Gossypol blood levels and inhibition of spermatogenesis in men taking gossypol as a contraceptive. A multicenter, international, dose-finding study.

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.

A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant.

To compare the contraceptive efficacy, tolerability, and bleeding patterns, 200 healthy female volunteers received, in an open, comparative, randomized, multicenter study in China, either a single-rod (Implanon) or a six-capsule (Norplant) contraceptive implant for 2 years with an optional extension of up to 4 years. Women were exposed to Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding/spotting days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. Similarly, with Norplant, the median number of bleeding/spotting days decreased from 34.5 to 18.0-23.0 days, respectively. The number of bleeding/spotting episodes during year 1 was 2.0 per 90-day reference period with Implanon and 3.0 per period with Norplant (p < 0.05 for periods 1-4). For the remaining 90-day periods, there was no statistical difference between the two groups. In general, there was less frequent bleeding with Implanon compared with Norplant, whereas the incidences of amenorrhea and infrequent bleeding were higher with Implanon than with Norplant. The mean overall incidence of prolonged bleeding fell markedly during the study, from 66.0% in reference period 1 to 27.3% in period 16 with Implanon and from 69.0% to 21.7% with Norplant, respectively. The most common adverse events were related to disturbed bleeding patterns, which were also the major reasons for discontinuation (Implanon n = 8; Norplant n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Implanon was inserted in a mean time of 0.61 min and Norplant in 3.90 min (p < 0.001). Similarly, the mean time required to remove the implant was significantly shorter for Implanon than for Norplant (2.18 min vs 11.25 min, p < 0.001). The maximum time required for removal of the implant was 10 min for the Implanon group and 60 min for the Norplant group. In both groups, blood pressure and hemoglobin were not affected, whereas body weight tended to increase. It can be concluded that both contraceptive systems demonstrated excellent contraceptive efficacy and were well tolerated. Compared with Norplant, there was less frequent bleeding with Implanon, whereas the incidence of infrequent bleeding and amenorrhea was higher. Implanon was significantly quicker to insert and to remove than was the multiple capsule system.

PIP: This study compares the contraceptive efficacy and bleeding patterns of a single-rod (Implanon) and a six-capsule (Norplant) contraceptive implant for 2 years, with an optional extension of up to 4 years, among 200 healthy female volunteers in China. Women were administered with Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. No pregnancies occurred during the study, demonstrating excellent contraceptive efficacy. The median number of bleeding/spotting (B/S) days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. With Norplant, the median number of B/S days decreased from 34.5 to 18.9-23.0 days. There was less frequent bleeding with Implanon than with Norplant. The most common adverse effects were related to disturbed bleeding patterns, which were also the main reasons for discontinuation (Implanon, n = 8; Norplant, n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Lastly, Implanon required less time for insertion and removal as compared to Norplant.

A long-term study of the efficacy and acceptability of a single-rod hormonal contraceptive implant (Implanon) in healthy women in China.

OBJECTIVE: To investigate the contraceptive efficacy, cycle control and acceptability of Implanon, a new single-rod, progestogen-only contraceptive implant. METHODS: In a non-comparative, open, multicenter study, a contraceptive implant containing the progestogen etonogestrel was inserted into 200 healthy women. The study duration was 2 years, with an optional extension up to 4 years. RESULTS: Women were exposed to Implanon for 644.6 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding-spotting days ranged between 18 and 21 and the median number of bleeding-spotting episodes was two. The mean overall incidence of prolonged bleeding fell markedly during the study, from 69% in the first reference period to 26% in the 16th period. The most common adverse events were related to disturbed bleeding pattern and amenorrhea. Heavy or prolonged bleeding caused 18 subjects to withdraw from the study. Only a few subjects discontinued the study early due to irregular bleeding (2%) or amenorrhea (2%). A slight increase in mean body weight was observed. The implant was removed in an average time of 2.9 min. CONCLUSIONS: Implanon demonstrated excellent contraceptive efficacy for 4 years of use and was well tolerated. The incidences of prolonged bleeding and amenorrhea both fell markedly with continued implant use. Because of its single-rod design, Implanon was quickly removed with few complications and proved to be a highly acceptable method of contraception.

Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem in Chinese women.

To provide pharmacokinetic data for safety evaluation on prolonged treatment with Cyclofem, which contains 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate in 0.5 mL microcrystalline aqueous suspension, the pharmacokinetic profiles of MPA after single and multiple administration of this monthly injectable contraceptive were investigated in Chinese women. Nine healthy fertile women received Cyclofem based on a once-a-month regiment for up to 1 year. Blood samples were collected immediately prior to drug administration and on days 1, 3, 5, 7, 14, 21, and 28 after injection. After the 1st, 6th, and 12th injection, the maximum serum concentrations (Cmax) of MPA were observed on days 3.4 +/- 0.9, 4.3 +/- 2.2, and 3.7 +/- 2.6, respectively. Cmax of serum MPA during the 1st, 6th, and 12th treatment cycles were 3.75 +/- 1.27, 5.54 +/- 1.79, and 5.55 +/- 1.80 nmol/L, whereas the areas under the curve (AUC0-28 days) were 55.84 +/- 28.15, 95.45 +/- 26.56, and 98.81 +/- 21.84 nmol/L.day, respectively. There was significant interindividual variation in the pharmacokinetics of MPA after intramuscular injection of Cyclofem. No significant change was demonstrated in mean residence time (MRT) of MPA after single and multiple injection. There was a tendency of increase in Cmax and AUC0-28 days of MPA during the first 6 months of treatment, whereas no further enhancement was found between the 6th and 12th injection (p > 0.05). Peak levels of estradiol (E2) observed in Cyclofem users were within the normal range of the preovulatory phase. Results of this long-term study suggest that no drug accumulation occurred after repeated administration of Cyclofem in the Chinese women.

PIP: To provide pharmacokinetic data for a safety evaluation of long-term use of the monthly injectable Cyclofem (25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate), 9 fertile Chinese women 27-34 years of age were enrolled in a 12-month clinical study. Serum samples were collected immediately prior to drug administration and on days 1, 3, 5, 7, 14, 21, and 28 after monthly injection. After injections 1, 6, and 12, maximum serum MPA concentrations were observed on days 3.4 +or- 0.9, 4.3 +or- 2.2, and 3.7 +or- 2.6, respectively. Maximum concentrations of serum MPA during treatment cycles 1, 6, and 12 were 3.75 +or- 1.27, 5.54 +or- 1.79, and 5.55 +or- 1.80 nmol/l, respectively, while the corresponding areas under the curve were 55.84 +or- 28.15, 95.45 +or- 26.56, and 98.81 +or- 21.84 nmol/l per day. There was significant interindividual variation in the pharmacokinetics of MPA after intramuscular injection. No significant change was recorded in mean MPA residence time after single and multiple injection. Noted was a trend of increases in MPA maximum serum concentration and areas under the curve during the first 6 months of treatment, followed by no further enhancement in the last 6 months. Peak estradiol levels were within the normal range of the preovulatory phase. These findings suggest that long-term Cyclofem use is not associated with drug accumulation. As a safe, highly effective formulation, Cyclofem offers women around the world yet another contraceptive choice.

A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese women. I. Contraceptive efficacy and sid effects.

