Pharmacological Reports最新文献

{"title":"Clozapine levels in inpatients with schizophrenia are not a predictor of rehospitalization: a naturalistic retrospective study.","authors":"Anna Mach, Przemysław Bieńkowski, Anna Wnorowska, Mateusz Sypniewski, Maria Radziwoń-Zaleska, Andrzej Pilc, Marcin Wojnar","doi":"10.1007/s43440-026-00861-7","DOIUrl":"10.1007/s43440-026-00861-7","url":null,"abstract":"<p><strong>Background: </strong>Although therapeutic drug monitoring (TDM) is recommended for personalized clozapine (CLO) dose titration, there are no widely accepted international guidelines regarding routine TDM during long-term outpatient CLO treatment and many clinicians have limited access to TDM. This retrospective, naturalistic study aimed to examine whether CLO and norclozapine (NCLO) concentrations measured only at the time of inpatient care could predict the risk of psychiatric rehospitalization after discharge, irrespective of the potential influence of confounding factors on long-term outcomes.</p><p><strong>Methods: </strong>A total of 141 blood samples from psychiatric inpatients (71 females and 70 males, aged from 18 to 74 years) were analyzed. Serum CLO and NCLO levels were determined with high-performance liquid chromatography coupled with a UV detector. We assessed the rates of rehospitalization over 360 days after discharge.</p><p><strong>Results: </strong>There was no correlation between either CLO or NCLO concentrations and psychiatric rehospitalization rates at any follow-up time points (day 90, 180, or 360). However, patients receiving CLO as a single psychotropic drug had significantly fewer rehospitalizations (assessed at 180 and 360 days of follow-up, p < 0.001) occurred among patients receiving CLO as a single psychotropic drug compared to combination therapy. The risk of rehospitalization was also higher in patients with a greater number of previous hospitalizations (OR = 1.15, p = 0.002) and in those taking additional psychotropic drugs (OR = 1.51, p = 0.010).</p><p><strong>Conclusions: </strong>Our naturalistic retrospective study (based on an in-hospital TDM database) showed no association between the baseline steady-state CLO and NCLO levels established during hospitalization and the risk of psychiatric rehospitalization. However, the use of CLO in combination with other psychotropic drugs and the number of previous hospitalizations correlated with the risk of rehospitalization.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1208-1216"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aripiprazole modulates splenic microbiota and immune response elicited by single prolonged stress in rats.","authors":"Peter Vargovic, Andrej Tillinger, Lubica Horvathova, Lila Dziewiczova, Jana Osacka","doi":"10.1007/s43440-026-00882-2","DOIUrl":"10.1007/s43440-026-00882-2","url":null,"abstract":"<p><strong>Background: </strong>Post-traumatic stress disorder (PTSD) is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenomedullary system, leading to immune imbalance and alterations in microbiota composition. Stress-induced disruption of intestinal barrier integrity may promote bacterial translocation to peripheral organs, including the spleen. Aripiprazole (ARI), an atypical antipsychotic proposed for PTSD treatment, also modulates the immune system and microbiota. This study investigated the effects of ARI on splenic microbiota composition and splenic neuroendocrine and immune responses in an animal model of PTSD.</p><p><strong>Methods: </strong>Rats were exposed to the single prolonged stress (SPS) paradigm to induce a PTSD-like phenotype and treated intraperitoneally with vehicle or ARI for 28 days. Anxiety-like behavior was assessed using the elevated plus maze. Splenic microbiota and gene expression were quantified by real-time PCR in isolated splenocytes following ex vivo stimulation with lipopolysaccharide or phorbol 12-myristate 13-acetate (PMA)/ionomycin.</p><p><strong>Results: </strong>SPS and SPS + ARI reduced the abundance of the phylum Bacteroidetes. SPS increased γ/δ-Proteobacteria and Lactobacillus abundance, effects attenuated by ARI. The presence of specific splenic bacteria correlated with anxiety-like behavior. While lipopolysaccharide-induced responses were unaffected, splenocytes from SPS-exposed rats exhibited increased expression of Th1- and Th17-related genes after PMA/ionomycin stimulation; this effect was reversed by ARI.