The Novel Atypical Antipsychotic Lurasidone Affects Cytochrome P450 Expression in the Liver and Peripheral Blood Lymphocytes.

Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not CYP2B2 mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction. At the same time, lurasidone decreases the expression of CYP2B, CYP2C11 (CYP2C11 protein only) and CYP2E1 but increases that of CYP3A2 (not CYP3A1) in lymphocyte cells. In conclusion, chronic treatment with lurasidone simultaneously and in the same way influences the expression and activity of CYP2B, CYP2C11, CYP2E1 and CYP3A2 in the liver and peripheral blood lymphocytes of rats. Thus, the lymphocyte cytochrome P450 profile may be utilized as an indicator of the hepatic cytochrome P450 profile in further clinical studies with lurasidone, and lymphocytes may serve as easily available surrogates for examining the impact of new drugs and chronic in vivo treatments on CYP enzyme expression, as well as to estimate drug-drug interactions and toxicity risk.

The Atypical Dopamine Transporter Inhibitor CE-158 Enhances Dopamine Neurotransmission in the Prefrontal Cortex of Male Rats: A Behavioral, Electrophysiological, and Microdialysis Study.

BACKGROUND: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, and motivation and reward. The atypical dopamine transporter inhibitor S,S stereoisomer of 5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole (CE-158) has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats. METHODS: Adult male rats were i.p. administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg and tested for extracellular dopamine in the medial prefrontal cortex by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition, working memory, and behavioral flexibility were also investigated. RESULTS: CE-158 dose-dependently potentiated dopamine neurotransmission in the medial prefrontal cortex as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg was sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro-psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by prepulse inhibition and Y maze. CONCLUSIONS: Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.

Impact of chronic potassium binder treatment on the clinical outcomes in patients with hyperkalemia: Results of a nationwide hospital-based cohort study.

Introduction: Hyperkalemia (HK) is a common disorder in patients with heart failure or chronic kidney disease, and potassium binders (PBs) are recommended to control serum potassium (S-K) levels. Although HK is often a chronic condition, short-term and intermittent PBs treatment has been largely applied to control S-K levels, and little is known about the impact of long-term and chronic PBs treatment on clinical outcomes. Method: This retrospective cohort study was conducted using a Japanese claims database (April 2008-September 2018). HK was defined as at least two S-K ≥5.1 mmol/L within a 12-month(M) interval. The index date was defined as the initial PB prescription date, and the S-K values were examined at 3M, 6M, and 12M after the index. The medication possession ratio (MPR) was used to evaluate the length of the prescribed period of PB, as prescription refill was not allowed in Japan. Clinical outcomes were analyzed by comparing MPR <80% to MPR ≥80% using Cox proportional hazards regression. Results: We found 4,321 patients with HK and were on initial PB treatments, and 993 and 3,328 patients were categorized in the MPR <80% and MPR ≥80% groups, respectively. The mean prescription days ±SD in the MPR <80% and MPR ≥80% groups were 114.7 ± 9.1 and 1151.2 ± 22.5, respectively. S-K value with adjustment by covariates in MPR <80% and MPR ≥80% groups were 5.62 (95% CI: 5.57-5.68) and 5.72 (95% CI: 5.68-5.76) at index followed by 4.65 (95% CI: 4.58-4.71) and 4.57 (95% CI: 4.51-4.62) at 3M, respectively. The hazard ratios of incidence rates in hospitalization was 1.41 (p < 0.001), introduction of renal replacement therapy was 1.25 (p < 0.003), recurrent HK was 1.67 (p < 0.001), and decreased eGFR was 1.41 (p < 0.001), respectively. Conclusion: These results indicate a higher risk of adverse outcomes when PBs were not prescribed chronically, whereas S-K levels were similarly controlled. Chronic control with continued PBs rather than temporary treatment may be associated with the reduction of adverse clinical outcomes in patients with HK.

A Participatory Approach Involving Patients with Cystic Fibrosis and Healthcare Professionals for the Co-Design of an Adherence-Enhancing Intervention Toolkit.

