Nuevas herramientas para la revisión de la medicación: PRM en pacientes en tratamiento con inhibidores de la bomba de protones / New tools for medication review: DRP in patients treatment with proton pump inhibitors

Objetivo Analizar mediante el programa de revisión de la medicación, Revisem®, la prevalencia de problemas relacionados con la medicación (PRM) en pacientes de la provincia de Valencia que estaban en tratamiento activo con inhibidores de la bomba de protones (IBP) en 2022. Diseño Estudio observacional descriptivo y retrospectivo. Material y métodos Se analizó el historial farmacoterapéutico (HFT) de 295 pacientes siguiendo los criterios propuestos por la Pharmaceutical Care Network Europe, utilizando la plataforma digital Revisem® del Muy Ilustre Colegio Oficial de Farmacéuticos de Valencia (MICOF). Resultados La edad media de los pacientes fue 81,8 ± 11,1 años y 66,4% fueron mujeres. Se detectó al menos un PRM en 97,3% de los pacientes. De los PRM analizados, 46,9% fueron interacciones, de las cuales 29,7% implicaban un IBP, siendo el omeprazol el de mayor frecuencia. Los PRM con IBP se relacionan de forma significativa con determinadas condiciones del paciente y grupos farmacológicos, como son el sexo femenino, la edad superior a 54 años y la polifarmacia. Conclusiones La plataforma digital Revisem®, permite la detección de una alta prevalencia de PRM a nivel provincial. La aplicación de nuevas herramientas tecnológicas para detectar la prevalencia de PRM es fundamental para optimizar los tratamientos de los pacientes. (AU)

Objective To analyze, using the medication review program, Revisem®, the prevalence of drug-related problems (DRP) in patients in the province of Valencia who were on active treatment with proton pump inhibitors (PPI) in 2022. Design Descriptive and retrospective observational study. Material and methods The pharmacotherapeutic history of 295 patients was analyzed following the criteria proposed by the Pharmaceutical Care Network Europe, using the Revisem® digital platform of the Muy Ilustre Colegio Oficial de Farmacéuticos (MICOF). Results The mean age of the patients was 81.8 ± 11.1 years and 66.4% were women. At least one DRP was detected in 97.3% of patients. 46.9% of the DRP analyzed were interactions, of which 29.7% involved a PPI, with omeprazole being the most frequent. DRPs with PPI are significantly related to certain patient conditions and pharmacological groups, such as female sex, age over 54 years and polypharmacy. Conclusions The application of the Revisem® digital platform allows the detection of a high prevalence of DRP at the provincial level. The application of new technological tools to detect the prevalence of DRP is essential to optimize patient treatments. (AU)

[New tools for medication review: DRP in patients treatment with proton pump inhibitors]. / Nuevas herramientas para la revisión de la medicación: PRM en pacientes en tratamiento con inhibidores de la bomba de protones.

OBJECTIVE: To analyze, using the medication review program, Revisem®, the prevalence of drug-related problems (DRP) in patients in the province of Valencia who were on active treatment with proton pump inhibitors (PPI) in 2022. DESIGN: Descriptive and retrospective observational study. MATERIAL AND METHODS: The pharmacotherapeutic history of 295 patients was analyzed following the criteria proposed by the Pharmaceutical Care Network Europe, using the Revisem® digital platform of the Muy Ilustre Colegio Oficial de Farmacéuticos (MICOF). RESULTS: The mean age of the patients was 81.8 ± 11.1 years and 66.4% were women. At least one DRP was detected in 97.3% of patients. 46.9% of the DRP analyzed were interactions, of which 29.7% involved a PPI, with omeprazole being the most frequent. DRPs with PPI are significantly related to certain patient conditions and pharmacological groups, such as female sex, age over 54 years and polypharmacy. CONCLUSIONS: The application of the Revisem® digital platform allows the detection of a high prevalence of DRP at the provincial level. The application of new technological tools to detect the prevalence of DRP is essential to optimize patient treatments.

Variation of the relative biological effectiveness with fractionation in proton therapy: Analysis of prostate cancer response.

