in human malaria. in uncomplicated malaria in central Thailand in 1981.11
high
cure
rate
We describe here two studies in which we treated Thai patients who had chloroquine-resistant falciparum malaria with intravenous amodiaquine and the oral combination amodiaquine and erythromycin.
Patients and Methods
Patients Introduction THE 4-aminoquinoline antimalarials were introduced into clinical practice nearly 40 years ago. Amodiaquine proved a remarkable advance; a single dose rapidly cleared asexual parasitaemias, including infections caused by quinineresistant malaria, and even when given parenterally, the drug was free of serious side-effects.1,2 However, chloroquine became more widely used. In 1950 Coatney3 first mentioned the possibility that the antimalarial activity of amodiaquine might result from metabolites rather than the parent drug. By contrast,
chloroquine itself, although subject to metabolism,
chief active agent. Parasite isolates from different countries which varied considerably in their in-vitro
appeared to be the
WE, Niblack GW, Johnson HK, Richie RE. Relationship of cadaveric renal transplant results to HLA tissue matching. Transplant Proc 1977; 9: 487-89. 9. Salvatierra O Jr, Perkins HA, Cochrun KC, Duca RM, Potter DE, Amend WJ, Feduska NJ. HLA typing and primary cadaver graft surival. Transplant Proc 1977; 8. Walker
9: 495-501. 10. Opelz G, Mickey M, Terasaki PI. Transplantation 1974; 17: 371. 11.Goeken NE, Nghiem DD, Corry RJ. Prospective HLA-DR matching in a single centre renal transplant program. Transplant Proc 1982; 14: 185-86. 12. Albrechtsen D, Bondevik H, Flatmark A, et al. Transplant Proc 1982; 14: 182-84. 13 Tate DG, Smith D, Lee HA, Slapak M. The effect of blood transfusion and HLA-DR matching on kidney survival in the Wessex Region. Br J Surg 1981 68: 823. 14. Gardner B, Harris KR, Digard NJ, et al. Do recipients ofa cadaveric renal allograft on Cyclosporin require prior transfusions? Experience of asingle unit. Transplant Proc
1985; 18: 1032-33. 15 Calabresi P, Parks RE Jr. Chemotherapy of neoplastic diseases. In: Goodman LS, Gilman AS, eds. The pharmacological basis of therapeutics, 6th ed. New York: Macmillan, 1980: 1283-87.
Patients admitted
Pra Pokklao Hospital, Chantaburi, eastern for study if asexual forms of Pfalciparum were found in a blood smear. One group of patients was given amodiaquine intravenously; they were older than 15 years and had moderately severe infections. Generally they had admission parasitaemias greater than 1%, required intravenous fluids, and many were nauseated and vomiting and unable to tolerate tablets. The second group were older than 5 years, had uncomplicated malaria, and were able to swallow tablets. Patients were excluded if they were over 65 years old; were severely ill with cerebral, renal, or other complications; had mixed infections; gave a history of recent antimalarial treatment; or if on admission quinine was detectable in their plasma or sulphonamides or 4-aminoquinolines in their urine. All patients or their relatives gave informed consent to investigation, treatment, and follow-up. The study was approved by
Thailand,
16. Whisler
were
to
eligible
RL, Lindsey JA, Procter KVW, et al. Characteristics of cyclosporin induction
prostaglandin levels from human peripheral blood monocytes. Transplantation 1984; 38: 377-81. 17. Bunjes D, Hardt C, RollinghoffM, et al. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 1981; 11: 657-61. 18. Keown PA, Stiller CR, Ulan RA, et al. Inhibition of the donor specific immune response by Cyclosporin A following renal transplantation. Transplant Proc 1981; of increased
3: 1669-72. 19.
Hutchinson IF, Shadur CA, Alberto Duarte JS, et al. Cyclosporin A spares selectively lymphocytes with donor specific suppressor characteristics. Transplantation 1981; 32: 210-16.
20. Tutschka
PJ. Cyclosporin A as a tool for experimental and clinical transplantation. Biomed Pharmacother 1982; 36: 341-44. 21 Dos Reis GA, Shevach EM. Effect of cyclosporin A on T cell function in vitro The mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell. J Immunol 1982; 129: 2360-67.
806 the ethical committee,
Faculty
of
Tropical Medicine,
TABLE I-CLINICAL DETAILS
Mahido
University, Bangkok. Methods
History and examination were recorded on standard forms Pretreatment investigations included full blood count, platele count; parasite count, electrolytes, blood urea nitrogen, creatipine. albumin, globulin, and aspartate aminotransferase. Urine waf tested for sulphonamides and 4-amino-quinolines, and plasm samples were stored for estimation of quinine (in Bangkok). Patient! were observed in hospital until the parasitaemia had cleared and the drug course was completed. Axillary temperature was measurec every 4 h until the patient had been afebrile for 24 h, then once a day. Blood smears were made every 8 h until the parasitaemia had cleared, then daily. Parasite counts were done on thick or thin films; depending on the parasite density. Patients whose parasitaemia cleared were asked to return 19 and 33 days after the start oi treatment, or at any time if symptoms returned. At these visits they were asked about fever and other symptoms and were examined. Thick and thin smears were checked for malaria parasites, and blood was taken for haematological and biochemical measurements including liver function tests. If no asexual forms were seen the parasitaemia was regarded as having cleared. In-vitro tests.-5 ml samples of heparinised venous blood were taken from 18 patients in the second study before treatment was started and transported to Bangkok the same day for storage in liquid nitrogen. 6 months later the thawed parasites were allowed to grow in continuous culture14 synchronised by the use of sorbitol. 15 The in-vitro microtechnique 16 was used to determine the susceptibility of parasites to chloroquine and amodiaquine. 50 µl RPMI 1640 medium (supplemented with 10% AB human serum) containing about 2 µl parasitised and non-parasitised erythrocytes with 0 - 3-0 - 5% parasitaemia was placed in each well of the microculture plate. Cultures were incubated in candle jars at 37°C for 30-48 h. A thick smear was then made from each well, stained with giemsa, and examined microscopically for parasite maturation. Drug inhibition was measured by comparing the number of schizonts in the control well with the number of schizonts in wells containing drug. The minimum inhibitory concentration (MIC) was defined as the lowest drug concentration in which schizont formation was≤1% of drug-free controls. Intravenous amodiaquine study.-Amodiaquine dihydrochloride (Parke-Davis) was dissolved in distilled water (30 mg/ml) and dispensed in glass vials (John Radcliffe Hospital, Oxford). A loading dose of 10 mg base/kg body weight was dissolved in 250 ml normal saline in glass bottles and infused over 4 h. Further doses of 5 mg base/kg as 4 h infusions were given at 24, 48, and 72 h. Precautions were taken to protect the drug from light. Intravenous fluids, intramuscular antipyretics (dipyrone 500 mg) and antiemetics (metoclopramide 10 mg) were given as required but no other drugs were given during the study period. Blood pressure and pulse rate were measured before, during, and after the infusion of amodiaquine and subsequently every 4 h. Oral amodiaquine and erythromycin.-Amodiaquine dihydrochloride tablets (’Camoquin’, Parke-Davis) were given in a loading dose of 600 mg base (400 mg base for patients weighing <40 kg). Three further doses of 400 mg base (200 mg base for those <40 kg) were given at 6, 24, and 48 h. Erythromycin estolate capsules (’Ilosone’, Eli Lilly) were given three times a day with meals for 5 days in doses of 750 mg (base) to those weighing <60 kg, 250 mg to those weighing <40 kg, and 500 mg to others.
