Novel approach to adherence assessment based on parent drug and metabolite pharmacokinetics: pilot study with spironolactone.

AIM: The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. MATERIALS AND METHODS: Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. RESULTS: With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. CONCLUSION: Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.

Adherence and blood pressure control in patients with primary aldosteronism.

PURPOSE: The aim of our study was to evaluate the adherence to mineralocorticoid receptor (MR) antagonists and other antihypertensive therapy and blood pressure control in conservatively treated patients with primary aldosteronism (PA). MATERIALS AND METHODS: Conservatively treated subjects with previously confirmed PA (n-50, 64.5 ± 9 years of age, 24% women) were investigated via our outpatient hypertension clinic. All subjects underwent regular examinations in our clinic. In addition to basic laboratory and clinical parameters, 24 h ambulatory blood pressure monitoring (ABPM) (Spacelabs) was evaluated. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by the means of liquid chromatography-mass spectrometry was performed in all patients. In case of spironolactone, its active metabolite canrenone was also evaluated. Total non-compliance was then defined as the absence of all measured antihypertensive drugs. Partial non-compliance was calculated as the absence of serum levels of at least one, but not all antihypertensive drugs prescribed. RESULTS: Good blood pressure control was detected (mean 24 h systolic/diastolic BP 130 ± 12/77 ± 9 mmHg). The average number of antihypertensive drugs was 3.9 ± 1.5. All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 ± 20 mg) and in the remaining 56% of subjects eplerenone was administered (average daily dose 80 ± 30 mg) due to spironolactone side effects. Assessment of antihypertensive drug concentrations revealed full adherence in 80% of all subjects, partial nonadherence was noted in the remaining 20% of subjects. MR antagonist levels were detected in almost all subjects (49 out of 50). CONCLUSIONS: Good blood pressure control and adherence to therapy were detected in conservatively treated patients with PA. Eplerenone had to be used quite often as male subjects did not tolerate dose escalation due to spironolactone side effects.

SNPs within CHRNA5-A3-B4 and CYP2A6/B6, nicotine metabolite concentrations and nicotine dependence treatment success in smokers.

AIM: Plasma values of nicotine and its metabolites are highly variable, and this variability has a strong genetic influence. In our study, we analysed the impact of common polymorphisms associated with smoking on the plasma values of nicotine, nicotine metabolites and their ratios and investigated the potential effect of these polymorphisms and nicotine metabolite ratios on the successful treatment of tobacco dependence. METHODS: Five variants (rs16969968, rs6474412, rs578776, rs4105144 and rs3733829) were genotyped in a group of highly dependent adult smokers (n=103). All smokers underwent intensive treatment for tobacco dependence; 33 smokers were still abstinent at the 12-month follow-up. RESULTS: The rs4105144 (CYP2A6, P<0.005) and rs3733829 (EGLN2, P<0.05) variants were significantly associated with plasma concentrations of 3OH-cotinine and with 3OH-cotinine: cotinine ratios. Similarly, the unweighted gene score was a significant (P<0.05) predictor of both cotinine:nicotine and 3OH-cotinine:cotinine ratios. No associations between the analysed polymorphisms or nicotine metabolite ratios and nicotine abstinence rate were observed. CONCLUSION: Although CYP2A6 and EGLN2 polymorphisms were associated with nicotine metabolism ratios, neither these polymorphisms nor the ratios were associated with abstinence rates.

Continued Smoking in Lung Transplant Patients: A Cross Sectional Survey.

INTRODUCTION: Smoking is associated with a higher incidence of post-lung transplantation complications and mortality. Prior to inclusion on the lung transplant waiting list in the Czech Republic, patients are supposed to be tobacco free for at least 6 months. Our aim was to determine the prevalence of smoking, validated by urinary cotinine, among patients post lung transplantation and prior to inclusion on the transplant waiting list. METHODS: Between 2009 and 2012, we conducted a cross-sectional survey of urinary cotinine to assess tobacco exposure in 203 patients in the Lung Transplant Program in the Czech Republic. We measured urinary cotinine in 163 patients prior to inclusion on the transplantation waiting list, and 53 patients post bilateral lung transplantation. RESULTS: 15.1% (95% CI 0.078 to 0.269) of all lung transplant recipients had urinary cotinine levels corresponding to active smoking; and a further 3.8% (95% CI 0.007 to 0.116) had borderline results. Compared to patients with other diagnoses, patients with COPD were 35 times more likely to resume smoking post- transplantation (95% CI 1.92 to 637.37, p-value 0.016). All patients who tested positive for urinary cotinine levels were offered smoking cessation support. Only one Tx patient sought treatment for tobacco dependence, but was unsuccessful. CONCLUSION: Smoking resumption may be an underrecognized risk for lung transplantation recipients, particularly among patients with chronic obstructive pulmonary disease. More rigorous screening, as well as support and treatment to stop smoking among these patients are needed.

