- Email: [email protected]
ENDORPHINS AND PAIN CONTROL
632 there was no relation with previous hormonal treatment. Several disorders are associated with circulating autoantibodies. These autoantibodies often react with cells or tissues from healthy donors, but, except in a few cases, the antigen determinant has not been characterised. The significance of our finding remains to be worked out. The cause of undescended testis is still unclear in cases where mechanical factors are absent,4 but there may be a disturbance of the hypothalamo-pituitary testicular axis with an early deficiency of LH secretion.5 Testicular descent usually happens in the last week in utero, so if autoantibodies play a role in maldescent they would have to act on the fetus. Preliminary results suggest that this may be so. We have detected such antibodies in 5 out of 12 mothers of cryptorchid children tested during the first week after delivery. The same antibodies ofIgG class were detected in the newborn babies. Longitudinal and collaborative studies are in progress. Polyendocrine disease apart, true autoimmunity against the pituitary gland has been mainly described in relation to pregnancy, 6, and profound qualitative and quantitative changes in hormone levels occur during pregnancy. Whether autoimmunity against pituitary is associated with pregnancy because of the release of pituitary antigens as pituitary size and vascularity increase remains a matter of speculation.
absorption experiments, and
We thank M. Brouillard and A.
Codjo
Neuroimmunology and Neuroendocrine Immunopathology Unit, Faculty of Medicine, 49045 Angers, France; Saint-Louis Surgical Clinic, Angers; General Medical Service C, CHU Angers; and Neonatal Centre, Obstetrics and Gynaecology CHU Angers
Clinic,
for technical
help.
A. POUPLARD-BARTHELAIX V. LEPINARD L. LUXEMBOURGER V. ROHMER J. BERTHELOT J. C. BIGORGNE
1.
Pouplard A, Bigorgne JC, Chevallier JM,
2. 3.
hypophysaire: Maladie autoimmune? Nouv Presse Méd 1980; 9: 1757-60. Pouplard A. Pituitary autoimmunity. Hormone Res 1982; 16: 289-97. Bottazzo GF, Doniach D. Pituitary autoimmunity: a review. J Roy Soc Med 1978; 71:
Rohmer
V, Poron MF. Insuffisance
433-36. 4. Spitz L. Maldescent of the testis. Arch Dis Child 1983; 58: 847-48. 5. Job JC, Grendel D. Endocrine aspects of cryptorchidism. Urol Clin N Am
anti-
1982; 9,
3:
procedure available for8 fetal blood sampling during the third
trimester of pregnancy. The fetal platelet count was very low on a Coulter counter S plus II, and this was confirmed by microscopy and blood smear. The platelet count (15X 109/1) was well below our reference range (253±36 SD; n = 22), at this period of gestation and was too low to permit identification of PLA phenotype. By the 37th week the pregnancy was proceeding normally and there was no ultrasound evidence of fetal porencephaly. AntiPLA-1 antibody was present in the mother’s serum. With the approval of the local ethics committee we suggested to the patient that in-utero transfusion of platelets a few hours before delivery be
attempted. The maturity of the fetal lungs was confirmed by the lecithin sphingomyelin ratio in amniotic fluid. 20 ml of washed maternal platelets containing 250 x 1010/1 platelets was prepared. 2 h later 10 ml fetal blood
withdrawn from the umbilical vein. Thromboconfirmed and 10 -5 ml of the platelet preparation was injected slowly into the umbilical vein. 6 h later the mother was delivered by caesarean section of a 2700 g healthy baby (Apgar 10). The platelet count in cord blood was 95 x 109/1. A further 8-5 ml of platelet concentrate was injected 15 min after birth via the umbilical cord. No other platelet transfusion was necessary. Subsequent platelet counts are summarised in the figure. Clinical and ultrasound examinations of the baby were normal 8 days after birth. The baby’s PLA phenotype was subsequently shown to be PLA-1 positive. We have done 400 fetal blood samplings by direct puncture of the umbilical cord under ultrasound without accident. The procedure can be repeated several times during pregnancy and permits fetal therapy via the intravenous route. This case suggests that intrauterine platelet transfusion just before the delivery of a fetus with NAIT can be used to avoid haemorrhage in the neonatal period. The effects of platelet transfusion are short-lived but repeated intravenous injections to the fetus may prevent or delay prenatal haemorrhage in cases of severe fetal thrombocytopenia.
cytopenia
was
was
Department of Prenatal Diagnosis and Fetology, Hôpital Notre Dame de 75014
Bon
Secours,
Paris, France
F. DAFFOS F. FORESTIER
353-60. 6.
