Biosensing Technologies for Therapeutic Drug Monitoring

Background and Rationale: Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients’ biofluids at designated intervals to allow a close and timely control of their dosage. This practice allows for rapid medical intervention in case of toxicity-related issues and/or adjustment of dosage to better fit the therapeutic demand. Currently, TDM is performed in centralized laboratories employing instruments, such as immunoassay analyzers and mass spectrometers that can be run only by trained personnel. However, the time required for the preparation, samples analysis, and data processing, together with the related financial cost, severely affects the application of TDM in medical practices. Therefore, a new generation of analytical tools is necessary to respond to the timely need of drug administration or reduction aiming at effectively treating oncologic patients. Aim of the Review: State-of-the-Art Technologies for TDM: Technological advances in the field of nanosciences and biosensors offer the unique opportunity to address such issues. The interest for the so-called nanobiosensors is considerably increasing, particularly in drug discovery and clinical chemistry, even though there are only few examples reporting their use for TDM. The techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. Conclusions: In this review, we described the most promising methodologies that, in our opinion, will bring TDM towards the next stage of clinical practice in the future

Practical fluorimetric assay for the detection of anticancer drug SN-38 in human plasma

The implementation of therapeutic drug monitoring in the routine clinical practice in oncology is mainly limited by the lack of therapeutic indexes for the majority of the anticancer drugs, and by the absence of suitable analytical tools, which can accurately quantify in real time the concentration of the administered drugs and their relevant metabolites in biological fluids. In this work, a simple and efficient fluorimetric determination of SN-38, the active metabolite of the anticancer drug irinotecan, was developed and applied to human plasma samples. The intrinsic fluorescence of SN-38 allowed its quantification in the range 10–500 ng mL −1 with a LOQ of 5.0 ng mL −1 and a LOD of 1.5 ng mL −1 . Low interferences due to main metabolites of irinotecan and comedications, commonly associated with administration of irinotecan, were observed. A validation study, according to FDA and EMA guidelines for bioanalytical method validation, was carried out and, finally, blind samples were analyzed in parallel with a HPLC-MS method obtaining an excellent agreement between the two techniques

Practical fluorimetric assay for the detection of anticancer drug SN-38 in human plasma

The implementation of therapeutic drug monitoring in the routine clinical practice in oncology is mainly limited by the lack of therapeutic indexes for the majority of the anticancer drugs, and by the absence of suitable analytical tools, which can accurately quantify in real time the concentration of the administered drugs and their relevant metabolites in biological fluids. In this work, a simple and efficient fluorimetric determination of SN-38, the active metabolite of the anticancer drug irinotecan, was developed and applied to human plasma samples. The intrinsic fluorescence of SN-38 allowed its quantification in the range 10–500 ng mL −1 with a LOQ of 5.0 ng mL −1 and a LOD of 1.5 ng mL −1 . Low interferences due to main metabolites of irinotecan and comedications, commonly associated with administration of irinotecan, were observed. A validation study, according to FDA and EMA guidelines for bioanalytical method validation, was carried out and, finally, blind samples were analyzed in parallel with a HPLC-MS method obtaining an excellent agreement between the two techniques

Prima applicazione degli indici diatomici EPI-D ed IBD nel monitoraggio del rio Picocca in provincia di Cagliari e confronto con l'IBE

Vengono riportati i risultati di una indagine finalizzata alla valutazione quali-quantitativa della comunità fitobentonica (EPI-D, IBD) del rio Picocca, in affiancamento al metodo IBE. I risultati di entrambi gli indici hanno evidenziato una buona qualità del corso d’acqua in tutte le stazion

Enzyme-based Electrochemical Biosensor for Therapeutic Drug Monitoring of Anticancer Drug Irinotecan

Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals, thus allowing a close and timely control of their dosage. To date, TDM in oncology can only be performed by trained personnel in centralized laboratories and core facilities employing conventional analytical techniques (e.g., MS). CPT-11 is an antineoplastic drug that inhibits topoisomerase type I, causing cell death, and is widely used in the treatment of colorectal cancer. CPT-11 was also found to directly inhibit acetylcholine esterase (AChE), an enzyme involved in neuromuscular junction. In this work, we describe an enzymatic biosensor, based on AChE and choline oxidase (ChOx), which can quantify CPT-11. ACh (acetylcholine) substrate is converted to choline, which is subsequently metabolized by ChOx to give betaine aldehyde and hydrogen peroxide. The latter one is then oxidized at a suitably polarized platinum electrode, providing a current transient proportional to the amount of ACh. Such an enzymatic process is hampered by CPT-11. The biosensor showed a ∼60% maximal inhibition toward AChE activity in the clinically relevant concentration range 10-10 000 ng/mL of CPT-11 in both simple (phosphate buffer) and complex (fetal bovine serum) matrixes, while its metabolites showed negligible effects. These findings could open new routes toward a real-time TDM in oncology, thus improving the therapeutic treatments and lowering the related costs

Outcomes after extracorporeal life support for postcardiotomy cardiogenic shock

BACKGROUND AND AIM OF THE STUDY: Extracorporeal life support (ECLS) may be necessary in refractory postcardiotomy cardiogenic shock (PCS) unresponsive to optimal medical treatment. We sought to analyze the results and temporal outcomes of ECLS for PCS. METHODS: We performed an observational analysis of our prospective database. In order to analyze the temporal trends of ECLS for PCS, patients were divided into two groups according to the period of ECLS implantation: Group I from January 2007-June 2012, Group II from July 2012-December 2017. The primary endpoint was survival to hospital discharge. RESULTS: During the study period, 90 patients required ECLS for PCS (Group I n = 29, 32%; Group II n = 61, 68%). Mean age was 57.5 +/- 15.0 years with 62% of males. Preoperative characteristics were comparable over the two periods. A high proportion of patients were in NYHA class III/IV (61%) or cardiogenic shock (22%). Group II showed a significantly higher proportion of miscellaneous cardiac surgery operations (23 vs 3%, P = 0.031). Crossclamp and cardiopulmonary bypass times were significantly shorter in Group II (85.4 vs 114.2 min, P = 0.023 and 135.2 vs 184.2 min, P = 0.022, respectively). The complication rate during ECLS support was comparable between both groups. Successful weaning from ECLS could be accomplished in 45 (50%) patients (Group I = 52% vs Group II = 49%, P = 0.822) after a mean support of 6.4 days. Thirty-five (39%) patients survived to hospital discharge (Group I = 41% vs Group II = 38%, P = 0.738). CONCLUSIONS: Outcomes following ECLS remained stable over an 11-year period. ECLS may be limited in patients with severe preoperative cardiac dysfunction. Our data suggest that these patients may be better served with less invasive, percutaneous procedures

Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.

The prototypical second messenger cAMP regulates a wide variety of physiological processes. It can simultaneously mediate diverse functions by acting locally in independently regulated microdomains. In mammalian cells, two types of adenylyl cyclase generate cAMP: G-protein-regulated transmembrane adenylyl cyclases and bicarbonate-, calcium- and ATP-regulated soluble adenylyl cyclase (sAC). Because each type of cyclase regulates distinct microdomains, methods to distinguish between them are needed to understand cAMP signaling. We developed a mass-spectrometry-based adenylyl cyclase assay, which we used to identify a new sAC-specific inhibitor, LRE1. LRE1 bound to the bicarbonate activator binding site and inhibited sAC via a unique allosteric mechanism. LRE1 prevented sAC-dependent processes in cellular and physiological systems, and it will facilitate exploration of the therapeutic potential of sAC inhibition