Free Combination Research Articles

The international expert consensus on management of external auditory canal carcinoma.

The objective of this consensus is to provide otolaryngologists with appropriate strategies in the management of external auditory canal (EAC) carcinoma. In the absence of randomized controlled trials, the consensus is based on expert opinions utilizing the Rand/UCLA appropriateness method [Fitch and Aguilar in The RAND/UCLA appropriateness method user's manual, RAND Corporation, Santa Monica, CA, 2001], drawing from existing literature and clinical experience. The management recommendations are structured around 12 key areas, including: definition and pathology, pathogenesis, clinical manifestations, work-up, tumor staging system, surgical management of primary tumor, surgical management of the parotid gland and the temporomandibular joint, lymph node metastasis, radiotherapy, chemotherapy, reconstruction, and follow-up. Management strategies for EAC carcinoma rely on tumor extension and histopathological features. Surgical removal with free surgical margins or combination with radiotherapy, chemotherapy are most often the best options. Given the rarity of the disease, prospective, randomized, multi-institutional clinical trials should be designed to enable reliable comparisons of the outcomes of EAC carcinoma treatments, thereby providing evidence-based clinical data to establish widely accepted guidelines. It emphasizes the need for a multidisciplinary team to be involved in the management of EAC carcinoma, and regular follow-up should be implemented postoperatively.

Real-world analysis exploring the association between anti-hypertensive therapy with perindopril-based single-pill combinations (SPC) and cardiovascular outcomes and all-cause mortality in Italy

Abstract Background/Introduction A combination of blood pressure (BP)-lowering medications is recommended by guidelines as an effective strategy to obtain rapid and optimal BP control in hypertensive patients. However, the prescription of multiple BP-lowering medications increases the pill burden, potentially reducing medication adherence. Guidelines also recommend using single pill combinations(SPCs) containing ≥2 anti-hypertensive medications as a practical approach to simplify treatment schedules and possibly improve adherence. Yet, real-world evidence on the association between SPC or free combination of BP-lowering medications and hyperthensive patient outcome remains limited. Purpose We compared the association of SPC versus free-pill combination(free) on cardiovascular outcomes and all-cause mortality in hypertensive patients treated with perindopril(PER)-based therapies in real clinical practice in Italy. Methods A retrospective analysis was conducted using administrative databases covering 6.7 million health-assisted Italian residents. Among adults with hospitalization discharge diagnosis or exemption code for hypertension between 2010 and 2021, the study included patients prescribed with a combination of PER with amlodipine(AML) and/or indapamide(IND), either as SPC or free or mixed (SPC plus separate pill) combinations. Results The analysis included 24,476 hypertensive subjects receiving a PER-based therapy, 22,663 (93%) of them using SPC, 1458 (6%) free and 355 (1.4%) mixed. The last cohort was not included in the analysis due to the small sample size (N=355). The patients in the free cohort were significantly older than those in the SPC cohort (69.5±12.3 vs. 64.3±12.2 years, p<0.001), showed a higher number of pre-existing comorbidities (0.5±0.8 vs. 0.4±0.7, p<0.001), and received a larger number of different medications (pill burden: 1.2±1.7 vs. 0.7±1.3, p<0.001). To minimize selection bias, the groups were balanced with propensity score and inverse probability weighting (IPW), adjusting for baseline covariates, including comorbidity profile and pill burden. The IPW-adjusted Kaplan-Meier plots and Cox’s proportional hazard model (Table 1) revealed that, compared with SPC users, patients on free regimens had a significantly increased risk of all-cause mortality (36%, p<0.001), all cardiovascular events (45%, p<0.001), ischemic heart disease (29%, p<0.05), cerebrovascular events (84%, p<0.001), and occurrence of the composite outcome cardiovascular events/all-cause mortality (40%, p<0.001). Conclusions This real-world data from a large Italian administrative dataset suggested that PER-based anti-hypertensive therapy with SPC results in significant clinical benefits in terms of lowered risk of cardiovascular/cerebrovascular events and all-cause mortality. Reducing pill burden and simplifying therapeutic schedules is of crucial importance to maximize the potential benefits derived from the prescription of anti-hypertensive treatment.