A phase III clinical study was carried out among 5680 fertile Chinese women to evaluate efficacy and side effects of three monthly injectable contraceptives: Mesigyna, Cyclofem and Chinese Injectable No. 1. When used in a once-a-month treatment schedule (part 1 of study), the effectiveness of Chinese Injectable No. 1 was unacceptably low; 36 pregnancies occurred during the first 1743 women-months of use, 16 before the second injection. The study was restarted with a revised injection schedule for Injectable No. 1: two injections separated by 9 +/- 1 days during the first month and subsequent injections given 10-12 days after the onset of bleeding, or if no bleeding occurred, 28 days after previous injection. In part 2 of the study, 988, 990 and 992 subjects were provided Mesigyna, Cyclofem and Injectable No. 1, respectively. Life-table pregnancy rates at one year were 0.41%, 0% and 0.77% (p < 0.05), respectively; the overall discontinuation rates at one year were 13.9%, 19.1% and 20.4% (p < 0.001). Discontinuation rates for bleeding problems were significantly different between the groups: discontinuation rates for amenorrhea were 0.58%, 3.71% and 0.68% (p < 0.001) for Mesigyna, Cyclofem and Injectable No. 1; for other bleeding problems, the rates were 4.88%, 8.38% and 12.64% (p < 0.001). There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight changes after one year of use were small: 0.73, 0.86 and 0.17 kg for the three groups, respectively. Both Mesigyna and Cyclofem were very effective for contraception, but Mesigyna appeared to be tolerated slightly better with regard to cycle control; the modified dose regimen for Injectable No. 1 also gave a low pregnancy rate but was associated with higher rates of discontinuation.

A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given by intramuscular injection to Chinese women. II. The comparison of bleeding patterns.

Between 1988 and 1992, a randomized phase III clinical trial was conducted in China to compare three monthly injectable contraceptives: Mesigyna, Cyclofem and Injectable No. 1. This paper presents a detailed analysis of the menstrual diaries provided by 5098 (89%) of the subjects. In total, 902, 903 and 913 diaries were analyzed to compare bleeding patterns induced by Mesigyna, Cyclofem and Injectable No. 1. The first withdrawal bleeding usually occurs 14-20 days after the first injection for all three of these preparations. Thereafter, 50% of Mesigyna users had precisely 3 bleeding/spotting episodes every 90 days, 50% of Cyclofem users had 2-3 and 50% of Injectable No. 1 users had 3-4 episodes every 90 days. Relative to users of Mesigyna or Cyclofem, Injectable No. 1 users had 2-3 more bleeding/spotting days, and a shorter length of bleeding/spotting-free intervals in each period. 63.7%, 41.4% and 60.6% of subjects using Mesigyna, Cyclofem and Injectable No. 1, respectively, had bleeding patterns similar to their untreated patterns in the first 90-day period. The percentages increased to 82.2% 67.8% and 75.0% in the fourth 90-day period. A total of 1815 diaries for Mesigyna and 1802 for Cyclofem were analyzed for more in depth comparison of these two methods. The number of bleeding/spotting days over four periods showed little difference between the two group, but there were more spotting days and there was greater individual variability among Cyclofem users.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Between October 1988 and July 1990, a randomized multicentered phase III clinical trial was conducted in three provinces of China to compare three monthly injectable contraceptives (Mesigyna [50 mg norethisterone enanthate + 5 mg estradiol valerate], Cyclofem [25 mg medroxyprogesterone acetate + 5 mg estradiol cypionate], and Injectable No.1 [250 mg 17-hydroxyprogesterone caproate + 5 mg estradiol valerate]). A detailed analysis of the menstrual diaries of 5098 women aged 18-35 years compared the vaginal bleeding patterns associated with the injectables. Women in all three groups experienced more bleeding/spotting (B/S) days, more bleeding episodes, shorter bleeding-free intervals, and larger variability during the first 90 days than during the following three 90-day periods (p 0.001). 90% of Cyclofem users had 1-4 B/S episodes. 90% of Mesigyna users had 2-4.2 B/S episodes. Cyclofem users had more spotting days than did Mesigyna users in each 90-day period (5-8 vs. 5-6). Acceptable bleeding patterns (i.e., bleeding patterns similar to untreated patterns) predominated, on the most part, in all four periods (63.7-82.2% for Mesigyna users, 41.4-67.8% for Cyclofem users, and 60.6-75% for Injectable No.1 users). Acceptability increased with each 90-day period for all three injectables. Acceptability of bleeding patterns was much higher among Mesigyna users than Cyclofem users (p 0.001). Prolonged bleeding, followed by irregular bleeding and frequent bleeding, were the most common bleeding disturbances. Irregular bleeding decreased with time. 79.1% of Mesigyna and Cyclofem users who finished the study had an acceptable pattern. 70.7% of women who stopped for non-bleeding reasons had an acceptable pattern compared to 31.3% of those who stopped for bleeding reasons. These findings show that Mesigyna users experienced better cycle control and more acceptable bleeding patterns than did the users of the other two injectables.