Purpose: Cystic fibrosis (CF) is an inherited life-shortening disease involving a significant treatment burden. Few interventions have been proven effective in improving adherence, and of these fewer have been adopted for implementation. Patient participation in research is increasingly desired in developing relevant health care services. A participatory approach was implemented in an adult CF center to co-design an adherence-enhancing intervention toolkit. We aimed to report on the participatory process and the results regarding the co-designed intervention. Patients and Methods: Two focus group sessions and four working sessions were conducted at 4-week intervals with three healthcare professionals (HCP; physician, nurse, physiotherapist), eight patients, and two researchers (sociologist, public health pharmacist). The two initial focus group sessions were dedicated to the collection of narratives about CF treatment experiences to identify drivers of adherence. The next four working sessions were dedicated to the reflection on solutions that could alleviate the difficulties identified and be used in current clinical practice. The researchers observed during all sessions the interactions between participants, group dynamics, and process of implementation of the collective reflection. Results: The process facilitated an active participation of patients and HCP, who contributed equally to the intervention development. The co-design adherence-enhancing intervention toolkit consisted in a self-questionnaire to be completed by patients before the medical consultation and used as a communication support during the consultation, plus a toolkit of solutions to be proposed by the HCP for each barrier identified by patients, and to be followed up during the next consultation. Conclusion: This study demonstrated that a participatory approach involving CF patients and HCP lead to the development of an adherence-enhancing intervention toolkit, using a 6-session format; the benefits of the co-designed intervention on the medication adherence have yet to be tested in a multicenter, open-label study in 3 centers in France.

Mood and behavior regulation: interaction of lithium and dopaminergic system.

Lithium is one of the most effect mood-stabilizing drugs prescribed especially for bipolar disorder. Lithium has wide range effects on different molecular factors and neural transmission including dopaminergic signaling. On the other hand, mesolimbic and mesocortical dopaminergic signaling is significantly involved in the pathophysiology of neuropsychiatric disorders. This review article aims to study lithium therapeutic mechanisms, dopaminergic signaling, and the interaction of lithium and dopamine. We concluded that acute and chronic lithium treatments often reduce dopamine synthesis and level in the brain. However, some studies have reported conflicting results following lithium treatment, especially chronic treatment. The dosage, duration, and type of lithium administration, and the brain region selected for measuring dopamine level were not significant differences in different chronic treatments used in previous studies. It was suggested that lithium has various mechanisms affecting dopaminergic signaling and mood, and that many molecular factors can be involved, including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), ß-catenin, protein kinase B (Akt), and glycogen synthase kinase-3 beta (GSK-3ß). Thus, molecular effects of lithium can be the most important mechanisms of lithium that also alter neural transmissions including dopaminergic signaling in mesolimbic and mesocortical pathways.

Chronic Use of Deslorelin in Dogs: Six Cases (2005-2022).

Deslorelin is currently registered for the induction of temporary infertility in male dogs, male cats, male ferrets, and also prepubertal female dogs, but research has shown its usefulness for other conditions requiring chronic treatment. This paper presents six cases of dogs chronically treated with deslorelin for indications such as benign prostatic hyperplasia, control of fertility, abnormal reproductive behavior and urinary incontinence. All animals were in good health during treatment. Treatment duration was 2-9 years. No short-term side effects were observed except for flare-up reactions, which were observed only in 1/4 intact males. Two dogs developed a neoplasia: a spayed bitch treated for urinary incontinence developed a pituitary carcinoma, and an intact male dog implanted for control of fertility developed a bladder carcinoma. While the pituitary carcinoma seems unlikely to be related to deslorelin, the bladder carcinoma could be due to the neutered condition of the dog (which was treated for 9 years) as urinary tract neoplasia is more common in dogs following gonadectomy. Chronic treatment with deslorelin is regarded as safe when an animal is being treated for life. The possibility that a pause in the treatment might be helpful for the animal should be investigated.

Antidepressant-induced increase in GluA2 expression does not translate in changes of AMPA receptor-mediated synaptic transmission at CA3/CA1 synapses in rats.