Enhancing glioblastoma cytotoxicity through encapsulating O6-benzylguanine and temozolomide in PEGylated liposomal nanocarrier: an in vitro study

Glioblastoma (GBM) (grade IV glioma) is the most fatal brain tumor, with a median survival of just 14 months despite current treatments. Temozolomide (TMZ), an alkylating agent used with radiation, faces challenges such as systemic toxicity, poor absorption, and drug resistance. To enhance TMZ effectiveness, we developed poly(ethylene glycol) (PEG) liposomes co-loaded with TMZ and O6-benzylguanine (O6-BG) for targeted glioma therapy. These liposomes, prepared using the thin-layer hydration method, had an average size of 146.33 ± 6.75 nm and a negative zeta potential (−49.6 ± 3.1 mV). Drug release was slower at physiological pH, with 66.84 ± 4.62% of TMZ and 69.70 ± 2.88% of O6-BG released, indicating stability at physiological conditions. The liposomes showed significantly higher cellular uptake (p < 0.05) than the free dye. The dual drug-loaded liposomes exhibited superior cytotoxicity against U87 glioma cells, with a lower IC50 value (3.99µg/mL) than the free drug combination, demonstrating enhanced anticancer efficacy. The liposome formulation induced higher apoptosis (19.42 ± 3.5%) by causing sub-G0/G1 cell cycle arrest. The novelty of our study lies in co-encapsulating TMZ and O6-BG within PEGylated liposomes, effectively overcoming drug resistance and improving targeted delivery for glioma treatment.

Choice Between Free Combination of Antihypertensive Agents and Fixed Dosed Combinations in the Treatment of Arterial Hypertension

Most patients with arterial hypertension require more than one antihypertensive drug for blood pressure target achievement. Some patients are recommended for a multi-pill antihypertensive regimen, others — treatment with fixed dosed combinations in one tablet. Analysis of elibrary and PubMed publications in the period mostly from 2014 to 2024 concerning the choice of two-component combined antihypertensive agents containing renin-angiotensin system inhibitor and diuretic or calcium channel blocker, revealed that fixed-dose combinations (FDC) use and taking one tablet once a day improves adherence to treatment and facilitates blood pressure control. Although the cost of FDC containing the renin-angiotensin-aldosterone system inhibitor and a thiazide/thiazide-like diuretic or calcium channel blocker is in most cases higher than the same drugs taken separately, the use of fixed combinations, increasing patient adherence to therapy, has clinical advantage in terms of the effectiveness of lowering blood pressure, which confirms their economic feasibility. On the other hand, the use of free combination therapy in two different tablets, when taken separately during the day, can sometimes provide a more sustained antihypertensive effect over 24 hours. Evidence of the effectiveness of blood pressure control for FDCs is often extrapolated from data on free combinations. In addition, FDCs are characterized by less detection of possible ineffectiveness of one of the components. The range of FDCs and the dosage ratios of the components presented in them is gradually expanding, but the choice among free combinations is still wider. In addition, the list of vital and essential drugs (VED) for 2024 does not contain FDCs for antihypertensive drugs, which excludes the possibility of free receiving them on a preferential basis and gives the opportunity for the manufacturer to set prices for them. Despite the fact that recently the scientific community has recommended the use of FDC antihypertensive drugs as initial therapy due to better compliance with the regimen, and therefore clinical effectiveness and economic feasibility, it cannot be said that there is no space left for free combinations of antihypertensive drugs in the treatment of arterial hypertension. The choice of doctor, frequency of prescription, share of purchases of the FDCs in the Russian Federation, review of their consumption requires further analysis.

Ionospheric plasma irregularities over Dronning Maud Land in Antarctica and associated space weather effects

Ionospheric plasma irregularities and associated space weather effects over Dronning Maud Land in Antarctica are studied with a multi-instrument approach. It is demonstrated during a substorm event that auroral particle precipitation associated with the edges of auroral arcs can lead to irregularities in the ionospheric plasma density that can have significant impact on trans-ionospheric radio waves. Both refractive and diffractive effects are observed on signals from the GNSS satellites, where the latter are identified by the ionospheric free linear combination approach and amplitude scintillation. Thus, intense auroral particle precipitation can lead to plasma irregularities at scales from several kilometers down to and below the Fresnel radius, and they can result in space weather effects which can lead to losing the integrity of the GNSS signals.

