Annales chirurgiae et gynaecologiae. Supplementum, 1985
Specimens from freshly biopsied human mammary and ovarian tumours and DMBA-induced rat mammary tu... more Specimens from freshly biopsied human mammary and ovarian tumours and DMBA-induced rat mammary tumours were transplanted under the renal capsule of normal, immunocompetent mice and rats. The growth of the tumour and the effects of chemotherapy to the host animals were evaluated by measuring the growth of the implanted tumour specimens. Morphological analysis of the tumours showed preserved histological structures and cellular function, as evidenced by the basement membrane component production seen using immunohistochemical stains and by the surface specialized structures, cell-to-cell contact and secretory activity observed in ultrastructural studies. Treatments with different types of drugs yielded tangible results within 6 days of transplantation, showing lymphoid infiltration and scar formation, but preserved vascular structures. The results suggest that tumours subjected to subrenal capsule assay retain their structure and function when transplanted, thus enabling the evaluatio...
International journal of clinical pharmacology, therapy, and toxicology, 1982
In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedicatio... more In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedication before minor surgery, 50 patients received placebo, an 50 patients no premedication. Both tofizopam and placebo significantly increased the subjective sedative effect of the patients, but there was no significant difference in any of the measured parameters between tofizopam and placebo. In another double-blind randomized study, 49 patients received 100 mg tofizopam three times orally before gynecologic operations and 49 patients received placebo. Compared with placebo, tofizopam had a stimulant action and decreased the excitement of the patients. The effect of tofizopam on apprehension + excitement was significantly better than that of placebo. According to these results, the active component seems to be an unknown metabolite of tofizopam causing a clear drug effect only after repeated oral doses of the parent drug. A slow accumulation in the central nervous system is also possible. I...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1995
Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxife... more Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking fo...
Diazepam (tensopam@) 10 mg was given orally t o 12 chronic alcoholic patients, at the beginning o... more Diazepam (tensopam@) 10 mg was given orally t o 12 chronic alcoholic patients, at the beginning of the alcohol-free period and to 14 controls. Diazepam in the plasma was determined gaschromatographically with a B3Ni-EC detector. During the absorption phase the plasma levels of diazepam were reduced to 44 % at 2 hours (P < 0.01) and 32 % at 3.5 hours (P < 0.001) in alcoholic patients compared with respective values of normal subjects. The reduced values, found in the alcoholic patients, may be due to disturbances in the gastro-intestinal absorption of diazepam, or to processes involving the portal vein or liver. Some alcoholic patients received a simultaneous treatment with neuroleptic or hypnotic drugs.
The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after... more The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r = 0.472, P less than 0.001, n = 97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P less than 0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P less than 0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nit...
Nitrazepam and its main metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjug... more Nitrazepam and its main metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjugated, were determined in the human urine after a single oral dose of 5 mg. The determinations were performed by GLC method using 63Ni-EC-detector for unchanged nitrazepam and nitrogen selective detector for the metabolites. Unchanged nitrazepam was poorly eliminated through the kidneys (about 1% of the dose). The interindividual variation of total excreted urinary metabolites was large ranging between 848-4933 microgram (17-99% of the dose during 7 days). Of this amount conjugated metabolites made up 57%. The urinary half-lives of free and conjugated-7-aminonitrazepam were (mean and ranges) 44 (23-65) and 46 (25-69) hrs, and of 7-acetamidonitrazepam 12 (5-31) and 18 (5-46) hrs, respectively. The half-lives of the excreted amounts of the metabolites did not correlate with any pharmacokinetic parameter of unchanged nitrazepam in serum.
International journal of clinical pharmacology and biopharmacy, 1979
The clinical effects of oxazepam and diazepam as oral premedicants were tested in a double-blind ... more The clinical effects of oxazepam and diazepam as oral premedicants were tested in a double-blind study of 60 children and 50 adults. The gas chromatographically measured concentrations of the active unconjugated forms of oxazepam and diazepam in the plasma were correlated to their clinical effects, as assessed both subjectively and objectively (sleep, sedation, apprehension, excitement, dizziness, emetic effect, headache, increase or decrease in systolic blood pressure, increase in pulse rate, venepuncture). No significant difference in the effects of these two benzodiazepine derivatives were observed, nor was there any obvious relationship between the plasma concentration and clinical effect.