</p><p><strong>Conclusion: </strong>ARI modulates SPS-induced alterations in splenic microbiota and attenuates heightened Th1- and Th17-associated responses, thereby contributing to the restoration of immune balance. Our findings underscore involvement of the gut-spleen-brain axis in PTSD pathogenesis and immunosuppressive/ microbiota-modulating effects of aripiprazole on splenic immune cells.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1102-1118"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment-emergent psychiatric adverse events in patient-reported outcomes during ketamine use for major depressive disorder: a retrospective analysis.","authors":"Aleksander Kwaśny, Alina Wilkowska, Michał Pastuszak, Krzysztof Pastuszak, Wiesław Jerzy Cubała","doi":"10.1007/s43440-026-00867-1","DOIUrl":"10.1007/s43440-026-00867-1","url":null,"abstract":"<p><strong>Background: </strong>Treatment-resistant depression (TRD) poses a significant therapeutic challenge, with remission often unattainable. Recognition and detection of treatment-emergent adverse events (TEAEs) are essential, as these events may significantly influence the quality of treatment response. This knowledge aids in personalizing care and selecting the best treatment strategy.</p><p><strong>Methods: </strong>In a retrospective analysis of an observational study of inpatients (n = 28) with TRD, who were administered 8 ketamine infusions as an add-on therapy, psychiatric TEAEs were assessed using the Inventory of Depressive Symptomatology Self-Report 30 (IDS SR-30) and defined as symptoms that were not present at baseline but emerged during ketamine administration. The protocol was registered at ClinicalTrials.gov on Jan 2, 2020 (NCT04226963).</p><p><strong>Results: </strong>Sleep disturbances were the most consistently reported psychiatric TEAEs, with nighttime sleep problems increasing by the 7th infusion and persisting at follow-up (n = 5), and early waking reported across timepoints (n = 3-4). Appetite and weight changes were also observed, with both increased and decreased appetite peaking early in treatment (n = 7 and n = 6 at the 3rd infusion) and persisting at lower levels at follow-up. In contrast, mood, cognitive, and most somatic symptoms were rare (≤ 2-4 participants), and suicidal ideation was minimal (n = 1 at the 3rd infusion and follow-up).</p><p><strong>Conclusions: </strong>This study identified sleep disturbances, appetite changes, and weight fluctuations as common patient-reported TEAEs during ketamine use for TRD inpatients. These preliminary results highlight the need for larger, controlled trials to gain a comprehensive understanding of ketamine's psychiatric safety profile.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1292-1300"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147974365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of combining mirogabalin with antidepressants in relieving hypersensitivity: evidence from a mouse model of neuropathic pain.","authors":"Renata Zajączkowska, Agata Ciechanowska, Katarzyna Pawlik, Katarzyna Ciapała, Wioletta Makuch, Jerzy Wordliczek, Magdalena Kocot-Kępska, Joanna Mika","doi":"10.1007/s43440-026-00862-6","DOIUrl":"10.1007/s43440-026-00862-6","url":null,"abstract":"<p><strong>Background: </strong>Neuropathic pain remains a significant clinical problem that necessitates the development of more effective treatment options. Compared with commonly used clinical drugs, such as gabapentin and pregabalin, mirogabalin is a novel gabapentinoid that exhibits greater affinity and selectivity for the α2δ-1/-2 subunits of voltage-gated calcium channels, properties associated with strong nociceptive modulation. The aim of this study was to determine whether and how mirogabalin influences neuropathy symptoms and the antinociceptive effects of antidepressants (amitriptyline and duloxetine).</p><p><strong>Methods: </strong>Studies were conducted in mice after chronic constriction injury of the sciatic nerve. On Day 7, a single intraperitoneal administration of mirogabalin (5-60 mg/kg), amitriptyline (1-10 mg/kg), or duloxetine (10-30 mg/kg) at various doses was performed. Additionally, mirogabalin (10 mg/kg) was chronically injected twice daily, while amitriptyline (5 mg/kg) or duloxetine (10 mg/kg) was administered once daily. Hypersensitivity was assessed using the von Frey and the cold plate tests.</p><p><strong>Results: </strong>Using a mouse model of neuropathy, a single injection of mirogabalin, amitriptyline, or duloxetine reduced tactile and thermal hypersensitivity to a similar degree, with the most durable effect observed with mirogabalin, persisting up to 6 hours. Repeated twice-daily intraperitoneal administration of mirogabalin combined with once-daily intraperitoneal dosing of amitriptyline or duloxetine resulted in a potentiated anti-nociceptive response in the used model.