The pharmacokinetics of 3-keto-desogestrel and ethinyl estradiol (EE) and the safety of Org5187 (150 mcg desogestrel and 30 mcg EE) in 17 healthy Japanese women (single dose--8, multiple dose--9) were studied after oral administration. After single dose administration, Tmax, Cmax elimination 1/2 life (t1/2beta), and the area under the curve (AUC) of 3-keto-desogestrel were 1.8 +or- 0, 7 hour; 3.9 +or- 1.36 pmol/ml, 19.1 +or- 13.0 hours; and 28.6 +or- 22.9 pmol h/ml, respectively. On the other hand, those after multiple dose were 1.2 +or- 0.6 hour (Tmax), 12.12 +or- 5.49 pmol/ml (Cmax), 22.0 +or- 9.6 hour (t1/2beta), and 97.2 +or- 36.8 pmol h/ml (AUC), respectively. Pharmacokinetic parameters of EE were 1.69 +or- ), 96 hour (Tmax), 0.638 +or-0.025 pmol/ml (Cmax), 20.0 +or- 12.3 hour (t1/2beta), and 7.0 +or- 4.12 pmol h/ml (AUC) after single dose, and 1.11 +or- 0.5 (Tmax), 1.180 +or- 0, 315 pmol/ml (Cmax), 23.7 +or- 8.8 hour (t1/2beta), 11.7 +or- 3, 3pmol h/ml (AUC) after multiple dose. The serum concentrations of 3-keto-desogestrel and EE reached a steady state on the 15th day after initiating administration. No differences were observed between Japanese and European female volunteers in the pharmacokinetics of 3-keto-desogestrel and EE. During the period of multiple dose treatment, neither irregular bleedings nor side effects leading to dropouts were observed. (author's)
To examine a change occurring in the coagulation-fibrinolytic system during oral contraceptive (OC) administration, the author measured fibrinopeptide A and Bbeta15-42 (FPA and FPBbeta15-42) over a long period of time. These are sensitive indicators of coagulation and fibrinolytic activity as well as coagulation fibrinolysis inhibiting factor plasma antithrombin III (AT III) and alpha2 plasmin inhibitor (alpha2 PI). The interesting results are listed as follows. 1) FPA showed almost no change during OC administration, nor was thrombin observed to have been produced. 2) FPB15-42 increased when the drug was administered 3-5 times and 11-12 times (p0.05) but showed significant difference when the drug was administered for the 18th and 24th times. 3) Plasma AT III activity decreased significantly (p0.05) when the drug was given for the 1st time but showed no change when the drug was administered 3-5 times. When administered 11-12 times, AT III was observed to decrease again, but repeat administrations did not cause AT III to decline; this was probably due to inurement. A similar change in immune activity concentration was observed but the change was slight. 4) When the drug was given 3-5 times following the 1st administration, a slight decrease (p0.1) occurred in alpha2 PI levels, but no change worth of mention was noted to occur thereafter. 5) In patients who received norethisterone 5 mg alone, no particular change was seen to occur in FPA, FPBbeta15-42, AT III, or alpha2 PI. Judging from the above results, especially that there was an increase in FPA, the decrease in AT III levels may be attributed not to a reduction in consumption but to a decrease in the AT III itself, due to estrogens. It is possible also that an increase in FPBbeta 15-42 led to plasmin production which was the reason so few thromboses were observed to form. (author's modified)
The effects of menfegol-coated condoms on sperm motility and viability were investigated. At 0.5 mg/ml and higher concentrations, mennfegol, a spermicidal agent, was found not only to suppress sperm motility buy also to kill the sperm completely, indicating that it has strong spermicidal potency. Normal semen samples were ejaculated directly into menfegol-coated or uncoated condoms. The sperm motility and viability were examined immediately after ejaculation. In the menfegol-coated condom, sperm motility was completely suppressed and no viable sperm were observed, whereas in the uncoated condom, most of the sperm were still alive, although their motility was virtually or completely suppressed. These results indicate that the menefegol-coated condom provides a new birth control method which enhances contraceptive efficacy with added spermicidal activity. (author's)