The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination... more The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination of three hypnotic and 6 benzodiazepine drugs was compared in vitro. In comparison to haemodialysis the efficacy of ultrafiltration by CSU was poor, as the mean per cent of CSU/haemodialysis (mg/hr) for 5 benzodiazepines was only 0.6-4.0% and for three hypnotics, phenobarbital 3.4%, pyrithyldione 8.2% and glutethimide 2.5% of the haemodialysis values. In haemodialysis in vitro phenobarbital, pyrithyldione, glutethimide and chlordiazepoxide were significantly and markedly more dialysable than 5 other benzodiazepines. The mean clearance of six benzodiazepine derivatives was about 2 to 3 times higher at blood flow rates of 200 ml/min. than 100 ml/min. In CSU experiments in vitro it was possible to remove approximately (as the mean percent of the initial dose) only the amount of five benzodiazepines corresponding to the per cent of the protein unbound fraction in the plasma (correlation r = ...
International journal of clinical pharmacology, therapy, and toxicology, 1982
By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation an... more By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation and 1 mg on the morning of operation (group 1), and another 41 received 100 mg pentobarbital orally the night before operation, followed by intramuscular scopolamine (0.006 mg/kg) + morphine (0.02 mg/kg) on the morning of operation (group 2). All patients received 0.5 mg atropine intravenously just before the induction of anesthesia. The patients in group 2 were better sedated and had less salivary secretion than those in group 1, but otherwise both were comparable. In group 2 the induction requirements of thiopentone were significantly decreased in comparison with group 1, again indicating a more potent sedative effect. Because even in the total scoring of the results there was no significant difference between the two groups, the easy oral route of administration of flunitrazepam offers a clinically relevant alternative to the conventional premedication. In some of these E.N.T. patients ...
Acta pathologica et microbiologica Scandinavica. Section C, Immunology, 1978
The effect of a single halothane anaesthesia on the secondary antibody response and the lymphocyt... more The effect of a single halothane anaesthesia on the secondary antibody response and the lymphocyte response in vitro to phytohaemagglutinin (PHA) and concanavalin A(Con A) was studied. The antigens used were bovine serum albumin (BSA) and killed Brucella abortus organisms (Brucella). IgG and IgM antibodies against these antigens were quantified by solid-phase radioimmunoassay. Lymphocyte transformation was studied by a whole blood micromethod. The chickens were anaesthetised for two hours with 2% v/v halothane. The halothane concentration of the blood was measured by gas chromatography at the end of the anaesthesia. Halothane anaesthesia had no effect on the secondary antibody response against BSA and Brucella. In contrast, it caused a significant decrease in the lymphocyte response to PHA and Con A. This suppression was transient, however, and full recovery of the lymphocyte function was observed by the first day after anaesthesia.
International journal of clinical pharmacology and biopharmacy, 1979
The concentrations of dapsone (DDS) and its acetylated derivatives (MADDS and DADDS) were determi... more The concentrations of dapsone (DDS) and its acetylated derivatives (MADDS and DADDS) were determined in the serum and saliva after one oral dose of dapsone until 72 hr. The peak serum concentrations of DDS and MADDS were reached, on average, at 3.8--4.3 hr after the dosage. The amounts of DADDS were negligible. The elimination half-life of the first order kinetics was, on average, at 20--21 hr for both DDS and MADDS. The study group included 6 rapid acetylators and 4 slow acetylators with the mean ratios MADDS/DDS 1.0 and 0.19, respectively. No difference in the pharmacokinetics of DDS or MADDS could be seen between the rapid and slow acetylators. The protein-free fractions of DDS and MADDS were 50 and 41 per cent, respectively, of the total serum concentrations as measured at 8 and 32 hr after the dosage. The salivary concentration of DDS was, on average, 49 per cent of the total serum concentration during the whole study period. The salivary concentration of MADDS was 40 per cent,...
