Cisplatin resistance is associated with reduced interferon-gamma-sensitivity and increased HER-2 expression in cultured ovarian carcinoma cells.

In ovarian carcinoma cells, the combination of interferon-gamma (IFN-gamma) and cisplatin (cDDP) has been reported to result in a synergistic amplification of antiproliferative activity. To assess whether IFN-gamma may also prevent the occurrence of cisplatin resistance, the human ovarian carcinoma cell line HTB-77 was treated repeatedly in an intermittent fashion with either cisplatin alone (HTB-77cDDP) or cisplatin plus IFN-gamma (HTB-77cDDP + IFN). After 8 months of treatment, both new lines (HTB-77cDDP or HTB-77cDDP + IFN) were found to be three times more resistant to cisplatin than the wild-type cells (HTB-77wt). IFN-gamma could not prevent the development of cisplatin resistance. Interestingly, both HTB-77cDDP and HTB-77cDDP + IFN cells were also less IFN-gamma sensitive than the parental line. Both cisplatin-resistant lines expressed p185HER-2 and HER-2 mRNA at a higher concentration than the HTB-77wt cells. IFN-gamma was in all three HTB-77 cell lines able to suppress the HER-2 message and its encoded protein. The expression of IFN-gamma-induced antigens, namely CA-125 and class II antigens of the major histocompatibility complex (HLA-DR), was markedly augmented by IFN-gamma in all three lines, whereby the most prominent effect was seen in HTB-77cDDP and HTB-77cDDP + IFN.

Pharmacokinetics of reboxetine in healthy volunteers. Single against repeated oral doses and lack of enzymatic alterations.

The pharmacokinetics of reboxetine have been investigated in 12 healthy male volunteers after a single 2 mg dose of reboxetine and at steady state, following the last administration of a multiple-dose regimen (2mg twice a day for 5 1/2 d). Reboxetine was analysed in plasma and urine samples collected up to 72 h post-dosing using an HPLC method with UV detection. The urinary excretion rate of 6-beta-hydroxycortisol, used as a marker for cytochrome P450IIIA activity, was also tested, and any possible alteration was correlated to reboxetine plasma levels. The dosing regimen was well tolerated by all subjects. Reboxetine pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the multiple-dosing regimen, no significant deviations from expectation based on linear superposition was observed. The accumulation ratio, based on repeated-dose/single-dose ratios of Cmax, AUC(0-12 h), and C(12 h) was approximately two. A slight rise was recorded for the average excretion rate of 6-beta-hydroxycortisol over 48 h by the end of treatment; however, the difference was not statistically significant and the mean excretion rates were within the normal reference range. Thus a significant induction of P450IIIA was not indicated.

Renal tubular effects of diuretics and X-ray contrast media. A comparative study of equimolar doses in healthy volunteers.

RATIONALE AND OBJECTIVES: The isotonic nonionic contrast medium iodixanol has been shown to increase urinary enzyme excretion less than the hypertonic contrast medium iopentol. The authors investigated whether this could be caused by different molar loads using enzyme excretion after diuretic administration as a model. METHODS: Matching molar doses of mannitol were given to two groups of 10 healthy volunteers. Furosemide was administered perorally to a third group of 10 persons. Urinary enzyme excretion was sequentially measured, and the results were compared to our previous findings after contrast-media administration. RESULTS: Equimolar doses of mannitol and contrast media (CM) induced similar changes in urine volume and free water clearance. Mannitol and furosemide increased the urinary excretion of N-acetyl-beta-glucosaminidase (NAG) and alkaline phosphatase (ALP) in the period 0 to 4 hours after administration, i.e. during peak diuresis, whereas both CM increased ALP significantly more, their effects still evident at 24 to 48 hours. Iodixanol had no effect on urinary NAG excretion, but iopentol increased NAG more than did mannitol. CONCLUSIONS: The early effect of CM on urinary enzyme excretion can be related, in part, to the increased diuresis, but the late effect apparent at 24 to 48 hours cannot be explained by the osmotic load of the CM.

Safety and tolerability of iodixanol in healthy volunteers with reference to two monomeric X-ray contrast media.

