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Cognitive dysfunction is a core feature of schizophrenia. Although treatment-resistant schizophrenia (TRS) exhibits wide-ranging neuropsychological deficits, factors defining cognitive prognosis in TRS are unclear. We aimed to clarify the association between cognitive dysfunction and factors, such as plasma concentrations of clozapine (CLZ), N-desmethylclozapine (NDMC), and homovanillic acid (HVA), due to differences in antipsychotic responses in patients with schizophrenia. This pilot cross-sectional study included 60 Japanese patients (35 with TRS and 25 with non-CLZ antipsychotic responders (AR)). Cognitive function was evaluated using the Brief Assessment of Cognition Short Form (BAC-SF). Plasma concentrations of HVA, CLZ, and NDMC were analyzed by high-performance liquid chromatography. The cognitive performance of patients with AR was better than that of patients with TRS in all tasks. No significant cognitive differences were detected between the CLZ responders and non-responders. The severity of negative and extrapyramidal symptoms was found to be potentially negatively associated with BAC-SF composite and several subtest scores. In patients with TRS, chlorpromazine equivalents and the CLZ/NDMC ratio were identified as factors negatively associated with Digit Sequencing and the Symbol Coding subtest scores of the BAC-SF, respectively. Our study suggests that patients with TRS experience worse cognitive dysfunction than those with AR, and CLZ responsiveness in TRS may be not associated with cognitive dysfunction. Additionally, higher chlorpromazine equivalents and the CLZ/NDMC ratio may be associated with severity of cognitive dysfunction in patients with TRS. Further studies are required to clarify the relationship between treatment response and cognitive dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

Medication nonadherence (MNA) in organ transplant recipients is associated with increased risk of rejection, allograft loss, patient death, and higher healthcare costs. Various approaches have been used in an attempt to reduce MNA. A patient support program (PSP) can be an invaluable tool for improving patient outcomes. The aim of this study was to analyze available data of PSP for kidney transplant recipients. A total of 3352 patients from all over the country were prospectively enrolled in the Parichay PSP between January 2021 and April 2023. Baseline demographic details were recorded. A monthly call was made thereafter. Data were analyzed for demographic details, compliance rate, dropouts, and tacrolimus levels when available. The Parichay PSP had enrolled a total of 1371 kidney transplant patients in 2021, 1620 in 2022, and 361 in 2023 (January-April) from different parts of India (North, 25%; East, 35%; South, 26%; West, 14%). (n=2626) Of the 2626 patients who received tacrolimus (Tacrograf), 2158 (82%) were male, with a mean age of 42 years. The majority of patients (61%) were age 28 to 48 years. A patient compliance rate of >90% was maintained for longer than 13 months (n = 1920; April 2022 to April 2023). Of the 3352 patients, 250 (7.4%) dropped out of the study. Thus, use of PSP ensured a compliance rate of 92.6% in this study. This analysis demonstrates that participation in a PSP can be a useful tool for monitoring compliance and tacrolimus therapeutic drug monitoring in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

• Tacrolimus (TAC) concentration was increased by red cell concentrates transfusion. • TAC rate had a significantly strong positive correlation with red blood cell parameter rates. • The changes in whole-blood TAC concentration and red blood cell parameters were correlated • The relationship in kidney transplant recipients was assessed for the first time. Tacrolimus (TAC) is a narrow therapeutic range drug that requires therapeutic drug monitoring. TAC concentration is measured using whole blood owing to its high red blood cell (RBC) transfer rate of 95%. The distribution and whole-blood TAC concentration may be affected by the transfusion of red cell concentrates (RCCs); however, this has not been studied in kidney transplant recipients (KTR). Therefore, we investigated the relationship between changes in whole-blood TAC concentration and RBC parameters before and after RCC transfusion in KTR. Fifteen KTR who received TAC and RCC transfusions were enrolled. The change rates of RBC parameters (RBC count, hemoglobin [Hgb], hematocrit [Hct]), and TAC concentration/dose before and after transfusion were calculated. The correlation between each RBC parameter and the TAC rate was evaluated. The TAC concentration and rate increased after RCC transfusion. Moreover, the TAC rate showed a significant and strong correlation with RBC count, Hgb, and Hct, with RBC count showing the highest correlation coefficient (r = 0.811, 0.766, and 0.764, respectively; p <.01). Serum creatinine and potassium levels remained stable, suggesting the absence of typical adverse effects associated with TAC, such as acute kidney injury or hyperkalemia. Changes in whole-blood TAC concentration and RBC parameters were correlated, and whole-blood TAC concentration increased after RCC transfusion. Therefore, the TAC dose should be adjusted accordingly. [ABSTRACT FROM AUTHOR]

• High-dose individualized ATG with TDM is safe. • Actual exposures of ATG can be well predicted. • The protocol is effective to prevent GvHD and rejection in this high-risk population. Graft-versus-host disease (GvHD) and rejection are main limitations of cord blood transplantation (CBT), more so in patients with severe inflammation or previous rejections. While rigorous T-cell depletion with antithymocyte globulin (ATG) is needed to prevent GvHD and rejection, overexposure to ATG leads to slow T-cell recovery after transplantation, especially in CBT. To evaluate high-dose, upfront ATG with individualized dosing and therapeutic drug monitoring (TDM) in pediatric CBT for patients at high risk for GvHD and rejection. Heavily inflamed patients and patients with a recent history of rejection were eligible for individualized high-dose ATG with real-time TDM. The ATG dosing scheme was adjusted to target a post-CBT exposure of <10 AU*day/mL, while achieving a pre-CBT exposure of 60–120 AU*day/mL; exposure levels previously defined for optimal efficacy and safety in terms of reduced GvHD and rejection, respectively. Main outcomes of interest included efficacy (target exposure attainment) and safety (incidence of GvHD and rejection). Other outcomes of interest included T-cell recovery and survival. Twenty-one patients were included ranging from 2 months to 18 years old, receiving an actual median cumulative dose of ATG of 13.3 mg/kg (range 6–30 mg/kg) starting at a median 15 days (range 12–17) prior to CBT. Dosing was adjusted in 14 patients (increased in 3 and decreased in 11 patients). Eighteen (86%) and 19 (91%) patients reached the target pre-CBT and post-CBT exposure, respectively. Cumulative incidence for acute GvHD was 34% (95% CI 23–45) and 5% (95% CI 0–10%) for grade 2–4 and grade 3–4, respectively; cumulative incidence of rejection was 9% (95% CI 2–16%). Overall survival was 75% (95% CI 65–85%). Individualized high-dose ATG with TDM is feasible and safe for patients with hyperinflammation in a CBT setting. We observe high target ATG exposure attainment, good immune reconstitution (despite very high doses of ATG) and acceptable rates of GvHD and rejection. [ABSTRACT FROM AUTHOR]

There is growing interest in clozapine clinical use, monitoring, and research, particularly adverse drug reactions (ADRs) other than agranulocytosis. In this study we focused on clozapine pharmacovigilance. Hence, we contacted clinicians and researchers in Latin America and requested information about local psychiatric services, clozapine availability, clinical use, and ADR monitoring with the VigiBase system. Only two countries have the minimum recommended number of psychiatric beds (15 per 100,000 residents): Uruguay (N = 34.9) and Argentina (N = 17). Bolivia is the only country where clozapine is unavailable. Nine out of twenty countries (45 %) reported ADRs to VigiBase. Argentina, Brazil, Chile, Colombia, and Mexico published national guidelines for schizophrenia treatment. Chile is the sole country with clozapine clinics with drug serum monitoring. Ethnicity-related drug titration in not described in package inserts in any country. We examined in detail the 9 most frequent and important clozapine ADRs in the worldwide database (pneumonia, sudden death, cardiac arrest, agranulocytosis, myocarditis, constipation, arrhythmia, seizure, and syncope). These 9 ADRs led to 294 reports with fatal outcomes in Argentina (N = 3), Brazil (N = 3), Chile (N = 2), and Peru (N = 1). Agranulocytosis was reported from 7 countries: constipation or seizures from 8 countries. Only two countries reported pneumonia and one country reported myocarditis. The number of clozapine reports in VigiBase has no relationship to the country's population. All Latin American countries underreport clozapine associated ADRs. Latin American governments, along with clinicians, researchers, and educators, should optimize clozapine use and monitoring for the benefit of people with severe mental and some neurological disorders. [ABSTRACT FROM AUTHOR]