BACKGROUND: In treatment planning for proton therapy a constant Relative Biological Effectiveness (RBE) of 1.1 is used, disregarding variations with linear energy transfer, clinical endpoint, or fractionation. PURPOSE: To present a methodology to analyze the variation of RBE with fractionation from clinical data of tumor control probability (TCP) and to apply it to study the response of prostate cancer to proton therapy. METHODS AND MATERIALS: We analyzed the dependence of the RBE on the dose per fraction by using the LQ model and the Poisson TCP formalism. Clinical tumor control probabilities for prostate cancer (low and intermediate risk) treated with photon and proton therapy for conventional fractionation (2 Gy(RBE)×37 fractions), moderate hypofractionation (3 Gy(RBE)×20 fractions) and hypofractionation (7.25 Gy(RBE)×5 fractions) were obtained from the literature and analyzed aiming at obtaining the RBE and its dependence on the dose per fraction. RESULTS: The theoretical analysis of the dependence of the RBE on the dose per fraction showed three distinct regions with RBE monotonically decreasing, increasing or staying constant with the dose per fraction, depending on the change of (α, ß) values between photon and proton irradiation (the equilibrium point being at (αp /ßp ) = (αX /ßX )(αX /αp )). An analysis of the clinical data showed RBE values that decline with increasing dose per fraction: for low risk RBE≈1.124, 1.119, and 1.102 for 1.82 Gy, 2.73 Gy and 6.59 Gy per fraction (physical proton doses), respectively; for intermediate risk RBE≈1.119 and 1.102 for 1.82 Gy and 6.59 Gy per fraction (physical proton doses), respectively. These values are nonetheless very close to the nominal 1.1 value. CONCLUSIONS: In this study, we have presented a methodology to analyze the RBE for different fractionations, and we used it to study clinical data for prostate cancer and evaluate the RBE versus dose per fraction. The analysis shows a monotonically decreasing RBE with increasing dose per fraction, which is expected from the LQ formalism and the changes in (α, ß) values between photon and proton irradiation. However, the calculations in this study have to be considered with care as they may be biased by limitations in the modeling assumptions and/or by the clinical data set used for the analysis.

Radiobiological Meta-Analysis of the Response of Prostate Cancer to Different Fractionations: Evaluation of the Linear-Quadratic Response at Large Doses and the Effect of Risk and ADT.

The purpose of this work was to investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, to evaluate potential departures from the linear-quadratic (LQ) response, to obtain the best-fitting parameters for low-(LR), intermediate-(IR), and high-risk (HR) prostate cancer and to investigate the effect of ADT on the radiobiological response. We constructed a dataset of the dose-response containing 87 entries/16,536 patients (35/5181 LR, 32/8146 IR, 20/3209 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fit to tumour control probability models based on the LQ model, linear-quadratic-linear (LQL) model, and a modification of the LQ (LQmod) model accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike information criterion (AIC) was used to compare the models. The AIC showed that the LQ model was superior to the LQL and LQmod models for all risks, except for IR, where the LQL model outperformed the other models. The analysis showed a low α/ß for all risks: 2.0 Gy for LR (95% confidence interval: 1.7-2.3), 3.4 Gy for IR (3.0-4.0), and 2.8 Gy for HR (1.4-4.2). The best fits did not show proliferation for LR and showed moderate proliferation for IR/HR. The addition of ADT was consistent with a suppression of proliferation. In conclusion, the LQ model described the response of prostate cancer better than the alternative models. Only for IR, the LQL model outperformed the LQ model, pointing out a possible saturation of radiation damage with increasing dose. This study confirmed a low α/ß for all risks.

A Biomathematical Model of Tumor Response to Radioimmunotherapy With αPDL1 and αCTLA4.

There is evidence of synergy between radiotherapy and immunotherapy. Radiotherapy can increase liberation of tumor antigens, causing activation of antitumor T-cells. This effect can be boosted with immunotherapy. Radioimmunotherapy has potential to increase tumor control rates. Biomathematical models of response to radioimmunotherapy may help on understanding of the mechanisms affecting response, and assist clinicians on the design of optimal treatment strategies. In this work we present a biomathematical model of tumor response to radioimmunotherapy. The model uses the linear-quadratic response of tumor cells to radiation (or variation of it), and builds on previous developments to include the radiation-induced immune effect. We have focused this study on the combined effect of radiotherapy and αPDL1/ αCTLA4 therapies. The model can fit preclinical data of volume dynamics and control obtained with different dose fractionations and αPDL1/ αCTLA4. A biomathematical study of optimal combination strategies suggests that a good understanding of the involved biological delays, the biokinetics of the immunotherapy drug, and the interplay between them, may be of paramount importance to design optimal radioimmunotherapy schedules. Biomathematical models like the one we present can help to interpret experimental data on the synergy between radiotherapy and immunotherapy, and to assist in the design of more effective treatments.

Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with 131I-CLR1404.

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with 124I/131I, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol's sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of 124I/131I. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case.

Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response.

BACKGROUND: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. METHODS: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b-) and activated (CD31+CD42b-CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. RESULTS: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH.

CD31+ Extracellular Vesicles From Patients With Type 2 Diabetes Shuttle a miRNA Signature Associated With Cardiovascular Complications.

Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications, but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead-based method to isolate plasma CD31+ EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31+ EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31+ EVs in a large (n = 218) cross-sectional cohort of patients categorized as having T2DM without complications, having T2DM with complications, and control subjects. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, and -451a efficiently identified T2DM patients with complications. Furthermore, another CD31+ EV-shuttled miRNA signature, i.e., miR-155, -320a, -342-3p, -376, and -422a, detected T2DM patients with a previous major adverse cardiovascular event. Many of these miRNAs significantly correlate with clinical variables held to play a key role in the development of complications. In addition, we show that CD31+ EVs from patients with T2DM are able to promote the expression of selected inflammatory mRNAs, i.e., CCL2, IL-1α, and TNFα, when administered to endothelial cells in vitro. Overall, these data suggest that the miRNA cargo of plasma CD31+ EVs is largely affected by T2DM and related complications, encouraging further research to explore the diagnostic potential and the functional role of these alterations.

Extracellular vesicles derived from Plasmodium-infected and non-infected red blood cells as targeted drug delivery vehicles.

Among several factors behind drug resistance evolution in malaria is the challenge of administering overall doses that are not toxic for the patient but that, locally, are sufficiently high to rapidly kill the parasites. Thus, a crucial antimalarial strategy is the development of drug delivery systems capable of targeting antimalarial compounds to Plasmodium with high specificity. In the present study, extracellular vesicles (EVs) have been evaluated as a drug delivery system for the treatment of malaria. EVs derived from naive red blood cells (RBCs) and from Plasmodium falciparum-infected RBCs (pRBCs) were isolated by ultrafiltration followed by size exclusion chromatography. Lipidomic characterization showed that there were no significant qualitative differences between the lipidomic profiles of pRBC-derived EVs (pRBC-EVs) and RBC-derived EVs (RBC-EVs). Both EVs were taken up by RBCs and pRBCs, although pRBC-EVs were more efficiently internalized than RBC-EVs, which suggested their potential use as drug delivery vehicles for these cells. When loaded into pRBC-EVs, the antimalarial drugs atovaquone and tafenoquine inhibited in vitro P. falciparum growth more efficiently than their free drug counterparts, indicating that pRBC-EVs can potentially increase the efficacy of several small hydrophobic drugs used for the treatment of malaria.

Postural stability in a population of dancers, healthy non-dancers, and vestibular neuritis patients.

INTRODUCTION: Several studies have indicated better balance control in dancers than in control participants, but some controversy remains. The aim of our study is to evaluate the postural stability in a cohort of dancers, non-dancers, compensated, and non-compensated unilateral vestibular neuritis (VN). METHODS: This is a prospective study of control subjects, dancers, and VN patients between June 2009 and December 2015. Dancers from the Dance Conservatory of Madrid and VN patients were referred to our department for analysis. After the clinical history, neuro-otological examination, audiogram, and caloric tests, the diagnosis was done. Results from clinical examination were used for the categorization of compensation situation. A computerized dynamic posturography was performed to every subject. RESULTS: Forty dancers and 38 women formed both 'dancer' and 'normal' cohorts. Forty-two compensated and 39 uncompensated patients formed both 'compensated' and 'uncompensated' cohorts. Dancers had significantly greater antero-posterior (AP) body sway than controls during condition 5 and 6 in the Sensory Organization Test (SOT) (p < .05). When we compared the uncompensated cohort with both control and dancers groups, we found significant greater body sway in every SOT studied condition (p < .05). While mean AP body say in SOT 5 and 6, showed greater values in compensated patients than the control group, the mean analysis did not show any statistical difference between the compensated and dancer groups, in such SOT conditions. CONCLUSIONS: Dancers demonstrated greater sways than non-dancers when they relied their postural control on vestibular input alone. Compensated patients had a similar posturographic pattern that the dancers cohort, suggesting a similar shift from visual to somatosensory information.

Evolution of broadly cross-reactive HIV-1-neutralizing activity: therapy-associated decline, positive association with detectable viremia, and partial restoration of B-cell subpopulations.

