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INTRODUCTION: The prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients' outcome are needed. In our trial we investigated safety and activity of nab-paclitaxel in combination with gemcitabine and oxaliplatin as first-line systemic treatment for patients with advanced BTC. METHODS: In this investigator-initiated, multicenter, dose-escalation, single-arm phase I/II trial, patients were accrued into cohorts of 3 patients and dose escalation was performed following the standard 3 + 3 rule. Primary endpoint was the proportion of patients free from progression at 6 months. Secondary endpoints included safety and tolerability of the combination; progression-free survival (PFS); overall survival (OS); objective response rate (ORR); duration of response. RESULTS: Between July 2017 and December 2020, 67 patients were treated. Among the 10 patients in the phase I, no dose-limiting toxicity was observed, and dose level 2 was defined as recommended phase II dose for the phase II part. At data cutoff, the 6-month PFS rate was 49.1 % (95 % CI 40.8-57.5 %) with 28 patients out of 57 free from progression or death at 6 months. Median PFS was 6.3 months (95 % CI 3.6-10.1) and median OS was 12.4 months (95 % CI 8-23). ORR was 20.89 %. Most common grade 3 and grade 1-2 drug-related adverse events were neutropenia and peripheral neuropathy, respectively. CONCLUSION: Triple chemotherapy demonstrated a favorable safety profile. However, the study did not meet its primary endpoint. Future studies will clarify the benefit of chemotherapy combinations in different settings. This trial is registered with ClinicalTrials.gov, NCT03943043.
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Desoxicitidina , Gemcitabina , Oxaliplatino , Paclitaxel , Humanos , Masculino , Femenino , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/mortalidad , Albúminas/administración & dosificación , Albúminas/efectos adversos , Albúminas/uso terapéutico , Adulto , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: This study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia. METHODS: Neonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey's post-hoc tests for group comparisons. RESULTS: Pup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024). CONCLUSION: Our findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD's neuroprotective effects. Further research is essential to explore CBD's clinical applications and its potential role in treating human neurodevelopmental disorders.
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Animales Recién Nacidos , Cannabidiol , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Animales , Cannabidiol/farmacología , Fármacos Neuroprotectores/farmacología , Ratas , Hipoxia/tratamiento farmacológico , Hipoxia/complicaciones , Masculino , Femenino , Trastornos del Neurodesarrollo/prevención & control , Trastornos del Neurodesarrollo/tratamiento farmacológico , Trastornos del Neurodesarrollo/etiología , Modelos Animales de EnfermedadRESUMEN
Cancer remains a leading cause of death, with increasing incidence. Conventional treatments offer limited efficacy and cause significant side effects, hence novel drugs with improved pharmacological properties and safety are required. Silvestrol (SLV) is a flavagline derived from some plants of the Aglaia genus that has shown potent anticancer effects, warranting further study. Despite its efficacy in inhibiting the growth of several types of cancer cells, SLV is characterized by an unfavorable pharmacokinetics that hamper its use as a drug. A consistent research over the recent years has led to develop novel SLV derivatives with comparable pharmacodynamics and an ameliorated pharmacokinetic profile, demonstrating potential applications in the clinical management of cancer. This comprehensive review aims to highlight the most recent data available on SLV and its synthetic derivatives, addressing their pharmacological profile and therapeutic potential in cancer treatment. A systematic literature review of both in vitro and in vivo studies focusing on anticancer effects, pharmacodynamics, and pharmacokinetics of these compounds is presented. Overall, literature data highlight that rationale chemical modifications of SLV are critical for the development of novel drugs with high efficacy on a broad variety of cancers and improved bioavailability in vivo. Nevertheless, SLV analogues need to be further studied to better understand their mechanisms of action, which can be partially different to SLV. Furthermore, clinical research is still required to assess their efficacy in humans and their safety.
