RANDOMISED CROSSOVER COMPARISON IN 10 HEALTHY VOLUNTEERS OF BIOAVAILABILITY FROM ENTERIC-COATED AND NON-COATED SODIUM FLUORIDE CAPSULES*
D-aminoacids and microwaves SIR,-Professor Lubec (March 31, p 792) fails to appreciate my (Feb 24, p 470) that bacterial cell walls contain D-aminoacids (D-alanine and D-glutamic acid) as structural units statement
AUC: area under curve. *EC-NaF and NEC-NaF 30 mg taken fasting, t30mg EC- NaF tablets specially produced for this trial with same coatmg as in commercially available tablets (also same as that used m usual procal tablets as shown by our earlier work’).
August, 1992). A greater bioavailability from NEC-capsules (by a factor of at least 1-6) was seen (table). Thus the 75 mg NEC mericon capsules correspond to 120 mg of our EC-NaF procal tablets. We have no experience of such high doses. Conversely, our EC-NaF regimen corresponds to a NEC-NaF regimen not much different from that (about 55 mg daily) used previously by Riggs and co-workerss,6 without substantial appendicular bone loss or an increase in AP. Furthermore, the patients with increased vertebral trabeculation and thickening of the end-plates ("fluoridic" vertebrae) had only one-sixth the fracture rate of the other patients.5 Ultimately, 60% of the patients so treated had fluoridic vertebrae and were thus protected, prompting Riggs et aF to state that "the substantial gain in bone mass may increase net bone strength". This view is contrary to your statement that it is likely that any dose of fluoride that increases bone density will result in new bone of inferior quality. That bioavailability is important has been demonstrated by Delmas et al,8 who compared EC-NaF (50 mg, 22mg of F ion) with monofluorophosphate (200 mg, 26 4 mg of F ion), and obtained with the latter drug (whose bioavailability equals that of NEC-NaF capsules8), a lumbar-BMD gain similar to that seen in the Mayo Clinic study.’ New crush fractures occurred in 6% of the EC-NaF group, versus 24% in the monofluorophosphate 8 group, a highly significant difference. Thus high bioavailability of fluoride can be deleterious to bone if the dose is not adjusted.9 One could wish for a larger therapeutic window for fluoride, but fluoride should not be condemned on the basis of the Mayo Clinic trial, especially since controlled studies with lower doses seemed promising. !0.11 Departments of Rheumatology and Biochemistry, CHARLES NAGANT DE DEUXCHAISNES Louvain University in Brussels. JEAN-PIERRE DEVOGELAER St-Luc University Hospital, 1200 Brussels, Belgium FRÉDÉRIC STEIN
Riggs BL, Hodgson SF,
O’Fallon WM, et al. Effect of fluonde treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09. 2. Nagant de Deuxchaisnes C, Devogelaer JP, Depresseux G, Malghem J, Maldague B. Treatment of the vertebral crush fracture syndrome with enteric-coated sodium fluonde tablets and calcium supplements. Bone Miner Res 1990; 5 (supply: S5-26. J 3. Devogelaer JP, Résumont P, Huaux JP, Nagant de Deuxchaisnes C. Effect of sodium fluonde on bone mineral content of the radius in postmenopausal osteoporosis. In: Christiansen C, Arnaud CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL, eds. Osteoporosis. Copenhagen: Aalborg Suftsbogtrykkeri, 1984: 689-91. 4. Devogelaer JP, Nagant de Deuxchaisnes C, Stein F. Bioavailability of enteric-mated sodium fluoride tablets as affected by the administration of calcium supplements at different time intervals. J Bone Miner Res 1990; 5 (suppl 1): S75-79. 5. Riggs BL, Hodgson SF, Hoffman DL, Kelly PJ, Johnson KA, Taves D. Treatment of primary osteoporosis with fluonde and calcium: clinical tolerance and fracture occurence. JAMA 1980; 242: 446-49. 6. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis. NEngl J Med 1982; 306: 446-50. 7 Riggs BL, Hodgson SF, Muhs J, Wahner HW. Fluoride treatment of osteoporosis: clinical and bone densitometric responses. In: Christiansen C, Johansen JS, Riis BJ, eds. Osteoporosis. Viborg Norhaven 1987: 817-23. 8. Delmas PD, Dupuis J, Duboeuf F, Chapuy MC, Meunier PJ. Treatment of vertebral osteoporosis with disodium monofluorophosphate. Comparison with sodium fluoride. J Bone Miner Res 1990; 5 (suppl 1). S143-47. 9 Heaney RP, Baylink DJ, Johnston CC Jr, et al. Fluoride therapy for the vertebral crush fracture syndrome. Ann Intern Med 1989; 111: 678-80. 10. Mamelle N, Meunier PJ, Dusan R, et al. Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 1988; ii: 361-65. 11. Buckle RM. 3 year study of sodium fluoride treatment on vertebral fracture incidence in osteoporosis J Bone Miner Res 1989, 4 (suppl 1) S186. 1.