Increased lipoprotein (a) as an additional factor in the failure to achieve target blood pressure levels and lipid spectrum optimal parameters in patients with arterial hypertension and multifocal atherosclerosis

Aim. To establish the frequency of achieving target of blood pressure (BP) levels and lipid spectrum parameters (LS) in patients with arterial hypertension (AH) and multifocal atherosclerotic lesion (MFAL) with normal and elevated levels of lipoprotein (a) (Lp(a)) in real clinical practice.Material and methods. The study included 110 patients with AH and MFAL, median age was 59.0 (51.0; 64.3) years. Depending on the level of Lp(a), all patients were divided into 2 groups: group 1 — 72 patients (65.5%), Lp(a) level was ≤50 mg/dl (13.2 (3.7; 21.1)), group 2 — 38 patients (34.5%) Lp(a) level was &gt;50 mg/dl (89.5 (62.5; 110.0)). The diagnosis of MFAL included damage to two or more arterial basins according to carotid artery, abdominal aorta and lower extremities arteries duplex scan. Patients of both groups received antihypertensive, lipid-lowering, and antiplatelet therapy.Results. Patients in groups 1 and 2 showed similar blood pressure levels and frequency of antihypertensive therapy use. In both groups, the majority of patients were on a free combination of antihypertensive drugs, only a third of patients used a fixed combination. In most cases, patients of both groups did not reach the target blood pressure levels (63.9% — group 1, 55.3% — group 2), despite the fact that the average blood pressure figures were relatively low (132;83 mmHg in each group). Drug control was also unsatisfactory in both groups, regardless of the level of Lp(a). However, all drug indicators were significantly worse in group 2, despite comparable lipid-lowering therapy, which more often included statin monotherapy. Combination therapy with lipid-lowering drugs was used in patients of groups 1 and 2 only in 20.8% and 10.5%, respectively. Parameters of low-grade inflammation high-sensitivity C-reactive protein and interleukin-6 did not differ between the groups and did not exceed the reference values.Conclusion. An increased level of Lp(a) may be accompanied by drug disorders and increased BP in patients with MFAL. Due to the lack of effective Lp(a) reducing therapy, the prevention of cardiovascular events in such patients should focus on BP and lipid spectrum correction. The use of fixed combinations, including antihypertensive and lipid-lowering drugs, can lead to improved adherence to therapy, increased BP and LS control.

The Unified Phenotype Ontology (uPheno): A framework for cross-species integrative phenomics.

Phenotypic data are critical for understanding biological mechanisms and consequences of genomic variation, and are pivotal for clinical use cases such as disease diagnostics and treatment development. For over a century, vast quantities of phenotype data have been collected in many different contexts covering a variety of organisms. The emerging field of phenomics focuses on integrating and interpreting these data to inform biological hypotheses. A major impediment in phenomics is the wide range of distinct and disconnected approaches to recording the observable characteristics of an organism. Phenotype data are collected and curated using free text, single terms or combinations of terms, using multiple vocabularies, terminologies, or ontologies. Integrating these heterogeneous and often siloed data enables the application of biological knowledge both within and across species. Existing integration efforts are typically limited to mappings between pairs of terminologies; a generic knowledge representation that captures the full range of cross-species phenomics data is much needed. We have developed the Unified Phenotype Ontology (uPheno) framework, a community effort to provide an integration layer over domain-specific phenotype ontologies, as a single, unified, logical representation. uPheno comprises (1) a system for consistent computational definition of phenotype terms using ontology design patterns, maintained as a community library; (2) a hierarchical vocabulary of species-neutral phenotype terms under which their species-specific counterparts are grouped; and (3) mapping tables between species-specific ontologies. This harmonized representation supports use cases such as cross-species integration of genotype-phenotype associations from different organisms and cross-species informed variant prioritization.

