Beurteilung der Therapietreue in der antihypertensiven Therapie basierend auf Therapeutischem Drug Monitoring (TDM)

Hypertonie stellt in der westlichen Welt die Haupttodesursache dar, obwohl sie im Hinblick auf die pharmakologischen Therapieoptionen gut behandelbar ist. Hauptursächlich ist hierfür eine, vor allem durch eine Non-Adhärenz (u.a. bedingt durch den asymptomatischen Charakter) und in selteneren Fällen eine aufgrund einer therapieresistente Hypertonie (TRH) verursachte, unzureichende Blutdruckkontrolle. Eine Möglichkeit zur Überprüfung der Therapietreue in der antihypertensiven Therapie ist der qualitative Nachweis der Arzneistoffe im Blut oder Urin. Unklar ist, inwiefern die Substanzen in einer biologischen Probe innerhalb des Dosierungsintervalls oder darüber hinaus nachweisbar sind und es zu einer Falschbeurteilung kommen kann. Daher wurde eine quantitative chromatographisch-tandem-massenspektrometrische Methode für das Therapeutische Drug Monitoring von blutdrucksenkenden Arzneistoffen entwickelt und analytisch vollständig validiert. Bei 38 Patienten mit überwachter Medikamenteneinnahme wurde die Aussagekraft der Methode hinsichtlich der Bestätigung einer Adhärenz zunächst mittels zweier Wirkstoffkonzentrationen im Serum (Tal- und Spitzenspiegel) überprüft. Zur Bewertung der Konzentrationen wurden zwei Konzepte evaluiert. Einerseits wurde die untere Grenze des therapeutischen Referenzbereiches (TRR, Literaturdaten) und andererseits die mittels Rechenmodell (Daten pharmakokinetischer Studien) individuell ermittelte, dosisbezogene Arzneimittelkonzentration (DRC) evaluiert. In einem zweiten Studienansatz wurde diese neue quantitative Methode an einem Kollektiv von 36 ambulanten Patienten (ohne überwachte Medikamenteneinnahme) angewendet und zur Überprüfung der Aussagekraft mit Ergebnissen des etablierten Urinscreenings verglichen. Die gemessenen Wirkstoffkonzentrationen von Atenolol (64 bis 564 ng/ml), Bisoprolol (2,5 bis 53 ng/ml), Metoprolol (5,8 bis 110 ng/ml), Nebivolol (0,32 bis 3,4 ng/ml), Hydrochlorothiazid (15 bis 606 ng/ml), Furosemid (22 ng/ml), Torasemid (17 bis 1829 ng/ml), Canrenon (25 bis 221 ng/ml), Amlodipin (2,4 bis 35 ng/ml), Lercanidipin (0,24 bis 21 ng/ml), Candesartan (6,0 bis 268 ng/ml), Telmisartan (22 bis 375 ng/ml) und Valsartan (115 bis 7962 ng/ml) haben gezeigt, dass die quantitative Analyse von Antihypertensiva in Serumproben und deren Auswertung auf Basis der individuell berechneten unteren DRC in der Beurteilung einer Adhärenz vielversprechend ist. Die Auswertung auf Basis der unteren Grenze des TRR signalisierte bei den stationären Patienten (überwachte Einnahme) innerhalb der Substanzklasse der Diuretika (ohne Torasemid) bei 16,7 %, der β-Blocker bei 29,4 %, der Calciumkanal-Blocker bei 14,8 % und der AT1-Antagonisten bei 25 % fälschlicherweise eine Non-Adhärenz. Die rein qualitative Urinanalyse zeigte im Falle der β-Blocker Atenolol, Bisoprolol und des Diuretikums HCT aufgrund einer hohen Bioverfügbarkeit, einer langen Halbwertszeit oder einer überwiegend renalen Ausscheidung der Muttersubstanz ein Nachweisfenster über das Dosierungsintervall hinaus, was bedingt, dass einige Patienten fälschlicherweise als adhärent gewertet wurden. Ein anderes Problem zeigte sich bei einigen Patienten, die mit dem AT1-Antagonist Candesartan oder dem Calciumkanal-Blocker Lercanidipin behandelt wurden und die als non-adhärent eingestuft wurden. Eine geringe Bioverfügbarkeit, eine hohe Metabolisierungsrate oder geringe renale Ausscheidung der unveränderten Arzneistoffe lies auf eine mangelhafte Nachweisbarkeit innerhalb des Dosierungsintervalls und damit auf eine eingeschränkte Beurteilbarkeit schließen. Aus den Untersuchungen ergibt sich, dass es bei Anwendung