Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial. 204 81

Oral contraceptives (OCs, long-acting progestins (LAPs), and IUDS are reviewed in terms of new information on safety and efficacy. OC formulations are described and their mechanism of action and efficacy indicated. Reports are provided for thromboembolism, hemorrhagic and thrombotic stroke, ischemic heart diseases, alterations in lipid and hypoprotein and carbohydrate metabolism, hypertension, coagulation changes, breast and cervical cancers, and such minor side effects as menstrual irregularities, nausea, headaches, weight gain, premenstrual syndrome effects, and mood and libido changes. Noncontraceptive health benefits and clinical considerations are discussed. Norplant, as the only long acting progestin available in the US is described in terms of its formulations, mechanism of action, sequelae and metabolic effects, menstrual irregularities, metabolic effects, nuisance side effects, candidates for insertion, method of insertion and removal, and continuation rates. 2 IUD types are identified as the only ones available in the US, Progestasert T and T-Cu-380A (Paragard). Mechanism of action, efficacy, candidates, major sequelae such as salpingitis, infertility, and uterine perforation, minor sequelae such as metrorrhagia and dysmenorrhea, and other considerations are indicated. OCs in the US contain an average of 35 mg of ethinyl estradiol and assorted progestins e.g.s, ethynodiol diacetate, norethindrone acetate, nortestosterone derivatives with a complex mechanism of action. The failure rate for use effectiveness is 6 pregnancies/100 woman years. Modern formulations have combined rates of no more than 50 to 100 adverse events/100,000 users. Some of the effects are indicated as follows: Thromboembolism accounts for 60% of adverse effects and appears to be declining along with hemorrhagic and thrombotic stroke, however, modern use studies are only partially available. Myocardial infarction related to OC use may be embolic, and has a low risk at 7/100,000 users. Low-dose contraceptives substantially reduce the associated risks. Those with risk factors need close monitoring. Norplant is useful for those not wanting to take a daily regimen and is commonly accompanied by menstrual irregularity and sometimes headaches. Continuation is 80% after the 1st year and 40% after 5 years. Candidates for IUDs are parous women in monogamous relationships, who are not at risk for salpingitis, which is related to IUD use, or sexually transmitted diseases. Continuation is 70% after 1 year compared with 50% of OC users.
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PMID:Modern trends in contraception. 212 11

The cardiovascular effects of oral contraceptives, as predicted by studies on serum lipid changes in users, are based on the progestin dose, androgenic potency and biologic effect of the estrogen in the pill. Women suffer 250,000 deaths per year in the U.S. resulting from cardiovascular disease, almost half as many as men. They have the same risk factors: high cholesterol, high blood pressure and smoking, and also have more risk from diabetes than men do. The serum HDL, especially HDL2, correlates closely and inversely with heart disease risk. Exogenous estrogens raise HDL and HDL2, and lower LDL, conferring protection against coronary disease, in direct proportion to dose. Progestins usually have adverse effects, in proportion to dose, but progestin potency and type also determine their effects. The estrane progestins norethindrone, norethindrone acetate and ethynodiol diacetate are less potent and much less androgenic, while the gonanes norgestrel and especially levonorgestrel are 5-20 times as potent and androgenic. Each pill needs to be considered as a unit. Several comparative studies are reviewed, corroborating the prediction that pills with higher progestin potency have adverse effects on serum lipids, compared to those with higher estrogen effect. For new lower dose multiphasics, the effects either way are minimal, but HDL2 is still significantly lowered by pills containing levonorgestrel. Progestin-only pills lower HDL2 17- 21%. It is prudent to follow and treat the long-term effects of oral contraceptives on blood lipids.
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PMID:Oral contraceptives and cardiovascular risk. Taking a safe course of action. 220 2

