Drug Combinations Research Articles

SEDATION AND LARYNGOSPASM IN PEDIATRIC SURGERY

Introduction: The use of anesthetics in pediatrics is essential for diagnostic and therapeutic procedures. The incidence of post-anesthetic respiratory complications is often avoidable with appropriate intervention. Laryngospasm, a reflex obstruction of the vocal cords, is more common in children. Objective: To discuss respiratory complications, with an emphasis on laryngospasm, during the use of anesthetics in pediatric procedures. Method: The Medical Literature Analysis and Retrieval System Online (MEDLINE, via PUBMED), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), and Virtual Health Library (VHL) databases were used. Seven articles were selected that met the systematic review criteria. Results: The incidence of laryngospasm is 0.87% in adults, 1.7% in children, and 2.82% in babies. In children, it occurs mainly during emergence from anesthesia. Risk factors include inadequate anesthesia, respiratory infections and multiple attempts at airway management. Drug combinations such as propofol, ketamine and fentanyl are used to minimize complications. Preventive measures include clearing secretions and adequate depth of anesthesia. Drugs such β2-adrenergic agonists, such as albuterol, are used to reduce respiratory resistance during intubation. Training strategies with low-cost simulators are effective for managing difficult airways in pediatrics. In pediatric surgery, the laryngeal mask is preferred to endotracheal intubation to reduce respiratory complications. Studies indicate that positive communication between anesthesia teams improves performance in critical situations. Conclusion: Laryngospasm is a serious complication in pediatric anesthesia, more common in children due to their anatomy and sensitive reflexes. Risk factors include respiratory infections, asthma, smoking, gastroesophageal reflux, and superficial anesthesia. Prevention involves the proper use of anesthetics, cleaning secretions and careful monitoring. Medications such as propofol, ketamine, and albuterol can reduce adverse effects. Simulator training and effective communication in anesthesia teams improve clinical performance. With proper management, most episodes are resolved without long-term complications.

Research Progress of Neoadjuvant Chemotherapy in Advanced Bladder Cancer

Systemic treatment, commonly referred to as chemotherapy, is a fundamental approach for treating muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer. Neoadjuvant chemotherapy has recently become a standard treatment for MIBC, significantly reducing tumor recurrence rates and improving patient outcomes. Patients may receive adjuvant chemotherapy involving various drug combinations to improve prognosis following surgery. MIBC patients who are unwilling or unable to undergo radical cystectomy and instead opt for bladder-sparing surgery may benefit from systemic chemotherapy combined with radiotherapy, wherein chemotherapy proves more impactful than radiotherapy. Over the past 30 years, cisplatin-based chemotherapy has been the main approach for treating metastatic bladder cancer. Recent advancements in the molecular understanding of bladder cancer have led to the use of targeted therapies, which have shown promising results. Immunotherapy for MIBC has only recently emerged, with clinical trial results indicating that immunotherapy offers better efficacy and fewer side effects for metastatic bladder cancer. In recent years, basic research on bladder cancer has been burgeoning, and clinical treatment methods have been improving accordingly. This article reviews the development of systemic treatment for bladder cancer.

In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides.

Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.

The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedulesfor the treatment ofearly-stagebreast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time. In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time. Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR(both in terms of administration schedule and drug combination)and TDRhave decreased, although patterns vary by drug combination. Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

Identification of angiogenesis-related subtypes and risk models for predicting the prognosis of gastric cancer patients

Gastric cancer (GC) is a leading cause of cancer-related mortality and is characterized by significant heterogeneity, highlighting the need for further studies aimed at personalized treatment strategies. Tumor angiogenesis is critical for tumor development and metastasis, yet its role in molecular subtyping and prognosis prediction remains underexplored. This study aims to identify angiogenesis-related subtypes and develop a prognostic model for GC patients. Using data from The Cancer Genome Atlas (TCGA), we performed consensus cluster analysis on differentially expressed angiogenesis-related genes (ARGs), identifying two patient subtypes with distinct survival outcomes. Differentially expressed genes between the subtypes were analyzed via Cox and LASSO regression, leading to the establishment of a subtype-based prognostic model using a machine learning algorithm. Patients were classified into high- and low-risk groups based on the risk score. Validation was performed using independent datasets (ICGC and GSE15459). We utilized a deconvolution algorithm to investigate the tumor immune microenvironment in different risk groups and conducted analyses on genetic profiling, sensitivity and combination of anti-tumor drug. Our study identified ten prognostic signature genes, enabling the calculation of a risk score to predict prognosis and overall survival. This provides critical data for stratified diagnosis and treatment upon patient admission, monitoring disease progression throughout the entire course, evaluating immunotherapy efficacy, and selecting personalized medications for GC patients.

