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Urinary excretion of prostaglandin E following the administration of furosemide and indomethacin to sick low-birth-weight infants
September 1978
512
The Journal ojPEDIATRlCS
Urinary excretion ofprostaglandin E following the administration offurosemide and indomethacin to sick low-birth-weight infants Urinary excretion ofprostaglandin E was measured in seven sick low-birth-weight infants. Four had 'severe hyaline membrane disease and aile had chronic bronchopulmonary dysplasia; all received furosemide. Two infants had patent ductus arteriosus and received indomethacin. Following administration offurosemide, ill'ine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4
± 0.04 to 1.3 ± 0.2 ng/mg Cr (mean ± SEM)
following administration offurosemide, hilt decreased in two patients following administration of indomethacin. The present results demonstrate that furosemide enhances urinary excretion of prostaglandin E by mechanisms which may reflect an increase in prostaglandin synthesis, a decrease in prostaglandin renal metabolism, or both. Indomethacin, which is a prostaglandin synthetase inhibitor. decreases the urinary excretion of prostaglandin E. These observations suggest that furosemide therapy in patients receiving indomethacin may he ineffective.
Zvl Friedman, 1\1.0., F.R.C.P.(C),* Laurence M. Demers, Ph.D., Keith H. Marks, M.B., M.R.C.P., F.C.P. (SA), Susan Uhrmann, M.D., and M. Jeffrey Maisels, M.B., B.Ch., Hershey, Pa.
PROSTAGLANDIN E is associated with marked alterations in urinary flow rate and the excretion of sodium.':" Diuresis and natriuresis have been observed after stimulation of endogenous secretion of prostaglandins by their precursor, arachidonic acid;' as well as after the infusion of exogenous prostaglandins in animals and in man.":" Indomethacin, which is a prostaglandin synthetase inhibitor, reduces the degree of natriuresis produced by furosemide,' suggesting that the furosemide effect might be mediated by renal prostaglandin. Recently, an increase in urinary prostaglandin E excretion was demonstrated following administration of furosemide to man." Furosemide and indomethacin are commonly used drugs in the management of sick, low-birth-weight infants
From the Division of Newborn Medicine, Department of Pediatrics and the Department of Pathology, The Milton S, Hershey Medical Center, The PennsyZ,'ania State University College of Medicine. Supported by a National Institute of Child and Human Development Grant ROI HOI1255-01. •Reprint address: Department of Pediatrics. The Milton S. Hershey Medlco! Center, Hershey, PA 17033.
Vol. 93, No.3, pp. 512-515
with hyaline membrane disease" and patent ductus arteriosus." In order to evaluate their effect on renal prostaglandin metabolism in sick infants, we measured the urinary excretion of prostaglandin E before and after the administration of these drugs. Our study demonstrated an increase in the urinary excretion of prostaglandin E following administration of furosemide and a decrease in the urinary excretion of prostaglandin E following administration of indomethacin. Abbreviations used HMO: hyaline membrane disease POA: patent ductus arteriosus
SUBJECT AND METHODS Patients. Seven low-birth-weight infants with weights appropriate for their gestation were selected for study. These patients were cared for by the staff of the Newborn Intensive Care Unit at The Milton S. Hershey Medical Center. Informed consent for these studies was obtained from the parents of each child after being approved by the Clinical Investigation Committee of The MSHMC. The 0022-3476178/0393-0512$00.40/0
e
1978 The C. V. Mosby Co.
Urinary excretion ofprostaglandin E
Volume 93 Number 3
5 13
Table. Th e effects of fu rosemide and indo me thaci n administration on urinary volume and sod iu m and calcium excretion in the study groups Age at
Patients
Urine volume ml/kg! 24 hr
Gestational age at birth (wk}
Birth weight (gm)
Sex
Diagnosis
lim e of study (day )
32 35 33 36 32
1,640 2,010 1,460 1,950 1,700
M M F M F
HM O H MO H MO HMO, capo HMO
2 2 3 23 3
58 36 47
30 28
1,230 1,260
F M
POA POA
15 13
37 90
Group I A.S.
N.E. PA R .T. J.Se. Group II S.S. T.B.