Spironolactone (Aldactone) appears to have potential as a treatment for androgen-excess syndromes, including hirsutism. In both men and women, spironolactone decreases the rate of testosterone production and increases its metabolic clearance. The 1st indication that this agent has an effect on hirsutism was serendipitous--an incidental finding in a patient who was being treated for hypertension. Subsequent studies have largely confirmed that women who are administered spironolactone exhibit no further progression in hair darkening and coarsening, a slowed growth rate of existing hair, and decreased hair shaft diameter. When combined with dexamethasone or an oral contraceptive, spironolactone seems to increase the intervals between hair growth treatments. It has been suggested, but not documented, that spironolactone could correct hyperandrogenic ovulation. This use should be avoided, however, due to potential anti-androgenic effects on the fetus. Minor side effects of treatment with spironolactone include time-limited lethargy, stomach upset, and menstrual irregularity. There is concern, however, that this agent may stimulate the breast and contribute to the development of breast cancer. Thus, it should not be used by patients with a family history of breast malignancies. In addition, the drug should not be used in pregnancy and users of reproductive age should be supplied with an effective contraceptive method. The present dosage recommendation is 100-200 mg of spironolactone/day in 2 divided doses combined with either 35 mcg ethinyl estradiol and 0.5 mg of norethindrone or with 50 mg of ethinyl estradiol and 1 mg of ethynodiol diacetate.
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PMID:Use of spironolactone in treatment of hirsutism. 235 84

Mechanism of action, indications, side effects and contraindications of oral contraceptive agents (OCA) are reviewed. OCA can be divided into two groups: consecutive and combined agents. Combined OCA contain both estrogens and gestagens and are taken for 3 weeks, while consecutive OCA contain only estrogens and are taken for 2 weeks followed by 1 week of combined OCA until the onset of menstruation. Biological activity of synthetic gestagens is estimated by a dosage which results in a delay of menstruation by 2 weeks. Gestagens norethindrone and norethynodrel were shown to be equally effective, while ethinodiol diacetate and norgestrel were 15-30 times more effective. Estrogen component of OCA is represented by ethinyl estradiol or mestranol. Combined OCA are more effective than consecutive OCA; probability of undesirable pregnancy during administration of combined OCA does not exceed 0.2%. The most frequent side-effects of OCA include nausea, headache, uterine hemorrhage, and changes in libido. OCA can affect the endocrine and reproductive systems. Major endocrine effects of OCA include changes in the cortisol metabolism in the adrenal glands, increase in the level of thyroid-binding globulin in the thyroid gland, changes in the glucose metabolism in the pancreas, inhibition of the luteinizing hormone releasing hormone in the hypothalamus with simultaneous decrease in the production of pituitary gonadotropins and inhibition of the ovulation. The most serious side-effects of OCA include cholelithiasis, thrombophlebitis, thromboembolism, liver adenoma, and myocardial infarction. Absolute contraindications to the use of OCA include hypertension, hyperlipidemia, breast or endometrial cancer, pregnancy, cardio-vascular diseases, liver diseases, and kidney insufficiency.
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PMID:[Principles of the use of oral contraceptive preparations]. 307 80

The present status of oral contraceptive steroids and the IUD, the 2 most effective and increasingly popular contraceptive methods (used by 41.6% of all U.S. married couples practicing contraception in 1970), is presented. Oral steroid contraceptives with varying quantity and activity of estrogen (ethinyl estradiol or mestranol) and progestogen (norethindrone, norethynodrel, ethynodiol diacetate, or norgestrel), are of 3 types: combination, sequential, and minidose progestogen alone. The most effective contraceptive available is the combined oral pill with a pregnancy rate of less than .2 % per 100 women after 1 year. Contraceptive action is exerted primarily through inhibition of ovulation and secondarily by alterations in cervical mucus, endometrial glands, the ovary, and in the oviduct and uterine muscle. In comparison, sequential oral contraceptives are less effective with greater side effects, and should only be used in women with amenorrhea. Effects of oral contraceptives other than contraception include those on the (1) the primary targets of the female reproductive system, (2) on other endocrine oragans and (3) on the remainder of the body. In the first group, changes may include transitory stromal fibrosis in the ovary, enlarged fibromyomata, intermenstrual bleeding or amenorrhea, increased amount of cervical mucus, polypoid hyperplasia of the endocervical glands, breast tenderness, and changes in lactation. Changes in the second category which may occur affect the adrenal glands, hypothalamus, the thyroid (increased thyroid-binding globulin), and pancreas (alterations in glucose metabolism). Effects on the rest of the body may include increase in serum lipids and changed atherogenic index, abnormalities in liver function, thromboembolism (incidence in oral contraceptive users 4.4 times that in non-users), melasma, alterations in the central nervous system with increased incidence of cerebral vascular accidents, hypertension, and increased body weight. Absolute contraindications to oral contraceptive therapy include cancer of the breast and uterus, pregnancy, active liver disease, hyperlipidemia, and history of gestational diabetes, thromboembolic phenomena or coronary artery disease. Relative contraindications include depression, migraine, myomata of the uterus, hypertension, epilipsy, oligomenorrhea and amenorrhea. Reliable epidemiologic data on IUDs from the Cooperative Statistical Program indicated first year pregnancy rate of 2.5%. Problems with the IUD include: 1) pregnancy with device in situ, which is associated with a higher incidence of spontaneous abortion; 2) ectopic pregnancy, which is prevented at a rate of only 90% compared with intrauterine pregnancies prevented in 97-98%; and 3) expulsions (20% of which are unnoticed), the expulsion rate being higher with decreasing age and parity, higher in the first than second year of use, and higher with smaller than larger devices. A major problem is discontinuation for medical reasons (15% rate in the first year), mainly bleeding and pain. Perforation, another serious complication, occurs initially at time of insertion with an incidence of 1 per 2500 insertions for the loop. IUDs were found to produce a sterile inflammatory tissue reaction, which is postulated as the primary causative factor for their contraceptive effect in humans.
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PMID:Current status of contraceptive steroids and the intrauterine device. 459 80

