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Acyclovir in human breast milk
Ho Yuen
6. Pahuja DN, DeLuca H. Stimulation of intestinal calcium transport and bone calcium mobilization by prolactin in vitamin D-deficient rats. Science 1981;214:1038-9. 7. Malven PV. Prolactin and other protein hormones in milk. J Anim Sci 1977;46:609-16. 8. Healy DL, Rattigan S, Hartmann PE, Herington AC, Burger HG. Prolactin in human milk: correlation with lactose, total protein, and a-lactalbumin levels. Am] Physiol I 980;238:E83-6. 9. Taketani Y, Mizuno M. Studies on prolactin in human milk. Endocrinol Jpn 1985;32:837-44. 10. Ho Yuen B. Immunoreactive prolactin in breast milk and plasma of women with hyperprolactinemia, galactorrhea and menstrual dysfunction. Int] Fertil 1986;31:67-70. 11. Lucas A, Gibbs .JAH, Lyster RLJ, Baum JD. Creamatocrit:
March 1988 Am J Obstet Gynecol
12. 13. 14. 15.
simple clinical technique for estimating fat concentration and energy value of human milk. Br Med .J 1978; 1: 1018-20. Djiane .J, Durand P, Kelly PA. Evolution of prolactin receptors in mammary gland during pregnancy and lactation. Endocrinology 1977; 100: 1348-56. Falconer IR, Rowe JM. Effect of prolactin on sodium and potassium concentrations in mammary alveolar tissue. Endocrinology 1977; 101: 181-6. Nolin .JM. Target cell prolactin. In: McKerns KW, ed. Structure and function of the gonadotropins. New York: Plenum Publishing Corp, 1978: 151-82. Baram T, Koch Y, Hazum E, Fridkin M. Gonadotropinreleasing hormone in milk. Science 1977; 198:300-2.
Acyclovir in human breast milk Laurence J. Meyer, PhD, MD: Paulo de Miranda, PhD," Nitin Sheth, PhD,c.d and Spotswood Spruance, MD"'< Salt Lake City, Utah, and Research Triangle Park, _North Carolina Acyclovir concentration was measured by radioimmunoassay in the serum and milk of a lactating woman who was treated with oral acyclovir for herpes zoster. Daily serum and milk samples showing milk concentrations that averaged being 3.24-fold higher than serum levels suggest a low infant dose. The elimination phase demonstrated a half-life of 2.8 hours in milk. (AM J OssTET GYNECOL 1988;158:586-8.)
Key words: Acyclovir, breast milk, pharmacokinetics
Although the pharmacokinetics of acyclovir in adults are well described, no published information on the excretion in human breast milk is available. Knowledge of a drug's excretion in human milk is essential for predicting the dose to a nursing infant and for counseling nursing mothers. Acyclovir is effective, administered both intravenously and orally, in treating herpes zoster infections in nonimmunocompromised hosts, and its use is expected to increase. We have analyzed serum and breast milk acyclovir concentrations in a woman treated with oral acyclovir for herpes zoster.
Case report The patient, a 31-year-old white woman, gravida 2, para 2, sought a physician's advice about a left arm
From the Division of Dermatology," Department of Internal Medicine, University of Utah School of Medicine; Burroughs Wei/come Co.,' Research Triangle Park; the Division of Infectious Disease,'·' Department of Internal Medicine, University of Utah School of Medicine; the Department of Pharmaceutics! College of Pharmacy, University of Utah. Received for publication March 27, 1987; revised July 13, 1987; accepted August 11, 1987. ReprinL5 not available.
586
Table I. Acyclovir concentrations in paired daily serum and milk specimens Acyclovir concentration (µ,glml) Day
Time after last dose (hr)
Milk
1 2 4 5
0.75* 5.0 4.25 5.5
1.26 0.78 1.07 1.06
I
Serum
0.16 0.92 0.23 0.33
*Sample taken 6 hours after previous dose.
