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Placental transfer of griseofulvin
1"\ r'\ 1\ Ill\ II I I I\ I II"\ 1\ T
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I r'\ I\ If"
lVI lVI U I'J I v 1-\ I I U I'J
~
IN BRIEF
Placental transfer of griseofulvin
umbilical cord by gravity drainage into a specially clf'anf'd tube. Tf dt:'iivery was by cesarean section. the uterus was incised to the membranes, and amniotic fluid was aspirated from the intact sac. All specimens were sealPd with polyethylt'llt"covered stoppers and refrigerated approximately :!l hours. The blood specimens thm were centrifuged and the serum decantt"d and held frozt•n until analyzed. Levels of griseofulvin were dPtermined hv a modification~ of the spectrophotofluorornt·~ric method of Bedford, Child, and Tomich.3. ' The specinu·JIS '"''ere extracted ·with ethyl ether (Spectrograde) and the residue dissolved in anhydrous nwthanol (reagent grade). The fluorescence of this solution was then compared with that of a standard griseofulvin solution. Both solutions wt>re activated at 295 m,u and analyzed at 420 mp..'' Rf'stiits from the blood specimf'ns which werr drawn just before the griseofulvin was administered were used as background values. Controls run with Semnal, Demerol, scopolamine and oxytocin. the only drugs the patients received, wen' found not to produce interference, The time between the administration of th<· griseofu lvin-microsized and delivery ranged betwet'n 2~/~ hours and 9)4 hours (Table I). In all instances the single oral dose of son mg. resulted in d<'tectable lewis in maternal and cord s<•nnn. The maternal levels ranged from 0.20 to 0.91 ,ttf!; pf'r milliliter of serum. Cord serum it'wls also were variable, 0.20 to 0.51 p.g per millilit<'r. There appeared to be no relationship lwtwf'en s<'rum levels and the time interval from drug admin-istration to the blood sampling. Maternal body weight also seemed unrelated to th(• serum ln·el. In the sam pies of amniotic fluid ·a 11 secured at cesarean section), there was no cl~~ t ectabl(• griseofulvin. Griseofulvin in nonpregnant individuals is not well absorbcd. 6 In normal, nonpregnant subjects (males), with th<" dosr f'rnploved in the l)rc>sent study, l('vels of about 1.18. fJ-~ per milliiirer of s.•rum ran lw anticipated at 4 hours-' The lrvels in the pre_gnant women were variable, and usu;tlly romidPrably lower than thos1~ sePn in non-
ALAN RUBIN, M.D. D. DVORNIK, PH .D.* Gynecean Institute for Gynecologic Research, and the Department of Obstetrics and Gynecology, Hospital and School of Medicine University of Pennsylvania, Philadelphia, ' Pennsj'lvania
G R I s Eo F u L vI N is an orally effective antifungal agent produced by Penicillium griseofulvum and other species of Penicillium. 1 Its possible effects upon the human fetus when administered to the pregnant woman are unknown. A first step in obtaining such information is to ascertain its degree of placental transfer, if any. Such data are presently unavailable. Arcordingly, normal women at term were given griseofulvin-microsized prior to elective cesarean section or before the elective induction of labor. Twelve healthy women at term were given 4 125 mg. capsules of griseofulvin-microsizedt with a swallow of water approximately 2Y2 hours prior to elective cesarean section or just before the beginning of the elective induction of labor (intrawnous infusion of ten units of oxytocin in 1,000 mi. of 5 per cent glucose in water, with amniotomy performed after good rontractions developed). Just prior to the ..administration of the griseofulvin, 10 mI. of blood was drawn from an antecubital VC'in by a disposable syringl' into a specially cleaned test tube. To avoid tracf> materials which might produce fluon'scence, the tubes had bern washed in chromsulfuric acid mixture, followed by thorough washing with water and rinsing with dilute methanol. At delivery an additional I 0 ml. of blood was similarly secured from the mothf'r. At the samf> time, 1 0 m!. of blood \vas ohtainPd from th~ *Department of Biochemistry t Ayerst Research Laboratories, Montreal.
tGrisactin, Ayt:"n~t Laboratories.
