Drug adherence and psychological factors in patients with apparently treatment-resistant hypertension: Yes but which ones?

The aim of the study was to assess drug adherence, as well as association of psychological factors with both drug adherence and severity of hypertension in two subtypes of patients with apparently treatment-resistant hypertension (ATRH): younger patients with uncomplicated hypertension (YURHTN) versus patients ≥60-year-old and/or with a history of cardio- or cerebrovascular complication (OCRHTN). Drug adherence was assessed in urine by targeted Liquid Chromatography-Mass Spectrometry. The severity of hypertension was assessed by 24-h ambulatory blood pressure adjusted for the number of antihypertensive drugs and for drug adherence. Psychological profile was assessed using five validated questionnaires. The proportion of totally non-adherent patients was three times higher (24.1 vs. 7.1%, P = 0.026) in the YURHTN (n = 54) than in OCRHTN subgroup (n = 43). Independent predictors of drug adherence in YURHTN were ability to use adaptive strategies, male sex and family history of hypertension, accounting for 39% of variability in drug adherence. In the same subgroup, independent predictors of severity of hypertension were somatization and lower recourse to planification, accounting for 40% of variability in the severity of hypertension. In contrast, in the OCRHTN subgroup, independent predictors of drug adherence and severity of hypertension were limited to the number of yearly admissions to the emergency room and the total number of prescribed drugs. In conclusion, poor drug adherence and altered psychological profiles appear to play a major role in younger patients with ATRH devoid of cardiovascular complication. This subgroup should be prioritized for chemical detection of drug adherence and psychological evaluation.

Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications.

BACKGROUND: Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients. OBJECTIVES: To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. METHODS: Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account. RESULTS: Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction. CONCLUSIONS: Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.

Psychological determinants of drug adherence and severity of hypertension in patients with apparently treatment-resistant vs. controlled hypertension.

PURPOSE: In a pilot study including 35 patients with apparently treatment-resistant hypertension (ATRH), we documented associations between psychological profile, drug adherence and severity of hypertension. The current study aims to confirm and expand our findings in a larger and more representative sample of patients with ATRH, using controlled hypertensive patients as the comparator. MATERIALS AND METHODS: Patients with ATRH were enrolled in hypertension centres from Brussels and Torino. The psychological profile was assessed using five validated questionnaires. Drug adherence was assessed by high-performance liquid chromatography-tandem mass spectrometry analysis of urine samples, and drug resistance by 24-hour ambulatory blood pressure was adjusted for drug adherence. RESULTS: The study sample totalised 144 patients, including 81 ATRH and 63 controlled hypertensive patients. The mean adherence level was significantly lower in the "resistant" group (78.9% versus 92.7% in controlled patients, p-value = .022). In patients with ATRH, independent predictors of poor drug adherence were somatisation, smoking and low acceptance level of difficult situations, accounting for 41% of the variability in drug adherence. Independent predictors of severity of hypertension were somatisation, smoking, more frequent admissions to the emergency department and low acceptation, accounting for 63% of the variability in the severity of hypertension. In contrast, in patients with controlled hypertension, the single predictors of either drug adherence or severity of hypertension were the number of years of hypertension and, for the severity of hypertension, alcohol consumption, accounting for only 15-20% of the variability. CONCLUSION: Psychological factors, mostly related to somatisation and expression of emotions are strong, independent predictors of both drug adherence and severity of hypertension in ATRH but not in controlled hypertensive patients.

This study included 144 patients with Apparently-Treatment Resistant (ATRH) or controlled Hypertension: Patients with ATRH were more often poorly adherent to antihypertensive treatment than controlled hypertensive patients.In patients with ARTH but not patients with controlled hypertension, psychological traits were strong, independent predictors of drug adherence and severity of hypertension, over and above demographic and health-related factors.In patients with ATRH, the tendency to somatize, i.e. expressing somatic symptoms that cannot be adequately explained by organic findings was the most potent predictor of both poor drug adherence and severity of hypertension.These patients also often presented alterations in the expression of emotions. It may be hypothesised that subjects who have difficulties identifying and expressing emotions with words will express them by physical complaints, and, in the mid-long term, might develop overt diseases.In addition to more classical lifestyle and drug management and irrespective of their drug adherence level, patients with ATRH may benefit in priority from psychological evaluation and interventions. However, this needs to be studied in an interventional trial in the future.

