DigitalUM :: Browsing by browse.metadata.contributordepartment "Farmacología"

Browsing by browse.metadata.contributordepartment "Farmacología"

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Open Access
30-day postoperative mortality and the effects of hospital preparedness during the COVID-19 pandemic: a pooled analysis of prospective international cohort studies
(Elsevier, 2026-01-29) García Pérez, Daniel; Nepogodiev, Dmitri; Kamarajah, Sivesh K.; Bhangu, Aneel; Aacharya, Radhika; Ahmed, Waheed-Ul-Rahman ; ElAmeer, Ehab; Blanco-Colino, Ruth; Elhadi, Muhammed; Ghosh, Dhruva; Glasbey, James C.; Isik, Arda; Jolly, Kate; Kaafarani, Haytham; Kadir, Bryar; Lederhuber, Hans; Leventoğlu, Sezai; Omar, Omar M.; Pata, Francesco; Picciochi, Maria; Pockney, Peter; NIHR Global Health Research Unit on Global Surgery; COVIDSurg Collaborative; Farmacología; Facultad de Farmacia
Background: Surgical services were poorly prepared for the COVID-19 pandemic, leading to widescale disruption to elective activity. This study aimed to identify actionable priorities to strengthen pandemic preparedness of surgical and hospital systems. Methods: This study pooled data from three international, prospective cohort studies including patients who had a positive SARS-CoV-2 test result in the seven days before or within 30 days after surgery. Patients were included across four pandemic time periods: Period 1 (January–May 2020), Period 2 (June–July 2020), Period 3 (October 2020), and Period 4 (December–March 2022). The primary outcome measure was 30-day postoperative mortality. Hierarchical logistic regression models were developed to explore association between pandemic periods (primary analysis) and hospital-level preparedness (secondary analysis) on 30-day postoperative mortality. Hospital preparedness was classified in to poorly-, moderately-, and highly-prepared tertiles based on Surgical Preparedness Index (SPI) score. Findings: A total of 31,751 patients were included from 1589 hospitals and 102 countries. From Period 1 through to Period 4 there was a decrease in the proportion of patients aged ≥70 years and with ASA grades 3–5.30-day postoperative mortality fell from Period 1 (18.4% [1378/7502]), Period 2 (9.9% [219/2234], adjusted odds ratio (aOR) 0.65, 95% confidence interval (CI) 0.53–0.78), Period 3 (10.5% [246/2427], aOR 0.60, 95% CI 0.50–0.71), through to Period 4 (5.8% [1132/19,588], aOR 0.33, 95% CI 0.30–0.37). During Period 4, SARS-CoV-2 vaccinated patients had lower mortality compared to unvaccinated patients (4.9% [603/12,361] versus 7.4% [529/7178], aOR 0.49, 95% CI 0.42–0.57). Compared to poorly-prepared hospitals (11.2% [1019/9071]), moderately-prepared (9.4% [857/9071], aOR 0.84, 95% CI 0.75–0.94) and highly-prepared hospitals (5.8% [530/9071], aOR 0.70, 95% CI 0.62–0.80) had lower mortality. Interpretation: Postoperative mortality decreased over the course of the COVID-19 pandemic and was lower in better prepared hospitals. Hospitals are critical national infrastructure and strengthening their preparedness by developing formal pandemic plans, establishing patient and procedure prioritisation protocols, and ring-fencing surgical beds would ensure safer surgical care during future pandemics.