882
Communications m brief
Volume 92 Number 6
883
Table I. Placental transfer of griseofulvin Griseofulvin (p.g/ml.) Subject
T. E. E. R. S.
T.
K. R. F. Z.
J.K. S. W. C. P. C. N.
B. P. H. J. L.J.
Body weight (pounds)
Hours after drug
Maternal blood
125 120 185 105 120 112 140 150 190 130 165 125
2Y, 2y2
0.91 0.30 0.20 0.51 0 20 0.20 0.51 0.51 0.41 0.71 0.30 0.41
2~
3Y4 gy, 3Vz 4 4Yz 5Yz 8V2
BY,
9Yt
pregnant individuals. Similar relatively low and unpredictable maternal and cord serum levels have been reported after the oral administration to pregnant women of antibacterial agents. 7 Such levels probably are related to prolonged and unpredictable emptying time of the stomach in pregnancy. Gastric emptying may be further interfered with by analgesics employed during labor. 8 However, the patients delivered by cesarean section received no such drugs. A single 500 mg. oral dose of griseofulvinmicrosized administered to pregnant women at term prior to the elective induction of labor or elenive cesarean section resulted in variable and lower blood levels than those usually observed from comparable doses given to nonpregnant individuals. Cord blood levels were lower than maternal levels. Griseofulvin was not detected in the amniotic fluid. REFERENCES
1. International Symposium on Griseofulvum and Dermatomycoses: Arch. Dermat. 81: 650, 1960. 2. Kraml, M., Dubuc, J., and Dvornik, D., J. Pharm. Sc. In press. 3. Bedford, C., Child, K. J., and Tomich, E. G.: Nature 184: 364, 1959. 4. Weinstein, G. D., and Blank, H.: Arch. Dermat. 81:746,1960. 5. Kraml, M., Dubuc, J., and Gaudry, R.: Antibiot. & Chemother. 12: 239, 1962. 6. Kraml, M., Dubuc, J., and Dvornik, D.: Arch. Dermat. 87: 179, 1963. 7. Kiefer, L., Rubin, A., McCoy, J. B., and Foltz, E. L.: AM. J. 0BsT. & GYNEC. 69: 174, 1955. 8. Rubin, A., and Winston, J.: J. Clin. Invest. 29: 1261, 1950.
I
Cord blood
Amniotic fluid
0.51 0.20 0.20 0.30 0.20 0.30 0.30 0.41 0.20 0.51 0.20 0.41
0.00 0.00 0.00
Splenoendometriosis CHARLES SINDER, M.D. GEORGE R. DOCHAT, M.D. NORMAN E. WENTSLER, M.D. Departments of Obstetrics and Gynecology, and Pathology, Akron General Hospital, Akron, Ohio
S P L E N o s 1 s and endometriosis as separate disease entities have been known to the medical profession for some time but, never to our knowledge, have both been found together. It is our intention to present such a case and to briefly review the literature. Mrs. M. B., a 50-year-old gravida v, para 3-02-3, was admitted to Akron General Hospital on Nov. 11, 1963, complaining of increasing urinary frequency and pelvic pressure. During the san1e period of time the asymmetrically enlarged uterus had been increasing in size. A splenectomy had been performed in December, 1955, for a splenic rupture following an automobile accident. On Nov. 12, 1963, operation was performed. Exploration of the abdominal and pelvic cavities revealed the spleen to be missing; adhesions were present in the splenic area as well as in the culde-sac between the sigmoid colon and uterus, and the latter organ was asymmetrically enlarged due to a fibroid in the left cornual area. Visualization of the pelvic contents disclosed purplish papillary growths studding the sigmoid colon and parietal peritoneum covering the left ureter and cul-desac, the left ovary, and the posterior serosal surface of the uterus. A biopsy was taken from the parietal peritoneum of the eul-de-sac and a cryotome section done: it was reported as endo-
vU
I r'\ I\ If"
lVI lVI U I'J I v 1-\ I I U I'J
~
IN BRIEF
Placental transfer of griseofulvin