7.
Mayfield RK, Levine JH, Gordon L, Power ST, Galbraith RM, Rawe SE. Lymphoid adenohypophysitis presenting as a pituitary tumor. Am J Med 1980; 69: 619-23. Richsmeier AJ, Richard AH, Bloodworthe JMB, Edward NE. Lymphoid hypophysitis with selective adrenocorticotropic hormone deficiency. Arch Intern Med 1980; 140: 1243-45.
Leucocyte Immunology Unit, Centre National de Transfusion Sanguine-Centre d’Hemobiologie Perinatale, Paris
Clinical Applications Service, CNTS, Hôpital Saint-Antoine, Paris
J. Y.
MULLER
M. F. REZNIKOFF-ETIEVANT B. HABIBI
of Prenatal
PRENATAL TREATMENT OF ALLOIMMUNE
THROMBOCYTOPENIA
SIR,-The frequency of neonatal alloimmune thrombocytopenia (NAIT) has been estimated at about 1 per 5000 births.l The PLA-11 platelet-specific antigen has been involved in the vast majority of the reported cases. 1,2 A PLA-1 negative mother acquires immunity to the PLA-1 antigen of her fetus, even though in 20% of typical clinical cases PLA-1 antibody cannot be demonstrated serologically.2 Risk factors are PLA-1 negativity, and HLA B8, DR3 positivity in mothers,3,4 and PLA-1 positivity in fathers. NAIT is a serious condition, and central nervous system bleeding is responsible for a high rate of morbidity and mortality. Most of these complications have been associated with delivery and other perinatal stresses and have justified caesarean section in at-risk pregnancies.5However, intracranial haemorrhage has also been observed during fetal lifeand no laboratory tests have been available to predict whether the infant will be affected or not. In 1982 a woman now aged 24 was delivered of her first daughter, who had NAIT with severe intracranial haemorrhage and neurological sequelae. The mother was PLA-1negative and HLADR3 positive; the father was PLA-1positive as was the child. AntiPLA-1 antibody was found in a blood sample taken 8 days after delivery. This woman was sent to us in the 32nd week of her second pregnancy for the prenatal testing of the PLA platelet phenotype of her fetus. 5 ml pure fetal blood were obtained by direct puncture of the umbilical cord with a needle guided by ultrasound,the only
Department Diagnosis and Fetology, Notre Dame de Bon Secours Hôpital
M. CAPELLA-PAVLOVSKY
Paediatric Service, Centre d’Hemobiologie Perinatale, Hôpital Saint-Vincent-De-Paul, Paris
P. MAIGRET
Leucocyte Immunology Unit, CNTS-Centre d’Hemobiologie Perinatale
C. KAPLAN
1. Shulman
NR, Marder VJ, Hiller MC, Collier EM. Platelet and leukocyte isoantigens and their antibodies: Serologic, physiologic and clinical studies Prog Hematol 1964,
6: 222. 2. Muller JY, Reznikoff-Etievant MF, Patereau C, Dangu C, Chesnel N. Thrombopénies néonatales alloimmunes: Etude clinique et biologique de 84 cas. Nouv Presse Méd
(in press). 3. Reznikoff-Etievant 4.
5. 6. 7.
MF, Dangu C, Lobet R. HLA B 8 and anti-PLA I alloimmunisation. Tissue Antigens 1981; 18: 66. Reznikoff-Etievant MF, Muller JY, Julien F, Patereau C. An immune response gene linked to MHC in man. Tissue Antigens 1983; 22: 39. Sitarz AL, Driscoll JM, Wolf JA. Management of isoimmune neonatal thrombocytopenia. Am J Gynecol 1976; 124: 39. Zalneraitis EL, Young RSK, Krishanamoorthy KS. Intracranial hemorrhage in utero as a complication of isoimmune thrombocytopenia. J Pediatr 1979; 95: 611 Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling via the umbilical cord using a needle guided by ultrasound: Report of 66 cases. Prenatal Diag 1983, 3: 271.