Chronic treatment with serotonin selective reuptake inhibitors or tryciclic antidepressant drugs in rodents has been shown to increase the expression of GluA1 and/or GluA2 AMPA receptor (AMPAR) subunits in several brain areas, including the hippocampus. These changes in AMPAR composition have been suggested to result in increased glutamatergic neurotransmission and possibly underlie enhanced hippocampal synaptic plasticity through the increased availability of calcium-permeable AMPARs, specifically at CA3/CA1 synapses. However, the possibility that chronic treatment with antidepressants actually results in strengthened glutamatergic neurotransmission in CA1 has poorly been investigated. Here, we studied whether chronic treatment with the multimodal antidepressant drug trazodone mimicked the effect of paroxetine on the expression of AMPAR subunits in male wistar rat hippocampus and whether these drugs produced a parallel facilitation of field excitatory postsynaptic potentials (fEPSP) responses evoked by activation of CA3/CA1 synapses in dorsal hippocampal slices. In addition, we investigated whether the quality of glutamatergic AMPARs involved in basal neurotransmission was changed by altered subunit expression, e.g. leading to appearance of calcium-permeable AMPARs. We found a significant increase in GluA2 subunit expression following treatment with trazodone or paroxetine for twenty-one days, but not after seven-days treatment. In contrast, we did not find any significant changes in fEPSP responses supporting either a facilitation of glutamatergic neurotransmission in basal conditions or the appearance of functional calcium-permeable AMPARs at CA3/CA1 pyramidal neuron synapses. Thus, neurochemically-detected increases in the expression of AMPAR subunits cannot directly be extrapolated in increased number of functioning receptors and/or facilitated basal neurotransmission.

Optimizing CFTR modulator therapy management for cystic fibrosis through the ReX platform.

Background: Cystic fibrosis (CF) is a chronic multi-systemic disease that requires a complex daily treatment regimen. Therefore, there is sub-optimal adherence to CF therapies, and it was shown to impact its clinical and economic burden. Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are high-cost medications that demonstrated significant benefit in clinical trials. The aim of this study was to evaluate the safety, usability, and efficacy of the ReX platform in medication management of CFTRm for the treatment of people with CF (pwCF). Methods: ReX is a patient engagement platform consisting of a cloud-based management system and a cell-enabled handheld device intended to dispense oral medication into the patient's mouth, following a pre-programmed treatment protocol. It provides real-time adherence data to caregivers and timely, personalized reminders to patients. This is a prospective multi-center open study for pwCFs older than 12 years, who had been prescribed CFTRm [elexacaftor/tezacaftor/ivacaftor (ETI) or tezacaftor/ivacaftor (TI)], and provided consent to use ReX platform to receive CFTRm and record their health condition. Study duration was 12-24 months, with clinic visits where physical examination, body mass index (BMI), and pulmonary function tests were performed, and user experience questionnaires were filled in. Results: Ten pwCFs from two CF centers in Israel were included. The mean age was 31.5 years (range 15-74 years); eight were taking ETI and two TI. Median adherence to CFTRm was 97.5% (range 70%-100%) in the first year and 94% (range 84%-99%) in the second year, which is higher than the previously reported CFTRm adherence of ∼80%. No adverse events related to the use of the platform were reported. Patients reported ReX to be valuable to their treatment management and user friendly. Estimated mean forced expiratory volume in 1 s (FEV1%) increased from 74.4% to 80.8% (p = 0.004) over 2 years. Similarly, estimated BMI percentile increased from 53.5 to 59.0 (p < 0.001). Conclusions: Using the ReX platform in medication management of pwCF treated by CFTRm is safe, easy to use, and effective in improving the adherence to treatment and the clinical outcomes. Consequently, this device may potentially reduce costs to healthcare providers. Further larger and long-term studies are required to examine the clinical benefits of the ReX platform.

Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4 R allosteric modulator) and 5-BDBD (P2X4 R antagonist) on the development of ARPKD in PCK/CrljCrl-Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP-mediated P2X4 R signaling with ivermectin for 6 weeks in high dose (50 mg/L; water supplementation) decreased the total body weight of PCK rats while the heart and kidney weight remained unaffected. Smaller doses of ivermectin (0.5 or 5 mg/L, 6 weeks) or the inhibition of P2X4 R signaling with 5-BDBD (18 mg/kg/day, food supplement for 8 weeks) showed no effect on electrolyte balance or the basic physiological parameters. Furthermore, cystic index analysis for kidneys and liver revealed no effect of smaller doses of ivermectin (0.5 or 5 mg/L) and 5-BDBD on the cyst development of PCK rats. We observed a slight increase in the cystic liver index on high ivermectin dose, possibly due to the cytotoxicity of the drug. In conclusion, this study revealed that pharmacological modulation of P2X4 R by ivermectin or 5-BDBD does not affect the development of ARPKD in PCK rats, which may provide insights for future studies on investigating the therapeutic potential of adenosine triphosphate (ATP)-P2 signaling in PKD diseases.

The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain.

The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug-drug interactions.

Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study.

Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.

Monitoring Pharmacological Treatment in Patients With Chronic Noncancer Pain.

Chronic pain has been not recognized as a chronic illness, and its far-reaching impacts are often ignored. Chronic noncancer pain (CNCP) is a chronic disease and health care professionals need recommendations on how to monitor treatments, patients and long-term side effects of the different medications used to control CNCP. CNCP patients make up a vulnerable population due to the various associated pathologies and the challenging socio-economic conditions experienced by many of these patients. CNCP is more common among older adults, females, cancer survivors, indigenous peoples, veterans, and populations affected by social inequities and discrimination. These social determinants can lead to a complex interplay between chronic pain, mental illness, and substance use disorders. Given these realities, long-term pharmacological and side effect surveillance is more complex. Follow-up of patients with CNCP is a challenge for physicians, and thus it is important to provide recommendations on how to monitor treatments and long-term side effects of the different medications used to control CNCP.

Chronic treatment with asenapine affects cytochrome P450 2D (CYP2D) in rat brain and liver. Pharmacological aspects.

Neuroleptics have to be used for a long time to produce a therapeutic effect. Cytochrome P450 2D (CYP2D) enzymes mediate alternative pathways of neurotransmitter synthesis (i.e. tyramine hydroxylation to dopamine and 5-methoxytryptamine O-demethylation to serotonin), and metabolism of neurosteroids. The aim of our present study was to examine the influence of chronic treatment with the new atypical neuroleptic asenapine on CYP2D in rat brain. In parallel, liver CYP2D was investigated for comparison. Asenapine added in vitro to microsomes of control rats competitively, but weakly inhibited the activity of CYP2D (brain: Ki = 385 µM; liver: Ki = 36 µM). However, prolonged administration of asenapine (0.3 mg/kg sc. for 2 weeks) significantly diminished the activity and protein level of CYP2D in the frontal cortex, nucleus accumbens, hippocampus and cerebellum, but did not affect the enzyme in the hypothalamus, brain stem, substantia nigra and the remainder of the brain. In contrast, asenapine enhanced the enzyme activity and protein level in the striatum. In the liver, chronically administered asenapine reduced the activity and protein level of CYP2D, and the CYP2D1 mRNA level. In conclusion, prolonged administration of asenapine alters the CYP2D expression in the brain structures and in the liver. Through affecting the CYP2D activity in the brain, asenapine may modify its pharmacological effect. By increasing the CYP2D expression/activity in the striatum, asenapine may accelerate the synthesis of dopamine (via tyramine hydroxylation) and serotonin (via 5-methoxytryptamine O-demethylation), and thus alleviate extrapyramidal symptoms. By reducing the CYP2D expression/activity in other brain structures asenapine may diminish the 21-hydroxylation of neurosteroids and thus have a beneficial influence on the symptoms of schizophrenia. In the liver, by reducing the CYP2D activity, asenapine may slow the biotransformation of concomitantly administered CYP2D substrates (drugs) during continuous treatment of schizophrenia or bipolar disorders.

Pharmacological treatment of migraine: Drug classes, mechanisms of action, clinical trials and new treatments.

Migraine is the sixth most prevalent disease globally, a major cause of disability, and it imposes an enormous personal and socio-economic burden. Migraine treatment is often limited by insufficient therapy response, leading to the need for individually adjusted treatment. In this review, we analyse historical and current pharmaceutical development approaches in acute and chronic migraine based on a comprehensive and systematic analysis of Food and Drug Administration (FDA)-approved drugs and those under investigation. The development of migraine therapeutics has significantly intensified during the last 3 years, as shown by our analysis of the trends of drug development between 1970 and 2020. The spectrum of drug targets has expanded considerably, which has been accompanied by an increase in the number of specialised clinical trials. This review highlights the mechanistic implications of FDA-approved and currently investigated drugs and discusses current and future therapeutic options based on identified drug classes of interest.

