Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions.

OBJECTIVE: Incomplete compliance is one of several possible causes of uncontrolled hypertension. Yet, non-compliance remains largely unrecognized and is falsely interpreted as treatment resistance, because it is difficult to confirm or exclude objectively. The goal of this study was to evaluate the potential benefits of electronic monitoring of drug compliance in the management of patients with resistant hypertension. METHODS: Forty-one hypertensive patients resistant to a three-drug regimen (average blood pressure 156/ 106 +/- 23/11 mmHg, mean +/- SD) were studied prospectively. They were informed that for the next 2 months, their presently prescribed drugs would be provided in electronic monitors, without any change in treatment, so as to provide the treating physician with a measure of their compliance. Thereafter, patients were offered the possibility of prolonging the monitoring of compliance for another 2 month period, during which treatment was adapted if necessary. RESULTS: Monitoring of compliance alone was associated with a significant improvement of blood pressure at 2 months (145/97 +/- 20/15 mmHg, P < 0.01). During monitoring, blood pressure was normalized (systolic < 140 mmHg or diastolic < 90 mmHg) in one-third of the patients and insufficient compliance was unmasked in another 20%. When analysed according to tertiles of compliance, patients with the lowest compliance exhibited significantly higher achieved diastolic blood pressures (P = 0.04). In 30 patients, compliance was monitored up to 4 months and drug therapy was adapted whenever necessary. In these patients, a further significant decrease in blood pressure was obtained (from 150/100 +/- 18/15 to 143/94 +/- 22/11 mmHg, P = 0.04/0.02). CONCLUSIONS: These results suggest that objective monitoring of compliance using electronic devices may be a useful step in the management of patients with refractory hypertension, as it enables physicians to take rational decisions based on reliable and objective data of drug compliance and hence to improve blood pressure control.

Cardiovascular risk estimation and eligibility for statin therapy using different scoring systems in Europe: a population-based study in Switzerland

BACKGROUND: Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10- year CHD risk. We compared the 10-year CHD risk assessments and eligibility percentages for statin therapy using three scoring algorithms currently used in Europe. METHODS: We studied 5683 women and men, aged 35-75, without overt cardiovascular disease (CVD), in a population-based study in Switzerland. We compared the 10-year CHD risk using three scoring schemes, i.e., the Framingham risk score (FRS) from the U.S. National Cholesterol Education Program's Adult Treatment Panel III (ATP III), the PROCAM scoring scheme from the International Atherosclerosis Society (IAS), and the European risk SCORE for low-risk countries, without and with extrapolation to 60 years as recommended by the European Society of Cardiology guidelines (ESC). With FRS and PROCAM, high-risk was defined as a 10- year risk of fatal or non-fatal CHD>20% and a 10-year risk of fatal CVD≥5% with SCORE. We compared the proportions of high-risk participants and eligibility for statin use according to these three schemes. For each guideline, we estimated the impact of increased statin use from current partial compliance to full compliance on potential CHD deaths averted over 10 years, using a success proportion of 27% for statins. RESULTS: Participants classified at high-risk (both genders) were 5.8% according to FRS and 3.0% to the PROCAM, whereas the European risk SCORE classified 12.5% at high-risk (15.4% with extrapolation to 60 years). For the primary prevention of CHD, 18.5% of participants were eligible for statin therapy using ATP III, 16.6% using IAS, and 10.3% using ESC (13.0% with extrapolation) because ESC guidelines recommend statin therapy only in high-risk subjects. In comparison with IAS, agreement to identify eligible adults for statins was good with ATP III, but moderate with ESC. Using a population perspective, a full compliance with ATP III guidelines would reduce up to 17.9% of the 24′ 310 CHD deaths expected over 10 years in Switzerland, 17.3% with IAS and 10.8% with ESC (11.5% with extrapolation). CONCLUSIONS: Full compliance with guidelines for statin therapy would result in substantial health benefits, but proportions of high-risk adults and eligible adults for statin use varied substantially depending on the scoring systems and corresponding guidelines used for estimating CHD risk in Europe.