Реализация пунктуационных тенденций естественной письменной речи в эпистолярных текстах низкого уровня грамотности (на примере употребления разделительных знаков препинания)

The research aims to identify the specific characteristics of the implementation of punctuation trends in natural written language as exemplified by the use of separating punctuation marks in a corpus of Russian epistolary texts written by semiliterate authors. The research is novel in that it is the first one to compare punctuation trends found in different genres of natural written language. Moreover, for the first time, the functions of separating punctuation marks in the middle and end of sentences in letters written by semiliterate authors were considered in relation to the main punctuation trends of natural written language. The research findings showed that most of the main punctuation trends of natural written language (economy, interchangeability, and universalization of punctuation marks, actualization of communicatively significant parts of the sentence (parcellation), individual free combination of marks) are realized when using separating punctuation marks in the middle of a sentence (comma, semicolon, colon, dash) and at the end of a sentence (period, exclamation mark) in letters written by semiliterate people; at the same time, the realization of natural written language trends does not depend on the productivity of the marks in the corpus. The most productive and active in realizing the communicative trends of natural written language are basic marks, a period and a comma, however, natural written language trends are also realized through other, less productive separating punctuation marks. As a result of the research, it was also found that the tendency toward unification of the functions of marks, characteristic of natural written language, is not realized in the corpus through separating punctuation marks due to their multifunctionality.

Stimuli-responsive gelatin-coated alginate nanocarriers: Targeted delivery of efflux pump inhibitor and antibacterial agents to control multidrug resistant P. aeruginosa

Multidrug resistance is an inescapable obstacle in healthcare settings. As the over-expression of efflux pumps is an important mediator of bacterial drug resistance, stimuli-responsive co-delivery nanosystems were developed for the sequential release of efflux pump inhibitors (EPI) and antibacterial agents. Gelatin-coated alginate nanocarriers (AlNCs@Gel) were developed containing ciprofloxacin (Cip) and quercetin (Que) as antibacterial/antibiofilm agents and EPI, respectively. Heat plot maps revealed a synergistic interaction of Cip with Que as the minimum inhibitory concentration value of Cip was reduced in the presence of EPI (quercetin) against P. aeruginosa. The encapsulation efficiency of 82 ± 1 % was observed for Cip while it was 70 ± 1 % for Que in Cip/AlNCs@Que/Gel nanocarriers. FTIR analyses confirmed an interaction between alginate and gelatin by the occurrence of a blue shift that is associated with electrostatic interactions between alginate and gelatin. These nanocarriers loaded with quercetin as EPI would release it preferentially in the presence of gelatinase enzyme and subsequently prevent the efflux of ciprofloxacin from bacterial cells. Membrane-permeability assay confirmed no permeabilization while viability studies exhibited superior bacterial inhibition, as Cip/EPI combination encapsulated in AlNCs@Gel effectively controlled the growth of P. aeruginosa as compared to antibiotic alone in AlNCs@Gel and free drug combinations. In vitro, cytotoxicity-analysis confirmed the biocompatibility of the developed core-shell nanocarriers. Furthermore, gelatin coating improved the physico-chemical properties of nanocarriers and the on-demand-release of EPI and antibiotic molecules. Thus, smartly designed AlNCs@Gel nanocarriers for the co-delivery of EPI and antibiotics present an innovative solution for preventing drug efflux from P. aeruginosa to control resistant infections.

P145 EFFICACY AND SAFETY OF PERINDOPRIL/INDAPAMIDE/AMLODIPINE/BISOPROLOL SINGLE PILL COMBINATION IN PATIENTS WITH ESSENTIAL HYPERTENSION UNCONTROLLED ON TRIPLE THERAPY: AN INTERNATIONAL, RANDOMIZED, DOUBLE-BLIND, PHASE III TRIAL