neuralgia. She was I year post partum. She had had chickenpox at 4 years of age, had no chronic medical problems, took no medications, and had no known allergies. Renal and hepatic functions were normal. Four days after the onset of the neuralgia, vesicles on an erythematous base developed on the left inner arm, anterior chest, and hand (dermatomes C6 to T3). Herpes zoster was diagnosed on clinical grounds, and a 5-day course of acyclovir, 200 mg orally five times a day, was prescribed. Milk and serum specimens were obtained to determine the relative concentrations of acyclovir in serum
Acyclovir in human breast milk 587
Volume 1!'>8 Number 3, Part I
z
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a: - o.5 > 0
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>-
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0
8
16
32
24
40
48
TIME AFTER LAST DOSE (HRS) Fig. I. Acyclovir concentration in serum (•) and breast milk (0) after final dose.
and simultaneously expressed milk and to determine the acyclovir half-life in milk during the elimination phase. A sample of whole blood (10 ml) was collected in uncoated tubes and allowed to clot. Serum was separated and stored at - 20° C until analyzed. Breast milk (0.5 to 2 ml) was also stored at - 20° C. No estimate of total breast milk production was available. Acyclovir was assayed by radioimmunoassay as previously described.'
2.0
x 1.0
z
0 I-
a:
Acyclovir concentration in immediate predose serum and simultaneous breast milk specimens are shown in Table I. The average concentration in serum was 0.33 µg/ml, and the average concentration in milk was 1.06 µg/ml, giving a ratio of 3.24. The profile of acyclovir elimination from serum and breast milk after the final dose is shown in Fig. 1. Fig. 2 shows a semilogarithmic plot of the elimination of acyclovir in breast milk over a period of 24 hours. This demonstrates first-order elimination with a halflife of 2.8 hours. The reason for detectable amounts of acyclovir found in 48-hour samples of both serum and milk is unknown.
Comment Factors influencing the excretion of a drug into breast milk include maternal metabolism, degree of protein binding, lipid solubility, and degree of ionization in milk and plasma.2 Acyclovir is well distributed in tissues, has low protein binding, and therefore might be expected to be concentrated in breast milk. The average ratio of milk to serum concentration during acyclovir administration was 3.24, which is m agreement with this prediction. Except for day 2, all milk speci-
x
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(.)
Results
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12
16
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TIME AFTER LAST DOSE
mens tested had higher levels than paired serum specimens. The hypothetical dose consumed by a nursing baby can be crudely estimated from these concentrations in milk. An average breast milk concentration of 1.06 µg/ml, multiplied by an estimated L/day milk production and consumption, gives a dose of approximately I mg/day.
Meyer et al.
These data suggest that the amount of acyclovir to which an infant would be exposed through the consumption of breast milk from a mother taking the oral drug is low, < 1 mg/day. However, no guidelines are available for the use of oral acyclovir in infants and young children. The use of oral acyclovir in nursing mothers is of low theoretical risk provided the infant has normal renal function.
March 1988 Am J Obstet Gynecol
REFERENCES I. Quinn RP, de Miranda P, Gerald L, Good SS. A sensitive radioimmunoassay for the antiviral agent BW 248U [9-(2-hydroxyethoxymethyl)guanine]. Anal Biochem 1979; 98:319-28. 2. Wilson JT, Brown RD, Cherek DR. Drug excretion in human breast milk. Principles, pharcokinetics, and projected consequences. Clin Pharmacokinet 1980;5: I.
Asymptomatic shedding of herpesvirus during labor Joan W. Simkovich, MD, Commander, MC, USN, and David E. Soper, MD Portsmouth, Virginia Cervical cultures of 2013 consecutive obstetric patients with no history of genital herpes simplex virus infection were used to determine the frequency of asymptomatic herpes simplex virus shedding in labor. Four (0.20%) of these patients had positive cultures. None of the exposed neonates developed clinical evidence of herpetic infection. (AM J 0BSTET GvNECOt 1988;158:588-9.)
