- Email: [email protected]
TRANSPLACENTAL PASSAGE OF DOXORUBICIN
75
HISTIDINE DECARBOXYLASE ACTIVITY IN CONTROL AND
PARKINSONIAN BRAINS
studied here or via other neurotransmitter systems which remain to be elucidated. The extent of the involvement of histaminergic neuronal systems in the genesis of parkinsonian symptoms requires further investigation. Laboratory of Experimental Medicine, C.H.U. Pitié-Salpétrière, Paris, France; and Neurobiology Unit, Centre Paul Broca, Paris
M. GARBARG
F. JAVOY-AGID J. C. SCHWARTZ Y. AGID
TRANSPLACENTAL PASSAGE OF DOXORUBICIN
SiR,—Roboz et al. reported that doxorubicin was not detectable in amniotic fluid 4
or
16 h after i.v. administration at
a
dose of 30
mg/m2to a woman 20 weeks’ pregnant. They suggested that this drug "is not transferred transplacentally to the fetus". We report here
study on a 22-year-old woman with Hodgkin’s 17 weeks’ gestation, had a therapeutic abortion, after treatment with the ABVD regimen2,3 (doxorubicin 40 mg i.v., bleomycin 15 mg i.v., vinblastine 9 mg i.v., and dacarbazine 600 mg i.v.). She weighed 64 kg, and her body surface area was 1.655 m 2 Before treatment and periodically afterwards blood was taken and plasma stored at -20°C. Termination was achieved by dilatation and suction curettage 15 h after doxorubicin. Amniotic fluid and fetal liver, kidney, lung, brain, intestine, and a striatal muscle (gastrocnemius) were collected. The fetal heart was lost during the termination procedure. a
lymphoma who, at
1 ml maternal plasma or 3 ml amniotic fluid were extracted with 8 ml chloroform-isopropanol (1:1) and the resulting gel was mixed with solid ammonium sulphate to give a saturated solution. The organic phase was evaporated under vacuum. Tissues were homogenised in water (1:3). 3 ml of homogenate (1 g tissue) was extracted twice with 15 ml of isopropanol after addition of 50 !il of 3% silver nitrate. The organic phase was evaporated under
Transplacental passage of doxorubicin (Dx). Upper part: chromatograms of extract from amniotic fluid (A7), fetal liver (B), mouse liver with 100 ng added Dx (C), and mouse liver without added Dx(D). Lower part: semilogarithmic plot of maternal plasma Dx concentrations and 15 h Dx concentrations in fetal liver, kidney, and lung. The fact that doxorubicin was not measurable in amniotic fluid is
probably related to the high distribution volume of this drug, which tends to concentrate more in tissues than in fluids,4 or to rapid efflux I
from this compartment.1 The transplacental pasage of doxorubicin to the fetus has important implications for the use of this drug in pregnant cancer patients. This potent cytotoxic agent is reported to be mutagenic and teratogenic in laboratory animals. 5,6 The absence of a chemical agent in amniotic fluid cannot be taken as proof of the absence of
transplacental passage. The generous contribution of the Italian Association for Cancer Research,
Milan, Italy, is gratefully acknowledged. Negri Institute for Pharmacological Research, 20157 Milan, Italy
MAURIZIO D’INCALCI MASSIMO BROGGINI
Obstetrics and Gynaecology Clinic I, University of Milan
MAURO BUSCAGLIA GIORGIO PARDI
Mario
vacuum.
Dried samples were then redissolved with 100 1 of mobile phase containing daunorubicin as external standard, and injected into a Perkin Elmer series 3B. high-performance liquid chromatograph with a fluorescence detector (Perkin Elmer 650/10) at an excitation wavelength of 475 nm and an emission wavelength of 580 nm. Separation was achieved by an isocratic solvent system 0 of acetonitrile:water:0 1 mo1/1 phosphoric acid (34:40:26) at a flow rate of 1 0 ml/mm on a 25 cm’LiChrosorb C-18’ column (10 l) (Merck-Darmstadt). The sensitivity limit of the assay was 5 ng/ml for fluids and 10 ng/g for tissues.