Impact of drug adherence on blood pressure response to alcohol-mediated renal denervation.

PURPOSE: While poor drug adherence is frequent in patients with resistant hypertension, detailed analyses of the impact of drug adherence on the success of renal denervation are scarce. We report drug adherence at baseline, changes in drug adherence, and the influence of these parameters on blood pressure changes at 6 and 12 months in patients treated with alcohol-mediated renal denervation as part of the Peregrine study. MATERIALS AND METHODS: Urinary detection of antihypertensive drugs was performed using high-performance liquid chromatography-tandem mass spectrometry. Full adherence, partial adherence, and complete non-adherence were defined as 0, 1, or ≥2 drugs not detected, respectively. RESULTS: Renal denervation was performed in 45 patients with uncontrolled hypertension on ≥3 antihypertensive medications (62% men, age 55 ± 10 years). At baseline, the proportion of fully, partially, and non-adherent patients was 62% (n = 28), 16% (n = 7), and 22% (n = 10), respectively. At 6 months, adherence improved by 21% (n = 9), remained unchanged at 49% (n = 21), and worsened by 30% (n = 13). Mean 24-h systolic blood pressure decreased by 10 ± 13, 10 ± 4, and 14 ± 19 mmHg in fully, partially, and non-adherent patients (p = 0.77), and by 14 ± 14, 8 ± 11, and 14 ± 18 mmHg in patients who improved, maintained, or decreased adherence, respectively (p = 0.35). The results at 12 months were similar. CONCLUSION: About 40% of patients with apparently treatment-resistant hypertension were not fully adherent at baseline, and adherence decreased further in 30%. Nevertheless, mean blood pressure changes after renal denervation were similar irrespective of drug adherence. Our results suggest that such patients may benefit from alcohol-mediated renal denervation, irrespective of drug adherence. These findings are hypothesis-generating and need to be confirmed in ongoing sham-controlled trials.

Adherence to antihypertensive drug treatment in kidney transplant recipients.

PURPOSE: Hypertension is a common cardiovascular co-morbidity after kidney transplantation and contributes to shortened graft and patient survival outcomes. However, by contrast with adherence to immunosuppressive drugs, adherence to antihypertensive treatment in kidney transplant recipients has been seldom explored. The aim of the current study was to assess adherence to antihypertensive drugs in kidney transplant recipients from the Cliniques Universitaires Saint-Luc and to look for demographic and clinical characteristics associated with drug adherence. METHODS: Demographic and clinical data were collected from medical files in a standardised case report form. Blood pressure was measured in the sitting position after 5 min rest, using validated oscillometric devices. Drug adherence was assessed by drug dosage in urine using liquid chromatography coupled with tandem mass spectrometry. RESULTS: Our analysis included 53 kidney transplants recipients (75% of men, mean age: 57.2 ± 12.6 years, time since kidney transplantation: 9.5 ± 7.3 years, blood pressure: 130 ± 16/78 ± 11 mmHg on 2.1 ± 1.1 antihypertensive drugs). The proportion of patients showing full drug adherence, partial drug adherence, and total non-adherence to antihypertensive drugs was 79% (N = 42), 15% (N = 8), and 6% (N = 3), respectively. Adherent patients did not differ from less or non- adherers in any of the analysed characteristics. CONCLUSION: The proportion of patients adhering to antihypertensive drug treatment among kidney transplant recipients appears similar to that reported for immunosuppressive drugs in renal transplanted patients (∼70%), but much higher than that observed in patients with drug-resistant hypertension (30-40%). Our results need further confirmation in a large, multicenter, prospective cohort.

Impact of rural versus urban setting on kidney markers: a cross-sectional study in South-Kivu, DRCongo.