Key words: Herpesvirus, labor Neonatal herpes is a disease associated with high rates of morbidity and mortality. Millions of dollars are being spent on prenatal screening programs in an attempt to identify the patient at risk for transmitting the virus to her infant during labor and delivery. The significance of asymptomatic shedding is still uncertain. Having embarked on a standard-of-care surveillance program, we became interested in determining the rate of asymptomatic herpesvirus shedding in a low-risk obstetric population during labor. Between July 1, 1984, and February 28, 1985, cervical cultures were obtained in 2013 obstetric patients at the time they presented in labor at Portsmouth Naval Hospital. Patients with a history of genital herpes and those with obvious herpetic lesions were excluded. A single cotton swab of the endocervix, ectocervix, and upper vagina was placed in Eagle's basal medium supplemented with Earle's salts, L-glutamine, 2% fetal bovine serum, penicillin, gentamicin, and amphotericin. The sample was stored at 4° C for a maximum of 12 hours. The medium was then inoculated into tissue culture tubes containing human diploid embryonic lung fibro-
From the Department of Obstetrics and Gynecology, Naval Hospital. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department of the Department of Defense. Received for publication March 2, 1987; revised August JO, 1987; accepted September 14, 1987. Reprint requesL1: D. E. Soper, MD, Box 34, Medical College of Virginia Station, Richmond, VA 23298.
588
Table I. Prevalence of asymptomatic herpes simplex virus in labor Positive Study
N
n
%
Tejani et al.' Hankins et al.2 Arvin et al.' Present study
1094 502 311 * 2013
I
1 3 4
0.09 0.20 0.96 0.20
*All patients had a history of recurrent genital herpes simplex virus infection.
blast cells of the Medical Research Council-5 strain. Cultures were reviewed every other day for 9 days for the presence of cytopathologic effect. If no cytopathologic effect was demonstrated by day 9, the culture was considered negative. Patients were contacted when a positive culture was noted, and the clinical significance of this finding was discussed with them. Cultures of the neonate were done, and the infant was followed up closely for the onset of signs or symptoms suggestive of herpes simplex viral infection. Four (0.20%) of the 2013 herpes cultures obtained in labor were positive. At the time of the culture all four patients had unruptured membranes. The subsequent lengths of time from rupture of the fetal membranes to delivery were 25 minutes, 41 minutes, 3 hours, and 7 hours. All neonates had negative cultures and none developed neonatal herpes. They were followed up for approximately 6 months to 1 year.
6. Pahuja DN, DeLuca H. Stimulation of intestinal calcium transport and bone calcium mobilization by prolactin in vitamin D-deficient rats. Science 1981;214:1038-9. 7. Malven PV. Prolactin and other protein hormones in milk. J Anim Sci 1977;46:609-16. 8. Healy DL, Rattigan S, Hartmann PE, Herington AC, Burger HG. Prolactin in human milk: correlation with lactose, total protein, and a-lactalbumin levels. Am] Physiol I 980;238:E83-6. 9. Taketani Y, Mizuno M. Studies on prolactin in human milk. Endocrinol Jpn 1985;32:837-44. 10. Ho Yuen B. Immunoreactive prolactin in breast milk and plasma of women with hyperprolactinemia, galactorrhea and menstrual dysfunction. Int] Fertil 1986;31:67-70. 11. Lucas A, Gibbs .JAH, Lyster RLJ, Baum JD. Creamatocrit:
March 1988 Am J Obstet Gynecol
12. 13. 14. 15.
simple clinical technique for estimating fat concentration and energy value of human milk. Br Med .J 1978; 1: 1018-20. Djiane .J, Durand P, Kelly PA. Evolution of prolactin receptors in mammary gland during pregnancy and lactation. Endocrinology 1977; 100: 1348-56. Falconer IR, Rowe JM. Effect of prolactin on sodium and potassium concentrations in mammary alveolar tissue. Endocrinology 1977; 101: 181-6. Nolin .JM. Target cell prolactin. In: McKerns KW, ed. Structure and function of the gonadotropins. New York: Plenum Publishing Corp, 1978: 151-82. Baram T, Koch Y, Hazum E, Fridkin M. Gonadotropinreleasing hormone in milk. Science 1977; 198:300-2.
Acyclovir in human breast milk Laurence J. Meyer, PhD, MD: Paulo de Miranda, PhD," Nitin Sheth, PhD,c.d and Spotswood Spruance, MD"'< Salt Lake City, Utah, and Research Triangle Park, _North Carolina Acyclovir concentration was measured by radioimmunoassay in the serum and milk of a lactating woman who was treated with oral acyclovir for herpes zoster. Daily serum and milk samples showing milk concentrations that averaged being 3.24-fold higher than serum levels suggest a low infant dose. The elimination phase demonstrated a half-life of 2.8 hours in milk. (AM J OssTET GYNECOL 1988;158:586-8.)
