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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.

•Connectome fingerprints are ubiquitous to individual brain functional organisation.•Functional connectivity traits mediate inter-individual differences in behaviour.•Psychedelics such as ayahuasca produce distinct effects on functional brain organisation.•We find a reallocation of keypoint fingerprinting edges under ayahuasca.•Inter-individual differences in edge behaviour predict experiential qualities. The knowledge that brain functional connectomes are unique and reliable has enabled behaviourally relevant inferences at a subject level. However, whether such “fingerprints” persist under altered states of consciousness is unknown. Ayahuasca is a potent serotonergic psychedelic which produces a widespread dysregulation of functional connectivity. Used communally in religious ceremonies, its shared use may highlight relevant novel interactions between mental state and functional connectome (FC) idiosyncrasy. Using 7T fMRI, we assessed resting-state static and dynamic FCs for 21 Santo Daime members after collective ayahuasca intake in an acute, within-subject study. Here, connectome fingerprinting revealed FCs showed reduced idiosyncrasy, accompanied by a spatiotemporal reallocation of keypoint edges. Importantly, we show that interindividual differences in higher-order FC motifs are relevant to experiential phenotypes, given that they can predict perceptual drug effects. Collectively, our findings offer an example of how individualised connectivity markers can be used to trace a subject's FC across altered states of consciousness.

Background: Naturalistic and placebo-controlled studies have suggested that ayahuasca, a traditional Amazonian beverage, could be helpful in the treatment of psychopathologies like depression and anxiety disorders by changing otherwise disturbed cognitive and emotional processes. To better understand its full therapeutic potential, one way is to study the effects on processes like flexible thinking, empathy, and well-being, which are normally compromised in stress-related psychopathologies. Materials and Methods: Volunteers attending ayahuasca ceremonies were asked to complete a test battery at three separate occasions: baseline, the morning after, and 1 week after the ceremony. We included the constructs of creative thinking (measured by Picture Concept Test), empathy (Multifaceted Empathy Test), satisfaction with life (Satisfaction with Life Scale), decentering (Experiences Questionnaire), and personality (Big Five Inventory) into the test battery. Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire, the Ego Dissolution Scale, and Visual Analogue Scales. Results: In total, 43 attendees (males = 22; females = 21) completed parts of the baseline assessment, 20 (males = 12; females = 8) completed assessments in the morning after the ceremony, and 19 (males = 14; females = 5) completed assessments at the 1-week follow-up. At one and 7 days post-ceremony, cognitive empathy, satisfaction with life, and decentering increased, while divergent thinking ( Fluency corrected for Originality ) decreased, when compared to baseline. Implicit emotional empathy increased at 1-week follow-up, whereas ratings of the trait neuroticism decreased. Conclusion: The study suggests that a single ingestion of ayahuasca in a social setting is associated with enhancement of subjective well-being, an enhanced ability to take an objective and non-judging stance towards the self (decentering), and the ability to correctly recognize emotions in others, compared to baseline, lasting up to 1 week post-ceremony. To understand the therapeutic potential related to these effects, further research with clinical populations is needed in which these effects can be assessed, including its link with therapeutic outcomes. Together, this will increase our understanding of the effectiveness and breadth of future therapeutic options.

5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a tryptamine with ultra-rapid onset and short duration of psychedelic effects. Prospective studies for other tryptamines have suggested beneficial effects on mental health outcomes. In preparation for a study in patients with depression, the present study GH001-HV-101 aimed to assess the impact of four different dose levels of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation as single doses of 2 ( N = 4), 6 ( N = 6), 12 ( N = 4) and 18 mg ( N = 4), and in an individualized dose escalation regimen ( N = 4) on the safety, tolerability, and the dose-related psychoactive effects in healthy volunteers ( N = 22). The psychedelic experience was assessed with a novel Peak Experience Scale (PES), the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). Further aims were to assess the impact of 5-MeO-DMT on cognitive functioning, mood, and well-being. Higher doses of 5-MeO-DMT produced significant increments in the intensity of the psychedelic experience ratings as compared to the lowest 2 mg dose on all questionnaires, except the CEQ. Prominent effects were observed following single doses of 6, 12, and 18 mg on PES and MEQ ratings, while maximal effects on PES, MEQ, EDI, and 5D-ASC ratings were observed following individualized dose escalation of 5-MeO-DMT. Measures of cognition, mood, and well-being were not affected by 5-MeO-DMT. Vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and resolved spontaneously. Individualized dose escalation of 5-MeO-DMT may be preferable over single dose administration for clinical applications that aim to maximize the experience to elicit a strong therapeutic response.

