Multiple-step model-experiment matching allows precise definition of dynamical leg parameters in human running.

The spring-loaded inverted pendulum (SLIP) model is a well established model for describing bouncy gaits like human running. The notion of spring-like leg behavior has led many researchers to compute the corresponding parameters, predominantly stiffness, in various experimental setups and in various ways. However, different methods yield different results, making the comparison between studies difficult. Further, a model simulation with experimentally obtained leg parameters typically results in comparatively large differences between model and experimental center of mass trajectories. Here, we pursue the opposite approach which is calculating model parameters that allow reproduction of an experimental sequence of steps. In addition, to capture energy fluctuations, an extension of the SLIP (ESLIP) is required and presented. The excellent match of the models with the experiment validates the description of human running by the SLIP with the obtained parameters which we hence call dynamical leg parameters.

Tuberculous meningitis in a lung transplanted patient.

A 57-year-old female lung transplant recipient developed tuberculosis after quadruple maintenance immunosuppression for acute cellular rejection with respiratory compromise. Deteriorating neurological status led to cerebral imaging and lumbar puncture, which showed Mycobacterium tuberculosis. Tuberculous meningitis with elevated intracranial pressure was treated for 2 weeks on a neurosurgical ward, and intensive care therapy was necessary for another 2 weeks. Complete neurological recovery was achieved after 3 months.

Integration of intrinsic muscle properties, feed-forward and feedback signals for generating and stabilizing hopping.

It was hypothesized that a tight integration of feed-forward and feedback-driven muscle activation with the characteristic intrinsic muscle properties is a key feature of locomotion in challenging environments. In this simulation study it was investigated whether a combination of feed-forward and feedback signals improves hopping stability compared with those simulations with one individual type of activation. In a reduced one-dimensional hopping model with a Hill-type muscle (one contractile element, neither serial nor parallel elastic elements), the level of detail of the muscle's force-length-velocity relation and the type of activation generation (feed-forward, feedback and combination of both) were varied to test their influence on periodic hopping. The stability of the hopping patterns was evaluated by return map analysis. It was found that the combination of feed-forward and proprioceptive feedback improved hopping stability. Furthermore, the nonlinear Hill-type representation of intrinsic muscle properties led to a faster reduction of perturbations than a linear approximation, independent of the type of activation. The results emphasize the ability of organisms to exploit the stabilizing properties of intrinsic muscle characteristics.

The role of intrinsic muscle properties for stable hopping--stability is achieved by the force-velocity relation.

A reductionist approach was presented to investigate which level of detail of the physiological muscle is required for stable locomotion. Periodic movements of a simplified one-dimensional hopping model with a Hill-type muscle (one contractile element, neither serial nor parallel elastic elements) were analyzed. Force-length and force-velocity relations of the muscle were varied in three levels of approximation (constant, linear and Hill-shaped nonlinear) resulting in nine different hopping models of different complexity. Stability of these models was evaluated by return map analysis and the performance by the maximum hopping height. The simplest model (constant force-length and constant force-velocity relations) outperformed all others in the maximum hopping height but was unstable. Stable hopping was achieved with linear and Hill-shaped nonlinear characteristic of the force-velocity relation. The characteristics of the force-length relation marginally influenced hopping stability. The results of this approach indicate that the intrinsic properties of the contractile element are responsible for stabilization of periodic movements. This connotes that (a) complex movements like legged locomotion could benefit from stabilizing effects of muscle properties, and (b) technical systems could benefit from the emerging stability when implementing biological characteristics into artificial muscles.

[Impaired cerebral autoregulation in asymptomatic patients with carotid artery stenosis: comparison of acetazolamide-SPECT and transcranial CO(2)-dopplersonography]. / Störung der zerebralen Perfusionsreserve.

PURPOSE: The indication for operation in patients with asymptomatic high-grade carotid artery stenosis is still under debate. Since impaired cerebrovascular autoregulation is associated with an increased risk for ischaemic events, assessment of cerebral vascular reactivity might be a valuable selection criterion for surgery. The aim of our study was therefore to evaluate the incidence of impaired autoregulation in asymptomatic patients with acetazolamide-single photon emission computed tomography (ACZ-SPECT) and transcranial CO (2)-dopplersonography (CO (2)-TCD). Furthermore, both methods were compared in regard to results and clinical practicability. METHODS: In 42 patients with high-grade (> 70 %) asymptomatic carotid artery stenosis, cerebral perfusion and vascular reactivity were assessed with resting and ACZ-enhanced SPECT scans. In 31 of these patients the CO (2) reactivity of cerebral perfusion was determined by TCD and expressed as normalized autoregulation reserve (NAR). RESULTS: Cerebral perfusion was decreased in 14.3 %. In ACZ-SPECT 26 % and in CO (2)-TCD 28 % revealed an impaired vascular reactivity. Conformity of both methods was high (kappa = 0.93). TCD was superior in practicability, but only applicable in 81 % due to a missing temporal bone window for insonation. CONCLUSION: In accordance ACZ-SPECT and CO (2)-TCD could detect impaired vascular reactivity in a quarter of asymptomatic patients. Both TCD and SPECT could be of value for preoperative selection in this group of patients, whereby sonography is recommended for daily diagnostic work-up.

Pregnancy rates for grade 2 embryos following administration of synthetic GnRH at the time of transfer in embryo-recipient cattle.