Key words: Acyclovir, breast milk, pharmacokinetics
Although the pharmacokinetics of acyclovir in adults are well described, no published information on the excretion in human breast milk is available. Knowledge of a drug's excretion in human milk is essential for predicting the dose to a nursing infant and for counseling nursing mothers. Acyclovir is effective, administered both intravenously and orally, in treating herpes zoster infections in nonimmunocompromised hosts, and its use is expected to increase. We have analyzed serum and breast milk acyclovir concentrations in a woman treated with oral acyclovir for herpes zoster.
Case report The patient, a 31-year-old white woman, gravida 2, para 2, sought a physician's advice about a left arm
From the Division of Dermatology," Department of Internal Medicine, University of Utah School of Medicine; Burroughs Wei/come Co.,' Research Triangle Park; the Division of Infectious Disease,'·' Department of Internal Medicine, University of Utah School of Medicine; the Department of Pharmaceutics! College of Pharmacy, University of Utah. Received for publication March 27, 1987; revised July 13, 1987; accepted August 11, 1987. ReprinL5 not available.
586
Table I. Acyclovir concentrations in paired daily serum and milk specimens Acyclovir concentration (µ,glml) Day
Time after last dose (hr)
Milk
1 2 4 5
0.75* 5.0 4.25 5.5
1.26 0.78 1.07 1.06
I
Serum
0.16 0.92 0.23 0.33
*Sample taken 6 hours after previous dose.
neuralgia. She was I year post partum. She had had chickenpox at 4 years of age, had no chronic medical problems, took no medications, and had no known allergies. Renal and hepatic functions were normal. Four days after the onset of the neuralgia, vesicles on an erythematous base developed on the left inner arm, anterior chest, and hand (dermatomes C6 to T3). Herpes zoster was diagnosed on clinical grounds, and a 5-day course of acyclovir, 200 mg orally five times a day, was prescribed. Milk and serum specimens were obtained to determine the relative concentrations of acyclovir in serum
Acyclovir in human breast milk 587
Volume 1!'>8 Number 3, Part I
z
1.5
0
I<(
a: 1z w (.)
z
::::
1.0
E
o ......
(.) c> ~
a: - o.5 > 0
_J (.)
>-
(.)
<(
0
8
16
32
24
40
48
TIME AFTER LAST DOSE (HRS) Fig. I. Acyclovir concentration in serum (•) and breast milk (0) after final dose.
and simultaneously expressed milk and to determine the acyclovir half-life in milk during the elimination phase. A sample of whole blood (10 ml) was collected in uncoated tubes and allowed to clot. Serum was separated and stored at - 20° C until analyzed. Breast milk (0.5 to 2 ml) was also stored at - 20° C. No estimate of total breast milk production was available. Acyclovir was assayed by radioimmunoassay as previously described.'
2.0
x 1.0
z
0 I-
a:
Acyclovir concentration in immediate predose serum and simultaneous breast milk specimens are shown in Table I. The average concentration in serum was 0.33 µg/ml, and the average concentration in milk was 1.06 µg/ml, giving a ratio of 3.24. The profile of acyclovir elimination from serum and breast milk after the final dose is shown in Fig. 1. Fig. 2 shows a semilogarithmic plot of the elimination of acyclovir in breast milk over a period of 24 hours. This demonstrates first-order elimination with a halflife of 2.8 hours. The reason for detectable amounts of acyclovir found in 48-hour samples of both serum and milk is unknown.
Comment Factors influencing the excretion of a drug into breast milk include maternal metabolism, degree of protein binding, lipid solubility, and degree of ionization in milk and plasma.2 Acyclovir is well distributed in tissues, has low protein binding, and therefore might be expected to be concentrated in breast milk. The average ratio of milk to serum concentration during acyclovir administration was 3.24, which is m agreement with this prediction. Except for day 2, all milk speci-
x
I-
z
w
(.)
Results
0.5
<(
z
::::
E
O'-
(.)
c>
~
a: -
0.1
> 0 _J (.)