Open Access
A Fast and Accurate Method for the Quantification of Doxycycline in Goat Plasma and Milk by HPLC Using a Fluorescence Detector
(2024-12-17) Martínez, José; Hernandis, Verónica; Badillo, Elena; Escudero, Elisa; Yuste Pérez, María Teresa; Galecio, Juan Sebastián; Marín, Pedro; Farmacología
Doxycycline is an antimicrobial agent used in veterinary medicine to treat a variety of bacterial infections. To date, no analytical technique utilising HPLC with fl uorescence detection has been documented for the quantifi cation of doxycycline concentrations in goat plasma or milk. Consequently, the objective of the present study was to propose a rapid HPLC assay with fl uorescence detection for the quantifi cation of doxycycline in the aforementioned samples, thereby facilitating the conduct of pharmacokinetic studies and the detection of residues in diverse goat tissues. Proteins were precipitated with methanol and trifl uoroacetic acid in a single step. Doxycycline was separated on a XBRIDGE C18 column using an isocratic method. Sample volume injected into the HPLC system was 50 µl. Fluorescence detection was conducted with an excitation wavelength of 380 nm and an emission wavelength of 520 nm. The retention times of doxycycline and danofl oxacin (internal standard) were determined to be 8.0 and 5.5 minutes, respectively. The calibration curves for plasma and milk exhibited linearity over the concentration range of 0.1 to 2 μg/mL. The limit of detection was 0.065 μg/ mL, while the limit of quantifi cation was 0.1 μg/mL in both matrices. The accuracy and precision of the method were consistently within the limits of 10.9% for plasma and 10.5% for milk. The fi ndings of this study may be employed in the quantifi cation of doxycycline in goat plasma and milk, thus facilitating the conduct of pharmacokinetic studies.
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A frontal route to middle and posterior cranial fossa: quantitative study for the lateral transorbital endoscopic approach and comparison with the subtemporal approach
(Elsevier, 2022-08-06) García Pérez, Daniel; Abarca, Javier; González López, Pablo; Nieto, Juan; Lagares, Alfonso; Paredes, Igor; Farmacología
Background Skull base lesions within the middle cranial fossa (MCF) remain challenging. Recent reports suggest that transorbital endoscopic approaches (TOEAs) might be particularly suitable to access the MCF and expose the lateral wall of the cavernous sinus and the Meckel's cave. Methods The present study was developed to compare the nuances of the subtemporal approach (STA) with those of the lateral TOEA (LTOEA) to the MCF and posterior cranial fossa (PCF) in cadaveric specimens. After orbital craniectomy, interdural opening of the cavernous sinus lateral wall (CSlw), exposure of the Gasserian ganglion, and extradural elevation of the temporal lobe was performed. Next, anterior endoscopic petrosectomy was performed and the PCF was accessed. We quantitatively analyzed and compared the angles of attack and distances between LTOEA and STA to different structures at the CSlw, petrous apex (PA), and PCF. Results Cadaveric dissection through the LTOEA completely exposed the CSlw and PA. LTOA exhibited larger distances than the STA to all targets. Importantly, these differences were greater at the PA and its surrounding key anatomic landmarks. The horizontal and vertical angles of attack allowed by the LTOA were smaller both for the CSlw and PA. However, these differences were not significant for the vertical angle of attack at the CSlw. Conclusions LTOEA provides a direct ventral route to the medial aspect of MCF, PA, and PCF. Although TOEAs are versatile approaches, the unfamiliar surgical anatomy and limited instrument maneuverability demand extensive cadaveric dissection before moving to the clinical setting.
Open Access
A novel liquid chromatography-fluorescence method for the determination of delafloxacin in human plasma
(Wiley, 2022-02-05) Hernandis Belenguer, Verónica; Escudero Pastor, Elisa; Marín Carrillo, Pedro; Farmacología
Delafloxacin is a novel fluoroquinolone antibiotic that was approved by the European Medicine Agency to treat bacterial infections of the skin and underlying tissues, and community-acquired pneumonia. Despite being in the market since 2019 in the European Union, there is no published liquid chromatography-fluorescence method for delafloxacin quantification in biological samples. A novel, rapid, and sensitive high-performance liquid chromatographic method was developed to determine delafloxacin in human plasma using its native fluorescence. Plasma delafloxacin concentrations were determined by reverse-phase chromatography with fluorescence detection at 405/450 nm of excitation/emission wavelengths. Delafloxacin was separated on a Kromasil C18 column 250 × 4.6 mm id, 5 µm using isocratic elution. The mobile phase was a mixture of 0.05% trifluoroacetic acid/acetonitrile (52/48). Retention times were 5.4 and 11.6 min for delafloxacin and valsartan (internal standard), respectively. Regression calibration curves were linear over the range of 0.1–2.5 µg/mL. The lower limit of detection was 0.05 µg/mL, and the lower limit of quantification was 0.1 µg/mL. Accuracy and precision were always <11%, and the limit of quantification was <16%. Mean recovery was 98.3%. This method can be applied to determine delafloxacin in human plasma and could be useful to perform pharmacokinetic studies.