All 14 patients of parasitaemia.
responded to treatment with disappearance Body temperature returned to normal in 37’8h (range 24-60). Parasite clearance times, which were not normally distributed, ranged between 18 h and 164 h (mean 64-9). 5 patients were completely cured, 6 had recurrent parasitaemia between days 14 and 29, and 3 patients did not return for follow-up. Patients with recurrent parasitaemia were treated with quinine and tetracycline and discharged when their parasitaemia had cleared. All patients had returned to the endemic area, so reinfection was possible. No patient showed evidence of cardiovascular poisoning. The range of blood-pressure readings before the loading dose was 132/90 mm Hg to 80/50 mm Hg and afterwards 130/90 mm Hg to 80/48 mm Hg, while the maximum fall in blood pressure was 10 mm Hg. There was no consistent change in pulse rate. 2 patients vomited 6 and 19 h and 1 patient had diarrhoea 30 h after the start of treatment. No adverse effects were seen in the rest. Amodiaquine leaked subcutaneously at the intravenous cannula site on two occasions but there was no evidence in these patients or any other of local tissue damage or inflammation.
Amodiaquine-erythromycin All 33 patients were acutely ill onadmission and 31 (94%) were febrile. 27 patients (8’ 2%) were experiencing their first or second attack of malaria. No patient had detectable urinary 4-aminoquinolines or plasma quinine. 2 patients whose urine was weakly positive for sulphonamide were not excluded. Haematological and biochemical measurements were within normal limits except for admission haematocrits in 4 patients (range 22’5-33%) and total bilirubin in 4 others (range 37 - 6-110 µmol/l; 2 - 24-35 mg/dl). Bilirubin levels fell to normal with clearance of parasitaemia. Patients received TABLE 11-ADMISSION LABORATORY RESULTS (MEAN±SD)
Results Intravenous Amodiaquine
All
patients studied (table I) gave a history of fever and and all were febrile (>37’ 5 °C) on admission. 4 patients rigors were drowsy though easily roused, but no patient was admitted with or developed evidence of cerebral, renal, or pulmonary involvement. In 12 patients parasitaemia was more than 1% (table II). 4 patients vomited before any 14
treatment was
given.
*Reitman-Frankel units/ml.
807 18 PLASMODIUM FALCIPARUM CHLOROQUINE AND AMODIAQUINE
TABLE III-IN-VITRO RESPONSE OF ISOLATES TO
___________
____-
_
_
_
_
_
I
.
I
*Comparison of MIC values for chloroquine and amodiaquine (after loganthmic transformation) using paired t test, p<0-001. doses of 41 mg amodiaquine base/kg (total) and 48 mg erythromycin base/kg daily for 5 days. 31 patients responded to treatment with a mean fever clearance time of 55-99 h (range 10-104) and mean parasite clearance time of 65’ 4 h (range 40-120). Of 29 patients who returned for follow-up, 14 (48%) were cured (S) and 15 (52%) had recurrent parasitaemia (Rl). The Rl patients, 1 patient who responded poorly (R2), and 1 patient whose parasitaemia rose after treatment started (R3) were treated with quinine and tetracycline. 12 patients vomited between 2 and 46 h after starting treatment and the dose was repeated after parenteral metoclopramide. 2 other patients became nauseated and diarrhoea developed in 1. At follow-up visits haematological and biochemical measurements, including white-cell count mean
and liver function tests, remained within normal limits.
In-vitro Tests 18 frozen Chantaburi isolates were adapted to in-vitro culture and all tests were successful for chloroquine and amodiaquine (table III). All the isolates were highly resistant to chloroquine by standard criteria (WHO, 1984). 17 isolates were more sensitive to amodiaquine than to chloroquine (p<0’001). The growth of 1 isolate was not inhibited by either drug at any concentration tested. In-vivo response could not be correlated with the MIC for amodiaquine. 1 isolate, from a patient with an R3 response, had an amodiaquine MIC of 320 nmol/1, which was close to the geometric mean (359 nmol/1). Another isolate, which was not inhibited by 5120 nmol/1, came from a patient who subsequently had an Rresponse.
Discussion
Chloroquine-resistant malaria has been recognised in Thailand for over 20 years" and this drug is now virtually useless against P falciparum. 13,18 Quinine resistance is also appearing. Quinine alone cures less than 25% of infections treated at the Bangkok Hospital for Tropical Diseases.19 In our study amodiaquine cleared the asexual parasitaemia in patients with falciparum malaria acquired along the Thai-
Kampuchean border; moderately
ill patients responded rapidly and their fever and parasite clearance times were comparable to those achieved with quinine. Intravenous chloroquine proved useless at Chantaburi.13 In view of the
excellent cure rate and the lack of serious toxic effects in our study, a role for intravenous amodiaquine in the treatment of severe falciparum malaria must be considered. Quinine is the only drug now recommended by the WHO for parenteral treatment of falciparum malaria.9 In Thailand no other
parenteral drug is available, so the emergence of has created a crisis in the chemotherapy of resistance quinine severe malaria. If amodiaquine were effective against highly quinine-resistant malaria, a safe intravenous regimen would be life-saving. Unlike quinine, amodiaquine does not stimulate insulin release (D. A. W., unpublished), so it would be particularly useful in severe malaria complicating 10,20 pregnancy and in cerebral malaria. metabolism Rapid hepatic probably accounts for the fact that amodiaquine is undectable in the blood after oral dosing in volunteers and in patients who nonetheless respond to treatment (I. G. Edwards et al, unpublished, and21). The metabolites formed, which include desethylamodiaquine, appear to be the chief antimalarial agents.2Thus the pharmacology of amodiaquine differs substantially from that of other 4-aminoquinolines. Clearly, if it is to be used to best advantage, regimens must be based on the pharmacokinetics of the parent drug and its metabolites. New drug assays should allow suitable regimens to be devised,21,22 although the comparative effectiveness and safety of amodiaquine and quinine against falciparum malaria can be assessed only by clinical trial. Since amodiaquine appears to be a pro-drug, the active metabolites should be used for in-vitro sensitivity testing. Preliminary work suggests that the antimalarial activity of amodiaquine and its desethylmetabolite are similar22 so test systems using the parent drug alone should provide a rough guide to in-vivo activity. However, in-vitro tests fail to mimic the complex drug-parasite interaction that takes place in vivo, and biotransformation of antimalarials also limits the usefulness of this technique as a reliable predictor of treatment response. Isolates from our patients who subsequently received oral amodiaquine and erythromycin were highly resistant in vitro to chloroquine but sensitive to amodiaquine, consistent with clinical experience. 13 However, the degree of in-vitro sensitivity did not match effective
patient
response.
