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Aim: Renal function is usually determined by means of creatinine-clearance, and of serum Cystatin C, the latter with increasing frequency. The present study analyses, whether the diagnostic accuracy of (99m)Tc-MAG(3) clearance is comparable to that of these modern serologic methods., Patients, Methods: 71 consecutive adult Caucasian patients (42 female, 29 male; age 50 +/- 16 yrs., range 20-83) who were referred to a nuclear medicine department for determination of bilateral renal function with (99m)Tc-MAG(3) were included. Following sufficient hydration, 10 ml of blood were taken for determination of Cystatin C and creatinine in serum prior to i.v. injection of the radiotracer. According to the recommendations of the National Kidney Foundation, glomerular filtration rate (GFR) was calculated from serum creatinine using either Cockcroft & Gault and Modification of Diet in Renal Disease (MDRD) study equation. These estimates of GFR served as reference. Cystatin C is a low molecular protein produced by all nuclear cells and is eliminated to 85 % by glomerular filtration. Analysis of (99m)Tc-MAG(3) clearance was performed by means of Bubeck's formula., Results: Linear regression analysis produced Pearson's correlation coefficients of r = 0.68 and r = -0.69 for the comparison of either Cystatin C and (99m)Tc-MAG(3) clearance with the Cockcroft & Gault equation. The comparison of Cystatin C and (99m)Tc-MAG(3) clearance with MDRD study equation resulted in correlation coefficients of r = 0.755 and r = -0.77. None of these differences were significant. The exclusion of renal impairment or the detection of an at least moderate renal impairment revealed again no significant differences between Cystatin C and (99m)Tc-MAG(3) clearance., Conclusions: Cystatin C and (99m)Tc-MAG(3) clearance are equally suited to exclude renal impairment or to detect a relevant renal impairment. Differences between both procedures are more likely a result of the applied reference method.

Single and multiple dose pharmacokinetics and absolute bioavailability of the calcium antagonist nimodipine (Nimotop) were investigated in 24 young (age: 22 - 40 years) and 24 elderly (age: 59 - 79 years) healthy subjects. There were no significant changes in blood pressure, heart rate, and ECG-parameters in both age groups, and no increase in frequency of adverse events was observed in the elderly. Following a single intravenous infusion of 15 micrograms/kg for 1 hour, there were no significant differences in nimodipine pharmacokinetics between young and elderly volunteers. Oral administration (single dose of 30 mg, 30 mg t.i.d. for 6 days), however, resulted in pronounced differences in AUC and Cmax between elderly and young subjects when the same doses were given. Under steady-state conditions the elderly reached significantly higher Cmax (g.mean/SD: 23.3/1.62 micrograms/l) and AUC-values (47.5/1.62 micrograms*h/l) than the young volunteers (13.5/2.03 micrograms/l, and 25.7/1.73 micrograms*h/l, respectively). The absolute bioavailability was 10.6/1.60% in the elderly and 5.4/2.11% in young subjects. The observed pharmacokinetic differences in the study most likely reflect the reduced metabolic clearance of nimodipine in the elderly.