To synthesize the information relevant for clinical practice on clozapine-antidepressant co-prescription concerning pharmacokinetic drug-drug interactions (DDI), adverse drug reactions (ADRs) associated with the co-prescription, antidepressant add-on for clozapine-resistant symptoms and antidepressant add-on for clozapine-induced ADRs. Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through April 2023. Data were synthesized narratively. ADRs are most often induced by the co-prescription of antidepressants that inhibit CYP enzymes (fluvoxamine, fluoxetine, paroxetine). Fluvoxamine add-on is hazardous because of its potent inhibition of clozapine metabolism and has few indications (lowering daily number of clozapine tablets, reducing norclozapine-induced metabolic disturbances and other dose-dependent clozapine-induced ADRs). ADR frequency may be reduced by therapeutic drug monitoring and knowledge of other factors impacting clozapine metabolism (pneumonia, inflammation, smoking, etc.). Improvement of negative symptoms is the most documented beneficial effect of antidepressant add-on for clozapine-resistant psychotic symptoms. The add-on antidepressant should be chosen according to its safety profile regarding DDI with clozapine: antidepressants inhibiting clozapine metabolism or increasing the anticholinergic load should be avoided. Other indications of antidepressant add-on (affective or obsessive compulsive symptoms, sialorrhea, and enuresis) are poorly documented. Antidepressant add-on to clozapine is associated with potential benefits in clozapine users as this strategy may contribute to reduce the burden of clozapine-resistant symptoms or of clozapine-induced ADRs. Further studies are needed to determine whether antidepressant add-on can reduce the risk of clozapine discontinuation. [Display omitted] [ABSTRACT FROM AUTHOR]

Danggui Longhui is a traditional Chinese medicine made from the dried root of Angelica sinensis. It is used in psychiatric patients in China to reduce associated constipation. In a population pharmacokinetic model in olanzapine patients from Beijing Anding Hospital, we demonstrate that dangguilonghui tablets doubled olanzapine clearance, indicating the induction of olanzapine metabolism. Olanzapine metabolism is similar to clozapine metabolism. Two cases of possible clozapine induction using dangguilonghui tablets 4 g/day were identified in Beijing Anding Hospital. Dividing the minimum therapeutic concentration of 350 ng/mL by the concentration-to-dose (C/D) ratio provides the minimum therapeutic dose. Case 1 was a female smoker on clozapine for 415 days. The mean of 6 clozapine C/D ratios associated with smoking provided a minimum therapeutic dose of 267 mg/day. There were 6 steady-state concentrations on the combination of valproic acid and dangguilonghui tablets, which provided a much higher minimum therapeutic dose of 833 mg/day. Four steady-state clozapine C/D ratios based on smoking and valproate after 4 months of carbamazepine 200 mg/day provided a minimum therapeutic dose of 603 mg/day. Case 2 was a female non-smoker on clozapine for 58 days. She had 3 clozapine C/D ratios on dangguilonghui tablets with a mean of 0.30 ng/mL providing a minimum therapeutic dose of 1167 mg/day. Future clinical studies with repeated measures need to replicate the possibility that dangguilonghui tablets are a moderate-to-strong inducer of clozapine metabolism as suggested by these two limited cases. [Display omitted] [ABSTRACT FROM AUTHOR]

Access to literature on clozapine in Russian language remains strikingly limited. We aimed to identify and translate clinical evidence on clozapine-based treatment outcomes. We performed a systematic review in PubMed, Embase and scientific indexes from former USSR states searching for articles published in Russian from the database inception till January 2023 and summarized the data in a scoping review (PROSPERO Reg. Number CRD42023386737). A total of 60 papers were included comprising eight main topic categories: 1) clozapine-related intoxications (n = 20), 2) effectiveness/efficacy and safety of clozapine treatment (n = 14), 3) adverse drug-induced reactions (ADRs) related to clozapine treatment (n = 9), 4) therapeutic drug monitoring for clozapine (n = 5), 5) combination of clozapine and non-pharmacological treatments (n = 4), 6) pharmacoepidemiology of clozapine (n = 3), 7) effects of clozapine on the brain electrical activity (n = 3), and 8) novel clozapine formulations (n = 2). Among clozapine-related intoxications there were reports of criminal poisoning, which was associated with low lethality. Worse outcomes were accompanied by systemic reactions to intoxications. Clinical benefits of hemoadsorption were reported in the management of clozapine-related intoxications. Only half of studies reporting clozapine effectiveness used standardized scales to assess outcomes. Clozapine superiority in treatment-resistant schizophrenia (TRS) was replicated in one trial. No reports of clozapine-related agranulocytosis were identified. Clozapine ranked among most prescribed antipsychotics for TRS and non-TRS. As clinical research in former USSR states is advancing to adopt western clinical research standards, comparability and extrapolation of findings is expected to increase, with transfer of older findings to clinical practice being particularly challenging. [ABSTRACT FROM AUTHOR]

Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9–11). Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented). [Display omitted] [ABSTRACT FROM AUTHOR]

To identify the risks and benefits of clozapine‑lithium co-prescription. Articles published in English or French were identified with a MEDLINE, Web of Sciences and PsycINFO search, from inception through January 2023, using the term 'clozapine' in combination with 'lithium'. Data were synthesized narratively. Of the 67 articles included in the review, more than half (n = 38, 56.7 %) were focused on clozapine-related blood dyscrasia. A body of evidence drawn from case reports and retrospective chart studies highlights the potential benefits of lithium prescription for clozapine-related neutropenia, since this strategy may avoid clozapine discontinuation or allow its rechallenge. The most documented adverse drug reactions (ADRs) associated with clozapine‑lithium co-prescription are neurotoxic events, which may be prevented or detected early by clinical, electroencephalographic and therapeutic drug monitoring. Causality assessment cannot be established for other reported ADRs occurring during clozapine‑lithium co-prescription. The benefits of the combined prescription on psychotic and/or mood symptoms are poorly documented. The risks and benefits of clozapine‑lithium co-prescription require further exploration as the combination might significantly contribute to reducing underprescription or premature discontinuation of clozapine. [ABSTRACT FROM AUTHOR]

• For elexacaftor-tezacaftor-ivacaftor (ETI) it is unclear whether drug exposure should be monitored by assessment of C min levels or AUC. • A correlation between C min and AUC was found, with correlation coefficients of 0.963, 0.908 and 0.860 for ETI, respectively. • Exposure of ETI may be monitored by assessment of C min levels. Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (C min) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured C min concentration and AUC was evaluated. Serial plasma samples, including C min , were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between C min and AUC 0–24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of C min levels. [ABSTRACT FROM AUTHOR]