umbilical cord by gravity drainage into a specially clf'anf'd tube. Tf dt:'iivery was by cesarean section. the uterus was incised to the membranes, and amniotic fluid was aspirated from the intact sac. All specimens were sealPd with polyethylt'llt"covered stoppers and refrigerated approximately :!l hours. The blood specimens thm were centrifuged and the serum decantt"d and held frozt•n until analyzed. Levels of griseofulvin were dPtermined hv a modification~ of the spectrophotofluorornt·~ric method of Bedford, Child, and Tomich.3. ' The specinu·JIS '"''ere extracted ·with ethyl ether (Spectrograde) and the residue dissolved in anhydrous nwthanol (reagent grade). The fluorescence of this solution was then compared with that of a standard griseofulvin solution. Both solutions wt>re activated at 295 m,u and analyzed at 420 mp..'' Rf'stiits from the blood specimf'ns which werr drawn just before the griseofulvin was administered were used as background values. Controls run with Semnal, Demerol, scopolamine and oxytocin. the only drugs the patients received, wen' found not to produce interference, The time between the administration of th<· griseofu lvin-microsized and delivery ranged betwet'n 2~/~ hours and 9)4 hours (Table I). In all instances the single oral dose of son mg. resulted in d<'tectable lewis in maternal and cord s<•nnn. The maternal levels ranged from 0.20 to 0.91 ,ttf!; pf'r milliliter of serum. Cord serum it'wls also were variable, 0.20 to 0.51 p.g per millilit<'r. There appeared to be no relationship lwtwf'en s<'rum levels and the time interval from drug admin-istration to the blood sampling. Maternal body weight also seemed unrelated to th(• serum ln·el. In the sam pies of amniotic fluid ·a 11 secured at cesarean section), there was no cl~~ t ectabl(• griseofulvin. Griseofulvin in nonpregnant individuals is not well absorbcd. 6 In normal, nonpregnant subjects (males), with th<" dosr f'rnploved in the l)rc>sent study, l('vels of about 1.18. fJ-~ per milliiirer of s.•rum ran lw anticipated at 4 hours-' The lrvels in the pre_gnant women were variable, and usu;tlly romidPrably lower than thos1~ sePn in non-
ALAN RUBIN, M.D. D. DVORNIK, PH .D.* Gynecean Institute for Gynecologic Research, and the Department of Obstetrics and Gynecology, Hospital and School of Medicine University of Pennsylvania, Philadelphia, ' Pennsj'lvania
G R I s Eo F u L vI N is an orally effective antifungal agent produced by Penicillium griseofulvum and other species of Penicillium. 1 Its possible effects upon the human fetus when administered to the pregnant woman are unknown. A first step in obtaining such information is to ascertain its degree of placental transfer, if any. Such data are presently unavailable. Arcordingly, normal women at term were given griseofulvin-microsized prior to elective cesarean section or before the elective induction of labor. Twelve healthy women at term were given 4 125 mg. capsules of griseofulvin-microsizedt with a swallow of water approximately 2Y2 hours prior to elective cesarean section or just before the beginning of the elective induction of labor (intrawnous infusion of ten units of oxytocin in 1,000 mi. of 5 per cent glucose in water, with amniotomy performed after good rontractions developed). Just prior to the ..administration of the griseofulvin, 10 mI. of blood was drawn from an antecubital VC'in by a disposable syringl' into a specially cleaned test tube. To avoid tracf> materials which might produce fluon'scence, the tubes had bern washed in chromsulfuric acid mixture, followed by thorough washing with water and rinsing with dilute methanol. At delivery an additional I 0 ml. of blood was similarly secured from the mothf'r. At the samf> time, 1 0 m!. of blood \vas ohtainPd from th~ *Department of Biochemistry t Ayerst Research Laboratories, Montreal.
tGrisactin, Ayt:"n~t Laboratories.
