Transdermal contraception.

This review summarizes the clinical studies involving the once-weekly Ortho Evra/Evra contraceptive patch. The patch delivers norelgestromin (NGMN), 150 microg, and ethinyl estradiol (EE), 20 microg, daily to the systemic circulation. The contraceptive patch provided ovulation suppression and cycle control similar to that of oral norgestimate 250 microg/EE 35 microg, significantly decreased mean maximum follicular diameter following a 3-day intentional delayed dosing phase when compared with oral levonorgestrel (LNG) 50/75/125 microg/EE 30/40/30 micorg and oral LNG 100 microg/EE 20 microg, and was as effective as oral LNG 50/75/125 microg/EE 30/40/30 microg and oral desogestrel 150 microg/EE 20 microg in altering cervical mucus composition (i.e., creating a scanty, viscous consistency). The contraceptive patch provided efficacy, cycle control, and safety comparable to that seen with oral LNG 50/75/125 microg/EE 30/40/30 microg, but women were able to correctly follow the weekly dosing regimen significantly more often than the daily oral contraceptive dosing regimen. Less than 2% of patches were replaced because of complete detachment in these trials. The patch was not associated with phototoxicity or photoallergy. The contraceptive patch, the only noninvasive, weekly birth control method that a woman can self-administer, will be a valuable addition to current contraceptive options.

Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches.

The primary objective of this open-label study was to determine the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE)following two consecutive applications of a contraceptive patch (ORTHO EVRA/EVRA). Twelve healthy women wore the first patch on their abdomen for 7 days and, after removal at 168 hours (day 7), wore a second patch for 10 days (i.e., 3 days beyond the intended 7-day wear period). Blood samples were collected before and at various times up to 456 hours (day 19) after application of the first patch for analysis of NGMN and EE. Mean serum concentrations of NGMN and EE remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the entire 7-day wear period after application of the first patch and for 10 days after application of the second patch; reference ranges are based on studies with ORTHO-CYCLEN/ Cilest. No patch detached spontaneously. No subject discontinued or experienced a serious adverse event.

Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra/Evra) under conditions of heat, humidity, and exercise.

The objectives of this randomized, open-label, three-period, incomplete block design study were to evaluate the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) delivered by the contraceptive patch, Ortho Evra/Evra, and to evaluate patch adhesion under conditions of heat, humidity, and exercise. During each treatment period, 30 healthy women wore Ortho Evra on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool water immersion, or a combination of activities). Blood samples were collected before and several times to 240 hours after patch application. Mean serum concentrations of NGMN and EE generally remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the 7-day wearperiodfor all activities. Only 1 (1.1%) of 87 patches completely detached spontaneously. Peel force measurements were comparable for all activities. Ortho Evra was well tolerated. In conclusion, Ortho Evra delivers efficacious concentrations of NGMN and EE and maintains adhesive reliability through 7 days of wear even under conditions of heat, humidity, and exercise.

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants.

This open-label, randomized study evaluated the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) following the application of a contraceptive patch (1/week) for three cycles (3 weeks/cycle). Healthy women (n = 24) wore a 20-cm(2) patch (ORTHO EVRA/EVRA) on either their abdomen or buttock during blood sampling weeks and on any of four approved sites at other times. Serum was analyzed for NGMN and EE from samples taken during Week 1 of Cycle 1 and Weeks 1-3 of Cycle 3. Steady-state conditions were achieved during the three-cycle study. The patch delivered NGMN and EE at steady-state concentrations within their reference ranges throughout three cycles of treatment; reference ranges are based on studies with ORTHO-CYCLEN/Cilest. Steady-state serum concentrations and area under the curve from 0 to 168 h increased only slightly from Cycle 1, Week 1 to Cycle 3, Week 3 for NGMN and EE, indicating minimal accumulation. Treatment was well tolerated, and patch adhesion was excellent.

Visual outcome of craniopharyngioma in children.

