Determinants, consequences and potential solutions to poor adherence to anti-osteoporosis treatment: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Osteoporosis Foundation (IOF).

Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions. INTRODUCTION: Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication. METHODS: A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken. RESULTS: Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few interventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it. CONCLUSION: These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions.

ESPACOMP Medication Adherence Reporting Guidelines (EMERGE): a reactive-Delphi study protocol.

INTRODUCTION: Medication adherence is fundamental to achieving optimal patient outcomes. Reporting research on medication adherence suffers from some issues-including conceptualisation, measurement and data analysis-that thwart its advancement. Using the ABC taxonomy for medication adherence as the conceptual basis, a steering committee of members of the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) launched an initiative to develop ESPACOMP Medication Adherence Reporting Guidelines (EMERGE). This paper is a protocol for a Delphi study that aims to build consensus among a group of topic experts regarding an item list that will support developing EMERGE. METHODS AND ANALYSIS: This study uses a reactive-Delphi design where a group of topic experts will be asked to rate the relevance and clarity of an initial list of items, in addition to suggesting further items and/or modifications of the initial items. The initial item list, generated by the EMERGE steering committee through a structured process, consists of 26 items distributed in 2 sections: 4 items representing the taxonomy-based minimum reporting criteria, and 22 items organised according to the common reporting sections. A purposive sample of experts will be selected from relevant disciplines and diverse geographical locations. Consensus will be achieved through predefined decision rules to keep, delete or modify the items. An iterative process of online survey rounds will be carried out until consensus is reached. ETHICS AND DISSEMINATION: An ethics approval was not required for the study according to the Swiss federal act on research involving human beings. The participating experts will be asked to give an informed consent. The results of this Delphi study will feed into EMERGE, which will be disseminated through peer-reviewed publications and presentations at conferences. Additionally, the steering committee will encourage their endorsement by registering the guidelines at the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network and other relevant organisations.

Commentary on "A Framework for Quantifying the Influence of Adherence and Dose Individualization".

Drugs that provide long durations of action after a last-taken dose are said to be "forgiving," as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,(1) based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug.

Methods for measuring, enhancing, and accounting for medication adherence in clinical trials.

Adherence to rationally prescribed medications is essential for effective pharmacotherapy. However, widely variable adherence to protocol-specified dosing regimens is prevalent among participants in ambulatory drug trials, mostly manifested in the form of underdosing. Drug actions are inherently dose and time dependent, and as a result, variable underdosing diminishes the actions of trial medications by various degrees. The ensuing combination of increased variability and decreased magnitude of trial drug actions reduces statistical power to discern between-group differences in drug actions. Variable underdosing has many adverse consequences, some of which can be mitigated by the combination of reliable measurements of ambulatory patients' adherence to trial and nontrial medications, measurement-guided management of adherence, statistically and pharmacometrically sound analyses, and modifications in trial design. Although nonadherence is prevalent across all therapeutic areas in which the patients are responsible for treatment administration, the significance of the adverse consequences depends on the characteristics of both the disease and the medications.

Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.

We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.

Effects on blood pressure and cardiovascular risk of variations in patients' adherence to prescribed antihypertensive drugs: role of duration of drug action.