Targeting colorectal cancer with Herba Patriniae and Coix seed: Network pharmacology, molecular docking, and in vitro validation

BACKGROUND Herba Patriniae and Coix seed (HC) constitute a widely utilized drug combination in the clinical management of colorectal cancer (CRC) that is known for its diuretic, anti-inflammatory, and swelling-reducing properties. Although its efficacy has been demonstrated in a clinical setting, the active compounds and their mechanisms of action in CRC treatment remain to be fully elucidated. AIM To identify the active, CRC-targeting components of HC and to elucidate the mechanisms of action involved. METHODS Active HC components were identified and screened using databases. Targets for each component were predicted. CRC-related targets were obtained from human gene databases. Interaction targets between HC and CRC were identified. A “drug-ingredient-target” network was created to identify the core components and targets involved. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to elucidate the key pathways involved. Molecular docking between core targets and key components was executed. In vitro experiments validated core monomers. RESULTS Nineteen active components of HC were identified, with acacetin as the primary active compound. The predictive analysis identified 454 targets of the active compounds in HC. Intersection mapping with 2685 CRC-related targets yielded 171 intervention targets, including 30 core targets. GO and KEGG analyses indicated that HC may influence the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Molecular docking showed that acacetin exhibited an optimal interaction with AKT1 , identifying PI3K , AKT , and P53 as key genes likely targeted by HC during CRC treatment. Acacetin inhibited HT-29 cell proliferation and migration, as well as promoted apoptosis, in vitro . Western blotting analysis revealed increased p53 and cleaved caspase-3 expression and decreased levels of p-PI3K , p-Akt , and survivin, which likely contributed to CRC apoptosis. CONCLUSION Acacetin, the principal active compound in the HC pair, inhibited the proliferation and migration of HT-29 cells and promoted apoptosis through the PI3K/Akt/p53 signaling pathway.

Transformer-based medication recommendation with a multiple graph augmentation strategy

Medication recommendation (MR) is a promising task that benefits both patients and medical practitioners. However, the individual differences in patients and drug–drug interactions (DDIs) in medication combinations are two key factors that severely limit the personalization and safety of the present MR models. To alleviate the challenges mentioned above, this paper proposes a novel MR model named Trans-GAHNet, which innovatively leverages transformer-based representation learning and constructs multiple graphs for drug information augmentation. More specifically, the transformer network architecture is deployed to fully encode the sequential EHR data for effective patient representations, which addresses the cold start issue and enhances the interpretability of representation learning. Next, multiple graphs are employed to capture the co-occurrence and exclusiveness in drug pairs and to mitigate potential DDIs in drug combinations, thereby enhancing the personalization and safety of the predicted medication combinations. Finally, extensive experiments on real-world datasets are conducted to evaluate the proposed model, and the experimental results demonstrate that Trans-GAHNet outperforms the state-of-the-art baseline models on multiple metrics, with Jaccard, F1 and PRAUC scores of 0.5238, 0.6786 and 0.7795, respectively.

Role of imaging techniques in the assessment of vulnerable plaques and the effectiveness of lipid-lowering therapy