Task force IV: Clinical use of ambulatory blood pressure monitoring. Participants of the 1999 Consensus Conference on Ambulatory Blood Pressure Monitoring

OBJECTIVE: To reach a consensus on the clinical use of ambulatory blood pressure monitoring (ABPM). METHODS: A task force on the clinical use of ABPM wrote this overview in preparation for the Seventh International Consensus Conference (23-25 September 1999, Leuven, Belgium). This article was amended to account for opinions aired at the conference and to reflect the common ground reached in the discussions. POINTS OF CONSENSUS: The Riva Rocci/Korotkoff technique, although it is prone to error, is easy and cheap to perform and remains worldwide the standard procedure for measuring blood pressure. ABPM should be performed only with properly validated devices as an accessory to conventional measurement of blood pressure. Ambulatory recording of blood pressure requires considerable investment in equipment and training and its use for screening purposes cannot be recommended. ABPM is most useful for identifying patients with white-coat hypertension (WCH), also known as isolated clinic hypertension, which is arbitrarily defined as a clinic blood pressure of more than 140 mmHg systolic or 90 mmHg diastolic in a patient with daytime ambulatory blood pressure below 135 mmHg systolic and 85 mmHg diastolic. Some experts consider a daytime blood pressure below 130 mmHg systolic and 80 mmHg diastolic optimal. Whether WCH predisposes subjects to sustained hypertension remains debated. However, outcome is better correlated to the ambulatory blood pressure than it is to the conventional blood pressure. Antihypertensive drugs lower the clinic blood pressure in patients with WCH but not the ambulatory blood pressure, and also do not improve prognosis. Nevertheless, WCH should not be left unattended. If no previous cardiovascular complications are present, treatment could be limited to follow-up and hygienic measures, which should also account for risk factors other than hypertension. ABPM is superior to conventional measurement of blood pressure not only for selecting patients for antihypertensive drug treatment but also for assessing the effects both of non-pharmacological and of pharmacological therapy. The ambulatory blood pressure should be reduced by treatment to below the thresholds applied for diagnosing sustained hypertension. ABPM makes the diagnosis and treatment of nocturnal hypertension possible and is especially indicated for patients with borderline hypertension, the elderly, pregnant women, patients with treatment-resistant hypertension and patients with symptoms suggestive of hypotension. In centres with sufficient financial resources, ABPM could become part of the routine assessment of patients with clinic hypertension. For patients with WCH, it should be repeated at annual or 6-monthly intervals. Variation of blood pressure throughout the day can be monitored only by ABPM, but several advantages of the latter technique can also be obtained by self-measurement of blood pressure, a less expensive method that is probably better suited to primary practice and use in developing countries. CONCLUSIONS: ABPM or equivalent methods for tracing the white-coat effect should become part of the routine diagnostic and therapeutic procedures applied to treated and untreated patients with elevated clinic blood pressures. Results of long-term outcome trials should better establish the advantage of further integrating ABPM as an accessory to conventional sphygmomanometry into the routine care of hypertensive patients and should provide more definite information on the long-term cost-effectiveness. Because such trials are not likely to be funded by the pharmaceutical industry, governments and health insurance companies should take responsibility in this regard.

Importance of influx and efflux systems and xenobiotic metabolizing enzymes in intratumoral disposition of anticancer agents.

In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.

Adolescent substance-use assessment: methodological issues in the use of the Adolescent Drug Abuse Diagnosis (ADAD).

