J. Robertson, L. Martinez, S. Gallegos, M. Leen-Mitchell, V. García, J. Neuman, J. Carey
{"title":"Accutane cases: a teratogen information service's approach.","authors":"J. Robertson, L. Martinez, S. Gallegos, M. Leen-Mitchell, V. García, J. Neuman, J. Carey","doi":"10.1002/TERA.10035","DOIUrl":"https://doi.org/10.1002/TERA.10035","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"24 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85612855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Globally, 500,000 children are born each year with spina bifida and anencephaly, two of the most common and severe birth defects (Berry et al., ’99). One causes permanent paralysis and the other fetal or infant death (Botto et al., ’99). For more than a decade, we have had randomized controlled trial proof that increased consumption of supplemental, synthetic folic acid will prevent approximately 375,000 of these birth defects each year (MRC Vitamin Study Research Group, ’91; Czeizel and Dudas, ’92). This prevention is urgent! To paraphrase Roosevelt, we can “in little time” implement fortification programs that will “do so much.” The advent of the polio vaccine brought a war-like urgency. In the US, within a few months of the conclusion of the trial establishing that the vaccine prevented polio, a massive amount of vaccine was produced, movie theaters across the country were rented to educate the medical community, and, within a year of the completion of the study, American children received 4.0 million doses of vaccine. Folic acid-preventable birth defects are as preventable as polio! Preventing these birth defects is equally urgent. The technology to fortify is simple and can be inexpensively and almost immediately implemented for large population groups.
全球每年有50万儿童出生时患有脊柱裂和无脑畸形，这是两种最常见和最严重的出生缺陷(Berry et al.， 1999)。一种导致永久性瘫痪，另一种导致胎儿或婴儿死亡(Botto etal .， 1999)。十多年来，我们有随机对照试验证明，增加补充合成叶酸的摄入，每年可以预防大约37.5万例出生缺陷(MRC维生素研究小组，1991年;Czeizel和Dudas， ' 92)。这种预防迫在眉睫!套用罗斯福的话说，我们可以“在很短的时间内”实施将“发挥很大作用”的强化计划。脊髓灰质炎疫苗的出现带来了战争般的紧迫感。在美国，在确定疫苗可以预防小儿麻痹症的试验结束后的几个月内，大量的疫苗被生产出来，全国各地的电影院被租用来教育医学界，在研究完成后的一年内，美国儿童接受了400万剂疫苗。叶酸——可预防的出生缺陷和脊髓灰质炎一样可预防!预防这些先天缺陷同样紧迫。加强防御的技术很简单，成本低廉，几乎可以立即适用于大量人口群体。
{"title":"Inertia on folic acid fortification: public health malpractice.","authors":"G. Oakley","doi":"10.1002/TERA.10079","DOIUrl":"https://doi.org/10.1002/TERA.10079","url":null,"abstract":"Globally, 500,000 children are born each year with spina bifida and anencephaly, two of the most common and severe birth defects (Berry et al., ’99). One causes permanent paralysis and the other fetal or infant death (Botto et al., ’99). For more than a decade, we have had randomized controlled trial proof that increased consumption of supplemental, synthetic folic acid will prevent approximately 375,000 of these birth defects each year (MRC Vitamin Study Research Group, ’91; Czeizel and Dudas, ’92). This prevention is urgent! To paraphrase Roosevelt, we can “in little time” implement fortification programs that will “do so much.” The advent of the polio vaccine brought a war-like urgency. In the US, within a few months of the conclusion of the trial establishing that the vaccine prevented polio, a massive amount of vaccine was produced, movie theaters across the country were rented to educate the medical community, and, within a year of the completion of the study, American children received 4.0 million doses of vaccine. Folic acid-preventable birth defects are as preventable as polio! Preventing these birth defects is equally urgent. The technology to fortify is simple and can be inexpensively and almost immediately implemented for large population groups.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"233 1","pages":"44-54"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77520899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND L-NAME (N(G)-nitro-(L)-arginine methyl ester), a nitric oxide synthase inhibitor, causes severe limb reduction malformations when gravid rats are treated intraperitoneally on gd-17. Hemorrhages, appearing within hours of L-NAME administration, and defects at term can be significantly reduced by co-treatment with PBN (alpha-phenyl-N-t-butylnitrone), a spin trap antioxidant. We have proposed that limb defects result from ischemia-reperfusion injury. We examine the role of xanthine oxidase and ROS formation in the limb effects of L-NAME. METHODS Gravidas were treated with L-NAME (50 mg/kg) in the presence or absence of allopurinol, a xanthine oxidase inhibitor. Spatial patterns of limb hemorrhage were determined promptly and at term as was digit length at the latter interval. Xanthine oxidase activities were assayed in control and treated limbs with and without allopurinol co-treatment. RESULTS Allopurinol significantly reduced hemorrhage severity in a dose-responsive fashion when fetuses were examined at term. Higher doses of allopurinol significantly preserved digit length. Xanthine oxidase activities in fetal limb were significantly increased by L-NAME treatment whereas co-treatment with allopurinol restored activities to near-control levels. CONCLUSIONS These findings support the role of excess reactive oxygen species (ROS) formation in L-NAME-induced limb reduction. We propose that nitric oxide (NO) depletion by L-NAME interferes with vascular integrity, and causes vasoconstriction. Resultant hypoxia stimulates superoxide formation and nitric oxide formation catalyzed by the inducible isoform of nitric oxide synthase. The reduction products of superoxide or the products of its reaction with nitric oxide oxidize or nitrate endothelial components resulting in limb reduction defects.