The low osmolar, non-ionic X-ray contrast media have shown a lower frequency of adverse events than the older ionic ones. In this study changes in routine clinical-chemical parameters in blood and urine, vital signs and adverse events were recorded in six groups of 10 healthy male volunteers receiving either iodixanol, a new non-ionic, dimeric X-ray contrast medium for general vascular use, or one of the two non-ionic, monomeric contrast media iopentol and iopamidol. Minor decreases were observed in the values for haemoglobin, haematocrit and erythrocytes 5 min and 3 days after injection of iodixanol. A minor increase was seen in platelets and total protein after 3 days. A transient increase in serum osmolality was seen 5 min after the injections of iopentol and iopamidol. This was not seen in any iodixanol group. The level of thyrotropin showed an increase in all groups at 3 days. It was back to normal within 21 days. No changes of clinical importance were seen regarding blood pressure, heart rate or ECG in any volunteer. No severe adverse events were reported. All events were of short duration, and of mild or moderate intensity. The results, however, may indicate a lower frequency of adverse events/discomfort after the administration of the dimeric iodixanol than the 2 monomeric contrast media iopentol and iopamidol.

Azithromycin pharmacokinetics and penetration to lymph.

The study of pharmacokinetics of azithromycin and penetration to peripheral human lymph was carried out in 14 healthy male volunteers taking 1 g orally after overnight fasting. Samples were analyzed by microbiological assay. The mean peak concentrations were 0.82 +/- 0.23 mg/l after 1.7 +/- 0.5 h in serum and 0.22 +/- 0.07 mg/l after 3.1 h in lymph. Nine of the 14 subjects showed a second and lower serum peak indicating the existence of enterohepatic circulation. The total areas under the serum concentrations curves (AUCs) till infinity were 7.9 +/- 3.1 mg. h/l compared to 4.4 +/- 1.2 mg.h/l in lymph. The mean lymph AUC was 68.1 +/- 20.7% of the serum AUC indicating a penetration ratio of 0.68. However, the actual amounts penetrating the tissues were much higher than this ratio suggests. Thus, after 6 h 81% of the drug was within the tissue compartment and after 120 h, 63% of the azithromycin was still present in the tissue compartment. The urinary recovery of azithromycin was 14.7 +/- 7.7% during the first 48 h. The serum curves and lymph curves displayed a distinctly slower phase of elimination after 12 h. The mean serum half-life was 5.4 +/- 3.4 h during the first 12 h (after the peak), whereas the value was 44.2 +/- 10.1 h during the interval 12-120 h. The corresponding half-life values for the peripheral lymph were 5.4 +/- 2.2 h and 50.8 +/- 11.6 h. Azithromycin possesses key pharmacokinetic properties that are prerequisites for a convenient once-daily dosage schedule which may improve patient compliance.

[Iodixanol. A new isotonic x-ray contrast medium]. / Iodixanol. Et nytt isotont røntgenkontrastmiddel.

In this phase I study, safety, tolerance and pharmacokinetics of iodixanol 300 mg I/ml, were evaluated in 40 healthy male volunteers using four dose levels. No clinically important influences on renal function parameters, hemodynamics, ECG or clinical-chemical parameters in blood and urine were observed. 17 adverse events including discomfort were reported, but only three of them (sensation of warmth) were classified as related to iodixanol. CT-investigations revealed a dose-related, reversible increase in kidney cortex density. However, iodixanol caused no changes in glomerular function, and the increase in excretion of tubular enzymes was less than caused by other nonionic x-ray contrast media. Further investigations will focus on the safety and efficacy of iodixanol in patients.

Quantification of fetal motor activity in early pregnancy.

Real-time ultrasonography in obstetrics has proved that active movements are already present in the first trimester of pregnancy. A new semi-automatic ultrasound method was developed for objective quantitative recording of fetal movements in early pregnancy using a real-time multi-linear array scanner and a Time-Distance recorder. The equipment registers changes in the distance between a fixed marker and the fetal structures displayed on the screen of the ultrasound scanner. The output signals are recorded on a polygraph. Fetal movements were recorded continuously for 30 min in 62 normal 10-, 11- and 12-week-old fetuses. The median number of movements did not differ significantly in the three groups, being 150, 159 and 154, respectively. The median time incidence of movements was 17, 18 and 17%, respectively. The method is now being applied in studies evaluating various drug effects on fetal motor behaviour in early pregnancy.

Pharmacokinetics of verapamil and norverapamil in patients with hypertension: a comparison of oral conventional and sustained release formulations.

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.

Influence of thiopental anaesthesia on fetal motor behaviour in early pregnancy.

