Illegally performed abortions are responsible for a significant amoun mortality that occurs in pregnant women around the world. Much of th mortality results from surgical abortion techniques which put women’s significant risk when performed by unskilled persons. Recently, medi techniques have been shown to be as effective as surgical procedures.
prostaglandin E1 analog, has gained notoriety for its abortifacient p its use in Brazil, where abortion is illegal. Cytotec has been teste and shown to be a safe, effective, inexpensive abortifacient. When i in Brazil, Cytotec could be purchased easily in drugstores and theref to provide women with a legally accessible, inexpensive, and safe meth abortions. However, due to lack of knowledge about the administratio abortifacient and restrictions placed on Cytotec sales by government entirely lived up to this potential. Despite the problems associate an abortifacient in Brazil, its use will likely continue. Because of medically induced abortions, drugs such as Cytotec are likely to be u in other countries as an alternative to surgical procedures.
The issue of abortion remains one of the most charged topics in care today. The legal status of abortion is debated perpetually in t throughout the world. From a legal perspective, 40% of the world’s p access to abortion on request, 12% have access if there are social, e indications, 23% have access only in cases where the life of the moth for 25% of the population, abortions are prohibited under any circums reality often nullifies the legal debate over abortion. Abortions in of legal status or of attempts by government to enforce legal codes. consequence of illegally performed abortions is the death of thousand unsafe procedures. It is estimated that 200,000 abortion-related dea resulting in 10-60% of all maternal death (numbers vary by country).< morbidity due to abortions include: pelvic infection, hemorrhage and lacerations, uterine perforation, and damage to the bladder and intes America, where abortion is illegal in most countries, abortion is the in women ages 15-39.<3> Estimates suggest that one in three to five abortions in Latin America result in hospitalization.<2> For women l where the law prohibits abortion, the issue is not whether they can h whether they can have safe abortions.
In Brazil, abortion is prohibited by law. The Brazilian Civil C rights of the fetus by explicitly prohibiting abortions except when t in jeopardy or when the pregnancy is the result of rape.<4> Determin abortions performed in Brazil is therefore problematic. However, rea for the year 1985 range from 324-822 abortions per 1,000 live births.
there were approximately 1,300,000 to 3,300,000 abortions performed i Typical methods for performing illegal abortions range from proc dilatation and curettage or vacuum aspiration performed clandestinely private medical office to administration of herbal abortifacients wit insertion of catheters by unskilled persons. The safety of such tech depending on the method, circumstance, and the person performing the But the fact that abortion is one of the top four causes of maternal and, in some areas the number one cause, proves that Brazilian women, around the world, need an alternative to unsafe abortions.<6> The women of Brazil thought they had found such an alternative w called Cytotec, which could be obtained legally, was introduced to th Did Cytotec fulfill this goal? To answer this question, this paper w efficacy of inducing abortion using Cytotec alone and then evaluate t experience with Cytotec. Finally, the use of Cytotec to induce abort discussed with respect to its future in Brazil and in other developin Cytotec, the brand name for Misoprostol, is a prostaglandin E1 a by G.D. Searle and Co. The drug was developed and approved for treat prevention of gastric and duodenal ulcers.<7> However, its effects a For many years, prostaglandins have been known for their abortif properties. Prostaglandin analogs act on uterine muscle, causing con potentially induce an abortion in a pregnant woman.<7> Various studi efficacy of prostaglandin analogs in inducing abortions during the f trimester of a pregnancy.<8> More recently, prostaglandin analogs, i have been used successfully in combination with mifepristone (an anti known as RU486) or with methotrexate to induce abortions.<9,10> The controlled studies to evaluate the efficacy of Cytotec used abortifacient are limited, but nonetheless illuminating. In a German the effect of orally administered Cytotec on the pregnancies of 300 p weeks gestation) was evaluated. Eleven percent of the women who rece 400 mcg of Cytotec and nine percent of the women who received two dos had spontaneous partial or complete abortions. This study suggested administered orally in doses of 400 mcg and 800 mcg, Cytotec is not a trimester abortifacient. Effects on pregnancy during the second and However, two subsequent studies done in Mozambique by Bugalho et that intravaginal administration of Cytotec can effectively induce ab women were given an initial intravaginal dose of 800 mcg of Cytotec, mcg at 18 hours if there was no cervical maturation or softening, fol mcg at 24 hours if the cervix remained unaffected. Of the 102 women w the initial dose of Cytotec, 100% aborted. Of the 26 cases who recei of Cytotec, 11 did not respond. In total 91% of the women successful expulsion of the fetus. Side effects associated with Cytotec were mi women showed signs of uterine wall perforation, endometritis or hemor paracetamol (a mild nonsteroidal anti-inflammatory drug) was the only (Only 20% of women required paracetamol.) Curettage was carried out expulsion of the fetus and the fetal membranes.