The packagelabel states that although normaloutcomes have been reported in pregnant women, characteristiccongenital cutis laxa and associated birth defects have been reported in infants
Trang 1Chemical name: 3-Mercapto-D-valine
CAS #: 52-67-5SMILES: C(C(C)(C)S)(C(O)=O)N
INTRODUCTION
Penicillamine has therapeutic utility as an antidote for copper and lead toxicity and is used in thetreatment of Wilson’s disease and cystinuria and as an adjunct in the treatment of rheumatoidarthritis Mechanistically, penicillamine chelates with a number of heavy metals to form stable,soluble complexes that are excreted in urine It also depresses circulating IgM rheumatoid factorand T cell but not B cell activity, and it combines with cystine to form a more soluble compound,thus preventing cystine calculi (Lacy et al., 2004) The drug is available by prescription asCuprimine®, among other trade names, and it carries a pregnancy risk factor of D The packagelabel states that although normaloutcomes have been reported (in pregnant women), characteristiccongenital cutis laxa and associated birth defects have been reported in infants born of motherswho received therapy with penicillamine during pregnancy (see below; also see PDR, 2002)
DEVELOPMENTAL TOXICOLOGY
Laboratory animal studies were conducted with the drug in mice, hamsters, and rats, and it isdevelopmentally toxic in all three species Given by the oral route, mice demonstrated cleft palate,increased abortion and resorptions, and decreased fetal body weight at high doses of 3.2 g/kg whenadministered 1 or 3 days during organogenesis (Myint, 1984) Similar doses in hamsters given on
1 day during organogenesis elicited fetal death, decreased fetal body weight, malformations of thecentral nervous system, and skeletal defects of the ribs and limbs (Wiley and Joneja, 1978) In rats,penicillamine given either by oral gavage or fed in the diet during organogenesis or throughoutgestation produced malformations (palate and skeletal defects), reduced fetal body weight, andincreased resorptions in the range of 360 to 1000 mg/kg (gavage) or 0.8% and higher (diet) inseveral studies (Steffek et al., 1972; Yamada et al., 1979; Mark-Savage et al., 1981) The dosesused in these experiments were multiple those used in human therapy (see below)
NH2
O
SH HO
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Trang 246 Human Developmental Toxicants
Developmental toxicity in the humanis largely manifested as congenital malformation of theconnective tissue of the skin, as tabulated in Table 1 Six cases of this disorder, termed cutis laxa, were described Schardein (2000) described the defect in detail In the cases reported, thegeneral condition of the infants appeared normal, except for the generalized senescence of theskin, with extensive wrinkling and folding, having the appearance of too much skin for the body.However, three of the patients died in infancy Intrauterine growth retardation was recorded in
a single case, and a single case of developmental delay was reported Neither effect is considered
a significant parameter in the developmental toxicity profile of the drug Clinically, the defect isapparently reversible: In the three surviving infants, the skin returned to normalexternally within
4 months, with normal physical and neurological development in two of the cases In each ofthe six cases, doses of 750 to 2000 mg/day orally had been administered, all in at least the firsttrimester These doses are close to the recommended therapeutic drug dosage of 900 mg to
2 g/dayorally Interestingly, cutis laxa has been produced in an animal model — the rat (Hurley
et al., 1982)
Six other cases of malformations were published in the literature but are not consideredpertinent to this discussion Rosa (1986) reported brain, eye and digits, brain and limb, andlimb and digits defects among four cases known to the U.S Food and Drug Administration Asingle case of cleft lip/palate was recorded in another case report (Martinez-Frias et al., 1998).Another case, a patient with multiple malformations consisting of congenital contractures,hydrocephalus, and muscle dysfunction, was also reported (Gal and Ravenel, 1984) Thesemalformations are dissimilar from the skin disorder recognized as a teratogenic finding and arelargely dissimilar from each other; thus, they are not considered to be causally related topenicillamine administration
Approximately 90 normalinfants born of women treated during pregnancy with the drug werereported (Gregory and Mansell, 1983; Gal and Ravenel, 1984; Dupont et al., 1990; Hartard andKunze, 1994; Berghella et al., 1997; see Schardein, 2000) The apparent risk for malformationappears to be about 5% The skin defects are considered by one group of experts to have a small
to moderate teratogenic risk (Friedman and Polifka, 2000) Several reviews of penicillaminedevelopmental toxicity were published (Endres, 1981; Roubenoff et al., 1988; Domingo, 1998;Sternlieb, 2000)
CHEMISTRY
Penicillamine is a hydrophilic chemical of relatively small size It is of average polarity as compared
to the other chemicals, and it can participate in donor/acceptor hydrogen bonding interactions Itscalculated properties are as follows
Functional Deficit Ref.