N(G)-硝基-(L)-精氨酸甲酯(N(G)-硝基-(L)-精氨酸甲酯)是一种一氧化氮合酶抑制剂，妊娠大鼠腹腔注射gd-17可导致严重的肢体复位畸形。与PBN (α -苯基- n -t-丁基硝基酮，一种自旋陷阱抗氧化剂)共同治疗可显著减少L-NAME给药后数小时内出现的出血和足月缺陷。我们认为肢体缺损是由缺血再灌注损伤引起的。我们研究了黄嘌呤氧化酶和ROS形成在L-NAME肢体效应中的作用。方法在黄嘌呤氧化酶抑制剂别嘌呤醇存在或不存在的情况下，用L-NAME (50 mg/kg)处理妊娠鼠。肢体出血的空间模式被及时确定，并在后期确定手指长度。用别嘌呤醇和不加别嘌呤醇共处理对照和处理肢体测定黄嘌呤氧化酶活性。结果在胎儿足月检查时，sallopurinol以剂量反应的方式显著降低出血严重程度。高剂量的别嘌呤醇能显著保持手指长度。L-NAME处理显著提高了胎儿肢体黄嘌呤氧化酶活性，而与别嘌呤醇联合处理则使黄嘌呤氧化酶活性恢复到接近控制水平。结论这些发现支持了过量活性氧(ROS)的形成在l - name诱导的肢体复位中的作用。我们认为L-NAME引起的一氧化氮(NO)耗竭干扰血管完整性，并导致血管收缩。由此产生的缺氧刺激超氧化物的形成和由一氧化氮合酶的诱导异构体催化的一氧化氮的形成。超氧化物的还原产物或其与一氧化氮反应的产物氧化或硝酸盐内皮成分导致肢体还原缺陷。
{"title":"Further evidence for the role of free radicals in the limb teratogenicity of L-NAME.","authors":"A. Fantel, R. Person","doi":"10.1002/TERA.10047","DOIUrl":"https://doi.org/10.1002/TERA.10047","url":null,"abstract":"BACKGROUND\u0000L-NAME (N(G)-nitro-(L)-arginine methyl ester), a nitric oxide synthase inhibitor, causes severe limb reduction malformations when gravid rats are treated intraperitoneally on gd-17. Hemorrhages, appearing within hours of L-NAME administration, and defects at term can be significantly reduced by co-treatment with PBN (alpha-phenyl-N-t-butylnitrone), a spin trap antioxidant. We have proposed that limb defects result from ischemia-reperfusion injury. We examine the role of xanthine oxidase and ROS formation in the limb effects of L-NAME.\u0000\u0000\u0000METHODS\u0000Gravidas were treated with L-NAME (50 mg/kg) in the presence or absence of allopurinol, a xanthine oxidase inhibitor. Spatial patterns of limb hemorrhage were determined promptly and at term as was digit length at the latter interval. Xanthine oxidase activities were assayed in control and treated limbs with and without allopurinol co-treatment.\u0000\u0000\u0000RESULTS\u0000Allopurinol significantly reduced hemorrhage severity in a dose-responsive fashion when fetuses were examined at term. Higher doses of allopurinol significantly preserved digit length. Xanthine oxidase activities in fetal limb were significantly increased by L-NAME treatment whereas co-treatment with allopurinol restored activities to near-control levels.\u0000\u0000\u0000CONCLUSIONS\u0000These findings support the role of excess reactive oxygen species (ROS) formation in L-NAME-induced limb reduction. We propose that nitric oxide (NO) depletion by L-NAME interferes with vascular integrity, and causes vasoconstriction. Resultant hypoxia stimulates superoxide formation and nitric oxide formation catalyzed by the inducible isoform of nitric oxide synthase. The reduction products of superoxide or the products of its reaction with nitric oxide oxidize or nitrate endothelial components resulting in limb reduction defects.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"15 1","pages":"24-32"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82911416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura J. Williams, Cara T Mai, L. Edmonds, G. Shaw, R. Kirby, C. Hobbs, L. Sever, L. Miller, F. Meaney, M. Levitt
BACKGROUND In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 microg of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification. METHODS Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases. RESULTS The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends. CONCLUSIONS The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.
