Risto Lammintausta

Medetomidine — a novel α2-adrenoceptor agonist: A review of its pharmacodynamic effects

Abstract 1. 1. The pharmacodynamic effects of medetomidine, a novel α2-adrenoceptor agonist, are reviewed. 2. 2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to α2-adrenoceptors. Its α 2 α 2 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at α2-adrenoceptors, a fact that also distinguishes it from clonidine. 3. 3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques. 4. 4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects. 5. 5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific α2-antagonists. 6. 6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at α2-adrenoceptors.

Effects of ospemifene and raloxifene on biochemical markers of bone turnover in postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2–4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.

Transfer of propranolol and sotalol across the human placenta: Their effect on maternal and fetal plasma renin activity

Abstract. Eighty milligrams of propranolol or sotalol was administered orally to two groups of 8 parturients who were to undergo elective cesarean section. This was performed 3 hours after drug administration. The transplacental passage of both drugs was registered in each patient. The maternal concentration of propranolol was approximately four times that in the umbilical circulation, while the sotalol level in maternal circulation was twice that in the umbilical circulation. The administration of beta‐adrenoceptor antagonists caused a significant decrease in maternal plasma renin activity. After these doses of beta blockers, no difference in the plasma renin activity was found in the umbilical circulation, when compared with the previous normal values at cesarean section.

Renin-angiotensin--aldosterone system and sodium in normal pregnancy: a longitudinal study.

Abstract. Plasma renin activity, the concentration of angiotensin I and the urinary excretion of aldosterone and sodium were studied longitudinally in 10 healthy primigravidae from the 10th week of pregnancy monthly until the 7th puerperal day. Plasma renin activity and angiotensin I levels were significantly elevated throughout pregnancy and showed maximal mean values at the 10th week, gradually returning to the level of nonpregnant women 7 days after delivery. They daily urinary excretion of aldosterone was also increased throughout pregnancy, but the mean values showed an increasing trend until 34th week. They returned to nonpregnant levels 7 days after delivery. There were no significant changes in the urinary excretion of sodium during pregnancy but the mean value was lower than in the nonpregnant control group. There was a significant positive correlation between urinary aldosterone and sodium values, while an almost significant negative correlation existed between urinary aldosterone and plasma renin activity, suggesting the priority of natriuresis in the regulation of aldosterone secretion during pregnancy. No correlation was found between plasma renin activity and urinary sodium excretion values.

The effect of estriol succinate therapy on plasma renin activity and urinary aldosterone in postmenopausal women

The effects of estriol succinate (Synapause, 2 mg daily) on the renin-aldosterone system and blood pressure (RR) were studied in 14 postmenopausal women after bilateral oophorectomy. Plasma renin activity (PRA) and daily urinary aldosterone excretion (dU-Ald) were determined 1 mth after the operation and before estrogen treatment, at the end of 2 mth therapy, and, for the third time, 2 mth after the termination of treatment with the drug. No changes in PRA, dU-Ald or RR were found in normotensive women, or in 3 women with hypertension in this group. Another group of 11 postmenopausal women was investigated after long-term estriol succinate therapy, which had lasted for 5-8 yr after oophorectomy. PRA, dU-Ald and RR were measured during treatment and 2 mth after terminating the therapy. No changes were found either in hormone differences in the mean levels of PRA or dU-Ald. The results suggest that estriol succinate is devoid of general harmful effects on the renin-aldosterone system during postmenopausal therapy for climacteric symptoms.

Desmethylselegiline, a Metabolite of Selegiline, Is an Irreversible Inhibitor of Monoamine Oxidase Type B in Humans

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO‐B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO‐B. This study investigated the inhibitory potential of MAO‐B and the pharmacokinetics of desmethylselegiline in humans. A double‐blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO‐B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO‐B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO‐B by both compounds. Desmethylselegiline caused a 63.7 ± 12.7% inhibition of platelet MAO‐B compared with 96.4 ± 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 ± 20 hours) than after selegiline administration (tmax, 1.4 ± 1.4 hours). The platelet MAO‐B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48‐hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration—time curve from time 0 to 24 hours (AUC0–24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO‐B and could possibly be used to treat Parkinsons disease in the same way as selegiline.

Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause

Ospemifene is a unique tissue-selective estrogen agonist/antagonist (also known as a selective estrogen receptor modulator [SERM]) with demonstrated efficacy in Phase 3 studies of postmenopausal women with vulvar and vaginal atrophy (VVA). This report describes preclinical studies on the effects of ospemifene in the ovariectomized (OVX) rat model of menopause. Ospemifene (10mg/kg/day) and the SERM comparator, raloxifene (10mg/kg/day) were administered for 2 weeks and both increased vaginal weight; ospemifene was more effective than raloxifene. In addition, ospemifene had a greater effect on increasing vaginal epithelial height compared with raloxifene. The effect on uterine weight was less pronounced for both ospemifene and raloxifene. The ED50 of ospemifene on vaginal epithelial height was 0.39mg/kg/day and the magnitude was nearly the same as was seen with the positive control, 17α-ethinyl estradiol (EE2). In a histological analysis of ospemifene-treated rat vaginas, basal cells were overlaid by 2 to 3 cell layers of thickened goblet-like mucified cells apically; however, the cornification observed with EE2 was absent. Estrogenic activity of ospemifene was confirmed by upregulation of progesterone receptors in vaginal epithelium and stroma. Ospemifene showed similar affinity for estrogen receptor (ER)-α and ER-β, but an overall lower affinity than estradiol. Ospemifene antagonized estrogen response element (ERE)-mediated transactivation on MCF-7 cells, confirming its anti-estrogenic activity in breast cancer cells. The dose response for ospemifene in the rat is consistent with that observed in clinical studies of ospemifene 30 and 60mg, showing that the OVX rat is a highly predictive model of SERM activity in postmenopausal VVA.

The effect of normal labor on the renin-angiotensin system in mother and fetus

Plasma renin activity (PRA) and angiotensin I concentration (AI) in mother, umbilical vessels, and amniotic fluid were measured during 11 elective cesarean sections and after 12 normal labors. During cesarean section, PRA and AI were significantly lower in umbilical vessels than in mother or in amniotic fluid. This finding reflects the steady state in the late pregnancy. PRA and AI were significantly higher in the umbilical vessels after normal labor in comparison to the levels of cesarean section. In the mother there was no difference in PRA after normal labor and during cesarean section, but AI was significantly higher after normal labor. After normal labor no difference of PRA between mother, umbilical vessels, and amniotic fluid was found. The rise of fetal PRA and AI as a reaction to uterine contractions may be of great importance in ensuring the fetoplacental circulation during the labor.

Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations.

Abstract Background: The metabolism of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, was investigated as part of its development. Methods: Metabolite identification, tentative quantitation, and CYP assignment of ospemifene were performed in human liver microsomes or homogenate incubations and in plasma samples from volunteer humans. The potential contributions of CYP enzymes were determined by recombinant human CYPs. Metabolite identification and tentative quantification were performed by liquid chromatography-mass spectrometry. Results: The relative abundances of metabolites produced were dependent on ospemifene concentration and liver preparation, but the largest quantities of 4- and 4′-hydroxy-ospemifene (and their glucuronides in smaller quantities) were produced in human liver microsomes at low ospemifene concentrations. Other metabolites were detected in in vitro incubation with human liver including a direct glucuronide of ospemifene and some metabolites with only minor abundance. In human plasma samples, 4-hydroxy-ospemifene was the most abundant metabolite, representing about 25% of the abundance of the parent compound. All the other metabolites detected in plasma, including 4′-hydroxy-ospemifene, represented <7% of the abundance of ospemifene. Several CYP enzymes participated in 4-hydroxylation, including CYP2C9, CYP2C19, CYP2B6, and CYP3A4, whereas CYP3A enzymes were the only ones to catalyze 4′-hydroxylation. Conclusions: In vitro incubations with liver preparations provided a rather reliable starting point in the search for potential metabolites in clinical settings. The in vitro metabolite profile is informative for the in vivo metabolite profile, especially regarding the major hydroxylated metabolites. However, it is anticipated that extended in vivo exposures may result in an increased production of more distal metabolites from major metabolites.

Oral bioavailability of ospemifene improves with food intake.

OBJECTIVE To assess the effect of concomitant food intake on the relative bioavailability of ospemifene and its main metabolite, 4-hydroxyospemifene, after single oral dosing. METHODS This was an open-label, randomized, balanced, two-treatment (fed vs. fasted), two-period, two-sequence cross-over study in 24 healthy male subjects. Single 60-mg doses of ospemifene were administered without food or with a high-fat, high-energy breakfast (860 kcal). In an extension study, a single 60-mg dose of ospemifene was given to 12 subjects with a low-fat, light breakfast (300 kcal). Additional information was acquired by determining tablet dissolution profiles in media which reflected fasted and fed intestinal conditions. RESULTS The AUC0-72 h and Cmax of ospemifene were 2.8- and 3.6-fold higher after a high-fat breakfast and 1.9- and 2.3-fold higher after a low-fat breakfast when compared with an overnight fast. The variability in both primary pharmacokinetic parameters was considerably reduced (by up to 50%) with a meal, indicating more consistent absorption of ospemifene with concomitant food intake. Dissolution in conditions simulating fed intestinal fluid (high bile acid concentration) was increased 3-fold compared with dissolution in simulated fasted intestinal fluid. CONCLUSIONS wood markedly enhanced the extent and predictability of ospemifene absorption. The increase in bioavailability was not linearly related with the fat content of the meal. In vitro dissolution results were consistent with these clinical observations. Administration with food enhances and standardizes the oral bioavailability of ospemifene. Thus, it is recommended that ospemifene tablets should be taken with food.