187
in vivo".6 They were referring to a clinical study in which there had been a median plasma alprazolam level of only 0 1 umol/1.’" Lenox is thus willing to link alprazolam’s therapeutic actions to its effects on PAF receptors at concentrations well below his own in-vitro research levels. Clinical plasma concentrations of triazolam were well known in 1987, when Lenox wrote that triazolam and alprazolam "are potent and specific antagonists of PAF" and that antagonism by these triazolobenzodiazepines "may be involved in mechanisms underlying the therapeutic effects of these drugs". If triazolam as a PAF antagonist may contribute to desired effects of triazolam then, in the absence of other explanation, we should suspect that triazolam as a PAF antagonist may contribute to the drug’s peculiar mental and physical ill-effects. The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
KIRSTINE ADAM IAN OSWALD
Upjohn. Technical report. U-33030. six-week tolerance study SPSM protocol no 321. Kalamazoo, Michigan: Upjohn, 1973. 2 Van der Kroef C. Het Halcion-syndrom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. 3. Upjohn. Summary of revised medical event analysis for protocol 321. Kalamazoo, Michigan Upjohn, 1991. 4 Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 5 Eberts FS, Philopoulos Y, Reineke LM, Vliek RW Triazolam disposition Clin Pharmacol Therap 1981; 29: 81-93. 6. Komecki E, Ehrlich YH, Lenox RH. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984; 1.
226: 1454-56
Framingham participants) of low-risk individuals from which high coronary risk cases have been removed. Yet when the MRFIT participants (high-risk hypertensives)3 and total Framingham group2 were analysed aJ or U shaped relation between DBP (or fall in DBP, and CHD was noted. The latest chapter in the saga is a Lancet editorial seeking a "decent burial" for theJ curve on the basis of study data that have not been analysed for the presence or absence and
of such a
1 Samuelsson OG, Wilhelmsen LW, Pennert KM, et al. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years follow-up of treated hypertensives in the primary prevention trial in Gothenburg, Sweden. J Hypertens 1990; 8: 547-55. 2. D’Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. The relation of low diastolic blood pressure to coronary heart disease death in the presence of myocardial infarction: the Framingham Study. Br Med J (in press) 3. Cohen JD, Butler SM, Cutler JA, Neaton JD (for the MRFIT Research Group). Relationship between blood pressure change and mortality among MRFIT hypertensives. Circulation 1991; 84: II-137 4. Coope J. Hypertension the cause of the J-curve. J Hum Hypertens 1990; 4: 1-4 5. Farnett L, Mulrow CD, Linn WD, et al. The J-curve phenomenon and the treatment
6.
7
of hypertension. JAMA 1991; 265: 489-95 Multiple Risk Factor Intervention Trial Research Group Mortality after 10 years for hypertensive participants in the multiple nsk factor intervention trial. Circulation 1990; 82: 1616-28. McMahon S, Peto R, Curler J, et al. Blood pressure, stroke and coronary heart disease I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74.
alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
Measurement of breath alcohol
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 9. Braquet P, Etienne A, Clostre F. Down-regulation of &bgr;2-adrenergic receptors by PAF-acether and its inhibition by the PAF-acether antagonist BN52021. Prostaglandins 1985; 30: 721. 10. Sheehan DV, Coleman JH, Greenblatt DJ, et al. Some biochemical correlates of panic attacks with agoraphobia and their response to a new treatment. J Clin Psychopharmacol 1984; 4: 66-75.
The J
curve
lives
SIR,-Your Nov 23 editorial (p 1299) points out that surrogate endpoints, such as thiazide or beta-blocker-induced changes in plasma lipids or insulin resistance, are an unsound basis for determining management in hypertension. However, you go on to say that the results of the Systolic Hypertension in the Elderly Program (SHEP) study in isolated systolic hypertension drive a stake through the heart of the J-curve hypothesis. The J curve for diastolic blood-pressure (DBP) death from myocardial infarction is not a hypothesis but a fact, though its mechanism may be debated. The curve has been demonstrated in large cohort and population studies and in well-conducted controlled trials in patients with hypertension (refs 1-4 are just examples), and is independent of the coronary risk factors, illness, and left-ventricular functionA recent assessment of the J curve by four independent reviewers5 covering only the highest quality published studies (over 14 000 patients) yielded a "best-fit" that confirmed the curve with a J point in the low-to-mid 80s DBP. The SHEP study has not yet been analysed as a test for theJ curve. A treatment which confers significant overall benefit (ie, low-dose chlorthalidone in SHEP) may be harmful to some patients. This was found in the MRFIT study6 in which patients in the special-care group experienced fewer coronary heart disease (CHD) deaths than those in the referred-care group, yet in the special-care group there was a strikingJ or U shaped relation between fall in DBP and death from myocardial infarctionprobably explained by previous clinical CHD.3 I am amazed at the reluctance of some doctors to accept the self-evident (to me) concept that a vital organ that is fed by a severely narrowed artery will have a much reduced circulatory reserve. Such an organ may be threatened when perfusion pressure is lowered to levels that are tolerated by well-vascularised organs. The concept is accepted for the brain and kidney but not for the heart. A major 1990 Lancet article dismissed theJ curve on the basis of a massive population (over 400 000, comprising mainly MRFIT screenees common
J. M. CRUICKSHANK
Wilmslow SK9 2AY, UK
7 Komecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the
8
curve.