Little is known about the stability of HIV-1 cross-neutralizing responses. Taking into account the fact that neutralization breadth has been positively associated with plasma viral load, there is no explanation for the presence of broadly neutralizing responses in a group of patients on treatment with undetectable viremia. In addition, the B-cell profile responsible for broadly cross-neutralizing responses is unknown. Here we studied the evolution of neutralizing responses and the B-cell subpopulation distribution in a group of patients with broadly cross-reactive HIV-1-neutralizing activity. We studied neutralization breadth evolution in a group of six previously identified broadly cross-neutralizing patients and six control patients during a 6-year period with a previously described minipanel of recombinant viruses from five different subtypes. B-cell subpopulation distribution during the study was also determined by multiparametric flow cytometry. Broadly cross-neutralizing activity was transient in four broad cross-neutralizers and stable, up to 4.6 years, in the other two. In four out of five broad cross-neutralizers who initiated treatment, a neutralization breadth loss occurred after viremia had been suppressed for as much as 20 months. B-cell subpopulation analyses revealed a significant increase in the frequency of naive B cells in broadly cross-reactive samples, compared with samples with less neutralization breadth (increased from 44% to 62%). We also observed a significant decrease in tissue-like and activated memory B cells (decreased from 19% to 12% and from 17% to 9%, respectively). Our data suggest that HIV-1 broadly cross-neutralizing activity is variable over time and associated with detectable viremia and partial B-cell restoration.

TrkC: a new predictive marker in breast cancer?

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.

Unrecognized delayed toxic lithium peak concentration in an acute poisoning with sustained release lithium product.

A 32-year-old female with a history of bipolar disorder was admitted after taking approximately 16 g of an extended-release lithium carbonate formulation in an attempted suicide. Five hours after consumption, the lithium serum level was 3.2 mEq/L. Fourteen hours after consumption, the lithium level was 5.1 mEq/L and the patient was asymptomatic. Due to a level > 4 mEq/L, the patient was transferred to a renal medicine service for hemodialysis. The lithium concentration 6 hours after the hemodialysis was 2.54 mEq/L. Thirty seven hours after the consumption (15 hours after hemodialysis), lithium levels increased up to 6.09 mEq/L. A second hemodialysis session was performed, which successfully reduced the serum lithium concentration to 1.86 mEq/L. Lithium levels 85 hours after the consumption were 0.61 mEq/L and the patient was transferred to the Psychiatry Department. Unrecognized delayed toxic peak lithium concentration may appear in an acute poisoning with a sustained release lithium product. Therefore, patients presenting with acute intoxication with extended release formulations should be managed with caution, and continued drug monitoring is suggested.

Optic neuritis with concurrent etanercept and isoniazid therapy.

OBJECTIVE: To report a case of optic neuritis associated with concurrent etanercept and isoniazid therapy. CASE SUMMARY: A 55-year-old man diagnosed as having rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, sulfasalazine, oral methotrexate, leflunomide, and deflazacort. Four months prior to admission, he had a Disease Activity Score of 6.06; treatment with etanercept was considered. Three months prior to admission, because of evidence of latent tuberculosis, isoniazid 300 mg once daily and pyridoxine 50 mg once daily were prescribed. Treatment with subcutaneous etanercept 25 mg twice weekly was started 5 days after isoniazid was initiated. Two weeks prior to admission, the patient developed blurred vision in his left eye. Ten days later, his vision worsened and he was hospitalized. The visual acuity in both eyes was 0.7, and a campimetric examination was compatible with optic neuritis. Magnetic resonance imaging of the brain revealed lesions suggesting demyelinating lesions. The clinical course was consistent with bilateral optic neuritis. Etanercept was stopped, and isoniazid was replaced with rifampin 600 mg once daily. The patient was treated with intravenous methylprednisolone hemisuccinate 1 g/day for 5 days followed by oral prednisolone, resulting in a minor subjective improvement in left eye visual acuity. He then received oral prednisone for 3 weeks, slowly tapering to discontinuation. DISCUSSION: No physiologic factors could have predisposed this patient to develop optic neuritis. He was not diagnosed with a demyelinating disease or underlying systemic condition. The optic neuritis was unlikely to be an early manifestation of multiple sclerosis based on the clinical course and the negative results of the imaging tests. Furthermore, there was a close temporal correlation between the drug exposure and the onset of symptoms. After discontinuation of etanercept and isoniazid therapy, the patient's general condition improved. Use of the Naranjo probability scale indicated a possible relationship between optic neuritis and combined etanercept-isoniazid therapy. CONCLUSIONS: Patients initiated on etanercept and isoniazid should be closely monitored for the development of adverse neurologic signs and effects. If optic neuritis is determined, etanercept and isoniazid should be discontinued immediately.