AIM: To determine the effects of imperfect adherence (i.e. occasionally missing prescribed doses), and the influence of rate of loss of antihypertensive effect during treatment interruption, on the predicted clinical effectiveness of antihypertensive drugs in reducing mean systolic blood pressure (SBP) and cardiovascular disease (CVD) risk. METHOD: The effects of imperfect adherence to antihypertensive treatment regimens were estimated using published patterns of missed doses, and taking into account the rate of loss of antihypertensive effect when doses are missed (loss of BP reduction in mmHg/day; the off-rate), which varies between drugs. Outcome measures were the predicted mean SBP reduction and CVD risk, determined from the Framingham Risk Equation for CVD. RESULTS: In patients taking 75% of prescribed doses (typical of clinical practice), only long-acting drugs with an off-rate of ∼1 mmHg/day were predicted to maintain almost the full mean SBP-lowering effect throughout the modelled period. In such patients, using shorter-acting drugs (e.g. an off-rate of ∼5-6 mmHg/day) was predicted to lead to a clinically relevant loss of mean SBP reduction of > 2 mmHg. This change also influenced the predicted CVD risk reduction; in patients with a baseline 10-year CVD risk of 27.0% and who were taking 75% of prescribed doses, a difference in off-rate from 1 to 5 mmHg/day led to a predicted 0.5% absolute increase in 10-year CVD risk. CONCLUSIONS: In patients who occasionally miss doses of antihypertensives, modest differences in the rate of loss of antihypertensive effect following treatment interruption may have a clinically relevant impact on SBP reduction and CVD risk. While clinicians must make every effort to counsel and encourage each of their patients to adhere to their prescribed medication, it may also be prudent to prescribe drugs with a low off-rate to mitigate the potential consequences of missing doses.

Risedronate dosing before breakfast compared with dosing later in the day in women with postmenopausal osteoporosis.

UNLABELLED: Two studies in postmenopausal women with osteoporosis provide information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, smaller increases in lumbar spine BMD were observed with flexible dosing versus before-breakfast dosing. Geographic region, compliance, and consistency of dosing time appear to affect the amount of increase in BMD observed with flexible dosing. INTRODUCTION: Two studies in postmenopausal women with osteoporosis provide additional information about the efficacy and safety of dosing oral risedronate 5 mg daily at a time other than before breakfast (i.e., 2 h before and 2 h after any food and drink other than plain water). METHODS: One study, flexible dosing, was a 6-month North American study in 730 patients randomized to before-breakfast dosing or flexible dosing later in the day. A second study, IMPACT, was a large (N = 2382), 1-year multinational study in patients that chose their dosing regimen (before breakfast or later in the day). These studies were used to examine the bone mineral density (BMD) response with different dosing regimens. RESULTS: A significant increase in lumbar spine BMD was observed for both treatment regimens in the two studies. However, in both studies, the flexible dosing group had a smaller increase from baseline compared to the before-breakfast regimen (ratio of flexible dosing to before breakfast: flexible dosing study, 0.52; IMPACT study, 0.75). In addition, a relationship between geographic region and BMD response was observed with flexible dosing in both studies. Patients in the flexible dosing group who had greater dosing compliance (based on the number of times the bottle was opened) and consistency of dosing time (bottle opened within a 1.5-h window) had a greater increase in lumbar spine BMD. CONCLUSION: Results of these two studies demonstrate that overall flexible dosing of risedronate leads to smaller BMD gains compared to before-breakfast dosing. This result may be due to poorer adherence to the flexible dosing instructions that may be more pronounced in patients in certain geographic regions. If patients cannot abide by before-breakfast dosing and flexible dosing is an approved option, one can expect suboptimal BMD results with flexible dosing.

Probabilistic intake assessment and body burden estimation of dioxin-like substances in background conditions and during a short food contamination episode.

The objective was to perform a dioxin body burden estimate based on a probabilistic intake assessment of PCDDs, PCDFs and dioxin-like PCBs because of the so-called 1999 'Belgian dioxin incident'. Monte Carlo simulation techniques were used to combine detailed 7-day food intake data on the individual level from a sample of 14-18-year-old adolescents with 'background' and 'incident-related' food contamination data. In background conditions, 3% of the adolescents had an intake <1 pg TEQ kg(-1) bw day(-1), while 85% had <4 pg TEQ kg(-1) bw day(-1). Milk and other dairy products were the basic source of dioxin-like contaminants, while fish constituted the main source at the higher percentiles of intake. During the dioxin incident, the estimated median dioxin intake showed a moderate increase. At the 99th percentile, the highest intake level, and the 95% upper bound uncertainty level, peak body burden-23.73 ng TEQ kg(-1) bw-remained below body burdens that in the experimental animal or in man are accompanied by a population-based observable increase in the incidence of adverse effects. The 1999 Belgian dioxin incident most likely did not affect public health in Belgium in a measurable way, although exceptions remain possible on the individual level.