Plasma and cerebrospinal-fluid (CSF) concentrations of diazepam, its main metabolite, N-demethyld... more Plasma and cerebrospinal-fluid (CSF) concentrations of diazepam, its main metabolite, N-demethyldiazepam, and free oxazepam were studied gas chromatographically in 49 patients suffering from neurological diseases, after a 10 mg intramuscular dose of diazepam. These determinations were made in three other patients after repeated intramuscular doses of 10 mg diazepam. In seven of the patients both free and plasma protein-bound diazepam, and N-demethyldiazepam were determined by ultracentrifugation after a single dose of 10 mg intramuscular diazepam. After a single dose of diazepam there was only 2-3 % of the total plasma concentration of diazepam and 1-4 % of that of N-demethyldiazepam in the CSF. After repeated doses of diazepam the same values were 3 % and 4 %, respectively. The plasma protein binding capacity of diazepam was 98 % and that of N-demethyldiazepam 97 %. Free diazepam and N-demethyldiazepam concentrations in the plasma were in equilibrium with their CSF concentrations. No accumulation of diazepam and N-demethyldiazepam could be found in the CSF. No free oxazepam was found.
The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied i... more The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied in postmenopausal women volunteers primed for 7 days with estradiol valerate (2 mg daily orally) which was continued throughout the study. A control group received estrogen only and a reference group estrogen with 60 mg tamoxifen for 5 days. No treatment opposed the action of the estrogen on the endometrium but both 68 mg toremifene and 60 mg tamoxifen statistically significantly decreased the maturity index of vaginal cells on day 13. A decrease was also evident on day 18 with 20 mg toremifene.
We previously reported the occurrence and function of plasma membrane estrogen receptors in cultu... more We previously reported the occurrence and function of plasma membrane estrogen receptors in cultured bovine adrenal medullary cells. Here we report the effects of raloxifene and tamoxifen, selective estrogen receptor modulators, on plasma membrane estrogen receptors and catecholamine synthesis and secretion in these cells. Raloxifene caused dual effects on the specific binding of [ 3 H]17b-estradiol to the plasma membranes isolated from bovine adrenal medulla; that is, it had a stimulatory effect at 1.0-10 nM but an inhibitory effect at 1.0-10 mM, whereas tamoxifen (1.0 nM-10 mM) increased binding at all concentrations (except for 100 nM). Tamoxifen at 100 nM caused a significant increase in basal 14 C-catecholamine synthesis from [ 14 C]tyrosine, whereas tamoxifen and raloxifene at higher concentrations attenuated basal and acetylcholine-induced 14 C-catecholamine synthesis. Raloxifene (0.3, 1.0, and 3-100 mM) and tamoxifen (10-100 mM) also suppressed catecholamine secretion and 45 Ca 2+ and 22 Na + influx, respectively, induced by acetylcholine. Raloxifene (1.0 mM) inhibited Na + current evoked by acetylcholine in Xenopus oocytes expressing a4b2 neuronal nicotinic acetylcholine receptors. The present findings suggest that raloxifene and tamoxifen at low concentrations allosterically modulate plasma membrane estrogen receptors and at high concentrations inhibit acetylcholineinduced catecholamine synthesis and secretion by inhibiting Na + and Ca 2+ influx in bovine adrenal medulla.
The concentrations of nitrazepam in the plasma and cerebrospinal-fluid (CSF) of 38 neurological p... more The concentrations of nitrazepam in the plasma and cerebrospinal-fluid (CSF) of 38 neurological patients were determined by gas chromatography 2-36 hours after a single 5 mg oral dose. The percentage ratio between the mean CSF and the plasma concentrations increased from 8.0% at 2 hours to 15.6% at 36 hours. This percentage rise was significant (P less than 0.001). The maximum concentration of nitrazepam in the plasma was 36.7 +/- 5.7 ng/ml (at 2 hours) and CSF 3.0 +/- 0.3 ng/ml (at 4 hours). During the beta-phase the half-life of nitrazepam in plasma was about 27 hours and in the CSF markedly longer about 68 hours, indicating a very slow elimination of nitrazepam from the CSF.
Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats ... more Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10,20, or 40 mg/kg) and toremifene (TOR; 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells a...
Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxife... more Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking for lathosterol by toremifene. Plant sterols and cholestanol were only inconsistently increased in serum. Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.
The Journal of Steroid Biochemistry and Molecular Biology, 2004
To investigate the differential short-term effects of selective estrogen receptor (ER) modulators... more To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.