Background and objectives: In hypertensive patients uncontrolled on triple therapy, guidelines recommend the addition of a fourth drug such as mineral corticoid receptor antagonists, or alternatively, a betablocker. They also support the use of SPCs at any step of the treatment to increase treatment adherence and BP control. Currently, no SPC of 4 drugs is available. This 4-month phase III trial aimed to demonstrate the superiority in BP reduction, ofperindopril/indapamide/amlodipine/bisoprolol (Per/Ind/Aml/Biso) SPC versus a free combination of Per/Ind/Aml in hypertensive patients uncontrolled on triple therapy at optimal doses. Methods: After a 2-month run-in period on the combination of Per/Ind/Aml at optimal doses (10/2.5/5 or 10/2.5/10 mg), patients with sustained uncontrolled essential hypertension with office SBP≥140mmHg and SBP at 24h-ambulatory blood pressure monitoring (ABPM)≥130mmHg received the quadruple SPC of Per/Ind/Aml/Biso (10/2.5/5/5 or 10/2.5/10/5 mg) or continued the same triple therapy for two additional months. Efficacy was assessed on office-SBP (primary endpoint), DBP, BP control, 24h-ABPM and home-BPM (HBPM). Results: 183 patients were randomized: 53.0% were men, mean age was 57.4±10.6 years, mean BMI was 28.2±2.6 kg/m2, and mean office SBP/DBP was 150.35±8.49/90.09±8.23mmHg. After two months, significantly greater decrease in office-SBP (-8.0mmHg, 95%CI [-11.9; -4.0]; p&lt;0.0001) was observed in the quadruple SPC group (n=80) versus the triple therapy group (n=83). Greater decrease in the 24h-systolic ABPM was achieved with the quadruple SPC therapy (-7.5mmHg, 95%CI [-10.9;-4.1]; p&lt;0.0001). Higher percentage of patients achieved 24h-ABPM and HBPM control in the SPC group 51.2% vs 20.7% (p&lt;0.0001) and 60.7% vs 25.4%, (p&lt;0.0001) respectively. After intentional 1-day SPC omission in patient volunteers (n=28), mean 24h-ABPM remained below the 130/80mmHg target, supporting the sustained efficacy of the SPC. Both treatments were well tolerated. Conclusion: The first quadruple SPC of Per/Ind/Aml/Biso demonstrated its superiority to the free combination of Per/Ind/Aml, offering a new alternative to treat effectively and safely patients with hypertension uncontrolled with a combination of Per/Ind/Aml at optimal doses.

Cost-effectiveness analysis comparing single-pill combination of perindopril/amlodipine/indapamide to the free equivalent combination in patients with hypertension from an Italian national health system perspective

ABSTRACT Objective To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy. Methods A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer’s perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates. Results A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy. Conclusions The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

A real-world analysis of adherence, biochemical outcomes, and healthcare costs in patients treated with rosuvastatin/ezetimibe as single-pill combination vs. free combination in Italy.

To compare medication adherence, lipid goal attainment, and healthcare costs between patients receiving a single-pill combination (SPC) vs. a free combination treatment (FCT) of rosuvastatin/ezetimibe (ROS/EZE) in Italy. Administrative databases of healthcare entities covering ∼7 million individuals were used to identify adults prescribed with ROS/EZE as SPC or FCT between January 2018 and June 2020. Adherence was calculated as the proportion of days covered (PDC) after cohort balancing by propensity score matching. Patients with available LDL cholesterol testing were assessed for the proportion of those who at baseline were above lipid targets recommended by ESC/EAS Guidelines for their cardiovascular risk category and reached the target during follow-up. Among 25 886 patients on SPC and 7309 on FCT, adherent patients were more represented in SPC than FCT cohort (56.8 vs. 44.5%, P < 0.001), and this difference remained significant (P < 0.001) after stratification by cardiovascular risk (very high, high, and other). The proportion of patients reaching LDL cholesterol target at 1 year follow-up was significantly (P < 0.001) higher in SPC vs. FCT cohort: 35.4 vs. 23.8% for very high cardiovascular risk, 46.9 vs. 23.1% for high risk and 71.6 vs. 49.5% for other risk. Total healthcare costs per patient at 1 year follow-up were lower in SPC vs. FCT users (2337€ vs. 1890€, P < 0.001). In both cohorts, costs were mainly driven by drug expenses and hospitalizations. This real-world analysis in dyslipidaemic patients found that treatment with ROS/EZE as SPC resulted in better adherence, higher chances of reaching lipid goals, and cost savings over FCT, in all cardiovascular risk categories.