Low dose estrogen tablets, containing less than 50 mcg of ethinyl estradiol, were formulated because of the recognized dose response relationship with the steroid content of the tablet and side effects. These new oral contraceptives (OCs) are as effective as the older high-dose OCs, and available evidence reports fewer side effects. This discussion reviews pharmacology of these new OCs, the mechanism of action, contraindications, side effects, and problems with the low-dose estrogen OC. Ethinyl estradiol is the only estrogen used in the low-dose combination OC. There are several synthetic progestins: norethindrone, norethindrone acetate, norgestrel, levonorgestrel, and ethynodiol diacetate. These progestins have different potencies so the pharmacologic activity cannot be accurately predicted based on the amount present in the tablet. The synthetic steroids in OCs are absorbed in the small intestine, metabolized in the liver, excreted in the bile and feces with a half-life of 24 hours. The low-dose estrogen combination preparation is taken 3 out of every 4 weeks. Its contraceptive effect is primarily a result of hypothalamic mediated gonadotropin suppression with subsequent inhibition of ovulation. Contraindications to taking the low-dose OC are the same as for the higher dose OC: thromboembolic or cardiovascular disease, estrogen dependent neoplasia, markedly impaired liver function, undiagnosed genital bleeding, congenital hyperlipidemia, pregnancy, and women over age 30 who smoke. Relative contraindications include hypertension, diabetes mellitus, migraine headaches, uterine myomas, and epilepsy. The often quoted 2-5-fold increased incidence of thromboembolic disease, myocardial infarction, and stroke is based on large epidemiologic studies involving patients taking the older higher dose OCs. Current data from patients taking the newer low-dose medication demonstrate minimal if any increased incidence of these problems in young women who do not smoke. The low-dose estrogen OCs have minimal effect on lipid levels. Early reports of patients using the low-dose OC have shown little if any increased incidence of hypertension. The low-dose contraceptives have little effect on glucose tolerance, and there is no evidence to show an increased incidence of overt diabetes in OC users. There is no evidence that use of the combination OC causes an increase in cancer of the cervix, uterus, or ovaries. Clinical complaints of nausea, breast discomfort, chloasma, weight changes, and depression are reduced with the low-dose estrogen preparation. Hypomenorrhea while taking the OC occasionally occurs because the lower dose of estrogen is insufficient to stimulate the endometrial growth in face of the predominant progestin-atrophy effect.
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PMID:Oral contraceptives in 1984. 649 Mar 38

Ethinyl estradiol is the only estrogen form used in low-dose oral contraceptive (OC) pills. Progestogenic compounds used in OCs include norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, and norethynodrel. The newest third generation progestins are desogestrel and norgestimate. The most important benefits associated with OC use are a decrease in benign breast disease, less incidence of ovarian and endometrial cancers, and a decrease in the incidence of pelvic inflammatory disease. The most serious risks to OC users who are over age 35 and smoke are deep vein thrombosis, pulmonary embolus, retinal thrombosis, or cardiovascular disease. Other risk factors for cardiovascular disease include obesity, diabetes, hypertension, increased serum cholesterol, and a family history of premature myocardial infarction. All users should have blood pressure checks 3 and 6 months after commencing pill use. OC preparations cause an increase in total cholesterol, triglycerides, low density lipoprotein (LDL), very low density lipoprotein (VLDL), and a decrease in high density lipoprotein (HDL), but norgestimate may actually increase HDL levels. Preparations with levonorgestrel may produce the greatest decrease in glucose tolerance, while those with 35 mcg of ethinyl estradiol and 0.5 mg of norethindrone have the least effect. OCs do not increase the risk of developing breast cancer, but can stimulate the growth of breast cancer once it has occurred. The incidence of gallbladder disease is increased slightly in OC using women who are predisposed. Hepatocellular adenomas are associated with combined OC use. Underweight women are more prone to side effects and need a very low potency preparation. A common problem encountered by patients on OCs is amenorrhea. This usually resolves after 3 cycles. Breakthrough bleeding is also very common. Post-pill amenorrhea is frequently found after stopping OCs. Combined oral contraceptives are a safe and effective contraceptive method for most women throughout their reproductive years.
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PMID:Combined oral contraceptive pills: a brief review. 783 35