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Antineoplásicos , Neoplasias , Triterpenos , Humanos , Animales , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Triterpenos/farmacocinética , Triterpenos/farmacología , Triterpenos/química , Desarrollo de Medicamentos/métodos , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , BenzofuranosRESUMEN
Introduction: To date, for all non-small cell lung cancer (NSCLC) cases, it is recommended to test for driver alterations to identify actionable therapeutic targets. In this light, comprehensive genomic profiling (CGP) with next generation sequencing (NGS) has progressively gained increasing importance in clinical practice. Here, with the aim of assessing the distribution and the real-world frequency of gene alterations and their correlation with patient characteristics, we present the outcomes obtained using FoundationOne (F1CDx) and FoundationLiquid CDx (F1L/F1LCDx) NGS-based profiling in a nationwide initiative for advanced NSCLC patients. Methods: F1CDx (324 genes) was used for tissue samples, and F1L (70 genes) or F1LCDx (324 genes) for liquid biopsy, aiming to explore the real-world occurrence of molecular alterations in aNSCLC and their relationship with patients' characteristics. Results: Overall, 232 advanced NSCLC patients from 11 Institutions were gathered [median age 63 years; never/former or current smokers 29.3/65.9%; adenocarcinoma/squamous 79.3/12.5%; F1CDx/F1L+F1LCDx 59.5/40.5%]. Alterations were found in 170 different genes. Median number of mutated genes per sample was 4 (IQR 3-6) and 2 (IQR 1-3) in the F1CDx and F1L/F1LCDx cohorts, respectively. TP53 (58%), KRAS (22%), CDKN2A/B (19%), and STK11 (17%) alterations were the most frequently detected. Actionability rates (tier I and II) were comparable: 36.2% F1CDx vs. 34% ctDNA NGS assays (29.5% and 40.9% F1L and F1LCDx, respectively). Alterations in KEAP1 were significantly associated with STK11 and KRAS, so as TP53 with RB1. Median tumor mutational burden was 6 (IQR 3-10) and was significantly higher in smokers. Median OS from metastatic diagnosis was 23 months (IQR 18.5-19.5) and significantly lower in patients harboring ≥3 gene mutations. Conditional three-year survival probabilities increased over time for patients profiled at initial diagnosis and exceeded those of individuals tested later in their clinical history after 12 months. Conclusion: This study confirms that NGS-based molecular profiling of aNSCLC on tissue or blood samples offers valuable predictive and prognostic insights.
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Icaritin is a natural prenylated flavonoid derived from the Chinese herb Epimedium. The compound has shown antitumor effects in various cancers, especially hepatocellular carcinoma (HCC). Icaritin exerts its anticancer activity by modulating multiple signaling pathways, such as IL-6/JAK/STAT3, ER-α36, and NF-κB, affecting the tumor microenvironment and immune system. Several clinical trials have evaluated the safety and efficacy of icaritin in advanced HCC patients with poor prognoses, who are unsuitable for conventional therapies. The results have demonstrated that icaritin can improve survival, delay progression, and produce clinical benefits in these patients, with a favorable safety profile and minimal adverse events. Moreover, icaritin can enhance the antitumor immune response by regulating the function and phenotype of various immune cells, such as CD8+ T cells, MDSCs, neutrophils, and macrophages. These findings suggest that icaritin is a promising candidate for immunotherapy in HCC and other cancers. However, further studies are needed to elucidate the molecular mechanisms and optimal dosing regimens of icaritin and its potential synergistic effects with other agents. Therefore, this comprehensive review of the scientific literature aims to summarize advances in the knowledge of icaritin in preclinical and clinical studies as well as the pharmacokinetic, metabolism, toxicity, and mechanisms action to recognize the main challenge, gaps, and opportunities to develop a medication that cancer patients can use. Thus, our main objective was to clarify the current state of icaritin for use as an anticancer drug.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles, leading to neuronal loss. Curcumin, a polyphenolic compound derived from Curcuma longa, has shown potential neuroprotective effects due to its anti-inflammatory and antioxidant properties. This review aims to synthesize current preclinical data on the anti-neuroinflammatory mechanisms of curcumin in the context of AD, addressing its pharmacokinetics, bioavailability, and potential as a therapeutic adjunct. An exhaustive literature search was conducted, focusing on recent studies within the last 10 years related to curcumin's impact on neuroinflammation and its neuroprotective role in AD. The review methodology included sourcing articles from specialized databases using specific medical subject headings terms to ensure precision and relevance. Curcumin demonstrates significant neuroprotective properties by modulating neuroinflammatory pathways, scavenging reactive oxygen species, and inhibiting the production of pro-inflammatory cytokines. Despite its potential, challenges remain regarding its limited bioavailability and the scarcity of comprehensive human clinical trials. Curcumin emerges as a promising therapeutic adjunct in AD due to its multimodal neuroprotective benefits. However, further research is required to overcome challenges related to bioavailability and to establish effective dosing regimens in human subjects. Developing novel delivery systems and formulations may enhance curcumin's therapeutic potential in AD treatment.