Английские топонимы с сильваническим компонентом как репрезентанты социально-экономического развития средневековой Англии (на примере «Англо-саксонских грамот» и «Книги Судного дня» / Domesday Book)

The aim of the paper is to determine the contribution of Old English sylvanic lexemes (wudu, hyrst, holt, lee, graf, wald) to the English toponymic system as conditioned by the socio-economic development of medieval England. The article discusses the semantics of the specified lexemes in the Old English period and its development as conditioned by social and economic processes and analyzes the toponyms of medieval England containing these lexemes as appellatives. The research is based on the material from the Anglo-Saxon Charters and toponymic dictionaries. The scientific novelty lies in the fact that toponyms with a sylvanic component from the Domesday Book are compared for the first time with the names of landmarks of previous centuries from the Anglo-Saxon Charters by their structure and semantics, which allows us to trace the dynamics of the formation of these toponyms. The results of the study showed that toponyms with the appellative wudu, hyrst, holt, lee, graf, wald are formed from free combinations of these terms with descriptors highlighting the distinctive features of the forest that were significant for medieval society (location, tree species, belonging, animals, vegetation, size, quality, color, function). The dynamics of the semantics of the lexemes-appellatives and the use of descriptors reflect changes in the categorization of space and the socio-economic development of medieval England. Active development of forest spaces during the medieval period was marked by a significant contribution of sylvanic lexemes to the toponymy of England (6% of toponyms found in dictionaries).

The use of intranasal sufentanil and/or s-ketamine for treatment of procedural pain in children in an ambulatory setting: A retrospective observational study.

Minor but painful medical procedures are often handled at the operating room. If safe and effective treatment options are available many procedures may be performed outside of the operating room. The objective of this study is to assess the adverse events of intranasal s-ketamine and/or sufentanil alone or as part of a multimodal analgesic regime for medical procedures outside of the operating room. Secondary outcomes included analgesic effect, doses and indications for use. Retrospective observational study. Tertiary care paediatric hospital. Children 1 year up till 18 years. Intranasal (IN) sufentanil (S), intranasal s-ketamine (K) or the free combination of the two drugs (SK). The frequency of adverse events including serious adverse events reported by intervention. Between 2004 and 2014, 2185 medical procedures were registered, including 652 procedures with IN SK, 1469 procedures with IN S and 64 procedures with IN K. The children's median age was 5.6 years (range 1.0-17.9). Medical procedures with at least one adverse event were 18% with IN SK, 25% with IN K and 18% with IN S. Common adverse events included episodes of vomiting (9%), nausea (8%) and dizziness (3%). In two patients receiving IN S, serious adverse events occurred. One patient had respiratory depression and bronchospasm and another patient with cerebral palsy had a seizure. Both were handled immediately and did not result in any sequelae. The median doses of intranasal sufentanil were 38% lower when combined with s-ketamine (IN SK free combination: sufentanil dose 0.5 μg/kg (range 0.2-1.3) and s-ketamine dose 0.5 mg/kg (range 0.2-1.5). IN S monotherapy, sufentanil dose 0.8 μg/kg (range 0.2-2.7)). Similar analgesic effect was reported for S and SK. Intranasal sufentanil and/or s-ketamine are feasible for the treatment of procedural pain in an ambulatory setting with appropriate per- and post-procedural observations and trained staff.

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.

The prevalence of monotherapy and combination therapy in hypertension in China from 2019 to 2021: A nationwide population-based cross-sectional study.

There are no nationwide surveys on antihypertensive drugs in China. In order to assess the current status of antihypertensive drug therapy in patients with hypertension and analyzed factors that may affect combination therapy, using convenience sampling, we recruited 305,624 patients with hypertension from the Chinese Cardiovascular Association Database-Hypertension Center between January 2019 and December 2021. Chi-squared test was performed to analyze the administered antihypertensive drug types and their combinations in different hospital settings. Logistic regression was used to assess the factors influencing combination therapy. We found around 33.1% of the participants had stage 2 and above hypertension, of which 67.9% were treated with combination therapy. In community or general hospitals, the most common monotherapy was calcium channel blockers (CCB), angiotensin-converting enzyme inhibitor/angiotensin II receptor inhibitor (ACEI/ARB) and diuretic were the main single-pill combinations (SPCs), and ACEI/ARB and CCB were the main free combination. From 2019 to 2021, the rates of combination therapy increased (58.8%-64.1%) with SPCs from 25.9% to 31.0% and free combination from 31.9% to 32.6%. Patients aged<60 years, with stage 2 and above hypertension, with an education level of high school and above, visiting general hospitals, living in the eastern region of China, with hypertension risk factors and comorbidities, and without anxiety or depression were more likely to receive combination therapy (all P<.05). The combination therapy use rate increased yearly and the rate of SPCs rose obviously. Individual, hospital, and regional differences in patients with hypertension influenced combination therapy.