The surge in opioid-related deaths, driven predominantly by fentanyl and its synthetic derivatives, has become a critical public health concern, which is particularly evident in the United States. While the situation is less severe in Europe, the European Monitoring Centre for Drugs and Drug Addiction reports a rise in drug overdose deaths, with emerging concerns about the impact of fentanyl-related molecules. Synthetic opioids, initially designed for medical use, have infiltrated illicit markets due to their low production costs and high potency, with carfentanil posing additional threats, including potential chemical weaponization. Existing overdose mitigation heavily relies on naloxone, requiring timely intervention and caregiver presence, while therapeutic prevention strategies face many access challenges. To provide an additional treatment option, we propose the use of a fentanyl-specific monoclonal antibody (mAb), as a non-opioid method of prophylaxis against fentanyl and carfentanil. This mAb shows protection from opioid effects in a pre-clinical murine model. mAbs could emerge as a versatile countermeasure in civilian and biodefense settings, offering a novel approach to combat opioid-associated mortality. • FenAb024 has picomolar affinity to fentanyl and minimal affinity loss to carfentanil • The antibody is robustly thermostable • FenAb024 is a fentanyl and carfentanil-binding IgG that protects from drug effects • Protection is strongly correlated with antibody and drug dosage [ABSTRACT FROM AUTHOR]

This work reports on the creation of an electrochemical sensor for the real-time monitoring of paclitaxel (PCX) concentrations in biological fluids. The sensor is based on a poly-melamine-reduced graphene oxide nanocomposite-modified glassy carbon electrode (p-Melamine/rGO/GCE). The electrochemical sensor revealed a linear relationship between the peak current of the DPVs and PCX concentrations between 1 and 1180 μM, with a detection limit of 12 nM. The Ip value of PCX dropped to 98.15% of the starting value after 25 days, indicating excellent stability and repeatability of the p-Melamine/rGO/GCE sensors, which were assessed for long-term stability. The sensor's peak currents of PCX did not exhibit any significant variation when 50 μM organic compounds and inorganic ions were present, suggesting that it could find application in clinical samples. Relative standard deviation values for recovery tests on prepared urine samples ranged from 3.36% to 4.72%. In the area of chemotherapeutic agent monitoring, this work presents a novel method that shows remarkable sensitivity and selectivity in the real-time monitoring of PCX concentrations in biological fluids. The suggested sensor offers a practical and affordable means of tracking PCX concentrations in biological fluids in real time, with potential uses in therapeutic medication monitoring and clinical diagnostics. [ABSTRACT FROM AUTHOR]

There is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. Patients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3 , CYP2D6*10 , and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. A total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. Only trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. The currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response. [ABSTRACT FROM AUTHOR]

Biomarkers are essential for clinical risk management in anorexia nervosa (AN). Biomarkers can inform decisions regarding AN treatment at specific steps during the therapeutic cycle. Biomarker research will help to define subgroups of people with AN and guide decisions on individually tailored therapies, including psychotherapy. Anti-hypothalamus autoantibodies, cytokines, and metabolically relevant hormones such as insulin and leptin may be novel future drug targets for the treatment of AN. Pharmacogenetic testing and therapeutic drug monitoring are available for research and clinical application in AN, but they are usually not utilized in clinical practice. In anorexia nervosa (AN), measurable biological parameters can inform the process of treating patients. Such biomarkers include established laboratory parameters as well as a range of potential future biomarkers, including genetic, metabolomic, microbiomic, endocrine, immunological, hematological, electrophysiological, and neuroimaging parameters. In this opinion article we discuss how these biomarkers can support diagnosic and therapeutic processes at specific steps during the AN treatment cycle, that is, the diagnosis, diagnostic specification, risk management, choice of therapy, therapy monitoring, and treatment review. History-taking, physical and neuropsychological examination, clinical observation, and judgment about treatment success by the patient, their carers, and members of the multidisciplinary team are essential to interpret laboratory and imaging data appropriately and to assess the full clinical picture. [ABSTRACT FROM AUTHOR]

In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUC follow-up) and target AUC follow-up achievement was defined as an AUC of 400–600 μg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUC follow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUC follow-up of 400–600 μg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer that seriously affects women's physical and mental health. Chemodynamic therapy (CDT) induces cell death by specifically generating Fenton/Fenton-like reactions within tumor cells. However, the weak acidity of the tumor microenvironment (TME) greatly weakens the effectiveness of CDT. This work constructed a kind of P-CAI DF /PT nanoparticles (NPs), composed of two Pluronic F127 (PF127) based polymers: one was PF127-CAI (P-CAI), composed by connecting PF127 with the carbonic anhydrase IX (CA IX) inhibitor (CAI); the other was PF127-SS-TPE (PT), composed of PF127 and the aggregation-induced emission molecule, tetraphenylethylene (TPE), via the linkage of disulfide bonds. The two polymers were employed to construct the doxorubicin (DOX) and ferrocene (Fc) co-loaded P-CAI DF /PT NPs through the film dispersion method. After being administrated via i.v. , P-CAI DF /PT could be accumulated in the TME by the enhanced permeability and retention (EPR) effect and engulfed by tumor cells. P-CAI induced intracellular acidification by inhibiting the overexpressed CA IX, thus promoting CDT by enhancing the Fc-mediated Fenton reaction. The acidification-enhanced CDT combined with the DOX-mediated chemotherapy could improve the therapeutic effect on TNBC. Moreover, P-CAI DF /PT also monitored the intracellular drug release processes through the fluorescence resonance energy transfer (FRET) effect depending on the inherent DOX/TPE pair. In conclusion, the P-CAI DF /PT nanosystem can achieve the combination therapy of acidification-enhanced CDT and chemotherapy as well as therapy monitoring, thus providing new ideas for the design and development of TNBC therapeutic agents. • A nanosystem co-loading with DOX and Fc, composed of two Pluronic F127-based functional polymers is built. • This nanosystem treats TNBC through intracellular acidification-enhanced CDT and DOX-mediated chemotherapy. • This nanosystem monitors the intracellular drug release through the FRET effect depending on its inherent DOX/TPE pair. [ABSTRACT FROM AUTHOR]

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5–31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13–30]). The mean change in MG-QOL15r was –10·4 (95% CI –18·9 to –1·3) with mycophenolate mofetil and –6·8 (–17·2 to 3·6) with azathioprine (mean difference –3·3, 95% CI –7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI –0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI –4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America. [ABSTRACT FROM AUTHOR]

• This prospective study identified drug thresholds predictive of adverse events. • An AUC 0-24 h of bedaquiline M2 (≥ 3.2 mg·h/l) was identified for QTcF prolongation. • A linezolid AUC 0-24 h ≥ 119.3 mg·h/l was identified for mitochondrial toxicity. • A cycloserine AUC 0-24 h ≥ 718.7 mg·h/l was identified for psychiatric disorders. • Therapeutic drug monitoring is suggested to minimize the risk of adverse events. This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC 0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC 0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs. [ABSTRACT FROM AUTHOR]

