Allogeneic adipose tissue-derived mesenchymal stem cells in ischaemic stroke (AMASCIS-02): A phase IIb, multicentre, double-blind, placebo-controlled clinical trial protocol

Introduction Stroke is a serious public health problem, given it is a major cause of disability worldwide despite the spread of recanalisation therapies. Enhancement of brain plasticity with stem cell administration is a promising innovative therapy to reduce sequelae in these patients. Methods and analysis We have developed a phase IIb, multicentre, randomised, double-blind, placebo-controlled clinical trial protocol to evaluate the safety and efficacy of intravenous administration of allogeneic adipose tissue-derived mesenchymal stem cells (AD-MSCs) in patients with acute ischaemic stroke, concurrently with conventional stroke treatment. Thirty patients will be randomised on a 1:1 basis to receive either intravenous placebo or allogeneic AD-MSCs as soon as possible within the first 4 days from stroke symptom onset. Patients will be followed up to 24 months after randomisation. The primary objective is the safety assessment of early intravenous administration of allogeneic AD-MSCs by reporting all adverse events and neurological or systemic complications in both treatment groups. Secondary objectives assess efficacy of early intravenous AD-MSC treatment in acute ischaemic stroke by evaluating changes in the modified Rankin Scale and the National Institutes of Health Stroke Scale throughout the follow-up period. In addition, brain repair biomarkers will be measured at various visits. Ethics and dissemination This clinical trial has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and by the Spanish Agency of Medication and Health Products and has been registered in Eudra CT (2019-001724-35) and ClinicalTrials.gov (NCT04280003). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentationsThis clinical trial has been promoted by the La Paz University Hospital Institute for Health Research—IdiPAZ (La Paz University Hospital—Universidad Autónoma de Madrid) and sponsored from a competitive grant from the Carlos III Health Institute Healthcare Research Fund, and cofunded by the European Regional Development Fund (ERDF) 'A way to make Europe'/'Investing in your future' (PIC18/00016). This clinical trial has been supported by Plataforma Española de Investigación Clínica y Ensayos Clínicos, SCReN (Spanish Clinical Research Network), funded by Carlos III Health Institute-General Subdirection for Evaluation and Promotion of Research, research PT17/0017/0013; State Plan for Scientific Investigation, Technology and Innovation (2017–2020) and cofunded by European Regional Development Fund/European Social fund 'A way to make Europe'/'Investing in your future' (grant ID PT17/0017/0013

Incidence of suspected serious adverse drug reactions in corona virus Ddsease-19 patients detected by a pharmacovigilance program by laboratory signals in a tertiary hospital in Spain: Cautionary data

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients vs. non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis, and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89–816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients, 95% CI 137.09–186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53–154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events

Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

Background: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. Objective: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.Methods: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. Results: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. Conclusion: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib

Developments in pharmacogenetics, pharmacogenomics, and personalized medicine

The development of Pharmacogenetics and Pharmacogenomics in Western Europe is highly relevant in the worldwide scenario. Despite the usually low institutional support, many research groups, composed of basic and clinical researchers, have been actively working for decades in this field. Their contributions made an international impact and paved the way for further studies and pharmacogenomics implementation in clinical practice. In this manuscript, that makes part of the Special Issue entitled Spanish Pharmacology, we present an analysis of the state of the art of Pharmacogenetics and Pharmacogenomics research in Europe, we compare it with the developments in Spain, and we summarize the most salient contributions since 1988 to the present, as well as recent developments in the clinical application of pharmacogenomics knowledge. Finally, we present some considerations on how we could improve translation to clinical practice in this specific scenari

Appropriate use of red blood cell transfusion in emergency departments: A study in five emergency departments

BACKGROUND: Transfusion of blood components continues to be an important therapeutic resource into the 21st century. Between 5 and 58% of transfusions carried out are estimated to be unnecessary. According to several studies, at least 20% of packed red blood cell transfusions (RBCT) are administered in hospital emergency departments (ED), but few data are available about the appropriateness of RBCT in this setting. This multicentre, cross-sectional observational study aims to assess the appropriateness of RBCT indications and transfused volumes in patients who attend ED. MATERIALS AND METHODS: The study cohort is made up of consecutive consenting adult patients (≥18 years old) who received RBCT in ED over a 3-month period and for whom relevant clinical data were collected and analysed. RESULTS: Data from 908 RBCT episodes (2±1 units per transfused patient) were analysed. RBCT was considered appropriate in 21.4% (n=195), with significant differences according to RBCT indication (p<0.001), hospital level (p<0.001) and prescribing physician (p=0.002). Pre-transfusion haemoglobin level (Hb) negatively correlated with RBCT appropriateness (r=-0.616; p<0.01). Only 72.4% of appropriate RBCT had a post-transfusion Hb assessment (n=516). Of these, 45% were considered to be over-transfused (n=232), with significant differences according to RBCT indication (p=0.012) and prescribing physician (p=0.047). Overall, 584/1,433 (41%) of evaluable RBC units were unnecessarily transfused. DISCUSSION: The appropriateness of RBCT in ED is similar to other hospital departments, but the rate of over-transfusion was high. These data support the need for a reassessment after transfusion of each RBC unit before further units are prescribed. In view of these results, we recommend that physicians should be made more aware of the need to prescribe RBCT appropriately in order to reduce over-transfusionThis project has received funding from the Spanish Ministry of Health, Social Policy and Equality through the SAS/2377/2010 call for granting aid for the promotion of independent clinical research (Department of Pharmacy and Health Products), file n. EC10-21

Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

Purpose: Imatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects. Methods: 26 volunteers were administered orally with single dose of 400 mg imatinib. 16–19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated. Results: The popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01). Conclusion: The two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteersThis work was part of the master these of Yi-Han Chien. There was no funding for this work. P. Zubiaur’s contract with CIBERehd is fnanced by the “Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología (IMPaCT, IMP/00009)”, Instituto de Salud Carlos III (ISCIII

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

Immunogenic dynamics and SARS-CoV-2 variant neutralisation of the heterologous ChAdOx1-S/BNT162b2 vaccination: Secondary analysis of the randomised CombiVacS study

Heterologous vaccination; Neutralisation; SARS-CoV-2Vacunación heteróloga; Neutralización; SARS-CoV-2Vacunació heteròloga; Neutralització; SARS-CoV-2Background The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180. Methods Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739). Findings In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49–5956·71) in the IG and 7298·22 BAU/mL (6739·41–7903·37) in the CG (p 1:100 at day 180 (19% and 22%, respectively). Interpretation Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180.Funded by Instituto de Salud Carlos III (ISCIII)

Identification and validation of clinical phenotypes with prognostic implications in patients admitted to hospital with COVID-19: a multicentre cohort study

REIPI-SEIMC COVID-19 group and COVID@HULP group.[Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality.[Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model.[Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p<0·0001). The predicted phenotypes in the internal validation cohort and external validation cohort showed similar mortality rates to the assigned phenotypes (internal validation cohort: 5·3% [95% CI 3·4–8·1] for phenotype A, 31·3% [28·5–34·2] for phenotype B, and 59·5% [48·8–69·3] for phenotype C; external validation cohort: 3·7% [2·0–6·4] for phenotype A, 23·7% [21·8–25·7] for phenotype B, and 51·4% [41·9–60·7] for phenotype C).[Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated.[Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.Peer reviewe

Utility of Lymphocyte Transformation Test for Assisting Updated Roussel Uclaf Causality Assessment Method in Drug-Induced Liver Injury: A Case-Control Study

Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2–5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84–0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92