Estudio de efectividad y seguridad de los agentes estimulantes de la eritropoyesis en el tratamiento de la anemia asociada a enfermedad renal crónica. Análisis de los factores que influyen en la respuesta / Effectiveness and Safety Study of the Stimulating Agents of Erythropoyesis in the Treatment of Anemia Associated with Chronic Kidney Disease. Analysis of the Factors that Influence the Response

Objetivos: Evaluar la efectividad y seguridad de darbepoetina α y epoetina β en la anemia asociada a ERC y estudiar los factores que influyen en la respuesta.Métodos: Estudio observacional, de cohortes, retrospectivo. Pacientes ≥18 años con ERC que inicia-ron tratamiento con AEE entre el 1 de enero 2014 y el 31 de diciembre 2015. Periodo máximo de seguimiento: 24 meses. Variables sociodemográficas, analíticas; de efectividad y relacionadas con la causa de fin de seguimiento. Análisis estadístico: modelos de regresión logística multivariante, regresión lineal múltiple. El estudio obtuvo dictamen favorable del Comité Ético de Investigación Clínica de Aragón (CEICA). Resultados: 198 pacientes: 59,1% varones, edad media: 75,3±12,4 años, 60% ERC estadio 4, Hb me-dia basal: 10,2±1,3 g/dL. El 71,2% inició darbepoetina α (dosis mediana: 18,7 (4,7-100,0) μg/semanal), el 28,8% epoetina β (6000,0 (466,7-20.000,0) UI/semanal). Los pacientes tratados con darbepoetina α presentaban estadios de ERC más avanzados (p<0,001); los que recibieron epoetina β más insuficiencia cardíaca (IC) (p=0,002) y cardiopatía isquémica (p=0,028). El 54,5% de los pacientes alcanzó el objetivo terapéutico a los 3 meses. El tratamiento con estatinas (OR:0,4 (IC95%: 0,174-0,996)) e insulina (OR:2,6 (IC95%:1,1-5,2)) se relacionaron con alcanzar la respuesta terapéutica. La Hb basal (Hb_b) y el Fe basal (Fe_b) influyeron en el ΔHb (%) (p<0,001 y 0,007 respectivamente). El 2,5% presentó un acci-dente cerebrovascular (ACV) isquémico en los 24 meses de seguimiento. El 35,9% (n=71) continuaba tratamiento con AEE a los 24 meses: 40,4% con darbepoetina α vs 24,6% con epoetina β (p=0,001). Conclusiones: Los AEE corrigen y mantienen la concentración de Hb de forma segura con dosis moderadas de AEE.(AU)

Objective: To evaluate the effectiveness and safety of darbepoetin α and epoetin β in anemia associat-ed with CKD and to study the factors that influence the response.Methods: It was carried out an observational, group and retrospective study. Patients ≥18 years of age with CKD who started treatment with ESA between January 1, 2014 and December 31, 2015. Maximum period of follow-up: 24 months. Sociodemographic, analytical, effectiveness and related to the cause of end of follow-up variables. Statistical analysis: multivariate logistic regression models, multiple linear regression. The study obtained a favorable opinion from the Aragón Clinical Research Ethics Committee (CEICA).Results: 198 patients: 59.1% men, mean age: 75.3 ± 12.4 years, 60% stage 4 CKD, mean baseline Hb: 10.2 ± 1.3 g / dL. 71.2% started darbepoetin α (median dose: 18.7 (4.7-100.0) μg / weekly), 28.8% epoetin β (6000.0 (466.7-20,000.0) IU /weekly). The patients treated with darbepoetin α had more advanced stages of CKD (p <0.001); those who re-ceived epoetin β plus heart failure (HF) (p = 0.002) and ischemic heart disease (p = 0.028). 54.5% of the patients reached the therapeutic objective at 3 months. Treatment with statins (OR: 0.4 (95% CI: 0.174-0.996)) and insulin (OR: 2.6 (95% CI: 1.1-5.2)) were related to achieving the therapeutic response. Baseline Hb (Hb_b) and basal Fe (Fe_b) influenced ΔHb (%) (p <0.001 and 0.007, respectively. 2.5% had an ischemic cerebrovascular accident (CVA) in the 24-month follow-up. 35.9% (n = 71) continued treat-ment with ESA at 24 months: 40.4% with darbepoe-tin α vs 24.6% with epoetin β (p = 0.001). Conclusions: ESAs safely correct and maintain Hb levels with moderate doses of ESAs.(AU)

The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms.

Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16ß; 2α and 16α; 2ß and 6ß, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose.

The pharmacotherapeutic management of hyperkalemia in patients with cardiovascular disease.

