Controlled release of levonorgestrel from biodegradable poly(D,L-lactide-co-glycolide) microspheres: in vitro and in vivo studies.

Poly(D,L-lactide-co-glycolide) (PLG) biodegradable microspheres containing a contraceptive drug, levonorgestrel (LNG), were prepared using both the solvent evaporation method and a modified solvent extraction-evaporation method. The microspheres prepared with the solvent evaporation process had porous surfaces with low product yields and poor encapsulation efficiencies. On the other hand, the microspheres prepared using the modified solvent extraction-evaporation method were nonporous with encapsulation efficiencies close to 100%. In vitro drug release showed the nonporous microspheres had a lower initial burst and a slightly prolonged duration of release than those porous microspheres. In vivo release kinetics of the low burst microspheres were determined by measuring LNG plasma levels after a single intramuscular injection to female rats. At a LNG dose of 41.1 mg/kg, average plasma LNG levels were 6-10 ng/ml in the first 24 h and subsequently remained above 1 ng/ml until 126 days. The duration above the minimum effective LNG plasma level of 0.2 ng/ml was 168 days. By comparison, a similar dose of LNG microcrystals used as control produced a much higher plasma level of 15-21 ng/ml in the first day followed by a fast and continuous decline of LNG levels with a duration of only about 35 days.

Some properties of an estimator for the basic reproduction number of the general epidemic model.

In this paper some properties of a convenient estimator, derived from a martingale estimating function, for the basic reproduction number of the general epidemic model are given for both finite and large samples. These properties give some guidelines for using this convenient estimator. It is shown that it underestimates the parameter and that the bias tends to zero when the population size and the initial number of infectives are increased simultaneously. The bias cannot be removed for a fixed number of introductory infectives. However, the estimator is asymptotically unbiased, conditional on a major outbreak. A simulation study shows that the central limit theorem applies for moderate population sizes.

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.

[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)

[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.

Hemostatic changes in women using a monthly injectable contraceptive for one year.

The effect of consecutively injecting a one-a-month contraceptive (norethisterone enantate 50 mg with estradiol valerate 5 mg) for one year on haematological parameters was evaluated in 42 Chinese women. The healthy volunteers were randomly allocated to either the treatment group (22) or a control group (20). Blood samples were collected in the follicular and luteal phases of a pretreatment cycle, on days 28 +/- 3 after the 1st, 3rd, 6th, 12th injections and in the luteal phase of the post-treatment cycle. The results showed that in both groups, prothrombin time and fibrinogen fluctuated significantly, and leucocyte count was not significantly changed during the whole course. Factor VIII-related antigen and antithrombin III (AT-III) antigen showed minor changes, although in the 3rd treatment cycle, the differences between the two groups in both parameters reached statistical significance. A progressive and significant decrease in Factor X and AT-III functional activity occurred with the monthly injectable treatment, decreasing by about 14% and 20%, respectively, after 12 months of treatment. Haemoglobin levels were increased in the treatment group after the 3rd injection and remained at the higher level during the study period. It is doubtful whether these changes are likely to be of clinical relevance.

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.