23 5 Chlorambucil Chemical name: 4-[ Bis (2-chloroethyl)amino]benzene butanoic acid Alternate name: Chloraminophene CAS #: 305-03-3 SMILES: c1(ccc(cc1)CCCC(O)=O)N(CCCl)CCCl INTRODUCTION Chlorambucil is an alkylating antineoplastic agent used therapeutically in the management of chronic lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma and several other malig- nancies. It is a derivative of mechlorethamine, another human developmental toxicant. As with other alkylators, chlorambucil interferes with DNA replication and RNA transcription by alkylation and cross-linking DNA strands (Lacy et al., 2004). The drug is commercially available as Leukeran ® and has a pregnancy risk factor of D (labeling states “can cause fetal harm when administered to a pregnant woman: it is probably teratogenic in humans”). DEVELOPMENTAL TOXICOLOGY A NIMALS The drug has been tested in the laboratory for developmental toxicity in rodents. As expected, the drug is teratogenic in mice (Didcock et al., 1956) and rats (Murphy et al., 1958) when given intraperitoneally either once or twice during organogenesis at doses ranging from 6 to 40 mg/kg/day. Digit, limb, and central nervous system defects and cleft palate were produced. The drug is also embryolethal and causes stunting in rodents at doses in the range of 5 to 10 mg/kg by the same route (Murphy et al., 1958; Tanimura et al., 1965). H UMANS Chlorambucil is also teratogenic in humans: Four cases of congenital malformation were identified from published accounts in the literature, as tabulated in Table 1. Doses administered resulting in N Cl Cl O HO 7229_book.fm Page 23 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 24 Human Developmental Toxicants this toxicity ranged from 4 to 24 mg/day orally, and treatments ranged from conception through the 20th week of gestation. These levels are greater than the usual therapeutic doses of 2 to 4 mg/day po. There does not appear to be a syndrome of malformations other than for near-identical malformations of the urogenital system in two of the four cases. Interestingly, similar if not identical defects were produced in rats treated with the drug (Monie, 1961). Case # 5 was a twin pregnancy, and the other infant was spared the defect. The malformations were accompanied in five of the six cases by infant death. No intrauterine growth retardation was recorded, contrary to a review of treatment with antineoplastic drug therapy in humans, including chlorambucil, which was said to result in 40% of infants having low birth weight (Nicholson, 1968). There were no postnatal functional alterations reported in the single surviving infant. Only four nonmalformed infants were reported after chlorambucil use (Baynes et al., 1968; Nicholson, 1968; Jacobs et al., 1981; Zuazu et al., 1991); therefore, based on this published information, the risk to developmental toxicity is high, on the order of 60%. CHEMISTRY Chlorambucil is an aniline mustard of near average size. The compound is hydrophobic and of low polarity. Chlorambucil can participate in hydrogen bonding. The calculated physicochemical and topological properties are as follows. P HYSICOCHEMICAL P ROPERTIES TABLE 1 Developmental Toxicity Profile of Chlorambucil in Humans Case Number Malformations Growth Retardation Death Functional Deficit Ref. 1 None ߜ Revol et al., 1962 2 Kidney and ureter Shotton and Monie, 1963 3 Eye ߜ Rugh and Skaredoff, 1965 4 None ߜ Nicholson, 1968 5 Kidney and ureter ߜ Steeger and Caldwell, 1980 6 Heart ߜ Thompson and Conklin, 1983 Parameter Value Molecular weight 304.216 g/mol Molecular volume 265.58 A 3 Density 1.210 g/cm 3 Surface area 340.92 A 2 LogP 2.911 HLB 3.293 Solubility parameter 22.992 J (0.5) /cm (1.5) Dispersion 20.768 J (0.5) /cm (1.5) Polarity 5.261 J (0.5) /cm (1.5) Hydrogen bonding 8.347 J (0.5) /cm (1.5) H bond acceptor 0.68 H bond donor 0.29 Percent hydrophilic surface 20.665 MR 80.194 Continued. 