</p><p><strong>Conclusions: </strong>These results may serve as a basis for further evaluation of the potential use of mirogabalin in the clinical treatment of neuropathic pain. Furthermore, they suggest that using mirogabalin together with amitriptyline or duloxetine may provide significant therapeutic benefits, enabling the use of lower doses of these medications, which may reduce the risk of adverse events.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1058-1073"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148043301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase-specific involvement of BDNF-TrkB signaling in HSV-1-induced herpetic pain and its transition to postherpetic neuralgia-like pain.","authors":"Ichiro Takasaki, Arata Inoue, Aoi Yoshida, Yuya Ashihara, Hiroyuki Mori","doi":"10.1007/s43440-026-00880-4","DOIUrl":"10.1007/s43440-026-00880-4","url":null,"abstract":"<p><strong>Background: </strong>Postherpetic neuralgia (PHN) is a chronic neuropathic pain condition that develops following herpes zoster, yet the molecular mechanisms underlying the transition from acute herpetic pain to chronic pain remain unclear. Brain-derived neurotrophic factor (BDNF)-TrkB signaling is implicated in central sensitization, but its role in virus-induced pain chronification is unknown. Therefore, this study investigated the temporal involvement of BDNF-TrkB signaling in acute herpetic pain and in the development of PHN-like pain.</p><p><strong>Methods: </strong>A herpes simplex virus type-1 (HSV-1)-induced mouse model of herpetic pain was used to evaluate temporal changes in neurotrophin and Trk receptor expression in the dorsal root ganglia (DRG) and spinal dorsal horn. Pharmacological interventions included intrathecal administration of anti-BDNF, anti-Trk receptor antibodies or TrkB-Fc chimera, and repeated systemic treatment with the TrkB antagonist ANA-12 during the acute phase. Mechanical allodynia was behaviorally assessed.</p><p><strong>Results: </strong>BDNF mRNA expression was significantly upregulated in ipsilateral DRG and spinal dorsal horn during the acute phase, whereas neurotrophin-3 remained unchanged and nerve growth factor showed only transient increases in DRG. No neurotrophin or Trk receptor changes were observed in established PHN-like pain. Intrathecal administration of anti-BDNF antibody, anti-TrkB antibody, or TrkB-Fc chimera significantly attenuated acute mechanical allodynia, whereas anti-TrkA and anti-TrkC antibodies showed no significant effects. None of these interventions affected established PHN-like pain. Repeated administration of the TrkB antagonist ANA-12 during the acute phase attenuated acute herpetic pain and significantly reduced the subsequent incidence of PHN-like pain.</p><p><strong>Discussion: </strong>BDNF-TrkB signaling plays a phase-specific role in herpetic pain, driving acute pain expression and the transition to chronic PHN-like pain but not pain maintenance. Early TrkB inhibition may represent a disease-modifying strategy to prevent viral pain chronification.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1074-1086"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the serotonin-alcohol crosstalk: the role of central serotonergic dysregulation in alcohol use disorder.","authors":"Magdalena Zaniewska","doi":"10.1007/s43440-026-00860-8","DOIUrl":"10.1007/s43440-026-00860-8","url":null,"abstract":"<p><p>Serotonin (5-hydroxytryptamine; 5-HT) is a key neuromodulator involved in the regulation of mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function has been implicated in alcohol use disorder (AUD) and comorbid depression. This review summarizes clinical and preclinical evidence on the role of 5-HT in AUD development, heterogeneity, and treatment response. Alterations in 5-HT function may be shaped by stress and genetic variation in serotonergic genes, including TPH2 and SLC6A4, contributing to individual vulnerability to AUD. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger's type II, characterized by early onset, violent, and antisocial behaviors. Consistently, Tph2-deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling Cloninger's type II alcohol dependence. Similarly, alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT_2A receptor binding, implicating raphe-prefrontal serotonergic projections as a critical pathway modulating vulnerability to AUD. Given the heterogeneity of AUD, the efficacy of selective 5-HT reuptake inhibitors (SSRIs) remains limited, with beneficial effects observed only in less severe, later-onset forms. Recently, serotonergic psychedelic-assisted therapies have attracted considerable interest as potential AUD treatments; mechanistically, their effects may be linked to activation of 5-HT_2A receptors in the prefrontal cortex - a brain region known to be dysfunctional in AUD. The reviewed literature highlights the need for improved stratification of AUD subtypes and validation of 5-HT-related biomarkers to guide personalized therapeutic approaches.