Annales chirurgiae et gynaecologiae. Supplementum, 1985
Specimens from freshly biopsied human mammary and ovarian tumours and DMBA-induced rat mammary tu... more Specimens from freshly biopsied human mammary and ovarian tumours and DMBA-induced rat mammary tumours were transplanted under the renal capsule of normal, immunocompetent mice and rats. The growth of the tumour and the effects of chemotherapy to the host animals were evaluated by measuring the growth of the implanted tumour specimens. Morphological analysis of the tumours showed preserved histological structures and cellular function, as evidenced by the basement membrane component production seen using immunohistochemical stains and by the surface specialized structures, cell-to-cell contact and secretory activity observed in ultrastructural studies. Treatments with different types of drugs yielded tangible results within 6 days of transplantation, showing lymphoid infiltration and scar formation, but preserved vascular structures. The results suggest that tumours subjected to subrenal capsule assay retain their structure and function when transplanted, thus enabling the evaluatio...
International journal of clinical pharmacology, therapy, and toxicology, 1982
In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedicatio... more In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedication before minor surgery, 50 patients received placebo, an 50 patients no premedication. Both tofizopam and placebo significantly increased the subjective sedative effect of the patients, but there was no significant difference in any of the measured parameters between tofizopam and placebo. In another double-blind randomized study, 49 patients received 100 mg tofizopam three times orally before gynecologic operations and 49 patients received placebo. Compared with placebo, tofizopam had a stimulant action and decreased the excitement of the patients. The effect of tofizopam on apprehension + excitement was significantly better than that of placebo. According to these results, the active component seems to be an unknown metabolite of tofizopam causing a clear drug effect only after repeated oral doses of the parent drug. A slow accumulation in the central nervous system is also possible. I...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 1995
Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxife... more Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking fo...
Diazepam (tensopam@) 10 mg was given orally t o 12 chronic alcoholic patients, at the beginning o... more Diazepam (tensopam@) 10 mg was given orally t o 12 chronic alcoholic patients, at the beginning of the alcohol-free period and to 14 controls. Diazepam in the plasma was determined gaschromatographically with a B3Ni-EC detector. During the absorption phase the plasma levels of diazepam were reduced to 44 % at 2 hours (P < 0.01) and 32 % at 3.5 hours (P < 0.001) in alcoholic patients compared with respective values of normal subjects. The reduced values, found in the alcoholic patients, may be due to disturbances in the gastro-intestinal absorption of diazepam, or to processes involving the portal vein or liver. Some alcoholic patients received a simultaneous treatment with neuroleptic or hypnotic drugs.
The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after... more The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r = 0.472, P less than 0.001, n = 97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P less than 0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P less than 0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nit...
Nitrazepam and its main metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjug... more Nitrazepam and its main metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjugated, were determined in the human urine after a single oral dose of 5 mg. The determinations were performed by GLC method using 63Ni-EC-detector for unchanged nitrazepam and nitrogen selective detector for the metabolites. Unchanged nitrazepam was poorly eliminated through the kidneys (about 1% of the dose). The interindividual variation of total excreted urinary metabolites was large ranging between 848-4933 microgram (17-99% of the dose during 7 days). Of this amount conjugated metabolites made up 57%. The urinary half-lives of free and conjugated-7-aminonitrazepam were (mean and ranges) 44 (23-65) and 46 (25-69) hrs, and of 7-acetamidonitrazepam 12 (5-31) and 18 (5-46) hrs, respectively. The half-lives of the excreted amounts of the metabolites did not correlate with any pharmacokinetic parameter of unchanged nitrazepam in serum.
International journal of clinical pharmacology and biopharmacy, 1979
The clinical effects of oxazepam and diazepam as oral premedicants were tested in a double-blind ... more The clinical effects of oxazepam and diazepam as oral premedicants were tested in a double-blind study of 60 children and 50 adults. The gas chromatographically measured concentrations of the active unconjugated forms of oxazepam and diazepam in the plasma were correlated to their clinical effects, as assessed both subjectively and objectively (sleep, sedation, apprehension, excitement, dizziness, emetic effect, headache, increase or decrease in systolic blood pressure, increase in pulse rate, venepuncture). No significant difference in the effects of these two benzodiazepine derivatives were observed, nor was there any obvious relationship between the plasma concentration and clinical effect.
