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Tolmetin sodium in the management of nephrogenic diabetes insipidus
Volume 10l Number 5
sant drugs may produce a similar state of confusion, with hallucinations, disorientation, anxiety, agitation, insomnia, and exacerbation of psychosis in a few susceptible individuals. 8 Many studies have suggested that carbamazepine has beneficial psychotr0Pic actions, so it is not surprising that it may also produce occasional adverse emotional reactions. Until it is more clear which factors may predispose children to behavioral toxicity, it may be prudent to initiate therapy cautiously and at a low dose in certain patients, especially those with preexisting psychopathologic problems or retardation. Five of our seven patients were eventually able to tolerate the drug when it was reintroduced slowly. This experience suggests that if carbamazepine is needed for seizure control, a previous adverse behavioral reaction is not an absolute contraindication to another careful trial.
Clinical and laboratory observations
787
REFERENCES 1. Huf R, and Schain R: Long-term experiences with carbamazepine (Tegretol) in children with seizures, J PEDIATR97:310, 1980. 2. Wallace S: Carbamazepine in childhood seizures, Dev Med Child Neurol 20:223, 1978. 3. Johnston MV, and Freeman JM: Pharmacologic advances in seizure control Pediatr Clin North Am 28:179, 1981. 4. Dodrill CB, and Troupin AS: Psychotropic effects of carbamazepine in epilepsy: A double blind comparison with phenytoin, Neurology 27:1023, 1977. 5. Sillanpaa M: Carbamazepine: Pharmacology and clinical uses, Acta Neurol Scand [Suppl] 88:97, 1981. 6. Livingston S, Pauli LL, and Berman W: Carbamazepine (Tegretol) in epilepsy, Dis Nerv Syst 35:103, 1974. 7. Stores A: Behavioral effects of antiepileptic drugs, Dev Med Child Neurol 17:647, 1975. 8. Goodman A, and Gilman L: The pharmacologic basis of therapeutics, New York, 1980, Macmillan, Inc.
Tolmetin sodium in the management of nephrogenic diabetes
insipidus Robert L. Chevalier, M.D., and Alan D. Rogol, M.D., Ph.D., Charlottesville, Va.
NEPHROGENIC DIABETES INSIPIDUS, a congenital disorder characterized by a lack of response of the collecting duct to circulating antidiuretic hormone, is a rare but debilitating condition in the small child. The generally recommended management with sodium restriction and diuretic therapy is usually unsuccessful because compliance with the low-salt diet is poor and diuretics are often ineffective, x Recent studies of the mechanism of renal water handling have shown that prostaglandins exert an inhibitory effect on the action of vasopressin to enhance collecting duct permeability. 2 Prostaglandin synthesis inhibitors have been tested in patients with NDI, with encouraging results? 4 However, virtually all nonsteroidal anti-inflammatory drugs have significant systemic toxicity and are not recommended for use in children. This From the Departments of Pediatrics and Pharmacology, University of Virginia School of Medicine. Reprint address: Robert L. Chevalier, M.D., Department of Pediatrics, Box 386, University of Virginia Medical Center, Charlottesville, VA 22908.
0022-3476/82/110787+03500.30/0 @ 1982 The C. V. Mosby Co.