of their peptidoglycan cell-wall structures. This is not merely "my view"; it is a fact.’ Lubec questions my claim that D-aminoacid oxidases would convert ingested D-aminoacids to tx-ketoacids. He also suggests that racemases could convert D-aminoacids to the L-isomers-a strange suggestion since aminoacid racemases occur only in bacteria, fungi, the earthworm, and some insects.2,3 His concern about the neurotoxicity of minute amounts of D-proline is strange because substantial amounts of other D-aminoacids are well tolerated: he himself refers to studies involving the ethical administration of D-methionine to man, and D-phenylalanine (a health-food product) is recommended as an analgesic. Finally, we have found that the D-aminoacid oxidase in the cerebellum of mice, sheep, and rats actually produces D-alanine.4,5 Department of Biochemistry, University of Western Australia,
Nedlands, Western Australia 6009
1. Ito E, Strominger JL. Enzymatic synthesis of the peptide in bacterial uridine nucleotides II: enzymatic synthesis and addition of D-alanyl-D-alanine. J Biol Chem 1962; 237: 2696-703. 2. Adams E. Aminoacid racemases and epimerases. In: Boyer PD, ed. The enzymes: vol VI, 3rd ed. New York: Academic Press, 1972: 479-507. 3. Cohen PP, Sallach HJ. In: Greenberg DM, ed. Metabolic pathways: vol II. New York: Academic Press, 1961: 53. 4. Keating PJ, Segal W. A proposed function for D-amino add oxidase in mammalian brain. 12th International Congress of Biochemistry (Perth, Western Australia, 1982); POS 001-216:145; Proc Aust Biochem Soc 1984; 16: 28. 5 Keating PJ. PhD thesis, University of Western Australia, 1990.
Intrapartum fetal ECG electrodes SIR,-Early recordings of the fetal electrocardiogram (ECG) during labour were made with nickel/silver wound-clip electrodes.1 Since this initial work, routine monitoring of the fetal heart rate has been done with electrodes, either clip or spiral, which are universally made of stainless steel. This material has mechanical advantages and is more biocompatible than silver but, as an electrode, it is inadequate for recording the ECG waveform. The heart rate is only part of the information that is available from the ECG, and there is interest in detailed analysis of the ECG waveform itself.2 The raw signal from a stainless steel electrode is far from ideal for this purpose. Stainless steel acts as a high pass filter and the metal does not adopt a stable potential with the scalp, resulting in pronounced drifting of the baseline (figure, upper trace). To some extent the signal can be improved by averaging and filtering. We feel that a better solution would be to return to silver-based electrodes. We have constructed such electrodes modelled on the Copeland clip (Surgicraft). These electrodes were silver plated, partly chloridised, and then coated with a biocompatible, electrically conducting polymer. The polymer coating overcomes the difficulty of silver chloride’s
SIL VER/SIL VER CHLORIDE
Representative segments of two intrapartum fetal ECG signals with different electrodes. Both
recordings filtered at 0 8-80
bioincompatibility with little effect on its electrical properties. The improvement in signal quality is striking (figure, lower trace). Electrodes of this kind would improve the reliability of fetal heart rate records and also greatly increase the range of possible analyses and interpretation of the individual fetal ECG waveforms.
These are the first data suggesting a protective effect of breastfeeding against UTI. Two medical students in two weeks came up with a clinically and biologically interesting hypothesis: will it be a challenge for "burnt-out" investigators who, you say, are fit only for the administration of confirmatory randomised trials?
Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Queen Charlotte’s and Chelsea Hospital, London W6 OXG, UK
D. G. PENMAN J. A. D. SPENCER
Department of Paediatrics, University of Naples, 80131 Naples, Italy
Laboratory of Applied Physiology, St Thomas’s Hospital Medical School, London SE1
D. R. S. GIBBONS D. M. BAND
1. Hon EH. Instrumentation of fetal heart rate and fetal electrocardiography. Am J Obstet Gynecol1963; 76: 772-84. 2. Arulkumaran S, Lilja H, Lindecrantz K, Ratnam SS, Thavarasah AS, Rosen KG. Fetal ECG waveform analysis should improve fetal surveillance in labour. J. Perinat Med 1990; 18: 13-22.
LIBERATORE GRAZIANO GREGORIO ZONA
Gabrielli O, Giorgi P, et al. Preliminary study of breastfeeding and bacterial adhesion to uroepithelial cells. Lancet 1990; 335: 569-71. 2. Kovar MG, Serdula MK, Marks JS, Fraser DW. Review of the epidemiologic evidence for an association between infant feeding and infant health. Pediatrics 1984; 74 (suppl): 702-27. 3. Siegel SR, Sokoloff B, Siegel B. Asymptomatic and symptomatic urinary tract infection in infancy. Am J Dis Child 1973; 125: 45-47. 4. Kunin CM. Epidemiology and natural history of urinary tract infection in school age children. Pediat Clin North Am 1971; 18: 509. 1.