Before
I
Sodium (meq/t}
After
Bef ore
102 201 104
16.5 13 .0 26.5
NS NS
I
Calcium mgldl
After
Before
57.5 82.0 67.0
1.35 0.85 0.65
NS NS 27 58
76.5 16.5
I
Aft er
2.35 4.03 1.12
NS NS 67.0 14.0
0.75 0.65
0.80 0.60
Abbreviations used : HM O = Hyalin e membrane disease; CBPO = chron ic bronchopulmonary dyspl asia: POA = patent ductus arteriosus; NS = studies not available.
p atients were divided into two groups: Grou p I consisted of four infants with HM D and on e with chro nic bronchopulmonary dysplasia. Group II included two infants who had PDA and congestive he art failure . The clinical data for the study group are shown in the Table. Fur osemide in a dose of 2.0 mg/kg was administered over thre e to five minutes to the infants in Group I in order to try to improve their pulmonary gas exchange ." Indomethacin was administe red via a nasogastric tube to the two infants with PDA in a dose of 0.15 mg/kg and 0.3 rug/kg, respectively, in an attempt to achi eve pharmacologic closure of the PDA.'o One of these infants received furosemide (2 rng/kg intravenously) 8 hours prior to administratio n of indomethacin . Urine was collected using U-bags (Hollister, Inc., Ch icago, Ill.) for 24 hours prior to an d follo wing the administration of the drugs, kep t frozen a t -20°C, and analyzed for sodium (by flame photometry), calcium (by atomic absorption), creatinine (by Jaffe reaction), and for prostaglandin E by rad ioimmunoassay as previously described." Prostaglandin radio immunoassays were performed with the use of antiserum prepared in rabbits against the alb umin conjugate of prostaglandin E, . Crossreactivity st udies with th e prostaglandin E antiserum indicated 100% cross-reactivity with prostaglandin E" 70% cross-reactivity with prostaglandin Eo , 9% crossreactivity with prostaglandin A" 1% cross-reactivity with prostaglandin AOl 0.4% cross-reactivity with prostaglandin B" 1.5% cross -reactivity with prostaglandin F ,«, and less than 1% cross-reactivity with other related prostaglandin compounds, including the 13,14 dihydro, 15 keto prosta glandin E metabolite.
R E S ULTS Urinary prostaglandin E. The changes in urinary excretion of prostaglan din E are shown in the Figure. An
increase in the urinary excretion of prostaglandin E in Group I infants from 0.40 ± 0.04 to 1.3 ± 0.20 ng/mg Cr (mean ± SEM) is evident following administration of furosemide. A decrease in the urinary excretion of prostaglandin E is seen following administration of indomethacin. No differences in prostaglandin E excretion were noted between the sexes. Urinary volume and excretion of sodium and calcium. The changes in urine volume and urinary excretion of sodium and calcium are shown in the Table. Following administration of furosemide there was a dramatic increase in urine volume and in the excretion of sodium and calcium. Following administration of indomethacin, a decrease in urine volume was noted but no changes in the excretion of sodium and calcium were observed.
DI SCUSSIO N As we have previously shown, sick low-bir th-weight infants respond to administration of fur osemide with diuresis, natriuresis, and calciuria.· Prostaglandin E excretion was also increased following furosemide administration, but this phenomenon was abolished by indomethacin, which is a. prostaglandin synthetase inhibitor . In contrast to the majority of other tissues, there is an anatomic separation of those areas in the kidney responsible for prostaglandin synthesis (the papilla and the medulla) from those responsible for meta bolism (the cortical area). This arrangement re quires that prostaglandins be metabolized in cells other than those responsible for their synthesis.'>" The transit of prostaglandins from sites of synthesis into the urine, and to sites of cortical inactivation or into the venous or lymphatic circulation , has not been thoroughly defined. However, the urinary prostaglandins arise from de novo renal prostaglandin synthesis rather than from extrarenal sites . This was suggested by the observa tion that prostaglandin metabo-
514
Friedman et al.
The Journal of Pediatrics September 1978
URINARY EXCRETION OF PGE
dramatically lowers aldosterone and plasma renin activity
in human volunteers.