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Enfermedad de Alzheimer , Antiinflamatorios , Curcumina , Fármacos Neuroprotectores , Curcumina/farmacología , Curcumina/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Fármacos Neuroprotectores/farmacología , Antiinflamatorios/farmacología , Animales , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Antioxidantes/farmacología , Curcuma/química , Disponibilidad BiológicaRESUMEN
This study aimed to modify chitosan (CS) by gamma irradiation and use it as a surface coating of nanoparticles (NPs) fabricated of poly lactic-co-glycolic acid (PLGA) to create mostly biocompatible nanosystems that can transport drugs to neurons. Gamma irradiation produced irradiated CS (CSγ) with a very low molecular weight (15.2-19.2 kDa). Coating NPs-PLGA with CSγ caused significant changes in their Z potential, making it slightly positive (from -21.7 ± 2.8 mV to +7.1 ± 2.3 mV) and in their particle size (184.4 0.4 ± 7.9 nm to 211.9 ± 14.04 nm). However, these changes were more pronounced in NPs coated with non-irradiated CS (Z potential = +54.0 ± 1.43 mV, size = 348.1 ± 16.44 nm). NPs coated with CSγ presented lower cytotoxicity and similar internalization levels in SH-SY5Y neuronal cells than NPs coated with non-irradiated CS, suggesting higher biocompatibility. Highly biocompatible NPs are desirable as nanocarriers to deliver drugs to the brain, as they help maintain the structure and function of the blood-brain barrier. Therefore, the NPs developed in this study could be evaluated as drug-delivery systems for treating brain diseases.
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Quitosano , Nanopartículas , Neuronas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quitosano/química , Humanos , Nanopartículas/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Portadores de Fármacos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Rayos gammaRESUMEN
INTRODUCTION: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected. METHODS: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes. CONCLUSIONS: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization.
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Neoplasias del Sistema Biliar , Colangiocarcinoma , Humanos , Italia/epidemiología , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/tratamiento farmacológico , Estudios Retrospectivos , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Femenino , Masculino , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Persona de Mediana Edad , AncianoRESUMEN
Malignant pleural mesothelioma (MPM) is a rare and challenging cancer associated with asbestos fiber exposure, which offers limited treatment options. Historically, platinum-based chemotherapy has been the primary approach, but recent developments have introduced immunotherapy as a promising alternative for the treatment of this disease. Nevertheless, the unique growth patterns and occasionally ambiguous progressive characteristics of MPM make the interpretation of radiological assessments complex. Immunotherapy further complicates matters by introducing unconventional treatment response patterns such as hyperprogression and pseudoprogression. Consequently, there is a growing imperative to integrate the standard RECIST criteria with the mesothelioma-specific mRECIST criteria (version 1.1), as outlined in iRECIST. This comprehensive review is driven by the intent to provide a valuable resource for radiologists and clinicians engaged in the diagnosis, treatment, and monitoring of MPM in the era of immunotherapy. Specifically, the current imaging methods employed for staging and follow-up will be exposed and discussed, with a focus on the technical specificities and the mRECIST 1.1 methodology. Furthermore, we will provide a discussion about major clinical trials related to the use of immunotherapy in MPM patients. Finally, the latest advancements in radiomics, the applications of artificial intelligence in MPM, and their potential impact on clinical practice for prognosis and therapy, are discussed.