A new method for the determination of furosemide (CAS 54-31-9) in plasma and urine by gas chromatography/mass spectrometry (GC/MS) has been developed. After acidification the samples were extracted by ethyl acetate and methylated by methyl iodide. The chromatography was carried out on a fused-silica capillary column with SE-54 stationary phase. Detection was performed by selected ion monitoring (ions 81 and 372 were monitored for furosemide and ions 363 and 406 for internal standard bumetanide). Limit of quantitation was 10 ng/ml for plasma and 40 ng/ml for urine and the calibration curves were linear up to 100,000 ng/ml.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Pharmacokinetic interactions following coadministration of fluoxetine and lithium were investigated in 10 young healthy subjects. Both drugs were administered orally in a non-blinded design with 3 consecutive treatment periods: single oral dose of lithium (32.4 mmol lithium as acetate, Quilonum; coadministration of single oral doses of lithium (32.4 mmol) and fluoxetine (Fluctin, 60 mg); and single oral dose of lithium after 7-day pretreatment with fluoxetine (20 mg t.i.d.). Periods 1 and 2 were separated by a 1-week washout phase, while period 3 followed on immediately after period 2. Lithium serum concentrations were practically identical in periods 1 and 3 (administration of lithium alone and after chronic fluoxetine dosing). However, in period 2, when the 2 drugs were coadministered as single oral doses, the lithium concentrations were lower in the first 4 hours after medication compared with treatment periods 1 and 3. Cmax was also significantly lower in period 2. The times to peak, however, were not significantly changed by any fluoxetine comedication. The parameters AUC0 --> infinity, t1/2, total clearance (Cltot) and renal clearance (Clren) determined after administration of lithium alone did not differ statistically from values determined after single or after repeated fluoxetine dosing. Coadministration of lithium and fluoxetine did not produce any clinically relevant changes in hemodynamics, ECGs or laboratory parameters. After single doses of both drugs the most frequently reported symptoms were gastrointestinal complaints, while mild sedative symptoms were predominant when lithium was given after repeated fluoxetine medication.(ABSTRACT TRUNCATED AT 250 WORDS)

The possible influence of chronic indometacin (CAS 53-86-1) medication on nimodipine (CAS 66085-59-4) pharmacokinetics was investigated in 24 elderly healthy subjects. Both drugs were orally administered in a non-blinded, randomized, twofold crossover design. The study periods with a 5-day treatment each were separated by a 2-week washout period. The Css,max of nimodipine was increased after the combined administration of nimodipine (30 mg t.i.d.) and indometacin (25 mg b.i.d.) as compared with those after nimodipine monotherapy: 24.2 +/- 14.7 micrograms/l vs. 19.7 +/- 10.3 micrograms/l. This increase, however, was not of an order to become clinically relevant. Nimodipine AUCss slightly increased under indometacin co-medication from 57.9 +/- 27.5 micrograms.h.l-1 to 62.8 +/- 26.6 micrograms.h.l-1, resulting in a mean relative bioavailability of nimodipine of 111% with a 90%-confidence interval of 96-128% for the combined medication. There was no evidence of any clinically relevant difference in hemodynamics and other findings between both treatments. The overall frequency of side effects was low after both medication regimens. The findings of this study indicate that a combined treatment with both compounds should not be associated with a clinically relevant interaction.

Nimodipine (30 mg t.i.d.) and propranolol (40 mg t.i.d.) were given orally to 24 healthy elderly subjects in a randomized, un-blinded, threefold crossover study. Each of the study periods lasted 8 days with a 5-day treatment phase separated by 2-week washout phases. Mean peak nimodipine plasma concentration was decreased after combined administration of the two drugs (16.1 +/- 8.1 micrograms/l vs. 12.4 +/- 9.5 micrograms/l). Nimodipine AUCss slightly decreased under propranolol co-medication from 44.9 +/- 15.1 micrograms x l/l to 38.8 +/- 22.5 micrograms x h/l, resulting in an AUC ratio of 88.8 +/- 44.5%. The relative bioavailability of propranolol was 104.1 +/- 38.3% after the combined propranolol and nimodipine medication, all other pharmacokinetic parameters remained unchanged. The pharmacological effects on the cardiovascular system were negligible after nimodipine alone. The reductions in blood pressure and pulse rate and the prolongations of typical ECG times observed after propranolol monotherapy and after the combination therapy were of similar size and were almost solely attributed to the action of the beta-blocker. The findings of this study indicate that chronic treatment with nimodipine together with propranolol should not be associated with a clinically relevant interaction.