Early abortion traditionally referred to abortion within 12 weeks of gestational age, but it is necessary to divide it into 3 stages: ultra early abortion for the one within 5 weeks of gestational age; very early abortion for the one within 8 weeks; early abortion for the one between 8 and 12 weeks. Progress and development in them are of IVF-ET and GIFT necessitated redefining pregnancy and resulted in great number of terms related to early pregnancy and abortion, which are not standardized and sometimes confusing. In connection with IVF-ET research, the following 3 stages of early pregnancy are recognized by Japanese doctors. Biochemical pregnancy is when plasma level of beta HCG is above norm. Early clinical pregnancy is when the Gestational sac is detected by ultrasonography but the heat beat of fetus is not yet confirmed. Established clinical pregnancy is when the heart beat of the fetus is confirmed via ultrasonography. Early abortion is divided into 2 stages: subclinical abortion (menstrual abortion), which is menstrual like fetus wastage in biomedical pregnancy, and clinical abortion in which a blighted ovum is detected by ultrasonic examination. Classification above is simple and easy but it heavily relies on measurement methods, results of which often fluctuate and are subject to change. It seems desirable to classify early abortion according to gestational age (GS). GS may be detected as early as 4 weeks, is above 10 mm in the maximum diameter at 5 weeks, and is detected in all cases at 6 weeks. Human chorionic gonadotropin (HCG) test by 1000 IU/1 sees positive response in almost all cases at 6 weeks, while HCG by 200 IU/1 sees the same at 5 weeks. The heart beat of the fetus is believed to commence at 4 weeks but it is not detected by ultrasonography at the earliest till the end of 5 weeks and in all cases till 8 weeks. The classification of ultra early abortion, very early abortion and early abortion, is based on above findings.
LDH-C4 is a specific isoenzyme, distinct from other LDH isoenzymes with regard to its locality and kinetic properties. Because about 80% of LDH in spermatozoa contains LDH-C4, it must be strongly related to very specific metabolic processes connected with sperm. In order to investigate the mechanism of action of gossypol, which is a new male contraceptive, the effects of gossypol on LDH-C4 were examined. LDH-C4 from human seminal plasma was purified by Oxamate-Sepharose 4B affinity column chromatography and AMP affinity column chromatography. The homogeneity of LDH-C4 was proved by agar gel electrophoresis and polyacrylamide disc gel electrophoresis. Gossypol was dissolved in 95% ethanol. LDH activity was analyzed spectrophotometrically. The cuvette contained 0.1 M PBS (pH 7.4), 0.2 mM pyruvate, and 0.115 mM NADH. Gossypol was added to give a final concentration of between 1 x 10 -6 M and 1 x 10 -4 M. Ethanol did not inhibit LDH-C4 activity, but gossypol did inhibit it in a dose-dependent manner when tested at a concentration of 5 x 10 -6 M, 1 x 10 -5 M, 5 x 10 -5 M, and 1 x 10 -4 M. (author's modified)
A clotting method and a single radial immunodiffusion flat plate method were used to study the effects of oral contraceptives (OCs) and loading with conjugated estrogens on plasma antithrombin 3 (AT 3). The changes of fibrinopeptide a (FPA) which is a new sensitive indicator of coagulation when OCs are given were investigated and the results are reported. After the 1st administration of OCs, the plasma AT 3 activity is markedly lowered. But after the 3rd-5th series of administrations, there were no significant changes seen. When administration was continued further until after the 12th cycle, the level became even lower than the control value. The immune activity changed in a similar fashion but only to a slight degree. When the plasma was loaded with conjugated estrogen, the plasma AT 3 concentration (immune activity) did not change at 2 mg/ml of conjugated estrogen but it decreased to 73% at 4 mg/ml and the immune activity was completely lost at 8 mg/ml. Furthermore, when incubated for 30 minutes, its decrease was rapid. FPA showed almost no changes when OCs were given and production of thrombin was not observed. Based on the above results, the decrease of plasma AT 3 was the reduction of AT 3 activity itself, rather than a exhaustive decline due to the production of thrombin. (author's modified)