>-
(.)
<(
f
0 :c
4
8
12
16
20
24
TIME AFTER LAST DOSE
mens tested had higher levels than paired serum specimens. The hypothetical dose consumed by a nursing baby can be crudely estimated from these concentrations in milk. An average breast milk concentration of 1.06 µg/ml, multiplied by an estimated L/day milk production and consumption, gives a dose of approximately I mg/day.
Meyer et al.
These data suggest that the amount of acyclovir to which an infant would be exposed through the consumption of breast milk from a mother taking the oral drug is low, < 1 mg/day. However, no guidelines are available for the use of oral acyclovir in infants and young children. The use of oral acyclovir in nursing mothers is of low theoretical risk provided the infant has normal renal function.
March 1988 Am J Obstet Gynecol
REFERENCES I. Quinn RP, de Miranda P, Gerald L, Good SS. A sensitive radioimmunoassay for the antiviral agent BW 248U [9-(2-hydroxyethoxymethyl)guanine]. Anal Biochem 1979; 98:319-28. 2. Wilson JT, Brown RD, Cherek DR. Drug excretion in human breast milk. Principles, pharcokinetics, and projected consequences. Clin Pharmacokinet 1980;5: I.
Asymptomatic shedding of herpesvirus during labor Joan W. Simkovich, MD, Commander, MC, USN, and David E. Soper, MD Portsmouth, Virginia Cervical cultures of 2013 consecutive obstetric patients with no history of genital herpes simplex virus infection were used to determine the frequency of asymptomatic herpes simplex virus shedding in labor. Four (0.20%) of these patients had positive cultures. None of the exposed neonates developed clinical evidence of herpetic infection. (AM J 0BSTET GvNECOt 1988;158:588-9.)
Key words: Herpesvirus, labor Neonatal herpes is a disease associated with high rates of morbidity and mortality. Millions of dollars are being spent on prenatal screening programs in an attempt to identify the patient at risk for transmitting the virus to her infant during labor and delivery. The significance of asymptomatic shedding is still uncertain. Having embarked on a standard-of-care surveillance program, we became interested in determining the rate of asymptomatic herpesvirus shedding in a low-risk obstetric population during labor. Between July 1, 1984, and February 28, 1985, cervical cultures were obtained in 2013 obstetric patients at the time they presented in labor at Portsmouth Naval Hospital. Patients with a history of genital herpes and those with obvious herpetic lesions were excluded. A single cotton swab of the endocervix, ectocervix, and upper vagina was placed in Eagle's basal medium supplemented with Earle's salts, L-glutamine, 2% fetal bovine serum, penicillin, gentamicin, and amphotericin. The sample was stored at 4° C for a maximum of 12 hours. The medium was then inoculated into tissue culture tubes containing human diploid embryonic lung fibro-
From the Department of Obstetrics and Gynecology, Naval Hospital. The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department of the Department of Defense. Received for publication March 2, 1987; revised August JO, 1987; accepted September 14, 1987. Reprint requesL1: D. E. Soper, MD, Box 34, Medical College of Virginia Station, Richmond, VA 23298.
588
Table I. Prevalence of asymptomatic herpes simplex virus in labor Positive Study
N
n
%
Tejani et al.' Hankins et al.2 Arvin et al.' Present study
1094 502 311 * 2013
I
1 3 4
0.09 0.20 0.96 0.20
*All patients had a history of recurrent genital herpes simplex virus infection.
blast cells of the Medical Research Council-5 strain. Cultures were reviewed every other day for 9 days for the presence of cytopathologic effect. If no cytopathologic effect was demonstrated by day 9, the culture was considered negative. Patients were contacted when a positive culture was noted, and the clinical significance of this finding was discussed with them. Cultures of the neonate were done, and the infant was followed up closely for the onset of signs or symptoms suggestive of herpes simplex viral infection. Four (0.20%) of the 2013 herpes cultures obtained in labor were positive. At the time of the culture all four patients had unruptured membranes. The subsequent lengths of time from rupture of the fetal membranes to delivery were 25 minutes, 41 minutes, 3 hours, and 7 hours. All neonates had negative cultures and none developed neonatal herpes. They were followed up for approximately 6 months to 1 year.