Possible drug interactions between the two calcium channel blockers nimodipine and nifedipine were investigated in 12 elderly patients with stable mild to moderate hypertension. Their individually adjusted nifedipine treatment had been unchanged for at least 5 weeks. There was no evidence of significant changes in nifedipine efficacy as seen from blood pressure and heart rate after a 7-day comedication of 30 mg nimodipine t.i.d. as compared with the findings after combined administration of nifedipine and placebo. Nifedipine steady-state trough and peak concentrations were not significantly altered by concomitant nimodipine administration. On the other hand, nifedipine did not affect nimodipine trough and peak concentrations when compared with published data. Differences in clinical chemistry or tolerance between both treatment regimens did not occur or were marginal, respectively. In conclusion, a clinically relevant drug interaction between nifedipine and nimodipine which might be potentially harmful for patients with hypertension was not observed in this study.

Possible interactions between the calcium channel blocker nimodipine and the hypoglycemic sulphonylurea glibenclamide were investigated in patients with type-2 diabetes mellitus. These 11 patients had taken their individually adjusted antidiabetic treatment unchanged for at least 3 months and showed a satisfactory stabilization on their disease. The concomitant administration of nimodipine 30 mg t.i.d. for 6 days did not change glibenclamide pharmacokinetics as compared with the findings after glibenclamide monotherapy. The normalized AUCss,norm were 11.6 (5.0) kg x h x 1(-1) at glibenclamide monotherapy and 12.3 (5.1) kg x h x 1(-1) after combined medication, resulting in an AUC-ratio for glibenclamide of 109 (23%). Mean elimination half-lives were determined as 2.7 (0.9) h after glibenclamide alone and 3.6 (1.9) h after nimodipine comedication. There was no evidence of significant alterations in glibenclamide efficiency as seen from glucose and insulin kinetics after the simultaneous administration of glibenclamide and nimodipine (insulin Cmax, 57.0 (30.8) mU/l after glibenclamide and 64.4 (32.1) mU/l after combined treatment). Nimodipine pharmacokinetics under nimodipine and glibenclamide steady-state conditions were similar to findings in literature: AUCss,norm 0.10 (0.04) microgram x h x 1(-1), Css,max 20.7 (8.3) microgram x 1(-1). Hemodynamics, clinical chemistry and tolerance did not differ during both treatments. Thus, a clinically relevant drug interaction between nimodipine 30 mg t.i.d. and glibenclamide during long-term treatment can be excluded.

A randomized phase-I study was performed in a clinical setting in 24 healthy young male subjects, aged 20 to 35 years, to investigate the influence of Ubretid on AChE inhibition following oral and i.m. administration in one of three medication schemes: -single oral (10 mg) and i.m. (0.5 mg) medication (randomized crossover), -multiple oral dosing (5 mg on trial days 1, 2, 3, 5, 7, 9, 11 and 13), -multiple oral dosing (5 mg on trial days 5 to 14) with initial i.m. loading doses (0.5 mg i.m. on trial days 1, 2 and 4). The multiple dosing schemes were chosen as they are both frequently used in clinical practice. The results of the AChE inhibition after Ubretid can be summarized as follows: repeated Ubretid administration as used in this trial did not lead to a cumulation of AChE inhibition. Statistical testing (page test) of maximum AChE inhibition on the last medication days gave no indication of an increased AChE inhibition towards the end of treatment. Compared with the i.m. administration, the Ubretid tablet had a bioavailability of 2.2 +/- 1.1% (mean +/- STD).

The safety and tolerance of increasing single oral doses of 20, 40, 80, 120, 180, 240 and 360 mg trospium chloride (Spasmo-lyt, CAS 10405-0204) were investigated in 29 healthy male volunteers in a double-blind placebo-controlled study. Blood pressure, heart rate, ECG, pupillary diameter, salivary secretion, and subjective reports of tolerance revealed no essential differences between placebo and trospium chloride in doses up to 120 mg. Starting with single doses of 180 mg, anticholinergic effects were observed with increasing intensity, i.e., dilatation of the pupils, reduction of salivary flow, and increase of heart rate. While the highest administered dose of 360 mg trospium chloride did not cause any relevant changes of vital parameters (blood pressure, pulse, ECG), it was subjectively rated as quite unpleasant. The data show that trospium chloride is well tolerated in single oral doses well above the current therapeutic daily dose of up to 40 mg.