Even early in the development of resistance to an antimalarial drug, radical cure of falciparum malaria with single drug therapy is difficult.23 In Thailand quinine, even when given for 10 days, usually fails to produce a radical cure unless tetracycline is added.24 In East Africa and Madagascar higher chloroquine doses produced better cure rates in uncomplicated chloroquine-resistant malaria, but overall the results were still unsatisfactory. 1,23,21 Parasite clearance rates were superior when amodiaquine was tried in uncomplicated malaria. However, recrudescence was a problem in Zanzibar,26 and was not investigated in the Kenyan study in which follow-up continued for only 14 days.8 Amodiaquine and tetracycline were curative in central Thailand," but the need for an alternative to tetracycline in children and pregnant women, and the demonstration of potentiating synergism between chloroquine and erythromycin have been strong incentives to test the antiplasmodial action of erythromycin.12 Combined with chloroquine, erythromycin produced a radical cure rate of only 1907o at Chantaburi,13 a better result than would be expected if chloroquine alone were used, but the high rate of recurrence was unacceptable for routine use. Our trial and a second study carried out with high-dosed erythromycin and chloroquine (L. Pang, personal communication) provide further evidence that erythromycin is an unsatisfactory addition to 4-aminoquinolines for the treatment of chloroquine-resistant falciparum malaria. 27 We thank the director, Dr Chaisit Dharakul, and the staff of Pra Pokklao and Khun Vanaporn Wuthiekanun for
Hospital; Khun Kamolrat Silamut
808 technical help; Dr Brian Wiffen and the staff of the pharmacy department, John Radcliffe Hospital, Oxford, for preparing the parenteral amodiaquine; and Khun Patchari Prakongpan and Ms Kristin Headlam for preparing the
manuscript. The study is part of the Wellcome-Mahidol University Tropical Medicine Research Programme financed by the Wellcome Trust of Great Britain.
Correspondence should be addressed to D. A. W., Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. REFERENCES 1.
Payne EH, Sharp EA, Nickel KC. Parenteral use of camoquin hydrochloride as an antimalarial. Am J Trop Med 1949; 29: 353-68. 2. Payne EH, Villarejos VM, Sharp EA, Reinertson JW, Wille WS. Intravenous amodiaquine (Camoquin) in naturally acquired and induced malaria. Am J Trop Med 1951, 31: 698-702. 3. Coatney GR, Cooper WC, White WC, Lints HA, Culwell WB, Eyles D. Studies in human malaria. XXIV Protective and therapeutic trials of SN10,751 (Camoquin) against the Chesson strain of Plasmodium vivax. J Natl Malaria Soc 1950; 9: 67-73. 4. Geary TG, Jensen JB. Lack of cross-resistance to 4-aminoquinolines in chloroquineresistant Plasmodium falciparum in vitro. J Parasitol 1983; 69: 97-105. 5. Hall AP, Segal HE, Pearlman EJ, Phintuyothin P, Kosakul S. Amodiaquine resistant falciparum malaria in Thailand. Am J Trop Med Hyg 1975; 24: 575-80. 6. Pinichpongse S, Doberstyn EB, Cullen JR, Uisunsri L, Thongsombun Y, Thimasarm K. An evaluation of five regimes for the outpatients therapy of falciparum malaria in Thailand 1980-81. Bull WHO 1982; 60: 907-12. 7. Spencer HC, Kipinger T, Agure R, Koech DK, Chulay JD. Plasmodium falciparum in Kisumu, Kenya differences in sensitivity to amodiaquine and chloroquine in vitro. J Infect Dis 1983; 148: 732-36. 8. Watkins WM, Sixsmith DG, Spencer HC, et al. Effectiveness of amodiaquine as treatment for chloroquine-resistant Plasmodium falciparum infections in Kenya Lancet 1984; i: 357-59. 9. WHO Scientific Group Advance in malaria chemotherapy. Technical Report Series 711 Geneva: World Health Organisation, 1984. 10 Looareesuwan S, Phillips RE, White NJ, et al. Quinine and severe falciparum malaria in late pregnancy. Lancet 1985; ii: 4-7 1 1. Noeypatimanond S, Malikul S, Benjapong W, Duriyanonda D, Ungkasvithongkul M. Treatment of Plasmodium falciparum malaria with a combination of amodiaquine and tetracycline in Central Thailand. Trans R Soc Trop Med Hyg 1983; 77: 338-40.
Reviews of Books Principles of Metastasis Leonard Weiss, Roswell Park Memorial Institute, Buffalo, New York. Orlando, Florida: Academic Press. 1985. Pp 425.$52.