1 Skin, gastrointestinal, vessels, bones Mjolnerod et al., 1971
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REFERENCES
Beck, R B et al (1981) Ultrastructural findings in fetal penicillamine syndrome In Abstracts from the 14th Annual March of Dimes Birth Defects Conference, San Diego, CA.
Berghella, V et al (1997) Successful pregnancy in a neurologically impaired woman with Wilson’s disease.
Am J Obstet Gynecol 176: 712–714.
Domingo, J L (1998) Developmental toxicity of metal chelating agents Reprod Toxicol 12: 499–510 Dupont, P., Irion, O., and Beguin, F (1990) Pregnancy in a patient with treated Wilson’s disease: A case report Am J Obstet Gynecol 163: 1527–1528.
Endres, W (1981) D-Penicillamine in pregnancy — to ban or not to ban Klin Wochenschr 59: 535–538 Friedman, J M and Polifka, J E (2000) Teratogenic Effects of Drugs A Resource for Clinicians (TERIS), Second ed., Johns Hopkins University Press, Baltimore, MD
Gal, P and Ravenel, S D (1984) Contractures and hydrocephalus with penicillamine and maternal sion J Clin Dysmorphol 2: 9–12.
hypoten-Gregory, M C and Mansell, M A (1983) Pregnancy and cystinuria Lancet 2: 1158–1160.
Harpey, J P et al (1983) Cutis laxa and low serum zinc after neonatal exposure to penicillamine Lancet 2:
Martinez-Frias, M L et al (1998) Prenatal exposure to penicillamine and oral clefts: Case report Am J Med Genet 76: 274–275.
Mjolnerod, O K et al (1971) Congenital connective-tissue defect probably due to D-penicillamine treatment
in pregnancy Lancet 1: 673–675.
Myint, B (1984) D-Penicillamine-induced cleft palate in mice Teratology 30: 333–340.
PDR ® (Physicians’ Desk Reference ® ) (2002) Medical Economics Co., Montvale, NJ.
Pinter, R., Hogge, W A., and McPherson, E (2004) Infant with severe penicillamine embryopathy born to
a woman with Wilson disease Am J Med Genet 128A: 294–298.
Rosa, F W (1986) Teratogen update: Penicillamine Teratology 33: 127–131.
Roubenoff, R et al (1988) Effects of anti-inflammatory and immunosuppressive drugs on pregnancy and fertility Sem Arthritis Rheum 18: 88–110
Schardein, J L (2000) Chemically Induced Birth Defects, Third ed., Marcel Dekker, New York, pp 640–641 Solomon, L et al (1977) Neonatal abnormalities associated with D-penicillamine treatment during pregnancy.
N Engl J Med 296: 54–55.
Steffek, A J., Verrusio, A C., and Watkins, C A (1972) Cleft palate in rodents after maternal treatment with various lathyrogenic agents Teratology 5: 33–40.
Sternlieb, I (2000) Wilson’s disease and pregnancy Hepatology 31: 531–532.
Wiley, M J and Joneja, M G (1978) Neural tube lesions in the offspring of hamsters given single oral doses
of lathyrogens early in gestation Acta Anat 100: 347–353.
Yamada, T et al (1979) Reproduction studies of D-penicillamine in rats 2 Teratogenicity study Oyo Yakuri
18: 561–569.