PURPOSE: To assess the visual outcome of children with craniopharyngioma and identify predictors of visual loss. METHODS: A retrospective analysis of all patients younger than 18 at presentation who were evaluated between 1984 and 1995 was performed. Visual outcome was assessed as a function of age, systemic symptoms, visual acuity at presentation, and need for postoperative radiotherapy. RESULTS: Thirty-one patients were identified, with a mean age of 7.7 years (range, 1.2 to 16.8 years) at the time of surgical resection. The initial visual acuity (known in 20 patients at presentation) in the better-seeing eye was > or = 20/40 in 14 (70%) patients and < 20/200 in 2 (10%) patients. Twelve (39%) patients presented with visual symptoms and 15 (48%) with systemic symptoms. All patients underwent surgical resection; some patients required multiple surgeries (52%) or adjuvant radiotherapy (48%). The mean postsurgical follow up was 6.5 years (range, 4 days to 25 years). Postoperative visual acuity was > or = 20/40 in the better eye in 22 (71%) patients; 8 (26%) patients had visual acuity < 20/200 in their better-seeing eye. Optic atrophy developed in 51 eyes of 27 patients (81%). CONCLUSIONS: Craniopharyngioma presents with visual symptoms in children and is associated with significant permanent visual dysfunction. Age younger than 6 years at presentation and visual symptoms at presentation were associated with a significantly poorer visual outcome. Craniopharyngioma should be considered in the differential diagnosis of every child with amblyopia, particularly when no amblyogenic factors such as anisometropia or strabismus are present.

Comparison of three tonometers for measuring intraocular pressure in rabbits.

PURPOSE: Rabbits are used commonly for the evaluation of drugs and surgery to lower intraocular pressure (IOP). The authors compared the accuracy and variability of three tonometers for measuring IOP in rabbits. METHODS: The anterior chamber of adult rabbits was cannulated with a 25-gauge needle connected to an elevated bottle of balanced salt solution. The bottle was raised and lowered to control IOP. A fluid-filled pressure transducer also was placed in the anterior chamber. Intraocular pressure was decreased in increments of 5 to 10 cm H2O from 50 to 0 mm Hg and was recorded with each of these instruments: the hand-held applanation tonometer, the Tono-pen XL, and the pneumatonometer. RESULTS: The Tono-pen XL and the hand-held applanation tonometer underestimated the IOP, whereas the pneumatonometer slightly overestimated IOP. Under close stopcock conditions, at IOPs between 3 and 30 mm Hg, the Tono-pen XL was as accurate as the pneumatonometer but had a smaller variance; the hand-held applanation tonometer had lower accuracy and higher variability. CONCLUSIONS: The Tono-pen XL is the tonometer of choice for measuring IOP in rabbits within the range of IOP 3 to 30 mm Hg. All tonometers were less accurate when the IOP was elevated markedly.

The pharmacokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions.

OBJECTIVE: Our purpose was to evaluate the pharmacokinetics of atosiban, an oxytocin antagonist, during and after intravenous infusion in pregnant patients having at least six contractions per hour. The relationship between atosiban infusion and uterine activity was also assessed. STUDY DESIGN: Plasma samples from eight pregnant patients treated with intravenous atosiban (300 micrograms/min for 6 to 12 hours) were analyzed for atosiban concentration by a specific radioimmunoassay procedure. Contraction rate data were obtained by external tocodynamometry for 1 hour before the infusion and during the subsequent infusion. RESULTS: The average steady-state plasma concentrations of patients receiving intravenous atosiban were 442 +/- 73 ng/ml (mean +/- SD), with steady state achieved by 1 hour after the start of the infusion. After the completion of the infusion, plasma concentrations declined rapidly in a biexponential manner with initial and terminal half-life estimates of 13 +/- 3 and 102 +/- 18 minutes, respectively. The effective half-life was 18 +/- 3 minutes. The plasma clearance of atosiban was relatively high (42 L/hr) and the volume of distribution (approximately 18 L) was consistent with distribution into extracellular fluid. Of the seven patients evaluated for uterine activity, the mean contraction rate decreased by 75% during the third hour of treatment and remained low until treatment termination. CONCLUSION: On the basis of earlier published reports, the pharmacokinetics of atosiban in pregnant patients are similar to those in nonpregnant women. Although the patient population was small, a consistent reduction in uterine activity was observed during atosiban infusion.