During the past twenty years, various instruments have been developed for the assessment of substance use in adolescents, mainly in the United States. However, few of them have been adapted to, and validated in, French-speaking populations. Consequently, although increasing alcohol and drug use among teenagers has become a major concern, the various health and social programs developed in response to this specific problem have received little attention with regard to follow-up and outcome assessment. A standardized multidimensional assessment instrument adapted for adolescents is needed to assess the individual needs of adolescents and assign them to the most appropriate treatment setting, to provide a single measurement within and across health and social systems, and to conduct treatment outcome evaluations. Moreover, having an available instrument makes it possible to develop longitudinal and transcultural research studies. For this reason, a French version of the Adolescent Drug Abuse Diagnosis (ADAD) was developed and validated at the University Child and Adolescent Psychiatric Clinic in Lausanne, Switzerland. This article aims to discuss the methodological issues that we faced when using the ADAD instrument in a 4-year longitudinal study including adolescent substance users. Methodological aspects relating to the content and format of the instrument, the assessment administration and the statistical analyses are discussed.

Clinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study.

BACKGROUND/AIMS: One of the causes of uncontrolled secondary hyperparathyroidism (sHPT) is patient's poor drug adherence. We evaluated the clinical benefits of an integrated care approach on the control of sHPT by cinacalcet. METHODS: Prospective, randomized, controlled, multicenter, open-label study. Fifty hemodialysis patients on a stable dose of cinacalcet were randomized to an integrated care approach (IC) or usual care approach (UC). In the IC group, cinacalcet adherence was monitored using an electronic system. Results were discussed with the patients in motivational interviews, and drug prescription adapted accordingly. In the UC group, drug adherence was monitored, but results were not available. RESULTS: At six months, 84% of patients in the IC group achieved recommended iPTH targets versus 55% in the UC group (P = 0.04). The mean cinacalcet taking adherence improved by 10.8% in the IC group and declined by 5.3% in the UC group (P = 0.02). Concomitantly, the mean dose of cinacalcet was reduced by 7.2 mg/day in the IC group and increased by 6.4 mg/day in the UC group (P = 0.03). CONCLUSIONS: The use of a drug adherence monitoring program in the management of sHPT in hemodialysis patients receiving cinacalcet improves drug adherence and iPTH control and allows a reduction in the dose of cinacalcet.

Ambulatory Blood Pressure and Adherence Monitoring: Diagnosing Pseudoresistant Hypertension.

A small proportion of the treated hypertensive population consistently has a blood pressure greater than 140/90 mm Hg despite a triple therapy including a diuretic, a calcium channel blocker, and a blocker of the renin-angiotensin system. According to guidelines, these patients have so-called resistant hypertension. The prevalence of this clinical condition is higher in tertiary than primary care centers and often is associated with chronic kidney disease, diabetes, obesity, and sleep apnea syndrome. Exclusion of pseudoresistant hypertension using ambulatory or home blood pressure monitoring is a crucial step in the investigation of patients with resistant hypertension. Thus, among the multiple factors to consider when investigating patients with resistant hypertension, ambulatory blood pressure monitoring should be performed very early. Among other factors to consider, physicians should investigate patient adherence to therapy, assess the adequacy of treatment, exclude interfering factors, and, finally, look for secondary forms of hypertension. Poor adherence to therapy accounts for 30% to 50% of cases of resistance to therapy depending on the methodology used to diagnose adherence problems. This review discusses the clinical factors implicated in the pathogenesis of resistant hypertension with a particular emphasis on pseudoresistance, drug adherence, and the use of ambulatory blood pressure monitoring for the diagnosis and management of resistant hypertension.

Suivi du patient après transplantation cardiaque: monitoring et adaptation de l'immunosuppression [Monitoring and adjustment of immunosuppression after heart transplantation].

