1157 consequent upon triazolam’s rapid elimination.5 What we do not know about are PAF-related withdrawal symptoms. After even a single disturbance of PAF mechanisms receptor sensitivity can be altered for weeks.6 Down-regulation of PAF receptors, after exposure to PAF, has been attributed to a reduction in receptor sensitivity. The effect on PAF-related function and any of PAF receptors, brought about by repeated administration of a PAF antagonist, such as triazolam or alprazolam, remain unknown. It can certainly be expected that triazolam use will be associated not only with conventional benzodiazepine withdrawal effects each day but also with withdrawal effects deriving from PAF mechanisms-and some of the bizarre consequences of triazolam use may be explained in this
up-regulation
way.
YEARS Lumbar BMD in with controls.
men
with total lactase
deficiency compared
is crucial to emphasise that some of the latter group could be mistaken as patients with a total deficiency in lactase, if tested by a respiratory hydrogen test or an oral lactose tolerance test, rather than by direct disaccharide activity measurement in a jejunal biopsy specimen. Part of the conflicting results with respect to the prevalence of osteoporosis could be explained by a less stringent definition of lactase deficiency. PAUL MAINGUET ISABELLE FAILLE
Gastroenterology and Rheumatology Units, University of Louvain, B-1200 Brussels, Belgium
LAURENCE DESTREBECQ JEAN-PIERRE DEVOGELAER CHARLES NAGANT DE DEUXCHAISNES
1. Mainguet P, Faille I, Destrebecq L, Devogelaer JP, Nagant de Deuxchaisnes C. Lifelong low calcium consumption m patients suffering from lactase deficiency. A role in development of osteoporosis? Nutritional aspects of osteoporosis. New York: Raven Press (in press) 2. Angus RM, Sambrook PN, Pocock NA, et al. A simple method for assessing calcium intake in Caucasian women. J Am Diet Assoc 1989; 89: 209-14. 3. Dahlqvist A. A method for assay of intestinal disaccharidases. Analyt Bwchem 1964; 7: 18-25. 4. Birge JJ, Keutmann HT, Cuatrecasas P, Whedon GD. Osteoporosis, intestinal lactase deficiency and low dietary calcium intake. N Egnl J Med 1967; 276: 445-48. 5. Fuss M, Pepersack T, Bergman P, Hurard T, Simon J, Corvilain J. Low calcium diet in idiopathic urolithiasis: a risk factor for osteopenia as great as in primary hyperparathyroidism. Br J Urol 1990; 65: 560-63. 6. Horowitz M, Wishart J, Mundy L, Nordin BEC. Lactose and calcium absorption in postmenopausal osteoporosis. Arch Intern Med 1987; 147: 534-36. 7. Finkenstedt G, Skrabal F, Gasser RW, Braunsteiner H. Lactose absorption, milk consumption and fasting blood glucose concentrations in women with idiopathic osteoporosis. Br Med J 1986; 292: 161-62. 8. Harma M, Alhava E. Is lactose malabsorption a risk factor in fractures of the elderly? Am Chir Gynaecol 1988; 77: 180-83.
When adverse effects of triazolam were noted early on in the Netherlands they were not confined to mental functions: the observations included blistering of hands, feet, and tongue.8 The notion that a sleeping drug might facilitate inflammatory reactions seemed as scarcely credible as had once the adverse effects of thalidomide. However, disturbance of PAF mechanisms could explain the association of triazolam with syncope (PAF is a potent hypotensive agent), an association finally acknowledged in the drug’s US package insert, in 1990. The US Food and Drug Administration lists adverse reactions notified under its spontaneous reporting system, and we have examined these for triazolam, flurazepam, and temazepam since their introduction, noting all reactions suggesting inflammation or altered micropermeability. These reactions included pharyngitis, glossitis, vasculitis, asthma, and facial oedema. The totals were temazepam 31, flurazepam 78, and triazolam 673. Though rough and ready, these figures should not be dismissed. In other FDA statistics "hostility" reactions are reported for 329 drugs; triazolam and alprazolam are first and second in the ranking.9 The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
1.