Agreement among optometrists, ophthalmologists, and residents in evaluating the optic disc for glaucoma.

PURPOSE: To determine the agreement among optometrists, ophthalmologists, and ophthalmology residents in assessing glaucomatous optic nerve damage. The authors also determined the sensitivity of each group of observers for identifying glaucomatous optic nerve damage. METHODS: Six optometrists, six general ophthalmologists, and six third-year ophthalmology residents evaluated 75 stereoscopic optic disc photographs. Observers estimated the vertical cup:disc ratio (C:D) and assessed the presence of glaucomatous damage. Agreement among and within observers was estimated by the kappa statistic (KW, k). The sensitivity and specificity for the identification of glaucomatous optic nerve damage were determined for each group of participants. RESULTS: Intraobserver agreement (KW 0.69-0.79) was greater than interobserver agreement (KW 0.56-0.68) in assessing the C:D ratio and glaucomatous optic nerve damage for optometrists, ophthalmologists, and residents. Interobserver agreement for ophthalmologists (KW 0.68) was substantial and significantly higher than for optometrists (KW 0.56) and residents (KW 0.56) when estimating the C:D ratio. Ophthalmologists and residents had higher sensitivity (78%) in identifying glaucomatous optic nerve damage than did optometrists (56%). The specificity for all three groups was relatively poor (range, 47%-60%). CONCLUSION: The moderate interobserver agreement across all three groups of observers suggests the need to develop standardized criteria for assessing glaucomatous optic disc damage. Ophthalmologists in this study have a higher interobserver agreement in estimating the C:D ratio and are more sensitive than optometrists in assessing glaucomatous optic nerve damage.

Pharmacokinetics and bioavailability of bemoradan, a long-acting inodilator in healthy males.

Bemoradan is a potent, long-acting orally active inodilator. The pharmacokinetics and bioavailability of bemoradan were studied in twelve normal males following oral administration of single, ascending doses of the bemoradan HCL salt in capsules. Plasma and urine levels of bemoradan were determined by HPLC (detection limits: approximately 0.5 ng/ml for plasma and 5 ng/ml for urine). Bemoradan was rapidly absorbed from the capsule formulation at all doses (Cmax occurred at 2.1-2.4 hours). Bemoradan was slowly eliminated from the body (harmonic mean t1/2 16-23 hours). There was a dose-proportional increase in the AUC (0-48) values of bemoradan in humans following the administration of 0.5, 1, 1.5 and 2 mg of bemoradan. The AUC (0-48) values increased to 2.3, 3.4 and 4.0 times when the dose was increased to 2, 3 and 4 times. Urinary excretion of unchanged bemoradan accounted for approximately 5-12% of the dose. Results from this study and previous studies in rats and dogs indicate that bemoradan is well and rapidly absorbed after oral dosing, has linear pharmacokinetics and long elimination half-lives across species.

Platelet hyperreactivity and inefficient spontaneous thrombolysis in patients at high risk from an acute coronary event.

We conducted a retrospective study to correlate thrombotic variables with the risk from an acute coronary event, using a new in vitro technique, which measures haemostasis, thrombolysis and coagulation from non-anticoagulated blood samples. The analysis was based on data from 63 patients who had undergone exercise radionuclide ventriculography, 50 of whom were considered to be at risk from an acute coronary event because they satisfied at least one of the following three criteria: (1) coronary angiography documented disease, (2) prior myocardial infarction, (3) ventriculography assessed provocable ischaemia. Fifty matched normal subjects were used as controls. Significantly enhanced haemostasis was measured in patients considered at risk from acute coronary event, and haemostatic activity was further increased in patients with provocable ischaemia. Haemostasis in eight patients at risk (provocable ischaemia), who continued with the medication during the test, did not differ significantly from the controls. Greatly reduced spontaneous thrombolytic activity was measured in all patients at risk from acute coronary events. These findings suggest the presence of hyperactive platelets in patients at risk from acute coronary events, with an additional risk of greatly reduced spontaneous thrombolytic activity.