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"945-980"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-target-directed drugs: new additions in 2025 and post-marketing safety surveillance of drugs marketed in 2022-2024.","authors":"Piotr Ryszkiewicz, Marta Baranowska-Kuczko, Barbara Malinowska, Eberhard Schlicker","doi":"10.1007/s43440-026-00879-x","DOIUrl":"10.1007/s43440-026-00879-x","url":null,"abstract":"<p><p>Polypharmacology is dedicated to the development of compounds acting on at least two targets (multi-target-directed ligands, MTDLs). In 2025, the European Medicines Agency (EMA) approved 38 drugs, and 11 out of them were MTDLs. Most of them are antibody-drug conjugates, bispecific antibodies, or kinase inhibitors, all of which are indicated for tumor treatment, including datopotamab deruxtecan (hormone receptor-positive, HER2-negative breast cancer), tisotumab vedotin (advanced cervical carcinoma), linvoseltamab (fourth-line treatment of multiple myeloma), and erdafitinib (advanced urothelial carcinoma). The small molecule tiratricol is an orphan drug, which is indicated for the treatment of the very rare Allan-Herndon-Dudley syndrome. The second part of the present review is dedicated to the post-marketing safety surveillance of MTDLs approved by the EMA in 2022-2024. For 19 out of the 27 MTDLs, which are still available on the European market, comprehensive pharmacovigilance studies, mainly based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), were found. New safety signals have been identified, including Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy. The analysis also revealed a more favorable safety profile of the MTDL tirzepatide (a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide analogue) compared to the single-targeted drug semaglutide (glucagon-like peptide-1 analogue), including lower reporting rates of acute kidney injury and no significant suicidality signal.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1022-1044"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Wistar-Kyoto rat as a model relevant to inattentive ADHD: substrain variability and affective comorbidity.","authors":"Natalia Gaik, Emil Dzierkacz, Agata Faron-Górecka","doi":"10.1007/s43440-026-00878-y","DOIUrl":"10.1007/s43440-026-00878-y","url":null,"abstract":"<p><p>Wistar-Kyoto (WKY) rats, originally used as a control group for spontaneously hypertensive rats, are increasingly recognized as a valuable model for studying selected neuropsychiatric disorders. This strain exhibits behavioral and neurobiological traits relevant to both depression and inattentive attention-deficit/hyperactivity disorder (ADHD), including behavioral inhibition, increased stress sensitivity, anhedonic behaviors, and deficits in sustained attention. At the same time, a significant challenge remains in the form of considerable variability among WKY substrains, resulting from genetic differences and the breeding practices employed by individual suppliers. This variability may limit the reproducibility of results, but it also holds research value, enabling the analysis of distinct dimensions of mental disorders within related animal models. The aim of this review is to integrate available data on the genealogy, genetic variability, and behavioral phenotypes of WKY rats, with particular emphasis on their relevance to ADHD research and on depression-related traits that may influence the interpretation of WKY rats as a reference or disease-relevant strain. The added value of the present review is therefore to provide an integrated ADHD-oriented perspective on the WKY strain, while also considering depression-related and treatment-response traits as biologically relevant components of its complex behavioral phenotype.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1005-1021"},"PeriodicalIF":4.