882
Communications m brief
Volume 92 Number 6
883
Table I. Placental transfer of griseofulvin Griseofulvin (p.g/ml.) Subject
T. E. E. R. S.
T.
K. R. F. Z.
J.K. S. W. C. P. C. N.
B. P. H. J. L.J.
Body weight (pounds)
Hours after drug
Maternal blood
125 120 185 105 120 112 140 150 190 130 165 125
2Y, 2y2
0.91 0.30 0.20 0.51 0 20 0.20 0.51 0.51 0.41 0.71 0.30 0.41
2~
3Y4 gy, 3Vz 4 4Yz 5Yz 8V2
BY,
9Yt
pregnant individuals. Similar relatively low and unpredictable maternal and cord serum levels have been reported after the oral administration to pregnant women of antibacterial agents. 7 Such levels probably are related to prolonged and unpredictable emptying time of the stomach in pregnancy. Gastric emptying may be further interfered with by analgesics employed during labor. 8 However, the patients delivered by cesarean section received no such drugs. A single 500 mg. oral dose of griseofulvinmicrosized administered to pregnant women at term prior to the elective induction of labor or elenive cesarean section resulted in variable and lower blood levels than those usually observed from comparable doses given to nonpregnant individuals. Cord blood levels were lower than maternal levels. Griseofulvin was not detected in the amniotic fluid. REFERENCES
1. International Symposium on Griseofulvum and Dermatomycoses: Arch. Dermat. 81: 650, 1960. 2. Kraml, M., Dubuc, J., and Dvornik, D., J. Pharm. Sc. In press. 3. Bedford, C., Child, K. J., and Tomich, E. G.: Nature 184: 364, 1959. 4. Weinstein, G. D., and Blank, H.: Arch. Dermat. 81:746,1960. 5. Kraml, M., Dubuc, J., and Gaudry, R.: Antibiot. & Chemother. 12: 239, 1962. 6. Kraml, M., Dubuc, J., and Dvornik, D.: Arch. Dermat. 87: 179, 1963. 7. Kiefer, L., Rubin, A., McCoy, J. B., and Foltz, E. L.: AM. J. 0BsT. & GYNEC. 69: 174, 1955. 8. Rubin, A., and Winston, J.: J. Clin. Invest. 29: 1261, 1950.
I
Cord blood
Amniotic fluid
0.51 0.20 0.20 0.30 0.20 0.30 0.30 0.41 0.20 0.51 0.20 0.41
0.00 0.00 0.00
Splenoendometriosis CHARLES SINDER, M.D. GEORGE R. DOCHAT, M.D. NORMAN E. WENTSLER, M.D. Departments of Obstetrics and Gynecology, and Pathology, Akron General Hospital, Akron, Ohio
S P L E N o s 1 s and endometriosis as separate disease entities have been known to the medical profession for some time but, never to our knowledge, have both been found together. It is our intention to present such a case and to briefly review the literature. Mrs. M. B., a 50-year-old gravida v, para 3-02-3, was admitted to Akron General Hospital on Nov. 11, 1963, complaining of increasing urinary frequency and pelvic pressure. During the san1e period of time the asymmetrically enlarged uterus had been increasing in size. A splenectomy had been performed in December, 1955, for a splenic rupture following an automobile accident. On Nov. 12, 1963, operation was performed. Exploration of the abdominal and pelvic cavities revealed the spleen to be missing; adhesions were present in the splenic area as well as in the culde-sac between the sigmoid colon and uterus, and the latter organ was asymmetrically enlarged due to a fibroid in the left cornual area. Visualization of the pelvic contents disclosed purplish papillary growths studding the sigmoid colon and parietal peritoneum covering the left ureter and cul-desac, the left ovary, and the posterior serosal surface of the uterus. A biopsy was taken from the parietal peritoneum of the eul-de-sac and a cryotome section done: it was reported as endo-