BACKGROUND: Most studies of chronic kidney disease (CKD) in Sub-Saharan Africa (SSA) have been conducted in urban settings. They relied on GFR estimated from serum creatinine alone and on the inexpensive, convenient urinary dipstick to assess proteinuria. The dipstick for proteinuria has not been directly compared with the gold standard albumin-to-creatinine ratio (ACR) in a large-sized study in SSA. We hereby assessed the influence of rural versus urban location on the level, interpretation, and diagnostic performance of proteinuria dipstick versus ACR. METHODS: In a cross-sectional population-based study of CKD in both urban (n = 587) and rural (n = 730) settings in South-Kivu, Democratic Republic of Congo (DRC), we assessed the prevalence, performance (sensitivity, specificity, positive predictive value and negative predictive value) and determinants of a positive dipstick proteinuria as compared with albuminuria (ACR). Albuminuria was subdivided into: A1 (< 30 mg/g creatinine), A2 (30 to 299 mg/g creatinine) and A3 (≥ 300 mg/g creatinine). RESULTS: The overall prevalence of positive dipstick proteinuria (≥ 1+) was 9.6 % (95 % CI, 7.9-11.3) and was higher in rural than in urban residents (13.1 % vs. 4.8 %, p < 0.001), whereas the prevalence of albuminuria (A2 or A3) was similar in both sites (6 % rural vs. 7.6 % urban, p = 0.31). In both sites, dipstick proteinuria ≥ 1 + had a poor sensitivity (< 50 %) and positive predictive value (< 11 %) for the detection of A2 or A3. The negative predictive value was 95 %. Diabetes [aOR 6.12 (1.52-24.53)] was a significant predictor of A3 whereas alkaline [aOR 7.45 (3.28-16.93)] and diluted urine [aOR 2.19 (1.35-3.57)] were the main predictors of positive dipstick proteinuria. CONCLUSIONS: ACR and dipstick proteinuria have similar positivity rates in the urban site whereas, in the rural site, dipstick was 2-fold more often positive than ACR. The poor sensitivity and positive predictive value of the dipstick as compared with ACR makes it unattractive as a screening tool in community studies of CKD in SSA.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.

BACKGROUND AND OBJECTIVE: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. METHODS: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. RESULTS: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. CONCLUSION: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.

Prevalence and Risk Factors of CKD in South Kivu, Democratic Republic of Congo: A Large-Scale Population Study.

BACKGROUND: The prevalence of chronic kidney disease (CKD) in African American individuals is high but whether this applies to native populations in sub-Saharan Africa is unclear. METHODS: In a cross-sectional study, we assessed the prevalence and risk factors of CKD in rural and urban adults in South Kivu, Democratic Republic of Congo. Glomerular filtration rate (GFR) was estimated using the CKD-Epidemiology Collaboration (CKD-EPI) equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both markers (eGFRcr-cys), without ethnic correction factor. CKD was defined as an eGFR <60 ml/min per 1.73 m2 and/or albuminuria (albumin-to-creatinine ratio ≥30 mg/g). RESULTS: A total of 1317 participants aged 41.1 ± 17.1 years (730 rural, 587 urban) were enrolled. The prevalence of hypertension (20.2%; 95% confidence interval [CI], 18-22.3), diabetes mellitus (4.3%; 95% CI, 3.2-5.4) and obesity (8.9%; 95% CI, 7.4-10.5) was higher in urban than rural participants (all P < 0.05). HIV infection prevalence was 0.41% (95% CI, 0.05-0.78). The prevalence of eGFRcr <60 ml/min per 1.73 m2 was 5.4% (95% CI, 4.2-6.7). The prevalence of albuminuria was 6.6% (95 % CI, 5.1-8.1). The overall prevalence of CKD was 12.2% (95% CI, 10.2-14.2) according to CKD-EPIcr. Factors independently associated with CKD-EPIcr were older age (adjusted odds ratio [aOR], 1.05 [1.04-1.07]), urban residence (aOR 1.86 [1.18-2.95]), female sex (aOR 1.66 [1.04-2.66]), hypertension (aOR 1.90 [1.15-3.12]), diabetes (aOR 2.03 [1.02-4.06]), and HIV infection (10.21 [2.75-37.85]). The results based on eGFRcys or eGFRcr-cys were largely consistent with the preceding. CONCLUSION: Overall, the burden of CKD is substantial (>11%), predominantly in the urban area, and largely driven by classic risk factors (gender, aging, HIV, hypertension, and diabetes).