7229_book.fm Page 24 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC Chlorambucil 25 T OPOLOGICAL P ROPERTIES (U NITLESS ) REFERENCES Baynes, T. L. S., Crickmay, G. F., and Vaughan Jones, R. (1968). Pregnancy in a case of chronic lymphatic leukemia. Br. J. Obstet. Gynaecol. 75: 1165–1168. Didcock, K. A., Jackson, D., and Robson, J. M. (1956). The action of some nucleotoxic substances in pregnancy. Br. J. Pharmacol. 11: 437–441. Jacobs, C. et al. (1981). Management of the pregnant patient with Hodgkin’s disease. Ann. Intern. Med. 95: 669–675. Lacy, C. F. et al. (2004). Drug Information Handbook (Pocket), 2004–2005 , Lexi-Comp. Inc., Hudson, OH. Monie, I. W. (1961). Chlorambucil-induced abnormalities of urogenital system of rat fetuses. Anat. Rec. 139: 145 . Water solubility –2.360 log (mol/M 3 ) Hydrophilic surface area 70.45 A 2 Polar surface area 43.70 A 2 HOMO –9.280 eV LUMO –0.005 eV Dipole 1.610 debye Parameter Value x0 14.088 x1 9.168 x2 7.443 xp3 5.271 xp4 4.120 xp5 3.078 xp6 2.052 xp7 1.275 xp8 0.843 xp9 0.525 xp10 0.286 xv0 12.330 xv1 7.416 xv2 5.035 xvp3 3.204 xvp4 2.299 xvp5 1.510 xvp6 0.877 xvp7 0.436 xvp8 0.283 xvp9 0.151 xvp10 0.067 k0 21.286 k1 17.053 k2 9.834 k3 6.817 ka1 16.444 ka2 9.319 ka3 6.389 Parameter Value 7229_book.fm Page 25 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 26 Human Developmental Toxicants Murphy, M. L., Moro, A. D., and Lacon, C. (1958). Comparative effects of five polyfunctional alkylating agents on the rat fetus, with additional notes on the chick embryo. Ann. NY Acad. Sci. 68: 762–782. Nicholson, H. O. (1968). Cytotoxic drugs in pregnancy. Review of reported cases. J. Obstet. Gynaecol. Br. Commonw. 75: 307–312. Revol, L. et al. (1962). [Hodgkin’s disease, lymphosarcoma, reticulosarcoma and pregnancy]. Nouv. Rev. Fr. Hematol. 2: 311–325. Rugh, R. and Skaredoff, L. (1965). Radiation and radiomimetic chlorambucil and the fetal retina. Arch. Ophthalmol. 74: 382–393. Shotton, D. and Monie, I. W. (1963). Possible teratogenic effect of chlorambucil on a human fetus. JAMA 186: 74–75. Steege, J. F. and Caldwell, D. S. (1980). Renal agenesis after first trimester exposure to chlorambucil. South. Med. J. 73: 1414–1415. Tanimura, T. et al. (1965). [Comparison of teratogenic effects between single and repeated administration of chemical agents]. Kaibogaku Zasshi 40: 13 . Thompson, J. and Conklin, K. A. (1983). Anesthetic management of a pregnant patient with scleroderma. Anesthesiology 59: 69–71. Zuazu, J. et al. (1991). Pregnancy outcome in hematologic malignancies. Cancer 67: 703–709. 7229_book.fm Page 26 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 27 6 Mechlorethamine Chemical name: 2-Chloro- N -(2-chloroethyl)- N -methylethanamine Alternate names: Nitrogen mustard, chlormethine CAS #: 51-75-2 SMILES: N(CCCl)(CCCl)C INTRODUCTION Mechlorethamine is an alkylating antineoplastic drug that has therapeutic utility in combination therapy for Hodgkin’s disease and non-Hodgkin’s lymphoma and other malignant lymphomas. The drug inhibits DNA and RNA synthesis via formation of carbonium ions by cross-linking strands of DNA, causing miscoding, breakage, and failure of replication. While the drug is not cell-phase specific, its effect is most pronounced in the S-phase, and cell proliferation is arrested in the G 2 phase (Lacy et al., 2004). The drug used commercially has the trade name Mustargen ® , among others, and it has a pregnancy risk factor of D (labeling states “can cause fetal harm when administered to a pregnant woman”). DEVELOPMENTAL TOXICOLOGY A NIMALS Mechlorethamine is teratogenic in all laboratory species tested. Parenteral routes of administration were used. In the mouse, subcutaneous or intraperitoneal injection caused digit anomalies and hydrocephalus, as well as growth retardation and embryolethality (Danforth and Center, 1954; Thalhammer and Heller-Szollosy, 1955). In rats, mechlorethamine elicited multiple malformations, death, and growth retardation following subcutaneous administration (Haskin, 1948). Malforma- tions were also produced in rabbits after intravenous dosing early in gestation (Gottschewski, 1964). In a seldom-used animal species, the ferret, malformations were induced in high incidence upon injection of mechlorethamine (Beck et al., 1976). Developmental toxicity was produced in animals at parenteral doses ranging from 1 μ g/g/day in mice, 0.1 mg/kg/day in rabbits, 0.5 mg/kg/day in ferrets, to 1 mg/kg/day in rats, in decreasing order of sensitivity. N Cl Cl 7229_book.fm Page 27 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 28 Human Developmental Toxicants H UMANS The drug has been associated with congenital malformation in the human as well. Recorded in the literature were at least eight cases from first trimester exposure as well as other developmental toxicity as shown in Table 1. The malformations recorded are diverse, having similarities in two cases with digit abnormalities and three with brain defects. The digit defects were similar to some recorded animal malformations. Further, in most cases, mechlorethamine was accompanied by combined antineoplastic drug treatment (especially procarbazine and vinblastine/vincristine as MOPP); thus, the teratogenic effect of this drug cannot be established with certainty. Malformations were accompanied by dysmaturity in one case and learning disability in a single case, neither of which are considered significant biological effects in the developmental toxicity parameter of this agent. Death or abortion occurred in the majority of the cases and was considered an associated feature of the developmental toxicity profile of mechlorethamine. Doses recorded in the cases, when stated, were 4 to 6 mg/m 2 po, and all cases are believed to have been limited to treatment in the first trimester. Therapeutic doses of this drug are much lower, 0.4 mg/kg (single dose) or 0.1 mg/kg (repeated doses) by the iv route, which are doses similar to the effect levels in animal studies. Based on the number of unaffected infants born after being exposed to mechlorethamine during the first trimester (Nicholson, 1968; Jones and Weinerman, 1979; McKeen et al., 1979; Whitehead et al., 1983; Andrieu and Ochoa-Molina, 1983; Green et al., 1991; see Schardein, 2000), the risk of developmental toxicity from this agent appears to be on the order of 22%. One group of experts stated the magnitude of teratogenic risk for this drug to be small to moderate (Friedman and Polifka, 2000). For more information, see the review article by Dein et al. (1984) on the developmental toxicity of mechlorethamine and other antineoplastic drugs useful in treating Hodgkin’s disease. CHEMISTRY Mechlorethamine is a nitrogen mustard of relatively small size. The chemical is hydrophobic. Its potential to engage in hydrogen bonding (as an acceptor) is relative low compared to the other TABLE 1 Developmental Toxicity Profile of Mechlorethamine in Humans Case Number Malformations Growth Retardation Death Functional Deficit Ref. 1 None ߜ Revol et al., 1962 2 None