AT a time when even the briefest of reports seems to require the combined efforts of many investigators a single author text automatically commands a certain degree of respect. When, as is the case here, the author cites well over 1200 references and gives every evidence not only of having read all of them but also of having reappraised many of their reported results in a careful and critical fashion, then respect is tinged with more than a slight feeling ofawe. Few people are as well qualified as Dr Weiss to examine the underlying principles and cellular interactions involved in tumour dissemination and to show us what we actually know about the process as distinct from what we think we know. Weiss presents his arguments in a lucid fashion backed by considerable cited detail; his views always are thought-provoking even when counter to those held by his reader. Where the book fails to convince it does so because of the nature of the topic under discussion. As Weiss points out in his preface, the metastatic process has to be viewed in terms of general pathobiology-a requirement that demands the synthesis of knowledge from disparate areas. Reviewers of multi-author texts frequently bemoan the lack of uniformity in style that such a format produces but it has the obvious virtue of assuring expertise in diverse areas. This book certainly has the desired uniformity of style but even an investigator with the stature of Weiss cannot hope to cover all the topics that impinge on the pathogenesis of metastasis with equal authority. Thus in certain sections there is a noticeably shallow feel that reflects the author’s lack of personal familiarity with the topic under discussion. However, when Weiss is on "home-ground" he is a formidable advocate of his ideas and this book, which is a heroic effort, must be counted an overall success. Clinicians who wish to learn of the attempts to understand metastasis at the cell biology level may come away from reading the
12. Warhurst DC, Robinson BL, Peters W. The chemotherapy of rodent malaria XXI. The blood schizonticidal action of erythromycin upon Plasmodium berghei. Ann Trop Med Parasitol 1976; 70: 253-85. 13. Phillips RE, Looareesuwan S, Karbwang J, et al. Failure of chloroquine-erythromycin and chloroquine-tetracycline combinations in the treatment of chloroquineresistant falciparum malaria in Eastern Thailand. Lancet 1984; i: 300-02. 14. Trager W, Jensen JB. Human malaria parasite in continuous culture. Science 1976; 193: 673-75 15. Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 1979; 65: 418-20 16. Rieckmann K, Sax LJ, Campbell GH, Mrema JS. Drug sensitivity of Plasmodium falciparum. An in vitro microtechnique Lancet 1978; i: 22-23 17. Harinasuta T. Chloroquine resistance in Plasmodium falciparum in Thailand. In. First Regional Symposium on Scientific Knowledge of Tropical Parasites. Singapore: University of Singapore, 1962: 148-53. 18. Thaithong S, Beale GH, Chutmongkonkul M. Susceptibility of Plasmodium falciparum to five drugs an in vitro study of isolates mainly from Thailand. Trans R Soc Trop Med Hyg 1983; 77: 228-31. 19 Suntharasamai P, Vanijanond S, Harinasuta T, Bunnag D. A double blind randomised trial of quinine vs. quinidine in chloroquine resistant falciparum malaria. Abstract, XI International Congress for Tropical Medicine and Malaria, Calgary, Canada. September 16-22, 1984. 20 White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309: 61-66. 21. Mihaly GW, Nichol DD, Edwards IG, et al. High-performance liquid chromatographic analysis of amodiaquine in human plasma. J Chromat 1985, 337: 166-71. 22. Churchill FC, Patchen LC, Campbell CC, Schwartz IK, Nguyen-Dinh P, Dickinson O. Amodiaquine as a pro-drug: importance of metabolites in the antimalarial effect of amodiaquine in humans. Life Sci 1985; 36: 53-62. 23. Schwartz IK, Payne D, Campbell CC, Khatib OJ. In vivo and in vitro assessment of chloroquine resistant Plasmodium falciparum malaria in Zanzibar. Lancet 1983,i: 1003-05. 24. Reacher M, Campbell CC, Freeman J, Doberstyn EB, Brandling-Bennett AD. Drug therapy for Plasmodium falciparum malaria resistant to pyrimethamine sulfadoxine (’Fansidar’) Lancet 1981; ii: 1066-68. 25. Deloron P, Le Bras J, Ramanamirija JA. Amodiaquine and chloroquine efficacy against Plasmodium falciparum in Madagascar. Lancet 1981; ii: 1303-04 26. Campbell CC, Payne D, Schwartz IK, Khatib OJ. Evaluation of amodiaquine treatment of chloroquine resistant Plasmodium falciparum malaria in Zanzibar, 1982. Am J Trop Med Hyg 1983; 32: 1216-20 27. Editorial Chemotherapy of malaria in mouse and man. Lancet 1984, i: 318-19.
with a fresh appreciation of how intractable the problem is at the experimental as well as the clinical level; experimentalists in the field of tumour spread will find the work required reading. text
Biology of Metastasis Laboratory, Imperial Cancer Research Fund Laboratories, London
The
1. R. HART
Epilepsies
Butterworths Internatzonal Medical Reviews 5. Edited by Roger J. Porter, National Institutes of Neurological and Communicative Disorders and Stroke, Bethesda, Maryland, and Paolo I. Morselli, Laboratoire d’Etudes et de Recherche, Synthelabo, Pans. London: Butterworths. 1985. Pp 396.
:C36.
EPILEPSY, for long regarded as a rather dull area of neurology, has been the subject of an enormous increase in interest and research in recent years. This is reflected in the publication of several authoritative reviews on the subject. As for previous books in the series, this volume is edited jointly by an American and a European. It is a multi-author work which is comprehensive in its coverage. Initial chapters review basic biochemical, neurotransmitter, and neurophysiological aspects of seizures; these are followed by accounts of epidemiology and classification. The value of various investigations is discussed, both familiar techniques (eg, electroencephalography) and newer procedures such as positron emission tomography. Therapy is reviewed in a number of chapters on pharmacology and surgery, and psychosocial problems associated with epilepsy are also covered. Readers will find this an excellent, up-to-date summary of the subject. Chapters inevitably vary a little in their coverage and European readers will be struck by what they might regard as unusual preferences for particular forms of drug therapy-eg, primidone and phenobarbitone for partial and tonic clonic seizures. However, overall it is difficult to be critical of this book which represents excellent value for money. It will be of interest and value to anyone charged with the care of epileptic patients. Department of Neurology, Walton Hospital, Liverpool
D. W. CHADWICK
INTRAVENOUS AMODIAQUINE AND ORAL
AMODIAQUINE/ERYTHROMYCIN
IN THE
TREATMENT OF CHLOROQUINE-RESISTANT FALCIPARUM MALARIA RODNEY E. PHILLIPS SORNCHAI LOOAREESUWAN NICHOLAS J. WHITE JUNTRA KARBWANG PANOSRI ATTANATH YUPIN BENJASURAT DAVID A. WARRELL
Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Nuffield Department of
University of Oxford; Liverpool School of Tropical Medicine; and Pra Pokklao Hospital, Chantaburi,
Clinical Medicine,
Thailand
Summary
In
eastern
Thailand,
14
adults with malaria were
falciparum amodiaquine dihydrochloride, loading dose 10 mg base/kg infused over 4 h followed by three further intravenous infusions of 5 mg base/kg at 24, 48, and 72 h. All patients were clinically cured—mean fever clearance time 37·8 h (range 24-60), mean parasite clearance time 64·9 h (18-164). There were no serious toxic effects. 33 patients aged over 5 years with uncomplicated falciparum malaria were given oral amodiaquine dihydrochloride (mean total dose 41 mg base/kg over 3 days) combined with erythromycin estolate (mean dose 48 mg base/kg daily for 5 days). 2 patients failed to respond. In the other 31 patients mean fever clearance time was 55·9 h (range 10-104) and mean parasite clearance time was 65·4 h (40-120). In both studies, more than half the patients followed-up had recurrent parasitaemia but reinfection could not be excluded. Parasites isolated from 18 patients were highly resistant to chloroquine in vitro. moderately
severe
treated with intravenous
were generally sensitive to in Africa and Thailand clinical trials In amodiaquine.4 more cleared parasitaemias than chloroquine.5-8 amodiaquine This difference between the two main 4-aminoquinolines could be exploited in several ways.
