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The "boom and bust phenomenon" is a pattern that has emerged in the development, introduction, and delivery of a number of significant new contraceptive products in the United States. When a new contraceptive product is introduced with great promise and publicity, it usually experiences a "boom" during which sales, demand, and expectations are high. This boom is often followed by a "bust" phase during which a product does not live up to expectations, initial excitement falls off, and a drop in sales and use ensues. The boom and bust phenomenon goes to the heart of what some have referred to as the failed promise of the contraception revolution by creating obstacles to significant expansion of contraceptive choice in the United States. Case studies of oral contraceptives, intrauterine devices, and Norplant(R) are used to illustrate the boom and bust phenomenon and the effect it has had in shaping the direction of advances in contraceptive technology.

PIP: The ¿boom and bust phenomenon¿ is a pattern that has emerged in the development, introduction, and delivery of many contraceptive products over the last several decades in the US. When a new contraceptive product is introduced with great promise and publicity, it experiences a ¿boom¿ phase during which sales, demand and expectations for the product are high. A ¿bust¿ phase usually follows this boom, during which a product does not appear to live up to expectations, initial excitement falls off, and a drop in sales and use ensues. The boom and bust phenomenon goes through the heart of what some have referred to as the failed promise of the contraception revolution by creating obstacles to significant expansion of contraceptive use in the US. In the paper, a number of forces that have influenced the use trends and public perceptions of 3 modern methods of contraception; namely, oral contraceptives, intrauterine devices, and Norplant are examined to illustrate how the boom and the bust cycle unfolds in the US contraceptive market and what impact this phenomenon has had in shaping the advances in contraceptive technology.

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The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only one man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects on the 7.5 mg/day dose group, 12 recovered sperm counts >20 million/mL within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. Eight of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

PIP: The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only 1 man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects in the 7.5 mg/day dose group, 12 recovered sperm counts higher than 20 million/ml within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. 8 of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

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PIP: Forecast for the family planning field is optimistic that in the next 20 years, women can use microbicides to protect themselves from untended pregnancies and sexually transmitted diseases such as gonorrhea, genital herpes, trichomoniasis, syphilis, and AIDS. The first line microbicides projected to be most likely developed will be those that loosely fall under the surfactant/detergent category. The Population Council of New York is conducting a study to evaluate the safety and acceptability of PC-515. PC-515, a microbicidal gel containing carrageenan, which is compatible with the nonoxynol-9 spermicide. The council is recently receiving a $4 million support from Bill and Belinda Gates Foundation for the development of the product. The Council is likewise scheduling phase III trials for its vaginal contraceptive rings to serve the same purpose. Meanwhile, male contraceptives, both systemic and nonsystemic, that will interfere with sperm maturation may be well seen in the next 20 years. Hormonal approaches such as testosterone enanthate, testosterone buciclate, which may be delivered by pill, implant, or injection, and the nonsystemic approaches that interrupt the maturation of sperm cells via action on the function of the epididymis are examined. The greatest challenge for any new method is that none of them is going to be what drug companies consider a "blockbuster drug.¿ Despite the promise of new contraceptive methods, discussions with subjects and education surrounding reproductive health on family planning and reproductive health will result to a real progress for the American population.^ieng

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PIP: In August 1999, the US Food and Drug Administration (FDA) approved Apri, a new oral contraceptive from Duramed Pharmaceuticals. Apri is available at approximately 30% less than the retail cost of comparable pills and is the first substitutable product equivalent to Ortho-Cept and Desogen, both of which contain 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Duramed, a longtime manufacturer of generic pharmaceuticals, has gained FDA approval for other women's health products in the last 2 years, including 1) medroxyprogesterone acetate tablets for treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance, 2) estropipate tablets for treatment of vasomotor symptoms of menopause and prevention of osteoporosis, and 3) estradiol tablets. In March 1999, Duramed also gained FDA approval for Cenestin, a conjugated estrogen drug product that is made of 9 synthetic estrogen components derived from a compound obtained from plant material. This drug is safe for short-term use in treating vasomotor symptoms such as hot flashes and sweating associated with menopause.^ieng