ߜ Nicholson, 1968 3 None ߜ Nicholson, 1968 4 None ߜ Nicholson, 1968 5 Multiple: bone, digits, brain, ear Garrett, 1974 6 Renal ߜ Mennuti et al., 1975 7 Heart ߜߜ Thomas and Peckham, 1976 8 Palate McKeen et al., 1979 9 Brain McKeen et al., 1979 10 Inner ear McKeen et al., 1979 11 None ߜ McKeen et al., 1979 12 None ߜ McKeen et al., 1979 13 Digits Thomas and Andes, 1982 14 Brain ߜ Zemlickis et al., 1993 7229_book.fm Page 28 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC Mechlorethamine 29 human developmental toxicants. The calculated physicochemical and topological parameters for mechlorethamine are listed below. P HYSICOCHEMICAL P ROPERTIES T OPOLOGICAL P ROPERTIES (U NITLESS ) Parameter Value Molecular weight 156.054 g/mol Molecular volume 134.15 A 3 Density 1.166 g/cm 3 Surface area 187.47 A 2 LogP 0.372 HLB 0.000 Solubility parameter 20.372 J (0.5) /cm (1.5) Dispersion 17.539 J (0.5) /cm (1.5) Polarity 8.087 J (0.5) /cm (1.5) Hydrogen bonding 6.483 J (0.5) /cm (1.5) H bond acceptor 0.13 H bond donor 0.00 Percent hydrophilic surface 0.70 MR 38.964 Water solubility 1.044 log (mol/M 3 ) Hydrophilic surface area 1.30 A 2 Polar surface area 3.24 A 2 HOMO –9.695 eV LUMO 0.867 eV Dipole 1.816 debye Parameter Value x0 6.406 x1 3.808 x2 2.682 xp3 1.563 xp4 1.130 xp5 0.289 xp6 0.144 xp7 0.000 xp8 0.000 xp9 0.000 xp10 0.000 xv0 6.543 xv1 3.683 xv2 2.437 xvp3 1.270 xvp4 0.978 xvp5 0.254 xvp6 0.144 xvp7 0.000 xvp8 0.000 xvp9 0.000 Continued. 7229_book.fm Page 29 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 30 Human Developmental Toxicants REFERENCES Andrieu, J. M. and Ochoa-Molina, M. E. (1983). Menstrual cycle, pregnancies and offspring before and after MOPP therapy for Hodgkin’s disease. Cancer 52: 435–438. Beck, F. et al. (1976). Comparison of the teratogenic effects of mustine hydrochloride in rats and ferrets. The value of the ferret as an experimental animal in teratology. Teratology 13: 151–160. Danforth, C. H. and Center, E. (1954). Nitrogen mustard as a teratogenic agent in the mouse. Proc. Soc. Exp. Biol. Med. 86: 705–707. Dein, R. A. et al. (1984). The reproductive potential of young men and women with Hodgkin’s disease. Obstet. Gynecol. Surv. 39: 474–482. 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. Garrett, M. J. (1974). Teratogenic effects of combination chemotherapy. Ann. Intern. Med. 80: 667 . Gottschewski, G. H. M. (1964). Mammalian blastopathies due to drugs. Nature 201: 1232–1233. Green, D. M. et al. (1991). Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N. Engl. J. Med. 325: 141–146. Haskin, D. (1948). Some effects of nitrogen mustard on the development of external body form in the fetal rat. Anat. Rec. 102: 493–511. Jones, R. T. and Weinerman, B. H. (1979). MOPP (nitrogen mustard, vincristine, procarbazine and prednisone) given during pregnancy. Obstet. Gynecol. 54: 477 . Lacy, C. F. et al. (2004). Drug Information Handbook (Pocket) 2004–2005 , Lexi-Comp, Inc., Hudson, OH. McKeen, E. A. et al. (1979). Pregnancy outcome in Hodgkin’s disease. Lancet 2: 590 . Mennuti, M. T., Shepard, T. H., and Mellman, W. J. (1975). Fetal renal malformation following treatment of Hodgkin’s disease during pregnancy. Obstet. Gynecol. 46: 194–196. Nicholson, H. O. (1968). Cytotoxic drugs in pregnancy. Review of reported cases. J. Obstet. Gynaecol. Br. Commonw. 75: 307–312. Revol, L. et al. (1962). [Hodgkin’s disease, lymphosarcoma, reticulosarcoma and pregnancy]. Nouv. Rev. Fr. Hematol. 2: 311–325. Schardein, J. L. (2000). Chemically Induced Birth Defects , Third ed., Marcel Dekker, New York, p. 585. Thalhammer, O. and Heller-Szollosy, E. (1955). Exogene Bildungfehler (“Missbildungen”) durch Lostinjekion bei der graviden Maus (Ein Beitrag zur Pathogenese von Bildungsfehlern). Z. Kinderheilk. 