To succeed with pregnancy a bovine embryo must overcome the luteolytic mechanism and achieve recognition of pregnancy. It is understood that well developed embryos are more successful in achieving recognition of pregnancy than poorly developed ones. Attempts have been made to assist this recognition of pregnancy by utilising a number of hormonal supplements with varying levels of success. A study was undertaken to test the hypothesis that supplementation with synthetic GnRH at the time of transfer of Grade 2 embryos will enhance pregnancy rates in recipients receiving this category of embryo. Pairs of fresh and frozen Grade 2 embryos (n = 38) from 34 donor animals were allocated to the trial. Thirty eight pairs of recipients were used and one of each pair was randomly assigned to receive treatment on the day of embryo transfer (Day 7) with 5 ml of gonadorelin, containing a synthetic gonadotrophin releasing hormone, 0.1 mg/ml. Pregnancy diagnosis was carried out from 42 days post-transfer by either palpation per rectum or ultrasound scanning. Treatment, embryo processing, side of transfer, parity of recipient, breed of recipient and breed of donor dam showed no statistically significant effect on pregnancy rate. The overall pregnancy rate in this study was within commercially accepted limits for Grade 2 embryos at 38.2%. The pregnancy rates were 34.2 and 42.1% for the GnRH-treated and control groups, respectively and were not significantly different at P < 0.05. The failure of this treatment to improve pregnancy rates could be due to its effect being transitory therefore allowing subsequent pregnancy loss. The timing of the treatment post-transfer, treatment dose and potency of the GnRH analogue may also play a role in this. Further study is required to determine the hormonal or follicular status of prospective candidates for treatment before applying this as a whole herd regime.

Ricin transport into cells: studies of endocytosis and intracellular transport.

The plant toxin ricin binds to both glycoproteins and glycolipids with terminal galactose, and the toxin will therefore be endocytosed by the different mechanisms operating in a given cell. After endocytosis the toxin is transported to the Golgi apparatus by a process that differs from the Rab9-dependent transport of mannose-6-phosphate receptors. Retrograde toxin transport from the Golgi apparatus to the endoplasmic reticulum (ER) seems to be a requirement for subsequent toxin translocation to the cytosol where the toxin inhibits protein synthesis enzymatically. By using ricin we have characterized different types of endocytosis and the transport steps used by this toxin.

Endosome to Golgi transport of ricin is regulated by cholesterol.

We have here studied the role of cholesterol in transport of ricin from endosomes to the Golgi apparatus. Ricin is endocytosed even when cells are depleted for cholesterol by using methyl-beta-cyclodextrin (m beta CD). However, as here shown, the intracellular transport of ricin from endosomes to the Golgi apparatus, measured by quantifying sulfation of a modified ricin molecule, is strongly inhibited when the cholesterol content of the cell is reduced. On the other hand, increasing the level of cholesterol by treating cells with mbetaCD saturated with cholesterol (m beta CD/chol) reduced the intracellular transport of ricin to the Golgi apparatus even more strongly. The intracellular transport routes affected include both Rab9-independent and Rab9-dependent pathways to the Golgi apparatus, since both sulfation of ricin after induced expression of mutant Rab9 (mRab9) to inhibit late endosome to Golgi transport and sulfation of a modified mannose 6-phosphate receptor (M6PR) were inhibited after removal or addition of cholesterol. Furthermore, the structure of the Golgi apparatus was affected by increased levels of cholesterol, as visualized by pronounced vesiculation and formation of smaller stacks. Thus, our results indicate that transport of ricin from endosomes to the Golgi apparatus is influenced by the cholesterol content of the cell.

Norgestomet implants, plasma progesterone concentrations and embryo transfer pregnancy rates in cattle.

A study was undertaken to test the hypothesis that supplementation with exogenous progestagen at the time of embryo transfer would enhance pregnancy rates in recipients. Two-hundred-and-seventy-two oestrus-synchronised crossbred heifer and cow recipients received 200 grade 1 and 72 grade 2 Simmental embryos transferred non-surgically. Heparinised blood samples were taken on day 6 and day 7 (oestrus = day 0) for the assessment of the endogenous plasma progesterone concentration. Half the recipients received an ear implant impregnated with 3 mg norgestomet on the day of embryo transfer. The pregnancy rates were 51.9 and 49.6 per cent for the norgestomet-treated and control groups, respectively. The pregnancy rate for grade 1 embryos was 56.0 per cent and for grade 2 embryos 36.1 per cent (P < 0.01). The breed of recipient, weekday of transfer, operator and condition score had no effect on pregnancy rate. The maiden heifers had a higher pregnancy rate (54.2 per cent) than the cows (46.2 per cent). The mean plasma progesterone concentrations of the pregnant and non-pregnant groups on day 6 were 6.7 ng/ml and 6.6 ng/ml, respectively, and 7.6 ng/ml in both groups on day 7.

Evaluation of Crestar, a synthetic progestogen regime, for synchronising oestrus in maiden heifers used as recipients of embryo transfers.

Crestar consists of an ear implant containing 3 mg norgestomet combined with an intramuscular injection of 3 mg norgestomet and 5 mg oestradiol valerate. Its effectiveness for synchronising oestrus in embryo transfer recipients was evaluated in comparison with a progesterone-releasing intravaginal device (PRID) and prostaglandin regimen, using 334 maiden heifers. The treatment devices were inserted on day 1, prostaglandin was administered to the PRID-treated heifers on day 8 and the devices were removed on day 10. High proportions of the heifers were seen in oestrus within five days of the removal of the devices after both the PRID prostaglandin (90.4 per cent) and Crestar (86.2 per cent) treatments. The interval from the removal of the device to the onset of oestrus was significantly shorter for Crestar than for PRID prostaglandin-treated heifers (45 vs 51 hours, P < 0.001), and the duration of oestrus was significantly longer (13 vs 10 hours, P < 0.01). The PRID prostaglandin treatment resulted in a higher degree of synchrony than the Crestar treatment (74.1 per cent vs 61.8 per cent, P < 0.05). There were no significant differences between the treatments in the proportions of the heifers selected as embryo transfer recipients or in the proportions which became pregnant after embryo transfer.

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.