Open Access
A prognostic model for use before elective surgery to estimate the risk of postoperative pulmonary complications (GSU-Pulmonary Score): a development and validation study in three international cohorts
(Elsevier, 2024-07) García Pérez, Daniel; NIHR Global Health Research Unit on Global Surgery; STARSurg Collaborative; Farmacología; Facultad de Farmacia
Background Pulmonary complications are the most common cause of death after surgery. This study aimed to derive and externally validate a novel prognostic model that can be used before elective surgery to estimate the risk of postoperative pulmonary complications and to support resource allocation and prioritisation during pandemic recovery. Methods: Data from an international, prospective cohort study were used to develop a novel prognostic risk model for pulmonary complications after lective surgery in adult patients (aged ≥18 years) across all operation and disease types. The primary outcome measure was postoperative pulmonary complications at 30 days after surgery, which was a composite of pneumonia, acute respiratory distress syndrome, and unexpected mechanical ventilation. Model development with candidate predictor variables was done in the GlobalSurg-CovidSurg Week dataset (global; October, 2020). Two structured machine learning techniques were explored (XGBoost and the least absolute shrinkage and selection operator [LASSO]), and the model with the best performance (GSU-Pulmonary Score) underwent internal validation using bootstrap resampling. The discrimination and calibration of the score were externally validated in two further prospective cohorts: CovidSurg-Cancer (worldwide; February to August, 2020, during the COVID-19 pandemic) and RECON (UK and Australasia; January to October, 2019, before the COVID-19 pandemic). The model was deployed as an online web application. The GlobalSurg-CovidSurg Week and CovidSurg-Cancer studies were registered with ClinicalTrials.gov, NCT04509986 and NCT04384926. Findings: Prognostic models were developed from 13 candidate predictor variables in data from 86 231 patients (1158 hospitals in 114 countries). External validation included 30 492 patients from CovidSurg-Cancer (726 hospitals in 75 countries) and 6789 from RECON (150 hospitals in three countries). The overall rates of pulmonary complications were 2·0% in derivation data, and 3·9% (CovidSurg-Cancer) and 4·7% (RECON) in the validation datasets. Penalised regression using LASSO had similar discrimination to XGBoost (area under the receiver operating curve [AUROC] 0·786, 95% CI 0·774–0·798 vs 0·785, 0·772–0·797), was more explainable, and required fewer covariables. The final GSU-Pulmonary Score included ten predictor variables and showed good discrimination and calibration upon internal validation (AUROC 0·773, 95% CI 0·751–0·795; Brier score 0·020, calibration in the large [CITL] 0·034, slope 0·954). The model performance was acceptable on external validation in CovidSurg-Cancer (AUROC 0·746, 95% CI 0·733–0·760; Brier score 0·036, CITL 0·109, slope 1·056), but with some miscalibration in RECON data (AUROC 0·716, 95% CI 0·689–0·744; Brier score 0·045, CITL 1·040, slope 1·009). Interpretation: This novel prognostic risk score uses simple predictor variables available at the time of a decision for elective surgery that can accurately stratify patients’ risk of postoperative pulmonary complications, including during SARS-CoV-2 outbreaks. It could inform surgical consent, resource allocation, and hospital-level prioritisation as elective surgery is upscaled to address global backlogs.