Capella-Pavlovsky M. Fetal blood sampling during the third of pregnancy. Br J Obstet Gynaecol 1984; 91: 118.
8. Daffos F, Forestier F, trimester
ENDORPHINS AND PAIN CONTROL
SIR,-Dr Willer and his colleagues (Aug 4, p 295) report that plasma (3-endorphins concentration is poorly related to pain control
633 in man, and suggest that the hypothesis that pituitary (3-endorphin plays a role in the modulation of pain should be reconsidered. We have presented direct evidence that, in normal man, plasma endorphins do not change with experimental pain.1 Unfortunately, by not citing our paper Willer et al create the impression that their
observations
are
original.
We have examined the effect of ischaemic pain on plasma immunoreactive &bgr;-endorphin/&bgr;-lipotropin (&bgr;END/&bgr;LPH), y-lipotropin (y-LPH), and corticotropin (ACTH) in 10 normal subjects. Experimental pain was induced by the submaximum effort tourniquet technique.2Ischaemic pain did not alter the plasma concentration of &bgr;END/&bgr;LPH, y-LPH, or ACTH, indicating that secretion of none of the POMC-derived peptides by the pituitary gland was stimulated. The finding that plasma noradrenaline increased by almost 100% with experimentally induced ischaemic pain, demonstrates that the stimulus used in our studies produced an adequate activation of the nervous system.3 Thus, our studies failed to establish a role for endorphins in the normal physiological response to pain. Other investigators, who used naloxone as a pharmacological tool, rather than direct measurement of plasma opioid peptides, have similarly failed to find evidence for a release of endorphins in response to pain.4-6 National Institutes of Health, Bethesda, MD 20205, USA
HANS-GEORG GÜLLNER
1. Güllner
H-G, Nicholson WE, Wilson MG, Bartter FC, Orth DN. The response of immunoreactive plasma adrenocorticotropin, &bgr;-endorphin/&bgr;-lipotropin, &ggr;-lipotropin and cortisol to experimentally induced pain in normal subjects. Clin Sci 1982; 63: 397-400. G, Egbert L, Markowitz R, Mosteller F, Beecher HK. An experimental
2 Smith
method sensitive
pain
5
morphine in man: the submaximum effort tourniquet technique. J Pharmacol Exp Ther 1966; 154: 324-32. Gullner H-G, Lake CR, Bartter FC. Experimental pain increases plasma norepinephrine in man. Clin Res 1981; 29: 430A. Grevert P, Goldstein A. Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects. Proc Natl Acad Sci USA 1977; 74: 1291-94 Grevert P, Goldstein A. Endorphins: naloxone fails to alter experimental pain or mood
6.
El-Sobky A, Dostrovsky JO, Wall PD. Lack of effect of naloxone on pain perception in
3 4
in
humans. Science 1978, 199: 1093-95
humans. Nature 1976; 263: 783-84.
NITROGLYCERIN LEVELS AFTER ADMINISTRATION VIA TRANSDERMAL THERAPEUTIC SYSTEM OR AS OINTMENT
SIR,-The letter by Dr Curry and colleagues (June 9, p 1297) calls for
Means ±SD of plasma concentrations reported
by Curry et al.