The aim was to evaluate the potential of various imaging methods in the diagnosis of vulnerable coronary plaques and their stabilization using various lipid-lowering therapy regimens.The sources were searched in the PubMed database using the following keywords: "vulnerable (unstable) plaque" AND "PCSK9 inhibitors" AND "intravascular ultrasound" OR "optical coherence tomography" OR "computed tomography angiography". As a result, 8 original clinical trials were selected that corresponded to the review purpose. We assessed the results of following studies on plaque imaging and their regression with various lipid-lowering therapy regimens: GLAGVO, ODYSSEY J, PACMAN-AMI, HUYGENS, ALTAIR, ARCHITECT, etc. The results of most studies have established the advantages of a combined regimen of lipid-lowering therapy (statin+PCSK9 inhibitor) in reducing the rate of cardiovascular events in com­parison with statin monotherapy. The reduction in plaque volume ranged from 0,95% to 2,13% in patients receiving a combination of lipid-lowering drugs, while in monotherapy, it increased from 0,05% to 0,92% (GLAGOV, PACMAN-AMI). The changes of minimum fibrous cap thickness varied from 18,0-62,67 µm with combined therapy and 13,2-33,19 µm with monotherapy (PACMAN-AMI, Gao F). Lipid arc regression was 57,5о in combination therapy (statin+PCSK9 inhibitor) and 31,4о in statin monotherapy (HUYGENS). Imaging diagnostic methods makes it possible to identify vulnerable plaques, which helps in consideration of combination lipid-lowering therapy. In addition, plaque visualization makes it possible to evaluate the treatment effectiveness.

Exploring potential therapeutic combinations for castration-sensitive prostate cancer using supercomputers: a proof of concept study

To address the challenge of finding new combination therapies against castration-sensitive prostate cancer, we introduce Vini, a computational tool that predicts the efficacy of drug combinations at the intracellular level by integrating data from the KEGG, DrugBank, Pubchem, Protein Data Bank, Uniprot, NCI-60 and COSMIC databases. Vini is a computational tool that predicts the efficacy of drugs and their combinations at the intracellular level. It addresses the problem comprehensively by considering all known target genes, proteins and small molecules and their mutual interactions involved in the onset and development of cancer. The results obtained point to new, previously unexplored combination therapies that could theoretically be promising candidates for the treatment of castration-sensitive prostate cancer and could prevent the inevitable progression of the cancer to the incurable castration-resistant stage. Furthermore, after analyzing the obtained triple combinations of drugs and their targets, the most common targets became clear: ALK, BCL-2, mTOR, DNA and androgen axis. These results may help to define future therapies against castration-sensitive prostate cancer. The use of the Vini computer model to explore therapeutic combinations represents an innovative approach in the search for effective treatments for castration-sensitive prostate cancer, which, if clinically validated, could potentially lead to new breakthrough therapies.

Single and Combinations of Rosuvastatin, Celecoxib, and Colchicine Effects on Biochemical and CBC Parameters of Wistar Albino Rats

Drug resistance became a well-known problem in different areas of pharmacology, including anti-cancer therapy and antibiotics. The overcoming of drug resistance either by different drugs or doses, increases the risk of tissue toxicity. The combination of single FDA-approved drugs became one of the solutions shorting the time for new drug approval, and lowering the cost of manufacturing and transporting of drug to pharmacy shelves. Every day a new combination is investigated to narrow the gap in different pharmacological requirements. Lipid-lowering and anti-inflammatory drugs are widely used and are widely available globally. The study aimed to investigate four probabilities of combinations of three single drugs Rosuvastatine (Ro), Celecoxib (Ce), and Colchicine (Co) on biochemical and Complete Blood Count parameters (CBC) to evaluate the reliability and probable effects of these drugs on normal body function. Nine groups (n=6) of Wistar Albino Rats were inoculated with single and combinations of drugs for eight days using the maximum normal human doses of each drug, blood samples were collected in the middle, and at the end of the experiment. Results showed that combinations induced abnormal biochemical, and CBC parameters in ALT, AST, Creatinine, and RBC parameters in all but one (Rosuvastatine-Celecoxibe-Colchicine) of the combination. The study concluded that the combination could be used except that showed a higher level of abnormal physiological parameters, and percussions should taken by more pharmacological and physiological investigation in a bigger scale of studies including longer durations and different animal models before the combinations utilized by human.