14 patients with obstructive azoospermia were treated with microsurgical vasovasostomy or epididymovasostomy. A total of 11 patients underwent 2-layer vasovasostomy, 6 cases following bilateral vasectomy and 5 cases suffering from bilateral vasal disruption by inguinal herniorrhaphy. 3 patients underwent end-to-end epididymovasostomy with Silber's specific tubule technique following bilateral epididymitis. After the operation, fertility was restored in 6 of 14 cases. The recovered sperm density was greater than 20 x 10 6/ml and sperm motility exceeded 50%. Pregnancy was achieved in 1 case following inguinal herniorrhaphy. Preoperative testicular biopsies carried out in 11 cases disclosed slight deterioration of spermatogenesis. Johnsen's mean score was 8.20 +or- 0.38 (mean +or- S.D.). The mean scores of the biopsies obtained from the cases obstructed for more than 20 years were significantly lower than those with less than a 20-year time period. After inguinal herniorrhaphy, reanastomosis of the vas deferens was difficult in order to restore fertility. This was due to the presence of longterm obstruction, defects in the vas deferens, or the absence of sperm granuloma at the vasectomy site. Epididymovasostomy restored fertility in 67% of the cases. The specific tubule technique was the most effective in the management of such pathological conditions. (author's modified)
An awareness of ovulation pain and the occurrence of premenstrual swelling of the breasts have been cited as methods of self-detection of ovulation and the ensuing fertile period. While these are part of the cervical mucus method and are occurrences which the woman herself can detect, so are the procedures which form the basis of the basal body temperature method and Ogino's method. The rate of utilization of these methods was examined in 408 women. 79% of the subjects had heard of Ogino's method, 15% were uninformed about it, and 7% did not respond. Only a few of those women who practiced it, however, did so correctly. There were 58% who had used the basal body temperature method, 40% who had not, and 2% who did not respond. A few of the women in this group used this method continuously. As many as 61% of the women did not respond to the question concerning the check for cervical mucus; the implication here is little interest in the method. When these subjects were excluded, 65% were aware of changes in the vulvar region, especially the sensation of moistness. Premenstrual swelling of the breasts was present in 47% and absent in 46%, with no response made by 7%. 37% of the women experienced ovulation pan, 52% did not, and 11% did not respond. Of the group who did experience ovulation pain, 6% had what they considered distinct pain. 27% of the women desired to utilize natural family planning, 8% did not, and 46% were undecided; 19% gave no response. There were more affirmative responses than negative ones. (author's modified)
The authors studied antithrombin 3 (AT3), alpha1 antitrypsin (alpha1 AT), and alpha2 macroglobulin (alpha2 M) in Japanese women taking oral contraceptives (OCs). These are the results. 1) In women receiving combined OCs (mestranol 0.1 mg and norethisterone 2 mg) for 20 days every cycle, serum AT3 activity had markedly decreased after completion of the 1st series. In successive series, no significant difference was observed between the values before and after treatment. AT3 activity was almost equal to that of control values in the 3rd-5th series of treatments and then displayed a tendency to decrease. Changes in plasma AT3 activity was almost the same as those in the serum. 2) A marked decrease in serum and plasma AT3 activity was also observed for women taking low dosage combined OCs (mestranol 0.05 mg and norethisterone 1 mg). It seemed ineffective to reduce the estrogen component of the OCs for purposes of preventing the decrease in AT3 activity. 3) Use of norethisterone alone, 5 mg/day for 20 days, did not induce remarkable changes in both serum and plasma AT3 activity, although it is considered 1 of the estrogenic gestagens. 4) AT3 activity in Japanese women was considerably higher than that reported in Western women. This perhaps could explain the low incidence of thromboembolic disease in Japanese women. 5) Serum alpha1 AT had significantly increased after the initial cycle and kept high concentrations for the succeeding 24 series. 6) OCs had no influence on the concentrations of alpha2 M and FDP in serum. (author's modified)
In 11 cases undergoing vasectomy for the purpose of contraception, and in 2 vasectomized men receiving reanastomosis to regain conceptive potential, their semen samples were obtained before and after the operation and changes in seminal levels in a variety of amino acids were compared. Seminal levels of amino acids were determined by employing auto amino acid analyzer (JLC-6AH). Preoperative values for seminal amino acids in their 11 patients underwent notable changes with vasectomy. The most prominent among the general decreases was a drop by as much as 51% for proline, followed by 48.9% for aspartic acid, over 30% each for threonine, glycine, alanine, valine, leucine, lysine, and arginine, 29.9% for isoleucine, 29% for