to
some comments
other than those
already
made
by
Dr
Taylor
(July 14, p 97). ’Transderm-Nitro’ was not developed merely to overcome the cosmetic problems of the ointments. The intention was to provide a method of administering nitroglycerin at a constant rate over a guaranteed period of 24 h in doses sufficient to produce therapeutic (anti-anginal) plasma levels. To compare visually the plasma concentrations produced by ointment and the transdermal therapeutic system, we have plotted the data from Curry’s table as a figure. Since standard deviations afford a more convenient basis for direct comparison of individual plasma levels than do standard errors of the mean, we have recalculated SD from SEM. The graph shows that the nitroglycerin concentrations found in the plasma after application of the ointment, and particularly after the first application, are widely dispersed. Since the SD extends into negative values, it is likely that both very low and very high individual plasma concentrations were measured in each series. The graph also shows that there is no significant difference between the means for the two treatments at any time. The only conclusion that can be drawn from Curry’s study is that the ointment occasionally gives rise to very high plasma levels, whereas those obtained with the transdermal system are much more reproducible. In a crossover tria11 twelve volunteers were treated successively with two 10 cm2transdermal systems (transderm-nitro) and three applications of 0 - 5 in (1 - 25 cm) of an ointment (’Nitro-bid) to an area of 10 cm2with 8 h between treatments. Plasma concentrations were measured after 2, 4, 8, 10, 12, 16, 18, 20, and 24 h and normalised to the same surface area. Statistical analysis revealed no significant difference at any time between the two treatments. The
permeability ot the skin to nitroglycerin is thus the same whether it is applied as ointment or with the transdermal system. The
larger
the
area
of skin
exposed
to
nitroglycerin
from any
vehicle, the greater will be the amount absorbed. In a large-scale study we found that, despite wide inter-individual and intraindividual variation, a 20 cm2transdermal system delivers twice as much nitroglycerin to the general circulation as a 10 cm2system.2 When an ointment is applied over a large surface area, it can give rise
higher plasma concentrations than a transdermal system with a smaller surface area. The transdermal system, however, ensures good stability and reproducibility of the plasma concentrations, which an ointment does not. The data published by Curry et al furnish excellent proof of the functional efficiency of the transdermal system. References 3-6 cited by Curry et al lend no support to the contention that "nitroglycerin skin patches are suspected of lacking efficacy". On the contrary, these publications clearly demonstrate the anti-anginal activity of these patches in coronary disease and their beneficial haemodynamic effects in heart failure. At least one of the cited papers mentions a further important aspect-namely, that about 24 h after application of the patch, the haemodynamic effects of nitrates may have been diminished by counter-regulatory vasoconstrictor mechanisms. This has been misinterpreted by some commentators as a sign that the efficacy of the patches is not sustained over 24 h, which is not true. There are many publications convincingly demonstrating the therapeutic efficacy of nitroglycerin patches over 24 h, over several weeks, or even over months in patients with coronary heart disease and in patients with heart failure.** to
*A list of 34 papers demonstrating the is available from P. R. I.
therapeutic usefulness of nitroglycerin
patches
Ciba-Geigy Biopharmaceutical Research Center, 92506 Rueil-Malmaison, France
J. HIRTZ
Ciba-Geigy Ltd, Basle, Switzerland
P. R. IMHOF P. FRANK HAUSER
1.
Shaw JE. Transdermal nitroglycerin systems. Vasc Med 1984; 2: 78-84. A, Gaudry D, Imhof PR, Fankhauser P. Availability of nitroglycerin administered transdermally by Transderm-nitro patches: Relationship between plasma level and release area. Presented at the 131 st annual meeting of the American Pharmaceutical Association (Montreal, May, 5-10, 1984).
2. Gerardin
absorption experiments, and
We thank M. Brouillard and A.
Codjo
Neuroimmunology and Neuroendocrine Immunopathology Unit, Faculty of Medicine, 49045 Angers, France; Saint-Louis Surgical Clinic, Angers; General Medical Service C, CHU Angers; and Neonatal Centre, Obstetrics and Gynaecology CHU Angers
Clinic,
for technical
help.
A. POUPLARD-BARTHELAIX V. LEPINARD L. LUXEMBOURGER V. ROHMER J. BERTHELOT J. C. BIGORGNE
1.
Pouplard A, Bigorgne JC, Chevallier JM,
2. 3.