<12> In the second study done by Bugalho et al., 121 women received a intravaginal dose of 800 mcg of Cytotec, 10 women received an initial and 28 women received 200 mcg initially. A second dose of the same s hours later if there was no evidence of abortion in progress. Final in six women, 400 mcg in 25 women, 600 mcg in 11, 800 mcg in 108, 1,20 1,600 in six. A successful abortion occurred in 89.9% of the women a gestation and 92.5% of the women at 14-22 weeks gestation. (Successf defined as being in an advanced stage of abortion after 48 hours.) In medical abortion, evacuation of the fetus and placenta, occurred. Ag minimal. None of the women required transfusions. There were no maj or deaths. No one reported vomiting, diarrhea, fever or sweating. A of the women required an analgesic stronger than paracetamol. For sa aspiration of the uterine cavity after expulsion was performed in all not appear to be necessary in most cases). The study did not docume cases in which tissue was obtained from the vacuum aspiration procedu In a recent randomized trial done in the United States by Jain a Cytotec was compared with prostaglandin E2, the agent most widely use induced second trimester abortions. In this study, 28 women between gestation were given 200 mcg of Cytotec intravaginally every 12 hours enrolled requested abortions because of intrauterine fetal death or me reasons. Live fetuses received a lethal intracardiac injection of po avoid mandatory postnatal efforts to resuscitate fetuses with severe Twenty five of the women had successful abortions within 24 hours and three women received an additional dose of 200 mcg of Cytotec at 24 h successful abortions between 24 and 36 hours. Complete abortion, def simultaneous passage of the fetus and the placenta, occurred in only treated with Cytotec. After fetal expulsion all women received oxyto curettage to remove any remaining products of conception.<14> While these studies show that Cytotec can be an effective aborti administered intravaginally in the first and second trimester, it is the conditions under which the studies were performed. The women in were monitored at regular intervals by trained personnel for appropri medication on the cervix. In addition, in each study, the women had aspiration or curettage procedure done after the abortion to ensure t conception were completely expelled.<12,13,14> This is noteworthy be products of conception are an important cause of morbidity.<14> In t study only 43% had expulsion of the fetus and placenta simultaneously who had remaining products of conception removed, would have been at or bleeding had they not undergone curettage after expulsion of the f and Mishell study used a specific population of women, those requesti because of intrauterine fetal death or medical or genetic reasons. I fetuses were treated with a lethal intracardiac injection of potassiu inducing an abortion with Cytotec.<14> It is unclear how, or if, the Cytotec’s efficacy as an abortifacient.
The data suggest that, under the supervision of trained personne sterile surgical facilities for performing curettage or aspiration pr Cytotec as an abortifacient is safe and associated with few side effe the future, Cytotec may be able to be given safely at home assuming t understand how to administer it properly and under what circumstance Use of Cytotec as an Abortifacient in Brazil Cytotec was introduced to Brazil in 1986. Biolab, a Brazilian l marketing the drug in 1988.<7> Despite the fact that Cytotec is not abortifacient, that the package insert specifically states that the d use by pregnant women because of its side effect of complete or incom miscarriage,<15> and that Cytotec’s manufacturer, G.D. Searle and Co.
its use as an abortifacient,* Brazilian women began using Cytotec for inducing abortions. A retrospective study done on pregnant women adm Fortaleza emergency room in 1988 found that Cytotec was the agent res cases of uterine bleeding (12% of admissions). In 1989 that number i (56% of admissions). And in 1990 it jumped to 524 (73% of admissions reports came from all over the country including Recife, Sno Paulo, an Janeiro.<16,17,18> Its use in other areas is probable though not doc Information about Cytotec spread via doctors, pharmacists, and The misuse of Cytotec as an abortifacient gained national recognition community when Dr. H. Coelho of the Federal University of Cear< discu problem at a seminar held by the National Institute for Quality Contr (INCQS).<19> A report from Biolab in 1991 indicated that 35% of Cyt in Brazil was as an abortifacient.<7> There was no doubt that Brazil experimenting with a new abortion technique.