prompted us to treat a child with N D I using tolmetin sodium (Tolectin), an inhibitor of prostaglandin synthesis with proved safety in children 2 years of age and older. 6
I
NDI: cAMP:
nephrogenic diabetes insipidus cyclic adenosine monophosphate
|
]
I
CASE REPORT The patient, a 39/12-year-old white boy, was diagnosed as having NDI at 6 months of age, but showed no response to a saltrestricted diet and hydrochlorothiazide. At 29/12 years of age he was admitted to the University of Virginia Medical Center for evaluation. Physical examination revealed a thin child with a height of 80 cm (below the fifth percentile), weight of 11 kg (below the fifth percentile), weight-for-height at the tenth percentile, blood pressure of 95/50 mm Hg, and pulse 105. There were no physical abnormalities. Urinalysis revealed a specific gravity of 1.002, pH 6, negative protein and glucose, and a benign sediment. Hematocrit was 37%, and electrolyte values were sodium 139 mEq/L, potassium 3.7 mEq/L, chloride 105 mEq/L, CO2 26 mEq/L, blood urea nitrogen 9 mg/dl, creatinine 0.7 mg/dl, calcium 10.3 mg/dl, and phosphate 4.4 mg/dl. Renal sonogram
788
Clinical and laboratory observations
The Journal of Pediatrics November 1982
Table. L a b o r a t o r y data
ccr (ml/min)
UNaV
Uosm
Costa
CH20
UcAMP
Therapy
Urine volume (ml/24 hr)
(mEq/24 hr)
UPOJ~2
(mOsmlkg)
(ml/min)
(ml/min)
(gmol/24 hr)
(ng/24 hr)
No therapy HCTZ alone HCTZ and tolmetin
3,380 3,050 2,038
18 22 22
34 70 97
48 94 174
0.41 0.70 0.82
1.94 1.25 0.60
-1.2 1.4
-32.5 13.5
Abbreviations: C,r = creatinine clearance; UN,V= urine sodium excretion; Uo,m= urine osmolality, Co,~ = osmolar clearance; Ca2o = free water clearance; U~^M~= urine cyclic AMP excretion; Ur~EZ= urine prostaglandin E2 excretion; HCTZ = hydrochlorothiazide.
was normal, with no obstruction or dilatation of the collecting system except for a distended bladder. The patient was subjected to fluid deprivation for four hours with close monitoring of weight and vital signs. During this time he voided 145 ml/hour with concomitant loss of 0.7 kg and rise in serum osmolality from 277 to 291 mOsm/kg, while the urine osmolality increased from 48 to 150 mOsm/kg. Following administration of aqueous vasopressin, 5 units intramuscularly, he voided 85 ml/hour over the next four hours, while serum osmolality increased to 296 mOsm/kg with no increase in urine osmolality. The following month, the patient was subjected to fluid deprivation for seven hours, during which he voided 123 ml/hour and lost 0.9 kg with a rise in serum osmolality from 279 to 302 mOsm/kg and in urine osmolality from 33 to 70 mOsm/kg. Four hours after administration of dDAVP, 20 #g per nasum, urine output was 100 ml/hour and urine osmolality remained 71 mOsm/kg. Treatment with hydrochlorothiazide was restarted at a dose of 12.5 mg twice daily, and tolmetin sodium, 100 mg three times daily, was also given. Within 24 hours of this regimen, the patient's urine output decreased markedly and he was discharged. The patient has continued to receive these medications for the past 12 months and is now able to sleep through the night without drinking or voiding. His disposition is much improved, appetite has increased significantly, and his weight has risen to the tenth percentile (weight-for-height, seventy-fifth percentile). To evaluate the effects of tolmetin sodium, the medication was discontinued for one week while hydrochlorothiazide therapy was maintained. Within 24 hours, the urine output increased markedly and nocturia returned. This sequence was repeated four months later with similar results. Two 24-hour urine samples were obtained after tolmetin had been withheld for one week and also one week following reinstitution of the drug. The results are summarized in the Table. Serum electrolytes, and renal, hepatic, and hematologic measurements have remained within normal limits. DISCUSSION In the present patient, tolmetin therapy was associated with a reduction in urine flow, increased urine osmolality, and suppression of prostaglandin E: excretion. C u r r e n t therapy for N D I consists primarily of a sodium-restricted diet a n d a d m i n i s t r a t i o n of diuretics. 7 T r e a t m e n t with thiazide diuretics causes volume contraction and enhanced