Generic drugs are essential for affordable medicine and improving accessibility to treatments. Bioequivalence (BE) is typically demonstrated by assessing a generic product's pharmacokinetics (PK) relative to a reference-listed drug (RLD). Accurately estimating cutaneous PK (cPK) at or near the site of action can be challenging for locally acting topical products. Certain cPK approaches are available for assessing local bioavailability (BA) in the skin. Stimulated Raman scattering (SRS) microscopy has unique capabilities enabling continuous, high spatial and temporal resolution and quantitative imaging of drugs within the skin. In this paper, we developed an approach based on SRS and a polymer-based standard reference for the evaluation of topical product BA and BE in human skin ex vivo. BE assessment of tazarotene-containing formulations was achieved using cPK parameters obtained within different skin microstructures. The establishment of BE between the RLD and an approved generic product was successfully demonstrated. Interestingly, within the constraints of the current study design the results suggest similar BA between the tested gel formulation and the reference cream formulation, despite the differences in the formulation/dosage form. Another formulation containing polyethylene glycol as the vehicle was demonstrated to be not bioequivalent to the RLD. Compared to using the SRS approach without a standard reference, the developed approach enabled more consistent and reproducible results, which is crucial in BE assessment. The abundant information from the developed approach can help to systematically identify key areas of study design that will enable a better comparison of topical products and support an assessment of BE. Stimulated Raman scattering (SRS) microscopy enables bioequivalence (BE) assessment of pharmacokinetics parameters obtained within different skin microstructures. The developed polymer standard reference normalizes the SRS intensity and enables more consistent results. [Display omitted] • Develop a method based on a stimulated Raman microscope to monitor drug in ex vivo human skin. • Develop a stable standard reference to remove the effects of signal fluctuations for monitoring drugs with high specificity. • Quantify the drug and assess the cutaneous bioequivalence of topical formulations using the developed method. • Demonstrate bioequivalence of an approved generic drug and corresponding RLD within different microstructures in the skin. • Demonstrate that the lab-made formulation with PEG, a distinct vehicle from the RLD cream, is not bioequivalent to the RLD. [ABSTRACT FROM AUTHOR]

Our study employs machine learning to predict serum valproic acid (VPA) concentrations, aiming to contribute to the development of non-invasive assays for therapeutic drug monitoring. Medical records from 2002 to 2019 were obtained from the Taiwan Chang Gung Research Database. Using various machine learning algorithms, we developed predictive models to classify serum VPA concentrations into two categories (1–50 μg/ml or 51–100 μg/ml) and predicted the exact concentration value. The models were trained on 5142 samples and tested on 644 independent samples. Accuracy was the main metric used to evaluate model performance, with a tolerance of 20 μg/ml for continuous variables. Furthermore, we identified important features and developed simplified models with fewer features. The models achieved an average accuracy of 0.80–0.86 for binary outcomes and 0.72–0.88 for continuous outcome. Ten top features associated with higher serum VPA levels included higher VPA last and daily doses, bipolar disorder or schizophrenia spectrum disorder diagnoses, elevated levels of serum albumin, calcium, and creatinine, low platelet count, low percentage of segmented white blood cells, and low red cell distribution width-coefficient of variation. The simplified models had an average accuracy of 0.82–0.86 for binary outcome and 0.70–0.86 for continuous outcome. The study's predictive model lacked external test data from outside the hospital for validation. Machine learning models have the potential to integrate real-world data and predict VPA concentrations, providing a promising tool for reducing the need for frequent monitoring of serum levels in clinical practice. • Use machine learning to predict serum valproic acid concentration from real-world data. • Models achieved 0.72–0.88 accuracy for various binary and continuous outcomes. • Higher serum albumin is one of the key features influencing higher serum valproic acid concentrations. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) has a high prevalence worldwide. Although the economic burden of depression increases annually, the proportion of patients with MDD receiving treatment did not increase between 2010 and 2018, suggesting an unmet treatment need. The burden of long-term treatment for depression is borne by patients. In this context, biomarkers associated with drug-treatment responses can be used as reference indicators to reduce unnecessary treatment and costs. Changes in biomolecules in response to drug treatment for depression and drug-treatment response markers have been studied extensively. The Hamilton Depression Rating Scale (HAM-D) is mainly used as an indicator of response and remission; however, it is difficult to determine whether the medication contributes to recovery when evaluating the effect of drug treatment for depression based on this assessment. Therefore, it is necessary to monitor the effect of medication compared to normal health conditions. Here, serum protein levels were compared using liquid chromatography-tandem mass spectrometry among a group of patients with depression who did not receive medication, a group of patients receiving medication, and a control group. Eight selected biomarkers, including Apolipoproteins A-I, Complement factor H, Complement C5, Complement C1q subcomponent subunit B, Alpha-2-HS-glycoprotein, Complement C1q subcomponent subunit C, Vitamin D-binding protein and Corticosteroid-binding globulin were distinguished between disease states, and protein levels in the drug-treated group were similar to those in the control group. These markers can be used to monitor the effectiveness of drug treatment. [Display omitted] • Evaluating recovery using the Hamilton Depression Rating Scale is difficult. • Biomarkers that indicate a recovery tendency can be used to monitor the effectiveness of drug treatment in MDD. • Several biological processes are associated with drug treatments for depression. [ABSTRACT FROM AUTHOR]

The spread of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, has strongly motivated the research and development of new anti-TB drugs. New strategies to facilitate drug combinations, including pharmacokinetics-guided dose optimization and toxicology studies of first- and second-line anti-TB drugs have also been introduced and recommended. Liquid chromatography-mass spectrometry (LC-MS) has arguably become the gold standard in the analysis of both endo- and exo-genous compounds. This technique has been applied successfully not only for therapeutic drug monitoring (TDM) but also for pharmacometabolomics analysis. TDM improves the effectiveness of treatment, reduces adverse drug reactions, and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window. Based on TDM, the dose would be optimized individually to achieve favorable outcomes. Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs, aiding in the discovery of potential biomarkers for TB diagnostics, treatment monitoring, and outcome evaluation. This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades. Besides, we discussed the advantages and disadvantages of this technique in practical use. The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted. Lastly, we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies (pharmacometrics, drug and vaccine developments, machine learning/artificial intelligence, among others) to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients. [Display omitted] • LC–MS facilitates routine TDM and pharmacometabolomics toward precision dosing. • LC–MS-based bioassay methods of anti-TB drugs and metabolites was summarized. • Perspectives on numerous advancements in TB management were highlighted. • Comprehensive approach was proposed to enhance clinical outcomes and eradicate TB. [ABSTRACT FROM AUTHOR]

Amikacin, an aminoglycoside, is a widely used parenteral antibiotic. Therapeutic drug monitoring (TDM) is recommended for aminoglycosides to avoid toxicity. However, the lack of infrastructure at most places precludes it. This pilot and novel study attempt to estimate the real-world serum levels of Amikacin in hospitalised patients. Thirty admitted patients, given Amikacin injections, were included in the study. In addition, 15 clinical specimens isolated with gram-negative bacteria were tested for minimum inhibitory concentration (MIC) value of Amikacin. Trough and peak serum levels of Amikacin were estimated by high-pressure liquid chromatography (HPLC). The average MIC value of Amikacin estimated in our laboratory was 3.92 mcg/mL. Peak and trough serum levels of Amikacin ranged from 12.1 to 66.4 mcg/ml and 1.1 to 20.7 mcg/ml, respectively. More than 83% of our patients achieved peak Amikacin levels of 15 mcg/mL, and 37% had trough levels above 5 mcg/mL. These levels are desirable watersheds as per available literature. Trough levels of Amikacin in all cases and a review of dosing according to MIC values are recommended to achieve drug safety and therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Objective: A mycophenolate sodium enteric-coated tablet has shown a satisfying anti-rejection effect in patients receiving solid organ transplantation. The current study evaluated the bioequivalence between the test (Ruiyirong®) vs. reference (Myfortic®) formulations by exploring equations for predicting their area under the concentration-time curve (AUC) using a limited sampling strategy in healthy subjects. Methods: Forty-eight healthy Chinese subjects were randomized into three administration sequences (testreference-reference, reference-reference-test, and reference-test-reference) to receive the Ruiyirong or Myfortic treatment on days I, 8, and 15. Results: The 90% confidential interval (Cl) of the geometric mean ratios (tesl/reference) of maximum plasma concentration (Cmax), the AUC from lime 0 to the last timepoint (AUCo,), and the AUC from 0 to infinity (AUCo-oo) was 92.90%-l 10.57%, 96.91%-101.80%, and 96.71 %-10l .84%, respectively. All these values fell into the bioequivalence criteria of 80.00%-125.00% (based on the criteria of the Food and Drug Administration). The adverse events were 10.4% in Ruiyirong test group and 14.6% in Myfortic reference group. Eight equations for estimating the AUC of the Ruiyirong test and Myfortic reference formulations were evaluated; most of them worked well with the R-value >0.8. Among the four chosen equations, the intragroup verification exhibited a high agreement with the R-value ranging from 0.857 to 0.971 and with the low predictive error (PE 5% with absolute PE > 15%). Meanwhile, the intergroup verification indicated a high inter-agreement with the R-value ranging from 0.896 to 0.974 (all P < 0.001). Conclusion: The Ruiyirong test vs. Myfortic reference formulations meet the bioequivalent criteria and are well tolerated. The further linear regression analysis explores eight equations predicting the AUC value and the chosen four equations for the Ruiyirong test and Mayfortic reference formulations are interchangeable. [ABSTRACT FROM AUTHOR]

