The Effect of Oral Contraceptive Hormones on Anterior Cruciate Ligament Strength.

BACKGROUND: Women are 2 to 9 times more likely to experience an anterior cruciate ligament (ACL) injury than men. Various hormones including relaxin, progesterone, and estrogen influence ACL strength. Oral contraceptives (OCs) alter these hormone levels; however, studies have yet to comprehensively compare different OCs' effects on the ACL. HYPOTHESIS: OCs with increased progestin-to-estrogen ratios will (1) increase ACL collagen expression, (2) decrease ACL matrix metalloproteinase expression, and (3) increase ACL strength. STUDY DESIGN: Controlled laboratory study. METHODS: Untreated female rats were compared with rats treated with 1 of 5 clinically used OCs: norethindrone (NE) only, NE plus ethinylestradiol (EE), etynodiol diacetate (ED) plus EE, norgestimate (NG) plus EE, and drospirenone (DS) plus EE. Doses were scaled from human doses to account for differences in bioavailability and body weight, and OCs were administered daily via oral gavage for 4 rat estrous cycles (20 days). A total of 36 rats were then sacrificed (6 rats/group). ACLs underwent biomechanical testing to assess ACL strength, stiffness, and maximum load before failure. ACL specimens were also isolated for quantitative real-time polymerase chain reaction analysis to assess collagen, matrix metalloproteinase, and relaxin receptor-1 expression. RESULTS: While the primary structural property of interest (ACL maximum load before failure) was not significantly improved by OC treatment, the main material property of interest (ACL strength) in rats treated with NE only, DS + EE, ED + EE, and NE + EE was significantly increased compared with untreated controls (P = .001, P = .004, P = .004, and P = .04, respectively). The order from strongest to weakest ACLs, which was also the same order as the highest to lowest progestin-to-estrogen ratios, was groups treated with NE only, DS + EE, ED + EE, NE + EE, and lastly NG + EE. Higher ratio formulations also increased the expression of type I collagen (P = .02) and decreased the expression of matrix metalloproteinase-1 (P = .04). CONCLUSION: OC formulations with higher progestin-to-estrogen ratios may be more protective for the ACL than formulations with lower ratios. CLINICAL RELEVANCE: OC formulations with high progestin-to-estrogen ratios may benefit female athletes by reducing their ACL injury risk by decreasing the effects of relaxin on the ACL.

Progestin-only pills for contraception.

BACKGROUND: The introduction of a new progestin-only oral contraceptive in Europe has renewed interest in this class of oral contraceptives. Unlike the more widely used combined oral contraceptives containing an estrogen plus progestin, these pills contain only a progestin (progestogen) and are taken without interruption. How these pills compare to others in their class or to combined oral contraceptives is not clear. OBJECTIVES: This review examined randomized controlled trials of progestin-only pills for differences in efficacy, acceptability, and continuation rates. SEARCH METHODS: Through October 2013, we searched the computerized databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), POPLINE, and LILACS for studies of progestin-only pills. We also searched for current trials via ClinicalTrials.gov and ICTRP. Previous searches also included EMBASE. SELECTION CRITERIA: We included all randomized controlled trials in any language that included progestin-only pills for contraception.  We incorporated any comparison with a progestin-only pill; this could include different doses, other progestin-only pills, combined oral contraceptives, or other contraceptives. DATA COLLECTION AND ANALYSIS: The first author abstracted the data and entered the information into RevMan 5. Another author performed a second, independent data abstraction to verify the initial data entry.We attempted to extract life-table rates (actuarial or continuous) and used the rate difference as the effect measure. Where life-table rates were not published, we used the incidence rate ratio (ratio of Pearl rates). Where only the crude number of events was published, we calculated the Peto odds ratio with 95% confidence interval (CI) using a fixed-effect model. For continuous variables, the mean difference (MD) was computed with 95% CI. Because of disparate exposures, we were not able to combine studies in meta-analysis. MAIN RESULTS: Six trials met the inclusion criteria. We have not found any new studies since the initial review. In the trial comparing the desogestrel versus levonorgestrel progestin-only pill, desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rate ratio was 0.27 (95% CI 0.06 to 1.19). However, the desogestrel progestin-only pill caused more bleeding problems, although this difference was not statistically significant. The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill found similar pregnancy rates. In the trial comparing ethynodiol diacetate versus a combined oral contraceptive, irregular cycles occurred in all women assigned to the progestin-only pill (odds ratio 135.96; 95% CI 7.61 to 2421.02). In a trial comparing two progestin-only and two combined oral contraceptives, the progestin-only pill containing levonorgestrel 30 µg had higher efficacy than did the pill containing norethisterone 350 µg. An early trial found megestrol acetate inferior to other progestin-only pills in terms of efficacy. A study of the timing of pill initiation after birth found no important differences, but high losses to follow up undermined the trial. AUTHORS' CONCLUSIONS: Evidence is insufficient to compare progestin-only pills to each other or to combined oral contraceptives.