* This information provided by G.D. Searle and Co.
Despite the fact that Cytotec is marketed in over 75 countries, abortifacient is virtually limited to Brazil.<7> Part of this select attributed to the accessibility of prescription drugs due to poorly r distribution. In Brazil, most drugs are sold at the discretion of ph warning labels restricting sales to people with a prescription.<20> any pharmacy and buy Cytotec without a prescription. If questioned, symptoms consistent with an ulcer would easily appease most pharmaci gladly sell the medication. This lack of regulation on the distribut Brazil opened a door for the use of Cytotec as an abortifacient, a do easily opened in other countries where distribution of medications is The pharmacists however, were not naive accomplices in the misus an abortifacient. In fact, pharmacists helped popularize this new ab selling Cytotec to clients interested specifically in inducing aborti 1991 in the Fortaleza area, 102 pharmacists were consulted for advice unwanted pregnancy. Of the pharmacists consulted, 67% gave advice an suggested using Cytotec.<19> Pharmacists also recommended other tech inducing abortions, but Cytotec was suggested most frequently.<21> (T TABLE 1. Advice given by pharmacists consulted about unwanted pregna Other drugs include plant extracts, hormones, and disopyramide.
Other drugs include plant extracts, hormones, and drugs administered via IM as prostigmine.
Source: Coelho HLL. O que est< em jogo no caso Cytotec. CiLncia Hoje. 1991;13 While the availability of prescription drugs may explain why Cyt popular in Brazil as an abortifacient and not in other countries, it Brazilian women chose this new medically induced procedure over more abortion methods such as catheter insertion. One explanation for the Cytotec is its low cost. On average, one could purchase Cytotec for treatment. This is an incredible benefit for women whose economic si allow them to pay the estimated $42 for catheter insertion or $144 fo Further insight into the reasons for choosing Cytotec over other from a report on interviews with 14 women (ages 18-40) from different used Cytotec to induce an abortion. Three important explanations eme interviews. First, using Cytotec made the decision to have an aborti relatives would often purchase Cytotec for the pregnant woman, someti she had decided to have an abortion. This eliminated the effort and search out someone to perform the procedure illegally. Second, the i reportedly very important. Women can administer the drug in their ow outside intervention, thereby sparing them the embarrassment of going And third, women reported that Cytotec is perceived as being a safer Cytotec seemed to be the solution, an easily obtainable, inexpen of abortion that allowed women privacy. What had yet to be seen was The data on Cytotec users in Brazil comes from hospital-based st include all women who unsuccessfully attempted to induce abortions an seek medical care due to the effects of their failed efforts. Such s little difference between users and non-users of Cytotec. Table 2 in information collected from three of the main hospital-based studies. al.(1994) study done in Fortaleza between July 1992 and February 199 women hospitalized after using Cytotec.<22> The Costa and Vessey stu de Janeiro between April and December 1991 and the Coelho et al.(1993 Fortaleza between January 1990 and July 1992 both include information women hospitalized for induced abortions.<18,23> TABLE 2. Demographics of women hospitalized after attempting to induce a Social class follows criteria from the AssociaHno Brasileira de Pesquisa de M5 classes, from A (higher) to E (lower).
The majority of women were in their third decade of life. In th study 61% of women were between the ages of 19-29. In the Coelho et 57% of the women were between the ages of 20-29. Most women had a pa three. Fifty-one percent had a parity of one to two in the Costa and 60% had a parity of one to three in the Coelho et al.(1994) study. S more likely than married women to be hospitalized for abortions. Per mothers ranged from 60-90%. Most women had minimal education. Seven percent and 83% of the women in the Costa and Vessey and Coelho et al respectively had not completed high school. Women were generally of socioeconomic class. These data suggest that Cytotec users, like wom methods to induce abortions, can be characterized as young, single, p women of lower social class with one to two children.