Benefit of serum drug monitoring complementing urine analysis to assess adherence to antihypertensive drugs in first-line therapy.

With obesity having doubled in the last decade, hypertension is on the rise. In one-third of hypertensive patients the metabolic syndrome is present. This might be one factor for the increasing number of prescriptions for angiotensin receptor blockers and calcium-channel blockers besides a more favorable risk-to-benefit ratio. The aim of the present study was to evaluate a therapeutic drug monitoring (TDM) method for assessment of adherence based on cut-offs in inpatients and to compare it to an established urine drug screening in outpatients. A method for quantification of calcium-channel blockers and angiotensin receptor blockers using high-performance liquid chromatography-tandem mass spectrometric analysis (LC-MS/MS) was developed and validated. The method was applied to serum samples of 32 patients under supervised medication to establish cut-off values for adherence assessment based on dose-related concentrations (DRC, calculated from pharmacokinetic data). Furthermore, corresponding urine and blood samples of 42 outpatients without supervised medication were analysed and the results compared with regard to adherence assessment. All serum concentrations measured for amlodipine (n = 40), lercanidipine (n = 14), candesartan (n = 10), telmisartan (n = 4) and valsartan (n = 10) in inpatients were above the patient specific lower DRC confirming adherence. Of 42 outpatients the identification of analytes in urine as well as the quantification in serum exhibited differing results. According to urinalysis, adherence was demonstrated in only 87.0% of prescriptions, compared to 91.3% for serum analyses. Differences were observed for amlodipine, lercanidipine and candesartan which can be explained by a higher specificity of the serum analysis approach due to pharmacokinetics. The present study confirms that assessing adherence based on serum drug concentrations with individually calculated lower DRCs is more accurate than using qualitative urine analysis. In particular, drugs with low bioavailability, low renal excretion or high metabolism rate such as lercanidipine and candesartan may lead to underestimation of adherence via urine analysis.

What is the optimal loading dose of broad-spectrum ß-lactam antibiotics in septic patients? Results from pharmacokinetic simulation modelling.

Optimal loading doses of ß-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum ß-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration. Pharmacodynamic (PD) targets were considered as drug concentrations exceeding at least 50% of time above four times the minimum inhibitory concentration (T>4 × MIC) of Pseudomonas aeruginosa, according to EUCAST criteria, for PIP, 70%T>4 × MIC for CAZ and FEP and 40%T>4 × MIC for MEM. The probability of target attainment (PTA) was derived by calculating the percentage of patients who attained the PK/PD target at each MIC. The optimal loading dose was defined as the one associated with a ≥90% probability to achieve the PD targets. Our simulation model identified an optimal loading dose for PIP of 8 g given as a 3-h infusion (PTA of 96.2%), for CAZ and FEP of 4 g given as a 3-h infusion (PTA of 96.5% and 98.4%, respectively), and for MEM of 2 g given as a 30-min infusion (PTA of 93.4%), with the following antibiotic dose administered 6 h thereafter regardless of the drug. A higher first dose of broad-spectrum ß-lactams should be given to adequately treat less-susceptible pathogens in septic patients. These findings need to be validated in a prospective study.

Biomarkers versus traditional risk factors to predict cardiovascular events in very old adults: cross-validated prospective cohort study.