sensitivity
to
chloroquine
If the safety and efficacy of parenteral amodiaquine were confirmed it could be invaluable for the treatment of severe falciparum malaria. The WHO Scientific Group believes that chloroquine is too dangerous for parenteral use.9 They recommend quinine for all cases of severe malaria, although
life-threatening hypoglycaemia develops in some patients so treated.1O If amodiaquine retained schizontocidal activity against quinine-resistant falciparum malaria, a parenteral form could be life-saving againstan otherwise untreatable infection. In Africa and western Asia, where chloroquine resistance is emerging, the wider use of amodiaquine might improve radical cure rates of uncomplicated falciparum malaria. severe,
The combination of tetracycline and
amodiaquine had a chloroquine-resistant Erythromycin shows potentiating synergism when combined with chloroquine2 against chloroquine-resistant Plasmodium berghei in micel2 but, in falciparum malaria the effects of the combination were unimpressive.13 The combination of amodiaquine and erythromycin has not been tried in human malaria. in uncomplicated malaria in central Thailand in 1981.11
high
cure
rate
We describe here two studies in which we treated Thai patients who had chloroquine-resistant falciparum malaria with intravenous amodiaquine and the oral combination amodiaquine and erythromycin.
Patients and Methods
Patients Introduction THE 4-aminoquinoline antimalarials were introduced into clinical practice nearly 40 years ago. Amodiaquine proved a remarkable advance; a single dose rapidly cleared asexual parasitaemias, including infections caused by quinineresistant malaria, and even when given parenterally, the drug was free of serious side-effects.1,2 However, chloroquine became more widely used. In 1950 Coatney3 first mentioned the possibility that the antimalarial activity of amodiaquine might result from metabolites rather than the parent drug. By contrast,
chloroquine itself, although subject to metabolism,
chief active agent. Parasite isolates from different countries which varied considerably in their in-vitro
appeared to be the
WE, Niblack GW, Johnson HK, Richie RE. Relationship of cadaveric renal transplant results to HLA tissue matching. Transplant Proc 1977; 9: 487-89. 9. Salvatierra O Jr, Perkins HA, Cochrun KC, Duca RM, Potter DE, Amend WJ, Feduska NJ. HLA typing and primary cadaver graft surival. Transplant Proc 1977; 8. Walker
9: 495-501. 10. Opelz G, Mickey M, Terasaki PI. Transplantation 1974; 17: 371. 11.Goeken NE, Nghiem DD, Corry RJ. Prospective HLA-DR matching in a single centre renal transplant program. Transplant Proc 1982; 14: 185-86. 12. Albrechtsen D, Bondevik H, Flatmark A, et al. Transplant Proc 1982; 14: 182-84. 13 Tate DG, Smith D, Lee HA, Slapak M. The effect of blood transfusion and HLA-DR matching on kidney survival in the Wessex Region. Br J Surg 1981 68: 823. 14. Gardner B, Harris KR, Digard NJ, et al. Do recipients ofa cadaveric renal allograft on Cyclosporin require prior transfusions? Experience of asingle unit. Transplant Proc
1985; 18: 1032-33. 15 Calabresi P, Parks RE Jr. Chemotherapy of neoplastic diseases. In: Goodman LS, Gilman AS, eds. The pharmacological basis of therapeutics, 6th ed. New York: Macmillan, 1980: 1283-87.
Patients admitted
Pra Pokklao Hospital, Chantaburi, eastern for study if asexual forms of Pfalciparum were found in a blood smear. One group of patients was given amodiaquine intravenously; they were older than 15 years and had moderately severe infections. Generally they had admission parasitaemias greater than 1%, required intravenous fluids, and many were nauseated and vomiting and unable to tolerate tablets. The second group were older than 5 years, had uncomplicated malaria, and were able to swallow tablets. Patients were excluded if they were over 65 years old; were severely ill with cerebral, renal, or other complications; had mixed infections; gave a history of recent antimalarial treatment; or if on admission quinine was detectable in their plasma or sulphonamides or 4-aminoquinolines in their urine. All patients or their relatives gave informed consent to investigation, treatment, and follow-up. The study was approved by
Thailand,
16. Whisler
were
to
eligible
RL, Lindsey JA, Procter KVW, et al. Characteristics of cyclosporin induction
prostaglandin levels from human peripheral blood monocytes. Transplantation 1984; 38: 377-81. 17. Bunjes D, Hardt C, RollinghoffM, et al. Cyclosporin A mediates immunosuppression of primary cytotoxic T cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 1981; 11: 657-61. 18. Keown PA, Stiller CR, Ulan RA, et al. Inhibition of the donor specific immune response by Cyclosporin A following renal transplantation. Transplant Proc 1981; of increased
3: 1669-72. 19.
Hutchinson IF, Shadur CA, Alberto Duarte JS, et al. Cyclosporin A spares selectively lymphocytes with donor specific suppressor characteristics. Transplantation 1981; 32: 210-16.
20. Tutschka
PJ. Cyclosporin A as a tool for experimental and clinical transplantation. Biomed Pharmacother 1982; 36: 341-44. 21 Dos Reis GA, Shevach EM. Effect of cyclosporin A on T cell function in vitro The mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell. J Immunol 1982; 129: 2360-67.
