The in-vitro mucosal conjugation of ethinyloestradiol and the bioavailability of oral contraceptive steroids in patients with treated and untreated coeliac disease.

The ethinyloestradiol (EO2) component of oral contraceptive steroids is extensively conjugated with sulphate by the gut wall. The ability of gastrointestinal mucosa to conjugate EO2 has been examined in vitro in samples of mucosa taken from normal women as well as from women with coeliac disease. The percentage conjugation per mg dry weight for normal tissue (n = 11) was 17.1 +/- 6.4 (mean +/- s.d.) while in untreated coeliac tissue (n = 6) the figure was 6.3 +/- 3.6% (P less than 0.01). In tissue from patients with treated coeliac disease (n = 5) the figure was 12.1 +/- 3.2%. Thus the ability of intestinal mucosa to conjugate ethinyloestradiol was significantly reduced in patients with coeliac disease, and restored towards normal following treatment. However, in patients with coeliac disease the pharmacokinetics of ethinyloestradiol were not significantly different from normal controls.

PIP: Physicians took several small intestinal mucosal samples from female patients with or with out celiac disease at the Royal Liverpool and Broadgreen Hospital in Liverpool, England, to determine in vitro the mucosa's ability to metabolize ethinyl estradiol and levonorgestrel. They compared this in vitro ability with the pharmacokinetics of the 2 steroids in 5 women with celiac disease. The percentage conjugation of ethinyl celiac mucosa (17.1% mg dry weight vs. 6.3% mg dry weight; p .01); it was also greater than it was for celiac mucosa from patients treated with a gluten-free diet (12.1% mg dry weight; p .05). The percentage of conjugate as sulphate was 85% for untreated celiac mucosa. Among the 5 celiac disease patients, no significant differences in any of the pharmacokinetic parameters for levonorgestrel or ethinyl estradiol existed between pre- and post-gluten free diet treatment. These parameters included area under the curve, volume of distribution, and bioavailability. The physicians were able to compare the in vitro ability of intestinal mucosa to metabolize ethinyl estradiol with 1st in vivo pharmacokinetics in 2 patients. In both cases, the in vitro mucosal conjugation rose while the in vivo bioavailability fell (4.4% to 12.1% and 75.4% to 43.2% for patient 1, and 3.6% to 9.1% and 86.7% to 55.2% for patient 2). These findings suggest that celiac disease weakens the ability of intestinal mucosa to conjugate ethinyl estradiol, but a gluten-free diet can adequately improve this ability.

Evaluation of Committee on Safety of Medicines yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics.

1. We have searched the adverse reactions register for the years 1968-84 in an attempt to evaluate data relating to reported pregnancies in women on oral contraceptive steroids (OCS) who concurrently received either an antiepileptic drug or an antibiotic. 2. A total of 43 pregnancies were reported in women on OC therapy who concurrently received antiepileptic drugs and 63 pregnancies in women receiving antibiotics. In addition the number of prescriptions for both antiepileptics and antibiotics in England are reported for the years 1973-84.

PIP: To assess the extent of interactions between oral contraceptives (OCs) and antiepileptic drugs and antibiotics, the UK Committee on Safety of Medicines yellow card reporting system of adverse drug reactions was searched for the years 1968-84. A total of 43 pregnancies were reported in women on OCs who concurrently received anticonvulsant drugs and there were 63 pregnancies in OC users who used antibiotics. The most common anti-epileptic drugs involved in reported adverse interactions with OCs were phenytoin (25 cases) and phenobarbitone (20 cases); the antibiotic most often implicated in adverse OC-drug interactions was penicillin (32 cases). The highest number of reports occurred in 1973 for anti-epileptics (6 cases) and in 1982 for antibiotics (14 cases). The largest number of reports included OCs containing ethinyl estradiol (30 mcg) and levonorgestrel (0.15 mg). Since only about 15% of physicians in the UK are believed to use the yellow card scheme for reporting adverse drug reactions, these data are not indicative of the actual prevalence of such reactions. However, they do indicate that contraceptive failure may occur in some women exposed to these 2 groups of commonly prescribed drugs. There is research evidence that broad spectrum antibiotics alter plasma concentrations of OC steroids. Caution should be used in generalizing these findings, however, until a clearer picture emerges as to which OC users are most susceptible to adverse drug interaction effects.

Lisinopril in essential hypertension: a six month comparative study with nifedipine.