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PIP: Research on male contraceptives is on a slow progress due to the difficulty in controlling the male reproductive system. While a variety of hormonal and nonhormonal approaches to suppress sperm production is being studied, researchers are currently looking into the process of inhibiting the sperm's fertilizing ability. Immucon, a Montreal-based firm, filed a US patent based on its claims that it can use a fragment of the protein P34H to neutralize the fertilizing capacity of the sperm at the level of the epididymis. Trials on rodents have already been conducted and studies on monkeys are about to begin. Allan Bosse, Immucon president, is hoping to be in Phase I in 2 years and 6 months. Moreover, scientists at the University of California at Davis have identified and studied other proteins such as PH-20 and PH-30 on the surface of sperm required for fertilization. Rodent studies showed that injection of these proteins in the animals resulted in the production of antibodies specific to these proteins, thus preventing the proteins from participating in the events of fertilization. Despite these research results, the production of a feasible male vaccine still has a long way to go.^ieng

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OmniComm Systems, Inc. (OMCM), Miami, Florida, announced it is partnering with Optima WorldWide, Ltd., to launch US testing of a vaginal gel for the potential prevention of pregnancy and the most common sexually transmitted diseases (STDs). Surete Gel, which is already being sold in China as a vaginal disinfectant and contraceptive, is being tested as a potential preventive agent for most STDs, including HIV. The concept of an antimicrobial product that prevents infectious sexual diseases has long been awaited by experts at the WHO and the US National Institutes of Health as an important weapon in preventing the global STD and HIV epidemics. OmniComm's Internet electronic data capture system, TrialMaster, and its web portal for trial investigators and participants, WebIPA.com, will manage long-term testing of Surete Gel worldwide. Stephen Drake, Optima, is hailing the partnership with OmniComm as a big step forward. "We are very pleased with this alliance as we complete trials on Surete Gel. This brings us closer to bringing a microbicide gel to the important US market while our vaginal disinfectant and contraceptive is already being introduced abroad". Optima is awaiting approval to sell Surete Gel in India and Thailand, as well as in several African and European nations. OmniComm is expanding its trial investigator base for Surete clinic trials in the US by enrolling experienced US investigators in the field of gynecology. A number of trial participants will be needed to take part in extensive testing before the product can be considered for approval in the US as more than a contraceptive. Surete complies with the US Food and Drug Administration monograph as a contraceptive. Anyone interested in taking part in those clinical trials--investigators or participants--must register thru OmniComm's web portal, WebIPA.com.

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PIP: FemCap is a vaginal barrier device for contraception for which approval is being sought from the US Food and Drug Administration. It is a silicone rubber that resembles the shape of a sailor's hat, with a dome that covers the cervix, a rim that fits into the cornices, and a brim that forms a seal against the vaginal wall and acts as a funnel to direct ejaculate fluid into the groove. This product is already available in Germany, Australia, and Switzerland. It comes in 3 sizes: small (22 mm), for women who have never been pregnant; medium (26 mm), for women who have been pregnant but have not had a vaginal delivery; large (30 mm), for women who have had a vaginal delivery. The advantages of this product include prevention of spread of sexually transmitted diseases, provision of contraception when needed without daily action required, no hormonal side effects, no effect on breast milk, can be stopped anytime, and easy to use. Development research that offers a strap for ease of removal is under way, while an efficacy study that compared the device with the diaphragm indicates that both performed in the range of most barrier methods.^ieng

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An international venture was launched in 1985 to fill a recognized gap in post-marketing surveillance of fertility-regulating methods. For this purpose a new task force was set up by the Special Programme of Research, Development, and Research Training in Human Reproduction, which is cosponsored by the United Nations Development Programme, the United Nations Population Fund, the World Bank, and WHO. Research priorities were chosen and epidemiological studies inaugurated, involving a total of 47 countries--mostly from the developing world. Important progress has been made, especially in helping to define the beneficial and possible adverse effects of oral contraceptives on the risk of neoplasia; in showing that the injectable contraceptive depot-medroxyprogesterone acetate protects against endometrial cancer and does not increase the overall risk of breast cancer, in clarifying which groups of women are susceptible to the rare cardiovascular complications of oral contraceptives (myocardial infarction, stroke, and venous thromboembolism); and in establishing the long-term effectiveness and safety of intrauterine devices. The research has already made a significant impact on family planning policies and practice. Critical appraisal of this venture, which has been modestly funded, confirms the value of mission-oriented research. It also illustrates the potential of collaboration that bridges the global divide between developing and developed countries.