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives m platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 3. Braquet P, Spinnewyn B, Demerle C, et al. The role of platelet-activating factor m cerebral ischemia and related disorders. Ann NY Acad Sci 1989; 559: 296-312. 4. Koltai M, Hosford D, Guinot P, Esanu A, Braquet P. Platelet activating factor (PAF): a review of its effects, antagonists and possible future clinical implications. Drugs
1991; 42: 9-29, 175-204. 5. Adam K, Oswald I. Can
a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 6. Cuss FM, Dixon CMS, Barnes PJ. Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet 1986; ii: 189-92. 7. Henson PM. Extracellular and intracellular activities of PAF. In: Snyder F, ed. Platelet-activating factor and related lipid mediators. New York: Plenum Press,
9.
SIR,- Triazolam (and alprazolam)
are
"up-regulated"
1987: 255-71. der Krocf C. Het
Halcion-syndroom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. Cowley G, Springen K, Iarovici D, Hager M. Sweet dreams or a nighmare? Newsweek 1991 (Aug 19): 38-44.
van
triazolobenzodiazepines
that differ from other benzodiazepines, such as diazepam, in being potent and specific inhibitors of the binding of PAF (plateletactivating factor) to its receptor. PAF, a phospholipid, got its name because one of its first identified actions was activation of platelets to aggregate, but it has physiological and pathological actions throughout the body.2 In the central nervous system, PAF may have a role in cell-to-cell communication1 and in brain ischaemia and injury.3 In man, PAF research has focused on cardiovascular function, allergic reactions, asthma, oedema, and inflammation, including skin weals.4 Discontinuance or withdrawal symptoms after use of a conventional benzodiazepine are attributed to changes that have with time been induced in benzodiazepine receptors. The receptors in sensitivity to their endogenous ligand by reason of their exposure to benzodiazepine. The daytime anxiety associated with triazolam has been explained as a withdrawal effect, are
Kornecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
2.
8.
Possible mechanism for adverse reactions to triazolam
KIRSTINE ADAM IAN OSWALD
Safety of DMPA SIR,- The World Health Organisation study on breast cancer depot-medroxyprogesterone acetate (DMPA) (Oct 5, p 833) finds no trend of increasing risk with duration of use, which reduces and
the likelihood of a causative association, and also reassures about the long-term effects of DMPA on risk of breast cancer. However, a small increase in risk was observed within the first 4 years of use, which, in practice meant that the risk, if real (and not caused, as it might yet prove to be, by a distortion such as surveillance bias), was mostly confined to women under the age of 35. The study team comment that this association is weak, and of the same order of magnitude as has been reported for young users of oral
contraceptives. At the World Congress of Obstetrics and Gynaecology in Singapore last month the results of this study with regard to endometrial cancer were also presented. These were of particular
up-regulation
way.
YEARS Lumbar BMD in with controls.
men
with total lactase
deficiency compared
is crucial to emphasise that some of the latter group could be mistaken as patients with a total deficiency in lactase, if tested by a respiratory hydrogen test or an oral lactose tolerance test, rather than by direct disaccharide activity measurement in a jejunal biopsy specimen. Part of the conflicting results with respect to the prevalence of osteoporosis could be explained by a less stringent definition of lactase deficiency. PAUL MAINGUET ISABELLE FAILLE
Gastroenterology and Rheumatology Units, University of Louvain, B-1200 Brussels, Belgium
LAURENCE DESTREBECQ JEAN-PIERRE DEVOGELAER CHARLES NAGANT DE DEUXCHAISNES
1. Mainguet P, Faille I, Destrebecq L, Devogelaer JP, Nagant de Deuxchaisnes C. Lifelong low calcium consumption m patients suffering from lactase deficiency. A role in development of osteoporosis? Nutritional aspects of osteoporosis. New York: Raven Press (in press) 2. Angus RM, Sambrook PN, Pocock NA, et al. A simple method for assessing calcium intake in Caucasian women. J Am Diet Assoc 1989; 89: 209-14. 3. Dahlqvist A. A method for assay of intestinal disaccharidases. Analyt Bwchem 1964; 7: 18-25. 4. Birge JJ, Keutmann HT, Cuatrecasas P, Whedon GD. Osteoporosis, intestinal lactase deficiency and low dietary calcium intake. N Egnl J Med 1967; 276: 445-48. 5. Fuss M, Pepersack T, Bergman P, Hurard T, Simon J, Corvilain J. Low calcium diet in idiopathic urolithiasis: a risk factor for osteopenia as great as in primary hyperparathyroidism. Br J Urol 1990; 65: 560-63. 6. Horowitz M, Wishart J, Mundy L, Nordin BEC. Lactose and calcium absorption in postmenopausal osteoporosis. Arch Intern Med 1987; 147: 534-36. 7. Finkenstedt G, Skrabal F, Gasser RW, Braunsteiner H. Lactose absorption, milk consumption and fasting blood glucose concentrations in women with idiopathic osteoporosis. Br Med J 1986; 292: 161-62. 8. Harma M, Alhava E. Is lactose malabsorption a risk factor in fractures of the elderly? Am Chir Gynaecol 1988; 77: 180-83.