The limitations of hospital-based studies such as those describe their failure to include a representative sample of the Cytotec user accurately characterize Cytotec users in Brazil it would be necessary on all of the women who attempted to induce abortions with Cytotec or sample of those women. Because of the legal restrictions on abortion information is virtually impossible. The data is therefore biased, p large numbers of women who successfully induced abortion with Cytotec went on to deliver their babies despite failed abortion attempts.
Reports on route of drug administration varied significantly fro Women administered the drug orally, intravaginally, and both orally an Includes oral and intravaginal administration.
Doses also varied significantly. Cytotec is sold in packs of 28 each. Reports indicate that doses ranged from one to 46 tablets with ranging from four to eight tablets. In the Costa and Vessey study th four tablets. In the Coelho et al.(1994) study, 53% of women using C tablets. Generally smaller doses were given at one time, and massive The reported gestational age at the time of induction ranged fro weeks up to 28 weeks with a majority of women using Cytotec in the f pregnancy. In the Costa and Vessey study, 74% of women used Cytotec weeks and eight percent used it at 20 weeks or later. In the Coelho 92% used Cytotec in the first 16 weeks of gestation. And in the Coel study, 90% took Cytotec at 12 weeks or less.<18,22,23> Efficacy and Safety of Cytotec Use in Brazil In examining the efficacy of using Cytotec as an abortifacient in faced with the difficulty of having only hospital-based data and the associated with using such data. If the women who present at the ho majority of the users, clearly Cytotec is not an effective abortifaci at home. If, on the other hand, the majority of women who use Cytote medical care because they have successful abortions with no adverse e probably a fairly effective method of inducing abortions when adminis long as women are instructed as to when they should seek medical care minimal morbidity arising from the few cases where Cytotec is not eff Despite the limitations of the data, hospital-based studies do c concerning the efficacy of Cytotec compared with other techniques of One study showed that while there was morbidity among Cytotec users, more women who used catheter insertion to induce abortions developed physical injuries or required blood transfusions.<18> In fact, Brazi have stated that they consider uterine bleeding, the major complicati Cytotec, less serious than uterine perforation or pelvic infections w associated with other methods of inducing abortions.<7> Essentially, Cytotec induces less life threatening morbidity tha methods, yet causes sufficient damage to warrant seeking medical care as a kind of “passport” to the hospital by allowing women admission where abortions can be performed legally (because the woman’s health For this “passport” to work, and in the interest of ensuring th administered properly and therefore safely, women need to be informed the drug and when it is necessary to seek medical attention. However are not appropriately informed on the use of the drug prior to admin indicated that 64% of women who took Cytotec on the advice of pharmac no instruction on how to use the drug.<15> In another study, only h purchasing the drug from pharmacists were given instructions on its u some women viewed their experience with Cytotec as negative in part b lacked information about the drug and did not know when to seek assis kind of ignorance when using any drug is dangerous, but when the drug cause serious complications such as infection and bleeding, it could b The final consideration with respect to efficacy and safety rela consequences for women whose abortion attempts fail and who subsequen babies. There is much evidence suggesting that Cytotec is teratogeni congenital malformations in children of mothers who unsuccessfully at abortions using Cytotec confirm this suspicion.<17,19,24> Ingestion pregnancy may cause malformations such as bone lesions resembling per hyperostosis, or limb defects like agenesis of the distal phalanges.< The teratogenicity of Cytotec is a significant public health thr estimates that 11% of women who deliver at term have used Cytotec in induce an abortion.<18> This further emphasizes the importance of ed about the use of Cytotec. Any woman who unsuccessfully attempts to abortion using Cytotec should immediately consult a physician.
Given the morbidity associated with the use of Cytotec, the rep teratagenicity, the illegal status of induced abortion in Brazil, and increase in abortion rates due to Cytotec’s use, the Brazilian govenm intervened. Regulations were enacted to limit Cytotec’s use as an ab the Ministry of Health implemented new guidelines under which the dru by authorized drugstores. Pharmacists could only sell Cytotec with physician, a copy of which had to be retained for official use. In s restrictions were implemented. In Cear<, the drug was totally banned and Minas Gerais it was limited to hospital use. And in Sno Paulo, d restricted to gastroenterological purposes; though hospitals could us gynecological purposes with the permission of the Ministry of Health The effects of these regulations can be seen in the change of Cy sales of Cytotec show a significant increase between 1988 and 1989 wh became aware of Cytotec’s abortifacient properties and its popularity sales dropped off significantly after 1991 when new regulations were The effect of the regulations is even more striking when comparing mo Cytotec. Sales decreased from 58,089 boxes in July 1991 to 23,959 bo 1991, the month following the imposition of the new regulation.<7> TABLE 4. Sales of Cytotec from 1986 to 1995 Cytotec introduced into the Brazilian market in August 1986 Source: Data for 1986-1992 from Barbosa RM, Arilha M. The Brazilian experience w Studies in Family Planning. 1993;24:236-240.