PIP: This article concerns the essential findings of the task force created by the Special Programme of Research, Development, and Research Training in Human Reproduction in 1985 to conduct research on the safety and efficacy of fertility-regulating methods. The task force had 9 research priorities which include: 1) effects of contraceptive use during lactation; 2) pelvic inflammatory disease and contraception; 3) cardiovascular disease and hormonal contraception; 4) cancer and hormonal contraception; 5) interactions between contraceptive use and disease; 6) morbidity due to female sterilization; 7) induced abortion; 8) safety of Norplant; and 9) IUDs. It then established epidemiological studies in 47 countries, which were mostly from the developing world. Some main achievements were: 1) identification of the beneficial and possible adverse effects of oral contraceptives (OCs) on the risk of neoplasia; 2) demonstrating that injectable depot-medroxyprogesterone acetate protects against endometrial cancer and does not increase the overall risk of breast cancer; 3) clarifying which groups of women are prone to the complications of OCs; and 4) establishing the long-term effectiveness and safety of IUDs. Furthermore, the valuable information produced by this research program has already had a significant impact on family planning policies and practice. This venture also strengthens the value of mission-oriented research and demonstrates the potential of collaborative research between developing and developed countries.

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Advances in contraceptive technology have made birth control more effective, convenient, and safe. We review the newer products and some under development, including the latest oral contraceptives, injectable progesterone, subdermal progestin implants, progesterone-releasing IUDs, emergency contraception, and male contraception.

PIP: This paper reviews the latest developments in oral contraceptives (OCs), long-acting contraceptives such as injectable progesterone, subdermal progestin implants, progesterone-releasing IUDs, emergency contraception, and male contraception. Latest developments of OCs contain much lower doses of estradiol than the older preparations and uses newer progestins with less androgenic activity, thus causing fewer side effects. Depot-medroxyprogesterone acetate injections every 3 months prevent conception by suppressing the luteinizing hormone surge, thereby inhibiting ovulation. These contraceptive options are good for women in whom compliance may be low. Subdermal progestin implants have a failure rate of 0.8/100 woman-years for the first 5 years of use, increasing to 2/100 woman-years by the 6th year. They acts primarily by rendering the cervical mucus impenetrable to sperm. The progesterone-releasing IUDs, on the other hand, induce decidualization of the endometrium, thus inhibiting implantation. Among the postcoital contraceptives briefly discussed in this paper are the combined OCs (ethinyl estradiol and norgestrel), progestin-only compounds, the copper IUD, and mifepristone. The new developments of condoms, which are the mainstay of male contraception, include the new polyurethane condom, which is thinner, stronger, and less allergenic.

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PIP: The goal of male hormonal contraception is to block spermatogenesis by suppressing the secretion of pituitary gonadotropins. Prospects are good for the development of such a male contraceptive, with at least one hormonal contraceptive for men potentially available within 5-7 years. Finding an acceptable, reversible, and preferably long-lasting hormonal contraceptive for men is a top priority of the World Health Organization (WHO). Considerable evidence suggests that an androgen, with or without a progestogen, can provide effective contraception and is well tolerated. Schering and Organon are planning to collaborate with WHO in developing hormonal contraception for men. Fred Wu of the University of Manchester, UK, will soon begin a trial comparing the effectiveness of new injectable testosterone undecanoate and testosterone buciclate formulations, with or without synthetic progestogens.^ieng