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Neoplasias Pulmonares , Mesotelioma Maligno , Neoplasias Pleurales , Humanos , Mesotelioma Maligno/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inteligencia Artificial , Neoplasias Pleurales/diagnóstico por imagen , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Terapia CombinadaRESUMEN
Molecular biomarker testing is increasingly becoming standard of care for advanced non-small cell lung cancer (NSCLC). Tissue and liquid biopsy-based next-generation sequencing (NGS) is now highly recommended and has become an integral part of the routine management of advanced NSCLC patients. This highly sensitive approach can simultaneously and efficiently detect multiple biomarkers even in scant samples. However full optimization of NGS in clinical practice requires accurate reporting and interpretation of NGS findings. Indeed, as the number of NSCLC biomarkers continues to grow, clinical reporting of NGS data is becoming increasingly complex. In this scenario, achieving standardization, simplification, and improved readability of NGS reports is key to ensuring timely and appropriate treatment decisions. In an effort to address the complexity and lengthy reporting of NGS mutation results, an Italian group of 14 healthcare professionals involved in NSCLC management convened in 2023 to address the content, structure, and ease-of-use of NGS reporting practices and proposed a standard report template for clinical use This article presents the key discussion points addressed by the Italian working group and describes the essential elements of the report template.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , ItaliaRESUMEN
Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.
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Enfermedad de Addison , Antineoplásicos Inmunológicos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias/terapia , Enfermedad de Addison/inducido químicamente , Enfermedad de Addison/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Dietary compounds in cancer prevention have gained significant consideration as a viable method. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are heterocyclic and bioactive chemicals found in cruciferous vegetables like broccoli, cauliflower, cabbage, and brussels sprouts. They are synthesized after glycolysis from the glucosinolate structure. Clinical and preclinical trials have evaluated the pharmacokinetic/pharmacodynamic, effectiveness, antioxidant, cancer-preventing (cervical dysplasia, prostate cancer, breast cancer), and anti-tumor activities of I3C and DIM involved with polyphenolic derivatives created in the digestion showing promising results. However, the exact mechanism by which they exert anti-cancer and apoptosis-inducing properties has yet to be entirely understood. Via this study, we update the existing knowledge of the state of anti-cancer investigation concerning I3C and DIM chemicals. We have also summarized; (i) the recent advancements in the use of I3C/DIM as therapeutic molecules since they represent potentially appealing anti-cancer agents, (ii) the available literature on the I3C and DIM characterization, and the challenges related to pharmacologic properties such as low solubility, and poor bioavailability, (iii) the synthesis and semi-synthetic derivatives, (iv) the mechanism of anti-tumor action in vitro/in vivo, (v) the action in cellular signaling pathways related to the regulation of apoptosis and anoikis as well as the cell cycle progression and cell proliferation such as peroxisome proliferator-activated receptor and PPARγ agonists; SR13668, Akt inhibitor, cyclins regulation, ER-dependent-independent pathways, and their current medical applications, to recognize research opportunities to potentially use these compounds instead chemotherapeutic synthetic drugs.
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Being the first or second cause of death worldwide, cancer represents the most significant clinical, social, and financial burden of any human illness. Despite recent progresses in cancer diagnosis and management, traditional cancer chemotherapies have shown several adverse side effects and loss of potency due to increased resistance. As a result, one of the current approaches is on with the search of bioactive anticancer compounds from natural sources. Neopeltolide is a marine-derived macrolide isolated from deep-water sponges collected off Jamaica's north coast. Its mechanism of action is still under research but represents a potentially promising novel drug for cancer therapy. In this review, we first illustrate the general structural characterization of neopeltolide, the semi-synthetic derivatives, and current medical applications. In addition, we reviewed its anticancer properties, primarily based on in vitro studies, and the possible clinical trials. Finally, we summarize the recent progress in the mechanism of antitumor action of neopeltolide. According to the information presented, we identified two principal challenges in the research, i) the effective dose which acts neopeltolide as an anticancer compound, and ii) to unequivocally establish the mechanism of action by which the compound exerts its antiproliferative effect.