hypophysaire: Maladie autoimmune? Nouv Presse Méd 1980; 9: 1757-60. Pouplard A. Pituitary autoimmunity. Hormone Res 1982; 16: 289-97. Bottazzo GF, Doniach D. Pituitary autoimmunity: a review. J Roy Soc Med 1978; 71:
Rohmer
V, Poron MF. Insuffisance
433-36. 4. Spitz L. Maldescent of the testis. Arch Dis Child 1983; 58: 847-48. 5. Job JC, Grendel D. Endocrine aspects of cryptorchidism. Urol Clin N Am
anti-
1982; 9,
3:
procedure available for8 fetal blood sampling during the third
trimester of pregnancy. The fetal platelet count was very low on a Coulter counter S plus II, and this was confirmed by microscopy and blood smear. The platelet count (15X 109/1) was well below our reference range (253±36 SD; n = 22), at this period of gestation and was too low to permit identification of PLA phenotype. By the 37th week the pregnancy was proceeding normally and there was no ultrasound evidence of fetal porencephaly. AntiPLA-1 antibody was present in the mother’s serum. With the approval of the local ethics committee we suggested to the patient that in-utero transfusion of platelets a few hours before delivery be
attempted. The maturity of the fetal lungs was confirmed by the lecithin sphingomyelin ratio in amniotic fluid. 20 ml of washed maternal platelets containing 250 x 1010/1 platelets was prepared. 2 h later 10 ml fetal blood
withdrawn from the umbilical vein. Thromboconfirmed and 10 -5 ml of the platelet preparation was injected slowly into the umbilical vein. 6 h later the mother was delivered by caesarean section of a 2700 g healthy baby (Apgar 10). The platelet count in cord blood was 95 x 109/1. A further 8-5 ml of platelet concentrate was injected 15 min after birth via the umbilical cord. No other platelet transfusion was necessary. Subsequent platelet counts are summarised in the figure. Clinical and ultrasound examinations of the baby were normal 8 days after birth. The baby’s PLA phenotype was subsequently shown to be PLA-1 positive. We have done 400 fetal blood samplings by direct puncture of the umbilical cord under ultrasound without accident. The procedure can be repeated several times during pregnancy and permits fetal therapy via the intravenous route. This case suggests that intrauterine platelet transfusion just before the delivery of a fetus with NAIT can be used to avoid haemorrhage in the neonatal period. The effects of platelet transfusion are short-lived but repeated intravenous injections to the fetus may prevent or delay prenatal haemorrhage in cases of severe fetal thrombocytopenia.
cytopenia
was
was
Department of Prenatal Diagnosis and Fetology, Hôpital Notre Dame de 75014
Bon
Secours,
Paris, France
F. DAFFOS F. FORESTIER
353-60. 6.
7.
Mayfield RK, Levine JH, Gordon L, Power ST, Galbraith RM, Rawe SE. Lymphoid adenohypophysitis presenting as a pituitary tumor. Am J Med 1980; 69: 619-23. Richsmeier AJ, Richard AH, Bloodworthe JMB, Edward NE. Lymphoid hypophysitis with selective adrenocorticotropic hormone deficiency. Arch Intern Med 1980; 140: 1243-45.
Leucocyte Immunology Unit, Centre National de Transfusion Sanguine-Centre d’Hemobiologie Perinatale, Paris
Clinical Applications Service, CNTS, Hôpital Saint-Antoine, Paris
J. Y.
MULLER
M. F. REZNIKOFF-ETIEVANT B. HABIBI
of Prenatal
PRENATAL TREATMENT OF ALLOIMMUNE
THROMBOCYTOPENIA
SIR,-The frequency of neonatal alloimmune thrombocytopenia (NAIT) has been estimated at about 1 per 5000 births.l The PLA-11 platelet-specific antigen has been involved in the vast majority of the reported cases. 1,2 A PLA-1 negative mother acquires immunity to the PLA-1 antigen of her fetus, even though in 20% of typical clinical cases PLA-1 antibody cannot be demonstrated serologically.2 Risk factors are PLA-1 negativity, and HLA B8, DR3 positivity in mothers,3,4 and PLA-1 positivity in fathers. NAIT is a serious condition, and central nervous system bleeding is responsible for a high rate of morbidity and mortality. Most of these complications have been associated with delivery and other perinatal stresses and have justified caesarean section in at-risk pregnancies.5However, intracranial haemorrhage has also been observed during fetal lifeand no laboratory tests have been available to predict whether the infant will be affected or not. In 1982 a woman now aged 24 was delivered of her first daughter, who had NAIT with severe intracranial haemorrhage and neurological sequelae. The mother was PLA-1negative and HLADR3 positive; the father was PLA-1positive as was the child. AntiPLA-1 antibody was found in a blood sample taken 8 days after delivery. This woman was sent to us in the 32nd week of her second pregnancy for the prenatal testing of the PLA platelet phenotype of her fetus. 5 ml pure fetal blood were obtained by direct puncture of the umbilical cord with a needle guided by ultrasound,the only
Department Diagnosis and Fetology, Notre Dame de Bon Secours Hôpital
M. CAPELLA-PAVLOVSKY
Paediatric Service, Centre d’Hemobiologie Perinatale, Hôpital Saint-Vincent-De-Paul, Paris
P. MAIGRET
Leucocyte Immunology Unit, CNTS-Centre d’Hemobiologie Perinatale
C. KAPLAN
1. Shulman
NR, Marder VJ, Hiller MC, Collier EM. Platelet and leukocyte isoantigens and their antibodies: Serologic, physiologic and clinical studies Prog Hematol 1964,
6: 222. 2. Muller JY, Reznikoff-Etievant MF, Patereau C, Dangu C, Chesnel N. Thrombopénies néonatales alloimmunes: Etude clinique et biologique de 84 cas. Nouv Presse Méd
(in press). 3. Reznikoff-Etievant 4.