Real-time ultrasonography has shown fetal motor activity to be present long before the mother is able to perceive any movements. The development of fetal movement patterns reflects neuromotor maturation of the fetal central nervous system. Drugs given to the mother may affect fetal neuromotor behaviour. In 20 first trimester pregnant women, applicants for legal abortion, fetal movements were objectively recorded before and after thiopental anaesthesia, using a semi-automatic method for quantitative recording of fetal movements displayed in real-time ultrasound image of the uterus. In ten patients randomly selected for premedication with morphine-scopolamine 1 h before surgery, fetal motor activity was practically abolished after the thiopental injection. In the other ten patients not so premedicated, the abolishment of fetal movements was delayed by 3 min. During the second minute after the thiopental injection, there was an increase both in the number and incidence of movements, as compared with the control period. In the latter group there was a positive correlation between the number of fetal movements and thiopental concentrations both in maternal plasma and placental tissue. The present method might be used for description of the pharmacodynamic effect of a drug distributed to the mother and traversing the placenta.

Relative bioavailability of oral low dose methotrexate. A comparison of 2 different formulations.

In 39 patients the bioavailability of methotrexate from the two tablets Emthexat 2.5 mg and Methotrexate 2.5 mg was assessed in a double-blind study after a single oral dose of 30 mg/m2 Methotrexate. There was a considerable inter-individual variation of the serum pharmacokinetics in regard to Cmax and tmax, independent on the MTX formulation. Emthexat 2.5 mg tablets and Methotrexate 2.5 mg tablets were bioequivalent according to the definition (AUCE greater than or equal to AUCM X 80%).

Pharmacokinetics and distribution of diazepam and oxazepam in early pregnancy.

The transfer of drugs from the mother to the fetus is important from the view of possible harmful as well as therapeutic effects on both mother and fetus. In the first trimester of pregnancy this has been sparsely investigated. In 66 first-trimester pregnant women, who had applied for legal termination of the pregnancy, we have calculated different pharmacokinetic parameters of two benzodiazepine derivatives, diazepam and oxazepam, after administration of a single oral dose of 10 or 25 mg to the mother. The calculated pharmacokinetic parameters were within the normal range for healthy adults. The pharmacological active metabolite n-desmethyldiazepam was measured in concentrations near the detection limit. The penetration of diazepam and oxazepam from maternal serum to placental tissue in a 4 h period after drug administration was 31.5% and 49%, respectively, indicating a rapid transfer.

Pharmacokinetics of iopentol in healthy volunteers.

Iopentol is a new non-ionic contrast medium. In order to study the pharmacokinetic properties, iopentol 350 mg I/ml was administered intravenously to healthy male volunteers at 3 dose levels (0.3, 0.6 and 1.2 g I/kg body weight). To evaluate renal excretion all subjects were given chromium-51-ethylenediaminetetraacetic acid (51Cr-EDTA) additionally to iopentol. The highest dose level group also received saline and 51Cr-EDTA about 3 weeks prior to iopentol. Serum, urine and faeces were sampled at different time intervals. Unmetabolized iopentol was excreted almost entirely in urine during the first 24 hours by means of glomerular filtration. A small fraction (2%) of the dose was excreted in faeces. No dose dependent pharmacokinetics was observed up to doses of 1.2 g I/kg body weight. The pharmacokinetic properties of iopentol make it a well suited contrast medium for vascular use.

The concentrations of ceftazidime and thiopental in maternal plasma, placental tissue and amniotic fluid in early pregnancy.

Studies on the transfer of drugs from mother to fetus in the first trimester of pregnancy are important because of the possible teratogenic effect on the fetus as well as possible therapeutic effect on both sides of the feto-maternal barrier. The purpose of this study was to measure drug concentrations in maternal plasma, placental tissue and amniotic fluid in a group of first-trimester abortion patients. Ceftazidime and thiopental were chosen as experimental drugs. The analyses were done with high pressure liquid chromatography. The penetration of ceftazidime into placental tissue and amniotic fluid was 20.6 and 2.2% from 1 to 4 h after drug administration. The corresponding values for thiopental were 54.3-71 and 1.5-7.4% from 5 to 15 min after drug administration, indicating a rapid transfer of both drugs across the feto-maternal barrier during this period in pregnancy.

Randomised controlled trial of ultrasonographic screening in pregnancy.

510 of 1009 pregnant women in the Trondheim area (Norway) were randomly selected for ultrasound examination at the 19th and 32nd weeks of pregnancy in addition to routine antenatal care. Among the screened women, twins were diagnosed earlier and there were slightly fewer post-term inductions (2.8% versus 4.0%) and fewer low-weight births (2.2% versus 3.6% less than 2500 g), but none of these differences was statistically significant. There were no differences in the condition of the newborn. Small-for-gestational-age births were more often diagnosed antenatally in the screened group and the mothers received more active treatment. During pregnancy, screened women were admitted to hospital more often than unscreened women (15.5% versus 9.2%). The study revealed no adverse short-term biological effects from ultrasound. The cost of the screening programme, including associated costs such as extra hospital admissions, was about US$ 250 per pregnancy.