[Termination of early pregnancy by two regimens of mifepristone with misoprostol: a multicentre clinical trial].

Six hundred women in early pregnancy (< 49 days), who requested medical abortion were randomly allocated into 3 groups. In group 1 (n = 301), an initial dose of mifepristone 50 mg was given, followed by 25 mg every 12 hours up to a total dose of 150 mg mifepristone, plus a single oral dose misoprostol 600 micrograms in the morning of the third day. In group 2 (n = 150), the same regimen of mifepristone was given, but dl-15-methyl-PGF2 alpha (PG05) 1 mg vaginal suppository was inserted on the third day. In group 3 (n = 149), a single dose of mifepristone 200 mg was given and misoprostol 600 micrograms was used as in group 1. The complete abortion rate were 95.3%, 97.3% and 95.4% incomplete abortion rate were 3.0%, 2.0% and 2.6% for group 1, 2 and 3, respectively. No significant difference of the two rates was shown among these 3 groups approximate 82% of the women had lower abdominal pain. The overall, occurrence of diarrhea in PG05 group (38.7%) was significantly higher than that in the other 2 groups (21.6 and 20.1%, respectively) (P < 0.001), and so was the occurrence of vomiting. It was concluded that misoprostol, as an orally-effective prostaglandin, in combination with 2 regimens of mifepristone for induced abortion during early pregnancy was as effective as PG05 vaginal suppository. In addition, it has the advantages of convenience for use, less side effects, easy storage and transfer, and low cost.

Termination of early pregnancy by two regimens of mifepristone with misoprostol and mifepristone with PG05--a multicentre randomized clinical trial in China.

A multicentre randomized open clinical trial was conducted to compare the efficacy and side effects of two regimens of mifepristone with misoprostol, and mifepristone with PG05 for termination of early pregnancy (amenorrhoea < = 49 days). Six-hundred women in early pregnancy, who requested medical abortion were randomly allocated into 3 groups. In group 1 (n = 301), an initial dose of mifepristone 50 mg was given, followed by 25 mg every 12 hours up to a total dose of 150 mg mifepristone, plus a single oral dose of misoprostol 600 micrograms in the morning of the third day. In group 2 (n = 150), the same regimen of mifepristone was given, but dl-15-methyl PGF2 alpha (PG05) 1 mg vaginal suppository was inserted on the third day. In group 3 (n = 149), a single dose of mifepristone 200 mg was given and misoprostol 600 micrograms was used as in group 1. The complete abortion rate were 94.4%, 97.3%, and 94.6% for group 1, 2 and 3, respectively. 3.0, 2.0 and 2.7% of women had incomplete abortion, and 1.7, 0.7 and 2.0% of women in the 3 groups were treatment failures; in the remaining 1% in group 1 and 0.7% in group 3, treatment outcome could not be determined. There were no significant differences among the 3 groups. Lower abdominal pain was the main complaint which was reported by 82% of the subjects after PGs administration. The incidence of diarrhoea in PG05 group (38.7%) was significantly higher than that in the other two groups (21.6 and 20.1%) (P < 0.001), and so was vomiting. It was concluded that misoprostol, as an orally effective prostaglandin, in combination with mifepristone for induced abortion of early pregnancy was as effective as PG05 vaginal suppository. Besides, it has advantages of convenience of use, less side effects, easy storage and transfer, and low cost.

Pharmacodynamic effects of once-a-month combined injectable contraceptives.