proximal t u b u l a r sodium chloride reabsorption such t h a t less chloride is available for reabsorption in the diluting s e g m e n t ) Since volume contraction m u s t be m a i n t a i n e d in order to e n h a n c e proximal t u b u l a r reabsorption, the patient must limit salt intake if diuretic t h e r a p y is to be effective.' Thus, the relatively high sodium output of our patient (6 to 9 m E q / k g 9 day) is consistent with a large dietary sodium intake and accounts for the failure of hydrochlorothiazide therapy alone. Renal water excretion is modulated by locally synthesized prostaglandins, which have been shown to antagonize the hydro-osmotic action of vasopressin in the m a m m a l i a n k i d n e y ) T h e m e c h a n i s m of this interaction remains to be clarified, however, and m a y vary with different physiologic a n d pathologic conditions. Prostaglandin E2 m a y directly inhibit vasopressin-stimulated adenylate cyclase activity a n d water flow in isolated epithelial m e m b r a n e s or in the renal collecting duct. 8 As shown in the Table, u r i n a r y cyclic adenosine monophosphate excretion did not change following tolmetin therapy in our patient. However, total urinary c A M P production m a y not reflect the complex interactions of prostaglandins, vasopressin, a n d adenylate cyclase, as administration of i n d o m e t h a c i n ( a n o t h e r prostaglandin synthesis inhibitor) m a y result in either increased or decreased c A M P excretion in patients with N D I . 5 Furthermore, indomethacin was associated with a n increased urine osmolality in an a n i m a l model of central diabetes insipidus, suggesting a l t e r n a t e modes of action of prostaglandins. 9 It is possible t h a t by reducing renal papillary plasma flow, i n d o m e t h a c i n m a y decrease medullary solute washout and thereby increase medullary tonicityY ~ In a previous report of two b r o t h e r s with N D I , the combination of indomethacin and chlorothiazide was noted to be more efficacious t h a n the prostaglandin inhibitor alone in reducing urine output4; for this reason, hydrochlorothiazide was continued in our patient. I n d o m e t h a c i n a n d chlorothiazide caused reduced creatinine clearance in both brothers, 4 a n d indomethacin alone has been associated with a decreased creatinine clearance in two other children
Volume 101 Number 5
with N D I ? Treatment with tolmetin did not result in a reduction in creatinine clearance, such that decreased glomerular filtration rate (with secondary enhanced proximal tubular reabsorption) could not be implicated as a mechanism of reduced urine flow in our patient. In contrast to indomethacin, tolmetin has been approved for use in children and has been relatively free of clinically significant adverse effects in children treated for juvenile rheumatoid arthritis. 6 However, gastrointestinal side effects may develop, and include nausea, vomiting, diarrhea, and dyspepsia." We conclude that the beneficial effects of tolmetin in our patient warrant consideration of its use in the child with N D I who has an unsatisfactory response to diuretic therapy and sodium restriction. We thank Dr. Tomas Berl, University of Colorado Medical Center, Denver, for performing urinary prostaglandin E2 determinations in his laboratory. We are also grateful to Fern Campbell for her participation in evaluation of this patient and to Lynne Damien for her excellent secretarial assistance.
REFERENCES 1, Earley LE, and Orloff J: The mechanism of antidiuresis associated with administration of hydrochlorothiazide to patients with vasopressin-resistent diabetes insipidus, J Clin Invest 41:1988, 1962. 2. Anderson R J, Berl T, McDonald KM, and Schrier RW: Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney, J Clin Invest 56:420, 1975. 3. Fichman M, Zia P, and Zipser R: Contribution of urine
Clinical and laboratory observations
4.
5.
6.
7.
8. 9.
10.
11.