OBJECTIVES: To test new cardiovascular (CV) risk models in very old adults with and without a history of CV disease (CVD), based on traditional risk factors and biomarkers. DESIGN: Cross-validated prospective cohort study. The models were tested in the BELFRAIL Study and externally validated in the Leiden 85-plus Study. SETTING: General practice, Belgium and The Netherlands. PARTICIPANTS: The BELFRAIL cohort consisted of 266 patients aged 80 years or older without a history of CVD and 260 with a history of CVD. The Leiden 85-plus Study consisted of 264 patients aged 85 years without a history of CVD and 282 with a history of CVD. OUTCOME MEASURES: The model with traditional risk factors and biomarkers, as well as the model using only biomarkers, was compared with the model with only traditional risk factors to predict 3-year CV morbidity and mortality. A competing-risk analysis was performed, and the continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI) and net benefit were used to compare the predictive value of the different models. RESULTS: Traditional risk factors poorly predicted CV mortality and morbidity. In participants without a history of CVD, adding N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) improved the prediction (NRI 0.56 (95% CI 0.16 to 0.99) and relative IDI 4.01 (95% CI 2.19 to 6.28)). In participants with a history of CVD, the NRI with the addition of NT-pro-BNP and high-sensitivity C reactive protein was 0.38 (95% CI 0.09 to 0.70), and the relative IDI was 0.53 (95% CI 0.23 to 0.90). Moreover, in participants without a history of CVD, NT-pro-BNP performed well as a stand-alone predictor (NRI 0.32 (95% CI -0.12 to 0.74) and relative IDI 3.44 (95% CI 1.56 to 6.09)). CONCLUSIONS: This study tested new risk models to predict CV morbidity and mortality in very old adults. Especially, NT-pro-BNP showed a strong added predictive value. This opens perspectives for clinicians who are in need of an easily applicable strategy for CV risk prediction in very old adults.

Measuring Intracellular Concentrations of Calcineurin Inhibitors: Expert Consensus from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Expert Panel.

BACKGROUND: Therapeutic drug monitoring (TDM) of the 2 calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporin A, has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection (AR) rates and treatment-related toxicities have been reduced. Irrespective, AR and toxicity still occur in patients who have undergone transplantation, showing blood CNI concentrations within the therapeutic range. Moreover, the AR rate is no longer decreasing. Hence, smarter TDM approaches are necessary. Because CNIs exert their action inside T lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. The intracellular CNI concentration may be more directly related to the drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the preanalytical and analytical stages, and standardization seems essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations. METHODS: Under the auspices of the International Association of TDM and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented preanalytical and analytical recommendations for measuring intracellular CNI concentrations.

Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial.

BACKGROUND: The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. OBJECTIVES: To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. METHODS: Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration-time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. RESULTS: Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. CONCLUSIONS: The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

Assessment of adherence to diuretics and ß-blockers by serum drug monitoring in comparison to urine analysis.

Purpose: Toxicological screenings for identifying antihypertensive drugs proved to be a useful tool for assessing adherence. However, misinterpretation may occur in case of highly metabolised drugs with low renal excretion, as well as for drugs with a prolonged detectability. The aim of the present study was to compare a recently developed therapeutic drug monitoring (TDM) method based on serum concentrations to an urine drug detection method for assessing adherence in outpatients.Materials and methods: Corresponding urine and blood samples were obtained at the same time from 26 outpatients without supervised medication. Urine and serum analyses were performed using established high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. Adherence was assumed if drugs were detectable in urine or if serum concentrations were above individually calculated lower dose-related concentrations (DRC) or literature-based therapeutic reference ranges (TRR) used as cut-off, respectively.Results: The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol (n = 6 patients), bisoprolol (n = 8), nebivolol (n = 6), canrenone (n = 6, metabolite of spironolactone), hydrochlorothiazide (n = 12) and furosemide (n = 2). On the basis of drug detectability in urine, adherence was assumed in 88% of prescriptions. In 81% (DRC) and 50% (TRR) of the serum analyses the cut-off value was exceeded, which confirms patients' adherence in a lower number. Differences in adherence rates were found in five patients, mainly for ß-blockers.Conclusion: This study suggests that assessment of adherence can be performed more precisely on the basis of serum drug concentrations with individually calculated lower DRC than by using the TRR or qualitative urinalysis.