The pharmacology and clinical assessment of existing first generation once-a-month combined injectable contraceptives, mainly Deladroxate and Chinese Injectable No. 1, are reviewed. Although these two types of monthly injectables have been used in some million women in China and Latin America, Deladroxate needs indepth re-evaluation of its long-term toxicity and possible accumulation. For injectable No. 1, its disadvantage of being administered on an erratic schedule will cause significant confusion in family planning practice. When used in a strict once-a-month schedule, it is not sufficiently effective for contraception. In order to attain predictable menstrual cycle control as well as high efficacy with a 30-day injection schedule, two improved once-a-month injectable formulations, Cyclofem and Mesigyna, were developed. Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna. Also, it is important to note that the second part of the injection cycle is dominated by the progestogen component of both monthly formulations. A longitudinal study indicated that there is no accumulation of norethisterone after 12 months of treatment with NET-EN 50 mg and estradiol valerate 5 mg.

PIP: About 1 million women in Latin America and China have used the 1st generation once-a-month combined injectable contraceptives Deladroxate and Chinese Injectable No. 1. Animal toxicity studies of Deladroxate found pituitary hyperplasia in rats, breast tumors in beagles, and accumulation of estradiol enanthate in the body. Thus, long-term toxicity and accumulation of Deladroxate need to be reevaluated. The erratic schedule of the Injectable No. 1 (initially administered on day 5 with 2 ampoules or 1 dose on day 5 and 1 dose on day 12; subsequent administration on the 10-12th day of the cycles) will confuse acceptors and family planning providers. Yet, a strict once-a-month cycle of Injectable No. 1 does not adequately protect against conception. Researchers have developed 2 improved once-a-month injectable formulations, Cyclofem and Mesigyna, to achieve good menstrual cycle control and high efficacy. The estrogen components of both formulations (estradiol valerate and cypionate) sufficiently elevate plasma estrogen levels for 7-11 days. One injection of both formulations inhibits follicle maturation for about 30 days and ovulation and corpus luteum formation for about 60 days. The doses of Cyclofem (25 mg depot-medroxyprogesterone acetate + 5 mg estradiol cypionate) and Mesigyna (50 mg norethindrone acetate + estradiol valerate) have been found to be optimal for use in large scale clinical trials. Not only are the absolute amounts of the progestogen and estrogen important, but also the progestogen/estrogen ratio. A lower estrogen dose in both Cyclofem and Mesigyna effects breakthrough ovulation. The progestogen component predominates the 2nd part of the injection cycle in both formulations. Norethindrone does not accumulate in the body after 12 months of treatment with Mesigyna.

[Pharmacokinetics of levonorgestrel after a single dose of biodegradable microspheres containing levonorgestrel in rats].

Pharmacokinetics of levonorgestrel (LNG) in the form of injectable microspheres made of biodegradable co-polymer of polylactic acid and polyglycolic acid(9: 1 PLGA) that contained 17.76% LNG, were tested in rats. Rats were given a single intramuscular injection (im) of LNG microspheres at doses of 20.4, 41.1 and 83.3 mg.kg-1. Six rats were treated with a single im of LNG microcrystals at dose of 35.0 mg.kg-1. Plasma samples obtained before injection and at various time after injection were analyzed for LNG by RIA method. Peak plasma LNG level of 67.66 nmol.L-1 was obtained 4.88 h after im of LNG microcrystals, T1/2 = 5.78 d, MRT = 10.16 d and T < 0.32 nmol.L-1 = 41.50 d. Plasma LNG levels among rats after im of three different doses of LNG microspheres showed similar biphasic changes. Cmax1 (the first phase) were 15.19, 33.61 and 38.55 nmol.L-1; Tp1 were 6, 4.67 and 4.33h; Ctrough were 1.21, 4.36 and 9.06 nmol.L-1; Ttrough were 55, 53.67 and 54.83 d; Cmax2 (the second phase) were 3.80, 9.48 and 19.68 nmol.L-1; Tp2 were 100.49, 102.21 and 89.27 d; AUC were 440.27, 1082.82 and 1931.47 nmol.d.L-1; MRT were 69.23, 65.12 and 63.25 d; T < 0.32 nmol.L-1 were 167.81, 169.73 and 167.23 d after im of LNG microspheres in doses of 20.4, 41.1 and 83.3 mg (LNG).kg-1, respectively. Cmax1, Ctrough, Cmax2 and AUC showed significantly positive correlation with LNG dose, while Tp1, Tp2, Ttrough, MRT and T < 0.32 nmol.L-1 did not.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of steroid contraceptive on serum levels of sex hormone binding globulin in women].