Pharmacokinetics and bioavailability of etintidine in beagle dogs: effects of routes of administration, doses, dosage forms, and chronic dosing.

Etintidine HCl is an H2 receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are: 1. Plasma levels of etintidine after i.v. administration of 200 mg of E followed a 3-exponential decay with a terminal t1/2 of 1.7h. 2. Following oral administration of 200 mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first-pass elimination. 3. A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg-1 and this relationship did not change with repeated dosing. 4. Some accumulation of etintidine took place during the 52 weeks of chronic dosing.

Disposition of norgestimate in the presence and absence of ethinyl estradiol after oral administration to humans.

The disposition of radioactivity following oral administration of 14C-norgestimate was compared to that following administration of the drug in combination with 3H-ethinyl estradiol in humans. Seven normal, healthy female subjects were each administered one capsule orally containing 14C-norgestimate either alone (74.4 muCi, 0.50 mg) or in combination (73.5 muCi, 0.49 mg) with 3H-ethinyl estradiol (103 muCi, 0.14 mg) in polyethylene glycol 400. Peak levels of radioactivity due to carbon-14 and tritium in plasma occurred within 2 hr after drug administration, followed by distribution and elimination phases. The mean apparent elimination half-life and mean cumulative elimination of radioactivity in the urine and feces following 14C-norgestimate administration were not significantly different than those following administration of the combination dose. Approximately 50% of the administered radioactivity due to carbon-14 was excreted in the urine following administration of 14C-norgestimate both in the presence and absence of coadministered 3H-ethinyl estradiol.

Comparative bioavailability of a lipophilic steroid.

17beta-Acetoxy-2alpha-chloro-3-(p-nitrophenoxy)imino-5alpha-androstane (I) is a lipophilic steroid with postimplantive antifertility activity in laboratory animals. The bioavailability of micronized I from solutions and suspensions was compared in four groups of adult female Wistar rats. Each group received varying concentrations of micronized 3H-I (specific activity of 0.38--8.94 muCi/mg) in sesame oil by oral gavage. Samples of whole blood and urine collected following drug administration were assayed for radioactive content. Calculation of the mean area under the blood radioactivity versus time curve, when corrected for the quantity of drug administered, indicated that a substantially larger fraction of the dose was absorbed in the two instances where I was present only in solution. A linear relationship between the amount of I absorbed based on whole blood radioactivity and urinary excretion and the administered dose was found primarily for groups receiving the drug in solution. Preliminary results in humans indicate that 3H-I was absorbed to a much greater extent following oral administration of the drug in sesame oil than when admixed with lactose.

Results of total correction of the tetralogy of Fallot. Long-term haemodynamic evaluation at rest and during exercise.

Postoperative haemodynamic evaluation was performed on 15 patients 7 to 14 years (mean, 11 years) after total intracardiac repair of Fallot's tetralogy. The average age of the patients at the time of postoperative catheterization was 20 years (range 12 to 29) and they were all asymptomatic. Before operation 11 patients were severely cyanosed and disabled and 4 had mild cyanosis with anoxic spells. The cardiac output and right heart pressures were measured at rest and after 5 minutes of submaximal exercise on a bicycle ergometer. It was shown that the degree of residual obstruction of the pulmonary outflow tract was slight and that the right ventricular/pulmonary arterial systolic gradient (RV/PA gradient) exceeded 20 mmHg (2-6 kPa) at rest in only 3 patients. The mean cardiac index at rest was 5-4 l min-1 m-2 which increased to 8-3 l min-1 m-2 during exercise. The response of the cardiac output during exercise was either normal or supranormal in 14 of the 15 patients. In the remaining patient the response was marginally below the normal range. Pulmonary valvular regurgitation was present in 8 patients but there was no detectable difference in the cardiac function of these patients compared with patients with competent pulmonary valves. Six of the patients investigated had also had cardiac catheterizations performed 1 to 4 years after operation. The results of the present study show that remarkably little change has occurred in their haemodynamic status in the intervening years. Though these results are encouraging, further studies are required to determine the eventual outcome of the RV pressure and volume overload.