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Dysmenorrhea is the combination of cramps and pain associated with the menstrual period, and the symptoms affect at least 30% of women worldwide. Tolerance to symptoms depends on each person's pain threshold; however, dysmenorrhea seriously affects daily activities and chronically reduces the quality of life. Some dysmenorrhea cases even require hospitalization due to unbearable symptoms of severe pain. Dysmenorrhea is an underestimated affectation and remains even in different first-world countries as a taboo subject, promoted by the establishment of an apparent policy of gender equality. A person with primary or secondary dysmenorrhea requires medical assistance in choosing the best treatment and an integral approach. This review intends to demonstrate the impact of dysmenorrhea on quality of life. We describe the pathophysiology of this disorder from a molecular point of view and perform a comprehensive compilation and analysis of the most critical findings in the therapeutic management of dysmenorrhea. Likewise, we propose an interdisciplinary approach to the phenomenon of dysmenorrhea at the cellular level in a concise way and the botanical, pharmacological, and medical applications for its management. Since dysmenorrhea symptoms can vary between individuals, medical treatment cannot be generalized and depends on each patient. Therefore, we hypothesized that a suitable strategy could result from the combination of pharmacological therapy aided by a non-pharmacological approach.
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Dismenorrea , Calidad de Vida , Femenino , Humanos , Dismenorrea/tratamiento farmacológico , Dimensión del DolorRESUMEN
The freeze-thaw (F/T) method is commonly employed during the processing and handling of drug substances to enhance their chemical and physical stability and obtain pharmaceutical applications such as hydrogels, emulsions, and nanosystems (e.g., supramolecular complexes of cyclodextrins and liposomes). Using F/T in manufacturing hydrogels successfully prevents the need for toxic cross-linking agents; moreover, their use promotes a concentrated product and better stability in emulsions. However, the use of F/T in these applications is limited by their characteristics (e.g., porosity, flexibility, swelling capacity, drug loading, and drug release capacity), which depend on the optimization of process conditions and the kind and ratio of polymers, temperature, time, and the number of cycles that involve high physical stress that could change properties associated to quality attributes. Therefore, is necessary the optimization of F/T conditions and variables. The current research regarding F/T is focused on enhancing the formulations, the process, and the use of this method in pharmaceutical, clinical, and biological areas. The present review aims to discuss different studies related to the impact and effects of the F/T process on the physical, mechanical, and chemical properties (porosity, swelling capacity) of diverse pharmaceutical applications with an emphasis on their formulation properties, the method and variables used, as well as challenges and opportunities in developing. Finally, we review the experimental approach for choosing the standard variables studied in the F/T method applying the systematic methodology of quality by design.
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Diverse neurological symptoms have been reported in patients with SARS-CoV-2 disease (COVID-19), including stroke, ataxia, meningitis, encephalitis, and cognitive impairment. These alterations can cause serious sequelae or death and are associated with the entry of SARS-CoV-2 into the Central Nervous System (CNS). This mini-review discusses the main proposed mechanisms by which SARS-CoV-2 interacts with the blood-brain barrier (BBB) and its involvement in the passage of drugs into the CNS. We performed a search in PubMed with the terms "COVID-19" or "SARS-CoV-2" and "blood-brain barrier injury" or "brain injury" from the year 2019 to 2022. We found proposed evidence that SARS-CoV-2 infects neurovascular cells and increases BBB permeability by increasing the expression of matrix metalloproteinase-9 that degrades type IV collagen in the basement membrane and through activating RhoA, which induces restructuring of the cytoskeleton and alters the integrity of the barrier. The breakdown of the BBB triggers a severe inflammatory response, causing the cytokine storm (release of IL-1ß, IL-6, TNF-α, etc.) characteristic of the severe phase of COVID-19, which includes the recruitment of macrophages and lymphocytes and the activation of astrocytes and microglia. We conclude that the increased permeability of the BBB would allow the passage of drugs that would not reach the brain in a normal physiological state, thus enhancing certain drugs' beneficial or adverse effects. We hope this article will encourage research on the impact of drugs on patients with COVID-19 and recovered patients with sequelae, focusing mainly on possible dose adjustments and changes in pharmacokinetic parameters.