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Trang 5Chemical name: 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol
Alternate names: Oleovitamin A, retinol
CAS #: 68-26-8SMILES: C1(C(CCCC=1C)(C)C)C=CC(=CC=CC(=CCO)C)C
INTRODUCTION
Vitamin A is a fat-soluble essential vitamin available from natural as well as synthetic sources Thevitamin promotes bone growth, tooth development, and reproduction; helps form and maintainhealthy skin, hair, and mucous membranes; and builds the body’s resistance to respiratory infections
It aids in the treatment of many eye disorders, and helps treat acne, impetigo, boils, carbuncles,and open ulcers when applied externally It is also used therapeutically in the treatment andprevention of vitamin A deficiency It has a long half-life and bioaccumulates (Hathcock et al.,1990) It is available commercially as an over-the-counter (OTC) preparation with the trade namesAquasol A® and Palmitate-A® among many other names Vitamin A has a package label withcontrasting pregnancy risk factors varying from A to X, the latter if used in excess of the recom-mended dietary allowance (RDA) doses (~1000 to 5000 IU/day) (Griffith, 1988) The RDA forpregnant women, depending on the source of information, is ~2700 (NRC, 1989) to 8000 IU/day(U.S Teratology Society, 1987)
DEVELOPMENTAL TOXICOLOGY
The studies described below are those related to excessvitamin A, as deficiency states of the vitaminalso have developmental toxicity properties Many studies conducted with different objectives werepublished for laboratory animals: The emphasis here is on representative responses by species, bythe oralroute (the same as that mainly used therapeutically in humans) The topical route has notbeen explored in this respect The response in animals is best shown as tabulated in Table 1 Amultitude of different malformations were recorded in these studies, but craniofacial, central nervoussystem, and skeletal defects appeared most commonly, according to one observer (Friedman andPolifka, 2000) In addition to structural malformations, learning skills and fine motor changes and
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other behavioral abnormalities were also observed following large doses of vitamin A in rats(Hutchings et al., 1973)
A number of malformations in humans have been reported in case reports, as tabulated in Table 2.Approximately 23 cases were recorded As with most other toxicologic dose relationships, allmalformations have occurred at megadoses, on the order of 30,000 IU/day or greater, according toseveral sources; doses of 10,000 IU/day or less are apparently considered safe during pregnancy(Miller et al., 1998; Weigand et al., 1998) Transport to the fetus is by passive diffusion (Wild etal., 1974), and there is little or no difference between maternal and fetal blood levels, irrespective
of when administered (Briggs et al., 2002) Most all developmentally effective doses in laboratoryanimals are many times greater than dietary and supplemental human doses An important result
in primates was a no observed effect level (NOEL) (7500 IU) that would correspond to a dose of300,000 IU/day in humans It appears that the rabbit is a good animal model for displaying similardefects as those shown in humans (Tzimas et al., 1997)
No discrete pattern of malformations is obvious from the recorded data given in Table 2 Variation
in intake and patterns of ingestion may account for some of the differences in malformations.However, ear, limb, craniofacial, urinary, heart and blood vessels, cleft lip/palate, and brain abnor-malities occurred most commonly in decreasing order (Rosa, 1993) These share a number ofsimilarities to those reported in animals The pattern of malformations is said by several investigators(Lungarotti et al., 1987; Rosa, 1991) to be a phenocopy of those defects induced by the vitamin Acongener, isotretinoin, a recognized potent human teratogen and developmental toxicant
These case reports are supported by at least one major epidemiological study — a prospectiveanalysis of 22,748 pregnancies of women who consumed dietary or supplemental vitamin A during
TABLE 1
Developmental Toxicity in Animals Administered Oral Vitamin A
Species
Developmental Toxic Dose (IU a ) Toxicity Reported
Treatment Interval
in Gestation (days) Ref.