Data for 1993-1995 obtained from G.D. Searle and Co.
In addition to govenment restrictions, reduction in production b following an agreement with the Ministry of Health contributed to the Cytotec. The media also influenced Cytotec sales. Intense newspaper the use of Cytotec created a negative image, reducing customer demand pharmacies and drugstores to let their inventories decline.<7> But decreased sales of Cytotec did not ensure control of its use Several studies document continued use of Cytotec as an abortifacient 1991.<18,22,23> In the Costa and Vessey study, 57% of women admitte public hospitals between April and December 1991 for induced abortion Cytotec.<18> In Fortaleza, where sales of Cytotec were totally bann al.(1993) noted 20 cases of Cytotec use among pregnant women admitted obstetric hospital in December 1991, with similar numbers of cases re June, 1992. The same study reports that 70% of all evacuations at th hospital in Fortaleza resulted from use of Cytotec.<23> The Coelho identified 102 women who used Cytotec to induce an abortion between J Continued use of Cytotec is likely due to clandestine sales.<22> no documentation in the literature, it is reasonable to assume that t significantly higher when sold on the “black market,” making it more d As has been noted, abortions take place regardless of legal sta government restrictions are futile. But since illegally performed ab significant morbidity and mortality, the legal status of abortion is determinant of safety for women trying to take control of their ferti crucial factor in determining the life or death of thousands of women In Brazil, women tried to protect themselves against unsafe abor experimenting with a new medically induced method of abortion. Cytot the needed alternative to “back alley” abortions. Many hoped it woul an easily obtainable, inexpensive, private, safe method of inducing a has thus far been undermined in two ways.
First, Cytotec can not be considered safe as it is currently use ensure the safety of Cytotec, women must be adequately counseled on administration and on signs which necessitate seeking further medical education and counseling efforts are sorely lacking in Brazil, a situ to change. Because abortion is illegal, means to inform the public o perform an abortion using Cytotec are severely limited.
And second, government intervention essentially eliminated much Cytotec appealing. Limiting sales has made a once easily accessible d obtain. A shift of sales to the “black market” has undoubtedly raise medication limiting its use by the lower classes who need it the most of the hands of the pharmacists and putting it into the hands of the the street has further intensified the problem of counseling women pr Cytotec, similar to other methods of abortion, is currently not easil Despite not fully achieving its goal, Cytotec undoubtedly has a There is no reason to believe that clandestine sales of Cytotec will will cease to exploit its abortifacient properties. The ramification are not entirely negative. While Cytotec’s potential to induce morbi unquestionable given the way it is currently administered in Brazil, severity of morbidity induced from illegally performed abortions with significantly less than that induced by traditional methods. As a “s inducing abortions, Cytotec may reduce morbidity and mortality rates Recommendations/Implications for Other Countries Perhaps the best way to reduce morbidity and mortality due to a ensure that unwanted pregnancies do not occur. Certainly considerabl efforts should focus on improving the availability and methods of fam since no one can ensure 100% control of fertility using current metho represents one approach to dealing with unwanted pregnancies. As suc to develop safe, accessible abortions for women who choose that optio Our present understanding of how to use Cytotec as an abortifaci infancy. It is clear that intravaginal administration of Cytotec can method of inducing abortions. However, further studies are needed to dosing and administration regimens and to determine if Cytotec can be skilled health workers present to intervene during the course of the Once optimal dosing and administration regimens are determined, physicians about these regimens will be needed. Physicians