Progestin-only pills for contraception.

BACKGROUND: The introduction of a new progestin-only oral contraceptive in Europe has renewed interest in this class of oral contraceptives. Unlike the more widely used combined oral contraceptives containing an estrogen plus progestin, these pills contain only a progestin (progestogen) and are taken without interruption. How these pills compare to others in their class or to combined oral contraceptives is not clear. OBJECTIVES: This review examined randomized controlled trials of progestin-only pills for differences in efficacy, acceptability, and continuation rates. SEARCH STRATEGY: We searched the computerized databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), POPLINE, LILACS, and EMBASE for studies of progestin-only pills. We also searched for current trials via ClinicalTrials.gov and ICTRP. SELECTION CRITERIA: We included all randomized controlled trials in any language that included progestin-only pills for contraception. We incorporated any comparison with a progestin-only pill; this could include different doses, other progestin-only pills, combined oral contraceptives, or other contraceptives. DATA COLLECTION AND ANALYSIS: The first author abstracted the data and entered the information into RevMan 5. Another author performed a second, independent data abstraction to verify the initial data entry. Because of disparate exposures, we were not able to combine studies in meta-analysis. MAIN RESULTS: Six trials met the inclusion criteria. In the trial comparing the desogestrel versus levonorgestrel progestin-only pill, desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rate ratio was 0.27 (95% CI 0.06 to 1.19). However, the desogestrel progestin-only pill caused more bleeding problems, although this difference was not statistically significant. The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill found similar pregnancy rates. In the trial comparing ethynodiol diacetate versus a combined oral contraceptive, irregular cycles occurred in all women assigned to the progestin-only pill (odds ratio 135.96; 95% CI 7.61 to 2421.02). In a trial comparing two progestin-only and two combined oral contraceptives, the progestin-only pill containing levonorgestrel 30 mug had higher efficacy than did the pill containing norethisterone 350 mug. An early trial found megestrol acetate inferior to other progestin-only pills in terms of efficacy. A study of the timing of pill initiation after birth found no important differences, but high losses to follow up undermined the trial. AUTHORS' CONCLUSIONS: Evidence is insufficient to compare progestin-only pills to each other or to combined oral contraceptives.

Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial.

A phase IV trial evaluated the efficacy and safety of a monophasic oral contraceptive formulation, ethynodiol diacetate, 1 mg, plus ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) (Demulen 1/35). Nine hundred eighty-three community-based obstetrician-gynecologists treated a total of 7,759 patients with EDA 1 mg with EE 35 micrograms for one to eight months. Clinical evaluation forms on 6,382 patients were amenable to analysis for safety (including breakthrough bleeding, ovarian cyst formation and complexion changes); 5,412 patients were evaluable for efficacy (prevention of pregnancy), with a total of 21,440 cycles recorded. The study results were interpreted in terms of the impact on clinical management of oral contraceptive users and the methods, strengths and weaknesses of phase IV trials, particularly as they relate to confirmation of the results reported here.

PIP: From August 1988-June 1989, 983 physicians participated in a phase IV trial by following 7759 women using the monophasic oral contraceptive (OC), Demulen 1/35 (1 mg ethynodiol diacetate and 35 ug ethinyl estradiol) to evaluate its efficacy and safety. The total number of cycles for the study stood at 21,440. In addition, the total woman-years stood at 1787. Only 6382 patients could be evaluated for safety. 4.4% of the patients had adverse reactions to the OC, but only 1.7% of all patients stopped taking it. The leading side effects included nausea (67 cases), headache (45), amenorrhea (42), emotional changes (30), breast pain (19), dysmenorrhea (12), and 11 cases of weight gain, abdominal/pelvic pain, and bloating. Of the 280 reported adverse reactions, only 87 (31%) were considered severe. The leading serious adverse reactions were depression (10) and hypertension (6). Only 5412 patients could be used to determine efficacy. The physicians initially reported 121 (2.2%) pregnancies during the study. The researchers learned that 33 of the 84 returned 2nd questionnaires (response rate, 70%) reported that the women conceived after enrollment but before taking the OC. 36 conceived while taking it, but 8 did not take it daily. Noncompliance may have contributed to pregnancy for the remaining 28 cases. Therefore the 36 confirmed pregnancies made for a failure rate of .7%. 85.7% of the pregnancies happened in the 1st 3 months of taking the OC. Either patient noncompliance or true medication failure accounted for treatment failure. Therefore it is important for physicians to instruct patients on how to take OCs correctly.