qualitativer Nachweismethoden aufgrund besonderer Pharmakokinetiken einzelner antihypertensiver Wirkstoffe zur Fehleinschätzung der Adhärenz kommen kann. Die neu entwickelte Methodik in Form einer quantitativen Serumanalyse ist unter Verwendung patientenindividueller Bewertungskriterien bei dieser Fragestellung überlegen.Hypertension is the main cause of death in the western world, despite the wide range of pharmacological treatment options. This is predominantly caused by insufficient blood pressure control, mainly due to non-adherence (inter alia due to its asymptomatic character) and more rarely to therapy-resistant hypertension (TRH). One possibility for adherence assessment in antihypertensive therapy is the qualitative detection of the drugs in blood or urine. What remains to be clarified is the extent to which the drugs are detectable in a biological sample within or beyond the dosage interval and whether this leads to a misjudgement. Therefore, a quantitative chromatographic tandem mass spectrometric method for therapeutic drug monitoring of antihypertensive drugs was developed and fully validated analytically. In 38 patients with monitored drug intake, the validity of the method was first evaluated based on two drug concentrations in the serum (trough and peak levels) to confirm adherence. Two approaches were evaluated to assess concentrations. On the one hand, the lower limit of the therapeutic reference range (TRR, literature data) and on the other hand the dose-related drug concentration (DRC) determined individually using a mathematical model (data from pharmacokinetic studies) were evaluated. In a second study approach, this new quantitative method was applied to a collective of 36 outpatients (without monitored drug intake) and compared with the results of the established qualitative urinalysis to verify the validity of the results. The measured concentrations of atenolol (64 to 564 ng/ml), bisoprolol (2.5 to 53 ng/ml), metoprolol (5.8 to 110 ng/ml), nebivolol (0.32 to 3,4 ng/ml), hydrochlorothiazide (15 to 606 ng/ml), furosemide (22 ng/ml), torasemide (17 to 1829 ng/ml), canrenone (25 to 221 ng/ml), amlodipine (2.4 to 35 ng/ml), lercanidipine (0.24 to 21 ng/ml), candesartan (6.0 to 268 ng/ml), telmisartan (22 to 375 ng/ml) and valsartan (115 to 7962 ng/ml) proved that the quantitative analysis of antihypertensive drugs in serum samples and the evaluation based on the individually calculated lower DRC is promising in the assessment of adherence. Evaluation based on the lower limit of TRR falsely indicated non-adherence in the inpatients (monitored drug intake) for 16.7% of diuretics (except torasemide), 29.4% of β blockers, 14.8% of calcium-channel blockers and 25% of angiotensin receptor blockers. In case of the β-blockers atenolol, bisoprolol and the diuretic HCT, the qualitative urinalysis showed a detectability beyond the dosage interval due to high bioavailability, a long half-life or a predominantly renal excretion of the parent substance, which led some patients to be falsely considered adherent. Another problem was observed in some patients treated with the angiotensin receptor blocker candesartan or the calcium-channel blocker lercanidipine being classified as non-adherent. A low bioavailability, a high metabolisation rate or a low renal excretion of the unchanged drugs indicated poor detectability within the dosage interval and thus limited assessability. The study results show that the use of qualitative detection methods may lead to misinterpretation of adherence due to the specific pharmacokinetics of an antihypertensive drug. The newly developed methodology based on quantitative serum analysis using patient-specific evaluation criteria is superior