•Insulin is unstable in hemolyzed blood, but stable in serum/plasma.•Insulin degrades in the presence of hemoglobin.•The globin part is mainly responsible for the degradation.•Modified A- and B-chains appear to be intermediate degradation products of insulin.•Acidification reduced in-vitro insulin degradation. Since lethal insulin injection has been used in murder and suicide cases, its non-ambiguous detection in postmortem, mostly hemolytic blood samples is still a problem. In the present study the stability of insulin and reasons for its loss in those blood samples were examined. When incubated with buffer, serum or with intact blood cell suspensions insulin concentrations were found to remain stable over time, but a significant loss of insulin was observed in hemolyzed blood samples. This was not due to an enzymatic cleavage, but predominantly to the presence of hemoglobin. Incubation of insulin with a hemoglobin solution containing the same hemoglobin content as hemolyzed blood caused a dramatic decrease of the insulin concentration. Degradation of insulin reached its maximum after 23h of incubation. The charge state of the ferric ion of hemoglobin could not be held accountable for the insulin-loss, but rather the protein part of hemoglobin. Alkylation experiments using iodoacetamide suggested that the thiol groups of the globin molecule are involved in the insulin loss preventing degradation at least partially. The same was observed by lowering the pH to 2.7 in the incubation mixture. Two degradation products of insulin were identified by mass spectrometry such as modified insulin A and B chains with 4 (A chain) and 2Da (B chain) lower masses. These results suggest that thiol groups of hemoglobin cause splitting of the disulfide bonds of insulin which immediately leads to the formation of new intramolecular disulfide bridges, a reaction which occurs in hemolytic blood and may explain the gradual loss of insulin in postmortem blood samples.

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.

The effects of acute and chronic intakes of high doses of alcohol on pain perception are well known, ranging from short-term analgesic effects to long-term sensitization and polyneuropathies. The short-term analgesic effects of ethanol consumption on subjective pain perception have been well studied in the literature. Recent advances in neuroimaging allow for an insight into pain-related structures in the brain, fostering the mechanistic understanding of the processing of nociceptive input and pain. We aimed to utilize EEG, combined with standardized noxious mechanical/thermal stimulation and subjective pain testing, to research the effects of acute alcohol intake on nociceptive processing and pain perception. We recruited 12 healthy subjects in an unblinded cross-over study design and aimed at achieving a blood alcohol level of 0.1%. Our data revealed a significant reduction in subjective pain ratings to noxious thermal and mechanical stimuli after alcohol ingestion. Our EEG data revealed suppressing effects on the cortical structures responsible for processing pain, the “pain matrix”. We conclude that in addition to its analgesic effects, as expressed by the reduction in subjective pain, alcohol has a further impact on the “pain matrix” and directly affects the salience to a nociceptive stimulus.

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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.

3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses. The current, first-in-human study ( N  = 14) assessed the impact of three escalating doses of 3-MMC (25, 50 and 100 mg) on vital signs, neurocognitive function, state of consciousness, appetite and drug desire, in a cross-over, placebo-controlled trial. A battery of neurocognitive tests and questionnaires as well as measures of vital signs were repeatedly administered up to 5 h after dosing. Overall, 3-MMC caused dose-dependent increases in heart rate and blood pressure, though not of clinical significance, and feelings of subjective high. Additionally, 3-MMC induced dose-related enhancement of task performance across several neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention and memory. Impulse control was not affected by 3-MMC. Participants also reported mild increases in dissociative and psychedelic effects, decreased appetite, and gave greater ratings of liking and wanting for 3-MMC that were transient over time. Overall, the cardiovascular, psychostimulant and psychotomimetic profile of 3-MMC appears consistent with that of compounds structurally related to amphetamine. It is concluded that low to moderate doses of 3-MMC were well tolerated and safe and that potential health risks might only occur at high or excessive doses of 3-MMC.