The latest therapeutic drug monitoring guidelines for vancomycin (VCM) recommend that area under the concentration-time curve is estimated based on model-informed precision dosing and used to evaluate efficacy and safety. Therefore, we predicted VCM concentrations in individual methicillin-resistant Staphylococcus aureus-infected patients using existing a physiologically based pharmacokinetic (PBPK) model and 1- and 2-compartment population pharmacokinetic (PPK) models and confirmed and verified the accuracy of the PBPK model in estimating VCM concentrations with the PPK model. The subjects of the study are 20 patients, and the predicted concentrations were evaluated by comparing the observed and predicted trough and peak values of VCM concentrations for individual patients. The results showed good correlation between the observed and predicted trough and peak concentrations of VCM was observed generally in the PBPK model, R2 values of 0.72, 0.62, and 0.40 with trough values of 0.49, 0.40, and 0.34 with peak values for PBPK model, 1-compartment, and 2-compartment model, respectively. Although the performance of the PBPK model is not as predictive as the PPK model, generally similar predictive trends were obtained, suggesting that it may be a valuable tool for rapid and accurate prediction of AUC for VCM. [ABSTRACT FROM AUTHOR]

Posaconazole is a potent, extended-spectrum triazole antifungal used for the treatment and prophylaxis of serious fungal infections. Previous reports have demonstrated hyperlipidemia resulted in significant changes in posaconazole pharmacokinetics and tissue distribution in rats. However, the effect of hyperlipidemia on the pharmacokinetics of posaconazole in patients has not yet been reported. We report a case of a 34-year-old woman who experienced a supratherapeutic posaconazole trough concentration (PTC) associated with hyperlipidemia after haploidentical hematopoietic stem cell transplantation (HSCT). The patient was admitted 13 months after HSCT for recurrent cough and sputum. She was treated with caspofungin due to developing invasive fungal infection of Candida tropicalis. After 10 days, caspofungin was discontinued due to the poor therapeutic efficacy and replaced with amphotericin B. Afterwards, the condition of the patient improved significantly and she was switched to daily oral posaconazole tablet. Therapeutic drug monitoring (TDM) of posaconazole showed a PTC was 3.2 mg/L. After discharge, she continued to receive posaconazole tablet as antifungal treatment. Two months later, laboratory tests at outpatient showed her blood lipid levels were significantly elevated and PTC was increased to 9.38 mg/L. Therefore, the posaconazole tablet was discontinued and she received lipid-lowering therapy. A few days later, the PTC was down to 5.22 mg/L. No medication errors and significant drug interactions were found. Hence, supratherapeutic PTC for this patient may be caused by hyperlipidemia which altered pharmacokinetics of posaconazole. Our findings highlight the need for close TDM in order to avoid supratherapeutic PTC if hyperlipidimia occurs during posaconazole use. [ABSTRACT FROM AUTHOR]

Although the loading dose (LD) of vancomycin (VCM) contributes to its efficacy, it may not be conducted adequately. Herein, the objective was to evaluate the effect of LD on patient prognosis using therapeutic drug monitoring by pharmacists and elucidate the impact of an antimicrobial stewardship program (ASP)-driven educational intervention on the LD implementation rate and patient prognosis. First, a retrospective cohort study was conducted involving 121 adult patients administered with VCM and compared with 28-day mortality in LD and non-LD groups. To avoid confounding, the propensity score method was employed. Second, post-training with ASP-driven lectures, a questionnaire survey was conducted for healthcare workers, including physicians, nurses, and pharmacists. The rates of VCM LD implementation and 28-day mortality were compared during a period of one year and 9 months between the pre-ASP (n = 38) and post-ASP (n = 33) groups. After propensity score matching, the 28-day mortality in the LD group was significantly improved, suggesting that the early increase in blood levels of VCM due to an LD is an important factor influencing patient prognosis. After the lecture, a questionnaire survey revealed that the understanding rates of "well" and "slightly well" for educational lectures exceeded 80% of all healthcare workers. The rate of LD implementation significantly increased to 63.6% (21/33) in the post-ASP group compared with 31.6% (12/38) in the pre-ASP group (p = 0.007), and the 28-day mortality declined from 23.7% (9/38) to 6.1% (2/33) (p = 0.041). This method of ASP-driven educational intervention would facilitate LD implementation, improving patient prognosis. [ABSTRACT FROM AUTHOR]

• Geospatial intelligence contributes to the formulation of public drug policies. • Concentrated individual cocaine seizures linked to specific geographical features. • News websites provide valuable insights into drug trafficking dynamics. • The identified routes and trends align with current literature on drug trafficking. • São Paulo: key node for Brazil's cocaine traffic and its international distribution. Cocaine trafficking threatens countries' national security and is a major public health challenge. Cocaine is transported from producer countries to consumer markets using various routes, methods, and transportation means. These routes develop in the geographical environment, are carefully planned and are geo-strategic objects that respond to the opportunities that drug trafficking organisations (DTOs) find to reduce the risks of interdiction. In this sense, individual drug seizure data (IDS) become essential indicators for identifying trends and understanding trafficking flows associated with drug trafficking routes. However, due to the illicit nature of DTOs, the availability of these data is considerably limited, hindering the ability to analyse and identify trends. This study presents a methodology for collecting and processing data from open-source information reported by Brazil's federal government news website. Using geospatial intelligence and natural language processing methods, we created a dataset with 939 records and 44 variables related to cocaine seizures in Brazil in 2022. We applied geospatial analysis techniques from this dataset to identify trends and potential cocaine trafficking flows. The results were broadly consistent with existing literature on drug trafficking. They demonstrated the potential of open-source information for environmental scanning and knowledge generation through geographic information science. The approach proposed in our research provides tools that can be used to complement drug trafficking monitoring and formulate public policies to strengthen prevention and enforcement strategies. [ABSTRACT FROM AUTHOR]

The silent pandemic of bacterial antimicrobial resistance is a leading cause of death worldwide, prolonging hospital stays and raising health-care costs. Poor incentives to develop novel pharmacological compounds and the misuse of antibiotics contribute to the bacterial antimicrobial resistance crisis. Therapeutic drug monitoring (TDM) based on blood analysis can help alleviate the emergence of bacterial antimicrobial resistance and effectively decreases the risk of toxic drug concentrations in patients' blood. Antibiotic tissue penetration can vary in patients who are critically or chronically ill and can potentially lead to treatment failure. Antibiotics such as β-lactams and glycopeptides are detectable in non-invasively collectable biofluids, such as sweat and exhaled breath. The emergence of wearable sensors enables easy access to these non-invasive biofluids, and thus a laboratory-independent analysis of various disease-associated biomarkers and drugs. In this Personal View, we introduce a three-level model for TDM of antibiotics to describe concentrations at the site of infection (SOI) by use of wearable sensors. Our model links blood-based drug measurement with the analysis of drug concentrations in non-invasively collectable biofluids stemming from the SOI to characterise drug concentrations at the SOI. Finally, we outline the necessary clinical and technical steps for the development of wearable sensing platforms for SOI applications. [ABSTRACT FROM AUTHOR]

Advanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on gene, tissues or cells. ATMPs have peculiar characteristics when compared with traditional medicines. In this regard, long-term safety and efficacy follow-up systems of individuals treated with ATMPs have become necessary and may present unique challenges, because unlike conventional drugs and biologics, these products can exert their effects for years after administration. This work seeks to assess the requirements foreseen in the regulatory frameworks for the post-marketing authorization safety and efficacy surveillance for ATMPs in Brazil, European Union (EU), Japan and United States, which are some of the members of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. We reviewed the scientific literature and official documents of regulatory agencies (RAs) in Brazil, the EU, Japan and the United States. RAs in the EU, US and Japan have developed regulatory guidelines for the post-marketing surveillance of ATMPs. These guidelines aim at implementing surveillance plans for monitoring adverse events, including late ones, after marketing authorization. All the ATMPs authorized by the RAs studied, submitted some type of post-marketing requirement to supplement safety and efficacy data, according to the regulations and terminology used by those jurisdictions. [ABSTRACT FROM AUTHOR]

In vivo lung perfusion (IVLP) is a novel isolated lung technique developed to enable the local, in situ administration of high-dose chemotherapy to treat metastatic lung cancer. Combination therapy using folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX) (FOLFOX) is routinely employed to treat several types of solid tumours in various tissues. However, F is characterized by large interpatient variability with respect to plasma concentration, which necessitates close monitoring during treatments using of this compound. Since plasma drug concentrations often do not reflect tissue drug concentrations, it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs. In this work, in vivo solid-phase microextraction (in vivo SPME) is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous (IV) trials. The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration (IVLP vs. IV) and the therapy itself. This study also shows that the immediate instrumental analysis of metabolomic samples is ideal, as long-term storage at −80 °C results in changes in the metabolite content in the sample extracts. [Display omitted] • Use of in vivo SPME during FOLFOX administration in pre-clinical IVLP and IV trials. • Therapeutic drug monitoring of FOLFOX and metabolites in porcine lung. • Pharmacometabolomic fingerprinting of porcine lung during FOLFOX administration. • In vivo SPME facilitates in situ monitoring of lung function with no tissue biopsy. [ABSTRACT FROM AUTHOR]

The development of functional biomaterials with real-time monitoring of mineralization processes, drug release and biodistribution has potential applications but remains an unsolved challenge. Herein, erbium- and ytterbium- containing mesoporous bioactive glass microspheres (MBGs:Er/Yb) with blue and red emission at an excitation wavelength of 980 nm were synthesized by a sol-gel combined with organic template method. As the concentration of Yb3+ ions gradually increases, the emission intensity of the MBGs:Er/Yb exhibits a clear concentration quenching effect. Combined with in vitro bioactivity tests, the optimal molar ratio of Er3+/Yb3+ was determined to be 4:3. Therefore, MBGs:4Er/3Yb was selected for in vitro biomineralization and drug release monitoring. The results of biomineralization monitoring show that the upconversion luminescence intensity is closely related to the degree of biomineralization. The upconversion luminescence intensity of MBGs:4Er/3Yb is quenched with the increase of the degree of biomineralization. The degree of luminescence quenching during biomineralization can be semiquantized. Drug release monitoring experiments showed that the anticancer drug doxorubicin hydrochloride (DOX) was successfully loaded into MBGs:4Er/3Yb and selectively quenched the green emission. When DOX was released, the green emission recovered stably, and I t / I 0 increased gradually. Moreover, there was a linear relationship between I t / I 0 and cumulative drug release, indicating that DOX-MBGs:4Er/3Yb is highly sensitive to DOX release, and monitoring the I t / I 0 values of DOX-MBGs:4Er/3Yb can achieve real-time tracking of the DOX release process to a certain extent. In conclusion, MBGs:4Er/3Yb has potential application as an upconversion luminescence biomonitoring material in the field of bone tissue engineering. Mesoporous bioactive glasses have great potential for applications in bone tissue repair due to their excellent biological properties, but the effective information of the repair process cannot be grasped in a timely manner. Therefore, real-time monitoring of mineralization and drug release processes will be beneficial to obtain the degree of healing and optimize the amount and distribution of drugs to improve targeted therapeutic effects. For biomaterials, in vitro biological properties determine their biological properties in vivo , where the environment is more complex and diverse, and thus in vitro biomonitoring is particularly crucial. The organic combination of physical properties and biological properties will also provide a feasible idea for the development of biomaterials. [Display omitted] [ABSTRACT FROM AUTHOR]

To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients. Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA). One hundred and forty-two patients received intravenous polymyxin B (1.33–6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected C max , but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower. Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45–90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated. [ABSTRACT FROM AUTHOR]

Augmented renal clearance (ARC) increases vancomycin (VCM) clearance. Therefore, higher VCM doses are recommended in patients with ARC; however, impacts of ARC on the area under the concentration–time curve (AUC) discrepancies between initial dosing design and therapeutic drug monitoring (TDM) period remains unclear. We retrospectively collected data from critically ill patients treated with VCM. The primary endpoint was the association between ARC and AUC 24–48h deviations. ARC and AUC deviation were defined as a serum creatinine clearance (CCr) ≥130 mL/min/1.73 m2 and an AUC at TDM 30% or more higher than the AUC at the initial dosing design, respectively. The pharmacokinetic profiles of VCM were analyzed with the trough levels or peak/trough levels using the Bayesian estimation software Practical AUC-guided TDM (PAT). Among 141 patients (median [IQR]; 66 [58–74] years old; 30% women), 35 (25%) had ARC. AUC deviations were significantly more frequent in the ARC group than in the non-ARC group (20/35 [57.1%] and 17/106 [16.0%] patients, respectively, p < 0.001). Age- and sex-adjusted multivariate analyses revealed that the number of VCM doses before TDM ≥5 (odds ratio, 2.56; 95% confidence interval [CI]: 1.01–6.44, p = 0.047) and CCr ≥130 mL/min/1.73 m2 were significantly associated with AUC deviations (odds ratio, 7.86; 95%CI: 2.91–21.19, p < 0.001). Our study clarifies that the AUC of VCM in patients with ARC is higher at the time of TDM than at the time of dosage design. [ABSTRACT FROM AUTHOR]

Mesoporous bioactive glasses have great potential for applications in the field of bone tissue repair due to their excellent biological properties, but effective information on the repair process is not available in a timely manner. Thus, real-time monitoring of mineralization and drug release processes will be beneficial to obtain the degree of healing and optimize the amount and distribution of drugs to improve targeted therapeutic effects. Here, erbium-doped mesoporous bioactive glass microspheres (Er/MBGs) were successfully synthesized by the sol-gel method, and the doping concentration of erbium was selected based on fluorescence, BET, and bioactivity tests. The results showed that 4Er/MBGs not only had the highest luminescence emission, higher specific surface area (418.8 m2/g) and mesopore volume (0.42 cm3/g) but also presented excellent bioactivity. Therefore, 4Er/MBGs were selected for in vitro real-time monitoring of mineralization and drug release. It has been shown that the luminescence intensity of 4Er/MBGs is linearly related to its mineralization degree; As the degree of mineralization increases in vitro , the intensity of the luminescence emission gradually decreases. The results of in vitro drug release monitoring experiments showed that 4Er/MBGs loaded with the anticancer drug doxorubicin (DOX) exhibited great pH responsiveness, and the loaded DOX selectively quenched the green emission of the microspheres. When the drug was released, the green emission recovered stably, and the signal value of the ratio R (I 650 nm/ I 510 nm) of the emission intensity of the red to the green of the microspheres gradually decreased. Monitoring changes in the value of the R signal is instructive for tracking the drug release process. Meanwhile, in vitro antibacterial experiments indicated that 4Er/MBGs had a strong inhibitory effect on E. coli and S. aureus , with antibacterial rates of up to 92.5% and 90.7%, respectively. Collectively, Er/MBGs have potential applications as optically functional materials in bone tissue engineering. [ABSTRACT FROM AUTHOR]