{"title":"Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.","authors":"Laura J. Williams, Cara T Mai, L. Edmonds, G. Shaw, R. Kirby, C. Hobbs, L. Sever, L. Miller, F. Meaney, M. Levitt","doi":"10.1002/TERA.10060","DOIUrl":"https://doi.org/10.1002/TERA.10060","url":null,"abstract":"BACKGROUND\u0000In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 microg of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification.\u0000\u0000\u0000METHODS\u0000Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases.\u0000\u0000\u0000RESULTS\u0000The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends.\u0000\u0000\u0000CONCLUSIONS\u0000The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"20 1","pages":"33-9"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74630362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Case-control study confirms the diagnosis-specific risk of maternal diabetes: Reply to harold kalter","authors":"C. Loffredo, C. Ferencz","doi":"10.1002/TERA.10045","DOIUrl":"https://doi.org/10.1002/TERA.10045","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"38 1","pages":"4-5"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88057349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: in 1993 all women of childbearing age in the Netherlands were advised to take a daily 0.5 mg folic acid pill to reduce the risk for neural tube defects. This study describes both recent and past awareness and use of folic acid supplements in relation to socioeconomic status in the Northern Netherlands. The consequences of a recent report of the Dutch Health Council report will be discussed as well. Methods: In the most recent cross-sectional study (November 2000), pregnant women filled out a questionnaire. Out of 473 women, 461 were willing to cooperate. The highest fulfilled level of education was taken as an indicator for socio-economic status. Results: Seventy-seven percent (n = 357) of the respondents had heard about folic acid before being pregnant. Sixty-three percent (n = 289) knew about the protective effect for NTDs and 33% (n = 151) knew the entire advised period. Sixty-one percent (n = 265) of the respondents used folic acid in some part of the advised period and 36% (n = 164) used it in the entire advised period. Higher educated women knew more about folic acid and used it significantly more often in the periconceptional period than lower educated women. Conclusions: Because compliance to proper use of folic acid was poor, food fortification in the Netherlands must be seriously considered. The Dutch Health Council wants to limit the fortification of food products to those products that are especially aimed for women who wish to become pregnant. The fortification of specific products instead of staple foods is a missed chance to reduce NTDs and possibly other birth defects and cardiovascular defects as well.