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OBJECTIVE: To assess the short term patient acceptability and aspects of use of the Lea's Shield(R). DESIGN: Observational study. Ten women were each invited to use the Lea's Shield on 10 occasions and to report their observations and experiences on structured questionnaires after each use. Thus, data on a maximum of 100 uses would become available for analysis. Answers were recorded on numerical scales and in descriptive terms. On conclusion of their study participation, patients and their partners were required to document their overall experience with the product. SETTING AND SUBJECTS: Women aged 18 to 40 years, self-selected from clients attending the Margaret Pyke Family Planning Centre. They had to be in a stable monogamous relationship, gynaecologically healthy, and willing to continue their use of oral contraceptives, IUD, or injectable. MAIN OUTCOME MEASURE: Ability to use the method without formal teaching, assessed after vaginal examination by the investigator at end of first visit. User satisfaction, as expressed in structured questionnaires and by premature withdrawal from trial. RESULTS: Ten women used Lea's Shield on a total of 70 occasions, of which 46(66 per cent) were associated with sexual intercourse. Five subjects withdrew from the trial prematurely on account of discomfort to either or both partners (four), and recurrent cystitis (one). At the enrolment visit, all but one woman inserted the device correctly without formal teaching, but there was considerable inter-patient variation in their responses concerning ease of insertion/removal, and comfort during subsequent uses. CONCLUSIONS: These preliminary observations suggest that the Lea's Shield may be acceptable to a highly select minority of women. However, much more research is required to permit a reliable assessment of its acceptability to the wider public. The product's potential for causing pain and discomfort also needs further exploration.

PIP: The cup-shaped, reusable, one-size Lea's Shield barrier contraceptive is commercially available in Canada and a few European countries. In advance of its introduction to the UK, a study was conducted to assess the short-term acceptability of this device. Enrolled were 10 clients 18-40 years of age from the Margaret Pyke Family Planning Center in London, England, who used the device a total of 70 times, 46 of which were associated with sexual intercourse. Nine women inserted the device correctly on the basis of reading the manufacturer's instructions. However, five women reported continued problems with insertion and seven found removal to be difficult, suggesting a need for formal instruction in use of the device. Ease of insertion, ease of removal, and female comfort scores fluctuated widely between both participants and episodes of use, with no trend of progressive improvement over time. Four women discontinued the trial because of discomfort to themselves and/or their partner and another women withdrew because of recurrent cystitis. These generally negative responses may impact on the product's use effectiveness.

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We studied the pharmacokinetics of 7 alpha-methyl-19-nortestosterone (MENT), a potent synthetic androgen, administered by subdermal implants. The implants contained 112 +/- 4 mg of MENT acetate in a polyethylene vinyl acetate copolymer. MENT acetate released from the implants is rapidly hydrolyzed to MENT in vivo. Fifteen healthy Finnish men were randomized to have either one, two, or four implants inserted in the medial aspect of the upper arm. The implants remained in place for 4 weeks. Blood samples were obtained before implant insertion, 1, 2, 3, and 4 weeks after insertion, and 1 and 2 weeks after removal. Serum MENT concentrations were determined by gas chromatography with mass selective detection. The MENT levels attained in each implant group remained at a steady level during the 4 weeks of implant use. The mean steady state MENT concentrations in the one, two, and four implant groups were 0.6, 1.4, and 2.3 nmol/L, respectively. Serum MENT concentrations during implant use were clearly dose dependent; the between-subject effect of implants as well as the differences between each pair of groups were all statistically significant. The release rate of MENT from one, two, and four implants was calculated to be approximately 0.3, 0.8, and 1.3 mg/day, respectively. This study suggests that MENT acetate implants are a promising method for long-term androgen administration in hypogonadism and male contraception.