PIP: To investigate the effect of steroids on the level of sex hormone binding globulin (SHBG), 24 women between ages 25 and 35 received one injection of 200 mg norethisterone enanthate (NET-EN). The mean serum SHBG level before the injection was 53.23 mnol/L, with a standard deviation of 23.23 mnol/L. Five days after the injection, the serum SHBG level was reduced to 41.99 +or- 17.06 nmol/L (P.05). 21 days after the injection, the serum SHBG level reached the lowest point of 14.72 +or- 10.01 nmol/L. The SHBG level gradually increased afterwards and did not recover to the premedication level at 84 days with 34.46 +or- 20.39 nmol/L. Two groups of women received oral administration of levonorgestrel (LNG) including one group of 10 women who received a single dose of 6 mg LNG plus 3 mg quinestrol (CEE) and another group of 8 women who received 3 doses of the same regimen as the single-dose group at an interval of 23 days between each dose. The mean premedication SHBG level of the single-dose group was 42.76 +or- 13.89 nmol/L, and it rose to 62.53 +or- 10.9 nmol/L on the seventh day after the administration (p.01). The serum SHBG level peaked at 71.33 +or- 5.77 days after the administration and this high level was sustained until 56 days. For the three doses group, the serum SHBG level prior to medication was 44.94 +or- 15.36 nmol/L. 9 days after the first administration, it reached 83.46 +or- 10.08 nmol/L and peaked at 16 days with 91.74 +or- 2.28 nmol/L. The high serum SHBG level sustained until 30 days after the third administration. The second and third administration of levonorgestrel did not have a significant effect on the SHBG level, as it had already reached a high level. The peak value of LNG blood concentration after the second and third administration was 6 times higher than the peak after the first administration.^ieng

Inhibitory effects of gossypol on corticosteroid 11-beta-hydroxysteroid dehydrogenase from guinea pig kidney: a possible mechanism for causing hypokalemia.

Inhibition of 11-beta-hydroxysteroid dehydrogenase (11-beta-OHSD) in the kidney can cause excess mineralocorticoid effect and hypokalemia. To find out if gossypol, a potential oral contraceptive for men that has been associated with cases of hypokalemia, inhibits this enzyme, its effect on guinea pig kidney was studied. Working with microsomes from the kidney cortex, and using corticosterone as the substrate, racemic gossypol was found to be a competitive inhibitor of 11-beta-OHSD with a Ki of 67 +/- 5 microM. The (+) enantiomer was a little more potent than the (-) enantiomer. Microsomes from the kidneys of animals given gossypol for 2 weeks had lower enzyme activities than saline-treated animals. Microsomes from a strain of hairless guinea pigs had lower intrinsic enzyme activity than the normal animals. We conclude that there is genetic variation in the activity of this enzyme and that it can be inhibited by gossypol.

[Drug evaluation of huperzine A in the treatment of senile memory disorders].

