L. Kangas

Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

The Transfer of Diazepam Across the Placenta During Labour

The transfer of diazepam through the placenta during labour was studied by the gas chromatographic method developed by us using a Ni63‐electron capture detector. 10 mg of diazepam was given intramuscularly to 37 patients during the first stage of labour 5‐401 min before delivery, after which blood samples were immediately collected from the umbilical cord and the maternal vein. Diazepam was found in all the plasma samples with very great individual variation in the concentrations. In one particular case, in which the delivery took place 5 minutes after the diazepam injection, the corresponding diazepam concentrations in the cord plasma and in the maternal plasma were 506 ng/ml and 504 ng/ml. In 31 cord plasma samples collected 26‐401 min after the diazepam injection the mean diazepam concentration was 70 ng/ml, and in the maternal plasma was 38 ng/ml. The average foetal/maternal concentration ratio during the same time period was 2.0 and in the whole series 1.8. Neither the diazepam concentrations in the cord plasma nor the foetal/maternal ratios of the concentrations had any significant influence on the Apgar scores of the newborns. The cause of the diazepam accumulation in the foetal circulation is unclear. The better binding of diazepam with the foetal plasma proteins is discussed. The importance of individual drug doses to parturients according to their weight is emphasized.

Human pharmacokinetics of nitrazepam: Effect of age and diseases

SummaryPlasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the β-phase half-life-mean 29 h in the young volunteers and 40 h in geriatric patients, and in the apparent volume of distribution during the β-phase of 2.4 vs 4.8 l/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the β-phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40–180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.

Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro

Several selective oestrogen receptor modulators (SERMs) with oestrogen agonist effects in bone cells and without increased risk of breast and endometrial cancer have been developed. Here, we have investigated the effects of different types of SERMs on osteoclast differentiation, bone resorption and apoptosis in vitro.

Comparison of two gas-liquid chromatographic methods for the determination of nitrazepam in plasma

Nitrazepam in plasma was determined by gas-liquid chromatography with a nickel-63 electron-capture detector, unchanged by a direct method and also by a hydrolysis method. The extraction in the direct method was carried out with benzenedichloromethane (90:10) and in the hydrolysis method with diethyl ether. The hydrolysis was performed with 6 N sulphuric acid. The hydrolysis product was extracted with toluene-n-heptane-ethyl acetate (80:20:5) directly from acid. Thus the commonly used change in pH was omitted. Nitrazepam concentrations in plasma were determined in 10 healthy volunteers after two oral doses (5 and 10 mg); 0.5 ml of plasma was used for each determination and clonazepam, methylbromazepam and methylnitrazepam were used as internal standards. The recoveries of the methods are almost quantitative (greater than 96%). The two methods are clinically comparable. The high sensitivity and specificity make these methods useful in clinical determinations of nitrazepam in plasma. Advantages and disadvantages of both methods are discussed.

Determination of nitrazepam and its main metabolites in urine by gas--liquid chromatography: use of electron capture and nitrogen-selective detectors.

Nitrazepam and its main urinary metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjugared, were determined from 24-h fractions of human urine after a single oral dose of 5 mg of nitrazepam. Nitrazepam and the metabolites were extracted before and after glusulase hydrolysis with benzene--dichloromethane (90:10) from a 1.0 ml sample. Methylnitrazepam and methylbromazepam served as internal standards. Recoveries were better than 90%. GLC analysis of nitrazepam was performed using a 63Ni electron-capture detector. The metabolites were measured by a dual flameless nitrogen selective detector. The detection limits were about 0.2 ng/ml for nitrazepam and 50 ng/ml for the metabolites. The nitrogen-selective detector responds similarly to all three compounds. The 63Ni electron-capture detector gives very poor response to 7-amino-nitrazepam but allows very sensitive detection of nitrazepam. Combined use of the two detectors gives valuable information about the metabolic profile of nitrazepam.

Midazolam versus atropine plus pethidine as premedication in children.

The effects of oral midazolam or intramuscular atropine and pethidine used as premedication in two groups of 35 children over 5 years of age were studied. There was some evidence that the anxiolytic effect of midazolam was rather better than that of atropine plus pethidine, but, in other respects, subjective assessments in the two patient groups were similar. Intramuscular atropine caused tachycardia and subjective side‐effects, nevertheless children appear to require anticholinergics during premedication because of excessive salivary secretion, especially during extubation. Oral midazolam is a new anxiolytic drug which can be used as an alternative to existing premedicant drugs, but, in children, it should still be combined with an anticholinergic agent. No correlation between serum levels of midazolam or atropine and their clinical effects was found.

Steroid receptors and response of ovarian cancer to hormones in vitro

Summary. Oestrogen receptor (ER) and progesterone receptor (PR) content and the response in vitro to tamoxifen (T), medroxyprogesterone acetate (MPA) and to a combination of the two hormones were determined in 21 epithelial ovarian carcinomas. The response was assessed by the level of adenosinetriphosphate in the cells. ER and PR were detected in 62% and 57%, respectively, with significant variations between the different histopathological cancer types. ER and PR predicted the response in vitro in 62% of the tumours exposed to the combined hormones, and in 38% and 33% of those exposed to T and MPA, respectively. The value of steroid‐receptor determinations in selecting the proper hormonal treatment in ovarian cancer is significantly reduced because of the high proportion of incorrect predictions.

Comparison of midazolam and flunitrazepam for night sedation. A randomised double-blind study.

In a double‐blind randomised study midazolam 15 mg and flunitrazepam 2 mg caused a significantly better nights sleep than placebo. Midazolam had a moderate sedative effect the following morning but, in other respects studied, no residual effects were found. In contrast, flunitrazepam decreased both the degree of apprehension and excitement the following morning. Flunitrazepam also inhibited salivary secretion and caused less cardiovascular changes than placebo or midazolam. The dose of thiopentone needed for induction of anaesthesia was significantly lower in those given flunitrazepam. The results show that midazolam is a potent sedative agent with a short duration of action.

Antidiuretic hormone concentrations following midazolam premedication

Midazolam given orally the night before and on the morning of operation had a distinct subjective pre‐operative sedative effect as compared with placebo. Patients receiving midazolam also experienced less apprehension and excitement before surgery, but in relation to quality of sleep, the difference between the two groups was not statistically significant. Antidiuretic hormone (ADH) concentrations were determined just before induction of anaesthesia and were significantly lower in the midazolam group (2.14 pg/ml, SD 0.96) than in the placebo group (3.07 pgjml, SD 1.73). Our results show that midazolam is a useful sedative anxiolytic oral premedicanl, which appears to prevent initiation of a stress reaction before induction of anaesthesia.