806 the ethical committee,
Faculty
of
Tropical Medicine,
TABLE I-CLINICAL DETAILS
Mahido
University, Bangkok. Methods
History and examination were recorded on standard forms Pretreatment investigations included full blood count, platele count; parasite count, electrolytes, blood urea nitrogen, creatipine. albumin, globulin, and aspartate aminotransferase. Urine waf tested for sulphonamides and 4-amino-quinolines, and plasm samples were stored for estimation of quinine (in Bangkok). Patient! were observed in hospital until the parasitaemia had cleared and the drug course was completed. Axillary temperature was measurec every 4 h until the patient had been afebrile for 24 h, then once a day. Blood smears were made every 8 h until the parasitaemia had cleared, then daily. Parasite counts were done on thick or thin films; depending on the parasite density. Patients whose parasitaemia cleared were asked to return 19 and 33 days after the start oi treatment, or at any time if symptoms returned. At these visits they were asked about fever and other symptoms and were examined. Thick and thin smears were checked for malaria parasites, and blood was taken for haematological and biochemical measurements including liver function tests. If no asexual forms were seen the parasitaemia was regarded as having cleared. In-vitro tests.-5 ml samples of heparinised venous blood were taken from 18 patients in the second study before treatment was started and transported to Bangkok the same day for storage in liquid nitrogen. 6 months later the thawed parasites were allowed to grow in continuous culture14 synchronised by the use of sorbitol. 15 The in-vitro microtechnique 16 was used to determine the susceptibility of parasites to chloroquine and amodiaquine. 50 µl RPMI 1640 medium (supplemented with 10% AB human serum) containing about 2 µl parasitised and non-parasitised erythrocytes with 0 - 3-0 - 5% parasitaemia was placed in each well of the microculture plate. Cultures were incubated in candle jars at 37°C for 30-48 h. A thick smear was then made from each well, stained with giemsa, and examined microscopically for parasite maturation. Drug inhibition was measured by comparing the number of schizonts in the control well with the number of schizonts in wells containing drug. The minimum inhibitory concentration (MIC) was defined as the lowest drug concentration in which schizont formation was≤1% of drug-free controls. Intravenous amodiaquine study.-Amodiaquine dihydrochloride (Parke-Davis) was dissolved in distilled water (30 mg/ml) and dispensed in glass vials (John Radcliffe Hospital, Oxford). A loading dose of 10 mg base/kg body weight was dissolved in 250 ml normal saline in glass bottles and infused over 4 h. Further doses of 5 mg base/kg as 4 h infusions were given at 24, 48, and 72 h. Precautions were taken to protect the drug from light. Intravenous fluids, intramuscular antipyretics (dipyrone 500 mg) and antiemetics (metoclopramide 10 mg) were given as required but no other drugs were given during the study period. Blood pressure and pulse rate were measured before, during, and after the infusion of amodiaquine and subsequently every 4 h. Oral amodiaquine and erythromycin.-Amodiaquine dihydrochloride tablets (’Camoquin’, Parke-Davis) were given in a loading dose of 600 mg base (400 mg base for patients weighing <40 kg). Three further doses of 400 mg base (200 mg base for those <40 kg) were given at 6, 24, and 48 h. Erythromycin estolate capsules (’Ilosone’, Eli Lilly) were given three times a day with meals for 5 days in doses of 750 mg (base) to those weighing <60 kg, 250 mg to those weighing <40 kg, and 500 mg to others.
All 14 patients of parasitaemia.
responded to treatment with disappearance Body temperature returned to normal in 37’8h (range 24-60). Parasite clearance times, which were not normally distributed, ranged between 18 h and 164 h (mean 64-9). 5 patients were completely cured, 6 had recurrent parasitaemia between days 14 and 29, and 3 patients did not return for follow-up. Patients with recurrent parasitaemia were treated with quinine and tetracycline and discharged when their parasitaemia had cleared. All patients had returned to the endemic area, so reinfection was possible. No patient showed evidence of cardiovascular poisoning. The range of blood-pressure readings before the loading dose was 132/90 mm Hg to 80/50 mm Hg and afterwards 130/90 mm Hg to 80/48 mm Hg, while the maximum fall in blood pressure was 10 mm Hg. There was no consistent change in pulse rate. 2 patients vomited 6 and 19 h and 1 patient had diarrhoea 30 h after the start of treatment. No adverse effects were seen in the rest. Amodiaquine leaked subcutaneously at the intravenous cannula site on two occasions but there was no evidence in these patients or any other of local tissue damage or inflammation.
Amodiaquine-erythromycin All 33 patients were acutely ill onadmission and 31 (94%) were febrile. 27 patients (8’ 2%) were experiencing their first or second attack of malaria. No patient had detectable urinary 4-aminoquinolines or plasma quinine. 2 patients whose urine was weakly positive for sulphonamide were not excluded. Haematological and biochemical measurements were within normal limits except for admission haematocrits in 4 patients (range 22’5-33%) and total bilirubin in 4 others (range 37 - 6-110 µmol/l; 2 - 24-35 mg/dl). Bilirubin levels fell to normal with clearance of parasitaemia. Patients received TABLE 11-ADMISSION LABORATORY RESULTS (MEAN±SD)
Results Intravenous Amodiaquine
All
patients studied (table I) gave a history of fever and and all were febrile (>37’ 5 °C) on admission. 4 patients rigors were drowsy though easily roused, but no patient was admitted with or developed evidence of cerebral, renal, or pulmonary involvement. In 12 patients parasitaemia was more than 1% (table II). 4 patients vomited before any 14
treatment was
given.
*Reitman-Frankel units/ml.
807 18 PLASMODIUM FALCIPARUM CHLOROQUINE AND AMODIAQUINE
TABLE III-IN-VITRO RESPONSE OF ISOLATES TO
___________
____-
_
_
_
_
_
I
.
I
*Comparison of MIC values for chloroquine and amodiaquine (after loganthmic transformation) using paired t test, p<0-001. doses of 41 mg amodiaquine base/kg (total) and 48 mg erythromycin base/kg daily for 5 days. 31 patients responded to treatment with a mean fever clearance time of 55-99 h (range 10-104) and mean parasite clearance time of 65’ 4 h (range 40-120). Of 29 patients who returned for follow-up, 14 (48%) were cured (S) and 15 (52%) had recurrent parasitaemia (Rl). The Rl patients, 1 patient who responded poorly (R2), and 1 patient whose parasitaemia rose after treatment started (R3) were treated with quinine and tetracycline. 12 patients vomited between 2 and 46 h after starting treatment and the dose was repeated after parenteral metoclopramide. 2 other patients became nauseated and diarrhoea developed in 1. At follow-up visits haematological and biochemical measurements, including white-cell count mean
and liver function tests, remained within normal limits.
In-vitro Tests 18 frozen Chantaburi isolates were adapted to in-vitro culture and all tests were successful for chloroquine and amodiaquine (table III). All the isolates were highly resistant to chloroquine by standard criteria (WHO, 1984). 17 isolates were more sensitive to amodiaquine than to chloroquine (p<0’001). The growth of 1 isolate was not inhibited by either drug at any concentration tested. In-vivo response could not be correlated with the MIC for amodiaquine. 1 isolate, from a patient with an R3 response, had an amodiaquine MIC of 320 nmol/1, which was close to the geometric mean (359 nmol/1). Another isolate, which was not inhibited by 5120 nmol/1, came from a patient who subsequently had an Rresponse.