Clinical experience with the progestogen-only pill.

Experience with the progestogen-only pill (POP) in a family planning clinic is presented. From the clinic records, 408 women were identified who had opted to use a POP. Of these, 50 women had used the POP during lactation and these were excluded from the analysis. The remaining 358 women used the POP for up to 150 months, giving a total of 18,125 women-months of use. Three pregnancies occurred, giving a Pearl Index of 0.2 per 100 women-years. Non-menstrual side effects were minor and were reported by 77 women. For the women who discontinued the POP, the main reason was menstrual irregularity (47.5%). However, despite the long-term use by most of the women, almost 40% maintained a mostly regular menstrual pattern. Our findings suggest that the POP provides a very acceptable method of oral contraception for many women and that it should be more actively promoted.

Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.

Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicentre open study carried out in General Practice and Family Planning clinics. Five pregnancies were reported, three of which were a result of patient failure. The net pregnancy rate at one year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between four and five days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small decrease in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

PIP: Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicenter open study carried out in General Practice and Family Planning clinics. 5 pregnancies were reported, 3 of which were a result of patient failure. The net pregnancy rate at 1 year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between 4 and 5 days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small increase in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

Progestins and oral contraceptive-induced lipoprotein changes: a prospective study.

In order to determine the effects on plasma lipoproteins of oral contraceptives containing progestins with varying androgenic potency, 136 healthy women were randomized into 3 groups and followed prospectively for one year while receiving either 50 mcg ethinyl estradiol and 1.0 mg ethynodiol diacetate (EED), 50 mcg ethinyl estradiol and 1.0 mg norethindrone acetate (ENA), or 50 mcg ethinyl estradiol and 0.5 mg d-1 norgestrel (ENG). Comparison was made to a self-selected group of 50 women using alternative means of contraception. Plasma cholesterol increased by 7-9% and triglycerides by 32-57% in all 3 groups (p less than 0.05). ENG use resulted in other significant lipoprotein changes including an 18% increase in low density lipoprotein cholesterol (LDL-C), a 13% fall in high density lipoprotein cholesterol (HDL-C) and a 27% decline in HDL2 cholesterol (HDL2-C) (p less than 0.05). Apoprotein A-I (Apo A-I) increased by 9% with ENA and by 11% with EED (p less than 0.05), but did not change significantly with ENG. This prospective study demonstrates that in oral contraceptive agents with identical estrogen, progestins with different androgenic potency produce major and different changes in plasma lipoproteins.

PIP: In order to determine the effects on plasma lipoproteins of oral contraceptives containing progestins with varying androgenic potency, 136 healthy women were randomized into 3 groups and followed prospectively for 1 year while receiving either 50 mcg ethinyl estradiol and 1.0 mg ethynodiol diacetate (EED), 50 mcg ethinyl estradiol and 1.0 mg norethindrone acetate (ENA), or 50 mcg ethinyl estradiol and 0.5 mg d-1 norgestrel (ENG). Comparison was made to a self-selected group of 50 women using alternative means of contraception. Plasma cholesterol increased by 7-9% and triglycerides by 32-57% in all 3 groups. ENG use resulted in other significant lipoprotein changes including an 18% increase in low density lipoprotein cholesterol, a 13% fall in high density lipoprotein cholesterol and a 27% decline in high density lipoprotein-2 cholesterol. Apoprotein A-1 increased by 9% with ENA and by 11% with EED, but did not change significantly with ENG. Khis prospective study demonstrates that in oral contraceptive agents with identical estrogen, progestins with different androgenic potency produce major and different changes in plasms lipoproteins.

Dose- and time-dependent effects of a dimeric ethynodiol-testosterone depot-preparation in female rat.

