Metabolic profiling of four synthetic stimulants, including the novel indanyl-cathinone 5-PPDi, after human hepatocyte incubation

Synthetic cathinones are new psychoactive substances that represent a health risk worldwide. For most of the 130 reported compounds, information about toxicology and/or metabolism is not available, which hampers their detection (and subsequent medical treatment) in intoxication cases. The principles of forensic analytical chemistry and the use of powerful analytical techniques are indispensable for stablishing the most appropriate biomarkers for these substances. Human metabolic fate of synthetic cathinones can be assessed by the analysis of urine and blood obtained from authentic consumers; however, this type of samples is limited and difficult to access. In this work, the metabolic behaviour of three synthetic cathinones (4-CEC, 4-CPrC and 5-PPDi) and one amphetamine (3-FEA) has been evaluated by incubation with pooled human hepatocytes and metabolite identification has been performed by high-resolution mass spectrometry. This in vitro approach has previously shown its feasibility for obtaining excretory human metabolites. 4-CEC and 3-FEA were not metabolised, and for 4-CPrC only two minor metabolites were obtained. On the contrary, for the recently reported 5-PPDi, twelve phase I metabolites were elucidated. Up to our knowledge, this is the first metabolic study of an indanyl-cathinone. Data reported in this paper will allow the detection of these synthetic stimulants in intoxication cases, and will facilitate future research on the metabolic behaviour of other indanyl-based cathinones

Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality—A population-based longitudinal study in primary care with weak opioids most commonly prescribed

Funding Information: This research was supported by the Fund of Scientific Research of the Pharmaceutical Society of Iceland and the Research Fund of the Icelandic College of Family Physicians. Publisher Copyright: Copyright © 2022 Linnet, Thorsteinsdottir, Sigurdsson, Sigurdsson and Gudmundsson.Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent. Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol). Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10–69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years’ use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314). Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25–3.09) and in Group 4 where it was 5.12 (95% CI 4.25–6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54–6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08–9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs. Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.Peer reviewe

Association between prescription of hypnotics/anxiolytics and mortality in multimorbid and non-multimorbid patients: a longitudinal cohort study in primary care

Publisher's version (útgefin grein).Objectives To assess the risk of mortality in primary care patients, multimorbid (≥2 chronic conditions) or not, prescribed hypnotics/anxiolytics. Design A longitudinal cohort study Setting Primary healthcare in the Reykjavik area. Participants 114 084 individuals (aged 10-79 years, average 38.5, SD 18.4) contacting general practitioners during 2009-2012 (mortality follow-up to 31 December 2016). Of those, the reference group comprised 58 560 persons who were neither multimorbid nor had redeemed prescriptions for hypnotics/anxiolytics. Participants (16 108) redeeming prescriptions for hypnotics/anxiolytics on a regular basis for 3 consecutive years were considered as consistent, long-term users. They were subdivided into low-dose (1-300 defined daily doses (DDD)/3 years), medium-dose (301-1095 DDDs/3 years) and high-dose users (>1095 DDDs/3 years). All six groups taking these drugs were compared with the reference group. Main outcome measures All-cause mortality. Results HRs were calculated with the no multimorbidity-no drug group as a reference, using Cox proportional hazards regression model adjusting for age, sex and the number of chronic conditions (n=111 767), patients with cancer excluded. During follow-up, 516 358 person-years in total, 1926 persons died. Mean follow-up was 1685 days (4.6 years), range 1-1826 days (5.0 years). For all multimorbid patients who took no drugs the HR was 1.14 (95% CI 1.00 to 1.30) compared with those without multimorbidity. HRs in the non-multimorbid participants varied from 1.49 to 3.35 (95% CI ranging from 1.03 to 4.11) with increasing doses of hypnotics/anxiolytics, and correspondingly from 1.55 to 3.52 (1.18 to 4.29) in multimorbid patients. Conclusions Mortality increased in a dose-dependent manner among both multimorbid and non-multimorbid patients taking hypnotics/anxiolytics. This increase was clearly associated with prescribing of these drugs. Their use should be limited to the recommended period of 2-4 up to 6 weeks; long-term use may incur increased risk and should be re-examined.This research was supported by the Research Fund of the Icelandic College of Family Physicians and the Fund of Scientific Research of the Pharmaceutical Society of Iceland.Peer Reviewe