Discussion
Chloroquine-resistant malaria has been recognised in Thailand for over 20 years" and this drug is now virtually useless against P falciparum. 13,18 Quinine resistance is also appearing. Quinine alone cures less than 25% of infections treated at the Bangkok Hospital for Tropical Diseases.19 In our study amodiaquine cleared the asexual parasitaemia in patients with falciparum malaria acquired along the Thai-
Kampuchean border; moderately
ill patients responded rapidly and their fever and parasite clearance times were comparable to those achieved with quinine. Intravenous chloroquine proved useless at Chantaburi.13 In view of the
excellent cure rate and the lack of serious toxic effects in our study, a role for intravenous amodiaquine in the treatment of severe falciparum malaria must be considered. Quinine is the only drug now recommended by the WHO for parenteral treatment of falciparum malaria.9 In Thailand no other
parenteral drug is available, so the emergence of has created a crisis in the chemotherapy of resistance quinine severe malaria. If amodiaquine were effective against highly quinine-resistant malaria, a safe intravenous regimen would be life-saving. Unlike quinine, amodiaquine does not stimulate insulin release (D. A. W., unpublished), so it would be particularly useful in severe malaria complicating 10,20 pregnancy and in cerebral malaria. metabolism Rapid hepatic probably accounts for the fact that amodiaquine is undectable in the blood after oral dosing in volunteers and in patients who nonetheless respond to treatment (I. G. Edwards et al, unpublished, and21). The metabolites formed, which include desethylamodiaquine, appear to be the chief antimalarial agents.2Thus the pharmacology of amodiaquine differs substantially from that of other 4-aminoquinolines. Clearly, if it is to be used to best advantage, regimens must be based on the pharmacokinetics of the parent drug and its metabolites. New drug assays should allow suitable regimens to be devised,21,22 although the comparative effectiveness and safety of amodiaquine and quinine against falciparum malaria can be assessed only by clinical trial. Since amodiaquine appears to be a pro-drug, the active metabolites should be used for in-vitro sensitivity testing. Preliminary work suggests that the antimalarial activity of amodiaquine and its desethylmetabolite are similar22 so test systems using the parent drug alone should provide a rough guide to in-vivo activity. However, in-vitro tests fail to mimic the complex drug-parasite interaction that takes place in vivo, and biotransformation of antimalarials also limits the usefulness of this technique as a reliable predictor of treatment response. Isolates from our patients who subsequently received oral amodiaquine and erythromycin were highly resistant in vitro to chloroquine but sensitive to amodiaquine, consistent with clinical experience. 13 However, the degree of in-vitro sensitivity did not match effective
patient
response.
Even early in the development of resistance to an antimalarial drug, radical cure of falciparum malaria with single drug therapy is difficult.23 In Thailand quinine, even when given for 10 days, usually fails to produce a radical cure unless tetracycline is added.24 In East Africa and Madagascar higher chloroquine doses produced better cure rates in uncomplicated chloroquine-resistant malaria, but overall the results were still unsatisfactory. 1,23,21 Parasite clearance rates were superior when amodiaquine was tried in uncomplicated malaria. However, recrudescence was a problem in Zanzibar,26 and was not investigated in the Kenyan study in which follow-up continued for only 14 days.8 Amodiaquine and tetracycline were curative in central Thailand," but the need for an alternative to tetracycline in children and pregnant women, and the demonstration of potentiating synergism between chloroquine and erythromycin have been strong incentives to test the antiplasmodial action of erythromycin.12 Combined with chloroquine, erythromycin produced a radical cure rate of only 1907o at Chantaburi,13 a better result than would be expected if chloroquine alone were used, but the high rate of recurrence was unacceptable for routine use. Our trial and a second study carried out with high-dosed erythromycin and chloroquine (L. Pang, personal communication) provide further evidence that erythromycin is an unsatisfactory addition to 4-aminoquinolines for the treatment of chloroquine-resistant falciparum malaria. 27 We thank the director, Dr Chaisit Dharakul, and the staff of Pra Pokklao and Khun Vanaporn Wuthiekanun for
Hospital; Khun Kamolrat Silamut
808 technical help; Dr Brian Wiffen and the staff of the pharmacy department, John Radcliffe Hospital, Oxford, for preparing the parenteral amodiaquine; and Khun Patchari Prakongpan and Ms Kristin Headlam for preparing the
manuscript. The study is part of the Wellcome-Mahidol University Tropical Medicine Research Programme financed by the Wellcome Trust of Great Britain.
Correspondence should be addressed to D. A. W., Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. REFERENCES 1.
Payne EH, Sharp EA, Nickel KC. Parenteral use of camoquin hydrochloride as an antimalarial. Am J Trop Med 1949; 29: 353-68. 2. Payne EH, Villarejos VM, Sharp EA, Reinertson JW, Wille WS. Intravenous amodiaquine (Camoquin) in naturally acquired and induced malaria. Am J Trop Med 1951, 31: 698-702. 3. Coatney GR, Cooper WC, White WC, Lints HA, Culwell WB, Eyles D. Studies in human malaria. XXIV Protective and therapeutic trials of SN10,751 (Camoquin) against the Chesson strain of Plasmodium vivax. J Natl Malaria Soc 1950; 9: 67-73. 4. Geary TG, Jensen JB. Lack of cross-resistance to 4-aminoquinolines in chloroquineresistant Plasmodium falciparum in vitro. J Parasitol 1983; 69: 97-105. 5. Hall AP, Segal HE, Pearlman EJ, Phintuyothin P, Kosakul S. Amodiaquine resistant falciparum malaria in Thailand. Am J Trop Med Hyg 1975; 24: 575-80. 6. Pinichpongse S, Doberstyn EB, Cullen JR, Uisunsri L, Thongsombun Y, Thimasarm K. An evaluation of five regimes for the outpatients therapy of falciparum malaria in Thailand 1980-81. Bull WHO 1982; 60: 907-12. 7. Spencer HC, Kipinger T, Agure R, Koech DK, Chulay JD. Plasmodium falciparum in Kisumu, Kenya differences in sensitivity to amodiaquine and chloroquine in vitro. J Infect Dis 1983; 148: 732-36. 8. Watkins WM, Sixsmith DG, Spencer HC, et al. Effectiveness of amodiaquine as treatment for chloroquine-resistant Plasmodium falciparum infections in Kenya Lancet 1984; i: 357-59. 9. WHO Scientific Group Advance in malaria chemotherapy. Technical Report Series 711 Geneva: World Health Organisation, 1984. 10 Looareesuwan S, Phillips RE, White NJ, et al. Quinine and severe falciparum malaria in late pregnancy. Lancet 1985; ii: 4-7 1 1. Noeypatimanond S, Malikul S, Benjapong W, Duriyanonda D, Ungkasvithongkul M. Treatment of Plasmodium falciparum malaria with a combination of amodiaquine and tetracycline in Central Thailand. Trans R Soc Trop Med Hyg 1983; 77: 338-40.
