99 SCREENING FOR NEURAL-TUBE DEFECTS
later he was able to relax and speak about his experience. The rise’in FG 7142 plasma levels coincided with the beginning of the wavelike drug effects (figure).
SIR,-We have recently assesses the ettects ot a screening programme, similar to that reported on by Professor Roberts and his colleagues in South Wales (June 11, p 1315), in the North East Thames region, based at Oldchurch Hospital. The period was June, 1980, to December, 1981. The full results are being submitted elsewhere but we would like to give some of them here for
FG 7142 inhibits specific binding of 3 H-flunitrazepam to brain specific BZ receptors. The affinity of FG 7142 is less than that of &bgr;-CCE, but FG 7142 is far less susceptible to metabolic breakdown in vivo. In rats FG 7142 mildly stimulates locomotor activity and, like &bgr;-CCE, reverses the anticonflict effect induced by benzodiazepines and phenobarbitone. It enhances conflict behaviour in mice.6,7 Although there is conflicting evidence, FG 7142, unlike some other 0-carbolines, does not cause convulsions or seizure-like EEG patterns in animals. 8- 10 FG 7142 has been called a partial inverse BZ receptor agonist. 1 1,12 Our results suggest that a compound which binds to BZ receptors and has a pharmacological profile opposite to that of benzodiazepines in animals may produce severe anxiety in man. The central effects, vegetative and cardiovascular symptoms, and hormonal changes observed are the same as those described for patients with severe anxiety and panic attacks. The development of severe anxiety in the only two studies (out of twelve) where plasma levels of FG 7142 were high (500-1200 ng/ml) indicates that the anxiety was drug induced. The reversal of anxiety and symptoms by an intravenous benzodiazepine supports the view that the anxiety induced by FG 7142 is mediated via BZ receptors. The BZ receptor antagonist Ro 15-1788, which has no major subjective effects in man, ]3,14 was not available at the time of the study. No other major or pharmacological effects of FG 7142 were detected which could have been the cause of severe anxiety. Nor is it likely that the anxiety experienced was due to a psychogenic horror trip, or to the experimental situation itself, in volunteers having had considerable experience of drug trials. We cannot explain the huge variation in inter-individual plasma concentrations of FG 7142.
Adverse reactions, such as severe anxiety, may thus ingestion of substances formerly classified as BZ antagonists, but which might better be classified as partial inverse agonists at BZ receptors. Tests to distinguish receptor antagonists and weak partial inverse agonists are becoming available. 6,1,1FG 7142 or related substances may provide a means for investigating the pathogenesis and mechanisms of anxiety in man.
We thank the following for assistance and helpful suggestions: Dr K.-J. Graf, L. Holler. E. Kaps, Dr W. Kehr, and C. Knittel. We also thank NIAMDD, Bethesda, Maryland for the prolactin radioimmunoassay material.
Schering AG, D-1000 Berlin 65, West Germany Research Laboratories, A/S Ferrosan, Soeborg, Denmark and St Hans Hospital, Roskilde
R. DOROW R. HOROWSKI G. PASCHELKE M. AMIN
EN, Paschelke G, Kehr W, Nielsen M, Braestrup C Does the reversal of the of phenobarbital by &bgr;-CCE and FG-7142 indicate benzodiazepine receptor-mediated anxiogenic properties? Europ J Pharmacol 1982; 82: 217-21. de Carvalho LP, Grecksch G, Chapourhier G, Rossier J. Anxiogenic and nonanxiogenic benzodiazepine antagonists. Nature 1983, 301: 64-66. Braestrup C, Schmiechen R, Neef G, Nielsen M, Petersen EN Interaction of convulsive ligands with benzodiazepine receptors. Science 1982; 216: 1241-43. Rossier J, Dodd R, Felblum S, Valin A, de Carbalho LP, Potier P, Naquet R. Methylamide &bgr;-carboline (FG 7142), an anxiogenic benzodiazepine antagonist, is also a proconvulsant. Lancet 1983; i: 77-78. Corda MG, Blaker WD, Mendelson WB, Guidotti A, Costa E. &bgr;-Carbolines enhance shock-induced suppression of drinking in rats. Proc Natl Acad Sci (USA) 1983; 8:
2072-76. 11. Jensen LH, Petersen EN, Braestrup C. Audiogenic seizures in DBA/2 mice discriminate sensitively between low efficacy benzodiazepine receptor agonists and inverse agonists Life Sci (in press). 12. Pole P. Bonetti EP, Schaffner R, Haefely W.A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro
15-1788, benzodiazepine tranquilizers, &bgr;-carbolines, and phenobarbitone. NaunynPharmacol 1982; 321: 260-64 13.Hunkeler W. Möhler H, Pieri L, Pole P, Bonetti EP, Cumin R, Schaffner R, Haefely
W Selective antagonists of benzodiazepines. Nature 1981; 290: 514-16. A Lambe R, Scully M, Brick I, O’Boyle C, Downie WW, Investigation in man of the efficacy of a benzodiazepine antagonist Ro 15-1788. Lancet 1981; ii: 8-10
Efficacy is defined as the proportion of cases of anencephaly and open spina bifida (OSB) in the study population detected and terminated as a consequence of the screening programme. At Oldchurch the overall efficacy rate was 65%, and that for OSB 63%. These compare with 56% and 40%, respectively, from Roberts’ results. The sensitivity of the screening test was 100% for anencephaly and 88% for OSB, compared with 78% and 73% in South Wales. This was despite the fact that the incidence in the North East Thames region is only half that in South Wales. All the affected pregnancies detected were terminated. Roberts et al conclude that their low efficacy rates are due to poor compliance, lack of sensitivity of the test, and failure to terminate, and they doubt whether efficacy levels in excess of 65% can be achieved in practice. This level is clearly affected by cultural factors and trends over time and it may be relevant that the South Wales study was done earlier than the North East Thames Study. Technical improvements in laboratory measurement and ultrasound have occurred since then and additional tests such as amniotic fluid acetylcholinesterase have become available. Our experience demonstrates that higher detection rates than those reported by Roberts et al can now be achieved and also the importance of an agreed and clear protocol for action following abnormal results. However, the most crucial factor in improving efficacy appears to be population compliance. The 1982 figures just available to us show that the proportion of the "at risk" population screened at Oldchurch was 89%. If previous levels of detection are maintained then efficacy rates in excess of 80% could be achieved. Medical/scientific Department, North East Thames RHA, 40 Eastbourne Terrace, London W2 3QR
Biochemistry Laboratory, Oldchurch Hospital, Romford, Essex
SIR,-The study by Professor Roberts and his colleagues of the of the serum-AFP screening programme in South Wales was aimed to cover a population of 15 682 pregnant women. Only 70% attended for an AFP test (many beyond the 19th gestational week) and the programme detected only 37 (56%) of the open neural tube defects (NTD) that occurred. However, Roberts et al may not be correct to conclude that implementation of a nationwide serumAFP screening programme for open NTD is not straightforward. Their low detection rate was due to poor coverage and untimely
With the analysis restricted to pregnant women who did have their serum-AFP measured the South Wales data favour serum-AFP screening, the detection rate being 84-4% for anencephaly and 77-3% for open spina bifida, figures which compare favourably with other UK’ -3 or US4 data. In our AFP screening programme in southern Hungary we kept costs down by using the ELISA technique, which is at least ten times cheaper than RIA. Blood samples were collected at pregnancy care centres. The policy is that every pregnant woman should attend at a centre three times during her pregnancy, and this is a tests.
of UK Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube defects. Maternal serum-alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Lancet 1977; i: 1323-32. 2. Ferguson-Smith MA, May HM, Vince JD, et al. Avoidance of anencephalic and spina bifida births by maternal serum-alpha-fetoprotein screening Lancer 1978; i: 1330-33. 3. Brock DJH, Barron L, Duncan P, Scrimgeour JB, Watt M. Significance of elevated mid-trimester maternal plasma-alpha-fetoprotein values. Lancet 1979; i: 1281-82. 4. Milunsky A, Alpert E, Neff RK, Frigoletto FD. Prenatal diagnosis of neural tube defects IV: Maternal serum alpha-fetoprotein screening. Obstet Gynecol 1980; 55: 60-66. 1.
100 RESULTS OF SERL’M-AFP SCREENING BY ELISA IN HUNGARY’S MODEL STUDY
MEASURED PEFR AT PISTON SPEED
piston. The piston’s speed was measured by a linear potentiometer. The output from the potentiometer was displayed on an oscilloscope so that the amplitude of the oscilloscope signal (in mV) was proportional to piston velocity. Sixty PEFR and piston speed
*2’ 5 x median
(ie, .55 ng/ml).