{"title":"Insufficient folic acid intake in the Netherlands: what about the future?","authors":"de Hermien Walle, D. Berg","doi":"10.1002/TERA.10078","DOIUrl":"https://doi.org/10.1002/TERA.10078","url":null,"abstract":"Background: in 1993 all women of childbearing age in the Netherlands were advised to take a daily 0.5 mg folic acid pill to reduce the risk for neural tube defects. This study describes both recent and past awareness and use of folic acid supplements in relation to socioeconomic status in the Northern Netherlands. The consequences of a recent report of the Dutch Health Council report will be discussed as well. Methods: In the most recent cross-sectional study (November 2000), pregnant women filled out a questionnaire. Out of 473 women, 461 were willing to cooperate. The highest fulfilled level of education was taken as an indicator for socio-economic status. Results: Seventy-seven percent (n = 357) of the respondents had heard about folic acid before being pregnant. Sixty-three percent (n = 289) knew about the protective effect for NTDs and 33% (n = 151) knew the entire advised period. Sixty-one percent (n = 265) of the respondents used folic acid in some part of the advised period and 36% (n = 164) used it in the entire advised period. Higher educated women knew more about folic acid and used it significantly more often in the periconceptional period than lower educated women. Conclusions: Because compliance to proper use of folic acid was poor, food fortification in the Netherlands must be seriously considered. The Dutch Health Council wants to limit the fortification of food products to those products that are especially aimed for women who wish to become pregnant. The fortification of specific products instead of staple foods is a missed chance to reduce NTDs and possibly other birth defects and cardiovascular defects as well.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"62 1","pages":"40-43"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76657410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND An altered frequency of specific dermal ridge patterns on fingertips, such as an increased number of arches, has been observed in children exposed in utero to anticonvulsants and other teratogens. Asymmetry of the distribution of dermal ridge patterns has been attributed to environmental exposures and genetic factors. METHODS We evaluated all of the dermal ridge patterns of 66 children who had been exposed to either the anticonvulsant phenytoin alone or phenytoin and phenobarbital. We determined the frequency of each pattern, concordance between the fingers on the left and right hands, sex differences and total ridge counts in the drug-exposed children and compared them to the findings in 716 unexposed comparison children. The frequency of each pattern was established in comparison to the most common type of pattern (ulnar loop), which showed that there were alterations in the frequency of arches, radial loops and whorls on specific fingers. RESULTS Eight (12.1%) of 66 children had three or more arch patterns, with all but one having been exposed to phenytoin and phenobarbital. Only one of these eight children was considered by the masked examiner to have fingernail hypoplasia. There was no evidence of asymmetry in the anticonvulsant-exposed children. There were minor differences in the distribution of total ridge count. CONCLUSIONS Subtle differences in several dermal ridge patterns, not just arch patterns, were present in anticonvulsant-exposed children, primarily in those exposed to polytherapy: phenytoin and phenobarbital.
{"title":"Effect of prenatal exposure to anticonvulsant drugs on dermal ridge patterns of fingers.","authors":"A. Bokhari, B. Coull, L. Holmes","doi":"10.1002/TERA.10044","DOIUrl":"https://doi.org/10.1002/TERA.10044","url":null,"abstract":"BACKGROUND\u0000An altered frequency of specific dermal ridge patterns on fingertips, such as an increased number of arches, has been observed in children exposed in utero to anticonvulsants and other teratogens. Asymmetry of the distribution of dermal ridge patterns has been attributed to environmental exposures and genetic factors.\u0000\u0000\u0000METHODS\u0000We evaluated all of the dermal ridge patterns of 66 children who had been exposed to either the anticonvulsant phenytoin alone or phenytoin and phenobarbital. We determined the frequency of each pattern, concordance between the fingers on the left and right hands, sex differences and total ridge counts in the drug-exposed children and compared them to the findings in 716 unexposed comparison children. The frequency of each pattern was established in comparison to the most common type of pattern (ulnar loop), which showed that there were alterations in the frequency of arches, radial loops and whorls on specific fingers.