The antihypertensive efficacy and tolerability of lisinopril, a new long acting angiotensin converting enzyme inhibitor, and nifedipine, in a retard formulation, were compared in a randomized six month double-blind study, in 45 patients with essential hypertension. Lisinopril, 20 to 80 mg once daily and nifedipine retard, 20 to 40 mg twice daily, were equally effective in lowering blood pressure and controlling hypertension. There were however significantly more adverse effects (P less than 0.01) reported with nifedipine. No significant differences were observed between groups for laboratory values, although the lisinopril group showed a significant reduction in urinary protein excretion compared to baseline values. Lisinopril and nifedipine have equal efficacy in the treatment of essential hypertension but in this study lisinopril was better tolerated than nifedipine.

Comparative pharmacokinetics of levonorgestrel and ethinyloestradiol following intravenous, oral and vaginal administration.

The plasma concentrations of levonorgestrel (LNG) and ethinyloestradiol (EE2) have been measured in a random crossover study in five healthy female volunteers given a combination oral contraceptive tablet (250 micrograms LNG and 50 micrograms EE2) by the oral route and per vaginum and also receiving the same dose intravenously. The fractional bioavailability of LNG after oral administration was 1.00 +/- 0.16 (mean +/- S.D.) and after vaginal insertion 0.88 +/- 0.16. The time to peak (tmax) was significantly longer and the peak concentration (Cmax) significantly reduced following vaginal administration. The fractional bioavailability of EE2 after oral dosing was 0.62 +/- 0.11 and after vaginal insertion 0.74 +/- 0.16; tmax was prolonged, hence absorption was slower from the vagina. The reduced rate of absorption was evident in the differences seen in the area under the curve for early time periods for both steroids. However, overall bioavailability is not reduced for either steroid when a single tablet is inserted into the vagina.

Haemodynamic effects of atenolol, labetalol, pindolol and captopril: a comparison in hypertensive patients with special reference to changes in limb blood flow, heart rate and left ventricular function.

1 To compare the haemodynamic effects of secondary characteristics of beta-adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with previously untreated mild to moderate hypertension were prescribed either atenolol 50-100 mg day-1, labetalol 200-800 mg day-1, pindolol 10-30 mg day-1 or captopril 25-100 mg day-1 and observed for 6 months. 2 Over this period: (a) All four drugs produced similar reductions in blood pressure at rest (P less than or equal to 0.01) and after exercise (P less than or equal to 0.01). (b) All four drugs significantly decreased resting forearm (P less than or equal to 0.01) and calf blood flow (P less than or equal to 0.01). They all also caused a significant reduction in the increased calf blood flow following exercise (P less than or equal to 0.01). (c) No drug produced a change in resting forearm vascular resistance, while resting calf vascular resistance was decreased by captopril and pindolol, unaltered by labetalol and increased by atenolol. Post-exercise calf vascular resistance was increased by atenolol, labetalol and pindolol but unaltered by captopril. (d) Although all four drugs produced a fall in resting heart rate this was significantly greater for atenolol and labetalol (P less than or equal to 0.01). All four treatments however significantly reduced the increase in heart rate following exercise (P less than or equal to 0.01). (e) No drug produced any significant change in resting and post-exercise stroke volume/ejection fraction. 3 It is concluded that despite differing modes of action all four drugs reduce limb blood flow. This primarily appears to be a consequence of reduced perfusion pressure associated with limited autoregulation of skeletal muscle circulation. The reduction in arterial vascular resistance produced by captopril and pindolol is inconsistent and does not appear of major benefit in preserving limb blood flow. The reduction in perfusion with the agents studied may in part be related to a fall in cardiac output associated with decreased heart rate. This suggests that captopril may exert antisympathetic activity when used as an antihypertensive agent.

Plasma concentrations of 3-keto-desogestrel after oral administration of desogestrel and intravenous administration of 3-keto-desogestrel.

The plasma concentrations of 3-keto-desogestrel have been measured by radioimmunoassay in a crossover study in nine healthy female volunteers given oral desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms) and intravenous (i.v.) 3-keto-desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms). Bioavailability ranged between 40.0 and 113% with a mean value ( +/- SD) of 76.1 +/- 22.5%. Only 3 subjects had a bioavailability of less than 70%. There was no significant difference in the elimination half life of 3-keto-desogestrel which was 12.6 +/- 4.1h following i.v. administration and 11.9 +/- 4.1h after oral administration of desogestrel.