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A prospective study to identify preoperative serum parameters for spinal implant infection detected by sonication fluid culture
(Springer, 2023-03-10) García Pérez, Daniel; García Posadas, Guillermo; San Juan, Rafael; Brañas, Patricia; Panero Pérez, Irene; Delgado Fernández, Juan; Paredes, Igor; Farmacología
Purpose Low-virulent microorganisms identified on pedicle screws by sonication fluid culture (SFC) are an important cause of implant loosening. While sonication of explanted material improves the detection rate, the risk of contamination exists and no standardized diagnostic criteria for chronic low-grade spinal implant-related infection (CLGSII) are stablished. Besides, the role of serum C-reactive protein (CRP) and procalcitonin (PCT) in CLGSII has not been adequately investigated. Methods Blood samples were collected prior to implant removal. To increase sensitivity, the explanted screws were sonicated and processed separately. Patients exhibiting at least one positive SFC were classified in the infection group (loose criteria). To increase specificity, the strict criteria only considered multiple positive SFC (≥ 3 implants and/or ≥ 50% of explanted devices) as meaningful for CLGSII. Factors which might promote implant infection were also recorded. Results Thirty-six patients and 200 screws were included. Among them, 18 (50%) patients had any positive SFCs (loose criteria), whereas 11 (31%) patients fulfilled the strict criteria for CLGSII. Higher serum protein level was the most accurate marker for the preoperative detection of CLGSSI, exhibiting an area under the curve of 0.702 (loose criteria) and 0.819 (strict criteria) for the diagnosis of CLGSII. CRP only exhibited a modest accuracy, whereas PCT was not a reliable biomarker. Patient history (spinal trauma, ICU hospitalization and/or previous wound-related complications) increased the likelihood of CLGSII. Conclusion Markers of systemic inflammation (serum protein level) and patient history should be employed to stratify preoperative risk of CLGSII and decide the best treatment strategy.
Open Access
Acute morphine, chronic morphine and morphine withdrawal differently affects pleiotrophin, midkine and receptor protein tyrosine phosphatase β/ζ regulation in the ventral tegmental area
(Springer, 2016-01-07) García Pérez, Daniel; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología; Facultad de Medicina
Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.
Open Access
An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits
(BioMed Central, 2021) Angela Alonso-García; Carlos Mario Cárceles-Rodríguez; Farouk Rezgui; Emilio Fernández-Varón; Sihem Bouriche; Farmacología; Facultades de la UMU::Facultad de Veterinaria
Background: Metformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile. Results: Metformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution. Conclusions: Metformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.
Open Access
Antimicrobial Susceptibility of Isolated from Sheep with Fibrinous Pneumonia
(Sciendo, 2023-07-01) Galecio, Juan Sebastián; Badillo, Elena; Escudero, Elisa; Corrales, Juan Carlos; Yuste Pérez, María Teresa; Marín, Pedro; Farmacología
Ovine respiratory complex is a signifi cant cause of death in sheep fl ocks, where Pasteurella multocida is the most frequent microorganisms isolated from animals with pneumonia. There is an urgent need to refi ne the use of different antimicrobials to avoid the problem of antimicrobial resistance and optimize the control of this disease in ovine livestock. The fi rst step in approaching this problem is gaining an insight into the antimicrobial susceptibility of ovine pathogens. This study evaluated the in vitro activity of tildipirosin, gamithromycin, oxytetracycline, and danofl oxacin against Pasteurella multocida strains isolated from sheep with fi brinous pneumonia. The strains were incubated following Clinical and Laboratory Standards Institute (CLSI) standard conditions and also with a modifi ed method by 25% supplementation with sheep serum. Minimum inhibitory concentrations (MIC) were determined using the broth microdilution technique. The lowest MIC90 under standard conditions and by supplementation with sheep serum was obtained with tildipirosin. Sheep serum signifi cantly reduced tildipirosin, gamithromycin, and danofl oxacin MIC values for Pasteurella multocida strains. In brief, the potency of tildipirosine, gamithromycin, and danofl oxacin against Pasteurella multocida increases when sheep serum is added to the culture media.