PIP: The authors studied the pharmacokinetics of 112 +or- 4 mg of MENT acetate in a polyethylene vinyl acetate copolymer. MENT acetate released from the implants is rapidly hydrolyzed to MENT in vivo. 15 healthy Finnish men were randomized to have either 1, 2, or 4 implants inserted in the medial aspect of the upper arm. The implants remained in place for 4 weeks. Blood samples were obtained before implant insertion, 1, 2, 3, and 4 weeks after insertion, and 1 and 2 weeks after removal. Serum MENT concentrations were determined by gas chromatography with mass selective detection. The MENT levels attained in each implant group remained at a steady level during the 4 weeks of implant use. The mean steady state MENT concentrations in the 1, 2, and 4 implant groups were 0.6, 1.4, and 2.3 nmol/l, respectively. Serum MENT concentrations during implant use were clearly dose dependent; the between-subject effect of implants as well as the differences between each pair of groups were all statistically significant. The release rate of MENT from 1, 2, and 4 implants was calculated to be approximately 0.3, 0.8, and 1.3 mg/day, respectively. The study suggests that MENT acetate implants are a promising method for long-term androgen administration in hypogonadism and male contraception.

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PIP: Current research efforts are addressing the potential use of nonoxynol-9 and other spermicides as an effective female-controlled contraceptive method. In the laboratory, nonoxynol-9 is lethal to organisms that cause gonorrhea, syphilis, trichomoniasis, genital herpes, and HIV, but findings of human studies have been inconsistent. Carrageenan, a compound derived from red seaweed, has been combined with nonoxynol-9 in an effort to develop a spermicide that will protect against HIV and pregnancy. A novel gel formulation that contains low amounts of octoxynol-9 and benzalkonium chloride is scheduled to enter a Phase III trial. The first part of the trial will determine the product's effectiveness in preventing pregnancy and halting the transmission of chlamydia and gonorrhea; the second will focus on HIV. Another Phase III clinical trial is testing a bioadhesive contraceptive gel that contains nonoxynol-9. Also under study is a vaginal sponge that contains low levels of nonoxynol-9 and benzalkonium chloride. Finally, researchers are evaluating the potential for precoating diaphragms and cervical caps with a spermicide.^ieng

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PIP: A study published March/April 1999 determined that the typical woman who uses reversible contraception throughout her reproductive years will discontinue contraceptive use for a method-related reason almost 10 times. Broadening the current range of contraceptive methods available to women, the contraceptive sponge, an over-the-counter barrier method, should be back on the market in fall 1999. In the late 1980s and early 1990s, the contraceptive sponge was being used by an estimated 400,000 women when it was pulled from the US market in 1995 due to manufacturing problems. A New Jersey pharmaceutical company recently announced that it has acquired rights to the sponge. Almost all of the "new" contraceptive methods marketed in recent years, as well as those slated to be marketed in the near future, are actually refinements of previously available methods. However, under increasing pressure to develop methods which could protect against sexually transmitted diseases, including HIV, as well as pregnancy, scientists are reported to be actively looking into more than 50 promising compounds, generally known as microbicides. Microbicide formulations, which could be available by 2001, could appeal to 6-12 million women in the US. Meanwhile, a number of formulations for pills, injectables, and implants for men are also being studied around the world, although it may be at least 10 years before a male method will be made available to the public.^ieng

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PIP: As the first dedicated emergency contraceptive pills (ECPs) are being marketed in the US, 2 companies are working to introduce progestin-only pills capable of conferring emergency contraceptive protection. Officials at Gynetics of Somerville, NJ, and Women's Capital Corp. of Seattle, Washington, and Washington, DC, are interested in pursuing dedicated progestin-only products after an international study in 1998 demonstrated the advantages of a levonorgestrel-only EC over the Yuzpe regimen used by Gynetics' Preven Emergency Contraception Kit. Gynetics has begun multinational phase III clinical trials on a levonorgestrel product which is expected to be approved in the US and Canada later in 1999 or in early 2000. Women's Capital Corp. completed the New Drug Application for its product in January and hopes to receive priority review status of 6 months or less. The company expects to submit an application for approval in Canada in the first part of 1999.^ieng

