118
At low levels of sympathetic tone, as happen at rest in mild-to-moderate heart failure, a nett agonist action is observed. This results in an increased cardiac output, due to a significant increase in stroke volume, which is achieved at a lower leftventricular filling pressure. These in-vivo observations are not the expected effects of a betal-blocker. In addition, Bohm et al found no increased force of contraction when atrial trabeculae were exposed to xamoterol in vitro. By contrast, clinical studies which used left-ventricular dP/dt as an index of contractility showed that xamoterol increased the force of contraction. Where the sympathetic tone is significantly increased (ie, on exercise in mild-to-moderate heart failure or at rest in patients with severe heart failure) a nett betal-antagonist action of xamoterol is observed. In clinical haemodynamic studies of xamoterol in mild-to-moderate heart failure during exercise the most consistent betal-antagonist effect has been a reduction in exercise heart rate. Thus clinical studies in mild-to-moderate heart failure confirm the beta,-adrenoceptor partial profile of xamoterol. The change from a nett agonist to a nett antagonist action happens at a plasma noradrenaline concentration of 400-500 pg/ml. Bohm et al obtained myocardial tissue from patients described as having moderate heart failure. However, no other clinical details were given and no plasma noradrenaline data were provided. Their results may therefore reflect findings in patients with more severe heart failure than had been recorded. Furthermore, their interpretation of changes in the force of contraction can be questioned. If xamoterol is purely a beta-blocker, why did it not produce a negative inotropic effect, as propranolol does, rather than no change? Nor should there have been the increase in adenylate cyclase activity, which Bohm et al demonstrated. The disparity between clinical findings in the experiments reported by Bohm et al may also reflect difficulties in extrapolating from isolated muscle experiments to the intact heart. Department of Cardiovascular Medicine, University of Birmingham, East Birmingham Hospital, Birmingham B9 5ST, UK
M. K. DAVIES
1. Virk SJS, Anfilogoff
NH, Lawson N, et al. The acute effects of intravenous xamoterol resting and exercise haemodynamics on patients with mild to moderate heart failure. Eur Heart J 1989; 10: 227-34. 2. Sato H, Inoue M, Matsuyama T, et al. Haemodynamic effects of the beta1 adrenoreceptor partial agonist xamoterol in relation to plasma norepinephrine levels during exercise in patients with left ventricular dysfunction. Circulation 1987; 75: 213-20. 3. Amende I, Simon R, Hood WP, Lichtlen PR. Acute effects of the cardioselective beta, partial agonist, corwin, on left ventricular function and myocardial metabolism in patients with dilated cardiomyopathy. Z Kardiol 1986; 75: 291-95. 4. Molajo AO, Bennett DH. Effect of xamoterol (ICI 118,587), a new beta, adrenoceptor partial agonist on resting haemodynamic vanables and exercise tolerance in patients with left ventricular dysfunction Br Heart J 1985; 54: 17-21. 5. Bhatia SJS, Swedberg K, Chatterjee K Acute haemodynamic and metabolic effects of ICI 118,587 (Corwin), a selective partial beta one agonist in patients with dilated cardiomyopathy. Am Heart J 1986; 111: 692-96. 6. Watanabe K, Hirokawa Y, Yokoyama A, et al. Acute and chronic effects of xamoterol (Corwin) in idiopathic dilated cardiomyopathy. Jap Circ J 1986; 50: 530. on
Induced differentiation of leukaemic cells SIR,-Dr Gabert and colleagues (Nov 11, p 1125) show that in most myeloid leukaemia patients thought to be clinically and cytogenetically cured after bone marrow transplantation (BMT), residual leukaemic cells expressing the bcr,iabl transcript were detected by the highly sensitive polymerase chain reaction (PCR) technique as long as 5 years after BMT, whether or not T-cell depletion of the graft had been carried out. chronic
The eradication of these residual leukaemic cells may be achieved
by differentiation induction therapy, which can induce terminal differentiation of the small number of myeloid leukaemic cells left after BMT and thus prevent the regrowth which is usually responsible for relapse in leukaemic patients. We have found that 1 oll1 retinoic acid-11 jjmoH1 cytarabine+22 mmollI hexamethylene bisacetamide (HMBA) induced terminal differentiation of more than 90% of blast cells from 22 patients with primary acute myeloid leukaemia and of almost 100% of blast cells from myeloid leukaemic patients with a leucocyte count of less than
000/ul after 6 days in primary culture.’ Clinically, retinoic acid increased the remission duration in myeloid leukaemic patients for up to 4 years without any significant hepatotoxicity or myelosuppression.2,3Also, the five phase I clinical trials of HMBA indicated no myelosuppression, and three more clinical trials of HMBA in myelodysplastic syndrome patients are in progress.4 Treatment with a monthly 5-day course of 20 mg/m2 daily retinoic acid orally + 10 mg/m2 subcutaneous cytarabine per day (in two doses) + a 24 gfm2 daily continuous infusion of HMBA until the disappearance of myeloid leukaemic cells expressing 6tr/ transcript, could be an effective post-BMT therapy. The complete cure of myeloid leukaemic patients may be achieved by BMT followed by differentiation induction therapy. 20
Leukaemia Research, Darwin College, University of Cambridge, Cambridge CB3 9EU, UK
H. T. HASSAN
1. Hassan
HT, Rees JKH. Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human AML blasts in primary culture. Haematol Oncol 1989; 7: 429-40. 2. Lie SO, Wathne K, Peterson LB, Slordehl SH, Norum KR. High dose retinol in children with AML remission. Eur J Haematol 1988; 40: 460-65 3. Curtis JE, Messner HA, Minden MD, Tritchler DL, McCulloch EA. Improved maintenance therapy for AML using 13-cis retinoic acid containing regimen. Proc AACR 1989; 30: 268, 1066A. 4. Egorin J. Clinical trials of polar differentiation agents. In: Waxman S, Rossi GB, Takaku F, eds. The status of differentiation therapy of cancer New York Raven Press, 1988: 389-404.