Introduction: Patients with cardiovascular diseases (CVD) are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone inhibitors (RAASIs). Because the occurrence or fear of hyperkalemia, RAASIs are frequently down-titrated or discontinued in patients with CVD, with consequent worse outcomes than patients who remain on maximum doses.Areas covered: This article reviews potassium homeostasis, epidemiology, risk factors, and outcomes of hyperkalemia, and efficacy and safety of the drugs used for acute and chronic treatment of hyperkalemia. A literature search was carried out using the PubMed and guidelines for the management of hyperkalemia.Expert opinion: The emergency treatment of hyperkalemia is not supported by high-quality evidence and clinical trials did not report drug effects on clinical outcomes. Two potassium binders, patiromer and sodium zirconium cyclosilicate, represent a new approach in the treatment of chronic hyperkalemia as they may allow the titration and maintenance of guidelines-recommended doses of RAASIs in patients with CVD who otherwise would not tolerate them due to the risk of hyperkalemia.Further studies are needed to evaluate the safety and efficacy of drug therapy and support the development of guidelines for acute and chronic hyperkalemia.

Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770.

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in CFTR, the most frequent of which is F508del. F508del causes ER retention and degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life at the plasma membrane. Despite the recent successes with small-molecule CFTR modulator drugs, the folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment of polarized bronchial epithelial monolayers with the VX-809+VX-770 combination resulted in epithelial dedifferentiation effects that we found were caused specifically by VX-809. Moreover, prolonged VX-770 exposure also led to the destabilization of VX-809-rescued F508del-CFTR. Notably, co-treatment with the physiological factor HGF prevented VX-809-mediated epithelial differentiation and reverted the destabilizing effect of VX-770 on VX-809-rescued CFTR. Here, we show that prolonged treatment with VX-661, a second-generation corrector developed based on VX-809 structure, does not perturb epithelial integrity of polarized bronchial epithelial monolayers. Yet, its efficacy is still affected by co-exposure to VX-770, the potentiator present in all VX-661-containing combination therapies approved in the United States and Europe for treatment of F508del-CFTR carriers. Importantly, we found that co-treatment with HGF still ameliorated the impact of VX-770 in F508del-CFTR functional rescue by VX-661, without increasing cell proliferation (Ki-67) or altering the overall expression of epithelial markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight the importance of evaluating the cellular effects of prolonged exposure to CFTR modulators and suggest that the benefits of adding HGF to current combination therapies should be further investigated.

Refining drug administration in a murine model of acute infection with Trypanosoma cruzi.

BACKGROUND: In animal research, "refinement" refers to modifications of husbandry or experimental procedures to enhance animal well-being and minimize or eliminate pain and distress. Evaluation of drug efficacy in mice models, such as those used to study Trypanosoma cruzi infection, require prolonged drug administration by the oral route (e.g. for 20 consecutive days). However, the orogastric gavage method can lead to significant discomfort, upper digestive or respiratory tract lesions, aspiration pneumonia and even accidental death. The aim of this work was to evaluate the effect of two administration methods (conventional oral gavage vs. a refined method using a disposable tip and automatic pipette) on the efficacy of benznidazole in a murine model of T. cruzi infection. RESULTS: Both administration methods led to a rapid and persistent reduction in parasitaemia. Absence of T. cruzi DNA (evaluated by real-time PCR) in blood, cardiac and skeletal muscle confirmed that treatment efficacy was not influenced by the administration method used. CONCLUSIONS: The proposed refined method for long-term oral drug administration may be a suitable strategy for assessing drug efficacy in mice models of Chagas disease and can be applied to similar murine infection models to reduce animal discomfort.

Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic Versus Acute Administration to Protect Heart, Brain, and Spinal Cord.

This article reviews novel approaches for omega-3 fatty acid (FA) therapeutics and the linked molecular mechanisms in cardiovascular and central nervous system (CNS) diseases. In vitro and in vivo research studies indicate that omega-3 FAs affect synergic mechanisms that include modulation of cell membrane fluidity, regulation of intracellular signaling pathways, and production of bioactive mediators. We compare how chronic and acute treatments with omega-3 FAs differentially trigger pathways of protection in heart, brain, and spinal cord injuries. We also summarize recent omega-3 FA randomized clinical trials and meta-analyses and discuss possible reasons for controversial results, with suggestions on improving the study design for future clinical trials. Acute treatment with omega-3 FAs offers a novel approach for preserving cardiac and neurological functions, and the combinations of acute treatment with chronic administration of omega-3 FAs might represent an additional therapeutic strategy for ameliorating adverse cardiovascular and CNS outcomes.