Reviews of Books Principles of Metastasis Leonard Weiss, Roswell Park Memorial Institute, Buffalo, New York. Orlando, Florida: Academic Press. 1985. Pp 425.$52.
AT a time when even the briefest of reports seems to require the combined efforts of many investigators a single author text automatically commands a certain degree of respect. When, as is the case here, the author cites well over 1200 references and gives every evidence not only of having read all of them but also of having reappraised many of their reported results in a careful and critical fashion, then respect is tinged with more than a slight feeling ofawe. Few people are as well qualified as Dr Weiss to examine the underlying principles and cellular interactions involved in tumour dissemination and to show us what we actually know about the process as distinct from what we think we know. Weiss presents his arguments in a lucid fashion backed by considerable cited detail; his views always are thought-provoking even when counter to those held by his reader. Where the book fails to convince it does so because of the nature of the topic under discussion. As Weiss points out in his preface, the metastatic process has to be viewed in terms of general pathobiology-a requirement that demands the synthesis of knowledge from disparate areas. Reviewers of multi-author texts frequently bemoan the lack of uniformity in style that such a format produces but it has the obvious virtue of assuring expertise in diverse areas. This book certainly has the desired uniformity of style but even an investigator with the stature of Weiss cannot hope to cover all the topics that impinge on the pathogenesis of metastasis with equal authority. Thus in certain sections there is a noticeably shallow feel that reflects the author’s lack of personal familiarity with the topic under discussion. However, when Weiss is on "home-ground" he is a formidable advocate of his ideas and this book, which is a heroic effort, must be counted an overall success. Clinicians who wish to learn of the attempts to understand metastasis at the cell biology level may come away from reading the
12. Warhurst DC, Robinson BL, Peters W. The chemotherapy of rodent malaria XXI. The blood schizonticidal action of erythromycin upon Plasmodium berghei. Ann Trop Med Parasitol 1976; 70: 253-85. 13. Phillips RE, Looareesuwan S, Karbwang J, et al. Failure of chloroquine-erythromycin and chloroquine-tetracycline combinations in the treatment of chloroquineresistant falciparum malaria in Eastern Thailand. Lancet 1984; i: 300-02. 14. Trager W, Jensen JB. Human malaria parasite in continuous culture. Science 1976; 193: 673-75 15. Lambros C, Vanderberg JP. Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 1979; 65: 418-20 16. Rieckmann K, Sax LJ, Campbell GH, Mrema JS. Drug sensitivity of Plasmodium falciparum. An in vitro microtechnique Lancet 1978; i: 22-23 17. Harinasuta T. Chloroquine resistance in Plasmodium falciparum in Thailand. In. First Regional Symposium on Scientific Knowledge of Tropical Parasites. Singapore: University of Singapore, 1962: 148-53. 18. Thaithong S, Beale GH, Chutmongkonkul M. Susceptibility of Plasmodium falciparum to five drugs an in vitro study of isolates mainly from Thailand. Trans R Soc Trop Med Hyg 1983; 77: 228-31. 19 Suntharasamai P, Vanijanond S, Harinasuta T, Bunnag D. A double blind randomised trial of quinine vs. quinidine in chloroquine resistant falciparum malaria. Abstract, XI International Congress for Tropical Medicine and Malaria, Calgary, Canada. September 16-22, 1984. 20 White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983; 309: 61-66. 21. Mihaly GW, Nichol DD, Edwards IG, et al. High-performance liquid chromatographic analysis of amodiaquine in human plasma. J Chromat 1985, 337: 166-71. 22. Churchill FC, Patchen LC, Campbell CC, Schwartz IK, Nguyen-Dinh P, Dickinson O. Amodiaquine as a pro-drug: importance of metabolites in the antimalarial effect of amodiaquine in humans. Life Sci 1985; 36: 53-62. 23. Schwartz IK, Payne D, Campbell CC, Khatib OJ. In vivo and in vitro assessment of chloroquine resistant Plasmodium falciparum malaria in Zanzibar. Lancet 1983,i: 1003-05. 24. Reacher M, Campbell CC, Freeman J, Doberstyn EB, Brandling-Bennett AD. Drug therapy for Plasmodium falciparum malaria resistant to pyrimethamine sulfadoxine (’Fansidar’) Lancet 1981; ii: 1066-68. 25. Deloron P, Le Bras J, Ramanamirija JA. Amodiaquine and chloroquine efficacy against Plasmodium falciparum in Madagascar. Lancet 1981; ii: 1303-04 26. Campbell CC, Payne D, Schwartz IK, Khatib OJ. Evaluation of amodiaquine treatment of chloroquine resistant Plasmodium falciparum malaria in Zanzibar, 1982. Am J Trop Med Hyg 1983; 32: 1216-20 27. Editorial Chemotherapy of malaria in mouse and man. Lancet 1984, i: 318-19.
with a fresh appreciation of how intractable the problem is at the experimental as well as the clinical level; experimentalists in the field of tumour spread will find the work required reading. text
Biology of Metastasis Laboratory, Imperial Cancer Research Fund Laboratories, London
The
1. R. HART
Epilepsies
Butterworths Internatzonal Medical Reviews 5. Edited by Roger J. Porter, National Institutes of Neurological and Communicative Disorders and Stroke, Bethesda, Maryland, and Paolo I. Morselli, Laboratoire d’Etudes et de Recherche, Synthelabo, Pans. London: Butterworths. 1985. Pp 396.
:C36.
EPILEPSY, for long regarded as a rather dull area of neurology, has been the subject of an enormous increase in interest and research in recent years. This is reflected in the publication of several authoritative reviews on the subject. As for previous books in the series, this volume is edited jointly by an American and a European. It is a multi-author work which is comprehensive in its coverage. Initial chapters review basic biochemical, neurotransmitter, and neurophysiological aspects of seizures; these are followed by accounts of epidemiology and classification. The value of various investigations is discussed, both familiar techniques (eg, electroencephalography) and newer procedures such as positron emission tomography. Therapy is reviewed in a number of chapters on pharmacology and surgery, and psychosocial problems associated with epilepsy are also covered. Readers will find this an excellent, up-to-date summary of the subject. Chapters inevitably vary a little in their coverage and European readers will be struck by what they might regard as unusual preferences for particular forms of drug therapy-eg, primidone and phenobarbitone for partial and tonic clonic seizures. However, overall it is difficult to be critical of this book which represents excellent value for money. It will be of interest and value to anyone charged with the care of epileptic patients. Department of Neurology, Walton Hospital, Liverpool
D. W. CHADWICK