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

A modular approach for integrative analysis of large-scale gene-expression and drug-response data

High-throughput technologies are now used to generate more than one type of data from the same biological samples. To properly integrate such data, we propose using co-modules, which describe coherent patterns across paired data sets, and conceive several modular methods for their identification. We first test these methods using in silico data, demonstrating that the integrative scheme of our Ping-Pong Algorithm uncovers drug-gene associations more accurately when considering noisy or complex data. Second, we provide an extensive comparative study using the gene-expression and drug-response data from the NCI-60 cell lines. Using information from the DrugBank and the Connectivity Map databases we show that the Ping-Pong Algorithm predicts drug-gene associations significantly better than other methods. Co-modules provide insights into possible mechanisms of action for a wide range of drugs and suggest new targets for therapy

Interest of qualitative and quantitative profiling of endocannabinoids for evaluation of their implication in drug addiction process

Introduction: In the middle of the 90's, the discovery of endogenous ligands for cannabinoid receptors opened a new era in this research field. Amides and esters of arachidonic acid have been identified as these endogenous ligands. Arachidonoylethanolamide (anandamide or AEA) and 2-Arachidonoylglycerol (2-AG) seem to be the most important of these lipid messengers. In addition, virodhamine (VA), noladin ether (2-AGE), and N-arachidonoyl dopamine (NADA) have been shown to bind to CB receptors with varying affinities. During recent years, it has become more evident that the EC system is part of fundamental regulatory mechanisms in many physiological processes such as stress and anxiety responses, depression, anorexia and bulimia, schizophrenia disorders, neuroprotection, Parkinson disease, anti-proliferative effects on cancer cells, drug addiction, and atherosclerosis. Aims: This work presents the problematic of EC analysis and the input of Information Dependant Acquisition based on hybrid triple quadrupole linear ion trap (QqQLIT) system for the profiling of these lipid mediators. Methods: The method was developed on a LC Ultimate 3000 series (Dionex, Sunnyvale, CA, USA) coupled to a QTrap 4000 system (Applied biosystems, Concord, ON, Canada). The ECs were separated on an XTerra C18 MS column (50 × 3.0 mm i.d., 3.5 μm) with a 5 min gradient elution. For confirmatory analysis, an information-dependant acquisition experiment was performed with selected reaction monitoring (SRM) as survey scan and enhanced produced ion (EPI) as dependant scan. Results: The assay was found to be linear in the concentration range of 0.1-5 ng/mL for AEA, 0.3-5 ng/mL for VA, 2-AGE, and NADA and 1-20 ng/mL for 2-AG using 0.5 mL of plasma. Repeatability and intermediate precision were found less than 15% over the tested concentration ranges. Under non-pathophysiological conditions, only AEA and 2-AG were actually detected in plasma with concentration ranges going from 104 to 537 pg/mL and from 2160 to 3990 pg/mL respectively. We have particularly focused our scopes on the evaluation of EC level changes in biological matrices through drug addiction and atherosclerosis processes. We will present preliminary data obtained during pilot study after administration of cannabis on human patients. Conclusion: ECs have been shown to play a key role in regulation of many pathophysiological processes. Medical research in these different fields continues to growth in order to understand and to highlight the predominant role of EC in the CNS and peripheral tissues signalisation. The profiling of these lipids needs to develop rapid, highly sensitive and selective analytical methods.

Electronic monitoring of compliance to lipid-lowering therapy in clinical practice

Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6-month course of lipid-lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 x 40 mg daily, provided in a MEMS package to record the date and time of each opening of the pillbox. Thirty-nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6-month therapy period. A high mean rate of compliance was achieved by MEMS using the following three indexes--compliance to total prescribed dose (88.8% +/- 13.5%), compliance to prescribed days (82.4% +/- 19.5%), and compliance to prescribed time of day (81.86% +/- 19.5%)--and by pill count (93.4% +/- 9.5%). In addition, the MEMS provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS. The results indicate that MEMS is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long-term lipid-lowering therapy.

Adolescent substance-use assessment: methodological issues in the use of the ADAD (Adolescent Drug Abuse Diagnosis).