Use of Out-of-Hospital Ethanol Administration to Improve Outcome in Mass Methanol Outbreaks.

STUDY OBJECTIVE: Methanol poisoning outbreaks are a global public health issue, with delayed treatment causing poor outcomes. Out-of-hospital ethanol administration may improve outcome, but the difficulty of conducting research in outbreaks has meant that its effects have never been assessed. We study the effect of out-of-hospital ethanol in patients treated during a methanol outbreak in the Czech Republic between 2012 and 2014. METHODS: This was an observational case-series study of 100 hospitalized patients with confirmed methanol poisoning. Out-of-hospital ethanol as a "first aid antidote" was administered by paramedic or medical staff before the confirmation of diagnosis to 30 patients; 70 patients did not receive out-of-hospital ethanol from the staff (12 patients self-administered ethanol shortly before presentation). RESULTS: The state of consciousness at first contact with paramedic or medical staff, delay to admission, and serum methanol concentration were similar among groups. The median serum ethanol level on admission in the patients with out-of-hospital administration by paramedic or medical staff was 84.3 mg/dL (interquartile range 32.7 to 129.5 mg/dL). No patients with positive serum ethanol level on admission died compared with 21 with negative serum ethanol level (0% versus 36.2%). Patients receiving out-of-hospital ethanol survived without visual and central nervous system sequelae more often than those not receiving it (90.5% versus 19.0%). A positive association was present between out-of-hospital ethanol administration by paramedic or medical staff, serum ethanol concentration on admission, and both total survival and survival without sequelae of poisoning. CONCLUSION: We found a positive association between out-of-hospital ethanol administration and improved clinical outcome. During mass methanol outbreaks, conscious adults with suspected poisoning should be considered for administration of out-of-hospital ethanol to reduce morbidity and mortality.

Fluctuations in serum ethanol concentration in the treatment of acute methanol poisoning: a prospective study of 21 patients.

OBJECTIVE: During the 2012 outbreak of mass methanol poisonings in the Czech Republic, ethanol, in the main, was used as an antidote. The complex pharmacokinetics of ethanol made it difficult to maintain the requisite 1000-1500 mg/L serum ethanol levels (S-EtOH). The aim of this study was to measure the fluctuations in S-EtOH during the treatment. METHODS: A prospective case series in 21 patients, median age 52 (27-79 years), 13 males and 8 females. Serum ethanol, methanol and formate were measured every 2-6 hours during the treatment. Follow-up clinical examination was carried out in 15/18 survivors. RESULTS: The majority of patients (17/21) were late presenters and on admission, almost half (10/21) had suffered a severe grade of intoxication according to the Poisoning Severity Score (PSS). The mean observation time was 90±20 h. The mean period of consistent maintenance of S-EtOH within the recommended therapeutic range lasted 28±7% of the total observation time. For 29±8% of the time, S-EtOH was >1500 mg/L with "peaks" of up to 3500 mg/L. For 44±10% of the observation time, S-EtOH was <1000 mg/L. The mean duration of sub-therapeutic concentration of S-EtOH and toxic serum levels of methanol >200 mg/L or formate >20 mg/L lasted 20±10% and 18±11% of the time of observation, respectively. Complications occurred in 14 (67%) of cases including significant fluctuations of S-EtOH in 9; aspiration pneumonia in 3 and delirium tremens in 2 cases. Other complications included sepsis, bleeding, acidosis rebound, intolerance and set clotting. The outcomes were: 11 survivors free of health impairment, 7 with sequelae and 3 deaths. There was no significant difference in mean duration of sub-therapeutic and supra-therapeutic concentrations of serum ethanol in patients who survived without sequelae and those with poor outcome (P > 0.05). CONCLUSION: Administration of ethanol according to the present guidelines of the AACT/EAPCCT is effective and relatively safe in the treatment of methanol poisoning during a mass outbreak(31). Physicians have to be most aware of fluctuations in serum ethanol at the end of short sessions of IHD and after changes in route from intravenous to oral. Rigorous monitoring of serum ethanol concentrations is pivotal for severely poisoned patients with PSS 3 and where there is suspected conversion of significant amounts of methanol to formic acid.

Is the measurement of serum formate concentration useful in the diagnostics of acute methanol poisoning? A prospective study of 38 patients.

The aim of this article was to study the role of serum formate (S-formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 - median age 51 [interquartile range (IQR) 37-62] years with confirmed methanol poisoning. S-formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S-formate. Asymptomatic patients had median S-formate of 1.9 (IQR 1.5-2.4) mmol/L. The median S-formate was 15.2 (IQR 13.9-17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1-18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8-18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long-term visual sequelae of poisoning had median S-formate of 16.1 (IQR 14.3-19.9) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2-19.5) mmol/L. In lethal cases, the median S-formate was 15.2 (IQR 13.8-15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S-formate ≥17.5 mmol/L, S-lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44-0.85 CI 95%) for S-formate, 0.75 (0.56-0.93 CI 95%) for 'S-formate+S-lactate' and only 0.54 (0.38-0.69 CI 95%) for serum methanol, which is lower than for S-formate (p < 0.05). The measurement of S-formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S-formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S-formate ≥11-12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.

Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning.

During an outbreak of methanol poisonings in the Czech Republic in 2012, we were able to study methanol and formate elimination half-lives during intermittent hemodialysis (IHD) and continuous veno-venous hemodialysis/hemodiafiltration (CVVHD/HDF) and the relative impact of dialysate and blood flow rates on elimination. Data were obtained from 11 IHD and 13 CVVHD/HDF patients. Serum methanol and formate concentrations were measured by gas chromatography and an enzymatic method. The groups were relatively comparable, but the CVVHD/HDF group was significantly more acidotic (mean pH 6.9 vs. 7.1 IHD). The mean elimination half-life of methanol was 3.7 and formate 1.6 h with IHD, versus 8.1 and 3.6 h, respectively, with CVVHD/HDF (both significant). The 54% greater reduction in methanol and 56% reduction in formate elimination half-life during IHD resulted from the higher blood and dialysate flow rates. Increased blood and dialysate flow on the CVVHD/HDF also increased elimination significantly. Thus, IHD is superior to CVVHD/HDF for more rapid methanol and formate elimination, and if CVVHD/HDF is the only treatment available then elimination is greater with greater blood and dialysate flow rates.

Paracetamol poisonings in the Czech and Slovak Republic and N-acetylcysteine treatment. Data analysis.

OBJECTIVES: Paracetamol overdose belongs to frequent calls to Toxicological Information Centre (TIC) in the Czech Republic and to the National Toxicological Information Centre (NTIC) in Slovakia. The aim of the study was to evaluate outcomes and side effects of paracetamol overdose in both countries. METHODS: Data concerning paracetamol poisoning extracted from TIC and NTIC databases 2000-2013 and discharge reports were analysed. Numbers and outcomes in patients presenting within 24 hours of a single paracetamol overdose were compared in relation to 3 paracetamol concentration bands (≤ 100 mg/l, 100-149 mg/l, and 150 mg/l). RESULTS: 5397 inquiries concerning paracetamol were recorded in TIS and NTIC. Data from 196 discharge reports with plasma level were studied. Median age of the patients was 18 (0.2-86) years. Eight/196 (4.1%) patients developed side effects after N-acetylcysteine (NAC) administration. 120 cases fulfilled time criteria of the study and were divided into 3 groups, where 55.7%, 73.1% and 96.9% patients have been treated with NAC. Among these 120 patients, favourable outcome was seen in 100%, 100%, and 92.8%, respectively. One death due to suicidal attempt with plasma level 407 mg/l presenting at 20 hours has been recorded among 120 patients. No patient without NAC treatment died due to acute overdose and plasma concentration ≤ 150 mg/I at 4 hours. CONCLUSIONS: These data support the opinion that NAC should not be used in patients with < 149 mg/l levels in absence of higher risk factors because of very low risk of hepatotoxicity on one side, and side effects on the other side.

Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis.

BACKGROUND: The aim of our study was to assess the prevalence of pseudo-resistance caused by noncompliance with treatment among patients with severe resistant hypertension and to analyze the contributing factors. METHOD: Three hundred and thirty-nine patients (195 men) with resistant essential hypertension were studied. The first group consisted of 176 patients admitted for hospitalization for exclusion of a secondary cause to our hypertension centre (103 men); the second one consisted of 163 out-patients (92 men) investigated for the first time in an out-patient hypertension clinic. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by means of liquid chromatography-mass spectrometry was performed in all patients. RESULTS: Our main finding is a surprisingly low compliance with drug treatment in out-patients with resistant hypertension (23% partially noncompliant and 24% totally noncompliant - in total, 47% prevalence of noncompliance). Eighty-one percent of hospitalized patients were positive, in 10% the results were partially positive and in 9% of the patients, the drugs were all negative. The compliance among hospitalized patients was probably better due to lower numbers of prescribed drugs and expected thorough investigation. More frequently, noncompliance was found in nonworking (potential purpose-built behaviour), younger and less well educated patients. The most frequent noncompliance was to doxazosine, spironolactone and hydrochlorothiazide. We have observed a surprisingly low compliance with treatment among out-patients with severe hypertension. CONCLUSION: We conclude that the evaluation of antihypertensive drugs concentrations is a useful and precise method for assessment of noncompliance in patients with resistant hypertension. This evaluation is useful before starting the diagnostic work-up of secondary forms of hypertension and before assignment patients into protocols with new therapy modalities such as renal denervation.