C I
2.0
CONTROL INDOMETHACIN F FUROSEM IDE • MALE o FEMALE
Furosemide and indomethacin are frequently administered to low-birth-weight infants who have respiratory distress or symptomatic PDA. Because of the central role of these drugs in affecting renal prostaglandins and the renin-angiotensin-aldosterone axis, and the known immaturity of renal function in low-birth-weight infants," further studies are necessary for better understanding the mechanism of the action of furosemide in this group of infants. Our studies suggest that the use of furosemide in infants with a symptomatic PDA may be ineffective after administration of indomethacin. Moreover, this detrimental effect of indomethacin may be prolonged, depending on the capabilities for indomethacin disposition in this group. of sick infants."
1.5
.
u
..
E ...... c:
1.0
0.5
\
oL-_-'-_--JL-_...J...._----'-_ _..J.-_-..l C
C
F
Figure. Changes of urinary excretion of prostaglandin E in five sick low-birth-weight infants before (C) and after (F) the administration of furosemide, and in two sick low-birth-weight infants before (C) and after (F) administration of indomethacin.
lites and not intact primary prostaglandins are found in the urine following parenteral administration.' I Increases in urinary flow rate and excretion of sodium are associated with the administration of prostaglandins.':" Diuresis and natriuresis have been observed following stimulation of endogenous prostaglandin secretion by its precursor fatty acid, arachidonic. acid! These effects have been confirmed in man," Alterations in these renal functions could result from changes attributable to the influence of prostaglandins on renal hemodynamics or by direct tubular epithelial effects. '" Recent reports indicate that administration of furosemide to healthy human volunteers results in a significant increase in the urinary excretion of prostaglandin E as well as in diuresis, natriuresis, and increase in plasma renin activity,' findings which are similar to those of our study. Moreover, indomethacin reduces the degree of natriuresis and affects the rise in plasma renin activity when administered following furosemide in man.': iu Patient S. S. (Group II), who received furosemide prior to administration of indomethacin, falls into this category. These observations suggest that furosemide's mechanism of action could be mediated by stimulation of intrarenal prostaglandin synthesis. In contrast, Tan and Mulrow" were unable to detect significant changes in urinary prostaglandin E, excretion in response to administration of furosemide, but demonstrated that indomethacin
We acknowledge the editorial assistance of Dr. Nicholas M, Nelson and the help of the residents and nurses of the Neonatal Intensive Care Unit. REFERENCES 1. Johnston HH, Herzog JP, and Lauler DP: Effect of prostaglandin E, on renal hemodynamics, sodium and water excretion, Am J Physiol 213:939, 1967. 2. Vander AJ: Direct effects of prostaglandin on renal function and renin release in anesthetized dog, Am J Physiol 214:218, 1968, 3, Lee JB: Natriuretic hormone and the renal prostaglandins, Prostaglandins 1:55, 1972. 4. Tannenbaum J, Slawinski JA, Oates JA, et al: Enhanced renal prostaglandin production in the dog. I. Effects on renal function, Circ Res 36:197, 1975. 5, Fujimoto S, and Lockett MF: The diuretic actions of prostaglandin E, and of noradrenaline, and the occurrence of a prostaglandin E,-like substance in the renal lymph of cats, J Physiol (London) 208:!, 1970. 6. Fichman M, and Horton R: Significance of the effects of prostaglandins on renal and adrenal function in man, Prostaglandins 3:629, 1973. 7. Patak RV. Mookerjie BK. Bentzel CJ, et al: Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man, Prostaglandins 10:649, 1975. 8. Abe K, Yasujima M, Chiba S, et al: Effectof furosemide on urinary excretion of prostaglandin E in normal volunteers and patients with essential hypertension, Prostaglandins 14:513, 1977. 9. Marks KH, Berman W Jr, Friedman Z, et al: Furosemide in hyaline membrane disease, Pediatr Res 11:575, 1977. 10. Heymann MA, Rudolph AM, and Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530. 1976. 11. Demers LM, and Gabbe SO: Placental prostaglandin levels in preeclampsia, Am J Obstet Gynecol 126:137, 1976, 12. Larson C, and Anggard E: Regional differences in the formation and metabolism of prostaglandins in the rabbit kidney, Em J Phnrmacol 21:30, 1973, 13. Friedman Z, and Demers L: Prostaglandin synthesis in human neonatal kidney, Pediatr Res 12:394, 1978, 14. Hamberg M, and Samuelsson B: On the metabolism of
Urinary excretion ofprostaglandin E
Volume 93 Number 3
prostaglandins E, and E. in man, J Biol Chern 246:6713, 1971. 15. Gross JB, and Bartter FC: Effect of prostaglandins E1> Al and F,a on renal handling of salt and water, Am J Physiol 225:218, 1973. 16. Frolich JC, Hollifield J, Wilkinson G, and Oates J: Effect of indomethacin on furosemide stimulated renin and sodium excretion. Circulation 52 (Supple IT):99, 1975.
