Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets.

OBJECTIVE: To investigate the pharmacokinetics of 10 microg and 25 microg 17beta-estradiol (E2) vaginal tablets in postmenopausal women with vaginal atrophy. METHODS: Fifty-eight women received either 10 microg or 25 microg estradiol vaginal tablets, administered once daily for 2 weeks, followed by twice-weekly dosing for 10 weeks. Blood samples were taken over 24 h at baseline (day -1) and days 1, 14, 82 and 83. Estradiol (E2), estrone (E1) and estrone sulfate (E1S) levels were quantified by gas chromatography-mass spectrometry (GCMS) and assessed by the average plasma concentration from time 0 to 24 h (C(ave)) derived from the area under the curve within 24 h (AUC((0-24))) divided by 24 h. RESULTS: Mean C(ave) values were 9.39 and 19.84 pg/ml on day 1, 6.56 and 18.29 pg/ml on day 14, and 4.64 and 9.41 pg/ml on day 83 for the 10 microg and 25 microg doses, respectively. After 12 weeks, E1 and E1S levels were slightly higher with the 25 microg dose and in the same range with the 10 microg dose, as compared to baseline. CONCLUSIONS: During 12 weeks' administration, 10 microg vaginal tablets resulted in at least 50% lower mean estradiol concentrations than with the 25 microg dose within 24 h after dosing. Administering the 25 microg dose, mean E2 levels during the first 2 weeks exceeded the published reference range for postmenopausal women using the GCMS method, while, with the 10 microg dose, mean E2 levels remained in that range from the beginning, indicating minimized estradiol absorption.

Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition.

OBJECTIVE: To characterize the lipophilic ACE inhibitor moexipril and its active metabolite moexiprilat regarding the duration of action, the susceptibility of the pharmacokinetics and pharmacodynamics to food intake and the concentration-dependent effect. METHODS: Three independent, open, randomized studies were performed in healthy subjects using crossover or parallel-group designs. In the first study, pharmacokinetics (AUC, Cmax, tmax, t 1/2) and ACE inhibition (up to 72 h) were investigated following single oral doses of 15 mg moexipril administered in the fasting and postprandial state (n = 24). The individual ACE inhibition data and plasma concentration data were fitted to an Emax model. In the second study, carried out in 52 volunteers, the pharmacokinetics were followed over 36 h following administration of 2 single oral doses of 15 mg moexipril. In the third study, the pharmacokinetics after multiple dosing of 15 mg moexipril once daily for 5 days were investigated in 12 young and 12 elderly subjects. RESULTS: Moexiprilat tmax was 1.5-2 h with only minor differences between single and multiple dosing. Compared to fasting, the postprandial moexiprilat Cmax and AUC (ratio fed/fasted 58.0%; 90% CI 52.2-64.5%) were distinctly reduced (ANOVA p = 0.0001). Moexiprilat showed a biphasic elimination phase with an average t 1/2 of 29-30 h. In contrast to the alpha-phase, the plasma concentrations during the terminal elimination phase were not affected by food. A relationship between ACE inhibition and plasma concentration was not observed. The average ACE inhibition over 72 h was 71 % in the fasting state and 74% in the postprandial state. ACE inhibition increased to about 80% after 24 h and decreased to about 60% at 72 h. The S-shaped concentration-effect curve indicated that a moexiprilat level of 1.3 ng/ml was sufficient to produce 50% inhibition of ACE. With repeated dosing there were no signs of drug accumulation and day-to-day drug levels were relatively constant. The trough concentrations at 24 h did not fall below the limit of 1-2 ng/ml, i.e. a 50% ACE inhibition. CONCLUSION: Moexiprilat showed an extended duration of action owing to a long terminal pharmacokinetic half-life and produced a persistent ACE inhibition. Although the pharmacokinetics were partly influenced by food intake, ACE inhibition was not affected. This might be explained by a second compartment directly related to the ACE which is less prone to food effects and the reaching of a ceiling in the sigmoidal concentration-effect curve even with the lower Cmax concentrations associated with the postprandial state.

Absolute bioavailability, pharmacokinetics, renal and biliary clearance of distigmine after a single oral dose in comparison to i.v. administration of 14C-distigmine-bromide in healthy volunteers.