The upper part of the figure shows the chromatograms of extracts of amniotic fluid, fetal liver, mouse liver with doxorubicin added, and mouse liver with no addition. The lower part shows the maternal plasma doxorubicin concentrations and the fetal tissue profile (15 h after doxorubicin exposure). The drug was not detectable in amniotic fluid (i.e., it was less than 1’ 66 ng/ml, the assay being done on 3 ml) or in brain, intestine, or gastrocnemius muscle (less than 10 ng/g). However, it did reach fetal liver, kidney, and lung in high concentrations (e.g., liver concentrations were about 10 times the concentrations in maternal plasma at the same
time). 1 Roboz
J, Gleicher N, Wu K, Chahinian P, Kerenyi T, Holland J. Does doxorubicin the placenta? Lancet 1979, i: 1382-83. 2 Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy for Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975; 36: 252-59. 3. Santoro A, Bonadonna G Prolonged disease-free survival in MOPP-resistant Hodgkin’s disease after treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). Cancer Chemother Pharmacol 1979; 2: 101-05.
SOLVENT ABUSE IN THE CENTRAL PACIFIC
SiR,-Your editorial on solvent abuse (Nov. 20) ends with the words: "The cause lies in the ills of society ..." Detractors from Western industrialised society will be interested to learn that benzine sniffing is widespread among the youth of these isolated Pacific islands, where conditions are about as far removed from modern urban life as it is possible to imagine. Reasons given for sniffing benzine include "I want to get drunk" and "I want to feel different", fairly common aspirations. We are investigating the possibility that sniffing benzine may have longer term effects. Of fourteen schizophrenics under the age of 35 so far questioned, nine have sniffed benzine at some time. We do yet have the figures for controls. Tungaru Central Hospital, Tarawa, Kiribati 4.
cross
5
6
A. M. DANIELS R. C. FAZAKERLEY
Benjamin RS, Riggs CE Jr, Bachur NR. Pharmacokinetics and metabolism of
adriamycm in man. Clin Pharmacol Ther 1973; 14: 595-600. Marquardt H, Philips FS, Sternberg SS. Tumorigenicity in vivo and induction of malignant transformation and mutagenesis in cell cultures by adriamycin and daunomycin. Cancer Res 1976; 36: 2065-69. Thompson DJ, Molello JA, LeBeau JE. Differential sensitivity ofthe rat and rabbit to to the teratogenic and embryo-toxic effects of eleven antineoplastic drugs Toxicol Appl Pharmacol 1978; 45: 353.
HISTIDINE DECARBOXYLASE ACTIVITY IN CONTROL AND
PARKINSONIAN BRAINS
studied here or via other neurotransmitter systems which remain to be elucidated. The extent of the involvement of histaminergic neuronal systems in the genesis of parkinsonian symptoms requires further investigation. Laboratory of Experimental Medicine, C.H.U. Pitié-Salpétrière, Paris, France; and Neurobiology Unit, Centre Paul Broca, Paris
M. GARBARG
F. JAVOY-AGID J. C. SCHWARTZ Y. AGID
TRANSPLACENTAL PASSAGE OF DOXORUBICIN
SiR,—Roboz et al. reported that doxorubicin was not detectable in amniotic fluid 4
or
16 h after i.v. administration at
a
dose of 30
mg/m2to a woman 20 weeks’ pregnant. They suggested that this drug "is not transferred transplacentally to the fetus". We report here
study on a 22-year-old woman with Hodgkin’s 17 weeks’ gestation, had a therapeutic abortion, after treatment with the ABVD regimen2,3 (doxorubicin 40 mg i.v., bleomycin 15 mg i.v., vinblastine 9 mg i.v., and dacarbazine 600 mg i.v.). She weighed 64 kg, and her body surface area was 1.655 m 2 Before treatment and periodically afterwards blood was taken and plasma stored at -20°C. Termination was achieved by dilatation and suction curettage 15 h after doxorubicin. Amniotic fluid and fetal liver, kidney, lung, brain, intestine, and a striatal muscle (gastrocnemius) were collected. The fetal heart was lost during the termination procedure. a
lymphoma who, at
1 ml maternal plasma or 3 ml amniotic fluid were extracted with 8 ml chloroform-isopropanol (1:1) and the resulting gel was mixed with solid ammonium sulphate to give a saturated solution. The organic phase was evaporated under vacuum. Tissues were homogenised in water (1:3). 3 ml of homogenate (1 g tissue) was extracted twice with 15 ml of isopropanol after addition of 50 !il of 3% silver nitrate. The organic phase was evaporated under
Transplacental passage of doxorubicin (Dx). Upper part: chromatograms of extract from amniotic fluid (A7), fetal liver (B), mouse liver with 100 ng added Dx (C), and mouse liver without added Dx(D). Lower part: semilogarithmic plot of maternal plasma Dx concentrations and 15 h Dx concentrations in fetal liver, kidney, and lung. The fact that doxorubicin was not measurable in amniotic fluid is
probably related to the high distribution volume of this drug, which tends to concentrate more in tissues than in fluids,4 or to rapid efflux I
from this compartment.1 The transplacental pasage of doxorubicin to the fetus has important implications for the use of this drug in pregnant cancer patients. This potent cytotoxic agent is reported to be mutagenic and teratogenic in laboratory animals. 5,6 The absence of a chemical agent in amniotic fluid cannot be taken as proof of the absence of
transplacental passage. The generous contribution of the Italian Association for Cancer Research,
Milan, Italy, is gratefully acknowledged. Negri Institute for Pharmacological Research, 20157 Milan, Italy
MAURIZIO D’INCALCI MASSIMO BROGGINI
Obstetrics and Gynaecology Clinic I, University of Milan
MAURO BUSCAGLIA GIORGIO PARDI
Mario
vacuum.