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PIP: Family Health International has initiated a 3-year multicenter clinical trial of the contraceptive efficacy, acceptability, and safety of over-the-counter spermicides containing nonoxynol-9. Although the active ingredients in marketed spermicides are generally safe, their effectiveness in final product formulations remains highly variable. 1800 women from 11 US centers will be randomly assigned to 1 of 5 spermicidal preparations and followed for 7 months. 3 of the preparations are gel products with varying amounts of nonoxynol-9, which will enable researchers to determine if the amount of spermicide influences efficacy. A suppository tablet and a film preparation have been included to assess whether the method of delivery affects efficacy.^ieng

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A prospective study of the Norplant-2 contraceptive subdermal implant system was conducted in Bangkok, Thailand. The objective of the study was to evaluate the efficacy, adverse effects, and overall acceptability of Norplant-2 implants. A total of 140 women were enrolled in a 3-year clinical trial. The mean age was 29 years. Of all the acceptors, 70% had completed primary school. The continuation rates at years 1, 2, and 3 were, respectively, 94%, 89%, and 83%. No accidental pregnancies occurred throughout the 3 years of use in this study. Personal reasons were the leading cause for termination of Norplant-2 implant use. The 3-year cumulative termination rate for personal reasons was 7.2%. These personal reasons were divorce, husband having vasectomy, and moving away from the study area. The other leading cause for termination was medical reasons; acne, headache, and pain at the implant site were the complaints. The termination rate for medical reasons in year 3 of the study was 4.6%. Prolonged menstrual flow was the other main reason for termination. The 3-year cumulative termination rate for menstrual irregularities was 3.8%. In this study, the cumulative termination for planned pregnancy at the end of the year 3 was only 1.6%. The incidence of difficult removals was 8%. Breakage of the rods on removal was encountered in the majority of these cases. The study findings presented suggest that the Norplant-2 implants are highly effective with high continuation rates. The Norplant-2 system could become another choice of long acting reversible contraception for Thai women.

PIP: Since 1986, Thailand's National Family Planning Program has included the Norplant 6-capsule implant system. The present paper reports the results of a 3-year Phase III clinical trial of the newly developed 2-rod system (Norplant-2). A total of 140 women (mean age, 29 years), in Bangkok, were enrolled and 103 women completed 3 years of method use. The continuation rates at 1, 2, and 3 years were 93.9%, 89.2%, and 82.8%, respectively. There were no accidental pregnancies during the 3-year study period. The 3-year cumulative termination rate was 7.2% for personal reasons (e.g., divorce, husband underwent vasectomy), 4.6% for medical reasons (e.g., acne, headache, pain at the implant site), and 3.8% for menstrual irregularities. A total of 125 acceptors underwent Norplant removal either during or at the end of the study period. The incidence of difficult removals was 8%. In most of these cases, the difficulty involved rod breakage. The average time required for removal was 3.4 minutes. These findings indicate that Norplant-2 is a safe, effective, acceptable contraceptive method appropriate for inclusion in Thailand's family planning program. The potential for fragmentation of the rods during removal requires careful monitoring, however.

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In a systematic search for vanadocene complexes with sperm immobilizing activity as a new class of contraceptive agents, we identified V(eta 5-C5H5)2((C2H5)2 NCS2)(BF4) (=[VCp2(DeDtc)](BF4)) as the most potent and stable spermicidal compound. Here we report the detailed biologic and physicochemical characterization of this lead spermicidal compound by computer-assisted sperm analysis, electron paramagnetic resonance spectroscopy, electrochemistry, and X-ray crystallography. [VCp2(DeDtc)](BF4) crystallized in the monoclinic space group P2(1)/c, with unit cell dimensions a = 7.0877(4) A, b = 22.2881(14) A, c = 11.8021(7) A, beta = 94.107(1) degree, V = 1859.6(2) A3. The final structure of [VCp2(DeDtc)](BF4) had an R factor of 0.0581 for 3191 independent reflections. The two sulfur atoms of the dithiocarbamate and centroids of the cyclopentadienyl rings in this vanadocene complex with unique contraceptive potential occupy four tetrahedral--like coordination sites about the central metal atom.