DualSyn: A dual-level feature interaction method to predict synergistic drug combinations

Drug combination therapy can reduce drug resistance and improve treatment efficacy, making it an increasingly promising cancer treatment method. Although existing computational methods have achieved significant success, predictions on unseen data remain a challenge. There are complex associations between drug pairs and cell lines, and existing models cannot capture more general feature interaction patterns among them, which hinders the ability of models to generalize from seen samples to unseen samples. To address this problem, we propose a dual-level feature interaction model called DualSyn to efficiently predict the synergy of drug combination therapy. This model first achieves interaction at the drug pair level through the drugs feature extraction module. We also designed two modules to further deepen the interaction at the drug pair and cell line level from two different perspectives. The high-order relation module is used to capture the high-order relationships among the three features, and the global information module focuses on preserving global information details. DualSyn not only improves the AUC by 2.15% compared with the state-of-the-art methods in the transductive task of the benchmark dataset, but also surpasses them in all four tasks under the inductive setting. Overall, DualSyn shows great potential in predicting and explaining drug synergistic therapies, providing a powerful new tool for future clinical applications.

The combination of sitagliptin and bee honey extract potentiates the anti-proliferative properties of 5-fluorouracil on Caco-2 cell line without detectable inflammatory events

BackgroundColon cancer originates in the colon, specifically the large intestine. It carries a poor prognosis and high mortality rate due to late diagnosis and migration. ObjectiveHere our objective was to evaluate the anticancer effects of sitagliptin (Sita) in colon cancer using Caco-2 cells. Additionally, we examined the role of bee honey extract in modulating cancer cell division and necrotic events commonly observed during drug treatments. MethodsWe monitored cell viability rate to evaluate the effect of bee honey extract compared to 5-fluorouracil (5-Fu), Sita, and their combinations. To gain further foresights into the implicated molecular interaction, we assessed the expression outline of Raf-1 and MEK, as proliferation effectors. Additionally, we examined the expression outline of p53 and Caspase 3, which are associated with programmed cell death (PCD), through western blot analysis. ResultsWe identified the Raf-1 expression pattern as a likely target for the drug combination and bee honey extract (HE), which effectively controlled colon cancer cell proliferation. Our study demonstrates that honey extract, either alone or in combination with drugs, can induce PCD by restoring the p53 and CASP-3 proteins. This was accompanied by a synergistic effect on the production of apoptotic cytokines, particularly interlukine-6 (IL-6) and IL-8, in cancer cells. Moreover, the treatment modulated the levels of pro-inflammatory cytokines, including IL-1α and IL-1β and anti-inflammatory cytokines, including IL-4 and IL-10. ConclusionOur findings shed light on honey extract and its combinations with 5-Fu and Sita in stimulating PCD and modulating cytokine production in Caco-2 cells.

Refining pain management in mice by comparing multimodal analgesia and NSAID monotherapy for neurosurgical procedures

While neurosurgical interventions are frequently used in laboratory mice, refinement efforts to optimize analgesic management based on multimodal approaches appear to be rather limited. Therefore, we compared the efficacy and tolerability of combinations of the non-steroidal anti-inflammatory drug carprofen, a sustained-release formulation of the opioid buprenorphine, and the local anesthetic bupivacaine with carprofen monotherapy. Female and male C57BL/6J mice were subjected to isoflurane anesthesia and an intracranial electrode implant procedure. Given the multidimensional nature of postsurgical pain and distress, various physiological, behavioral, and biochemical parameters were applied for their assessment. The analysis revealed alterations in Neuro scores, home cage locomotion, body weight, nest building, mouse grimace scales, and fecal corticosterone metabolites. A composite measure scheme allowed the allocation of individual mice to severity classes. The comparison between groups failed to indicate the superiority of multimodal regimens over high-dose NSAID monotherapy. In conclusion, our findings confirmed the informative value of various parameters for assessment of pain and distress following neurosurgical procedures in mice. While all drug regimens were well tolerated in control mice, our data suggest that the total drug load should be carefully considered for perioperative management. Future studies would be of interest to assess potential synergies of drug combinations with lower doses of carprofen.