515
17. Tan SY, and Mulrow PJ: Inhibition of the renin-aldosterone response to furosemide by indomethacin, J Clin Endocrinol Metab 45:174, 1977. 18. Siegel SR, and Oh W: Renal function as a marker of human fetal maturation. Acta Pediatr Scand 65:481, 1976. 19. Friedman Z. Whitman Y, Maisels MJ, et al: Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants, J Clin Pharmacol (in press).
Brief clinical and laboratory observations Central nervous system toxicity associated with ingestion ofpropylene glycol Karunyan Arulanantharn, M.B., D.C.H.," and Myron Genel, M.D., New Haven, Conn.
PROPYLENE GLYCOL, a polyalcohol, is widely used as a solvent in the preparation of oral and injectable drugs,
cosmetics, lotions, and ointments. It is generally considered to be a stable, pharmacologically inert substance with low systemic toxicity.':" However, a published report has attributed acute toxic symptoms to the ingestion of propylene glycol which was used as the solvent for medication.' We report the clinical course of a patient who developed seizures associated with the long-term ingestion of medication with propylene glycol as its cosolvent. These episodes remitted when the ingestion of propylene glycol was discontinued. CASE REPORT
The patient, an II-year-old Puerto Rican boy, had manifestations of the candidiasis-endocrinopathy syndrome with hypoparathyroidism, chronic mucocutaneous candidiasis, alopecia total is, and intestinal malabsorption. Treatment of hypoparathyroidism with an oral vitamin D preparation and supplemental oral calcium was not effective in maintaining an eucalcemic state, From the Department of Pediatrics, Yale University School of Medicine. Supported in part by Clinical Research Center Grant RR-125 from the GCRC Branch. Division of Research Resources. National Lnstitutes oj Health. • Reprint address: Research Department. Newington Children's Hospital. Newington, CT 06111.
0022-3476/78/0393-0515$00.20/0 e 1978 The C. V. Mosby Co.
possibly due to poor absorption of the fat soluble vitamin D. In order to overcome this problem, a preparation of vitamin 0 in the form of dihydrotachysterol was made using propylene glycol, a water miscible substance, as the vehicle. The solution was prepared as follows: 1 gm of DHT was dissolved in 20 rnl of absolute alcohol with propylene glycol USP added to make the concentration of DHT 1 mg/rnl. With the use of 2 to 4 ml twice daily and oral calcium supplement, the serum calcium returned to normal. The patient was also maintained on a low-fat diet with oral medium-chain triglyceride added. Abbreviations used DHT: dihydrotachysterol CNS: central nervous system Thirteen months after beginning treatment with the new preparation of DHT, the patient developed repeated seizures. These grand mal seizures were followed by a period of unconsciousness lasting 20 to 30 minutes from which there was spontaneous recovery. These episodes often occurred two to four hours after the evening dose of DHT. On repeated occasions the serum calcium, magnesium, electrolytes, and blood sugar measurements were normal, as were adrenal and thyroid function studies. The frequency of seizures increased in spite of treatment with anticonvulsants; in a four-week period, 15 to 16 months after starting the medication dissolved in the propylene glycol, the patient had seven such episodes. The electroencephalogram was abnormal with high amplitude. sharp wave activity indicating increased cerebral irritability.
