Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator

AIMS: The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. METHODS: The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. RESULTS: Levormeloxifene was tolerated well after single doses in the range of 2.5--320 mg and multiple once daily dosing in the range of 20--160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20--160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19--25% and 28--35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2--3 h), a slow elimination (mean t1/2: 4.8--8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3--5). CONCLUSIONS: Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.     

Expectations of treatment and satisfaction with dentofacial appearance in orthodontic patients.

The aim of this study was to investigate correlations between satisfaction with dental and facial appearance and expectations of orthodontic treatment. The effects of sex and age on these variables were also explored. A sample of 154 patients who applied for orthodontic treatment at the Academic Centre of Dentistry Amsterdam, The Netherlands, completed 2 questionnaires, containing 16 items on satisfaction with facial appearance and 23 items on expectations of orthodontic treatment. First, the structure of the questionnaires was analyzed. Next, correlations between patients' expectations, satisfaction with facial appearance, age, and sex were examined. A multiple regression analysis was used to estimate the effect of the initial facial satisfaction on expectations of orthodontic treatment. Principal components analysis of the questionnaire about expectations showed 4 factors with an Eigenvalue greater than 1, accounting for 72% of the total variance. These were defined as "general well-being," "self-image/appearance," "future dental health," and "oral function." We found that "satisfaction with facial appearance" could be divided into 2 factors, each with an Eigenvalue greater than 1, accounting for 64% of the total variance. These were interpreted as "general facial appearance" and "dental appearance." Significant correlations were found between satisfaction with dental appearance and patients' expectations. These correlations were invariant over gender, but not over age. It was concluded that satisfaction with dental appearance is a significant predictor of orthodontic patients' expectations of treatment.     

Persistent vacuous chewing in rats following neuroleptic treatment: relationship to dopaminergic and cholinergic function

In order to relate the effects of pharmacological intervention to neuroleptic induced increases in oral activity rats were treated continuously (7 mg/kg per week) or discontinuously (7 mg/kg per week or 2 mg/kg per week) with haloperidol for 6 months. Only the two intermittently treated groups developed persisting increases in vacuous chewing movements (VCM) following drug withdrawal. Opposed to control animals and continuously treated rats, the discontinuously treated groups demonstrated significant elevation in mouth movements following stimulation with the dopamine (DA) D₁ receptor agonist SK&F 38393 (23 mg/kg), whereas they did not response to an acute challenge with the selective DA D₁ receptor antagonist NNC-756 (0.1 mg/kg). The DA D₂ receptor antagonist raclopride (1 mg/kg) provoked a general fall in VCM; however, this was only significant in rats treated intermittently with haloperidol 7 mg/kg per week and in control rats. Intermittent neuroleptic treatment also increased apomorphine-induced stereotypy. The effect of challenge with the anticholinergic drug scopolamine (0.25 mg/kg) was not related to oral activity; furthermore, the finding of severe agitation in rats tested with the latter drug points to caution in the interpretation of rating of rats treated with anticholinergics. These results support that intermittent ingestion of neuroleptic drugs lead to long-lasting increases in VCM. They also suggest a relation of persisting elevated oral activity to supersensitivity to DA receptor agonists, as opposed to subsensitivity to D₁ receptor antagonists.     

Perceived self-efficacy gained from, and health effects of, a rehabilitation program after hip joint replacement

OBJECTIVE: To examine whether a routine multidisciplinary inpatient rehabilitation program can increase patient self-efficacy, and to investigate the effects of high self-efficacy at admission, and increases in self-efficacy, on health changes in patients who undergo such rehabilitation after hip joint replacement. METHODS: Participants in this longitudinal study were 1,065 patients who underwent inpatient rehabilitation after hip joint replacement. Questionnaires were administered at admission, discharge, and 6-month followup. The main outcome variables were disability, pain, depressive symptomatology, and self-efficacy to cope with disability and pain. RESULTS: Significant improvements from admission to discharge from the inpatient rehabilitation program in disability, pain, depressive symptoms, and self-efficacy were found. In addition, higher levels of self-efficacy at admission and larger increases in self-efficacy over the course of the program predicted larger health changes (i.e., greater decreases in disability, pain, and depressive symptoms). Results were generally similar for health changes from discharge to 6-month followup. CONCLUSION: A routine multidisciplinary inpatient rehabilitation program after hip joint replacement can result in enhanced self-efficacy.     

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.     

Adaptation of diverse lyme disease spirochetes in a natural rodent reservoir host

We compared the relative reservoir competence of European wood mice for two genospecies of Lyme disease spirochetes by analyzing susceptibility, intrinsic incubation period, and degree and duration of infectivity. Borrelia afzelii, specializing in particular reservoir hosts, is better adapted to those hosts than is the more generalist genospecies B. burgdorferi sensu stricto.     

Influence of routes and administration parameters on antibody response of pigs following DNA vaccination

Using the nucleoprotein of porcine reproductive and respiratory syndrome virus as model antigen, we optimised parameters for gene gun vaccination of pigs, including firing pressure and vaccination site. As criteria for optimisation, we characterised particle penetration and local tissue damage by histology. For selected combinations, vaccination efficiency in terms of antibody response was studied. Gene gun vaccination on ear alone was as efficient as a multi-site (ear, thorax, inguinal area, tongue mucosa) gene gun approach, and more efficient than combined intramuscular (i.m.)/intradermal (i.d.) injection of plasmid DNA. This indicates, that the ear is an attractive site for gene gun vaccination of pigs.