Embargo
Antimicrobial susceptibility of Rhodococcus equi strains isolated from foals in Chile
(2023-06-22) Badillo Puerta, Elena; Zúñiga, María Paz; Abalos, Pedro; Valencia, Eduardo David; Marín, Pedro; Escudero, Elisa; Galecio, Juan Sebastián; Farmacología
Rhodococcus equi is responsible for foal pneumonia worldwide, with a significant economic impact on the production and breeding of horses. In Chile, the first case was reported in 2000, and since then, its incidence has been increasing. Distinctive characteristics of R. equi as an intracellular pathogen in macrophages, emergence of virulence plasmids encoding surface lipoprotein antigens, and appearance of antibiotic resistance against macrolides and rifampicin have significantly complicated the treatment of R. equi pneumonia in foals. Therefore, in vitro susceptibility studies of first-line and newer antibiotics against R. equi are the first step to establishing effective treatments and optimizing new therapeutic options. The aim of the present study is to determine the susceptibility profile of fourteen strains of R. equi isolated from foals in Chile to several antibiotics of the macrolide group including azithromycin, amikacin, tildipirosin and gamithromycin as well as others such as rifampicin, doxycycline and ceftiofur. Identification of R. equi in collected isolates from foals in Chile has been performed by CAMP test and PCR based on detecting of the gene encoding the 16 S rRNA. The presence of genes encoding virulence plasmids was also determined using PCR. Results obtained have demonstrated presence of virulent R. equi strains in Chile. In vitro susceptibility pattern to different antibiotics has shown better results for doxycycline and rifampicin similar to previous studies performed. Current macrolides have been evaluated in order to consider alternative treatment options in a context of emerging resistance to classic macrolides and rifampicin, obtaining better results with gamithromycin (MIC range of 0.125 to 128 mg/ml) than with tildipirosin (MIC range of 16 to 128 mg/ml). An adequate diagnosis of bacterial susceptibility based on antibiograms is necessary to treat the Rhodococcus equi infection in foals.
Open Access
ASC oligomer favors caspase-1CARD domain recruitment after intracellular potassium efflux
(Rockefeller University Press, 2023-07-04) Martín Sánchez, María Rosario Fátima; Compan, Vincent; Peñín Franch, Alejandro; Tapia Abellán, Ana; Gómez, Ana I.; Baños Gregori, María C.; Schmidt, Florian I.; Pelegrín Vivancos, Pablo; Farmacología
Signaling through the inflammasome is important for the inflammatory response. Low concentrations of intracellular K+ areassociated with the specific oligomerization and activation of the NLRP3 inflammasome, a type of inflammasome involved insterile inflammation. After NLRP3 oligomerization, ASC protein binds and forms oligomeric filaments that culminate in largeprotein complexes named ASC specks. ASC specks are also initiated from different inflammasome scaffolds, such as AIM2,NLRC4, or Pyrin. ASC oligomers recruit caspase-1 and then induce its activation through interactions between their respectivecaspase activation and recruitment domains (CARD). So far, ASC oligomerization and caspase-1 activation are K+-independentprocesses. Here, we found that when there is low intracellular K+, ASC oligomers change their structure independently ofNLRP3 and make the ASCCARD domain more accessible for the recruitment of the pro-caspase-1CARD domain. Therefore,conditions that decrease intracellular K+ not only drive NLRP3 responses but also enhance the recruitment of the pro-caspase-1 CARD domain into the ASC specks.
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Atlanto-occipital dislocation with concomitant severe traumatic brain injury: a retrospective study at a level 1 trauma center
(Elsevier, 2022-02-09) García Pérez, Daniel; Panero, Irene; Lagares, Alfonso; Gómez, Pedro Antonio; Alén, José F.; Paredes, Igor; Farmacología
Background Traumatic atlanto-occipital dislocation (AOD) is a life-threatening injury. Although traumatic brain injury (TBI) is associated with increased mortality in AOD patients, a detailed individual analysis of these patients is lacking in the literature. Methods Patients ≥16 years old who were diagnosed of AOD with concomitant severe TBI from 2010 to 2020 were included in this retrospective study. We examined the epidemiology, injury mechanisms, associated injuries, and outcomes of these patients. Results Eight patients were included. Six patients died before any intervention could be performed, and two patients underwent an occipito-cervical fixation, showing a notorious neurologic improvement on follow-up. Cardiorespiratory arrest (CRA) was a strong predictor of subsequent death. CT signs of diffuse axonal injury (DAI) were present in most patients and were confirmed by magnetic resonance imaging (MRI) in survivors. Although TBI was not the main cause of death, it was responsible for the delayed neurological improvement and deferred stabilization. The average sensitivity of the different used methodologies for AOD diagnosis ranged from 0.50 to 1.00, being the Basion Dens Interval (BDI) and the Condyle-C1 interval (CCI) sum the most reliable criteria. Non-survivors tended to show greater distraction measurements. The high incidence of condylar avulsion fractures suggests that their visualization on the initial CT study should heighten the suspicion for AOD. Conclusions Our data suggest that patients with AOD and concomitant severe TBI might be salvageable patients. In those who survive beyond the first hospital days and show neurological improvement, surgical treatment should be performed as they can achieve an important neurologic recovery.