The Flat, The Bows, Wilmslow Park,
SIR,-"Be careful about reading health books", said Mark Twain, "you may die of a misprint". I learned from Dr Hahn (Dec 21/28, p 1602) that he and his colleagues have been using ethanol to monitor fluid absorption during TURP since 1986; that it can lead "breath alcohol [concentration of] about 0-25 mg/ml" but that the operation need not be stopped "until 2 litres have been absorbed (breath alcohol about 0-50 mg/ml)". A breath alcohol concentration of 0-50 mg/ml is some 1428 times the legal limit for driving in the UK (which is 35 ug/100 ml, or 0-35 ug/ml, or 0-00035 mg/ml) and would mean that the patients had 100 % ethanol circulating in their veins. I feel sure that there must be a misprint somewhere; but where? And who was responsible for it? Does the fault lie with the author? Is the mistake in the units of volume or of mass? This is not an isolated example of the confusion that can arise as a result of the misuse (or misprinting) of units of measurement. Such errors occur in refereed journals just as often as in unrefereed ones, but do make reports containing such errors potentially, and sometimes positively, harmful. I recall that some years ago some colleagues and I found ourselves unable to reproduce important work published by a very well known group of researchers into experimental hyperlipidaemia until it dawned on us that the amount of substance (cobalt chloride) that they claimed to have used in their experiments was exactly 100 times the amount they actually had used. to a
School of
Biological Sciences, University of Surrey,
VINCENT MARKS
Guildford GU2 5XH, UK
** This letter has been shown follows.-ED. L.
to
Dr Hahn, whose
reply
SIR,-Breath alcohol analysers in Sweden are calibrated to the corresponding blood ethanol concentration. These devices are usually purchased to establish whether drivers are being intoxicated, which is defmed (in Sweden) by a blood alcohol concentration above 0-40 mg/ml. Breath ethanol concentration is consistently 2300 times lower than that of blood ethanol. We have studied the blood-breath partition coefficient for ethanol in TURP patients in an investigation of ethanol monitoring (Acta Anaesthesiol Scand 1991; 35: 393-97), but all papers on ethanol monitoring during irrigating fluid absorption express breath alcohol in terms of the corresponding blood ethanol concentration. I could have avoided
in vivo".6 They were referring to a clinical study in which there had been a median plasma alprazolam level of only 0 1 umol/1.’" Lenox is thus willing to link alprazolam’s therapeutic actions to its effects on PAF receptors at concentrations well below his own in-vitro research levels. Clinical plasma concentrations of triazolam were well known in 1987, when Lenox wrote that triazolam and alprazolam "are potent and specific antagonists of PAF" and that antagonism by these triazolobenzodiazepines "may be involved in mechanisms underlying the therapeutic effects of these drugs". If triazolam as a PAF antagonist may contribute to desired effects of triazolam then, in the absence of other explanation, we should suspect that triazolam as a PAF antagonist may contribute to the drug’s peculiar mental and physical ill-effects. The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
KIRSTINE ADAM IAN OSWALD
Upjohn. Technical report. U-33030. six-week tolerance study SPSM protocol no 321. Kalamazoo, Michigan: Upjohn, 1973. 2 Van der Kroef C. Het Halcion-syndrom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. 3. Upjohn. Summary of revised medical event analysis for protocol 321. Kalamazoo, Michigan Upjohn, 1991. 4 Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 5 Eberts FS, Philopoulos Y, Reineke LM, Vliek RW Triazolam disposition Clin Pharmacol Therap 1981; 29: 81-93. 6. Komecki E, Ehrlich YH, Lenox RH. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984; 1.
226: 1454-56
Framingham participants) of low-risk individuals from which high coronary risk cases have been removed. Yet when the MRFIT participants (high-risk hypertensives)3 and total Framingham group2 were analysed aJ or U shaped relation between DBP (or fall in DBP, and CHD was noted. The latest chapter in the saga is a Lancet editorial seeking a "decent burial" for theJ curve on the basis of study data that have not been analysed for the presence or absence and
of such a
1 Samuelsson OG, Wilhelmsen LW, Pennert KM, et al. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years follow-up of treated hypertensives in the primary prevention trial in Gothenburg, Sweden. J Hypertens 1990; 8: 547-55. 2. D’Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. The relation of low diastolic blood pressure to coronary heart disease death in the presence of myocardial infarction: the Framingham Study. Br Med J (in press) 3. Cohen JD, Butler SM, Cutler JA, Neaton JD (for the MRFIT Research Group). Relationship between blood pressure change and mortality among MRFIT hypertensives. Circulation 1991; 84: II-137 4. Coope J. Hypertension the cause of the J-curve. J Hum Hypertens 1990; 4: 1-4 5. Farnett L, Mulrow CD, Linn WD, et al. The J-curve phenomenon and the treatment
6.