Dried samples were then redissolved with 100 1 of mobile phase containing daunorubicin as external standard, and injected into a Perkin Elmer series 3B. high-performance liquid chromatograph with a fluorescence detector (Perkin Elmer 650/10) at an excitation wavelength of 475 nm and an emission wavelength of 580 nm. Separation was achieved by an isocratic solvent system 0 of acetonitrile:water:0 1 mo1/1 phosphoric acid (34:40:26) at a flow rate of 1 0 ml/mm on a 25 cm’LiChrosorb C-18’ column (10 l) (Merck-Darmstadt). The sensitivity limit of the assay was 5 ng/ml for fluids and 10 ng/g for tissues.
The upper part of the figure shows the chromatograms of extracts of amniotic fluid, fetal liver, mouse liver with doxorubicin added, and mouse liver with no addition. The lower part shows the maternal plasma doxorubicin concentrations and the fetal tissue profile (15 h after doxorubicin exposure). The drug was not detectable in amniotic fluid (i.e., it was less than 1’ 66 ng/ml, the assay being done on 3 ml) or in brain, intestine, or gastrocnemius muscle (less than 10 ng/g). However, it did reach fetal liver, kidney, and lung in high concentrations (e.g., liver concentrations were about 10 times the concentrations in maternal plasma at the same
time). 1 Roboz
J, Gleicher N, Wu K, Chahinian P, Kerenyi T, Holland J. Does doxorubicin the placenta? Lancet 1979, i: 1382-83. 2 Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy for Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975; 36: 252-59. 3. Santoro A, Bonadonna G Prolonged disease-free survival in MOPP-resistant Hodgkin’s disease after treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). Cancer Chemother Pharmacol 1979; 2: 101-05.
SOLVENT ABUSE IN THE CENTRAL PACIFIC
SiR,-Your editorial on solvent abuse (Nov. 20) ends with the words: "The cause lies in the ills of society ..." Detractors from Western industrialised society will be interested to learn that benzine sniffing is widespread among the youth of these isolated Pacific islands, where conditions are about as far removed from modern urban life as it is possible to imagine. Reasons given for sniffing benzine include "I want to get drunk" and "I want to feel different", fairly common aspirations. We are investigating the possibility that sniffing benzine may have longer term effects. Of fourteen schizophrenics under the age of 35 so far questioned, nine have sniffed benzine at some time. We do yet have the figures for controls. Tungaru Central Hospital, Tarawa, Kiribati 4.
cross
5
6
A. M. DANIELS R. C. FAZAKERLEY
Benjamin RS, Riggs CE Jr, Bachur NR. Pharmacokinetics and metabolism of
adriamycm in man. Clin Pharmacol Ther 1973; 14: 595-600. Marquardt H, Philips FS, Sternberg SS. Tumorigenicity in vivo and induction of malignant transformation and mutagenesis in cell cultures by adriamycin and daunomycin. Cancer Res 1976; 36: 2065-69. Thompson DJ, Molello JA, LeBeau JE. Differential sensitivity ofthe rat and rabbit to to the teratogenic and embryo-toxic effects of eleven antineoplastic drugs Toxicol Appl Pharmacol 1978; 45: 353.