512
The Journal ojPEDIATRlCS
Urinary excretion ofprostaglandin E following the administration offurosemide and indomethacin to sick low-birth-weight infants Urinary excretion ofprostaglandin E was measured in seven sick low-birth-weight infants. Four had 'severe hyaline membrane disease and aile had chronic bronchopulmonary dysplasia; all received furosemide. Two infants had patent ductus arteriosus and received indomethacin. Following administration offurosemide, ill'ine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4
± 0.04 to 1.3 ± 0.2 ng/mg Cr (mean ± SEM)
following administration offurosemide, hilt decreased in two patients following administration of indomethacin. The present results demonstrate that furosemide enhances urinary excretion of prostaglandin E by mechanisms which may reflect an increase in prostaglandin synthesis, a decrease in prostaglandin renal metabolism, or both. Indomethacin, which is a prostaglandin synthetase inhibitor. decreases the urinary excretion of prostaglandin E. These observations suggest that furosemide therapy in patients receiving indomethacin may he ineffective.
Zvl Friedman, 1\1.0., F.R.C.P.(C),* Laurence M. Demers, Ph.D., Keith H. Marks, M.B., M.R.C.P., F.C.P. (SA), Susan Uhrmann, M.D., and M. Jeffrey Maisels, M.B., B.Ch., Hershey, Pa.
PROSTAGLANDIN E is associated with marked alterations in urinary flow rate and the excretion of sodium.':" Diuresis and natriuresis have been observed after stimulation of endogenous secretion of prostaglandins by their precursor, arachidonic acid;' as well as after the infusion of exogenous prostaglandins in animals and in man.":" Indomethacin, which is a prostaglandin synthetase inhibitor, reduces the degree of natriuresis produced by furosemide,' suggesting that the furosemide effect might be mediated by renal prostaglandin. Recently, an increase in urinary prostaglandin E excretion was demonstrated following administration of furosemide to man." Furosemide and indomethacin are commonly used drugs in the management of sick, low-birth-weight infants
From the Division of Newborn Medicine, Department of Pediatrics and the Department of Pathology, The Milton S, Hershey Medical Center, The PennsyZ,'ania State University College of Medicine. Supported by a National Institute of Child and Human Development Grant ROI HOI1255-01. •Reprint address: Department of Pediatrics. The Milton S. Hershey Medlco! Center, Hershey, PA 17033.
Vol. 93, No.3, pp. 512-515
with hyaline membrane disease" and patent ductus arteriosus." In order to evaluate their effect on renal prostaglandin metabolism in sick infants, we measured the urinary excretion of prostaglandin E before and after the administration of these drugs. Our study demonstrated an increase in the urinary excretion of prostaglandin E following administration of furosemide and a decrease in the urinary excretion of prostaglandin E following administration of indomethacin. Abbreviations used HMO: hyaline membrane disease POA: patent ductus arteriosus
SUBJECT AND METHODS Patients. Seven low-birth-weight infants with weights appropriate for their gestation were selected for study. These patients were cared for by the staff of the Newborn Intensive Care Unit at The Milton S. Hershey Medical Center. Informed consent for these studies was obtained from the parents of each child after being approved by the Clinical Investigation Committee of The MSHMC. The 0022-3476178/0393-0512$00.40/0
e
1978 The C. V. Mosby Co.
Urinary excretion ofprostaglandin E
Volume 93 Number 3
5 13
Table. Th e effects of fu rosemide and indo me thaci n administration on urinary volume and sod iu m and calcium excretion in the study groups Age at
Patients
Urine volume ml/kg! 24 hr
Gestational age at birth (wk}
Birth weight (gm)
Sex
Diagnosis
lim e of study (day )
32 35 33 36 32
1,640 2,010 1,460 1,950 1,700
M M F M F
HM O H MO H MO HMO, capo HMO
2 2 3 23 3
58 36 47
30 28
1,230 1,260
F M
POA POA
15 13
37 90
Group I A.S.
N.E. PA R .T. J.Se. Group II S.S. T.B.