The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination... more The efficacy of haemodialysis and controlled sequential ultrafiltration (CSU) for the elimination of three hypnotic and 6 benzodiazepine drugs was compared in vitro. In comparison to haemodialysis the efficacy of ultrafiltration by CSU was poor, as the mean per cent of CSU/haemodialysis (mg/hr) for 5 benzodiazepines was only 0.6-4.0% and for three hypnotics, phenobarbital 3.4%, pyrithyldione 8.2% and glutethimide 2.5% of the haemodialysis values. In haemodialysis in vitro phenobarbital, pyrithyldione, glutethimide and chlordiazepoxide were significantly and markedly more dialysable than 5 other benzodiazepines. The mean clearance of six benzodiazepine derivatives was about 2 to 3 times higher at blood flow rates of 200 ml/min. than 100 ml/min. In CSU experiments in vitro it was possible to remove approximately (as the mean percent of the initial dose) only the amount of five benzodiazepines corresponding to the per cent of the protein unbound fraction in the plasma (correlation r = ...
International journal of clinical pharmacology, therapy, and toxicology, 1982
By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation an... more By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation and 1 mg on the morning of operation (group 1), and another 41 received 100 mg pentobarbital orally the night before operation, followed by intramuscular scopolamine (0.006 mg/kg) + morphine (0.02 mg/kg) on the morning of operation (group 2). All patients received 0.5 mg atropine intravenously just before the induction of anesthesia. The patients in group 2 were better sedated and had less salivary secretion than those in group 1, but otherwise both were comparable. In group 2 the induction requirements of thiopentone were significantly decreased in comparison with group 1, again indicating a more potent sedative effect. Because even in the total scoring of the results there was no significant difference between the two groups, the easy oral route of administration of flunitrazepam offers a clinically relevant alternative to the conventional premedication. In some of these E.N.T. patients ...
Acta pathologica et microbiologica Scandinavica. Section C, Immunology, 1978
The effect of a single halothane anaesthesia on the secondary antibody response and the lymphocyt... more The effect of a single halothane anaesthesia on the secondary antibody response and the lymphocyte response in vitro to phytohaemagglutinin (PHA) and concanavalin A(Con A) was studied. The antigens used were bovine serum albumin (BSA) and killed Brucella abortus organisms (Brucella). IgG and IgM antibodies against these antigens were quantified by solid-phase radioimmunoassay. Lymphocyte transformation was studied by a whole blood micromethod. The chickens were anaesthetised for two hours with 2% v/v halothane. The halothane concentration of the blood was measured by gas chromatography at the end of the anaesthesia. Halothane anaesthesia had no effect on the secondary antibody response against BSA and Brucella. In contrast, it caused a significant decrease in the lymphocyte response to PHA and Con A. This suppression was transient, however, and full recovery of the lymphocyte function was observed by the first day after anaesthesia.
International journal of clinical pharmacology and biopharmacy, 1979
The concentrations of dapsone (DDS) and its acetylated derivatives (MADDS and DADDS) were determi... more The concentrations of dapsone (DDS) and its acetylated derivatives (MADDS and DADDS) were determined in the serum and saliva after one oral dose of dapsone until 72 hr. The peak serum concentrations of DDS and MADDS were reached, on average, at 3.8--4.3 hr after the dosage. The amounts of DADDS were negligible. The elimination half-life of the first order kinetics was, on average, at 20--21 hr for both DDS and MADDS. The study group included 6 rapid acetylators and 4 slow acetylators with the mean ratios MADDS/DDS 1.0 and 0.19, respectively. No difference in the pharmacokinetics of DDS or MADDS could be seen between the rapid and slow acetylators. The protein-free fractions of DDS and MADDS were 50 and 41 per cent, respectively, of the total serum concentrations as measured at 8 and 32 hr after the dosage. The salivary concentration of DDS was, on average, 49 per cent of the total serum concentration during the whole study period. The salivary concentration of MADDS was 40 per cent,...