Non-infectious factors associated with macroscopic and microscopic lung lesions in slaughter pigs from farrow-to-finish herds.

A cross-sectional epidemiological study was conducted in 150 randomly selected farrow-to-finish herds to investigate which non-infectious factors might act as risk indicators for the prevalence and severity of macroscopic and microscopic lung lesions in slaughter pigs. Data were collected during herd visits through inspections of the pigs and through interviews with the farmers. Macroscopic lung lesions of pneumonia and pleuritis were recorded at slaughter from 25 pigs per herd, and microscopic lung lesions of lymphohistiocytic infiltration were recorded from 10 pigs per herd. The median herd level prevalences were 24 per cent for pneumonia, 16 per cent for pleuritis and 60 per cent for lymphohistiocytic infiltration. Pneumonia lesions were negatively associated with pleuritis lesions and positively associated with lymphohistiocytic infiltration. Pleuritis lesions were negatively associated with lymphohistiocytic infiltration. The prevalence and the severity of pneumonia lesions were increased by a high frequency of purchasing gilts and by a slaughter date in January to February. The presence of a growing unit also increased the severity of pneumonia. The prevalence and the severity of pleuritis lesions were higher when there were more pig herds in the municipality, and when there were poor biosecurity measures, and their prevalence was increased by a slaughter date in January to February, and their severity by a slaughter date in March to April. An increase in the airspace stocking density in the finishing unit also increased the prevalence of pleuritis. The prevalence and the severity of lymphohistiocytic infiltration in the lung tissue were higher in herds purchasing gilts. Pigs raised in pens with slatted floors were also at higher risk of more severe lesions of lymphohistiocytic infiltration.

Herd factors associated with the seroprevalences of four major respiratory pathogens in slaughter pigs from farrow-to-finish pig herds.

The objective of this study was to investigate sero-epidemiological aspects of Mycoplasma hyopneumoniae (Mh), influenza H1N1 and H3N2 viruses and Aujeszky disease virus (ADV) in fattening pigs from 150 randomly selected farrow-to-finish pig herds. Different herd factors were examined as potential risk indicators for the percentage of pigs with antibodies against the 4 pathogens. The median within-herd seroprevalences of the pathogens were: Mh 76%, H1N1 100%, H3N2 40% and ADV 53%. There was a positive association between the seroprevalences of both influenza viruses, and a negative association between the seroprevalences of ADV and H1N1. The percentage of pigs seropositive for Mh increased with the purchase of gilts and with the season (slaughter date in March-April). The within-herd seroprevalences of both influenza viruses were higher in the case of a higher density of pig herds in the municipality. A higher number of fattening pigs per pen additionally increased the risk of being seropositive for H3N2. The percentage of pigs with anti-gE-antibodies against the wild type ADV increased with higher airspace stocking density in the finishing unit, increasing herd size, increasing number of pig herds in the municipality and slaughter date in March-April. Increased seroprevalences for these 4 respiratory pathogens were mostly associated with pig density in the herd and its vicinity, the winter period, and with the purchase of gilts. Purchase of gilts, number of fattening pigs per pen and airspace stocking density are risk factors that can be managed directly by farmers striving to attain a high respiratory health status of pigs.

Risk indicators for the seroprevalence of Mycoplasma hyopneumoniae, porcine influenza viruses and Aujeszky's disease virus in slaughter pigs from fattening pig herds.