During the past twenty years, various instruments have been developed for the assessment of substance use in adolescents, mainly in the United States. However, few of them have been adapted to, and validated in, French-speaking populations. Consequently, although increasing alcohol and drug use among teenagers has become a major concern, the various health and social programs developed in response to this specific problem have received little attention with regard to follow-up and outcome assessment. A standardized multidimensional assessment instrument adapted for adolescents is needed to assess the individual needs of adolescents and assign them to the most appropriate treatment setting, to provide a single measurement within and across health and social systems, and to conduct treatment outcome evaluations. Moreover, having an available instrument makes it possible to develop longitudinal and trans-cultural research studies. For this reason, a French version of the Adolescent Drug Abuse Diagnosis (ADAD) was developed and validated at the University Child and Adolescent Psychiatric Clinic in Lausanne, Switzerland. This paper aims to discuss the methodological issues that we faced when using the ADAD instrument in a 4-year longitudinal study including adolescent substance users. Methodological aspects relating to the content and format of the instrument, the assessment administration and the statistical analyses are discussed.

L'hémisphérotomie péri-insulaire: technique chirurgicale, monitoring EEG intraopératoire et résultats sur le contrôle de l'épilepsie [Periinsular hemispherotomy: surgical technique, intraoperative EEG monitoring and results on seizure outcome]

Peri-insular hemispherotomy is a surgical technique used in the treatment of drug-resistant epilepsy of hemispheric origin. It is based on the exposure of insula and semi-circular sulci, providing access to the lateral ventricle through a supra- and infra-insular window. From inside the ventricle, a parasagittal callosotomy is performed. The basal and medial portion of the frontal lobe is isolated. Projections to the anterior commissure are interrupted at the time of amygdala resection. The hippocampal tail and fimbria-fornix are disrupted posteriorly. We report our experience of 18 cases treated with this approach. More than half of them presented with congenital epilepsy. Neuronavigation was useful in precisely determining the center and extent of the craniotomy, as well as the direction of tractotomies and callosotomy, allowing minimal exposure and blood loss. Intra-operative monitoring by scalp EEG on the contralateral hemisphere was used to follow the progression of the number of interictal spikes during the disconnection procedure. Approximately 90% of patients were in Engel's Class I. We observed one case who presented with transient postoperative neurological deterioration probably due to CSF overdrainage and documented one case of incomplete disconnection in a patient presenting with hemimegalencephaly who needed a second operation. We observed a good correlation between a significant decrease in the number of spikes at the end of the procedure and seizure outcome. Peri-insular hemispherotomy provides a functional disconnection of the hemisphere with minimal resection of cerebral tissue. It is an efficient technique with a low complication rate. Intra-operative EEG monitoring might be used as a predictive factor of completeness of the disconnection and consequently, seizure outcome.

Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance.

Thanks to decades of research, gait analysis has become an efficient tool. However, mainly due to the price of the motion capture systems, standard gait laboratories have the capability to measure only a few consecutive steps of ground walking. Recently, wearable systems were proposed to measure human motion without volume limitation. Although accurate, these systems are incompatible with most of existing calibration procedures and several years of research will be necessary for their validation. A new approach consisting of using a stationary system with a small capture volume for the calibration procedure and then to measure gait using a wearable system could be very advantageous. It could benefit from the knowledge related to stationary systems, allow long distance monitoring and provide new descriptive parameters. The aim of this study was to demonstrate the potential of this approach. Thus, a combined system was proposed to measure the 3D lower body joints angles and segmental angular velocities. It was then assessed in terms of reliability towards the calibration procedure, repeatability and concurrent validity. The dispersion of the joint angles across calibrations was comparable to those of stationary systems and good reliability was obtained for the angular velocities. The repeatability results confirmed that mean cycle kinematics of long distance walks could be used for subjects' comparison and pointed out an interest for the variability between cycles. Finally, kinematics differences were observed between participants with different ankle conditions. In conclusion, this study demonstrated the potential of a mixed approach for human movement analysis.