\u0000\u0000\u0000RESULTS\u0000Eight (12.1%) of 66 children had three or more arch patterns, with all but one having been exposed to phenytoin and phenobarbital. Only one of these eight children was considered by the masked examiner to have fingernail hypoplasia. There was no evidence of asymmetry in the anticonvulsant-exposed children. There were minor differences in the distribution of total ridge count.\u0000\u0000\u0000CONCLUSIONS\u0000Subtle differences in several dermal ridge patterns, not just arch patterns, were present in anticonvulsant-exposed children, primarily in those exposed to polytherapy: phenytoin and phenobarbital.","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"23 1","pages":"19-23"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91275125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Azathioprine (AZA) and its active metabolite, 6-mercaptopurine (6-MP), are purine analogues that interfere with the synthesis of adenine and guanine ribonucleosides. These ribonucleosides are important precursors of DNA and RNA. Because AZA and 6-MP act predominantly on rapidly dividing cells such as the T lymphocytes, these drugs are not only cytotoxic but also immunosuppressive and anti-inflammatory. The effects are dose-related, small doses of either drug are anti-inflammatory, but larger doses are immunosuppressive and cytotoxic (Goldstein, ’87). 6-MP has been used in cancer chemotherapy, primarily in childhood and adult leukemias and usually in combination with other drugs. 6-MP is also used to treat autoimmune diseases, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) (Bermas and Hill, ’95; Ramsey-Goldman and Schilling, ’97). Initial oral doses for treatment of leukemia range between 2.5–5 mg/kg/d. For maintenance therapy of leukemia, doses range between 1.5–2.5 mg/kg/d. Similar doses (1.5–2.5 mg/kg/d) are used to treat IBD (Present et al., ’80; Botoman et al., ’98; USP DI, ’01), but the use of 6-MP as an immunosuppressant has been largely superseded by AZA, which has been shown to possess a better therapeutic index (Van Scoik et al., ’85; Goldstein, ’87; Chabner et al., ’96). AZA is no longer used as an antineoplastic agent (Ostensen, ’92), but is employed in the treatment of autoimmune disorders at doses between 1–2.5 mg/kg/d and at doses between 1–5 mg/kg/d as part of immunosuppressive regimens to prevent transplant rejection (Botoman et al., ’98; USP DI, ’01). The majority of patients affected by autoimmune diseases are women, in whom the peak incidence occurs between 16 and 55 years of age (Weterman, ’89; Brent et al., ’97; Esplin and Branch, ’97). Successful treatment with cytotoxic and immunosuppressant drugs such as AZA has greatly improved the feasibility of pregnancy in affected women, many of whom must continue to take the medications throughout gestation to prevent relapse. Similarly, women who become pregnant after organ transplantation continue immunosuppressive therapy to prevent rejection if they have been on immunosuppressive therapy before pregnancy. In some patients who become ill with an immunopathic or malignant disease while pregnant, treatment with 6-MP or AZA may be initiated during gestation. The use of cytotoxic immunosuppressants during pregnancy raises concern about possible adverse effects in the developing embryo or fetus, but the potential teratogenicity of AZA and 6-MP is difficult to evaluate in humans. These agents are used to treat patients who have severe illness, and it is often impossible to determine if adverse effects that occur in the embryo/fetus resulted from a particular treatment, the maternal illness, or some other factor (Brent et al., ’97). Also, because of the severity of the illness and the complications that ensue, combination thera