789
volume to the elevated urinary prostaglandin E in Bartter's syndrome and central and nephrogenic diabetes insipidus, in Samuelsson B, Ramwell PW, and Paoletti R, editors: Advances in prostaglandin and thromboxane research, vol 7, New York, 1980, Raven Press, p 1193. Blachar Y, Zadik Z, Shemesh M, Kaplan BS, and Levin S: The effect of inhibition of prostaglandin synthesis on free water and osmolar clearances in patients with hereditary nephrogenic diabetes insipidus, Int J Pediatr Nephrol 1:48, 1980. Usberti M, Dechaux M, Grillot M, Seligmann R, Pavlovitch H, Loirat C, Sachs C, and Broyer M: Renal prostaglandin E2 in nephrogenic diabetes insipidus: Effects of inhibition of prostaglandin synthesis by indomethacin, J PEDIATR97:476, 1980. Levison JE, Baum J, Brewer E Jr, Fink C, Hanson V, and Schaller J: Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis, J PEDIATR91:799, 1977. Nawar T, and Genest J: Non-hormonal drugs for the treatment of diabetes insipidus, Can Med Assoc J 107:1225, 1972. Zusman RM: Prostaglandins and water excretion, Ann Rev Med 32:359, 1981. Dunn M J, Kinter LB, Beeuwkes R III, Shier D, Greeley HP, and Valtin H: Interaction of vasopressin and renal prostaglandins in the homozygous diabetes insipidus rat, in Samuelsson B, Ramwell PW, and Paoletti R, editors: Advances in prostaglandin and thromboxane research, vol 7, New York, 1980, Raven Press, p 1009. Solez K, Fox JA, Miller M, and Heptinstall RH: Effects of indomethacin on renal inner medullary plasma flow, Prostaglandins 7:91, 1974. Simon LS, and Mills JA: Nonsteroidal anti-inflammatory drugs, N Engl J Med 302:1237, 1980.
Hydrochlorothiazide disposition in a mother and her breast -fed infant Marvin E. Miller, M.D., Richard D. Cohn, Ph.D., and Peter H. Burghart, M.S. Rochester, N . Y . , and Willow Grove, Pa.
HYDROCHLOROTHIAZIDE is commonly used in the treatment of hypertension. W e had the opportunity to
From the Department of Pediatrics, University of Rochester School of Medicine; and National Medical Services, Inc. Reprint address: Marvin E. Miller, M.D., Department of Pediatrics, Box 777, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, N Y 14642.
0022-3476/82/110789+03500.30/0 @ 1982 The C. V. Mosby Co.
evaluate the disposition of hydrochlorothiazide in a lactating mother and her breast-fed baby. HPLC:
high-performance liquid chromatography
CASE REPORT A 30-year-old white woman who had been taking hydrochlorothiazide for 389 years for hypertension was breast-feeding her
sant drugs may produce a similar state of confusion, with hallucinations, disorientation, anxiety, agitation, insomnia, and exacerbation of psychosis in a few susceptible individuals. 8 Many studies have suggested that carbamazepine has beneficial psychotr0Pic actions, so it is not surprising that it may also produce occasional adverse emotional reactions. Until it is more clear which factors may predispose children to behavioral toxicity, it may be prudent to initiate therapy cautiously and at a low dose in certain patients, especially those with preexisting psychopathologic problems or retardation. Five of our seven patients were eventually able to tolerate the drug when it was reintroduced slowly. This experience suggests that if carbamazepine is needed for seizure control, a previous adverse behavioral reaction is not an absolute contraindication to another careful trial.
Clinical and laboratory observations
787
REFERENCES 1. Huf R, and Schain R: Long-term experiences with carbamazepine (Tegretol) in children with seizures, J PEDIATR97:310, 1980. 2. Wallace S: Carbamazepine in childhood seizures, Dev Med Child Neurol 20:223, 1978. 3. Johnston MV, and Freeman JM: Pharmacologic advances in seizure control Pediatr Clin North Am 28:179, 1981. 4. Dodrill CB, and Troupin AS: Psychotropic effects of carbamazepine in epilepsy: A double blind comparison with phenytoin, Neurology 27:1023, 1977. 5. Sillanpaa M: Carbamazepine: Pharmacology and clinical uses, Acta Neurol Scand [Suppl] 88:97, 1981. 6. Livingston S, Pauli LL, and Berman W: Carbamazepine (Tegretol) in epilepsy, Dis Nerv Syst 35:103, 1974. 7. Stores A: Behavioral effects of antiepileptic drugs, Dev Med Child Neurol 17:647, 1975. 8. Goodman A, and Gilman L: The pharmacologic basis of therapeutics, New York, 1980, Macmillan, Inc.