Plasma and cerebrospinal-fluid (CSF) concentrations of diazepam, its main metabolite, N-demethyld... more Plasma and cerebrospinal-fluid (CSF) concentrations of diazepam, its main metabolite, N-demethyldiazepam, and free oxazepam were studied gas chromatographically in 49 patients suffering from neurological diseases, after a 10 mg intramuscular dose of diazepam. These determinations were made in three other patients after repeated intramuscular doses of 10 mg diazepam. In seven of the patients both free and plasma protein-bound diazepam, and N-demethyldiazepam were determined by ultracentrifugation after a single dose of 10 mg intramuscular diazepam. After a single dose of diazepam there was only 2-3 % of the total plasma concentration of diazepam and 1-4 % of that of N-demethyldiazepam in the CSF. After repeated doses of diazepam the same values were 3 % and 4 %, respectively. The plasma protein binding capacity of diazepam was 98 % and that of N-demethyldiazepam 97 %. Free diazepam and N-demethyldiazepam concentrations in the plasma were in equilibrium with their CSF concentrations. No accumulation of diazepam and N-demethyldiazepam could be found in the CSF. No free oxazepam was found.
The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied i... more The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied in postmenopausal women volunteers primed for 7 days with estradiol valerate (2 mg daily orally) which was continued throughout the study. A control group received estrogen only and a reference group estrogen with 60 mg tamoxifen for 5 days. No treatment opposed the action of the estrogen on the endometrium but both 68 mg toremifene and 60 mg tamoxifen statistically significantly decreased the maturity index of vaginal cells on day 13. A decrease was also evident on day 18 with 20 mg toremifene.
We previously reported the occurrence and function of plasma membrane estrogen receptors in cultu... more We previously reported the occurrence and function of plasma membrane estrogen receptors in cultured bovine adrenal medullary cells. Here we report the effects of raloxifene and tamoxifen, selective estrogen receptor modulators, on plasma membrane estrogen receptors and catecholamine synthesis and secretion in these cells. Raloxifene caused dual effects on the specific binding of [ 3 H]17b-estradiol to the plasma membranes isolated from bovine adrenal medulla; that is, it had a stimulatory effect at 1.0-10 nM but an inhibitory effect at 1.0-10 mM, whereas tamoxifen (1.0 nM-10 mM) increased binding at all concentrations (except for 100 nM). Tamoxifen at 100 nM caused a significant increase in basal 14 C-catecholamine synthesis from [ 14 C]tyrosine, whereas tamoxifen and raloxifene at higher concentrations attenuated basal and acetylcholine-induced 14 C-catecholamine synthesis. Raloxifene (0.3, 1.0, and 3-100 mM) and tamoxifen (10-100 mM) also suppressed catecholamine secretion and 45 Ca 2+ and 22 Na + influx, respectively, induced by acetylcholine. Raloxifene (1.0 mM) inhibited Na + current evoked by acetylcholine in Xenopus oocytes expressing a4b2 neuronal nicotinic acetylcholine receptors. The present findings suggest that raloxifene and tamoxifen at low concentrations allosterically modulate plasma membrane estrogen receptors and at high concentrations inhibit acetylcholineinduced catecholamine synthesis and secretion by inhibiting Na + and Ca 2+ influx in bovine adrenal medulla.
The concentrations of nitrazepam in the plasma and cerebrospinal-fluid (CSF) of 38 neurological p... more The concentrations of nitrazepam in the plasma and cerebrospinal-fluid (CSF) of 38 neurological patients were determined by gas chromatography 2-36 hours after a single 5 mg oral dose. The percentage ratio between the mean CSF and the plasma concentrations increased from 8.0% at 2 hours to 15.6% at 36 hours. This percentage rise was significant (P less than 0.001). The maximum concentration of nitrazepam in the plasma was 36.7 +/- 5.7 ng/ml (at 2 hours) and CSF 3.0 +/- 0.3 ng/ml (at 4 hours). During the beta-phase the half-life of nitrazepam in plasma was about 27 hours and in the CSF markedly longer about 68 hours, indicating a very slow elimination of nitrazepam from the CSF.
Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats ... more Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10,20, or 40 mg/kg) and toremifene (TOR; 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells a...
Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxife... more Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism. The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography. Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking for lathosterol by toremifene. Plant sterols and cholestanol were only inconsistently increased in serum. Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.
The Journal of Steroid Biochemistry and Molecular Biology, 2004
To investigate the differential short-term effects of selective estrogen receptor (ER) modulators... more To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.
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Papers by L. Kangas