How primary healthcare in Iceland swiftly changed its strategy in response to the COVID-19 pandemic

Funding Information: Contributors All authors contributed to the planning, conduct and reporting of the study. ELS, JSJ, MOT, HH, KL worked on acquisition of the data. ELS, ABB and JSJ drafted the manuscript with input from MOT, HH, KL and JAS which was critically reviewed by all the authors. HH performed the statistical analysis. ELS, ABB, JSJ, MOT, HH, KL, JAS read and approved the final version of the manuscript. Funding This research was supported by the Research Fund of the Icelandic College of Family Physicians. Publisher Copyright: ©Objective To describe how the primary healthcare (PHC) in Iceland changed its strategy to handle the COVID-19 pandemic. Design Descriptive observational study. Setting Reykjavik, the capital of Iceland. Population The Reykjavik area has a total of 233 000 inhabitants. Main outcome measures The number and the mode of consultations carried out. Drug prescriptions and changes in the 10 most common diagnoses made in PHC. Laboratory tests including COVID-19 tests. Average numbers in March and April 2020 compared with the same months in 2018 and 2019. Results Pragmatic strategies and new tasks were rapidly applied to the clinical work to meet the foreseen healthcare needs caused by the pandemic. The number of daytime consultations increased by 35% or from 780 to 1051/1000 inhabitants (p<0.001) during the study period. Telephone and web-based consultations increased by 127% (p<0.001). The same tendency was observed in out-of-hours services. The number of consultations in maternity and well-child care decreased only by 4% (p=0.003). Changes were seen in the 10 most common diagnoses. Most noteworthy, apart from a high number of COVID-19 suspected disease, was that immunisation, depression, hypothyroidism and lumbago were not among the top 10 diagnoses during the epidemic period. The number of drug prescriptions increased by 10.3% (from 494 to 545 per 1000 inhabitants, p<0.001). The number of prescriptions from telephone and web-based consultations rose by 55.6%. No changes were observed in antibiotics prescriptions. Conclusions As the first point of contact in the COVID-19 pandemic, the PHC in Iceland managed to change its strategy swiftly while preserving traditional maternity and well-child care, indicating a very solid PHC with substantial flexibility in its organisation.Peer reviewe

Association between prescription of hypnotics/anxiolytics and mortality in multimorbid and non-multimorbid patients: a longitudinal cohort study in primary care.

ObjectivesTo assess the risk of mortality in primary care patients, multimorbid (≥2 chronic conditions) or not, prescribed hypnotics/anxiolytics.DesignA longitudinal cohort studysettingPrimary healthcare in the Reykjavik area.Participants114 084 individuals (aged 10–79 years, average 38.5, SD 18.4) contacting general practitioners during 2009–2012 (mortality follow-up to 31 December 2016). Of those, the reference group comprised 58 560 persons who were neither multimorbid nor had redeemed prescriptions for hypnotics/anxiolytics. Participants (16 108) redeeming prescriptions for hypnotics/anxiolytics on a regular basis for 3 consecutive years were considered as consistent, long-term users. They were subdivided into low-dose (1–300 defined daily doses (DDD)/3 years),medium-dose (301–1095 DDDs/3 years) and high-dose users (>1095 DDDs/3 years). All six groups taking these drugs were compared with the reference group.Main outcome measuresAll-cause mortality.resultsHRs were calculated with the no multimorbidity—no drug group as a reference, using Cox proportional hazards regression model adjusting for age, sex and the number of chronic conditions (n=111 767), patients with cancer excluded. During follow-up, 516 358 person-years in total,1926 persons died. Mean follow-up was 1685 days (4.6years), range 1–1826 days (5.0 years). For all multimorbid patients who took no drugs the HR was 1.14 (95% CI 1.00 to 1.30) compared with those without multimorbidity. HRs in the non-multimorbid participants varied from 1.49 to 3.35(95% CI ranging from 1.03 to 4.11) with increasing doses of hypnotics/anxiolytics, and correspondingly from 1.55 to 3.52 (1.18 to 4.29) in multimorbid patients.ConclusionsMortality increased in a dose-dependent manner among both multimorbid and non-multimorbid patients taking hypnotics/anxiolytics. This increase was clearly associated with prescribing of these drugs. Their use should be limited to the recommended period of 2–4 up to 6 weeks; long-term usemay incur increased risk and should be re-examined