Tolmetin sodium in the management of nephrogenic diabetes
insipidus Robert L. Chevalier, M.D., and Alan D. Rogol, M.D., Ph.D., Charlottesville, Va.
NEPHROGENIC DIABETES INSIPIDUS, a congenital disorder characterized by a lack of response of the collecting duct to circulating antidiuretic hormone, is a rare but debilitating condition in the small child. The generally recommended management with sodium restriction and diuretic therapy is usually unsuccessful because compliance with the low-salt diet is poor and diuretics are often ineffective, x Recent studies of the mechanism of renal water handling have shown that prostaglandins exert an inhibitory effect on the action of vasopressin to enhance collecting duct permeability. 2 Prostaglandin synthesis inhibitors have been tested in patients with NDI, with encouraging results? 4 However, virtually all nonsteroidal anti-inflammatory drugs have significant systemic toxicity and are not recommended for use in children. This From the Departments of Pediatrics and Pharmacology, University of Virginia School of Medicine. Reprint address: Robert L. Chevalier, M.D., Department of Pediatrics, Box 386, University of Virginia Medical Center, Charlottesville, VA 22908.
0022-3476/82/110787+03500.30/0 @ 1982 The C. V. Mosby Co.
prompted us to treat a child with N D I using tolmetin sodium (Tolectin), an inhibitor of prostaglandin synthesis with proved safety in children 2 years of age and older. 6
I
NDI: cAMP:
nephrogenic diabetes insipidus cyclic adenosine monophosphate
|
]
I
CASE REPORT The patient, a 39/12-year-old white boy, was diagnosed as having NDI at 6 months of age, but showed no response to a saltrestricted diet and hydrochlorothiazide. At 29/12 years of age he was admitted to the University of Virginia Medical Center for evaluation. Physical examination revealed a thin child with a height of 80 cm (below the fifth percentile), weight of 11 kg (below the fifth percentile), weight-for-height at the tenth percentile, blood pressure of 95/50 mm Hg, and pulse 105. There were no physical abnormalities. Urinalysis revealed a specific gravity of 1.002, pH 6, negative protein and glucose, and a benign sediment. Hematocrit was 37%, and electrolyte values were sodium 139 mEq/L, potassium 3.7 mEq/L, chloride 105 mEq/L, CO2 26 mEq/L, blood urea nitrogen 9 mg/dl, creatinine 0.7 mg/dl, calcium 10.3 mg/dl, and phosphate 4.4 mg/dl. Renal sonogram
788
Clinical and laboratory observations
The Journal of Pediatrics November 1982
Table. L a b o r a t o r y data
ccr (ml/min)
UNaV
Uosm
Costa
CH20
UcAMP
Therapy
Urine volume (ml/24 hr)
(mEq/24 hr)
UPOJ~2
(mOsmlkg)
(ml/min)
(ml/min)
(gmol/24 hr)
(ng/24 hr)
No therapy HCTZ alone HCTZ and tolmetin
3,380 3,050 2,038
18 22 22
34 70 97
48 94 174
0.41 0.70 0.82
1.94 1.25 0.60
-1.2 1.4
-32.5 13.5
Abbreviations: C,r = creatinine clearance; UN,V= urine sodium excretion; Uo,m= urine osmolality, Co,~ = osmolar clearance; Ca2o = free water clearance; U~^M~= urine cyclic AMP excretion; Ur~EZ= urine prostaglandin E2 excretion; HCTZ = hydrochlorothiazide.