Obese hypertensive patients with cardiovascular risk factor clustering have increased plasma nonesterified fatty acid levels and are at high risk for atherosclerotic events. Our previous studies demonstrated that oleic acid induces a mitogenic response in rat aortic smooth muscle cells (RASMCs) through protein kinase C (PKC)- and extracellular signal-regulated kinase (ERK)-dependent pathways. In the present study we investigated the possibility that the generation of reactive oxygen species (ROS) constitutes a critical component of the oleic acid-induced mitogenic signaling pathway in RASMCs. We studied the effect(s) of oleic acid on the generation of ROS using the oxidant-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate. Relative fluorescence intensity and fluorescent images were obtained with laser confocal scanning microscopy from 1 to 5 minutes, since preliminary studies demonstrated that the peak fluorescence intensity occurred within 5 minutes. Oleic acid (100 micromol/L) induced a time-dependent increase of cell fluorescence that was >8-fold of that seen in control cells at 5 minutes. This was blocked by catalase, which suggests that H2O2 was the principal ROS. The oleic acid-induced increases in H2O2 were blocked when PKC was inhibited with the use of bisindolylmaleimide and when PKC activity was downregulated by exposing RASMCs to phorbol 12-myristate 13-acetate for 24 hours. Stearic and elaidic acids, which are weak PKC activators, did not significantly increase H2O2 production. The increase of H2O2 in response to oleic acid was inhibited by the antioxidant N-acetylcysteine. N-Acetylcysteine also completely blocked ERK activation and the increase of thymidine incorporation in response to oleic acid. The data suggest that generation of H2O2 in RASMCs exposed to oleic acid is PKC dependent. Moreover, H2O2 production emerges as a critical intermediary event in the oleic acid-mediated mitogenic signaling pathway between the activation of PKC and ERK. These observations raise the possibility that the elevated plasma nonesterified fatty acids, including oleic acid, in obese hypertensive patients contribute to vascular growth and remodeling by a PKC-dependent mechanism to generate ROS that subsequently activate ERK.
Hypertension 1998 Dec
PMID:Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. 985 64

Our previous experiments demonstrated upregulation of the renin-angiotensin system in macrophages, including angiotensin II type 1 (AT1) and type 2 (AT2) receptors, during transformation from monocytes. We investigated the role of angiotensin II in oxidative stress of monocytes/macrophages, which plays a role in the advance of atherosclerosis. THP1, a human monocytic leukemia cell line, was differentiated to macrophages by adding of phorbol 12-myristate 13-acetate for 24 hours. The intracellular production of peroxide was measured by a cytofluorometric assay with 2', 7'-dichlorofluorescein-diacetate with a flow cytometer scan. Peroxide was detected in monocytes and upregulated during the transformation to macrophages by 3.18+/-0.52 times in relative fluorescein of peak value (P<0.01). Angiotensin II (1 micromol/L) induced oxidative stress in macrophages, with the peak at 15 minutes by 451+/-223%, and returned to the control level within 1 hour. EC50 was 5.4x10(-9) mol/L. AT1 antagonist (CV11974, 1 micromol/L) significantly decreased angiotensin II-induced oxidative stress in macrophages, but AT2 antagonist (PD123319, 1 micromol/L) did not. Of interest, AT1 antagonist also decreased basal levels of peroxide production in macrophages in a dose-dependent manner. These results suggest that upregulation of the expression of AT1 receptor in macrophages contributes in part to upregulation of peroxide production. AT1 receptor antagonists may be useful to suppress oxidative stress of macrophages in atherosclerotic lesions.
Hypertension 1999 Jan
PMID:Angiotensin II type 1 receptor-mediated peroxide production in human macrophages. 993 Nov 26


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