Breastfeeding and urinary tract infection SIR,-Your May 12 editorial about case-control studies and the creativity of "hundreds of small research studies" prompts us to record an example of what may be further evidence of the potential of the case-control approach. Discussion with medical students, engaged in basic epidemiology training, of a Lancet paper on breastfeeding and bacterial adhesion to uroepithelial cells1 led to a case-control study of exposure to breastfeeding and urinary tract infection (UTI) in infants. It is not known if human milk protects against UTL.2 The 62 cases were all infants aged 0-6 months who were admitted to the university department of paediatrics between Jan 1,1980, and Dec 31,1988, and whose diagnosis was UTI, confirmed by at least one urine culture, done in our hospital, that yielded more than 100 000 organisms/ml of a single species. The children had one or more of the following: failure to thrive, vomiting, diarrhoea, and fever. Two groups of controls-matched by sex, age (within 15 days), father’s occupation, geographical area of residence, birth order, type of delivery, and month of admission-were chosen by systematic sampling. 62 controls were seen at our well-baby clinic; they were healthy and no urine cultures were done (in healthy infants asymptomatic bacteriuria is very unusuaP). The other 62 controls had been admitted to our hospital with an acute illness and had negative urine cultures. None of the males, cases or controls, had been circumcised. Data on breastfeeding were complete from the clinical records of both cases and controls. The proportion of infants who had been put to the breast at all was 47% in the cases and 82% and 87% in the controls (p < 0’001), and the mean duration of breastfeeding was 60, 61, and 61 days. For the purpose of analysis we defined an infant as breast-fed if he or she had had breast milk up to the day of the admission or outpatient visit (or at least until 3 days before). The factors for which we matched cases and controls are not confounders for UTI4 so the table gives the results for the unmatched analysis; matched and unmatched relative risk estimates were almost identical. CHARACTERISTICS OF CASES AND CONTROLS
Evening primrose oil and atopic eczema SiR,—Dr Sharpe and Dr Farr (May 26, p 1283) suggest that because, by an accident of randomisation, the groups assigned to
evening primrose oil (’Epogam’) in some trialsl,2 were more seriously affected than thoseassigned to placebo, the statistical analyses were inappropriate. In two examples given, patients assigned to epogam started off worse ded up better than those assigned to placebo. The change in res onse to epogam was significantly greater than the change in response to placebo.
Sharpe and Farr refer your readers to a paper by Altman and Dore on the importance of baseline values3 which states that if there are differences in baseline that might be important "the analysis should be modified by, for instance, regression modelling or analysis of change from initial values". The latter is what Bordoni et all and Schalin-Karrila et aF did. Sharpe and Farr also ignore the significant reduction in steroid use by patients on epogam in one of the two trials.2 In view of the possible side-effects of long-term topical steroid use this reduction is important. Your correspondents also miss the point of Wright and Burton’s trial4 and of four others described in the meta-analysis papery These trials were crossover in design so that differences in baseline between patients are irrelevant. In these trials improvement on epogam, whether given first or second, were consistently and significantly greater than those on placebo. There was a substantial carryover effect of epogam and crossover trials are probably inappropriate for the assessment of such a long-acting agent. However, carryover does not happen in the absence of a real effect, and its presence leads to an underestimate of the efficacy of active treatment.
Sharpe and Farr’s criticisms are directed against the only agent among the seven top-selling drugs for atopic eczema in the UK which has been tested in published, double-blind, placebocontrolled trials in the disease. Untested in this way are ’Betnovate’, ’Dermovate’, ’Eumovate’, ’Locoid’, ’Oilatum’, and ’Synalar’. In view of the possible risks of long-term steroids doctors should ask why the drugs they are prescribing so freely for atopic eczema have not been tested rigorously. Scotia Pharmaceuticals Ltd, Guildford, Surrey GU1 1 BA, UK
DAVID F. HORROBIN CHARLES STEWART
1. Bordoni A, Biagi PL, Masi M, et al. Evening primrose oil (Efamol) in the treatment of children with atopic eczema. Drugs Exp Clin Res 1987; 14: 291-97.
2. Schalin-Karrila M, Manila L, Jansen CT, Uotila P. Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol 1987; 117: 11-19. 3. Altman DG, Doré CJ Randomisation and baseline comparisons in clinical trials. Lancet 1990; 335: 149-53. 4.
Wnght S, Burton JL. Oral evening primrose seed oil improves atopic eczema. Lancet 1982; ii: 1220-22.
5 Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema: relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol
1989; 121: 75-90.