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Introduction: cardiovascular complications due to COVID-19 infection are very frequent. However, these complications are rarely reported as a vaccine reaction. Case presentation: a female patient with no significant cardiovascular history developed functional class deterioration 14 days after her third dose of the BBIBP-CorV vaccine, along with three syncopal episodes. She was seen at a primary care level and an electrocardiogram was ordered which showed Mobitz 2 atrioventricular block which progressed to a complete block. Molecular tests for COVID-19 infection were negative, as were immunological studies for collagen disease, Chagas, and viral myocarditis. A transthoracic echocardiogram showed no regional kinetic disturbances, and the ejection fraction was preserved at 60%. Cardiac magnetic resonance imaging showed edema in the T2-STIR sequences, and subepicardial enhancement in the medial distal lateral region was compatible with acute myocarditis. The patient required a permanent pacemaker. Discussion: electrical or mechanical dysfunction secondary to a COVID-19 vaccine is anecdotal, with few reports in the literature. In a review of both the 2021 European Society of Cardiology and the 2018 American Heart Association Guidelines on cardiac pacing and cardiac resynchronization therapy, no recommendation was found for these types of events associated with COVID-19 or following vaccination. An international network should be created to report these events and thus determine general management guidelines. For now, the recommendations must be individualized for these patients. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2602).
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Each year, cancer claims the lives of around 10.0 million people worldwide. Food components have been shown to alter numerous intracellular signaling events that frequently go awry during carcinogenesis. Many studies suggest that dietary behaviors involving the consumption of antioxidant-rich foods, as well as caloric restriction, may play an important role in cancer prevention. Gene expression patterns, such as genetic polymorphisms, can influence the response to food components by altering their specific action on targets, as well as absorption, metabolism, and distribution, among other things. This review discusses two significant cancer prevention techniques: a vitamin-rich diet and caloric restriction. It also discusses the possible molecular interactions between the two dietary strategies and the first clues of a probable synergy that would come from combining caloric restriction with antioxidant use. Caloric restriction diets have positive effects on life expectancy and enable avoidance of age-related illnesses. As a result, this manuscript is based on the degenerative nature of cancer and intends to shed light on the biochemical features of not just calorie restriction but also vitamins. Both are thought to have an effect on oxidative stress, autophagy, and signaling pathways involved in energy metabolism and mitochondrial functions.