Epidemiological aspects of Mycoplasma hyopneumoniae (Mh), influenza H1N1 and H3N2 viruses, and Aujeszky's disease virus (ADV) were investigated in slaughter pigs from 50 fattening pig herds. Herd factors as potential risk indicators for respiratory disease were obtained by means of a questionnaire. At slaughter, blood samples were collected from each herd, and the proportion of seropositive pigs per herd was assessed for each of these pathogens. The median herd-level seroprevalence of the agents were: Mh 88%, H1N1 100%, H3N2 60% and ADV 90%. The percentage of herds in which all investigated fattening pigs were seronegative for these agents was: Mh 0%, H1N1 0%, H3N2 12% and ADV 18%. The percentage of herds in which all investigated fattening pigs were seropositive for these agents was: Mh 8%, H1N1 71%, H3N2 22% and ADV 40%. A positive association was found between influenza H1N1 and H3N2 viruses, and a negative association between influenza H3N2 virus and ADV. There were no risk indicators for the seroprevalence of Mh. Three risk indicators were associated with the seroprevalence of influenza H1N1 virus: a fully slatted floor, an increasing number of pigs in the municipality and dry feeding. Three risk indicators were found for the seroprevalence of influenza H3N2 virus: purchase of pigs from > or = two herds, an increasing number of pigs in the municipality and natural ventilation. The seroprevalence of ADV was influenced by two risk indicators: an increasing number of pig herds in the municipality and an increasing number of pigs per pen.

Effect of vaccination against Mycoplasma hyopneumoniae in pig herds with an all-in/all-out production system.

A multi-site field study was conducted to evaluate an inactivated Mycoplasma hyopneumoniae (Mh) vaccine in 14 pig herds infected by Mh and practising an all-in/all-out production system. In each herd, a vaccinated and control group of 250 pigs each were compared during the growing/finishing period with respect to performance parameters (major variables) and by means of clinical, serological and pathological parameters (ancillary variables). Mh vaccination significantly (P < 0.05) improved daily weight gain (+22 g), feed conversion ratio (-0.07), medication costs (-0.476 ECU/pig) (1 ECU = US$1.0269542), prevalence of pneumonia lesions (-14%) and severity of pneumonia lesions (-3%). Mortality rate, severity of coughing and carcass quality were not significantly influenced by Mh vaccination. Serological results of Mh and other respiratory pathogens are presented and discussed. A cost-benefit analysis based on significantly improved performance parameters demonstrated that Mh vaccination was economically attractive as it resulted in an increase of the net return to labour with 1.300 ECU per finishing pig sold. The sensitivity of the economic benefit was illustrated towards fluctuations in pig finishing prices.

The impact of compliance in pharmacokinetic studies.

In population pharmacokinetic (PK) studies, one observes just a few concentration measures spread out in time, on a sizable sample of the target population. Common-sense dictates that for estimation of a drug exposure-plasma concentration relationship, one needs accurate information on drug intake history besides the concentration measures. The population PK literature is well aware of this. Studies of simulated compliance behaviour have helped quantify the problem with naive compliance estimators and pointed towards a solution. In this paper we look at actually observed compliance patterns recorded via electronic monitoring. We simulate a documented pharmacokinetic model from the hypertensive literature on top of these and come to some interesting findings. In this clinical trial the problem of noncompliance is much more dramatic than simulated compliance patterns suggested so far. The systematic errors made by compliance naive estimators can be corrected when using timing explicit hierarchical nonlinear models and accurate information on a number of previous dose timings. When it is possible to observe irregular drug intake times in a well-controlled study, a substantial amount of precision is retrieved from the same number of data points. In general, the estimators of PK parameters benefit greatly from information that enters through greater variation in the drug-exposure process. Here we find support for the claim that noncompliance as a rich natural experiment of dosing variation can be a blessing rather than a curse from the information/learning point of view.

The effect of vaccination against Mycoplasma hypopneumoniae in pig herds with a continuous production system.