AIM: The aim of the study was to determine the absolute bioavailability and pharmacokinetics after a single dose oral administration in comparison to i.v. administration of 14C-labelled distigmine-bromide (14C-Ubretid) in healthy male volunteers. RESULTS: After the intravenous administration, distigmine is eliminated from the body by renal excretion (85%), and for a small fraction by biliary excretion in the feces (4%). This situation is reversed after an oral administration, where 6.5% of the dose is recovered from the urine and 88% from the feces. This means that distigmine after oral administration is hardly absorbed, the calculated bioavailability is 4.65%. CONCLUSION: The mean absorption time (MAT) after oral administration was 10 h, influencing the t(1/2alpha) (1.4 vs 4.5 h) and the t(1/2beta) (60 vs 70 h) to higher values than after the i.v. administration (p < 0.05).

Safety and tolerability of naproxen ophthalmic solution in comparison to placebo.

BACKGROUND: Naproxen is a classic non-steroidal anti-inflammatory drug (NSAID) with established analgesic and anti-inflammatory potency. Its action is related to cyclooxygenase inhibition and consequent decrease in prostaglandin concentration in various fluids and tissues. Since prostaglandin release is involved in several ocular alterations, various NSAID eye drops have come into use in the clinical setting during the last decade. SUBJECTS, MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled, three-way crossover design phase I was performed in 12 healthy volunteers to determine both tolerance and safety of a new NSAID ophthalmic solution containing sodium naproxen (0.1% and 0.2%). Both single dose and repeated dose (TID for 6 days) instillation were performed. Evaluation was entirely based upon tolerance criteria. Subjective and objective signs of ocular irritation and subject comfort preference were evaluated. Also medical examination, hematology, blood chemistry and urine analysis were also assessed to evaluate any possible effect of the test drugs and control. RESULTS: Neither ophthalmic tolerance parameters nor vital signs or laboratory parameters were influenced by treatments. A slight hyperemia of the conjunctiva was the only change observed in the eye during the study, whereas the only symptom mentioned was burning. CONCLUSION: It is concluded that both tolerability and safety of 0.1% and 0.2% naproxen solution are acceptable after single and repeated conjunctival administration.

Pharmacokinetics and Tolerability of a New Hydroxyethyl Starch (HES) Specification [HES (130/0.4)] after Single-Dose Infusion of 6% or 10% Solutions in Healthy Volunteers.

OBJECTIVE: To investigate the pharmacokinetic profile and tolerability of a single-dose infusion of the new hydroxyethyl starch (HES) specification, HES (130/0.4), 6% and 10% solutions in healthy volunteers. STUDY DESIGN: In an open, randomised, single-dose, parallel-group study, 12 healthy volunteers (in each group) received intravenous infusions of 500ml of a new HES specification [HES (130/0.4)] of either 6% or 10% solution within 30 minutes. RESULTS: Plasma elimination initially occurred with an alpha half-life of approximately 0.5 to 0.75 hour. A half-life of approximately 12 hours was reported for the terminal phase. Between 60 to 70% of the total plasma elimination was due to renal excretion. The total plasma clearances of 31.4 ml/min and 26.0 ml/min for the 6 and 10% solutions, respectively, were higher than those reported for other HES specifications. The volume of distribution in the central compartment was approximately 5.9L, which roughly corresponded to the blood volume. Single doses of 6% and 10% HES (130/0.4) were well tolerated. CONCLUSION: The new HES specification demonstrated favourable pharmacokinetic properties compared with other HES specifications of medium or high molecular weight. No clinically relevant plasma accumulation and related undesired effects on haemostasis are expected to occur under multiple-dose conditions.

Bioequivalence evaluation of two preparations containing the highly variable compound selegiline (L-deprenyl).

Selegiline, used in the treatment of Parkinson's disease, inhibits the intracerebral degradation of dopamine and the uptake of catecholamines. Due to a high volume of distribution and also a high rate of biotransformation the concentrations of selegiline in plasma are rather low. In addition, there are indications that selegiline binds to erythrocytes. An open, randomized, 2-way cross-over study was performed in 24 healthy male volunteers to determine bioavailability and pharmacokinetic parameters of 2 oral selegiline preparations after single dose administration. Statistical tests were applied to the pharmacokinetic parameters AUCinf, AUC0-8, AUCz, Cmax and tmax. The terminal half-lives t1/2 for selegiline with geometric means of 1.69 h (n = 22) and 1.76 h (n = 21) for treatments A and B and for N-desmethyl-selegiline with geometric means of 1.98 h and 1.96 h for treatments A and B agreed very well. AUCinf of selegiline could be compared between treatments for 14 subjects only. The geometric mean ratio was 97.80% with a 90% confidence interval that ranged from 79.58%-120.17% and thus exceeded the (80%, 125%) range by a very small margin. After correction for the actual dose contained in each of the 2 preparations the geometric mean ratio was calculated to 98.39% with a 90% confidence interval that ranged from 80.06%-120.90% and thus was fully contained within the (80%, 125%) acceptance range. Treatments also agreed very well with respect to AUCinf of N-desmethyl-selegiline, the active metabolite of selegiline, with a geometric mean ratio of 96.14% with a 90% confidence interval that ranged from 92.41%-100.01% so that bioequivalence of the 2 treatments could be shown very clearly with respect to this metabolite. The AUC of N-desmethyl-selegiline in serum is about 6-fold higher than that of the parent drug. It is assessed with low variability. Thus, it is reasonable to base the judgement for or against bioequivalence primarily on the data obtained for the metabolite although "a larger acceptance range may be acceptable if inevitable and clinically acceptable" for the parent compound selegiline which certainly can be classified as a "highly variable compound".