5. 6. 7.
MF, Dangu C, Lobet R. HLA B 8 and anti-PLA I alloimmunisation. Tissue Antigens 1981; 18: 66. Reznikoff-Etievant MF, Muller JY, Julien F, Patereau C. An immune response gene linked to MHC in man. Tissue Antigens 1983; 22: 39. Sitarz AL, Driscoll JM, Wolf JA. Management of isoimmune neonatal thrombocytopenia. Am J Gynecol 1976; 124: 39. Zalneraitis EL, Young RSK, Krishanamoorthy KS. Intracranial hemorrhage in utero as a complication of isoimmune thrombocytopenia. J Pediatr 1979; 95: 611 Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling via the umbilical cord using a needle guided by ultrasound: Report of 66 cases. Prenatal Diag 1983, 3: 271.
Capella-Pavlovsky M. Fetal blood sampling during the third of pregnancy. Br J Obstet Gynaecol 1984; 91: 118.
8. Daffos F, Forestier F, trimester
ENDORPHINS AND PAIN CONTROL
SIR,-Dr Willer and his colleagues (Aug 4, p 295) report that plasma (3-endorphins concentration is poorly related to pain control
633 in man, and suggest that the hypothesis that pituitary (3-endorphin plays a role in the modulation of pain should be reconsidered. We have presented direct evidence that, in normal man, plasma endorphins do not change with experimental pain.1 Unfortunately, by not citing our paper Willer et al create the impression that their
observations
are
original.
We have examined the effect of ischaemic pain on plasma immunoreactive &bgr;-endorphin/&bgr;-lipotropin (&bgr;END/&bgr;LPH), y-lipotropin (y-LPH), and corticotropin (ACTH) in 10 normal subjects. Experimental pain was induced by the submaximum effort tourniquet technique.2Ischaemic pain did not alter the plasma concentration of &bgr;END/&bgr;LPH, y-LPH, or ACTH, indicating that secretion of none of the POMC-derived peptides by the pituitary gland was stimulated. The finding that plasma noradrenaline increased by almost 100% with experimentally induced ischaemic pain, demonstrates that the stimulus used in our studies produced an adequate activation of the nervous system.3 Thus, our studies failed to establish a role for endorphins in the normal physiological response to pain. Other investigators, who used naloxone as a pharmacological tool, rather than direct measurement of plasma opioid peptides, have similarly failed to find evidence for a release of endorphins in response to pain.4-6 National Institutes of Health, Bethesda, MD 20205, USA
HANS-GEORG GÜLLNER
1. Güllner
H-G, Nicholson WE, Wilson MG, Bartter FC, Orth DN. The response of immunoreactive plasma adrenocorticotropin, &bgr;-endorphin/&bgr;-lipotropin, &ggr;-lipotropin and cortisol to experimentally induced pain in normal subjects. Clin Sci 1982; 63: 397-400. G, Egbert L, Markowitz R, Mosteller F, Beecher HK. An experimental
2 Smith
method sensitive
pain
5
morphine in man: the submaximum effort tourniquet technique. J Pharmacol Exp Ther 1966; 154: 324-32. Gullner H-G, Lake CR, Bartter FC. Experimental pain increases plasma norepinephrine in man. Clin Res 1981; 29: 430A. Grevert P, Goldstein A. Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects. Proc Natl Acad Sci USA 1977; 74: 1291-94 Grevert P, Goldstein A. Endorphins: naloxone fails to alter experimental pain or mood
6.