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Restricción Calórica , Neoplasias , Humanos , Antioxidantes , Vitaminas/farmacología , Dieta , Neoplasias/prevención & control , Vitamina KRESUMEN
Introduction: Ferrokinetic alterations are associated with the worsening of cardiovascular diseases, their role being unknown in depth. Objective: To determine the association between ferrokinetic with acute myocardial infarction with and without ST elevation in patients with coronary disease. Methods: Analytical observational study in a sample of 72 patients who were admitted to a Coronary Care Unit of a fourth level Institution during the period from July 2017 to May 2018. The statistical association analysis was performed with the Chi-square test. Results: The main gender affected was male, in ages over 56 years. The main comorbidity was arterial hyperten-sion in 53.7% for ST-elevation infarction and in 74.2% for non-ST-elevation infarction. The prevalent ferrokinetic alteration was iron deficiency, in 36.6% of the patients with ST elevation and in 41.9% without ST elevation. Low hemoglobin levels were present on admission in 24.4% of patients with ST elevation and in 32.3% of those without ST elevation, associated with low hemoglobin values on day 7 of hospitalization. Deaths occurred in 2.77%, which presented low iron levels without anemia and infarction with ST elevation and shock. The gender variable presented a statistically significant association (p = 0.034) with the serum iron level. Conclusions: Iron deficiency is a very common disorder with a higher mortality rate, so these parameters should be evaluated in cardiovascular diseases
Introducción: Las alteraciones ferrocinéticas se asocian con un empeoramiento de las enfermedades cardiovasculares, pero se desconoce en profundidad su papel.Objetivo: Determinar la asociación entre la ferrocinética con el infarto agudo al miocardio con y sin elevación del segmento ST en pacientes con enfermedad coronaria. Métodos: Estudio observacional analítico en una muestra de 72 pacientes que ingresaron a una unidad de cuidados coronarios de una institución de cuarto nivel durante el lapso de julio de 2017 a mayo de 2018. El análisis de asociación estadística se realizó con la prueba de chi cuadrado. Resultados: El principal género afectado fue el masculino, en edades superiores a 56 años. La principal comorbilidad fue hipertensión arterial, en un 53,7 % para infarto con elevación del segmento ST, y en un 74,2 % para infarto sin elevación de dicho segmento. La alteración ferrocinética prevalente fue el déficit de hierro, en un 36,6 % de los pacientes con elevación del intervalo ST y en un 41,9 % sin elevación del segmento ST. Las concentraciones bajas de hemoglobina estuvieron presentes al ingreso en el 24,4 % de los pacientes con elevación del ST y en el 32,3 % de aquellos sin elevación del ST, aso-ciado con valores bajos de hemoglobina al séptimo día de hospitalización. Ocurrieron fallecimientos en el 2,77 %, con cantidades bajas de hierro sin anemia e infarto con elevación del segmento ST y choque. La variable género presentó asociación estadísticamente significativa (p = 0,034) con el nivel de hierro sérico. Conclusiones: La ferropenia es una alteración muy frecuente con una relación de mayor mortalidad, por lo que estos parámetros deberían evaluarse en enfermedades cardiovasculares
Introdução: Os distúrbios ferrocinéticos estão associados à piora da doença cardiovascular, mas seu papel é pouco conhecido. Objetivo: Determinar a associação entre a ferrocinética e o infarto agudo do miocárdio com e sem elevação do segmento ST em pacientes com doença cardíaca coronária. Métodos: Estudo observacional analítico em uma amostra de 72 pacientes admitidos em uma unidade de tratamento coronariano de uma instituição de quarto nível durante o período de julho de 2017 a maio de 2018. A análise de associação estatística foi realizada usando o teste do qui-quadrado. Resultados: O principal gênero afetado foi o masculino, com idade superior a 56 anos. A principal comorbidade foi a hipertensão, em 53,7% para infarto do miocárdio com elevação do segmento ST e 74,2% para infarto do miocárdio sem elevação do segmento ST. O distúrbio ferrocinético preva-lente foi a deficiência de ferro em 36,6% dos pacientes com elevação do segmento ST e 41,9% sem elevação do segmento ST. Concentrações baixas de hemoglobina estavam presentes na admissão em 24,4% dos pacientes com elevação do segmento ST e em 32,3% daqueles sem elevação do segmento ST, associadas a valores baixos de hemoglobina ao sétimo dia de hospitalização. Ocorreram mortes em 2,77%, com baixo teor de ferro sem anemia e infarto com elevação do segmento ST e choque. O gênero foi associado de forma estatisticamente significativa (p = 0,034) ao nível de ferro sérico. Conclusões: A deficiência de ferro é um distúrbio muito comum com uma associação com o aumento da mortalidade, por tanto, esses parâmetros devem ser avaliados em doenças cardiovasculares