Before
I
Sodium (meq/t}
After
Bef ore
102 201 104
16.5 13 .0 26.5
NS NS
I
Calcium mgldl
After
Before
57.5 82.0 67.0
1.35 0.85 0.65
NS NS 27 58
76.5 16.5
I
Aft er
2.35 4.03 1.12
NS NS 67.0 14.0
0.75 0.65
0.80 0.60
Abbreviations used : HM O = Hyalin e membrane disease; CBPO = chron ic bronchopulmonary dyspl asia: POA = patent ductus arteriosus; NS = studies not available.
p atients were divided into two groups: Grou p I consisted of four infants with HM D and on e with chro nic bronchopulmonary dysplasia. Group II included two infants who had PDA and congestive he art failure . The clinical data for the study group are shown in the Table. Fur osemide in a dose of 2.0 mg/kg was administered over thre e to five minutes to the infants in Group I in order to try to improve their pulmonary gas exchange ." Indomethacin was administe red via a nasogastric tube to the two infants with PDA in a dose of 0.15 mg/kg and 0.3 rug/kg, respectively, in an attempt to achi eve pharmacologic closure of the PDA.'o One of these infants received furosemide (2 rng/kg intravenously) 8 hours prior to administratio n of indomethacin . Urine was collected using U-bags (Hollister, Inc., Ch icago, Ill.) for 24 hours prior to an d follo wing the administration of the drugs, kep t frozen a t -20°C, and analyzed for sodium (by flame photometry), calcium (by atomic absorption), creatinine (by Jaffe reaction), and for prostaglandin E by rad ioimmunoassay as previously described." Prostaglandin radio immunoassays were performed with the use of antiserum prepared in rabbits against the alb umin conjugate of prostaglandin E, . Crossreactivity st udies with th e prostaglandin E antiserum indicated 100% cross-reactivity with prostaglandin E" 70% cross-reactivity with prostaglandin Eo , 9% crossreactivity with prostaglandin A" 1% cross-reactivity with prostaglandin AOl 0.4% cross-reactivity with prostaglandin B" 1.5% cross -reactivity with prostaglandin F ,«, and less than 1% cross-reactivity with other related prostaglandin compounds, including the 13,14 dihydro, 15 keto prosta glandin E metabolite.
R E S ULTS Urinary prostaglandin E. The changes in urinary excretion of prostaglan din E are shown in the Figure. An
increase in the urinary excretion of prostaglandin E in Group I infants from 0.40 ± 0.04 to 1.3 ± 0.20 ng/mg Cr (mean ± SEM) is evident following administration of furosemide. A decrease in the urinary excretion of prostaglandin E is seen following administration of indomethacin. No differences in prostaglandin E excretion were noted between the sexes. Urinary volume and excretion of sodium and calcium. The changes in urine volume and urinary excretion of sodium and calcium are shown in the Table. Following administration of furosemide there was a dramatic increase in urine volume and in the excretion of sodium and calcium. Following administration of indomethacin, a decrease in urine volume was noted but no changes in the excretion of sodium and calcium were observed.
DI SCUSSIO N As we have previously shown, sick low-bir th-weight infants respond to administration of fur osemide with diuresis, natriuresis, and calciuria.· Prostaglandin E excretion was also increased following furosemide administration, but this phenomenon was abolished by indomethacin, which is a. prostaglandin synthetase inhibitor . In contrast to the majority of other tissues, there is an anatomic separation of those areas in the kidney responsible for prostaglandin synthesis (the papilla and the medulla) from those responsible for meta bolism (the cortical area). This arrangement re quires that prostaglandins be metabolized in cells other than those responsible for their synthesis.'>" The transit of prostaglandins from sites of synthesis into the urine, and to sites of cortical inactivation or into the venous or lymphatic circulation , has not been thoroughly defined. However, the urinary prostaglandins arise from de novo renal prostaglandin synthesis rather than from extrarenal sites . This was suggested by the observa tion that prostaglandin metabo-
514
Friedman et al.
The Journal of Pediatrics September 1978
URINARY EXCRETION OF PGE
dramatically lowers aldosterone and plasma renin activity
in human volunteers.