The time- and dose-dependent effects of a dimeric ethynodiol-testosterone ester upon intact and hemi-castrated female rats were compared to those of equivalent doses of norethisterone enanthate plus testosterone enanthate. In intact rats, serum LH was markedly suppressed for at least 8 weeks after a single i.m. injection of 10 or 20 mg of the dimer which exceeded the depot-effect of the combination of the enanthates. A biphasic time-and dose-dependent effect of the dimeric ester upon ovarian and uterine weight was observed. During first 2 weeks following the injection there was a pronounced enlargement of corpora lutea and a marked enhancement of progesterone secretion, probably due to a direct stimulation by the androgens. At the same time, the uteri were markedly enlarged. During the following weeks, the ovaries became progressively smaller and showed degenerative changes, the steroid levels decreased and the uteri became atrophic. When hemi-castrated rats were injected once with 1 and 5 mg of the dimer, LH became suppressed, and the compensatory hypertrophy of the ovary was inhibited. At higher doses, the weight of the ovary and uterus was increased, and the luteal function was stimulated. The results indicate that, even though the gonadotropins are suppressed, there is possibly a direct stimulatory effect of high doses of the intact dimeric molecule upon the uterus, while the stimulation of the corpus luteum function is due to an interference of the transiently elevated testosterone level with ovarian steroid biosynthesis.

Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol diacetate administration.

Twelve women with established lactation of 4-8 weeks duration were given a low-dose progestogen-only contraceptive, ethynodiol diacetate 0.5 mg (Femulen) daily. On the seventh and eight day of the study, prior to the mother's taking the pill, a blood sample was taken from her and from the infant. Further blood samples were collected from the mother 4 and 12 hours later. Breast milk samples were collected at every feed on day 7 and day 8. Ethynodiol diacetate is rapidly metabolised in humans, changing into the metabolite norethisterone which is found in both blood and milk. Hence, norethisterone concentrations were estimated. On day 7 and day 8, four hours after ingestion of the pill, the median norethisterone maternal plasma concentration was 1.60 ng/ml and it fell to a median level of 0.30 ng/ml prior to the next dose of the pill. At this time the median infant concentration was 0.10 ng/ml but the maximum observed level was 0.50 ng/ml. In the breast milk the norethisterone concentration appears to peak at around 4-8 hours following the ingestion of the pill. The maximum observed concentration in breast milk was 0.84 ng/ml. The amount of norethisterone ingested by the infant averaged 0.02% (6.65 micrograms) of the dose of ethynodiol diacetate ingested by the mother. The maximum observed on any one day was 0.07% (27.52 micrograms). The above results indicate that the amount of progestogen ingested by the infant from its mother's milk is small and is unlikely to pose a risk to the infant.

A prospective controlled study of the effect on blood pressure of contraceptive preparations containing different types and dosages of progestogen.

A prospective controlled study investigated the effects of oral contraceptives on blood pressure in 485 women who were between 17 and 46 years of age and had blood pressures of less than 140/90 mmHg at entry. The women were divided into seven groups depending on the chosen method of contraception: intrauterine device or barrier method (control group): ethinyl oestradiol 30 micrograms plus levonorgestrel 150 micrograms (Microgynon-30 or Ovranette); norethisterone 350 micrograms (Micronor); norgestrel 75 micrograms (Neogest); norethisterone oenanthate 200 mg intramuscularly every 2 months for the first 6 months, then every 3 months thereafter; ethinyl oestradiol 30 micrograms plus ethynodiol diacetate 2 mg (Conova-30); and ethynodiol diacetate 500 micrograms (Femulen). Blood pressures were measured every 3 months by the family planning clinic nurse under standardized conditions using an Elag-Köln automatic sphygmomanometer. After one year, blood pressure had risen significantly (P less than 0.05) in the 137 women taking ethinyl oestradiol plus levonorgestrel (mean systolic and diastolic rises 6.4 and 2.7 mmHg respectively) and in the 91 women taking ethinyl oestradiol plus ethynodiol diacetate (mean systolic and diastolic rises 6.2 and 3.0 mmHg respectively). The 94 women taking the progestogen-only preparations and the 143 women in the control group showed no increases in blood pressure. These data were confirmed after 2 years of follow-up.

PIP: A prospective, controlled study investigated the effects of oral contraceptives (OCs) on blood pressure in 485 women who were between 17-46 years old and had blood pressures of 140/90 mmHg at entry. The women were divided into 7 groups depending on the chosen method of contraception: 1) IUD or barrier method (controls); 2) ethinyl estradiol 30 mcg plus levonorgestrel 150 mcg (Microgynon 30 or Ovranette); 3) norethisterone 350 mcg (Micronor); 4) norgestrel 75 mcg (Neogest); 5) norethisterone enanthate 200 mcg intramuscularly every 2 months for the 1st 6 months, then every 3 months thereafter; 6) ethinyl estradiol 30 mcg plus ethynodiol diacetate 2 mg (Conova 30); 7) and ethynodiol diacetate 500 mcg (Femulen). Blood pressures were measured every 3 months by the family planning clinic nurse under standardized conditions using an Elag-Koln automatic sphygmomanometer. After 1 year, blood pressure had risen significantly (P0.05) in the 137 women taking ethinyl estradiol plus levonorgestrel (mean systolic and diastolic rises 6.4 and 2.7 mmHg respectively) and in the 91 women taking ethinyl estradiol plus ethynodiol diacetate (mean systolic and diastolic rises 6.2 and 3.0 mmHg respectively). The 94 women taking the progestogen-only preparations and the 143 women in the control group showed no increases in blood pressure. These data were confirmed after 2 years of follow-up.