Open Access
Binge ethanol and MDMA combination exacerbates HSP27 and Trx-1 (biomarkers of toxic cardiac effects) expression in right ventricle
(Elsevier, 2019-01) Navarro-Zaragoza, Javier; Ros-Simó, Clara; Valverde, Olga; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
Aims Oxidative stress caused by exposure to drugs of abuse such as ethanol or 3, 4 methylenedioxymethamphetamine (MDMA) may derive from direct or indirect effects in many organs including the heart. The aim of the present work was to evaluate cardiac sympathetic activity and the expression and activation of two antioxidant proteins: heat shock protein27 (HSP27) and thioredoxin-1 (Trx-1) after voluntary binge ethanol consumption, alone and in combination with MDMA. Material and Methods Adolescent mice received MDMA, ethanol or both. Drinking in the dark (DID) procedure was used as a model of binge. HSP27 expression and phosphorylation at serine 82 (pHSP27), Trx-1 expression, tyrosine hydroxylase (TH) and TH phosphorylated at serine 31 (pTH) were evaluated in adolescent mice 48h and 7 days after treatments in the right ventricle. TH, HSP27 expression and phosphorylation and Trx-1 expression were measured by quantitative blot immunolabeling using specific antibodies. Key Findings The expression of HSP27, pHSP27, Trx-1, total TH and pTH in the right ventricle was increased after binge ethanol or MDMA alone. In addition, the combination of binge ethanol+MDMA enhanced TH expression and phosphorylation versus their individual administration. Significance These results indicate that this combination could produce higher activation of sympathetic pathways, which could trigger an increased cell stress. On the other hand, increased HSP27, 3 pHSP27 and Trx-1 expression in the right ventricle by ethanol+MDMA could be a protective mechanism to reduce the adverse effects of oxidative stress caused by both drugs of abuse.
Open Access
Bioequivalence study of lumefantrine rectal enema and the commercially available generic oral suspension. A pilot study
(Society of Pharmaceutical Sciences and Research (SPSR), 2024-05-01) Mhango, E. K. G.; Marín, P.; Escudero, E.; Yuste Pérez, María Teresa; Eiriksson, F. F.; Snorradottir, B. S.; Sveinbjornsson, B. R.; Gizurarson, S.; Farmacología
Children under five years of age, with severe or cerebral malaria, cannot consume oral medication especially if they are vomiting or are unconscious. In such situations they are given an injectable drug until they can tolerate oral medication. The situation is bad in Sub-Saharan Africa, especially in rural areas as children are sometimes referred to the closest referral health care facility for proper management. The aim of this study was therefore to conduct a pilot study to estimate the bioavailability of lumefantrine (LF) when administered as a rectal enema, and compare it with a commercially available oral suspension, in rabbits. The study was conducted on six healthy rabbits in an open randomized, crossover three sequence, single dose study, where each rabbit received rectal and oral formulations. The oral formulation was administered under fed and fasted conditions. A two-week washout period was allowed between the experiments. LF was quantified in rabbit plasma using ultraperformance liquid chromatography tandem mass spectrometry (UPLC MS/MS). Results showed that the relative bioavailability of rectal LF was about four times higher than oral. The observed data suggest that a significant adjustment in the dose will be required when LF is administered via the rectal route. The data provide important information for the next step in finding a method to provide a rescue treatment for children with severe or cerebral malaria.
Open Access
Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP
(2020-11) Rocío Guerrero Bautista, Aurelio Franco García; Juana María Hidalgo Céspedes, Francisco José Fernández Gómez; M. Victoria Milanés Maquilón, M. Cristina Núñez Parra; Farmacología
Background: Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. Aims: To assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress and a cocaine prime in mice after a period of abstinence. Methods: Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. Results: An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression does not seem to occur via the canonic pathway involving Akt/mTOR. Conclusions: Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.