7
of hypertension. JAMA 1991; 265: 489-95 Multiple Risk Factor Intervention Trial Research Group Mortality after 10 years for hypertensive participants in the multiple nsk factor intervention trial. Circulation 1990; 82: 1616-28. McMahon S, Peto R, Curler J, et al. Blood pressure, stroke and coronary heart disease I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74.
alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
Measurement of breath alcohol
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 9. Braquet P, Etienne A, Clostre F. Down-regulation of &bgr;2-adrenergic receptors by PAF-acether and its inhibition by the PAF-acether antagonist BN52021. Prostaglandins 1985; 30: 721. 10. Sheehan DV, Coleman JH, Greenblatt DJ, et al. Some biochemical correlates of panic attacks with agoraphobia and their response to a new treatment. J Clin Psychopharmacol 1984; 4: 66-75.
The J
curve
lives
SIR,-Your Nov 23 editorial (p 1299) points out that surrogate endpoints, such as thiazide or beta-blocker-induced changes in plasma lipids or insulin resistance, are an unsound basis for determining management in hypertension. However, you go on to say that the results of the Systolic Hypertension in the Elderly Program (SHEP) study in isolated systolic hypertension drive a stake through the heart of the J-curve hypothesis. The J curve for diastolic blood-pressure (DBP) death from myocardial infarction is not a hypothesis but a fact, though its mechanism may be debated. The curve has been demonstrated in large cohort and population studies and in well-conducted controlled trials in patients with hypertension (refs 1-4 are just examples), and is independent of the coronary risk factors, illness, and left-ventricular functionA recent assessment of the J curve by four independent reviewers5 covering only the highest quality published studies (over 14 000 patients) yielded a "best-fit" that confirmed the curve with a J point in the low-to-mid 80s DBP. The SHEP study has not yet been analysed as a test for theJ curve. A treatment which confers significant overall benefit (ie, low-dose chlorthalidone in SHEP) may be harmful to some patients. This was found in the MRFIT study6 in which patients in the special-care group experienced fewer coronary heart disease (CHD) deaths than those in the referred-care group, yet in the special-care group there was a strikingJ or U shaped relation between fall in DBP and death from myocardial infarctionprobably explained by previous clinical CHD.3 I am amazed at the reluctance of some doctors to accept the self-evident (to me) concept that a vital organ that is fed by a severely narrowed artery will have a much reduced circulatory reserve. Such an organ may be threatened when perfusion pressure is lowered to levels that are tolerated by well-vascularised organs. The concept is accepted for the brain and kidney but not for the heart. A major 1990 Lancet article dismissed theJ curve on the basis of a massive population (over 400 000, comprising mainly MRFIT screenees common
J. M. CRUICKSHANK
Wilmslow SK9 2AY, UK
7 Komecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the
8
curve.
The Flat, The Bows, Wilmslow Park,
SIR,-"Be careful about reading health books", said Mark Twain, "you may die of a misprint". I learned from Dr Hahn (Dec 21/28, p 1602) that he and his colleagues have been using ethanol to monitor fluid absorption during TURP since 1986; that it can lead "breath alcohol [concentration of] about 0-25 mg/ml" but that the operation need not be stopped "until 2 litres have been absorbed (breath alcohol about 0-50 mg/ml)". A breath alcohol concentration of 0-50 mg/ml is some 1428 times the legal limit for driving in the UK (which is 35 ug/100 ml, or 0-35 ug/ml, or 0-00035 mg/ml) and would mean that the patients had 100 % ethanol circulating in their veins. I feel sure that there must be a misprint somewhere; but where? And who was responsible for it? Does the fault lie with the author? Is the mistake in the units of volume or of mass? This is not an isolated example of the confusion that can arise as a result of the misuse (or misprinting) of units of measurement. Such errors occur in refereed journals just as often as in unrefereed ones, but do make reports containing such errors potentially, and sometimes positively, harmful. I recall that some years ago some colleagues and I found ourselves unable to reproduce important work published by a very well known group of researchers into experimental hyperlipidaemia until it dawned on us that the amount of substance (cobalt chloride) that they claimed to have used in their experiments was exactly 100 times the amount they actually had used. to a
School of
Biological Sciences, University of Surrey,
VINCENT MARKS
Guildford GU2 5XH, UK
** This letter has been shown follows.-ED. L.
to
Dr Hahn, whose
reply
SIR,-Breath alcohol analysers in Sweden are calibrated to the corresponding blood ethanol concentration. These devices are usually purchased to establish whether drivers are being intoxicated, which is defmed (in Sweden) by a blood alcohol concentration above 0-40 mg/ml. Breath ethanol concentration is consistently 2300 times lower than that of blood ethanol. We have studied the blood-breath partition coefficient for ethanol in TURP patients in an investigation of ethanol monitoring (Acta Anaesthesiol Scand 1991; 35: 393-97), but all papers on ethanol monitoring during irrigating fluid absorption express breath alcohol in terms of the corresponding blood ethanol concentration. I could have avoided