Association between prescription of hypnotics/anxiolytics and mortality in multimorbid and non-multimorbid patients: a longitudinal cohort study in primary care

ObjectivesTo assess the risk of mortality in primary care patients, multimorbid (≥2 chronic conditions) or not, prescribed hypnotics/anxiolytics.DesignA longitudinal cohort studySettingPrimary healthcare in the Reykjavik area.Participants114 084 individuals (aged 10–79 years, average 38.5, SD 18.4) contacting general practitioners during 2009–2012 (mortality follow-up to 31 December 2016). Of those, the reference group comprised 58 560 persons who were neither multimorbid nor had redeemed prescriptions for hypnotics/anxiolytics. Participants (16 108) redeeming prescriptions for hypnotics/anxiolytics on a regular basis for 3 consecutive years were considered as consistent, long-term users. They were subdivided into low-dose (1–300 defined daily doses (DDD)/3 years), medium-dose (301–1095 DDDs/3 years) and high-dose users (&gt;1095 DDDs/3 years). All six groups taking these drugs were compared with the reference group.Main outcome measuresAll-cause mortality.ResultsHRs were calculated with the no multimorbidity—no drug group as a reference, using Cox proportional hazards regression model adjusting for age, sex and the number of chronic conditions (n=111 767), patients with cancer excluded. During follow-up, 516 358 person-years in total, 1926 persons died. Mean follow-up was 1685 days (4.6 years), range 1–1826 days (5.0 years). For all multimorbid patients who took no drugs the HR was 1.14 (95% CI 1.00 to 1.30) compared with those without multimorbidity. HRs in the non-multimorbid participants varied from 1.49 to 3.35 (95% CI ranging from 1.03 to 4.11) with increasing doses of hypnotics/anxiolytics, and correspondingly from 1.55 to 3.52 (1.18 to 4.29) in multimorbid patients.ConclusionsMortality increased in a dose-dependent manner among both multimorbid and non-multimorbid patients taking hypnotics/anxiolytics. This increase was clearly associated with prescribing of these drugs. Their use should be limited to the recommended period of 2–4 up to 6 weeks; long-term use may incur increased risk and should be re-examined.</jats:sec

How primary healthcare in Iceland swiftly changed its strategy in response to the COVID-19 pandemic

Objective To describe how the primary healthcare (PHC) in Iceland changed its strategy to handle the COVID-19 pandemic.Design Descriptive observational study.Setting Reykjavik, the capital of Iceland.Population The Reykjavik area has a total of 233 000 inhabitants.Main outcome measures The number and the mode of consultations carried out. Drug prescriptions and changes in the 10 most common diagnoses made in PHC. Laboratory tests including COVID-19 tests. Average numbers in March and April 2020 compared with the same months in 2018 and 2019.Results Pragmatic strategies and new tasks were rapidly applied to the clinical work to meet the foreseen healthcare needs caused by the pandemic. The number of daytime consultations increased by 35% or from 780 to 1051/1000 inhabitants (p&lt;0.001) during the study period. Telephone and web-based consultations increased by 127% (p&lt;0.001). The same tendency was observed in out-of-hours services. The number of consultations in maternity and well-child care decreased only by 4% (p=0.003). Changes were seen in the 10 most common diagnoses. Most noteworthy, apart from a high number of COVID-19 suspected disease, was that immunisation, depression, hypothyroidism and lumbago were not among the top 10 diagnoses during the epidemic period. The number of drug prescriptions increased by 10.3% (from 494 to 545 per 1000 inhabitants, p&lt;0.001). The number of prescriptions from telephone and web-based consultations rose by 55.6%. No changes were observed in antibiotics prescriptions.Conclusions As the first point of contact in the COVID-19 pandemic, the PHC in Iceland managed to change its strategy swiftly while preserving traditional maternity and well-child care, indicating a very solid PHC with substantial flexibility in its organisation