C I
2.0
CONTROL INDOMETHACIN F FUROSEM IDE • MALE o FEMALE
Furosemide and indomethacin are frequently administered to low-birth-weight infants who have respiratory distress or symptomatic PDA. Because of the central role of these drugs in affecting renal prostaglandins and the renin-angiotensin-aldosterone axis, and the known immaturity of renal function in low-birth-weight infants," further studies are necessary for better understanding the mechanism of the action of furosemide in this group of infants. Our studies suggest that the use of furosemide in infants with a symptomatic PDA may be ineffective after administration of indomethacin. Moreover, this detrimental effect of indomethacin may be prolonged, depending on the capabilities for indomethacin disposition in this group. of sick infants."
1.5
.
u
..
E ...... c:
1.0
0.5
\
oL-_-'-_--JL-_...J...._----'-_ _..J.-_-..l C
C
F
Figure. Changes of urinary excretion of prostaglandin E in five sick low-birth-weight infants before (C) and after (F) the administration of furosemide, and in two sick low-birth-weight infants before (C) and after (F) administration of indomethacin.
lites and not intact primary prostaglandins are found in the urine following parenteral administration.' I Increases in urinary flow rate and excretion of sodium are associated with the administration of prostaglandins.':" Diuresis and natriuresis have been observed following stimulation of endogenous prostaglandin secretion by its precursor fatty acid, arachidonic. acid! These effects have been confirmed in man," Alterations in these renal functions could result from changes attributable to the influence of prostaglandins on renal hemodynamics or by direct tubular epithelial effects. '" Recent reports indicate that administration of furosemide to healthy human volunteers results in a significant increase in the urinary excretion of prostaglandin E as well as in diuresis, natriuresis, and increase in plasma renin activity,' findings which are similar to those of our study. Moreover, indomethacin reduces the degree of natriuresis and affects the rise in plasma renin activity when administered following furosemide in man.': iu Patient S. S. (Group II), who received furosemide prior to administration of indomethacin, falls into this category. These observations suggest that furosemide's mechanism of action could be mediated by stimulation of intrarenal prostaglandin synthesis. In contrast, Tan and Mulrow" were unable to detect significant changes in urinary prostaglandin E, excretion in response to administration of furosemide, but demonstrated that indomethacin
We acknowledge the editorial assistance of Dr. Nicholas M, Nelson and the help of the residents and nurses of the Neonatal Intensive Care Unit. REFERENCES 1. Johnston HH, Herzog JP, and Lauler DP: Effect of prostaglandin E, on renal hemodynamics, sodium and water excretion, Am J Physiol 213:939, 1967. 2. Vander AJ: Direct effects of prostaglandin on renal function and renin release in anesthetized dog, Am J Physiol 214:218, 1968, 3, Lee JB: Natriuretic hormone and the renal prostaglandins, Prostaglandins 1:55, 1972. 4. Tannenbaum J, Slawinski JA, Oates JA, et al: Enhanced renal prostaglandin production in the dog. I. Effects on renal function, Circ Res 36:197, 1975. 5, Fujimoto S, and Lockett MF: The diuretic actions of prostaglandin E, and of noradrenaline, and the occurrence of a prostaglandin E,-like substance in the renal lymph of cats, J Physiol (London) 208:!, 1970. 6. Fichman M, and Horton R: Significance of the effects of prostaglandins on renal and adrenal function in man, Prostaglandins 3:629, 1973. 7. Patak RV. Mookerjie BK. Bentzel CJ, et al: Antagonism of the effects of furosemide by indomethacin in normal and hypertensive man, Prostaglandins 10:649, 1975. 8. Abe K, Yasujima M, Chiba S, et al: Effectof furosemide on urinary excretion of prostaglandin E in normal volunteers and patients with essential hypertension, Prostaglandins 14:513, 1977. 9. Marks KH, Berman W Jr, Friedman Z, et al: Furosemide in hyaline membrane disease, Pediatr Res 11:575, 1977. 10. Heymann MA, Rudolph AM, and Silverman NH: Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis, N Engl J Med 295:530. 1976. 11. Demers LM, and Gabbe SO: Placental prostaglandin levels in preeclampsia, Am J Obstet Gynecol 126:137, 1976, 12. Larson C, and Anggard E: Regional differences in the formation and metabolism of prostaglandins in the rabbit kidney, Em J Phnrmacol 21:30, 1973, 13. Friedman Z, and Demers L: Prostaglandin synthesis in human neonatal kidney, Pediatr Res 12:394, 1978, 14. Hamberg M, and Samuelsson B: On the metabolism of
Urinary excretion ofprostaglandin E
Volume 93 Number 3
prostaglandins E, and E. in man, J Biol Chern 246:6713, 1971. 15. Gross JB, and Bartter FC: Effect of prostaglandins E1> Al and F,a on renal handling of salt and water, Am J Physiol 225:218, 1973. 16. Frolich JC, Hollifield J, Wilkinson G, and Oates J: Effect of indomethacin on furosemide stimulated renin and sodium excretion. Circulation 52 (Supple IT):99, 1975.