Asunto(s)
Infarto , Hemoglobinas , Ferritinas , HierroRESUMEN
Introducción: la enfermedad por COVID-19 puede provocar una gran variedad de problemas de salud a largo plazo, como deterioro de la función pulmonar, reducción del rendimiento del ejercicio y disminución de la calidad de vida. Nuestro estudio tuvo como objetivo investigar la eficacia, viabilidad y seguridad de la rehabilitación pulmonar en pacientes con COVID-19 y comparar los resultados entre pacientes con un curso leve/moderado y grave/crítico de la enfermedad. Material y métodos: los pacientes en la fase posaguda de un curso leve a crítico de COVID-19 ingresados en un programa integral de rehabilitación pulmonar, se incluyeron en este estudio de cohorte prospectivo y observacional. Se evaluaron antes y después varias medidas de rendimiento del ejercicio, distancia de caminata de 6 minutos, función pulmonar (capacidad vital forzada (CVF)) y calidad de vida (encuesta de salud de formato corto de 36 preguntas (SF-36)). Se incluyeron 43 pacientes en el estudio (20 con COVID leve/moderado y 23 con COVID grave/crítico). Resultados: al ingreso los pacientes tenían una distancia de caminata reducida (leve: mediana 401 m, rango intercuartílico (IQR) 335-467 m; severo: 108 m, 84-132 m); una CVF deteriorada (leve: 72 %, severo: 35 %), y una puntuación baja de salud mental SF-36 (leve: 52 puntos, severo: 32 puntos. Los pacientes recibieron sesiones ajustadas a sus capacidades físicas y en ambos subgrupos mejoraron en la prueba de caminata de 6 minutos (leve/moderada: +54 m, severo/crítico: +117 m, ambos p <0.002), en CVF (leve/moderada: + 8.9 % , p = 0.004; severo/crítico: + 12.4 %, p <0.003) y en el componente mental SF-36 (leve / moderado: +6.8 puntos, p = 0.062; severo/crítico: +16.7 puntos, -p <0,005). Discusión y conclusiones: un programa de ejercicio bien estructurado resulta en un beneficio en las esferas de capacidad aeróbica, volúmenes pulmonares y calidad de vida; en tal sentido, se recomienda ampliar las muestras poblacionales para poder aplicar nuestro protocolo a otros centros encargados de la rehabilitación de pacientes con COVID-19.
Introduction: COVID-19 disease can cause a wide variety of long-term health problems, such as impaired lung function, reduced exercise performance, and decreased quality of life. Our study aimed to investigate the efficacy, feasibility, and safety of pulmonary rehabilitation in patients with COVID-19 and to compare the results between patients with a mild/moderate and severe/critical course of the disease. Materials and Methods: Patients in the post-acute phase of a mild to critical course of COVID-19 admitted to a comprehensive pulmonary rehabilitation program were included in this prospective, observational cohort study. Various measures of exercise performance, 6-minute walk distance, lung function (forced vital capacity (FVC)), and quality of life (36-question short-form health survey (SF-36)) were assessed before and after. We include 43 patients in this study (20 with mild/moderate COVID and 23 with severe/critical COVID-19). Results: At admission, patients had reduced walking distance (mild: median 401 m, interquartile range (IQR) 335-467 m; severe: 108 m, 84-132 m), impaired FVC (mild: 72%, severe: 35%,) and a low SF-36 mental health score (mild: 52 points, severe: 32 points). This patients received sessions adjusted to their physical abilities, and in both subgroups the patients improved on the walking test of 6 min (mild/moderate: +54m, severe/critical: +117m, both p < 0.002), FVC (mild/moderate: +8.9%, p=0.004; severe/critical: +12.4%, p <0.003) and mental component SF-36 (mild / moderate: +6.8 points, p = 0.062; severe / critical: +16.7 points, -p <0.005). Discussion and Conclusions: A well-structured exercise program results in a benefit in the patients' spheres of aerobic capacity, lung volumes and quality of life, in this sense it is recommended to expand population samples to be able to apply our protocol to other centers in charge of the rehabilitation of COVID 19 patients.