• Among patients with IS under DOAC therapy, 42.9% had low drug level (< 50 ng/mL). • Low DOAC concentration predicts poor functional outcome at three months after IS. • Low DOAC concentration is associated with stroke-in-evolution after IS. • For acute ICH, the DOAC concentration is not associated with hematoma growth. This study aimed to investigate the association between direct oral anticoagulant (DOAC) concentration upon acute ischemic stroke (IS) or intracranial hemorrhage (ICH) and stroke outcomes. Patients aged ≥20 years treated with DOACs, including dabigatran, rivaroxaban, apixaban, or edoxaban, and developed acute IS or ICH were enrolled to measure DOAC concentration at the time of hospital presentation by using ultrahigh-performance liquid chromatography with tandem mass spectrometry. Ischemic stroke patients was categorized into low (<50 ng/mL) and effective (≥50 ng/mL) groups. The primary outcome was poor functional outcomes at 3 months (modified Rankin Scale scores of 4–6). A total of 138 patients were enrolled, including 105 IS (76.1%) and 33 ICH patients. In the IS cohort, the average DOAC concentration was 85.7 ± 88.6 ng/mL (low DOAC concentration: 42.9%). Low level group had numerically higher NIHSS (14 versus 9, p = 0.37), significantly poorer functional outcomes at 3 months (odds ratio [OR], 5.08 [1.32, 19.63]), and higher chance of stroke-in-evolution (OR, 6.83 [1.64, 28.41]). In the ICH cohort, the average DOAC concentration was 128.9 ± 111.9 ng/mL. Reversal therapy was administered in 60.6% of patients. Hematoma growth occurred in 35.7% patients. The DOAC concentration was similar across patients with or without reversal therapy, and with or without hematoma growth. Among DOAC users who developed IS, low drug concentrations at hospital presentation predicted poor outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring and Model-informed precision dosing allow dose individualization to increase drug effectivity and reduce toxicity. To evaluate the available evidence on the clinical efficacy of individualized antimicrobial dosing optimization. Data sources : PubMed, Embase, Web of Science, and Cochrane Library databases from database inception to 11 November 2022. Published peer-reviewed randomized controlled trials. Human subjects aged ≥18 years receiving an antibiotic or antifungal drug. Patients receiving individualized antimicrobial dose adjustment. Cochrane risk-of-bias tool for randomized trials. The primary outcome was the risk of mortality. Secondary outcomes included target attainment, treatment failure, clinical and microbiological cure, length of stay, treatment duration, and adverse events. Effect sizes were pooled using a random-effects model. Statistical heterogeneity was assessed by inconsistency testing (I2). Ten randomized controlled trials were included in the meta-analysis (1241 participants; n = 624 in the individualized antimicrobial dosing group and n = 617 in the control group). Individualized antimicrobial dose optimization was associated with a numerical decrease in mortality (risk ratio [RR] = 0.86; 95% CI, 0.71–1.05), without reaching statistical significance. Moreover, it was associated with significantly higher target attainment rates (RR = 1.41; 95% CI, 1.13–1.76) and a significant decrease in treatment failure (RR = 0.70; 95% CI, 0.54–0.92). Individualized antimicrobial dose optimization was associated with improvement, but not significant in clinical cure (RR = 1.33; 95% CI, 0.94–1.33) and microbiological outcome (RR = 1.25; CI, 1.00–1.57), as well as with a significant decrease in the risk of nephrotoxicity (RR = 0.55; 95% CI, 0.31–0.97). This meta-analysis demonstrated that target attainment, treatment failure, and nephrotoxicity were significantly improved in patients who underwent individualized antimicrobial dose optimization. It showed an improvement in mortality, clinical cure or microbiological outcome, although not significant. [Display omitted] [ABSTRACT FROM AUTHOR]

The liver is well known for its immunotolerance, but rejection without immunosuppression is frequently encountered post liver transplantation, especially in humans.1 Indeed, the amount of immunosuppression required post liver transplant is less compared to other organ transplants like kidney, heart, and intestine.2 Reports of successful weaning of immunosuppression have been reported but are not practiced for fear of unwanted alloimmune response leading to rejection. Life-long immunosuppression is needed in most patients for graft survival but is associated with side effects like renal dysfunction, metabolic abnormalities, or risk of de novo malignancies. Also, the appropriate dose of immunosuppression to achieve adequate graft function and prevention of toxicities is very important. One shoe does not fit all. There are significant individual variations in response and side effect profile. Also, the level of immunosuppression varies with the underlying liver disease like autoimmune disease requires higher immunosuppression. Thus, monitoring the adequate immunosuppression with the minimization of drug toxicity is imperative post-transplant. Unfortunately, the current methods for immunosuppression monitoring rely on testing the immunosuppressive drug levels rather than the immune system activity. We have discussed the concept of alloreactivity, available methods of immunosuppression and drug monitoring and investigational methods in this review. [ABSTRACT FROM AUTHOR]

Although phage therapy has been in existence for a century, a recent resurgence in interest has occurred because of the continued emergence of antimicrobial resistance and the rising use of indwelling medical devices, resulting in biofilm-associated infections, for which conventional antibiotics are of limited use. Despite this, the clinical successes have been inconsistent because of multiple reasons, including (1) the narrow host range of phages, (2) challenges with concentrating phages at the site of infection, (3) development of resistance of bacteria to phages and (4) immune neutralization. Microbiologic assays have the potential to help guide the course of clinical therapy and improve outcomes. Methods developed decades ago remain the mainstay of phage diagnostics and recently, newer diagnostics are closing the gap needed to further advance clinical phage therapy. To review the current state of clinical phage microbiology and identify gaps. A PubMed search was performed using the terms "phage microbiology", "phage susceptibility test", "phage host range", "phage biofilm", and "phage therapeutic monitoring". Phage susceptibility testing, biofilm assays, phage-antibiotic combination testing, therapeutic drug monitoring, and immune monitoring assays are the current foundation for clinical phage diagnostics. Standardization of these assays and better understanding as to if and how they should be used in terms of clinical management of patients receiving phage therapy is needed. A substantial gap between in vitro studies and in vivo outcomes indicates that further work is needed in phage pharmacokinetics to accurately assay phage particles at the site of infection; recapitulate in vivo biofilm; capture the complex interactions between phages and antibiotics, phages and their target bacteria, among phages in a cocktail, and with the superhost immune system. [ABSTRACT FROM AUTHOR]