Comparative Efficacy of Mometasone Nasal Spray Combined with different Doses of Desloratadine, and Montelukast in Childhood Allergic Rhinitis: A Randomized Clinical Trial

Allergic rhinitis is a common childhood disease. Although various drugs have been used to treat allergic rhinitis, including nasal corticosteroids, antileukotrienes, and antihistamines, there is still controversy about the optimal dose and the best combination with the highest efficacy. Higher doses of antihistamines are recommended for better control of urticaria, but there is insufficient evidence regarding the efficacy of increased doses of antihistamines in allergic rhinitis. The aim of the study was to evaluate the effectiveness of different drug combinations in the treatment of children with allergic rhinitis. Sixty-four children with persistent moderate to severe allergic rhinitis were enrolled and randomly divided into 4 groups. All children received mometasone furoate nasal spray once daily. In addition to mometasone, each group received one of the following drugs or drug combinations: daily desloratadine, twice daily desloratadine, montelukast, or a combination of desloratadine and montelukast. The severity of symptoms before and after the intervention was evaluated based on the total nasal symptoms score, including sneezing, nasal congestion, nasal itching, and rhinorrhea. Sixty patients completed the study. The reduction of nasal congestion score and total nasal symptoms score in the groups receiving desloratadine twice a day and desloratadine plus montelukast was superior to the daily desloratadine group and daily montelukast groups According to this work, the treatment of allergic rhinitis with mometasone nasal spray with desloratadine twice a day or with the combination of desloratadine and montelukast was more effective than other treatment regimens.

Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carrier would be a favorable approach to overcome these limitations. Hence, a tumor-targeted peptide (TTP) conjugated amphiphilic tri-block copolymer was developed to make targeted polymer nanoparticles (TTP-PNPs) serving as a vehicle for carrying gemcitabine (Gem), paclitaxel (PTX), and their combination (Gem + PTX). The TTP-PNPs in the form of empty polymer (P), single drug-loaded [P(Gem) and P(PTX)], and dual drug-loaded [P(Gem + PTX)] polymer nanoformulations exhibited stable and homogenous spherical shapes with 110–160 nm size. These nanoformulations demonstrated excellent stability under in vitro physiological conditions and led to an efficient release of the drugs in the presence of reduced glutathione (GSH). The efficacy of these nanoparticles was thoroughly evaluated in vitro and in vivo, demonstrating a notable capacity to selectively target and restrict PDAC cells (PANC-1 and KPC) growth. The cellular uptake and biodistribution study showed a significantly higher tumor-targeting ability of TTP-PNPs than PNPs without TTP. Notably, P(Gem + PTX) exhibited the lowest IC50 compared to all other controls and showed heightened synergistic effects in both cell lines. Furthermore, P(Gem + PTX) showed a significantly better tumor reduction and median overall survival in mouse models than single drug-loaded TTP-PNPs or a combination of free drugs (Gem + PTX). In summary, our TTP-PNP system shows great promise as a novel platform for delivering Gem + PTX specifically to pancreatic cancer (PC), maximizing the therapeutic benefits with lower concentrations of the drugs and potentially reducing toxic side effects.

Hypomagnesemia as a predictor of the efficacy of combination EGFR-targeted drugs versus EGFR ADCs alone in HNSCC.

146 Background: EGFR-targeted drugs and ADCs in combination with EGFR-conjugated chemotherapy drugs can both cause hypomagnesemia. However, the predictive value of hypomagnesemia in response to treatment for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: This study retrospectively analyzed patients who participated in clinical trials of EGFR-targeted drugs and EGFR ADCs for HNSCC and solid tumors, from February 24, 2022, to March 25, 2024. The primary endpoint of the study was time to treatment failure (TTF). Results: This study conducted a retrospective analysis of 68 patients . All patients exhibited normal baseline serum magnesium levels prior to treatment, but following two cycles of treatment, varying degrees of hypomagnesemia were observed among them. Among the 46 patients who received 2 cycles of combination therapy with EGFR-targeted drugs, 33 were hypomagnesemia and 13 were normal serum magnesium, ORR[90.9%vs. 8.5%,(P=0.002)] (Table), TTF [151 days (95% CI: 212-380) vs. 87 days (95% CI: 52-230), HR 0.576 (95% CI: 0.270–1.230,P = 0.021)]. Among the 22 patients who received EGFR ADC alone for 2 cycles, 8 were hypomagnesemia and 14 were normal serum magnesium, ORR [37.5% vs.28.6%, (P=0.549)] (Table), TTF [97.5 days (95% CI: 68-300) vs. 108.5 days (95% CI: 60-160), HR of 0.877 (95% CI: 0.339–2.263; P = 0.547)]. Conclusions: The study demonstrates that, the occurrence of hypomagnesemia is associated with ORR and TTF following two cycles of combination of EFGR-targeted drugs, not observed in patients receiving EGFR ADCs as monotherapy in HNSCC. [Table: see text]