76: 351 . Thomas, L. and Andes, W. A. (1982). Fetal anomaly associated with successful chemotherapy for Hodgkin’s disease during the first trimester of pregnancy. Clin. Res. 30: 424A. Thomas, P. R. M. and Peckham, M. J. (1976). The investigation and management of Hodgkin’s disease in the pregnant patient. Cancer 38: 1443–1451. Whitehead, E. et al. (1983). The effect of combination chemotherapy on ovarian function in women treated for Hodgkin’s disease. Cancer 52: 988–993. Zemlickis, D. et al. (1993). Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratog. Carcinog. Mutag. 13: 139–143. xvp10 0.000 k0 5.418 k1 8.000 k2 5.143 k3 5.000 ka1 8.540 ka2 5.673 ka3 5.540 Parameter Value 7229_book.fm Page 30 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 31 7 Cytarabine Chemical name: 1- β - D -Arabinofuranosylcytosine Alternate names: Ara-C, cytosine arabinoside, aracytidine CAS #: 147-94-4 SMILES: C1(N2C(N=C(C=C2)N)=O)OC(C(C1O)O)CO INTRODUCTION Cytarabine is a purine antimetabolite used therapeutically as an antineoplastic agent, as it is active in treating leukemia and lymphoma. Its mechanism of action is by inhibition of DNA synthesis, through conversion to its active compound, aracytidine triphosphate, which is incorporated into DNA, inhibiting DNA polymerase and resulting in decreased DNA synthesis and repair; it is rapidly metabolized (Lacy et al., 2004). The drug is specific for the S phase of the cell cycle. Commercially available as Cytosar ® , it has a pregnancy risk factor of D. (This category would indicate that the drug can cause fetal harm when administered to a pregnant woman.) DEVELOPMENTAL TOXICOLOGY A NIMALS Among animal studies, cytarabine is teratogenic, and it increased fetal mortality and inhibited fetal body weight when given to mice during the organogenesis period of gestation (Puig et al., 1991). Cleft palate, renoureteral agenesis or hypoplasia, and poly- or oligodactyly in association with maternal toxicity were observed at intraperitoneal (IP) dose levels of 2 and 8 mg/kg/day, and resorption and decreased fetal body weight were observed at the higher dose. In an earlier study in mice, researchers recorded microcephaly with microscopic central nervous system malformations at a higher dose of 30 mg/kg/day ip (Kasubuchi et al., 1973). In another study, researchers observed the full pattern of developmental toxicity at an intravenous dose of 1.5 mg/kg/day during organo- genesis in the same species (Nomura et al., 1969). In the rat, IP doses over a wide range (20 to 800 mg/kg/day) during 4 days of organogenesis produced cleft palate, limb, tail, and digit malfor- mations, and fetal death in the offspring (Chaube et al., 1968). Toxicity was also recorded in the N O N NH 2 HO OH OH O 7229_book.fm Page 31 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC 32 Human Developmental Toxicants 2-day-old neonatal rat at doses of 4 mg/kg for 5 days by the IP route (Gough et al., 1982). The toxicity was manifested by weight gain suppression, delayed hair growth, toxic clinical signs, cerebellar hypoplasia, retinal dysplasia, and delayed nephrogenesis. H UMANS There are a few recorded cases of malformation in humans (Table 1). Of some 16 cases illustrating developmental toxicity in humans with cytarabine (and usually combined antineoplastic therapy), 3 had malformations, all with digit defects, accompanied by large bone (leg) malformations in 2 of the cases. Dosage was not specified except in one case, at 160 mg/day intravenously in the first 2 months of pregnancy. Therapeutic