Mouse 3,000–10,000 Multiple M b 8–13 various Kalter and Warkany, 1959;
Giroud and Martinet, 1959
Rat 35,000–160,000 Craniofacial and brain M,
postnatal behavioral changes
4–18 various Cohlan, 1953; Hutchings et
al., 1973; Kutz et al., 1985 Guinea pig 50,000 Jaw and tongue defects, D c 10–13 Giroud and Martinet, 1959 Hamster 20,000 Multiple M 7–10 Marin-Padilla and Ferm,
1965 Rabbit 41,000 Multiple M, D 5–14 Giroud and Martinet, 1958 Cat 1,000,000–2,000,000 Multiple M, D (5 breedings) Freytag and Morris, 1997
1967 Pig 3,000,000–10,000,000 Eye M 12–42 various Palludan, 1966
Cyno monkey 7,500–80,000 Multiple M, D (maternal
Trang 7Vitamin A 51
their pregnancies in quantities of 5000 to >15,000 IU/day (Rothman et al., 1995) Of this cohort,there were 339 (1.5%) infants born with malformations, 121 of whom had defects occurring insites that originated in the cranial neural crest, primarily craniofacial and cardiac defects, abnor-malities commonly induced by retinoids in general For women taking >10,000 IU/day, the relativerisk was 4.8 (95% confidence interval [CI], 2.2 to 10.5) and 2.2 (95% CI, 1.3 to 3.8) for allmalformations, regardless of origin The apparent threshold was near 10,000 IU/day of supplementalvitamin A These data supported the conclusion that high dietary intake of vitamin A appeared to
be teratogenic, especially among women who had consumed these levels before the seventhgestational week The authors concluded that about 1 infant in 57 exposed to vitamin A supple-mented at these levels had a malformation attributable to it
In contrast, a number of other fairly recent epidemiological studies comprising over 43,000pregnancies do not support the premise that vitamin A has teratogenic properties, but the limitingfactor may be that dosages in the studies reported were in the range of 8000 to ~10,000 IU/day(Martinez-Frias and Salvador, 1990; Werler et al., 1990; Shaw et al., 1997; Mills et al., 1997;Czeizel and Rockenbaur, 1998; Khoury et al., 1998; Mastroiacovo et al., 1999) Doses of thismagnitude are generally considered safe and not teratogenic (Miller et al., 1998; Wiegand et al.,
Functional Deficit Ref.
4 Multiple: brain, kidney, adrenals, jaw Stange et al., 1978
5 Multiple: limbs, ears, face Von Lennep et al., 1985
12 Multiple: face, ears, palate Rosa et al., 1986 (FDA case)
16 Multiple: ears, vertebrae, limbs,
digits
Rosa et al., 1986 (FDA case)
17 Multiple: lip/palate, jaw, face, eye Rosa et al., 1986 (cited)
18 Multiple: ears, skull, nose, lip, jaw,
tongue, skin, digits, gastrointestinal, heart, kidney, liver
Lungarotti et al., 1987
Trang 852 Human Developmental Toxicants
1998) For one study of this group (Dudas and Czeizel, 1992), researchers reported dose istration of only 6000 IU/day, which would not be expected to be active Two other studies of thegroup contained subsets of women who received higher doses (40,000 to 50,000 IU/day) and whodid not illustrate an enhanced number of malformations (Martinez-Frias and Salvador, 1990;Mastroiacovo et al., 1999) However, too few subjects were evaluated to make significant state-ments related to safety The U.S Teratology Society (1987) has officially sanctioned doses of
admin-8000 IU/day as being safe during pregnancy and considers doses of 25,000 IU/day and higher aspotentially teratogenic
It appears from analysis of these data that vitamin A supplementation or dietary intake duringpregnancy of approximately 10,000 IU/day or less is a safe procedure with respect to teratogenicpotential, and that quantities in excess of that dosage offer some risk of toxicity One group ofexperts indicates a similar risk, and suggests further that doses of >25,000 IU/day have an unde-termined (but perhaps real teratogenic risk) (Friedman and Polifka, 2000) It does not appear thatother classes of developmental toxicity are affected by excessive quantities of the vitamin, onlystructural malformation
A number of pertinent reviews addressing the toxicity of vitamin A excess in animals as well
as humans were published (Gal et al., 1972; Geelen, 1979; Bendich and Lanseth, 1989; Hathcock
et al., 1990; Pinnock and Alderman, 1992; Rosa, 1993; Monga, 1997; Miller et al., 1998)
CHEMISTRY
Vitamin A, structurally similar to tretinoin, is a highly hydrophobic compound that is larger in size
in comparison to the other toxicants within this compilation The compound contains a network ofconjugated double bonds within its structure It is of relatively low polarity The calculated phys-icochemical and topological properties are as follows
Trang 9Vitamin A 53
REFERENCES
Bendich, A and Lanseth, L (1989) Safety of vitamin A Am J Clin Nutr 49: 358–371.