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148423135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics of total and free mycophenolic acid in plasma in paediatric patients with nephrotic syndrome including salivary concentrations and the pharmacodynamics.","authors":"Astrid Heida, Danuta Ostalska-Nowicka, Jacek Zachwieja, Nynke G L Jager, Rob Ter Heine, Joanna Sobiak","doi":"10.1007/s43440-026-00885-z","DOIUrl":"https://doi.org/10.1007/s43440-026-00885-z","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic drug monitoring (TDM) may optimize dosing of mycophenolate mofetil (MMF) in patients with nephrotic syndrome, but it is not routinely implemented. When performed, TDM typically relies on total mycophenolic acid (MPA) concentrations, although only unbound MPA is pharmacologically active. This study aimed to develop a population pharmacokinetic (PK) model characterizing the PK and pharmacodynamics (PD) of total and unbound MPA in plasma and saliva of paediatric nephrotic syndrome patients following oral MMF.</p><p><strong>Methods: </strong>PK/PD data from 62 children (47 full and 21 limited sampling curves) were analysed using nonlinear mixed-effects modelling.</p><p><strong>Results: </strong>A two-compartment model with first-order absorption best describes unbound MPA PK. Protein binding was captured using a nonlinear saturable binding equation. The final population PK parameter estimates (for unbound MPA) were absorption rate constant (k_a), 1.81 h^-1 (relative standard error (RSE): 8%); apparent clearance (Cl/F), 2550 L h^-1 (RSE: 8%); apparent central volume (V_c/F), 1590 L (RSE: 27%); apparent peripheral volume (V_p/F), 239,000 L (RSE: 52%); apparent intercompartmental clearance (Q/F), 1940 L h^-1 (RSE: 13%); maximal binding capacity (B_max), 196 µmol (RSE: 44%); dissociation constant (K_d), 0.75 µmol L^-1 (RSE: 49%). Saliva and unbound plasma MPA showed a proportional relationship (saliva/plasma ratio: 1.34, RSE: 24%). The PK-PD relationship between unbound MPA and inosine monophosphate dehydrogenase (IMPDH) activity was described by a sigmoid inhibitory effect model with a baseline parameter. The population estimates were baseline effect, 66.4 (RSE: 21%); unbound plasma concentration for 50% inhibition, 0.0251 (RSE: 27%); shape parameter, 0.559 (RSE:22%). A limited sampling strategy allowed acceptable prediction of unbound MPA area under the concentration-time curve from 0 to 12 hours (AUC_0-12 h) but not IMPDH activity.</p><p><strong>Conclusion: </strong>The developed model provides a foundation for model-informed precision dosing of MMF in children with nephrotic syndrome.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated hypoxia-inducible factor-1α in pediatric patients with patent ductus arteriosus: a pilot study.","authors":"Oksana Trębacz, Patrycja Florek, Jacek Podlewski, Teresa Iwaniec, Wojciech Tarała, Piotr Weryński, Łukasz Niemiec, Bernadeta Szewczyk","doi":"10.1007/s43440-026-00883-1","DOIUrl":"https://doi.org/10.1007/s43440-026-00883-1","url":null,"abstract":"<p><strong>Background: </strong>Children with complex cyanotic congenital heart disease (CHD) and with pulmonary hypertension (PH) commonly experience hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of cellular responses to low oxygen, and its levels are elevated in these conditions. However, HIF-1α concentrations in non-cyanotic CHD, such as patent ductus arteriosus (PDA), remain largely unknown. This study aimed to evaluate circulating serum HIF-1α levels in patients with PDA and compare them with those in healthy children and in patients with complex CHD after Fontan palliation.</p><p><strong>Methods: </strong>Eighty children were assigned to three groups: PDA group (n = 34), Fontan group (n = 23), and healthy controls (n = 23). Complete blood counts, serum HIF-1α levels, and baseline clinical characteristics were collected. Multiple regression analysis was performed to identify predictors of HIF-1α variability. Receiver operating characteristic (ROC) curves were analyzed to evaluate the ability of selected variables to predict increased HIF-1α levels.</p><p><strong>Results: </strong>Patients with PDA exhibited the highest median [IQR] HIF-1α levels (0.62 [0.41-1.18] ng/mL), compared to patients in the Fontan group (0.52 [0.34-0.73] ng/mL), and healthy controls (0.48 [0.33-0.63] ng/mL) (p = 0.03). In the combined CHD cohort, hemoglobin, age, and red blood cell count formed the best predictive model, explaining 53.9% of HIF-1α variance (p < 0.01). Hematocrit < 36.6% and hemoglobin < 12.9 g/dL showed the best diagnostic accuracy for identifying HIF-1α > 1.1 ng/mL.</p><p><strong>Conclusions: </strong>Children with PDA, even without PH, exhibit elevated circulating HIF-1α. Further research is needed to clarify the clinical relevance of HIF-1α in non-cyanotic CHD.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}