515
17. Tan SY, and Mulrow PJ: Inhibition of the renin-aldosterone response to furosemide by indomethacin, J Clin Endocrinol Metab 45:174, 1977. 18. Siegel SR, and Oh W: Renal function as a marker of human fetal maturation. Acta Pediatr Scand 65:481, 1976. 19. Friedman Z. Whitman Y, Maisels MJ, et al: Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants, J Clin Pharmacol (in press).
Brief clinical and laboratory observations Central nervous system toxicity associated with ingestion ofpropylene glycol Karunyan Arulanantharn, M.B., D.C.H.," and Myron Genel, M.D., New Haven, Conn.
PROPYLENE GLYCOL, a polyalcohol, is widely used as a solvent in the preparation of oral and injectable drugs,
cosmetics, lotions, and ointments. It is generally considered to be a stable, pharmacologically inert substance with low systemic toxicity.':" However, a published report has attributed acute toxic symptoms to the ingestion of propylene glycol which was used as the solvent for medication.' We report the clinical course of a patient who developed seizures associated with the long-term ingestion of medication with propylene glycol as its cosolvent. These episodes remitted when the ingestion of propylene glycol was discontinued. CASE REPORT
The patient, an II-year-old Puerto Rican boy, had manifestations of the candidiasis-endocrinopathy syndrome with hypoparathyroidism, chronic mucocutaneous candidiasis, alopecia total is, and intestinal malabsorption. Treatment of hypoparathyroidism with an oral vitamin D preparation and supplemental oral calcium was not effective in maintaining an eucalcemic state, From the Department of Pediatrics, Yale University School of Medicine. Supported in part by Clinical Research Center Grant RR-125 from the GCRC Branch. Division of Research Resources. National Lnstitutes oj Health. • Reprint address: Research Department. Newington Children's Hospital. Newington, CT 06111.
0022-3476/78/0393-0515$00.20/0 e 1978 The C. V. Mosby Co.
possibly due to poor absorption of the fat soluble vitamin D. In order to overcome this problem, a preparation of vitamin 0 in the form of dihydrotachysterol was made using propylene glycol, a water miscible substance, as the vehicle. The solution was prepared as follows: 1 gm of DHT was dissolved in 20 rnl of absolute alcohol with propylene glycol USP added to make the concentration of DHT 1 mg/rnl. With the use of 2 to 4 ml twice daily and oral calcium supplement, the serum calcium returned to normal. The patient was also maintained on a low-fat diet with oral medium-chain triglyceride added. Abbreviations used DHT: dihydrotachysterol CNS: central nervous system Thirteen months after beginning treatment with the new preparation of DHT, the patient developed repeated seizures. These grand mal seizures were followed by a period of unconsciousness lasting 20 to 30 minutes from which there was spontaneous recovery. These episodes often occurred two to four hours after the evening dose of DHT. On repeated occasions the serum calcium, magnesium, electrolytes, and blood sugar measurements were normal, as were adrenal and thyroid function studies. The frequency of seizures increased in spite of treatment with anticonvulsants; in a four-week period, 15 to 16 months after starting the medication dissolved in the propylene glycol, the patient had seven such episodes. The electroencephalogram was abnormal with high amplitude. sharp wave activity indicating increased cerebral irritability.