requirement if the woman is to obtain a cash allowance on delivery. Women
of their attendances for the 16th
gestational week. In this way we were able to do serum-AFP screening with a coverage of 90%. Of the 29 232 women in this pregnancy population 26 686 had the test. Women having a raised serum-AFP were told the significance of the test and referred for ultrasonography and a blood sample was obtained. The table summarises the findings. Of the 347 women with a raised serum-AFP level, 214 (61-6%) had abnormal pregnancies. Among the undetected 12 open closures 3 were anencephalics (2 with a normal AFP and 1 not tested), 8 open spina bifidas (3 not screened, 3 with normal AFP levels, and 2 tested later than the 21st gestational week), and 1 abdominal wall defect
(not screened). We conclude that, with proper organisation, AFP screening is an effective measure in prenatal detection of open closure defects and other abnormal pregnancies. In our experience an ELISA-based screening programme makes an important contribution to improved pregnancy care. In Hungary a nationwide programme backed by Ministry of Health is now in operation. Reference Laboratory, Institute of Microbiology, University Medical School, H-7643 Pécs, Hungary
Department of Obstetrics and Gynaecology, County Hospital, Pécs
A. S. PACSA
Laboratory, County Hospital, Zalaegerszeg
PEAK EXPIRATORY FLOW RATE AT HIGH ALTITUDE
StR,-Peak expiratory flow rate (PEFR) has been reported to fall in subjects ascending to high altitude.l,2 Reports that a marked reduction in PEFR occurs in acute mountain sickness led to this test being used in a study of workers at the observatories on top of Mauna Kea (4200 m) on Hawaii. Telescope staff live at sea-level and commute daily to the summit. In 19 workers examined on forty-four ascents, PEFR (miniWright peak flow meter) readings fell from 60l:i:52 (SD) 1/min at sea-level to 580±52 at 3000 m and 560±56 on the mountain top. PEFR thus fell by 3-5% (not significant) and 6-8% (p<0-001), respectively, compared with sea-level. On return to sea-level, mean PEFR was 603±49 1/min. The manufacturers (Airmed, Clement Clarke International Ltd) did not know how lower air density affects performance of the PEFR meter. This effect has been investigated on Mauna Kea. We attached a peak flow meter to the outlet of a fixed volume chamber which could be evacuated at different speeds by a hand-operated
measurements were made at sea-level, 3000 m, and 4200 m, with ambient air or a low density gas (100% helium) in the test chamber. From graphs ofPEFR plotted against piston speed PEFR values at a constant piston speed (equivalent to 50 mV) were obtained by interpolation for the two gases at each location (table). The slope of the line of log PEFR versus log density was 0’ 28. Therefore, as an approximation, PEFR readings are proportional to gas density 1/4. The density of saturated expired air (mouth temperature 34 °C) at 4200 m is 42% lower than at sea-level. Thus, with the density correction derived above, for a given true PEFR the flow meter reading should be about 10% lower at the summit of Mauna Kea than at sea-level. However, the mean observed PEFR fell by only 7% on ascent. This suggests that in contrast to earlier reports, true PEFR does not fall at high altitude; indeed it may even increase slightly, the less dense gas facilitating maximal expiratory
changes density on the performance of must be determined before these tests pulmonary testing equipment are applied to high altitude physiology. The effect of
Department of Pathology, Royal Liverpool Hospital, Liverpool L78XW UK Infrared
Telescope of Royal Observatory (Edinburgh),
Hilo, Hawaii, USA
R. W. PARKER
ANTITHYMOCYTE GLOBULIN IN SEVERE APLASTIC ANAEMIA: HOW MUCH?
SIR,-Severe aplastic anaemia is nearly always rapidly fatal. Allogeneic bone marrow transplantation is suggested for patients with a compatible donor in the family.4 However, Speck et al5 have demonstrated that results just as good can be achieved with antithymocyte globulin (ATG), with lower risks. The best dose of6 ATG is not known: daily doses of 40 mg/kg (x 4),2 20 mg/kg (x 8),6 and 10 mg/kg (X 5),7 have been proposed. We present here a retrospective study of the efficiency of ATG according to the dose. ATG (Institut Merieux, Lyon) was made up in ampoules containing 85 mg of protein and perfused via a central catheter over 6 h for 5 or 6 days. The treatment was preceded by intravenous injection of chlorpheniramine 2 mg and methylprednisolone 60 mg to improve immediate tolerance. The patients were also given, when necessary, irradiated red blood cells or platelets. Thirteen patients were treated; two received a second course of treatment with higher doses because of failure of the first course and the impossibility of bone-marrow transplantation. The patients’ characteristics, total dose of ATG, and clinical course are presented in the table. Five patients received less than 60 mg/kg: there were four failures and one transitory improvement. Among the five DP, Roberts A, Fry DL. Effect of gas density and viscosity on the maximal expiratory flow-volume relationship. J Clin Invest 1963; 42: 1705-13 4. Gordon-Smith EC. Management of aplastic anaemia. Br J Haematol 1983; 53: 185-88 5. Speck B, Gratwohl A, Nissen C, et al. Treatment of severe aplastic anaemia with antilymphocyte globulin or bone marrow transplantation. Br Med J 1982; 282: 3. Schilder
Singh I, Khanna PK, Srivastava MC, Ladan L, Roy SB, Subramanyam CSV. Acute mountain sickness. N Engl J Med 1969, 280: 175-84. Stockley RA. Green ID. Cardiopulmonary function before, during and after a twentyone-day Himalayan trek Postgrad Med J 1979; 55: 496-500.
Champlain R, Ho W, Gale RP. Antithymocyle globulin treatment in patients with aplastic anaemia: a prospective randomized trial. N Engl J Med 1983; 308: 113-18 Gluckman E, Devergie A, Faille A, et al. Treatment of severe aplastic anaemia with antilymphocyte globulin and androgens. Exp Hematol 1978; 6: 679-87.