Effect of sinorphan on plasma atrial natriuretic factor in congestive heart failure SIR,- The peptide hormone atrial natriuretic factor (ANF) has diuretic, natriuretic, vasorelaxant, and renin-aldosterone lowering properties but its poor oral absorption and rapid in-vivo inactivation have prevented therapeutic use. One approach to this problem has been to delay the inactivation of endogenous ANF by inhibiting the peptidase enzyme enkephalinase (EC 3.4.24.11; atriopeptidase). Inhibitor drugs, designed about 10 years ago to protect endogenous enkephalins,l do indeed delay the in-vivo inactivation of exogenous ANF and elicit ANF-like responses in rodents.2-4 Two such inhibitors--one administered intravenously,S the other orally3enhance circulating levels of ANF and elicit significant diuretic and natriuretic responses in healthy volunteers. One of them (UK 69 578) was reported to enhance plasma ANF levels in patients with mild (grade 2) chronic heart failure, a condition in which ANF is already raised. We have confirmed and extended this observation for another enkephalinase inhibitor, sinorphan, which is active by mouth. Sinorphan was given to patients with severe congestive heart failure (grade 3 or 4). Sinorphan is a prodrug of (S)-thiorphanl and is about 20 times as potent an inhibitor as UK 69 578 against the pure peptidase, at therapeutic dosage it lacks significant inhibitory potency against other peptidases. In a tolerance study in twelve patients with congestive heart failure, a single dose of sinorphan at 10, 20, or 40 mg was well tolerated and significantly increased plasma ANF. Then effects on haemodynamic and biological indices were studied in twelve male patients with severe heart failure (left-ventricular ejection fraction 20-11 [2 6] %) receiving either 30 or 60 mg three times a day for 2 days after a drug-free placebo period of 36 h. Despite baseline ANF levels about 30 times normal (and about 6 times greater than those in Northridge’s study4) 60 mg sinorphan elicited on the first day of treatment a 2-3 fold rise in the circulating ANF level which peaked at 3 h (figure). Comparison of ANF levels and enkephalinase activities in plasma suggests that roughly halving inhibition of peptidase activity almost doubles the hormone level, as was similarly found in healthy volunteers.3,5 On the second day of treatment with 60 mg sinorphan an ANF response of similar amplitude occurred: for instance, 3 h after oral administration plasma ANF rose to 1340(186) pg/ml, compared with 1266 (255) on the first day and 541 (91) after placebo (p < 001). In another series of five patients 30 mg sinorphan led to a significant rise in plasma ANF, the concentration nearly doubling by 2-3 h after oral administration (not shown); this suggests that the response is maximal or nearly so at this dosage.
119
malaria infections in travellers from West Africa
Epidemic alert:
SIR,-Frequent reference has been made to the rise in incidence of Plasmodium falciparum malaria in non-immune travellers.1,2 This has been attributed to the increased number of travellers to Africa exposed to infection, and to greater risk of breakthrough as a result of the spread of chloroquine-resistant P falciparum malaria. Chloroquine-resistant malaria was first reported in East Africa in 1978, but has only lately been observed in West Africa.’ The dilemma of chemoprophylaxis against P falciparum infectionswhether to prescribe effective but potentially toxic antimalarial drugs (eg, pyrimethamine/sulphadoxine, pyrimethamine/dapsone) or safe but less effective antimalarials (eg, chloroquine and proguanil)-has thus largely been confined to travellers visiting Effects of 60 mg
sinorphan (oral) on plasma ANF and enkephalinase activity in seven patients with severe congestive heart failure. Data as mean
(SEM).’p<0’05;"p<0’01.