An inactivated Mycoplasma hyopneumoniae vaccine was evaluated in five pig herds clinically infected with enzootic pneumonia and practising a continuous production system in the growing/finishing unit. In each herd, a vaccinated and control group of approximately 47 pigs each were individually monitored from birth until slaughter. Vaccinated pigs received the first dose at about 1 week of age and the second approximately 3 weeks later. During all production stages, an equal number of vaccinated and control pigs was present in the same pen. Both groups were compared with respect to zootechnical parameters (major variables) and by means of serological, pathological, and bacteriological parameters (ancillary variables). Daily weight gain was improved by 14 gr/day during the period from 8 days of age until slaughter (P = 0.0486) and by 25 gr/day during the growing/finishing period (P = 0.0067). Mortality rate, and the costs for curative medication were not significantly improved by vaccination. The results of the ancillary variables are presented and discussed.

Comparing compliance patterns between randomized treatments.

When two equally efficacious drugs enter the market, the one with the better compliance is likely to be more widely used. Special management of the delivery may produce increased compliance. In this paper we analyze a trial of a single drug dosing prescription with patients randomized to either daily self monitoring of the outcome (blood pressure) or not. The study used Medication Event Monitoring Systems (MEMS) to record each exact time and date when a patient opened the pill container. No established method is available for comparing these high-dimensional compliance patterns between groups. This paper investigates several summary measures that highlight different dimensions of the pattern and the drug context in which they may be meaningful. Further, we examine conditional and marginal models that enable comparisons of the full pattern of daily dosing indicators for subjects between the groups. We found no simple difference in average compliance levels, but we found an interesting interaction between treatment and time: similar compliance existed initially among patients in both randomized groups, with a stronger decline over time for patients who did not monitor their blood pressure. We discuss how a balance between simplicity of interpretation and efficiency of data use may be sought in this case.

Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50.

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.

Psychological approaches during conscious sedation. Hypnosis versus stress reducing strategies: a prospective randomized study.

Stress reducing strategies are useful in patients undergoing surgery. Hypnosis is also known to alleviate acute and chronic pain. We therefore compared the effectiveness of these two psychological approaches for reducing perioperative discomfort during conscious sedation for plastic surgery. Sixty patients scheduled for elective plastic surgery under local anesthesia and intravenous sedation (midazolam and alfentanil upon request) were included in the study after providing informed consent. They were randomly allocated to either stress reducing strategies (control: CONT) or hypnosis (HYP) during the entire surgical procedure. Both techniques were performed by the same anesthesiologist (MEF). Patient behavior was noted during surgery by a psychologist, the patient noted anxiety, pain, perceived control before, during and after surgery, and postoperative nausea and vomiting (PONV). Patient satisfaction and surgical conditions were also recorded. Peri- and postoperative anxiety and pain were significantly lower in the HYP group. This reduction in anxiety and pain were achieved despite a significant reduction in intraoperative requirements for midazolam and alfentanil in the HYP group (alfentanil: 8.7 +/- 0.9 microg kg(-1)/h(-1) vs. 19.4 +/- 2 microg kg(-1)/h(-1), P < 0.001; midazolam: 0.04 +/- 0.003 mg kg(-1)/h(-1) vs. 0.09 +/- 0.01 mg kg(-1)/h(-1), P < 0.001). Patients in the HYP group reported an impression of more intraoperative control than those in the CONT group (P < 0.01). PONV were significantly reduced in the HYP group (6.5% vs. 30.8%, P < 0.001). Surgical conditions were better in the HYP group. Less signs of patient discomfort and pain were observed by the psychologist in the HYP group (P < 0.001). Vital signs were significantly more stable in the HYP group. Patient satisfaction score was significantly higher in the HYP group (P < 0.004). This study suggests that hypnosis provides better perioperative pain and anxiety relief, allows for significant reductions in alfentanil and midazolam requirements, and improves patient satisfaction and surgical conditions as compared with conventional stress reducing strategies support in patients receiving conscious sedation for plastic surgery.

Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro.

The effect of four KATP channel openers (KCOs) on the firing rate of CA1 pyramidal cells and A10 dopaminergic neurons was investigated using extracellular recording techniques in rat brain slices. Pinacidil, lemakalim, diazoxide and a new compound, BPDZ44, had an inhibitory effect on the electrical activity of CA1 pyramidal cells. They all had a similar potency. Only BPDZ44 and diazoxide inhibited the firing rate of A10 dopamine neurons. The sulfonylurea glipizide (1 microM) antagonized the effect of BPDZ44 and diazoxide on A10 neurons but failed to antagonize the effect of KCOs on CA1 pyramidal cells. These results show that differences exist among KCOs in their ability to decrease the electrical activity of various populations of central neurons.

Effect of propofol on in vitro lipid peroxidation induced by different free radical generating systems: a comparison with vitamin E.

Propofol has been reported to have antioxidant properties and to inhibit lipid peroxidation. In this study, we examined the ability of propofol to inhibit lipid peroxidation induced by three free radical systems (hydroxyl, ferryl, and oxo-ferryl radicals), and we compared the effect of propofol with that of vitamin E, an endogenous antioxidant. Lipid peroxidation was induced by exposing a linoleic acid emulsion to either water gamma radiation, a ferrous iron-ascorbate solution, or human hemoglobin, generating the hydroxyl, ferryl, and oxo-ferryl radicals, respectively. Each experiment was performed in triplicate with and without propofol or vitamin E at concentrations between 10(-5) and 10(-4) M. Lipid peroxidation was quantified by gas chromatography measurement of the pentane released (nmoles) from lipid decomposition. In each condition, a significant dose-response relationship was found between the release of pentane and the concentration of either propofol or vitamin E. The antioxidant activities of both agents were similar but significantly higher against the hydroxyl than the ferryl and oxo-ferryl radicals. The study suggests that propofol could be beneficial as an anesthetic or sedative drug in patients presenting pathologies associated with free radical reactions.

Plasma concentration of estradiol following transdermal administration of Systen 50 or Menorest 50.

Circulating levels of 17 beta estradiol (E2) following the administration of fixed doses of E2, show a great variability in kinetics depending upon the product administrated, the routes of administration, and the interindividual variations in absorption and metabolism. This might have important implications both in terms of tolerance and effectiveness. Two new forms of transdermal E2 (SYSTEN Cilag and MENOREST Rhone-Poulenc Rorer) have been recently accepted in Europe for the treatment of climacteric symptoms. The present study was undertaken to compare the pharmacokinetic characteristics of plasma E2 profile under these two drugs. It was carried out in 30 healthy postmenopausal volunteers according to good clinical practice after informed consent, as a single blind, randomised, cross-over study during the classical wearing period of 4 days. Plasma E2 concentration was determined 24 hours before, 1/2 hour before and then 2, 4, 8, 12, 24, 48, 72, 84, 96 hours after the first patch administration. E2 measurement was performed using a specific direct radioimmunoassay developed in the FRH laboratories. The main criteria for this method were an intraassay coefficient of variation (CV) less than 6%, an interassay CV less than 8% in a concentration range of 15-140 pg/ml and a quantitative detection limit (LOQ) of 2.7 pg/ml with a 20% CV. The following kinetic parameters were analysed: C(max), C(mean), C96 and MRT. The bioequivalence was assessed by analysis of variance of C(max), C(mean), C96 and AuC after logarithmic transformation, complemented by Westlake test (95%). Data show that these two products are identical in terms of C(max) but C(mean), C96 and AuC are statistically greater when MENOREST 50(R) is administered; furthermore, E2 levels decrease more rapidly and more deeply with SYSTEN 50 than MENOREST 50. The differences of pharmacokinetic profiles after administration of two different forms of the same dose of 50 micrograms transdermal 17 beta estradiol might have important medical consequences.