PIP: In order to define its bioavailability, plasma concentration of 3-keto-desogestrel, the active metabolite of the progestogen desogestrel, was radioimmunoassayed in 9 women after a single iv dose of 150 ug or a single oral dose of 150 ug in combination with 30 ug ethinyl estradiol. Desogestrel is 13-ethyl-11-methylene-18, 19-dinor-17alpha-preg-4-en-20-yn-17-ol, the progestogen in the effective combined oral contraceptive Marvelon (Organon). The drug was given early in the menstrual cycle to each woman twice in a crossover design, 4 weeks apart. Bioavailability was calculated as the ratio of area under the plasma concentration time curve of the oral to the area under the curve of the iv dose. There was no significant difference in the elimination half-life of 3-keto-desogestrel by oral or iv administration: 11.9 and 12.6 hours. Mean plasma clearance, calculated by dose given divided by area under the curve, was 12.13 1/hour by oral, and 8.7 by iv routes. Bioavailability ranged from 40 to 113%, a wide individual variation, as seen in previous studies. Although mean bioavailability was 76%, the value was above 70% in 6 women, and 40.0, 54.7 and 64.1% in 3 others. This indicates that bioconversion was near quantitative. The reason for the variation cannot be ascertained from these data. Despite variability in bioavailability, the desogestrel combined oral contraceptive is reported to be very effective, as well as less androgenic than pills containing levonorgestrel.

Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol.

The effect of a single dose of paracetamol (1 g) on plasma concentrations of the oral contraceptive steroids ethinyloestradiol (EE2) and levonorgestrel (LNG) has been studied in six healthy female volunteers. The area under the plasma concentration-time curve (AUC0-24) of EE2 was significantly increased following paracetamol administration by 22% (control 2221 +/- 291; following paracetamol, 2702 +/- 452 pg ml-1 h; mean +/- s.d.; P less than or equal to 0.05). The greatest effect was evident in the time period 0-3 h. There was a significant decrease in the AUC of EE2-sulphate after paracetamol (7736 +/- 3791 pg ml-1 h) compared with control (13161 +/- 4535 pg ml-1 h; P less than or equal to 0.05). Plasma concentrations of LNG were unaltered by concurrent paracetamol administration. We conclude that the administration of a single 1 g dose of paracetamol causes an increase in plasma concentrations of EE2 as a result of a reduction in the sulphation of the steroid. This interaction may be of clinical significance in women on oral contraceptive steroids who regularly take paracetamol.

PIP: The availability of the oral contraceptive steroids ethinyl estradiol (EE) and levonorgestrel in plasma after a single dose of 1 g paracetamol (acetaminophen) was quantitated. 6 women aged 21-24 who had been taking combined oral contraceptives for at least 3 months took a single dose of 1 g paracetamol, followed 1 hour later by a single dose of Ovran (50 mcg EE and 250 mch levonorgestrel) after an overnight fast. EE and levonorgestrel were radioimmunoassayed, and EE sulfate was determined by radioimmunoassay after incubation with sulfatase. In blood sampled over a 24 hour period, the area under the concentration curve for EE during the 1st 3 hours rose significantly after paracetamol (22%, p0.05). EE sulfate concentration was significantly lower (p0.05). There was no change in plasma concentration of levonorgestrel. The results suggest that paracetamol increases circulating EE by limiting available sulfation of the steroid.

Comparative efficacy of lisinopril and nifedipine retard in essential hypertension: a double-blind, placebo-controlled trial.

Lisinopril, a long-acting angiotensin converting enzyme inhibitor, and the calcium channel blocker nifedipine in its retard formulation, were compared as monotherapy in a group of 45 patients with essential hypertension. Lisinopril in single daily doses (range 20-80 mg, median dose 40 mg) and nifedipine retard in twice daily doses (total daily dose range 40-80 mg, median dose 60 mg) were equally effective in controlling hypertension. The lisinopril group (n = 30), at baseline supine blood pressure 178/109 +/- 23/9 mm Hg (mean +/- 1 SD), after 12 weeks' therapy measured 148/88 +/- 27/14 mm Hg; the nifedipine group (n = 15), at baseline 185/110 +/- 23/11 mm Hg, after 12 weeks' therapy measured 151/89 +/- 14/10 mm Hg. The number of patients who experienced clinical adverse effects was significantly greater in the nifedipine group: 8 of 15 (53%) compared to 4 of 30 (13%) in the lisinopril group. The commonest adverse effects of patients on nifedipine were swollen ankles, flushing, and headache. Two patients on nifedipine were withdrawn from the study because of their adverse experiences. Of the patients on lisinopril there were single reports of flushing, ankle swelling, tiredness, and chest pain. No patient withdrew from lisinopril because of an adverse experience. No adverse laboratory experiences were recorded in either group. In conclusion, lisinopril and nifedipine retard were equally effective in controlling essential hypertension. Lisinopril was, however, better tolerated during this study.