doses are in the range of 100 mg to 3 g/m 2 /day. Intrauterine growth retardation was recorded in two cases in the published literature; intrauterine death in many cases; and functional deficit, defined as a slight retardation in postnatal motor milestones, in a single case (in this case the patient also had multiple anatomic malformations). Neither growth retardation nor functional deficits are considered representative characteristics of the developmental toxicity profile of cytarabine based on the few cases reported. In addition to the developmental effects, chromosomal abnormalities were also reported in several case reports (Maurer et al., 1971; Schleuning and Clemm, 1987). Paternal use of cytarabine combined with other antineoplastic drugs prior to conception was said to result in congenital anomalies (Russell et al., 1976). Based on the number of published cases of unaffected infants born following first trimester exposure to cytarabine (Lilleyman et al., 1977; Catanzarite and Ferguson, 1984; Reynoso et al., 1987; Juarez et al., 1988; see Schardein, 2000), the risk for developmental toxicity in the human associated with cytarabine is rather high, especially due to intrauterine death, at approximately 64%. The teratogenic risk of cytarabine is considered by one group of experts to be small to moderate in extent (Friedman and Polifka, 2000). Several thorough reviews of cytarabine combined therapy and pregnancy outcome were published (Catanzarite and Ferguson, 1984; Caliguri and Mayer, 1989). CHEMISTRY Cytarabine is a hydrophobic chemical of near average size as compared with the other human developmental toxicants. It is polar and capable of engaging in donor/acceptor hydrogen bonding interactions. The calculated physicochemical and topological properties are as follows. TABLE 1 Developmental Toxicity Profile of Cytarabine in Humans Cas Number Malformations Growth Retardation Death Functional Deficit Ref. 1–11 None ߜ Newcomb et al., 1978; O’Donnell et al., 1979; Homer et al., 1979; Pizzuto et al., 1980; Taylor and Blom, 1980; DeSouza et al., 1982; Plows, 1982; Cantini and Yanes, 1984; Fassas et al., 1984; Volkenandt et al., 1987; Juarez et al., 1988 12 None ߜ Pizzuto et al., 1980 13 Multiple: ear, bone, digits Wagner et al., 1980 14 Digits Schafer, 1981 15 None ߜ Juarez et al., 1988 16 Multiple: face, digits, bone, brain ߜ Artlich et al., 1994 7229_book.fm Page 32 Friday, June 30, 2006 3:08 PM © 2007 by Taylor & Francis Group, LLC [...]... 407.56 A2 6.164 2. 205 18.436 J(0.5)/cm(1.5) 17. 428 J(0.5)/cm(1.5) 1.4 32 J(0.5)/cm(1.5) 5.840 J(0.5)/cm(1.5) 0. 52 0.31 15.94 93 .29 4 –4. 127 log (mol/M3) 64.94 A2 40.46 A2 –7.849 eV –1.531 eV 5.7 62 debye TOPOLOGICAL PROPERTIES (UNITLESS) Parameter x0 x1 x2 xp3 xp4 xp5 xp6 xp7 xp8 xp9 © 20 07 by Taylor & Francis Group, LLC Value 16.751 10 .22 0 9.813 6.409 5.058 2. 824 2. 2 72 0.9 72 0.697 0.377 Continued 722 9_book.fm... A3 1.368 g/cm3 24 9. 02 A2 –0.959 21 .540 36.455 J(0.5)/cm(1.5) 23 .28 5 J(0.5)/cm(1.5) 12. 664 J(0.5)/cm(1.5) 25 . 028 J(0.5)/cm(1.5) 2. 10 1 .21 100.00 57.6 92 4.405 log (mol/M3) 24 9. 02 A2 133.99 A2 –9.505 eV –0.568 eV 5.984 debye TOPOLOGICAL PROPERTIES (UNITLESS) Parameter x0 x1 x2 xp3 xp4 xp5 xp6 xp7 xp8 xp9 xp10 xv0 xv1 xv2 xvp3 xvp4 xvp5 xvp6 xvp7 xvp8 xvp9 xvp10 k0 k1 k2 k3 ka1 ka2 ka3 © 20 07 by Taylor... xvp10 k0 k1 k2 k3 ka1 ka2 ka3 © 20 07 by Taylor & Francis Group, LLC Value 12. 577 8.041 7.346 6.395 5. 026 3.584 2. 4 12 1.351 0.765 0.460 0.196 8.801 5.014 3.771 2. 643 1. 729 1. 027 0.530 0 .25 1 0.119 0.056 0.018 20 .918 13.4 32 5. 325 2. 560 12. 301 4.607 2. 