Pharmacokinetics and relative bioavailability of the marketed prajmalium bitartrate tablet (Neo-Gilurytmal, CAS 2589-47-1) compared to an oral solution were investigated in an open, randomized, single-dose two-fold crossover study in 20 healthy male volunteers. One subject was identified to be a poor metabolizer. In the study population with normal metabolic status the two oral formulations proved to be bioequivalent with regard to the pharmacokinetic parameters Cmax, AUC(0-Tlast), AUC(0-infinity) and Ae(24h). tmax was prolonged after administration of the tablets. The relative bioavailability of prajmalium bitartrate from the tablet amounted to 112%. The poor metabolizer demonstrated in both oral formulations high plasma concentrations, increased AUCs and prolonged terminal half-lives as well as increased renal excretion of prajmalium bitartrate.

Potentiation of the pressor effect of tyramine (TYR) by intravenous (i.v.) injection during moclobemide treatment was investigated in healthy volunteers and in depressed patients. The TYR sensitivity factor (TSF) is calculated as the ratio between the dose of TYR required to raise systolic blood pressure by 30 mmHg (TYR 30) without drug and that required with drug. After single-dose administration the TYR 30 for 100 mg moclobemide was 1.8 mg, and those for moclobemide 200 and 300 mg 1.6, compared with 3.2 for placebo, giving corresponding TSF values of 1.7, 2.0 and 2.0 respectively. Twenty-four hours after moclobemide intake, only the 300-mg dose yielded a mean TYR 30 value significantly different from placebo. The same doses of moclobemide given 3 times daily for 1 week resulted in a peak TSF of 2.0 with 100 mg, 2.9 with 200 mg and 3.3 with 300 mg (the latter dose being higher than normally recommended for 3 times daily administration). Nevertheless, 24 h after the last 300-mg dose the TSF was 1.2, similar to that of a single dose. In a study of 17 depressed female patients treated with moclobemide 100 mg 3 times daily, no relevant differences were found in TSF values from those of the volunteers. The authors conclude that, because of the short-lasting, reversible and selective MAO-A-inhibiting effect of moclobemide, there is no marked interaction with tyramine given by i.v. injection. No relevant difference was seen between depressed patients and healthy volunteers in the tyramine pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)

In 58 patients suffering from either stenosis or insufficiency of a single heart valve, gated blood pool scintigraphy was performed to determine the ejection fraction as well as the peak filling and peak ejection rates. It could be demonstrated that in patients with valvular disorders the ejection fraction was only moderately decreased, generally remaining in the lower reference range. The peak filling and ejection rates showed no pathologic changes with the exception of patients with aortic regurgitation where these rates were significantly decreased. Thus, the estimation of left ventricular peak filling and ejection rates may permit diagnosis of myocardial impairment in patients with valvular disease even under resting conditions.

The importance of scintigrpahy in the diagnosis of liver and spleen tumors is well known. There is, however, up to this time only poor information regarding the use of scintigraphy in follow up studies in patients with liver and spleen metastases undergoing cytostatic therapy. We had the opportunity to investigate 30 patients in whom Hodgkin's disease, Zollinger-Ellison syndrome, ovarian, breast or bronchial and GI malignancy was confirmed by histology. The scintigraphic examinations were performed by means of a scintillation camera using 99mTc sulfur colloid as radiotracer. In each case, three views of the organ were recorded firstly prior to therapy and (at least) once again during or after therapy respectively. The results of liver and spleen scintigraphy were compared with clinical findings, laboratory tests, laparoscopy and histopathology. In 13 of our patients, diminution of metastases was detected. In one patient an increase of the size of the tumors was seen after temporary improvement. In 8 patients, there was no change of the metastatic pattern after cytostatic therapy. 6 patients showed an increase of liver metastases under therapy. Two patients with normal liver scintigraphy in whom clinical and laboratory findings indicated liver involvement yielded no evidence of metastasis at autopsy. In 13 cases, the diagnosis of liver metastasis was detected earlier by scintigraphy than by laboratory tests.