Pharmacokinetics of contraceptive steroids in patients with cystic fibrosis.

The pharmacokinetics of the commonly used contraceptive steroids ethinyloestradiol and levonorgestrel were investigated after oral and intravenous administration in six women with cystic fibrosis. The results were compared with data obtained from healthy women of similar age. The total body clearance of ethinyloestradiol was significantly higher in the patients with cystic fibrosis (0.61 (SD 0.19) l/h/kg) than in control women (0.32 (0.16) l/h/kg; p less than 0.02). In addition, the oral bioavailability of ethinyloestradiol was greater in women with cystic fibrosis than in controls (76.9% (11.7%) compared with 47.3% (7.5%); p less than 0.001). As a result of these two changes, the area under the plasma concentration--time curve after an oral dose of ethinyloestradiol was similar in patients and controls. The pharmacokinetics of levonorgestrel did not differ significantly between patients with cystic fibrosis and healthy women. The data suggest that women with cystic fibrosis will receive similar contraceptive protection from these steroids as do healthy women.

PIP: The pharmacokinetics of the contraceptive steroids ethinyl estradiol and levonorgestrel following oral an intravenous administration were investigated in 6 women with cystic fibrosis. The results were compared with data from healthy controls of similar ages. The bioavailability of ethinyl estradiol was significantly greater in women with cystic fibrosis (76.9%) than in controls (47.3%), but the area under curve after oral administration was similar in both groups. There was a significantly greater total body clearance in women with cystic fibrosis (0.61 1/hr/kg) than in controls (0.32 1/hr/kg). The volume of distribution was not significantly different in patients and controls; thus there was a tendency (nonsignificant) for the elimination half-life and area under curve after the intravenous dose to be less in the women with cystic fibrosis. In terms of levonorgestrel, there were no significant differences between subjects and controls in any of the pharmacokinetic variables studied. These results suggest that the absorption of ethinyl estradiol and levonorgestrel is not impaired by cystic fibrosis. Women with this disease will achieve plasma concentrations of these steroids after an oral dose of a combined oral contraceptive similar to those obtained in healthy women. However, patients with cystic fibrosis should be monitored closely while taking the pill to ensure that vaginal blood loss is regular with no evidence of breakthrough bleeding.

The bioavailability of ethinyloestradiol and levonorgestrel in patients with an ileostomy.

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostomy following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 +/- 10.9% (+/- S.D.) compared to a control value of 45.0 +/- 6.1% (p greater than or equal to 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 +/- 13.1% compared to 104.6 +/- 22.3% in the controls (p greater than or equal to 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

Pharmacokinetics of oral contraceptive steroids following the administration of the antimalarial drugs primaquine and chloroquine.

The effects of a single dose of two antimalarial drugs chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (O.C.) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyloestradiol (EE2) and levonorgestrel were measured by radioimmunoassay following administration of a single dose of O.C. (30 micrograms EE2 + 150 micrograms levonorgestrel) in the absence and presence of the antimalarial drugs (PQ, 45 mg; CQ, 300 mg). Neither CQ or PQ given 1 h before the O.C. had any significant effect on plasma concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of O.C.'s. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

PIP: The effects of a single dose of 2 antimalarial drugs, chloroquine (CQ) and primaquine (PQ) on the pharmacokinetics of a combined oral contraceptive (OC) have been studied in volunteers. Each woman was studied on 3 separate occasions over 3 cycles and plasma concentrations of ethinyl estradiol (EE2) and levonorgestreal were measured by radioimmunoassay following administration of a single dose of OC (30 mcg EE2+150 mcg levonorgestrel) in the absence and presence of the antimalarial drugs (PQ--45 mg; CQ--300 mg). Neither drug given 1 hour before the OC had any significant effect on pharmacokinetic concentrations of EE2 or levonorgestrel or on any pharmacokinetic parameter determined. There is therefore, no evidence that CQ or PQ interfere with the hepatic handling of OCs. This is in contrast to previously reported inhibitory effects of PQ on the metabolism of antipyrine.