When adverse effects of triazolam were noted early on in the Netherlands they were not confined to mental functions: the observations included blistering of hands, feet, and tongue.8 The notion that a sleeping drug might facilitate inflammatory reactions seemed as scarcely credible as had once the adverse effects of thalidomide. However, disturbance of PAF mechanisms could explain the association of triazolam with syncope (PAF is a potent hypotensive agent), an association finally acknowledged in the drug’s US package insert, in 1990. The US Food and Drug Administration lists adverse reactions notified under its spontaneous reporting system, and we have examined these for triazolam, flurazepam, and temazepam since their introduction, noting all reactions suggesting inflammation or altered micropermeability. These reactions included pharyngitis, glossitis, vasculitis, asthma, and facial oedema. The totals were temazepam 31, flurazepam 78, and triazolam 673. Though rough and ready, these figures should not be dismissed. In other FDA statistics "hostility" reactions are reported for 329 drugs; triazolam and alprazolam are first and second in the ranking.9 The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
1.
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives m platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 3. Braquet P, Spinnewyn B, Demerle C, et al. The role of platelet-activating factor m cerebral ischemia and related disorders. Ann NY Acad Sci 1989; 559: 296-312. 4. Koltai M, Hosford D, Guinot P, Esanu A, Braquet P. Platelet activating factor (PAF): a review of its effects, antagonists and possible future clinical implications. Drugs
1991; 42: 9-29, 175-204. 5. Adam K, Oswald I. Can
a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 6. Cuss FM, Dixon CMS, Barnes PJ. Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet 1986; ii: 189-92. 7. Henson PM. Extracellular and intracellular activities of PAF. In: Snyder F, ed. Platelet-activating factor and related lipid mediators. New York: Plenum Press,
9.
SIR,- Triazolam (and alprazolam)
are
"up-regulated"
1987: 255-71. der Krocf C. Het
Halcion-syndroom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. Cowley G, Springen K, Iarovici D, Hager M. Sweet dreams or a nighmare? Newsweek 1991 (Aug 19): 38-44.
van
triazolobenzodiazepines
that differ from other benzodiazepines, such as diazepam, in being potent and specific inhibitors of the binding of PAF (plateletactivating factor) to its receptor. PAF, a phospholipid, got its name because one of its first identified actions was activation of platelets to aggregate, but it has physiological and pathological actions throughout the body.2 In the central nervous system, PAF may have a role in cell-to-cell communication1 and in brain ischaemia and injury.3 In man, PAF research has focused on cardiovascular function, allergic reactions, asthma, oedema, and inflammation, including skin weals.4 Discontinuance or withdrawal symptoms after use of a conventional benzodiazepine are attributed to changes that have with time been induced in benzodiazepine receptors. The receptors in sensitivity to their endogenous ligand by reason of their exposure to benzodiazepine. The daytime anxiety associated with triazolam has been explained as a withdrawal effect, are
Kornecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
2.
8.
Possible mechanism for adverse reactions to triazolam
KIRSTINE ADAM IAN OSWALD
Safety of DMPA SIR,- The World Health Organisation study on breast cancer depot-medroxyprogesterone acetate (DMPA) (Oct 5, p 833) finds no trend of increasing risk with duration of use, which reduces and
the likelihood of a causative association, and also reassures about the long-term effects of DMPA on risk of breast cancer. However, a small increase in risk was observed within the first 4 years of use, which, in practice meant that the risk, if real (and not caused, as it might yet prove to be, by a distortion such as surveillance bias), was mostly confined to women under the age of 35. The study team comment that this association is weak, and of the same order of magnitude as has been reported for young users of oral
contraceptives. At the World Congress of Obstetrics and Gynaecology in Singapore last month the results of this study with regard to endometrial cancer were also presented. These were of particular