Quantitative scintigraphy of the heart after equilibrium distribution of a radioactive tracer permits the measurement of time activity curves in the left ventricle during a representative heart cycle with great statistical accuracy. In the range of ventricular volumes which usually occur, the time activity curve corresponds with sufficient accuracy to the ventricular volume variation during one heart cycle. In cardiological terms, the parameters ejection fraction as well as maximum rates of ejection and filling have proved useful for evaluation of hemodynamic performance. By application of Fourier's analysis, criteria are to be attained in addition for evaluation of the volume curve as a whole. Thus the entire information contained in the volume curve is completely described in a Fourier spectrum. Because of the statistical noise, the volume curves drawn up from scintigraphic techniques require smoothing procedures, especially in determination of the differential quotients of ejection and filling rate. Smoothing by means of sliding average procedures causes a systematic deformation of the systolic dip and other similar regions of the curve, since the curve smoothened in this way does not converge towards the original curve at these points. Resynthesis after Fouier transformation seems to be an ideal method of smoothing because of its convergence in the minimum quadratic error for the type of function concerned.

The parameters relating to functional scintigraphy of the heart (average circulation time, peak time) depend not only on the method (injection technique, radiopharmaceutical), but also on biological factors. Failure to take these into consideration may result in an erroneous interpretation of the findings. Circulation time in normal children aged 6 to 14 years, as determined by isotope methods is significantly shorter than in normal adults. Patients with compensated heart disease, as well trained athletes, show significantly shorter than in normal adults. Patients with compensated heart disease, as well trained athletes, show significant increase in all portions of the circulation time, when compared with normals of similar ages. This indicates that deviation in the haemodynamics of the circulation as shown by functional scintigraphy, can only be interpreted in the light of clinical findings.

The effect of previous administration of vitamin B 12 on the Schilling test was examined in 10 patients, repeating the test during and 10 days after vitamin B 12 treatment. Under vitamin B 12 medication, the patients showed a significantly decreased vitamin B 12 urinary excretion. Ten days after vitamin B 12, repeat Schilling test demonstrated comparable results with baseline values except for one patient, who persistently had a low value.

In 39 patients without thyroid disorder the influence of radiographic contrast media (Conray 60, Biligram) on the thyroid function was studied. 6 weeks after the application of the iodine compounds a significant increase of T3 in blood serum could be established being accompanied by decreased TSH level and reduced response of TSH rpoduction to TRH injection. These findings showed to be even more marked 6 months later. It is assumed that the observed hormonal changes may possibly be due to a persistent Wolff-Chaikoff block induced by diffusion of free iodide and subsequent shifting of the intrathyroidal MIT/DIT ratio, which is finally followed by an increase of T3-levels in serum.

Quantitative nuclear cardiography was applied to 400 patients with valvular heart disease proven by heart catheterisation. The study yielded the following results: 1. The parameters used were directly related to th4 cardiac index, the enddiastolic volume of the left ventricle and the pressures in the pulmonary vascular system. 2. The method proved to be highly sensitive in stating whether there was a hemodynamically effective valvular disease present or not. Differential diagnosis, however, was not possible. 3. The prolongation of the circulation times correlated with the hemodynamic severity of the disease. 4. The method could be used in evaluation of corrective surgery and for follow-up after operation.

A 63-year-old male patient with a small cell bronchial carcinoma on cytotoxic therapy was followed up with the use of liver scintigraphy. In the various scintigrams the remission as well as the late reappearance of the liver metastasis was demonstrated. The abnormalities in the liver scintigrams correlated with the biochemical changes throughout the course.