Three explorative studies on the efficacy of the antihistamine mebhydroline (Omeril).

The efficacy of a multiple oral dose treatment with mebhydroline (Omeril coated tablets, 100 mg t.i.d.) was examined in 3 studies which were performed in a randomized, double-blind and placebo-controlled 2-way cross-over design. A second target was to investigate the suitability of different pharmacodynamic models for testing the efficacy of antihistamines. Study A involved a nasal provocation with a specific allergen in 11 symptom-free patients suffering from seasonal allergic rhinitis. In study B, a nasal provocation with histamine was investigated in 11 healthy volunteers. Study C involved a cutaneous provocation with a specific allergen in 12 symptom-free patients suffering from seasonal allergic rhinitis/atopy. The mebhydroline treatment's superiority over placebo was shown statistically at the 95% confidence level for the symptoms itchy nose in study A and for nasal congestion in study B. In study C, allergen-induced weals (planimetric measurement) and itching (visual analog scale) were significantly changed by mebhydroline. A qualitative evaluation revealed a reaction intensity that differed between the 2 treatments to a clinically relevant degree, however, without reaching significance. On the basis of the data it is expected that the clinical efficacy of mebhydroline may be further substantiated in confirmatory clinical trials which should include placebo and positive controls. The test methods used differed in their suitability for measuring the pharmacodynamic effects of antihistamines. Overall, the most clear-cut results were seen in hay fever patients using a specific allergen for provocation. The planimetric assessment of weal response should be preferred as a cutaneous model. Both AR and AARM have their clinical relevance. Based on highly significant results of a subgroup analysis there are indications in favor to AR, but momentary there is no definite conclusion in favor of or against either of the 2 methods.

Gastrointestinal blood loss induced by three different non-steroidal anti-inflammatory drugs.

A clinical study was performed on 18 healthy volunteers to compare the gastrointestinal daily blood loss induced by oral intake of three different non-steroidal anti-inflammatory drugs, lysine clonixinate (CAS 55837-30-4), ibuprofen (CAS 15687-27-1) and acetylsalicylic acid (CAS 50-78-2 ASA). For quantitative determination of gastrointestinal blood loss, autologous erythrocytes were radiolabelled in vitro with 51Cr and reinfused at study start. The amount of radioactivity excreted in faeces was measured during a placebo baseline phase of three days, a treatment phase of five days with thrice daily dosing of ASA, ibuprofen or lysine clonixinate and a subsequent wash-out phase of five days. The highest increase of mean daily blood loss over baseline was observed after treatment with ASA (+ 1.66 ml/d versus baseline). Treatment with ibuprofen led to an increase of mean daily blood loss by + 0.52 ml/d. During treatment with lysine clonixinate the mean increase of daily blood loss was +0.32 ml/d versus baseline. In the ibuprofen and lysine clonixinate treatment groups the values of mean daily blood loss decreased during the wash-out phase with respect to the verum phase, whereas the mean daily blood loss during the wash-out phase after treatment with ASA even increased in comparison to the verum phase (mean daily blood loss: +2.07 ml/d versus baseline.

[NMR tomography of the liver with the new contrast agent Gd-BOPTA. The results of an in-vivo phase-I test]. / Kernspintomographie der Leber mit dem neuen Kontrastmittel Gd-BOPTA. Ergebnisse einer In-vivo-Phase-I-Prüfung.