was normal, with no obstruction or dilatation of the collecting system except for a distended bladder. The patient was subjected to fluid deprivation for four hours with close monitoring of weight and vital signs. During this time he voided 145 ml/hour with concomitant loss of 0.7 kg and rise in serum osmolality from 277 to 291 mOsm/kg, while the urine osmolality increased from 48 to 150 mOsm/kg. Following administration of aqueous vasopressin, 5 units intramuscularly, he voided 85 ml/hour over the next four hours, while serum osmolality increased to 296 mOsm/kg with no increase in urine osmolality. The following month, the patient was subjected to fluid deprivation for seven hours, during which he voided 123 ml/hour and lost 0.9 kg with a rise in serum osmolality from 279 to 302 mOsm/kg and in urine osmolality from 33 to 70 mOsm/kg. Four hours after administration of dDAVP, 20 #g per nasum, urine output was 100 ml/hour and urine osmolality remained 71 mOsm/kg. Treatment with hydrochlorothiazide was restarted at a dose of 12.5 mg twice daily, and tolmetin sodium, 100 mg three times daily, was also given. Within 24 hours of this regimen, the patient's urine output decreased markedly and he was discharged. The patient has continued to receive these medications for the past 12 months and is now able to sleep through the night without drinking or voiding. His disposition is much improved, appetite has increased significantly, and his weight has risen to the tenth percentile (weight-for-height, seventy-fifth percentile). To evaluate the effects of tolmetin sodium, the medication was discontinued for one week while hydrochlorothiazide therapy was maintained. Within 24 hours, the urine output increased markedly and nocturia returned. This sequence was repeated four months later with similar results. Two 24-hour urine samples were obtained after tolmetin had been withheld for one week and also one week following reinstitution of the drug. The results are summarized in the Table. Serum electrolytes, and renal, hepatic, and hematologic measurements have remained within normal limits. DISCUSSION In the present patient, tolmetin therapy was associated with a reduction in urine flow, increased urine osmolality, and suppression of prostaglandin E: excretion. C u r r e n t therapy for N D I consists primarily of a sodium-restricted diet a n d a d m i n i s t r a t i o n of diuretics. 7 T r e a t m e n t with thiazide diuretics causes volume contraction and enhanced
proximal t u b u l a r sodium chloride reabsorption such t h a t less chloride is available for reabsorption in the diluting s e g m e n t ) Since volume contraction m u s t be m a i n t a i n e d in order to e n h a n c e proximal t u b u l a r reabsorption, the patient must limit salt intake if diuretic t h e r a p y is to be effective.' Thus, the relatively high sodium output of our patient (6 to 9 m E q / k g 9 day) is consistent with a large dietary sodium intake and accounts for the failure of hydrochlorothiazide therapy alone. Renal water excretion is modulated by locally synthesized prostaglandins, which have been shown to antagonize the hydro-osmotic action of vasopressin in the m a m m a l i a n k i d n e y ) T h e m e c h a n i s m of this interaction remains to be clarified, however, and m a y vary with different physiologic a n d pathologic conditions. Prostaglandin E2 m a y directly inhibit vasopressin-stimulated adenylate cyclase activity a n d water flow in isolated epithelial m e m b r a n e s or in the renal collecting duct. 8 As shown in the Table, u r i n a r y cyclic adenosine monophosphate excretion did not change following tolmetin therapy in our patient. However, total urinary c A M P production m a y not reflect the complex interactions of prostaglandins, vasopressin, a n d adenylate cyclase, as administration of i n d o m e t h a c i n ( a n o t h e r prostaglandin synthesis inhibitor) m a y result in either increased or decreased c A M P excretion in patients with N D I . 5 Furthermore, indomethacin was associated with a n increased urine osmolality in an a n i m a l model of central diabetes insipidus, suggesting a l t e r n a t e modes of action of prostaglandins. 9 It is possible t h a t by reducing renal papillary plasma flow, i n d o m e t h a c i n m a y decrease medullary solute washout and thereby increase medullary tonicityY ~ In a previous report of two b r o t h e r s with N D I , the combination of indomethacin and chlorothiazide was noted to be more efficacious t h a n the prostaglandin inhibitor alone in reducing urine output4; for this reason, hydrochlorothiazide was continued in our patient. I n d o m e t h a c i n a n d chlorothiazide caused reduced creatinine clearance in both brothers, 4 a n d indomethacin alone has been associated with a decreased creatinine clearance in two other children
Volume 101 Number 5
with N D I ? Treatment with tolmetin did not result in a reduction in creatinine clearance, such that decreased glomerular filtration rate (with secondary enhanced proximal tubular reabsorption) could not be implicated as a mechanism of reduced urine flow in our patient. In contrast to indomethacin, tolmetin has been approved for use in children and has been relatively free of clinically significant adverse effects in children treated for juvenile rheumatoid arthritis. 6 However, gastrointestinal side effects may develop, and include nausea, vomiting, diarrhea, and dyspepsia." We conclude that the beneficial effects of tolmetin in our patient warrant consideration of its use in the child with N D I who has an unsatisfactory response to diuretic therapy and sodium restriction. We thank Dr. Tomas Berl, University of Colorado Medical Center, Denver, for performing urinary prostaglandin E2 determinations in his laboratory. We are also grateful to Fern Campbell for her participation in evaluation of this patient and to Lynne Damien for her excellent secretarial assistance.