[Planning of the treatment of atypical hyperplasia of the endometrium in patients with uterine myoma]. / Planirovanie lecheniia atipicheskoi giperplazii éndometriia u bol'nykh miomoí matki.

The results of a two-stage hormonal treatment of 62 cases of atypical hyperplasia of the endometrium were analysed. Within the first 6 months, patients received 24.0-28.0 g of hydroxyprogesterone capronate each. Six courses of steroid contraceptives such as non-ovlon and bisecurin were given during the second stage when regression of endometrial precancer had already been registered. The results proved hormonal therapy to be highly effective in managing atypical hyperplasia of the endometrium. Complete response was observed in 67.7% of patients. Coexistent uterine myoma affected the efficacy of treatment adversely: only 4 out of 14 patients with atypical hyperplasia of the endometrium with concomitant myoma were good responders. Hormonal treatment was ineffective mainly in cases of myoma of sizes exceeding 8 weeks of gestation and in pre- and postmenopausal patients. This makes the case for surgery.

Serum and placenta levels of ethynylestradiol in presence of ethynodiol diacetate after oral administration.

The ethynylestradiol concentration--in the presence of ethynodiol diacetate--in serum after oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 h after administration, and even after 12 h a significant amount of free ethynylestradiol was present in the serum. The transfer of ethynylestradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta/serum quotients were calculated for the ethynylestradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethynylestradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.

PIP: The ethinyl estradiol concentration--in the presence of ethynodiol diacetate--in serum following oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 hour after administration, and even after 12 hours, a significant amount of free ethinyl estradiol was present in the serum. The transfer of ethinyl estradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta serum quotients were calculated for the ethinyl estradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethinyl estradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.

[Blood serum iron concentration in women using contraceptive agent Angravid-Polfa]. / Zachowanie sie poziomu zelaza w surowicy krwi kobiet stosujacych preparat Angravid-Polfa w celach antykoncepcyjnych.

PIP: The blood-serum iron concentrations were examined in women using Anagravid (Polfa) as an oral contraceptive (OC). The examined subjects used the preparation for 6 months and their results were compared with those women not using a progestogen contraceptive. The results underwent statistical analysis. It was demonstrated that in the group of patients using Anagravid, the blood-serum iron concentrations were significantly higher when compared with those women who did not receive OCs. The mechanism of this phenomenon remains unclear. (author's modified)^ieng

Oral contraceptives and systemic lupus erythematosus.

PIP: This case report discusses a young woman who developed systemic lupus erythematosus (SLE) 4 weeks after the start of oral contraceptive therapy; she improved only with withdrawal of oral contraceptives. 16 months after cessation of oral contraceptives, she remains completely asymptomatic, has not needed therapy for 1 year, has completed a normal pregnancy, and is in the second month of her second pregnancy. This woman had a false positive serologic prenuptial syphilis test. She had been given Demulen (1 mgm of ethynodiol diacetate and 50 mcgm of ethynil estradiol).^ieng

Bioavailability and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.

Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half lives of 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself.

PIP: Bioavailability and pharmacokinetics of norethisterone (NE) were studied in 12 women, aged 21-37 years, after oral doses of ethynodiol diacetate (EDA). Plasma NE levels, measured by radioimmunoassay, were used to compare the bioavailability of EDA tablets (Ovulen 50; 1 mg EDA plus .05 mg ethinyl estradiol) with that of a standard oral solution of EDA. The 3 different batches of tablets studied showed different in vitro dissolution rates, 82.6%, 94.6%, and 99% at 3 hours. No marked differences were seen in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak plasma NE levels were reached within 4 hours of EDA administration in solution or tablets. Following the peak, NE plasma levels declined in 2 phases, with mean terminal elimination 1/2-lives of 4-6.9 hours. These results have shown that small variations in in vitro dissolution rates do not affect the bioavailability of NE from tablets containing EDA.