A phase 1 study on 8 normals has been carried out to determine the effectiveness and safety during MRI of a new hepatobiliary contrast medium Gd-BOPTA for causing enhancement of the upper abdominal organs. Gradient echo sequences (flash), T1 and T2-weighted spin echo sequences and turbo-flash sequences were used. The contrast medium was given as a single infusion in various concentrations (0.005, 0.05, 0.1, and 0.2 mmol/kg body weight). Optimal contrast of liver parenchyma was obtained with a dose of 0.05-0.1 mmol/kg body weight, resulting in contrast increase of 149.1% during gradient echo sequences and 107.8% during T1 spin echo sequences. In general, the increased contrast lasted for about two hours. Because of the biliary and renal excretion there was an enormous increase in signal intensity of the bile ducts and a significant increase in the kidneys and ureters. The results of the first in-vivo trial of Gd-BOPTA encourages the performance of further clinical studies of this new hepatobiliary contrast medium.

Gadobenate dimeglumine--a new contrast agent for MR imaging: preliminary evaluation in healthy volunteers.

Gadobenate dimeglumine (formerly known as Gd-BOPTA) is a recently developed paramagnetic contrast agent that undergoes biliary as well as renal excretion. It may, therefore, be useful in MR imaging of the liver. Its safety, tolerance, and usefulness in visualizing hepatobiliary structures were studied in eight healthy subjects. Axial abdominal images were obtained with T1-weighted spin-echo and gradient-echo sequences at 1.5 T before and after IV administration of gadobenate dimeglumine in doses of 0.005, 0.05, 0.1, and 0.2 mmol/kg body weight. Two subjects received each dose. Administration of 0.1 mmol/kg resulted in a maximum liver enhancement of 149% on the gradient-echo sequence and of 90% on the T1-weighted spin-echo sequence 60 min after injection. The contrast enhancement of the liver remained virtually constant for 2 hr. The signal-to-noise ratio of the biliary tract increased from 38 to 121 after 2 hr on gradient-echo images. In addition, there was significant contrast enhancement of the kidneys. Optimal visualization of the liver parenchyma was achieved with doses of 0.05 and 0.1 mmol gadobenate dimeglumine/kg. Mild to moderate side effects such as nausea and retching, a sense of warmth at the infusion site, and transient pruritus lasting 1 min were reported by three (38%) of the subjects. The initial results of the first application of gadobenate dimeglumine in humans are encouraging because the contrast agent appears to be reasonably well tolerated at the doses appropriate for hepatobiliary imaging. Further clinical studies of this contrast agent are warranted to assess its effect on liver lesion conspicuity and the frequency with which side effects occur.

Acute hypothyroidism slows the rate of left ventricular diastolic relaxation.

The effect of acute thyroid hormone deficiency on left ventricular diastolic filling was studied by radionuclide ventriculography with simultaneous right heart catheterization in nine athyreotic patients without cardiovascular disease. The patients were studied when they were hypothyroid and when they were euthyroid on replacement therapy. Peak filling rate and the time to peak filling were used to characterize diastolic function. The time to peak filling was defined as the interval from end-systole on the radionuclide time-volume curve to the time of occurrence of peak filling. The peak filling rate was determined in absolute terms from the normalized radionuclide peak filling rate and from the end-diastolic volume, which was derived from the radionuclide ejection fraction and from the thermodilution stroke volume. In all patients, the values for peak filling rate were lower in the hypothyroid than in the euthyroid state (287 +/- 91 mL/s vs. 400 +/- 118 mL/s, delta = 41 +/- 13%, p less than 0.01). Peak filling always occurred during the first half of the diastolic interval. The time to peak filling was not significantly affected by the thyroid state (170 +/- 10 ms vs. 159 +/- 21 ms, delta = 7 +/- 10%). Left ventricular filling pressure as reflected by the pulmonary capillary wedge pressure and end-systolic volume were similar in both thyroid states (6 +/- 2 mmHg vs. 8 +/- 2 mmHg (1 mmHg = 133.32 Pa) and 32 +/- 11 mL vs. 32 +/- 7 mL, respectively). The data suggest that the rate of active diastolic relaxation is decreased in short-duration hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular function at rest and during exercise in acute hypothyroidism.

The effect of hypothyroidism on left ventricular function at rest and during exercise was studied in nine patients without demonstrable cardiovascular disease who had had total thyroidectomy and ablative radioiodine treatment for thyroid cancer. Radionuclide ventriculography and simultaneous right heart catheterisation were performed while the patients were hypothyroid two weeks after stopping triiodothyronine treatment (to permit routine screening for metastases) and while they were euthyroid on thyroxine replacement treatment. When the patients were hypothyroid, cardiac output, stroke volume, and end diastolic volume at rest were all lower and peripheral resistance was higher than when they were euthyroid. Pulmonary capillary wedge pressure, right atrial pressure, heart rate, left ventricular ejection fraction, and the systolic pressure:volume relation of the left ventricle, which was used as an estimate of the contractile state, were not significantly different when the patients were hypothyroid or euthyroid. During exercise, heart rate, cardiac output, end diastolic volume, and stroke volume were higher when the patients were euthyroid than when they were hypothyroid. Again, pulmonary capillary wedge pressure, ejection fraction, and the systolic pressure:volume relation were similar in both thyroid states. The data suggest that the alterations in cardiac performance seen in short term hypothyroidism are primarily related to changes in loading conditions and exercise heart rate; they do not suggest that acute thyroid hormone deficiency has a major effect on the contractile properties of the myocardium.