Simultaneous spectrophotometric and chromatographic determination of Ketorolac and Dexamethasone: Overall assessment regarding environmental Impact, Practicality, and functionality principles

Determination of a drug combination that contains a minor component that is also a poorly UV absorbing analyte represents greet challenges in drug analysis. A fixed-dose ophthalmic combination of ketorolac tromethamine (KET) and dexamethasone sodium phosphate (DEX) (in the ratio of 5:1) is used to relieve post-surgical inflammation and seasonal allergic conjunctivitis due to their analgesic and anti-inflammatory activity. Five spectrophotometric methods and a reversed phase chromatographic separation method were developed and validated for simultaneous determination of both drugs in lab-prepared eye drops. Direct spectrophotometric determination of KET (the major, highly UV absorbing analyte) was achieved from the zero-order UV absorption spectra at 323 nm while DEX (which is the minor, poorly UV absorbing analyte) was quantified after applying several spectrophotometric methods. Either fundamental zero-order spectra or ratio spectra were used, and measurements were done at either single or dual wavelengths. The developed methods were: isosbestic point method, absorption factor method, dual wavelength method, ratio difference UV spectrophotometric method, and simultaneous equation method. The developed spectrophotometric methods determine KET in the linearity range of 2.0–12.0 μg/mL and DEX in the range of 5.0 – 35.0 μg/mL. For accurate spectrophotometric determination of DEX in the ratio of the dosage form, multiple standard addition method was applied. HPLC technique was also applied for separation and quantification of both drugs. Chromatographic separation was attained by using Hypersil ODS-C18 (150 x 4.6 mm, 5 μm) column. The mobile phase was composed of 50 % methanol: 50 % phosphate buffer (pH 2.5). The column compartment was maintained at 25 °C. Flow rate was adjusted at 1.2 mL/min and detection was performed by DAD at 254 nm. The linearity of HPLC method was 5.0–100.0 μg/mL, and 5.0–50.0 μg/mL for KET and DEX, respectively. Simultaneous determination of both drugs was applied to lab-prepared eye drops that contain also benzalkonium chloride as inactive ingredient. The developed methods determined the cited drugs with good and acceptable % recovery. The results of the developed methods and a reported HPLC method were compared using one-way ANOVA test, F-test and student’s t-test at confidence level 95 %, and they show no significant statistical difference. Assessment of greenness of the developed methods in comparison with reported HPLC method was performed using different tools, including analytical eco-scale, GAPI and AGREE. HPLC-EAT was also performed to ensure greenness of developed HPLC method. Moreover, assessment of practicality, applicability, and functionality of developed and reported methods was evaluated by BAGI metric tool and WAC calculator, respectively. The developed methods allow simple, rapid, and accurate analysis of quality control samples that contain KET and DEX.

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT).

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.

Achado incidental de taquicardia supraventricular com evolução para Flutter atrial após cardioversão elétrica em neonato

Cardiac arrhythmias in newborns, although rare, are often associated with prematurity and congenital heart defects. Atrial flutter, a tachyarrhythmia with a continuous, elevated atrial rhythm, occurs in about 1% of pediatric cases and usually in previously healthy hearts. Supraventricular tachycardia (SVT), an abnormality in electrical conduction above the ventricles, can cause symptoms such as difficulty feeding and irritability. In neonates, SVT may be asymptomatic for long periods but may lead to sudden hemodynamic decompensation. Treatment includes antiarrhythmic medications, with adenosine being the first line. In refractory cases, such as the one described, amiodarone and synchronized electrical cardioversion may be necessary. The case reported describes a newborn with SVT and persistent Atrial Flutter, treated with adenosine, amiodarone and synchronized electrical cardioversion, resulting in normalization of the heart rhythm. The patient progressed well with oral amiodarone, with no sequelae. The combination of drugs and electrical cardioversion is effective for treating complex neonatal arrhythmias.

Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth-by 100 to 140 times-in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.