To identify pediatric patients who require therapeutic drug monitoring (TDM) of levetiracetam (LEV). We retrospectively investigated 2413 routine therapeutic drug monitoring data on serum LEV concentration from 1398 pediatric patients (age, 0–15 years). Samples were grouped by age (infants, < 1 year; preschool children, 1–5 years; primary school children, 6–11 years; and adolescents, 12–15 years), and the LEV concentration-to-dose (CD) ratio was calculated. The mean CD ratio was highest in adolescents (analysis of variance, p < 0.001); 22.5 % and 15.7 % higher in adolescents than in preschool children and school children, respectively (Scheffé test, p < 0.001); and higher in infants than in preschool children. Preschool children had the lowest ratio and tended to show an increase in the ratio from age 2 to 5 years. Use of enzyme-inducing antiseizure medication reduced the CD ratio by 6.1 % in infants, 12.2 % in preschool children, 5.9 % in primary school children, and 9.4 % in adolescents. The mean CD ratio was 2.7 %, 26.9 %, and 39.3 % higher in preschool children, primary school children, and adolescents with defined chronic kidney disease (CKD) than in the respective age group of patients without CKD. The therapeutic concentration range for a long-term LEV therapy was 11 to 32 μg/mL. LEV pharmacokinetics are significantly different between infant and preschool children, so TDM of LEV is clinically useful in these patients. In pediatric patients at higher risk for CKD, glomerular filtration rate and LEV levels should be carefully monitored. [ABSTRACT FROM AUTHOR]

Appropriate specimen collection and storage is essential to preserve sample integrity and ensure accurate test results. The default collection containers for blood drug concentrations are tubes without gel separators to avoid possible drug adsorption. However, routine chemistry tests are generally collected in gel separator tubes due to their convenient transport and processing; collection of an additional gel-free tube is often required for drug measurements. Citrated whole blood was pooled, spiked with drug, and transferred to three tubes (red, SST gold, RST orange) containing calcium chloride. Blood was allowed to clot, centrifuged and stored at ambient temperature (24 h) or refrigerated (7 days). At defined times, serum drug concentrations were determined (Roche cobas c502). Based on these results, specimen collection requirements were updated to allow serum separator tubes for 17 assays. Of the 21 assays evaluated, 18 displayed acceptable stability in both gel-containing tubes (acetaminophen, amikacin, carbamazepine, digoxin, ethanol, gentamicin, lamotrigine, levetiracetam, lithium, methotrexate, phenobarbital, phenytoin, salicylate, theophylline, tobramycin, valproic acid, vancomycin, voriconazole). Three drugs displayed strong decreases in measured concentrations after storage in one or both gel-containing tubes (total tricyclics, lidocaine, and free phenytoin). Following adoption of gel-containing tubes, 94% of the five most frequently ordered drug monitoring tests in the Emergency Department were collected in serum separator tubes. Evaluation of the stability and accuracy of commonly monitored drugs revealed that the majority were not affected by exposure to gel separator material under conditions similar to outpatient clinic storage, courier transport, and laboratory storage. Expanding the collection requirements for appropriate drugs to include gel separator tubes decreases the number of specimens drawn and the complexity of laboratory workflows. [ABSTRACT FROM AUTHOR]

Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC 0-24 of 400–600 mg h/L at the steady-state. The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended. [ABSTRACT FROM AUTHOR]

It is found that there are great differences in the efficacy of quetiapine at the same dose in many patients with bipolar disorders. Therefore, therapeutic drug monitoring (TDM) is a valuable tool for guiding treatment with quetiapine. The aims of this study were to assess the relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage. The study design was prospective and observational. Within the naturalistic setting of a routine TDM service at the First Affiliated Hospital, Zhejiang University School of Medicine. Psychiatric symptoms were assessed using the HAMD (Hamilton Depression Scale), YRMS (Young manic rating scale) and CUDOS-M (Clinically Useful Depression Outcome Scale-Mixed Subscale). The decline of HAMD and YMRS scores was were used to assess clinical outcome of bipolar disorders respectively. 169 inpatients (23.7 % male, 76.3 % female) were enrolled in the study. We found that there was a strong correlation between quetiapine serum concentrations and clinical outcomes (r s = 0.702, p < 0.001). While, quetiapine daily dose was not correlated with clinical outcome. We found that when the quetiapine serum level is >146.85 ng/ml in depression episodes patients could obtain a satisfactory treatment effect after 2 weeks of hospitalization. We found a significant positive relationship between serum concentration and clinical outcome, and also determined the serum concentration of quetiapine for the treatment of bipolar depression. • This is the first study about the relationship between TDM of quetiapine and clinical treatment response in BD. • The main finding is that there is a correlation between TDM of quetiapine and clinical outcome in bipolar disorders. [ABSTRACT FROM AUTHOR]

Fluoropyrimidine drugs (FP) are the backbone of many chemotherapy protocols for treating solid tumours. The rate-limiting step of fluoropyrimidine catabolism is dihydropyrimidine dehydrogenase (DPD), and deficiency in DPD activity can result in severe and even fatal toxicity. In this review, we survey the evidence-based pharmacogenetics and therapeutic recommendations regarding DPYD (the gene encoding DPD) genotyping and DPD phenotyping to prevent toxicity and optimize dosing adaptation before FP administration. The French experience of mandatory DPD-deficiency screening prior to initiating FP is discussed. • EMA recommends DPD testing (DPYD variants or uracilemia) before FP-based chemotherapy. • Genotyping relevance of the 4 consensual DPYD variants is restricted to Caucasians. • DPYD genotype-guided FP dose reduction is clinically validated, contrary to uracilemia. • Impact of DPD -guided FP dose reduction on efficacy needs further investigation. • 5FU therapeutic drug monitoring is recommended in partial DPD-deficient patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • We validated a LC-MS/MS method using a protein G immunocapture method to quantify the fusion protein belatacept in human samples. • Belatacept trough concentrations obtained by LC-MS/MS analysis ranged from 5.1 to 15.0 mg.L−1, with a median of 8.9 mg.L−1. • The inter-individual variability (expressed as the coefficient of variation) of the trough belatacept concentration was 33%. • This LC-MS/MS method opens the field of therapeutic drug monitoring of belatacept. Therapeutic drug monitoring is the cornerstone of immunosuppressive treatment in transplantation. The immunosuppressive drugs used in kidney transplant patients are mostly comprised of biologics, including therapeutic monoclonal antibodies (mAbs) and fusion proteins. Therefore, a specific and sensitive analytical technique that can universally quantify mAbs, as well as fusion proteins, is essential for clinical pharmacokinetics studies. In this short communication, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantification of the fusion protein belatacept in the plasma of kidney-transplant patients. Sample preparation was based on our previously published and implementable electrospray ionization LC-MS/MS method that allows the simultaneous quantification of seven mAbs. Immunocapture was made possible by the Fc domain of belatacept and identification/quantification by the choice of MRM transitions of peptides. The temporal evolution of the belatacept concentration after intravenous infusion and inter-individual variability of trough concentrations were assessed in 17 human plasma samples. The belatacept calibration curves were linear from 1 to 200 mg.L−1 and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Residual belatacept concentrations (n = 8) ranged from 5.1 to 15.0 mg.L−1, with a median of 8.9 mg.L−1 and an inter-individual CV of 33.0%. Our generic LC-MS/MS method allows the quantification of fusion proteins, such as belatacept, and could be used for therapeutic drug monitoring. This method provides a useful tool to study the intra-patient variability of belatacept and the association between belatacept exposure and its therapeutic effects. [ABSTRACT FROM AUTHOR]

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe 3 O 4 @Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe 3 O 4 @Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe 3 O 4 @Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T 2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe 3 O 4 @Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment. GO-Fe 3 O 4 @Au@Ag-MPBA-DOX was fabricated as Surface Enhanced Raman Scattering (SERS) substrate for real-time monitoring the dynamic process of DOX release by tracking the SERS of 4-MPBA under acidic tumor microenvironments. [Display omitted] [ABSTRACT FROM AUTHOR]