Evaluation of the dose-related concentration approach in therapeutic drug monitoring of diuretics and β-blockers – drug classes with low adherence in antihypertensive therapy

Detection of antihypertensive drugs in biological samples is an important tool to assess the adherence of hypertensive patients. Urine and serum/plasma screenings based on qualitative results may lead to misinterpretations regarding drugs with a prolonged detectability. The aim of the present study was to develop a method that can be used for therapeutic drug monitoring (TDM) of antihypertensive drugs with focus on adherence assessment. Therefore, a method for quantification of four diuretics and four β-blockers using high-performance liquid chromatography-mass spectrometric analysis (LC-MS/MS) of combined acidic and basic serum extracts was developed and validated. The method was applied to 40 serum samples from 20 patients in a supervised medication setting (trough and peak serum samples). Literature data on therapeutic concentration ranges, as well as dose-related drug concentrations (calculated from data of pharmacokinetic studies) were used to evaluate adherence assessment criteria. Concentrations were measured for bisoprolol (n = 9 patients), metoprolol (n = 7), nebivolol (n = 1), canrenone (n = 2, metabolite of spironolactone), hydrochlorothiazide (n = 10) and torasemide (n = 8). The measured concentrations were within the therapeutic reference ranges, except for 24% of the samples (mainly β-blockers). In contrast, all measured concentrations were above the lower dose-related concentration (DRC), which appears superior in evaluating adherence. In conclusion, the quantitative analysis of antihypertensive drugs in serum samples and its evaluation on the basis of the individually calculated lower DRC is a promising tool to differentially assess adherence. This method could possibly detect a lack of adherence or other causes of insufficient therapy more reliably than qualitative methods

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

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. 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. The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol ( = 6 patients), bisoprolol ( = 8), nebivolol ( = 6), canrenone ( = 6, metabolite of spironolactone), hydrochlorothiazide ( = 12) and furosemide ( = 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 β-blockers. 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

Adherence to antihypertensive drug treatment in kidney transplant recipients.

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. 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. 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% ( = 42), 15% ( = 8), and 6% ( = 3), respectively. Adherent patients did not differ from less or non- adherers in any of the analysed characteristics. 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

Benefit of serum drug monitoring complementing urine analysis to assess adherence to antihypertensive drugs in firstline 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

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

Assessment of the acute effects of 2C-B vs psilocybin on subjective experience, mood and cognition

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it’s acute effects and distinctions from classical progenitors have yet to be characterised in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared to placebo, as indexed by the Digit Symbol Substitution Test (DSST), Tower of London (TOL) and Spatial Memory Task (SMT). Neither compound produced empathogenic effects on the Multifaceted Empathy Test (MET). 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorisation of 2C-B as a subjectively “lighter” psychedelic. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B’s experiential overlaps

Assessment of the acute effects of 2C-B vs. psilocybin on subjective experience, mood, and cognition

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a hallucinogenic phenethylamine derived from mescaline. Observational and preclinical data have suggested it to be capable of producing both subjective and emotional effects on par with other classical psychedelics and entactogens. Whereas it is the most prevalently used novel serotonergic hallucinogen to date, it's acute effects and distinctions from classical progenitors have yet to be characterized in a controlled study. We assessed for the first time the immediate acute subjective, cognitive, and cardiovascular effects of 2C-B (20 mg) in comparison to psilocybin (15 mg) and placebo in a within-subjects, double-blind, placebo-controlled study of 22 healthy psychedelic-experienced participants. 2C-B elicited alterations of waking consciousness of a psychedelic nature, with dysphoria, subjective impairment, auditory alterations, and affective elements of ego dissolution largest under psilocybin. Participants demonstrated equivalent psychomotor slowing and spatial memory impairments under either compound compared with placebo, as indexed by the Digit Symbol Substitution Test, Tower of London, and Spatial Memory Task. Neither compound produced empathogenic effects on the Multifaceted Empathy Test. 2C-B induced transient pressor effects to a similar degree as psilocybin. The duration of self-reported effects of 2C-B was shorter than that of psilocybin, largely resolving within 6 hours. Present findings support the categorization of 2C-B as a psychedelic of moderate experiential depth at doses given. Tailored dose-effect studies are needed to discern the pharmacokinetic dependency of 2C-B's experiential overlaps

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

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