Bernhardt, I B and Dorsey, D J (1974) Hypervitaminosis A and congenital renal anomalies in a human infant Obstet Gynecol 43: 750–755.
Briggs, G G., Freeman, R K., and Yaffe, S J (2002) Drugs in Pregnancy and Lactation A Reference Guide
to Fetal and Neonatal Risk, Sixth ed., Lippincott Williams & Wilkins, Philadelphia.
Cohlan, S Q (1953) Excessive intake of vitamin A during pregnancy as a cause of congenital anomalies in the rat Am J Dis Child 86: 348–349
Czeizel, A E and Rockenbaur, M (1998) Prevention of congenital abnormalities of vitamin A Int J Vitam Nutr Res 68: 219–231.
Dudas, I and Czeizel, A E (1992) Use of 6000 IU vitamin A during early pregnancy without teratogenic effect Teratology 45: 335–336
Evans, K and Hickey-Dwyer, M U (1991) Cleft anterior segment with maternal hypervitaminosis A Br J Ophthalmol 75: 691–692.
Freytag, T L and Morris, J G (1997) Chronic administration of excess vitamin A in the domestic cat results
in low teratogenicity FASEB 11: A412.
Friedman, J M and Polifka, J E (2000) Teratogenic Effects of Drugs A Resource for Clinicians (TERIS), Second ed., Johns Hopkins University Press, Baltimore, MD.
Trang 1054 Human Developmental Toxicants
Gal, I., Sharman, I M., and Pryse-Davis, J (1972) Vitamin A in relation to human congenital malformations.
Adv Teratol 5: 143–159.
Geelen, J A G (1979) Hypervitaminosis A induced teratogenesis CRC Crit Rev Toxicol 7: 351–375 Giroud, A and Martinet, M (1958) Repercussions de l’hypervitaminose a chez l’embryon de lapin C R Soc Biol (Paris) 152: 931–932.
Giroud, A and Martinet, M (1959) Teratogenese par hypervitaminose a chez le rat, la souris, le cobaye, et
le lapin Arch Fr Pediatr 16: 971–975.
Griffith, H W (1988) Complete Guide to Vitamins, Minerals and Supplements, Fisher Books, Tucson, AZ,
p 23.
Hathcock, J N et al (1990) Evaluation of vitamin-A toxicity Am J Clin Nutr 52: 183–202.
Hendrickx, A G., Hummler, H., and Oneda, S (1997) Vitamin A teratogenicity and risk assessment in the cynomolgus monkey Teratology 55: 68
Hendrickx, A G et al (2000) Vitamin A teratogenicity and risk assessment in the macaque retinoid model.
Reprod Toxicol 14: 311–323.
Hutchings, D E., Gibbon, J., and Kaufman, M A (1973) Maternal vitamin A excess during the early fetal period: Effects on learning and development in the offspring Dev Psychobiol 6: 445–457 Kalter, H and Warkany, J (1959) Teratogenic action of hypervitaminosis A in strains of inbred mice Anat Rec 133: 396–397.
Khoury, M J., Moore, C A., and Mulinare, J (1998) Do vitamin supplements in early pregnancy increase the risk of birth defects in the offspring? A population-based case-control study Teratology 53: 91 Kutz, S A et al (1985) Vitamin A acetate: A behavioral teratology study in rats II Toxicologist 5: 106 Lungarotti, M S et al (1987) Multiple congenital anomalies associated with apparently normal maternal intake of vitamin A: A phenocopy of the isotretinoin syndrome Am J Med Genet 27: 245–248 Marin-Padilla, M and Ferm, V H (1965) Somite necrosis and developmental malformations induced by vitamin A in the golden hamster J Embryol Exp Morphol 13: 1–8.
Martinez-Frias, M L and Salvador, J (1990) Epidemiological aspects of prenatal exposure to high doses of vitamin A in Spain Eur J Epidemiol 6: 118–123.
Mastroiacovo, P et al (1999) High vitamin A intake in early pregnancy and major malformations: A multicenter prospective controlled study Teratology 59: 7–11.
Miller, R K et al (1998) Periconceptual vitamin A use: How much is teratogenic? Reprod Toxicol 12: 75–88 Mills, J L et al (1997) Vitamin A and birth defects Am J Obstet Gynecol 177: 31–36.