Huperzine A is an alkaloid which was first isolated from Huperzia serrata (Thumb) Trev by Zhejiang Academy of Medical Sciences and Shanghai Institute of Materia Medica, Chinese Academy of Sciences. It exhibits a significant anticholinesterase activity and has been used on myasthenia gravis patients. The therapeutic effects were studied by random, match and double-blind method on 56 patients of multi-infarct dementia or senile dementia and 104 patients of senile and presenile simple memory disorders. The curative effects were evaluated by Wechsler memory scale. The im dose for multi-infarct dementia was 0.05 mg bid for 4 wk, whereas that for senile and presenile simple memory disorders was 0.03 mg bid for 2 wk. Saline was used on control group. The result showed that the curative effect of huperzine A was significant. Only a few patients felt slight dizziness and this did not affect the therapeutic effects.

Clinical experience with triphasic oral contraceptive (Triquilar) in 527 women in China.

From October 1987 to May 1989, a total number of 527 women completed a total of 6,291 treatment cycles in 6 centers in China for the study of a triphasic oral contraceptive - Triquilar. The mean age of subjects was 30.21 +/- 2.84 years. There were 7 pregnancies during the study period. Among them, five were patient failures because of missed pill or incorrect intake; one had taken barbiturates along with Triquilar. Only one woman became pregnant in the 11th treatment cycle without any reason being found. In most cases, menstrual flow decreased and dysmenorrhea improved as treatment continued. Of the total treatment cycles, the incidence of missed withdrawal bleeding was 0.25%, spotting 0.97%, and breakthrough bleeding 0.48%. Nausea and vomiting was the most common side effect and accounted for 6.4% of the total treatment cycles. This was followed by breast tenderness (3.7%), dizziness (2.4%) and headache (1.6%). Most of the side effects occurred during the first few cycles and were alleviated later. By the end of one year, the total dropout was 64 cases. The reasons for discontinuing treatment were: pregnancy 1.33 (per hundred women), menstrual disturbances 0.76, side effects 3.80, other medical reasons 2.09, and personal reasons 4.18. The results confirm that Triquilar is an effective oral contraceptive with good cycle control and low incidence of side effects. No serious reaction has been reported. It has been well accepted by the Chinese women. However, due to the low dosage of steroids, it is of utmost importance to avoid errors in its use.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics of norethindrone enanthate 200 mg after intramuscular injection in 25 Chinese women].

Pharmacokinetic profile was studied in 25 healthy fertile Chinese female volunteers after im norethindrone enanthate (NET-EN) 200 mg. The results were compared with the data from British women in our previous paper. Following a single im NET-EN 200 mg, the times to reach peak levels of NET-EN and NET were 4.0 +/- 2.8 d and 5.4 +/- 2.0 d, and their peak values were 5.0 +/- 1.8 and 12.6 +/- 0.9 ng.ml-1, respectively. Mean elimination T1/2 of NET was significantly longer than that of NET-EN. Mean apparent elimination T1/2 were 14.8 +/- 3.8 d for and 11.4 +/- 5.7 d for NET-EN. The elimination rate of NET in Chinese women was significantly slower than that in British women. There was no significant ethnic difference in absorption kinetics of NET and NET-EN.

Relationship between hormone profiles and the restoration of spermatogenesis in men treated with gossypol.

Gossypol acetic acid was administered orally to 35 male volunteers at a dose of 20 mg once a day for 52-70 days in the loading phase and twice a week for 22 months in the maintenance phase. Sperm counts and the serum concentrations of LH, FSH, prolactin, testosterone and oestradiol were monitored regularly during treatment and for a follow-up period of 12 months. At around 90 days after treatment, all treated participants approached or attained azoospermia and remained at this level throughout the maintenance phase. By the end of the follow-up phase, eight treated men were still azoospermic, while sperm counts in the other 27 men were restored to normal levels. The only hormone that changed significantly during and after the treatment was FSH. From the 6th month of the treatment to the end of the follow-up phase, serum concentrations of FSH in the eight participants that reached irreversible azoospermia were significantly higher than in the other 27 men or in controls. It is suggested that monitoring of FSH levels might be of diagnostic use for identifying those participants with irreversible azoospermia during gossypol treatment.

Pharmacokinetics of norethisterone oenanthate in humans.

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.