[Radionuclide ventriculography--a noninvasive method of diagnosis and quantification of tricuspid valve insufficiency]. / Die Radionuklidventrikulographie--eine nichtinvasive Methode zur Diagnose und Quantifizierung der Trikuspidalklappeninsuffizienz.

The diagnosis of tricuspid regurgitation (TR) is difficult to make by simple clinical methods or by invasive techniques. Contrast echocardiography and Doppler echocardiography have improved diagnostic results, but a golden standard is still not available. Radionuclide ventriculography (RNV) is a well-established method for the detection and quantification of a volume load on the left ventricle: the regurgitation fraction can simply be derived from the regurgitant index as the ratio of enddiastolic-endsystolic count-rate differences between the left and right ventricle. In left heart valvular regurgitation a regurgitant index exceeding the upper normal limit can be expected. This study was performed to evaluate the diagnostic accuracy of an abnormally low regurgitant index in detecting TR, which is accompanied by an isolated volume load on the right ventricle. A series of 33 patients with TR on physical examination and cardiac catheterization underwent RNV and was compared with 48 patients with right ventricular enlargement or pressure load on the right ventricle. In addition, the specificity of the method was evaluated in 470 consecutive patients with various forms of heart disease. In 18 out of 20 subjects with isolated TR a regurgitant index below the lower normal limit was found. The remaining 2 cases with minor TR had a regurgitant index within the normal range, which is 0.89 to 1.97 in this laboratory. In patients with additional volume load on the left ventricle, the sensitivity of the method was found to be low, as could be expected from the principle of the method. The time-activity curve over the liver was usually in phase with that recorded over the atria in subjects with TR. Therefore, the additional examination of a region of interest over the liver was particularly useful in these patients with concomitant aortic or mitral valve regurgitation. None of the 48 patients with right ventricular enlargement or pressure load on the right ventricle had a falsely positive result. A total of 17 out of 470 consecutive patients had a regurgitant index below the normal range; left ventricular function was severely impaired in 9 of these patients. The remaining subjects had a regurgitant index slightly below the lower normal limit. In conclusion, RNV has a high sensitivity in the diagnosis of TR in patients without left heart valvular regurgitation and a high specificity in patients without severely impaired left ventricular function and without left-to-right shunt through an atrial septal defect.(ABSTRACT TRUNCATED AT 400 WORDS)

Tumor scintigraphy with 131I anti CEA monoclonal antibodies and F(ab')2 in colorectal cancer.

In 14 patients with proven local recurrence of colorectal cancer or metastases in liver and/or lungs, the sensitivity (SE) in detecting tumor sites was estimated in a single-blind study using conventional planar whole body scintigraphy. Nine patients received F(ab')2 and five received MAB by intravenous infusion over 30 min with a dose of 40-200 MBq after skin testing and thyroid blocking, scanning was performed 1-7 days later. All but one patient had elevated plasma CEA levels with a mean of 25.5 +/- 31.9 ng/ml. The scans were interpreted by two independent observers. In five of the nine patients receiving F(ab')2, the tumor site could be visualized, yielding a sensitivity of 55%. No tumor sites were identified with MAB. The highest tumor uptake was recorded in a patient with additional ovarian cancer with the activity accumulating in the ovarian cancer. The optimum time for imaging was 3 or 4 days after injection. There was no correlation between positive imaging and plasma CEA levels which ranged from 1.9 ng/ml to 100 ng/ml in the positive cases. The thyroid uptake on the sixth day was 0.68% +/- 0.2% of the total dose given despite thyroid blocking. Bone uptake of 131I was also observed, this was mild in four patients, moderate in three but high in one patient, especially on days one to four. Thus, only anti-CEA F(ab')2 seem to be of clinical interest for further evaluation in localizing colorectal cancer. Regarding the still low sensitivity of 55%, further improvement can be expected by gaining experience, using more appropriate isotopes such as 111In and SPECT. The estimated radiation side effects on thyroid and bone marrow are only modest.