El-Sobky A, Dostrovsky JO, Wall PD. Lack of effect of naloxone on pain perception in
3 4
in
humans. Science 1978, 199: 1093-95
humans. Nature 1976; 263: 783-84.
NITROGLYCERIN LEVELS AFTER ADMINISTRATION VIA TRANSDERMAL THERAPEUTIC SYSTEM OR AS OINTMENT
SIR,-The letter by Dr Curry and colleagues (June 9, p 1297) calls for
Means ±SD of plasma concentrations reported
by Curry et al.
to
some comments
other than those
already
made
by
Dr
Taylor
(July 14, p 97). ’Transderm-Nitro’ was not developed merely to overcome the cosmetic problems of the ointments. The intention was to provide a method of administering nitroglycerin at a constant rate over a guaranteed period of 24 h in doses sufficient to produce therapeutic (anti-anginal) plasma levels. To compare visually the plasma concentrations produced by ointment and the transdermal therapeutic system, we have plotted the data from Curry’s table as a figure. Since standard deviations afford a more convenient basis for direct comparison of individual plasma levels than do standard errors of the mean, we have recalculated SD from SEM. The graph shows that the nitroglycerin concentrations found in the plasma after application of the ointment, and particularly after the first application, are widely dispersed. Since the SD extends into negative values, it is likely that both very low and very high individual plasma concentrations were measured in each series. The graph also shows that there is no significant difference between the means for the two treatments at any time. The only conclusion that can be drawn from Curry’s study is that the ointment occasionally gives rise to very high plasma levels, whereas those obtained with the transdermal system are much more reproducible. In a crossover tria11 twelve volunteers were treated successively with two 10 cm2transdermal systems (transderm-nitro) and three applications of 0 - 5 in (1 - 25 cm) of an ointment (’Nitro-bid) to an area of 10 cm2with 8 h between treatments. Plasma concentrations were measured after 2, 4, 8, 10, 12, 16, 18, 20, and 24 h and normalised to the same surface area. Statistical analysis revealed no significant difference at any time between the two treatments. The
permeability ot the skin to nitroglycerin is thus the same whether it is applied as ointment or with the transdermal system. The
larger
the
area
of skin
exposed
to
nitroglycerin
from any
vehicle, the greater will be the amount absorbed. In a large-scale study we found that, despite wide inter-individual and intraindividual variation, a 20 cm2transdermal system delivers twice as much nitroglycerin to the general circulation as a 10 cm2system.2 When an ointment is applied over a large surface area, it can give rise
higher plasma concentrations than a transdermal system with a smaller surface area. The transdermal system, however, ensures good stability and reproducibility of the plasma concentrations, which an ointment does not. The data published by Curry et al furnish excellent proof of the functional efficiency of the transdermal system. References 3-6 cited by Curry et al lend no support to the contention that "nitroglycerin skin patches are suspected of lacking efficacy". On the contrary, these publications clearly demonstrate the anti-anginal activity of these patches in coronary disease and their beneficial haemodynamic effects in heart failure. At least one of the cited papers mentions a further important aspect-namely, that about 24 h after application of the patch, the haemodynamic effects of nitrates may have been diminished by counter-regulatory vasoconstrictor mechanisms. This has been misinterpreted by some commentators as a sign that the efficacy of the patches is not sustained over 24 h, which is not true. There are many publications convincingly demonstrating the therapeutic efficacy of nitroglycerin patches over 24 h, over several weeks, or even over months in patients with coronary heart disease and in patients with heart failure.** to
*A list of 34 papers demonstrating the is available from P. R. I.
therapeutic usefulness of nitroglycerin
patches
Ciba-Geigy Biopharmaceutical Research Center, 92506 Rueil-Malmaison, France
J. HIRTZ
Ciba-Geigy Ltd, Basle, Switzerland
P. R. IMHOF P. FRANK HAUSER
1.
Shaw JE. Transdermal nitroglycerin systems. Vasc Med 1984; 2: 78-84. A, Gaudry D, Imhof PR, Fankhauser P. Availability of nitroglycerin administered transdermally by Transderm-nitro patches: Relationship between plasma level and release area. Presented at the 131 st annual meeting of the American Pharmaceutical Association (Montreal, May, 5-10, 1984).
2. Gerardin