REFERENCES 1, Earley LE, and Orloff J: The mechanism of antidiuresis associated with administration of hydrochlorothiazide to patients with vasopressin-resistent diabetes insipidus, J Clin Invest 41:1988, 1962. 2. Anderson R J, Berl T, McDonald KM, and Schrier RW: Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney, J Clin Invest 56:420, 1975. 3. Fichman M, Zia P, and Zipser R: Contribution of urine
Clinical and laboratory observations
4.
5.
6.
7.
8. 9.
10.
11.
789
volume to the elevated urinary prostaglandin E in Bartter's syndrome and central and nephrogenic diabetes insipidus, in Samuelsson B, Ramwell PW, and Paoletti R, editors: Advances in prostaglandin and thromboxane research, vol 7, New York, 1980, Raven Press, p 1193. Blachar Y, Zadik Z, Shemesh M, Kaplan BS, and Levin S: The effect of inhibition of prostaglandin synthesis on free water and osmolar clearances in patients with hereditary nephrogenic diabetes insipidus, Int J Pediatr Nephrol 1:48, 1980. Usberti M, Dechaux M, Grillot M, Seligmann R, Pavlovitch H, Loirat C, Sachs C, and Broyer M: Renal prostaglandin E2 in nephrogenic diabetes insipidus: Effects of inhibition of prostaglandin synthesis by indomethacin, J PEDIATR97:476, 1980. Levison JE, Baum J, Brewer E Jr, Fink C, Hanson V, and Schaller J: Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis, J PEDIATR91:799, 1977. Nawar T, and Genest J: Non-hormonal drugs for the treatment of diabetes insipidus, Can Med Assoc J 107:1225, 1972. Zusman RM: Prostaglandins and water excretion, Ann Rev Med 32:359, 1981. Dunn M J, Kinter LB, Beeuwkes R III, Shier D, Greeley HP, and Valtin H: Interaction of vasopressin and renal prostaglandins in the homozygous diabetes insipidus rat, in Samuelsson B, Ramwell PW, and Paoletti R, editors: Advances in prostaglandin and thromboxane research, vol 7, New York, 1980, Raven Press, p 1009. Solez K, Fox JA, Miller M, and Heptinstall RH: Effects of indomethacin on renal inner medullary plasma flow, Prostaglandins 7:91, 1974. Simon LS, and Mills JA: Nonsteroidal anti-inflammatory drugs, N Engl J Med 302:1237, 1980.
Hydrochlorothiazide disposition in a mother and her breast -fed infant Marvin E. Miller, M.D., Richard D. Cohn, Ph.D., and Peter H. Burghart, M.S. Rochester, N . Y . , and Willow Grove, Pa.
HYDROCHLOROTHIAZIDE is commonly used in the treatment of hypertension. W e had the opportunity to
From the Department of Pediatrics, University of Rochester School of Medicine; and National Medical Services, Inc. Reprint address: Marvin E. Miller, M.D., Department of Pediatrics, Box 777, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, N Y 14642.
0022-3476/82/110789+03500.30/0 @ 1982 The C. V. Mosby Co.
evaluate the disposition of hydrochlorothiazide in a lactating mother and her breast-fed baby. HPLC:
high-performance liquid chromatography
CASE REPORT A 30-year-old white woman who had been taking hydrochlorothiazide for 389 years for hypertension was breast-feeding her