Open Access
Carbamazepine overdose after psychiatric conditions: A case study for Postmortem Analysis in Human Bone
(2022-06-13) Fernández López, Lucía; Mancini, Rosanna; Rottolo, Maria Concetta; Navarro Zaragoza, Javier; Hernández del Rincón, Juan Pedro; Falcón Romero, María; Farmacología
Carbamazepine is the main option used as a preventive medication to treat bipolar disorder when there is no response to lithium. Carbamazepine toxicity is defined as serum levels greater than 12 μg/mL, with severe toxicity occurring over 40 μg/mL, reduced to 30 μg/mL when combined with pharmacological treatment, i.e., benzodiazepines or antidepressants. For these reasons, it is necessary to find a validated tool to determine carbamazepine levels in an autopsy to rule out suicide or to know if the death was a consequence of an adverse drug reaction (ADR), especially when only bones can be accessed. We have validated a tool to detect and quantify drug concentration in bone. Our results showed a peak for carbamazepine at minute 12 and a mass fragment of 193 m/z. This case study is the first time in the literature that carbamazepine has been detected and quantified in bone. These results demonstrate that carbamazepine can be detected in bone tissue from forensic cases, but almost more importantly, that the method proposed is valid, reliable, and trustworthy.
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Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor
(Elsevier, 2014-01-05) Navarro Zaragoza, Javier; Martínez Laorden, Elena; Mora, L.; Hidalgo, J.; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.
Open Access
Cardiac protective role of heat shock protein 27 in the stress induced by drugs of abuse
(2020-05-21) Javier Navarro-Zaragoza * , María Victoria Milanés, María Luisa Laorden and Pilar Almela; Martínez Laorden, Elena; Navarro Zaragoza, Javier; Milanés Maquilón, María Victoria; Laorden Carrasco, María Luisa; Almela Rojo, Pilar; Farmacología; Facultad de Medicina
Open Access
Case report: SARS-CoV-2 infection-Are we dedeemed? A report of Candida spondylodiscitis as a late complication
(Frontiers Media, 2021-11-26) Moreno-Gómez, Luis Miguel; Esteban-Sinovas, Olga; García Pérez, Daniel; García-Posadas, Guillermo; Delgado-Fernández, Juan; Paredes, Igor; Farmacología; Facultad de Farmacia
Background: We describe a case of candida spondylodiscitis secondary to coronavirus disease (COVID-19). Case report: A 47-year-old man diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) required prolonged admission to the intensive care unit (ICU). Four months later, he was diagnosed with thoracic candida spondylodiscitis. Medical management was insufficient, so he eventually underwent surgery. Discussions: Fungal infections seem to be more likely in patients with COVID-19, but it is unknown whether they are directly attributed to COVID-19 or other surrounding factors. Regardless of the answer, the diagnosis is complicated, and the mortality rate is high. Lessons: COVID-19 is posing a challenge to the society, and new and unexpected diseases that had once disappeared have risen again. It is our duty to suspect them and to treat them in the most effective way possible.
Open Access
Caso insólito de absceso cerebral por Mycobacterium bovis complicado con fístula supurativa y revisión de la bibliografía
(Viguera editores, 2019) Panero, Irene; San Juan, Rafael; Eiriz, Carla; García Pérez, Daniel; Paredes, Igor; González, Carlos; Recio, Raúl; Carretero, Octavio; Lagares, Alfonso; Gómez, Pedro A.; Farmacología; Facultades de la UMU::Facultad de Medicina
Introduction: Mycobacterium bovis is an infrequent cause of central nervous system tuberculosis in Spain, with few cases described in the literature. Since compulsory pasteurization of milk and implementation of eradication programs on infected cattle, human sporadic illness with this organism has dramatically declined in developed countries. Case report: A 71-year-old immunocompromised male, who presented a calvarial lytic lesion. A craniotomy for the total resection of the lesion was performed and the microbiology results were positive for M. bovis, therefore antituberculous therapy was initiated. Despite of the correct treatment, the patient developed a tuberculous abscess that required an aggressive surgical management followed by a suppurative fistula. Based on the treatment of tuberculous lymphadenitis, we decided to perform a conservative management with antituberculous therapy (isoniazid + rifampicin + ethambutol + moxifloxacin + steroids during 12 months) and avoided new surgical cleanings of the surgical bed obtaining a good response and a good clinical evolution. Conclusions: As far as we know, this is the first case reported of a suppurative fistula after the resection of a cerebral abscess caused by M. bovis, therefore, there is no report in the literature about the treatment of this complication.