The effect of cotrimoxazole on oral contraceptive steroids in women.

Nine women taking long-term oral contraceptive steroids (Trinordiol) were studied during a cycle while taking cotrimoxazole (1 gm twice daily) and the results were compared to the previous control cycle. During the cotrimoxazole cycle, there was a significant increase in the plasma concentration of ethynylestradiol (EE). In plasma samples taken on 4 successive days 10-12 hours after dosing, the plasma EE concentration rose from 29.3 +/- 5.0 pg/ml to 38.2 +/- 5.8 pg/ml (mean +/- S.E. P less than or equal to 0.02). In samples taken 24 hours after dosing, the increase was from 18.9 +/- 2.5 pg/ml to 27.8 +/- 4.0 pg/ml (P less than or equal to 0.05). Plasma F.S.H. values in these latter samples, decreased from 4.8 +/- 0.6 mIu/ml to 3.4 +/- 0.5 mIu/ml (P less than or equal to 0.01). No significant changes were noted in the plasma concentrations of levonorgestrel or progesterone. The rise in plasma concentration of EE during cotrimoxazole therapy is attributed to an inhibition of the metabolism of EE by cotrimoxazole as has been shown with other drugs. Short courses of cotrimoxazole are unlikely to cause any adverse effects on contraceptive control when given to women taking long-term oral contraceptive steroids.

Urinary concentrations of steroid glucuronides in women taking oral contraceptives.

The aim of this study was to use measurements of urinary steroid glucuronides to confirm the suppression of ovulation of ovulation in women taking oral contraceptives. Urinary concentrations of oestrone-3-glucuronide (E1G) and pregnanediol-3 alpha-glucuronide (Pd-3-G) were measured by radioimmunoassay in early morning urine samples from six normally-menstruating women and six women who were taking combined oral contraceptives. In the normally-menstruating women, E1G concentrations, and the E1G/Pd-3-G ratio, increased 2-3 fold before ovulation. There was no midcycle increase in either measure in women taking oral contraceptives. We suggest that measurement of these steroid metabolites provides a means of assessing the anti-ovulatory effects of oral contraceptives.

The biliary and urinary metabolites of [3H]17 alpha-ethynylestradiol in women.

The metabolism of 17 alpha-ethynyl[6,7-3H]estradiol (3H-EE2) (50 micrograms) given orally was studied in two groups of women: (a) six subjects from whom duodenal bile samples were obtained after 4 h by endoscopic aspiration; (b) two subjects with bile-duct (T-tube) drainage. The first group eliminated 16.6 +/- 7.8% (mean +/- S.D.) of the dose in urine over 72 h, the second group 28.6% and 27.5%. Biliary excretion by the latter was 41.9% and 28.3% of the dose, respectively, during the first 24 h after dosing. The metabolites excreted in bile and urine were largely polar conjugates: 1-12% of the 3H was ether extractable. Approx. 70-90% of urinary and biliary 3H was extractable following beta-glucuronidase-arylsulphohydrolase hydrolysis. Both beta-glucuronides and arylsulphates were excreted. Unchanged 3H-EE2 was the principal 3H-labelled component of the glucuronide and arylsulphate fractions of bile, and it was a major component of urinary fractions. 2-Hydroxy-EE2 and 2-methoxy-EE2 were identified as conjugated biliary metabolites.

Incidence of coronary artery disease in patients with valvular heart disease.

The case notes, cardiac catheterisation data, and coronary arteriograms of 239 patients investigated for valvular heart disease during a five year period were reviewed. Angina present in 13 of 95 patients with isolated mitral valve disease, 43 of 90 patients with isolated aortic valve disease, and 18 of 54 patients with combined mitral and aortic valve disease. Significant coronary artery disease was present in 85 per cent of patients with mitral valve disease and angina, but in only 33 per cent of patients with aortic valve disease and angina. Patients with no chest pain still had a high incidence of coronary artery disease, significant coronary obstruction being present in 22 per cent with mitral valve disease, 22 per cent with aortic valve disease, and 11 per cent with combine mitral and aortic valve disease. Several possible clinical markers of coronary artery disease were examined but none was found to be of practical help. There was, however, a significant inverse relation between severity of coronary artery disease and severity of valve disease in patients with aortic valve disease. Asymptomatic coronary artery disease is not uncommon in patients with valvular heart disease and if it is policy to perform coronary artery bypass grafting in such patients, routine coronary arteriography must be part of the preoperative investigation.