serine, 26.4% for phenylalanine, 24.1% for tyrosine, and 23.6% for glutamine. On the other hand, of the 2 patients undergoing reanastomosis of the vas deferens, the 1 who achieved impregnation after the operation showed remarkably low preoperative levels in almost all seminal plasma amino acids. After the operation and with the appearance of sperm in the semen, however, amino acid levels rose; at 4 months, when impregnation was confirmed, some varieties were noted at a 1.5-9.5 fold increase over preoperative values. In the other reanastomosis patient, although sperm did not appear at the 2 week postoperative sampling, values of various amino acids in the seminal plasma had risen 1.4-6.3 times the preoperative level. The fact that vasectomy caused various free amnio acids to decrease markedly in the seminal plasma may tell us that amino acids, equivalent in amount to their decreases, probably had originated from the testicles and epididymides located above the vas deferens. On the other hand, reanastomosis of the vas deferens caused various free amino acids within the fluid of the testicles and epididymides to flow into the semen, elevating the level of total seminal amino acids. Therefore, when increases in free amino acids in seminal plasma do not accompany the appearance of sperm, it may be interpreted that some problems in the testicles or epididymides are responsible for impairing otherwise successful reanastomosis of the vas deferens. Thus, it seems appropriate to conclude that success or failure of reanastomosis of the vas deferens can be judged by determining amino acids in seminal plasma without resorting to seminalvesiculography. (author's)
Newly designed intravaginal polyurethane sponges containing the spermicide nonoxynol-9 were developed for contraceptive purposes. The sponges were made by the polymerization of urethane monomers in a solution of nonoxynol-9. This new biomaterial is analogous to a large, thick cervical cup with a dimple in the center for ease of insertion and positioning to the cervix (and external os). There is no need for precoital planning or preparation for usage of this sponge. The release of the spermicidal agent from the sponges was 1st determined by soaking the sponges in saline and squeezing the nonoxynol-9 solution from them. In order to determine the actual amount of nonoxynol-9 released from the sponge, 2 analytic techniques were used. 1 method was ultraviolet spectoscopy and its accuracy ranged from 85-97%. The other was bioassay for the spermicidal activity and its accuracy ranged from 100-124%. To simulate the actual wearing of the sponge by a patient, the sponges were soaked in a large volume of saline and almost 50% of the spermicidal agent was released during the first 24 hours. In conjunction with the laboratory studies, a limited study to determine acceptability of the devices was investigated in normal women. The women were asked to wear the sponges for 1, 2, 3, 4, 5, 6, and 7 consecutive days. It was found that all women in the population could not tolerate the sponge longer than 5 days due to the odor. Thus, with the good release rates for 2-4 days and patient acceptability for 2 days of wear, a protocol for the use of the intravaginal sponge as a 2-day device was established. (author's)
A new vaginal contraceptive in the form of a film containing the spermicide, polyoxyethylene nonylphenyl ether (C-Film) was put into clinical trials. To evaluate spermicidal activity of C-film, an in vitro test was performed. After 1 minute, no motile sperm could be seen in the C-film solution which was diluted 32 times by a 5% glucose solution. When the sperm contacted the C-film solution diluted 8 times, the sperm stopped moving. C-film was used by 168 women for 1 and one-half years from December 1977 to May 1979 for a total period of 2161 months. Only 1 pregnancy occurred, thus giving a pregnancy rate of 0.56/100 women-years. During the use of C-film, 16 cases (9.5%) complained about an increase of vaginal discharge, 8 cases (4.8%) felt unfamiliar with the insertion, and 7 cases (4.2%) complained about unusual feelings caused by the presence of the C-film. A total of 9 cases (5.4%) stopped using C-film; 3 due to irritation, 2 due to troublesome use; and others due to vaginal discharge, burning sensation, pregnancy, and reasons unknown. No significant changes were observed in the vaginal bacteriology, cervical cytology, liver function, or renal function. The study indicates that C-film is very effective, well-tolerated, and has a low incidence of side effects. (Authors' modified)