need to k properly instruct their patients who use Cytotec. In countries wher disseminating such information may be problematic. This issue will h Such research should not be limited to Cytotec. Medically induc advantages over other abortion techniques. As a noninvasive techniqu induced abortions do not require personnel with sophisticated surgica with advanced technology. This has huge implications for developing surgically trained health care workers are in short supply and for ar countries where similar shortages of skilled personnel and facilities variety of medical abortion regimens have been shown to be effective Cytotec alone and Cytotec in combination with RU486 or methotrexate) women around the world will be turning more and more to medical method World Health Organization. The Prevention and Management of Uns Abortion. Report of a technical Working group. Geneva, 12-15 A 2. Paxman JM, Rizo A, Brown L, Benson J. The clandestine epidemic: of unsafe abortion in Latin America. Studies in Family Planning 3. Woodroffe C. Medical abortion and the availability of RU486-are being ignored in developing countries? Health Policy and Pl 4. Dias HP. Bioethics: implications for medical practice and deont standards in Brazil. Bulletin of the Pan American Health Organi 5. Singh S, Wulf D. Estimating abortion levels in Brazil, Colombia hospital admissions and fertility survey data. International Fa 6. Laguardia KD, Rotholz MV, Belfort P. A 10-year review of matern in a municipal hospital in Rio de Janeiro: a cause for concern. 7. Barbosa RM, Arilha M. The Brazilian experience with Cytotec. S Bygdeman M. The use of prostaglandins and their analogues for a Clinics in Obstetrics and Gynaecology. 1984;11:573-584.
9. McKinley C, Thong KJ, Baird DT. The effect of dose of mifeprist gestation on the efficacy of medical abortion with mifepristone Human Reproduction. 1993;8:1502-1505.
10. Hausknecht RU. Methotrexate and misoprostol to terminate early The New England Journal of Medicine. 1995;333:337-340.
11. Rabe T, Basse H, Thuro H, Kiesel L, Runnebaum B. Effect of the analog misoprostol on the pregnant uterus in the first trimester 12. Bugalho A, Bique C, Almeida L, Bergstrom S. Pregnancy interrupt misoprostol. Gynecologic and Obstetric Investigation. 1993;36:226-2 13. Bugalho A, Bique C, Almeida L, Faundes A. The effectiveness of i misoprostol (Cytotec) in inducing abortion after eleven weeks of Studies in Family Planning. 1993;24:319-323.
14. Jain JK, Mishell DR. A comparison of intravaginal misoprostol w prostaglandin E2 for termination of second-trimester pregnancy. England Journal of Medicine. 1994;331:290-293.
15. Coelho HLL, Misago C, Fonseca WVC, Sousa DSC, Araujo JML. Sellin abortifacients over the counter in pharmacies in Fortaleza, Braz 16. Barros JAC. A medicalizaHno da mulher no Brazil. In: Wolffers Janssen J, eds. O Marketing Da Fertilidade. Sno Paulo: Hucite 17. Gonzalez CH, Vargas FR, et al. Limb deficiency with or without sequence in seven Brazilian children associated with misoprostol trimester of pregnancy. American Journal of Medical Genetics. 18. Costa SH, Vessey MP. Misoprostol and illegal abortion in Rio de 19. Sch`nh`fer PS. Brazil: misuse of misoprostol as an abortifacien malformations. The Lancet. 1991;337:1534-1535.
20. Paulo LG, Zanini AC. AutomedicaHno no Brasil. Rev Ass Med Bras 21. Coelho HLL. O que est< em jogo no caso cytotec. CiLncia Hoje. 22. Coelho HL, Teixeira AC, et al. Misoprostol: the experience of Fortaleza, Brazil. Contraception. 1994;49:101-110.
23. Coelho HLL, Teixeira AC et al. Misoprostol and illegal abortion Brazil. The Lancet. 1993;341:1261-1263.
24. Fonseca W, Alencar AJ, Pereira RM, Misago C. Congenital malform scalp and cranium after failed first trimester abortion attempt Clinical Dysmorphology. 1993;2:76-80.


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Pharmaceutical analysis and Quality control Ph-343 Submitted to: Submitted by: Date of submission: 20 – 02 - 07 APPLICATIONS OF HPLC 1.The wide verity of packing materials allows the separation ofmost chemical species. Chemical Separations can be accomplished using HPLC by utilizing the fact that certain compounds have differentmigration rates given a particular co

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