Comparative in vitro antimicrobial potency, stability, colouration and dissolution time of generics versus innovator of meropenem in Europe.

Meropenem generics are often imposed on prescribers, however scarce information is available on key properties such as antimicrobial potency, stability and colouration in solution, and dissolution time. This study aimed to generate comparative information for products available in Europe. The originator (ASTRA) and four generics (HOSPIRA, SANDOZ, FRESENIUS and AUROVIT) were compared for: (i) MICs against Pseudomonas aeruginosa clinical isolates (range, 0.125-191 mg/L); (ii) colouration (visual and photometry) and stability of concentrated solutions for prolonged or continuous infusion and maintained at 25-37 °C for up to 8 h (acceptable limit, ≥90% of original concentration); and (iii) dissolution time of concentrated solutions (50 mg/mL [for bolus administration]: turbidimetry and nursing personnel assessment). No significant difference was observed for MICs (except 2/80 isolates). For concentrated solutions storage: (i) SANDOZ produced about two times more yellow-coloured degradation products than the other preparations; (ii) meropenem loss was time-, concentration- and temperature-dependent; (iii) FRESENIUS was the least stable (limit for 1 g/48 mL, ~8 h at 25 °C and 4.5 h at 37 °C); (iv) at 2 g/48 mL, the storage time limit was 5-6 h at 25 °C and ~3 h at 37 °C for all preparations. Complete dissolution (turbidimetry) required 240 s for generics (120 s for ASTRA), and nurses reported longer but highly variable times for generics. Substantial differences between innovator and generics have been identified that could impact on their clinical use and/or make multicentric studies difficult to interpret, requiring suitability studies in the environments of their intended use.

Intentional acetylsalicylic acid acute intoxication and its clinical management.

In the last decade, our knowledge about OTC drug intoxication has been expanded much further relative to previous years, though the absence of antidotes in some cases results in healthcare professionals using symptomatic treatment. This case report reminds the reader of the importance of clinical and toxicology laboratories in the management of acute salicylate intoxication in order to avoid hemodialysis.

Predictors of blood pressure control in patients with resistant hypertension after intensive management in two expert centres: the Brussels-Torino experience.

Background: Management of resistant hypertension (RHTN) is challenging and often implies the use of complex polypharmacy and interventional therapies. The main objectives of this study were (i) to describe the characteristics of patients with RHTN referred to two expert centres; (ii) to identify predictors of blood pressure (BP) control after intensive management. Methods: We reviewed electronic medical files of all patients referred for RHTN to the Brussels and Torino centres, and extracted detailed clinical data, informations on drug adherence and psychological profile. All patients with confirmed diagnosis of RHTN, according to office and ambulatory BP monitoring (ABPM) measurements, were considered eligible. Results: 313 patients (51% men; age: 56 ± 12 years; office BP 177/98 mmHg; 24-hour ABPM 153/90 mmHg) were included. At the end of follow-up (median: 2 years [1-4]), only 26% of patients (n = 81) reached BP control. When compared to patients remaining resistant, patients eventually controlled had lower pulse pressure (71 vs. 82 mmHg, p < 0.001), less often myocardial infarction (6% vs. 20%, p < 0.005) and showed a higher recourse to cognitive reappraisal as far as emotion regulation is concerned (4.8 ± 1.1 vs. 3.9 ± 1.2, p = 0.009; ERQ Questionnaire). In a multivariate analysis looking for predictors of controlled BP, only the psychological characteristic of cognitive reappraisal (i.e., changing one's thoughts about a potentially emotion-eliciting event) remained significant (OR 2.06 [1.10; 3.84], p = 0.02). Conclusions: Even in expert centres, only a minority of patients with RHTN reached BP control, irrespective of the centre involved or the interventions applied. Patients who eventually responded to therapy had lower arterial stiffness and less cardiac organ damage. Furthermore, besides vascular damage, the single predictor of BP control was the ability to modify the emotional impact of stressful situations.