Monga, M (1997) Vitamin A and its congeners Semin Perinatol 21: 135–142.
Mounoud, R L., Klein, D., and Weber, F (1975) [A case of Goldenhar syndrome: Acute vitamin A intoxication
in the mother during pregnancy] J Genet Hum 23: 135–154.
NRC (National Research Council) (1989) Recommended Dietary Allowances, 10th ed., Washington, D.C., National Academy Press.
Palludan, B (1966) Swine in teratological research In Swine in Biomedical Research, L K Bustad and R.
O McClellan, Eds., Battelle Memorial Institute, Columbus, OH, pp 51–78
Pilotti, G and Scorta, A (1965) Hypervitaminosis A during pregnancy and neonatal malformations of the urinary system Minerva Gynecol 17: 1103–1108.
Pinnock, C B and Alderman, C P (1992) The potential for teratogenicity of vitamin-A and its congeners.
Med J Aust 157: 804–809.
Rosa, F (1991) Detecting human retinoid embryopathy Teratology 43: 419
Rosa, F W (1993) Retinoid embryopathy in humans In Retinoids in Clinical Practice, G Koren, Ed., Marcel Dekker, New York, pp 77–109.
Rosa, F W., Wilk, A L., and Kelsey, F O (1986) Teratogen update: Vitamin A congeners Teratology 33: 355–364.
Rothman, K J et al (1995) Teratogenicity of high vitamin A intake N Engl J Med 333: 1369–1373 Shaw, G M et al (1997) Periconceptual intake of vitamin A among women and risk of neural tube defect- affected pregnancies Teratology 55: 132–133.
Stange, L., Carlstrom, K., and Erikkson, M (1978) Hypervitaminosis A in early human pregnancy and malformations of the central nervous system Acta Obstet Gynecol Scand 57: 289–291.
Tzimas, G., Elmazar, M M A., and Nau, H (1997) Why is the rat not an appropriate species to be used for teratogenic risk assessment of high vitamin A intake by humans Teratology 56: 390
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Trang 11Wiersig, D and Swenson, M J (1967) Teratogenicity of vitamin A in the canine Fed Proc 26: 486
Wild, J., Schorah, C J., and Smithells, R W (1974) Vitamin A, pregnancy, and oral contraceptives Br Med.
Trang 12Chemical name: 5H-Dibenz[b,f]azepine-5-carboxamide
CAS #: 298-46-4SMILES: N1(c2c(cccc2)C=Cc3c1cccc3)C(N)=O
INTRODUCTION
Carbamazepine is a tricyclic anticonvulsant drug that has activity against partial seizures of complexsymptomology, generalized tonic-clonic seizures, and mixed seizure patterns, and provides painrelief of trigeminal or glosspharyngeal neuralgia (Lacy et al., 2004) Therapeutic efficacy has beenfound for carbamazepine in the treatment of bipolar and other affective disorders, resistant schizo-phrenia, ethanol withdrawal, restless leg syndrome, and posttraumatic disorders Its mechanism ofaction is not clearly understood, but it is related chemically to the tricyclic antidepressants, and itschemical moiety of a carbonyl group at the 5-position is essential for its potent antiseizure activity(Hardman et al., 2001) Carbamazepine is available commercially by prescription under the tradenames Carbatrol®, Epitol®, and Tegretol®, among others, and it has a pregnancy risk category of
D Stated on the package label is that the drug “can cause fetal harm when administered to apregnant woman” (PDR, 2002)
DEVELOPMENTAL TOXICOLOGY
In laboratory animal studies, carbamazepine was developmentally toxic in both mice and rats whengiven orally during the organogenesis period of gestation In mice, doses in the range of 40 to 240mg/kg/day were teratogenic, inducing central nervous system defects (McElhatton and Sullivan,1977), and in rats given 600 mg/kg/day, a maternally toxic dose, the drug elicited skeletal andvisceral abnormalities, reduced fetal weight, and resorption (Vorhees et al., 1990) Dose levels used
in rodents were many times greater than therapeutic doses in humans (see below)
It should be mentioned at the onset that studies of induction of malformations in the humanbyanticonvulsants is problematic in that treatment is usually in the form of combined therapy with
O N
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