136 722 9_book.fm Page 34 Friday, June 30, 20 06 3:08 PM 34 Human Developmental Toxicants REFERENCES Artlich, A et al (1994) Teratogenic effects in a case... systemically to animals Acta Dermatol Venereol Suppl (Stockh.) 74: 36–40 © 20 07 by Taylor & Francis Group, LLC 722 9_book.fm Page 41 Friday, June 30, 20 06 3:08 PM 9 Propranolol Chemical name: 1-[ (1-Methylethyl)amino ]-3 -( 1-naphthalenyloxy -2 - propanol) CAS #: 52 5-6 6-6 SMILES: c12c(OCC(CNC(C)C)O)cccc1cccc2 H N OH O INTRODUCTION Propranolol is a β-blocking drug with therapeutic utility as an antianginal and antiarrhythmic... Continued 722 9_book.fm Page 38 Friday, June 30, 20 06 3:08 PM 38 Human Developmental Toxicants Parameter Value xp10 xv0 xv1 xv2 xvp3 xvp4 xvp5 xvp6 xvp7 xvp8 xvp9 xvp10 k0 k1 k2 k3 ka1 ka2 ka3 0. 324 14.441 7.867 6.761 4. 125 2. 875 1.499 1.101 0.346 0.199 0.100 0.0 82 28.931 20 .046 9.333 7. 422 18.379 8.0 92 6.330 REFERENCES Camera, G and Pregliasco, P (19 92) Ear malformation in baby born to mother using... LUMO Dipole 1. 025 g/cm3 311 .27 A2 2. 434 6. 328 22 .636 J(0.5)/cm(1.5) 19.644 J(0.5)/cm(1.5) 2. 607 J(0.5)/cm(1.5) 10.941 J(0.5)/cm(1.5) 0.73 0.44 33.86 76. 123 –0.140 log (mol/M3) 105.39 A2 41.49 A2 –8.0 72 eV –0.108 eV 3.681 debye TOPOLOGICAL PROPERTIES (UNITLESS) Parameter x0 x1 x2 xp3 xp4 xp5 xp6 xp7 xp8 xp9 xp10 xv0 xv1 xv2 xvp3 xvp4 xvp5 xvp6 xvp7 xvp8 xvp9 xvp10 k0 k1 k2 k3 ka1 ka2 ka3 © 20 07 by Taylor... 9.165 8.053 5.990 4.691 4.018 2. 338 1.638 1.1 32 0.790 0.403 11.466 6.686 5.005 2. 943 1.938 1.380 0.635 0.369 0 .22 1 0.131 0.058 23 .694 15.390 7.695 4.795 13.999 6.661 4. 028 722 9_book.fm Page 44 Friday, June 30, 20 06 3:08 PM 44 Human Developmental Toxicants REFERENCES Boice, J L (19 82) Propranolol during pregnancy JAMA 24 8: 1834 Briggs, G G., Freeman, R K., and Yaffe, S J (20 05) Drugs in Pregnancy and... (1968) The teratogenic effect of 1- -D-arabinofuranosylcytosine in the rat Protection by deoxycytidine Biochem Pharmacol 17: 121 3– 121 6 DeSouza, J J L et al (19 82) Acute leukaemia in pregnancy S Afr Med J 62: 29 5 29 6 Fassas, A et al (1984) Chemotherapy for acute leukemia during pregnancy: Five case reports Nouv Rev Fr Hematol 26 : 19 24 Friedman, J M and Polifka, J E (20 00) Teratogenic Effects of Drugs... (1987) Acute leukemia during pregnancy Lancet 2: 1 521 –1 522 Wagner, V M et al (1980) Congenital abnormalities in baby born to cytarabine treated mother Lancet 2: 98–99 © 20 07 by Taylor & Francis Group, LLC 722 9_book.fm Page 35 Friday, June 30, 20 06 3:08 PM 8 Tretinoin Chemical name: All-trans retinoic acid Alternate name: Vitamin A acid CAS #: 30 2- 7 9-4 SMILES: C1(C(CCCC=1C)(C)C)C=CC(=CC=CC(=CC(O)=O)C)C... comparison to the other human developmental toxicants It can participate in hydrogen bonding, both as acceptor and donor The calculated physicochemical and topological properties are listed below PHYSICOCHEMICAL PROPERTIES Parameter Molecular weight Molecular volume © 20 07 by Taylor & Francis Group, LLC Value 25 9.347 g/mol 25 3 .21 A3 Continued 722 9_book.fm Page 43 Friday, June 30, 20 06 3:08 PM Propranolol . 0.018 k0 20 .918 k1 13.4 32 k2 5. 325 k3 2. 560 ka1 12. 301 ka2 4.607 ka3 2. 136 722 9_book.fm Page 33 Friday, June 30, 20 06 3:08 PM © 20 07 by Taylor & Francis Group, LLC 34 Human Developmental Toxicants . 703–709. 722 9_book.fm Page 26 Friday, June 30, 20 06 3:08 PM © 20 07 by Taylor & Francis Group, LLC 27 6 Mechlorethamine Chemical name: 2- Chloro- N -( 2- chloroethyl )- N -methylethanamine Alternate. 7.443 xp3 5 .27 1 xp4 4. 120 xp5 3.078 xp6 2. 0 52 xp7 1 .27 5 xp8 0.843 xp9 0. 525 xp10 0 .28 6 xv0 12. 330 xv1 7.416 xv2 5.035 xvp3 3 .20 4 xvp4 2. 299 xvp5 1.510 xvp6 0.877 xvp7 0.436 xvp8 0 .28 3 xvp9 0.151 xvp10