PIP: This paper describes the detailed biologic and physiochemical characterization of a lead spermicidal compound by computer-assisted sperm analysis, spectroscopy, electrochemistry, and X-ray crystallography. Vanadocene dithiocarbamato complex at physiologic pH was identified as the most potent and stable spermicidal compound. Its structural integrity has been confirmed through UV-visible spectrum, electron paramagnetic resonance spectroscopy and electrochemical studies. In addition, the three-dimensional solid state structural characterization of this complex has been achieved by single crystal X-ray diffraction. Extensive studies have been performed on the stabilizing effects of the dithiocarbamate ligand for higher oxidation state metal ions like vanadium. Overall, this study confirms and extends previous studies of the spermicidal activity of vanadocenes. However, the molecular targets of vanadocenes as a new class of spermicidal agent and the structure activity relationships affecting their spermicidal activity remain unknown. Hence, future studies aimed at determining the structure activity relationships critical for the sperm immobilizing function of vanadocenes are recommended.

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The safety and tolerability as well as pharmacokinetics of a new selective antiprogestagen, Org 31710, were studied after oral administration of single doses of 10, 25, 50, or 75 mg to 24 healthy male volunteers. Per dose-group, five subjects received active and one subject received placebo treatment. In subjects receiving 75 mg, the effects of Org 31710 on serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were also studied. No adverse or seriously adverse events were observed. All doses of Org 31710 were well tolerated. Characterization of the Org 31710 plasma pharmacokinetics revealed a statistically significant deviation from linearity: the dose normalized Cmax (nCmax) and dose normalized area under the curve (nAUC) values were significantly lower for the higher dosages (p < 0.05). Furthermore, tmax tended to decrease (from 1.6 to 0.9 h), whereas the elimination half-life (t1/2) tended to increase (from on average 45 to 57 h) with increasing dose. Org 31710 did not have any effect on serum levels of FSH, LH, and testosterone. In conclusion, Org 31710 appears to be a safe and well-tolerated compound in the dosage range studied.

PIP: The pharmacokinetics, safety, and tolerability of a new selective antiprogestagen--Org 31710--were investigated in 24 healthy Dutch men. Single oral doses of 10, 25, 50, or 75 mg were administered. In each dose group, 5 subjects received Org 31710 and 1 was given placebo. All dosages were well tolerated and no clinically relevant adverse events were recorded. Plasma pharmacokinetic characterizations revealed a statistically significant deviation from linearity after single doses of 10-75 mg of Org 31710. The dose-normalized maximum plasma concentrations was significantly higher in the 10 mg group and significantly lower in the 75 mg group compared with the 25 mg and 50 mg groups. Mean values of the normalized area under the plasma concentration time curve at 10 and 25 mg were significantly higher than values at higher dosages. The time to reach maximum plasma concentration decreased from 1.6 to 0.9 hours with increasing Org 31710 dose, while the elimination half-life increased from 45 to 57 hours. Serum levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were not affected by a single dose of 75 mg of Org 31710. These findings demonstrate the safety and tolerability of the novel antiprogestagen Org 31710. The low antiglucocorticoid activity of Org 31710 represents a potential advantage over RU 486.

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PIP: Clinical studies of nonoxynol-9 (N-9) products such as vaginal sponges link the spermicide to vaginal and vulval irritation, even at low doses. Since such irritation may facilitate infection with sexually transmitted diseases (STDs), the chief of the US National Institute of Allergy and Infectious Diseases' STD branch does not recommend that women use the product in their vaginas. Existing products containing N-9 continue to be tested against STDs and HIV, while new ways to prevent STDs and HIV infection are progressing to early clinical trials. New topical, nonirritating microbicides for preventing STDs are promising and will be featured at the May meeting of the American Society of Microbiology as products which could offer women safe, convenient, and almost undetectable protection. Examples include PRO 2000, a naphthalene sulphonate polymer; the "invisible condom," a gel; GEDA Plus, a gel; protegrins; and a "vaginal vitamin," a gelatin suppository. While condom use must continue to be encouraged and STDs treated, placing something into the vagina to either prevent or cure infection is within the realm of existing medical science.^ieng

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