In recent literature numerous papers have been published concerning the accuracy of scintigraphic detection of liver metastases. Unfortunately however, the problem of false positive results is not particularly discussed in these papers. Because of the lack of information it was our aim to compare our own scintigraphic results with postmortem histopathological findings. Our investigations were carried out in 139 patients with various types of malignancy. Included in the investigations were 20 patients with primary liver tumor. The interval between scintigraphic examination and the histological verification ranged from 3 days to 1 year. In 62 of the patients with liver metastases, histopathology revealed liver metastases, while 77 patients showed no liver involvement. We arrived at the correct diagnosis "liver metastasis" in 50 out of 62 patients (80.6%). False negative scintigrams (19.4%) were found in most of the respective cases when diffuse malignant involvement such as leukemia and Hodgkin's disease was present, and also when the size of the metastases was less than 2 cm in diameter. Fifty six out of 77 patients (72.7%) without histopathological evidence of liver metastases revealed negative scintigrams. Twenty one (27.3%) false positive scintigrams were mostly due to (diffuse) nonmalignant disease e.g. fibrosis and cirrhosis. The overall accuracy of liver scintigraphy in our study was 76.2%. In 18 of 20 (90%) patients with focal liver disease correct diagnosis was established. 7 patients with benign liver tumors and 11 of 13 patients with hepatocellular carcinoma showed focal defects. Considering the fact that liver scintigraphy is a non-invasive procedure, it can be recommended as screening method. In connection with sonography and computer tomography liver scintigraphy can undoubtedly improve the diagnostic accuracy in detecting liver metastases and primary liver tumors.

Scintigraphic evaluation of the heart function is performed by means of sequential camera scintigraphy following i.v. injection of a 99mTc albumin bolus. The first tracer passage is registered during 30 seconds. About 10 minutes later--after equilibration of the tracer in the blood pool--volume curves of the left ventricle are recorded from a series of about 500 heart cycles. The principles of a computer program which has been developed for this method are described and discussed in detail.

Radio-active plastic microspheres with an average diameter of 15 mu were used in eight dogs to measure renal perfusion and the results compared with time-activity curves before and after constriction of the left renal artery. It was shown that the values obtained for renal blood flow by functional scintigraphy are not accurate, particularly for moderate or low blood flow. The reason for this is primarily the distortion of the intravenously injected radio-active bolus and the consequent deviation from the so-called delta function.

The bioavailability of orally administered sodium 2-mercaptoethane sulfonate (mesna, Uromitexan drink ampoules) was tested in 18 healthy probands and in 5 tumor patients. Following single oral administration of 20 or 40 mg/kg mesna, 52.4% and 52.6%, respectively, of the dose were excreted in the urine as reactive thiol groups, the remainder as mesna disulfide (dimesna), the only metabolite of mesna; after i.v. injection of 20 mg/kg mesna, 48.7% of the dose administered appeared as thiol groups in the urine. Not until after 13.1 h (20 mg/kg p.o.) and 18.5 h (40 mg/kg p.o.), respectively, concentration drops below the minimum concentration of 100 micrograms/ml presumed to be still reliably protective. However, the elimination pattern and the time when the threshold concentration is reached are subject to marked individual variation. After i.v. administration of 20 mg/kg mesna and 9 times oral administration of 20 mg/kg mesna (the first dose concurrently with the i.v. injection, thereafter every 4 h), or 7 times oral administration of 20 mg/kg mesna (the first dose again concurrently with the i.v. injection, thereafter every 5 h), the percentage of the total dose administered appearing as thiol groups in the urine averaged 41.9% and 37.6%, respectively, up to 17 or 18 h after the last dose. Comparison of periods covering the same time of the day showed the total amount excreted to be higher on day 2 than on day 1.(ABSTRACT TRUNCATED AT 250 WORDS)