硫唑嘌呤(AZA)及其活性代谢物6-巯基嘌呤(6-MP)是嘌呤类似物，可干扰腺嘌呤和鸟嘌呤核糖核苷的合成。这些核糖核苷是DNA和RNA的重要前体。由于AZA和6-MP主要作用于快速分裂的细胞，如T淋巴细胞，这些药物不仅具有细胞毒性，而且具有免疫抑制和抗炎作用。效果与剂量有关，小剂量的任何一种药物都具有抗炎作用，但大剂量的药物具有免疫抑制和细胞毒性(Goldstein， ' 87)。6-MP已用于癌症化疗，主要用于儿童和成人白血病，通常与其他药物联合使用。6-MP也用于治疗自身免疫性疾病，如炎症性肠病(IBD)、系统性红斑狼疮(SLE)和类风湿性关节炎(RA) (Bermas and Hill, 1995;Ramsey-Goldman and Schilling, 1997)。治疗白血病的初始口服剂量范围为2.5 - 5mg /kg/d。对于白血病的维持治疗，剂量范围为1.5-2.5 mg/kg/d。类似剂量(1.5-2.5 mg/kg/d)用于治疗IBD (Present et al.， 1980;Botoman et al.， 1998;USP DI， ' 01)，但6-MP作为免疫抑制剂的使用已在很大程度上被AZA所取代，AZA已被证明具有更好的治疗指数(Van Scoik等人，' 85;戈尔茨坦,87;Chabner et al.， 1996)。AZA不再被用作抗肿瘤药物(Ostensen, 1992年)，但被用于治疗自身免疫性疾病，剂量在1-2.5 mg/kg/d和1-5 mg/kg/d之间，作为免疫抑制方案的一部分，以防止移植排斥反应(Botoman等人，1998年;uspdi， ' 01)。受自身免疫性疾病影响的大多数患者是女性，其发病率高峰发生在16至55岁之间(Weterman, 1989;Brent et al.， 1997;Esplin and Branch, 1997)。细胞毒性和免疫抑制药物(如AZA)的成功治疗大大提高了受影响妇女怀孕的可行性，其中许多人必须在整个妊娠期间继续服用药物以防止复发。同样，在器官移植后怀孕的妇女如果在怀孕前接受过免疫抑制治疗，则继续免疫抑制治疗以防止排斥反应。在一些怀孕期间患有免疫病变或恶性疾病的患者中，可以在妊娠期间开始使用6-MP或AZA治疗。妊娠期间使用细胞毒性免疫抑制剂引起了对发育中的胚胎或胎儿可能产生的不良影响的担忧，但AZA和6-MP在人类中的潜在致畸性难以评估。这些药物用于治疗患有严重疾病的患者，通常无法确定胚胎/胎儿中发生的不良反应是由特定治疗、母体疾病还是其他因素引起的(Brent et al.， 1997)。此外，由于疾病的严重性和随之而来的并发症，联合治疗是常见的。药物组合的使用以及剂量的变化进一步阻碍了将观察到的不良反应归因于特定治疗的努力。本文将回顾有关6-巯基嘌呤和AZA的药理学及其对胚胎和胎儿的不良影响的人类和动物数据。
{"title":"Teratogen update: azathioprine and 6-mercaptopurine.","authors":"J. Polifka, J. Friedman","doi":"10.1002/TERA.10043","DOIUrl":"https://doi.org/10.1002/TERA.10043","url":null,"abstract":"Azathioprine (AZA) and its active metabolite, 6-mercaptopurine (6-MP), are purine analogues that interfere with the synthesis of adenine and guanine ribonucleosides. These ribonucleosides are important precursors of DNA and RNA. Because AZA and 6-MP act predominantly on rapidly dividing cells such as the T lymphocytes, these drugs are not only cytotoxic but also immunosuppressive and anti-inflammatory. The effects are dose-related, small doses of either drug are anti-inflammatory, but larger doses are immunosuppressive and cytotoxic (Goldstein, ’87). 6-MP has been used in cancer chemotherapy, primarily in childhood and adult leukemias and usually in combination with other drugs. 6-MP is also used to treat autoimmune diseases, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) (Bermas and Hill, ’95; Ramsey-Goldman and Schilling, ’97). Initial oral doses for treatment of leukemia range between 2.5–5 mg/kg/d. For maintenance therapy of leukemia, doses range between 1.5–2.5 mg/kg/d. Similar doses (1.5–2.5 mg/kg/d) are used to treat IBD (Present et al., ’80; Botoman et al., ’98; USP DI, ’01), but the use of 6-MP as an immunosuppressant has been largely superseded by AZA, which has been shown to possess a better therapeutic index (Van Scoik et al., ’85; Goldstein, ’87; Chabner et al., ’96). AZA is no longer used as an antineoplastic agent (Ostensen, ’92), but is employed in the treatment of autoimmune disorders at doses between 1–2.5 mg/kg/d and at doses between 1–5 mg/kg/d as part of immunosuppressive regimens to prevent transplant rejection (Botoman et al., ’98; USP DI, ’01). The majority of patients affected by autoimmune diseases are women, in whom the peak incidence occurs between 16 and 55 years of age (Weterman, ’89; Brent et al., ’97; Esplin and Branch, ’97). Successful treatment with cytotoxic and immunosuppressant drugs such as AZA has greatly improved the feasibility of pregnancy in affected women, many of whom must continue to take the medications throughout gestation to prevent relapse. Similarly, women who become pregnant after organ transplantation continue immunosuppressive therapy to prevent rejection if they have been on immunosuppressive therapy before pregnancy. In some patients who become ill with an immunopathic or malignant disease while pregnant, treatment with 6-MP or AZA may be initiated during gestation. The use of cytotoxic immunosuppressants during pregnancy raises concern about possible adverse effects in the developing embryo or fetus, but the potential teratogenicity of AZA and 6-MP is difficult to evaluate in humans. These agents are used to treat patients who have severe illness, and it is often impossible to determine if adverse effects that occur in the embryo/fetus resulted from a particular treatment, the maternal illness, or some other factor (Brent et al., ’97). Also, because of the severity of the illness and the complications that ensue, combination thera","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"13 1","pages":"240-61"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86060340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dose response in human teratology.","authors":"T. Shepard","doi":"10.1002/TERA.10059","DOIUrl":"https://doi.org/10.1002/TERA.10059","url":null,"abstract":"","PeriodicalId":22211,"journal":{"name":"Teratology","volume":"95 1","pages":"199-200"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79459682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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