The rise in plasma ANF was associated with two typical responses to ANF-namely, a fall in plasma renin activity (by about 20% 1-3 h after 60 mg sinorphan; not shown) and a lowered puhnonary capillary pressure (PCP). Baseline PCP, recorded 24 h after’Swan Ganz’gauge implantation, were 19.4 (2’ 3) and 18.4 ( 1 6) mm Hg in patients scheduled to receive 30 mg and 60 mg sinorphan, respectively. 3 h after drug administration, at the peak of plasma ANF, PCP fell to 17-6 (3-4) (9%; not significant) and 12-4 (2-0) mm Hg (29%; p < 0-04), respectively. Similar changes were recorded on the second day of treatment with 60 mg sinorphan (26 %; p < 0-02), paired Student’s t test. This action of sinorphan was well tolerated and not accompanied by any significant change in cardiac output, heart rate, or mean arterial blood pressure. Our results establish that enkephalinase inhibition represents an effective means of raising ANF levels, even in severe congestive heart failure, and that this may improve haemodynamic indices. Controlled trials with long-term sinorphan, now in progress, will assess the potential of this approach in the management of
cardiovascular diseases.
J. C. KAHN Hôpital de
M. PATEY
Poissy
J. L. DUBOIS-RANDE
Cardiology Service, Créteil
P. MERLET A. CASTAIGNE
Laboratoire Bioprojet
J. M. LECOMTE
Hôpital
Henri Mondor,
C. LIM-ALEXANDRE
Cardiology Service,
D. DUBOC
Hôpital Cochin, Paris
Neurobiology and Pharmacology Unit, Centre Paul Broca de l’INSERM, 75014 Paris, France
C. GROS J. C. SCHWARTZ
East Africa. Lack of travel statistics and of patterns of chemoprophylactic drug use have hampered our understanding of the risks of malaria and the relative efficacy of chemoprophylactic regimens. Since 1986, denominator data from the Office of Population Censuses and Surveys (OPCS) have been made available to estimate the number of travellers visiting malarious countries each year, by category of travel. The most frequently visited countries with endemic Pfalciparnum are Nigeria, Ghana, and The Gambia in West Africa, and Kenya and Tanzania in East Africa. Malaria attack rates may be calculated by linking these data with numerators obtained through national surveillance of imported malaria infections in Britain.4 Both surveillance systems are continuous and data collection and analysis have remained consistent from year to year. The annual rate of infection among travellers returning to Britain from West Africa has risen sharply (figure). In 1986, malaria attack rates were below 0-4% for visitors to countries in West Africa and below 0-2% for East Africa. By 1988, attack rates had increased to 0-8% for Nigeria and to 1-4% for Ghana. In contrast, attack rates for East Africa did not increase. In West Africa, the group of travellers known to be at greatest risk of P falciparum infection are those immigrants settled in Britain who return to their country of origin to visit relatives.2 This group seldom take chemoprophylaxis-in 1987, over half such cases had not done SO.5 The risk of malaria in these travellers increased two to three-fold between 1986 and 1988 (table). A second group of travellers to West Africa, who have hitherto been well protected by prophylaxis, are business travellers. The rate of infection in such travellers to Nigeria, as with immigrants, rose 2’5-fold. However, in business travellers to Ghana, infection rates rose over 8-fold. In contrast, in East Africa, there has been no increase in risk among business travellers. Malaria prevention research continues to focus on East Africa,"6 the region of acquisition of most fatal infections. Our data indicate that the malaria situation in East Africa is stable, whereas infection from West Africa is rapidly increasing. These findings are supported by the increased frequency of malaria infection in USA Peace Corps volunteers in West Africa.’ The emergence of chloroquine resistance seems to only partly account for the sharp rise in infection rates. The number of patients with
I Sdiwarrrr JC. Enkephalinase inhibitors as drugs. In: Sandler M, Smith HJ, eds. Design of enzyme inhibitors as drugs. New York: Oxford University Press, 1989: 206-20. 2 Lafferty HM, Gunning M, et al. Enkephalinase inhibition increases plasma atrial natriuretic penide levels, glomerular filtration natriuretic peptide levels, glomerular filtration rate and urinary sodium excretion in rats with reduced renal mass. Circ Res 1989; 65: 640-46. 3. Gros C, Souque A, et al Protection of atrial natriuretic factor against degradation, diuretic and natriuretic responses after m vivo inhibition of enkephalinase (EC 34.24.11). Proc Natl Acad Sci (USA) 1989; 86: 7580-85. 4. Olins GM, Krieter PA, et al. Specific inhibitors of endopeptidase 24-11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo. Molec Cell Endocrinol 1989, 61: 201-08. 5 Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet 1989; ii: 591-93. 6 Schwartz JC, Gros C, Bralet J, Lecomte JM. Enkephalinase inhibitors’ ANF-like
activity and potential clinical applications. research. Amsterdam Elsevier (in press). 7 Goetz KL Physiology and E1-E15.
In: Harms
AF, ed. Trends
in
drug
pathophysiology of atrial peprides Am J Physiol 1988; 254: Malaria attack rates in
returning
British residents, 1986-88.