Green synthesis of zinc oxide nanoparticles (ZnO-NPs) by Streptomyces baarnensis and its active metabolite (Ka): a promising combination against multidrug-resistant ESKAPE pathogens and cytotoxicity

Various eco-friendly techniques are being researched for synthesizing ZnO-NPs, known for their bioactivity. This study aimed at biosynthesizing ZnO-NPs using Streptomyces baarnensis MH-133, characterizing their physicochemical properties, investigating antibacterial activity, and enhancement of their efficacy by combining them with a water-insoluble active compound (Ka) in a nanoemulsion form. Ka is a pure compound of 9-Ethyl-1,4,6,9,10-pentahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione obtained previously from our strain of Streptomyces baarnensis MH-133. Biosynthesized ZnO-NPs employing Streptomyces baarnensis MH-133 filtrate and zinc sulfate (ZnSO4.7H2O) as a precursor were purified and characterized by physicochemical investigation. High-resolution-transmission electron microscopy (HR-TEM) verified the effective biosynthesis of ZnO-NPs (size < 12 nm), whereas dynamic light scattering (DLS) analysis showed an average size of 17.5 nm. X-ray diffraction (XRD) exhibited characteristic diffraction patterns that confirmed crystalline structure. ZnO-NPs efficiently inhibited both Gram-positive and Gram-negative bacteria (MICs: 31.25–125 µg/ml). The pure compound (Ka) was combined with ZnO-NPs to improve effectiveness and reduce dose using checkerboard microdilution. Niteen treatments of Ka and ZnO-NPs combinations obtained by checkerboard matrix inhibited Klebsiella pneumonia. Eleven combinations had fractional inhibitory concentration index (FICi) between 1.03 and 2, meaning indifferent, another five combinations resulted from additive FICi (0.625–1) and only one combination with FICi of 0.5, indicating synergy. In the case of methicillin-resistant S. aureus (MRSA), Ka-ZnO-NPs combinations yielded 23 treatments with varying degrees of interaction. The results showed eleven treatments with indifferent interaction, eight additive interactions, and two synergies with FICi of 0.5 and 0.375. The combinations that exhibited synergy action were transformed into a nanoemulsion form to improve their solubility and bioavailability. The HR-TEM analysis of the nanoemulsion revealed spherical oil particles with a granulated core smaller than 200 nm and no signs of aggregation. Effective dispersion was confirmed by DLS analysis which indicated that Ka-ZnO-NPs nanoemulsion droplets have an average size of 53.1 nm and a polydispersity index (PI) of 0.523. The killing kinetic assay assessed the viability of methicillin-resistant Staphylococcus aureus (MRSA) and K. pneumonia post-treatment with Ka-ZnO-NPs combinations either in non-formulated or nanoemulsion form. Results showed Ka-ZnO-NPs combinations show concentration and time-dependent manner, with higher efficacy in nanoemulsion form. The findings indicated that Ka-ZnO-NPs without formulation at MIC values killed K. pneumonia after 24 h but not MRSA. Our nanoemulsion loaded with the previously mentioned combinations at MIC value showed bactericidal effect at MIC concentration of Ka-ZnO-NPs combination after 12 and 18 h of incubation against MRSA and K. pneumonia, respectively, compared to free combinations. At half MIC value, nanoemulsion increased the activity of the combinations to cause a bacteriostatic effect on MRSA and K. pneumonia after 24 h of incubation. The free combination showed a bacteriostatic impact for 6 h before the bacteria regrew to increase log10 colony forming unit (CFU)/ml over the initial level. Similarly, the cytotoxicity study revealed that the combination in nanoemulsion form decreased the cytotoxicity against kidney epithelial cells of the African green monkey (VERO) cell line. The IC50 for Ka-ZnO-NPs non-formulated treatment was 8.17/1.69 (µg/µg)/ml, but in nano-emulsion, it was 22.94 + 4.77 (µg/µg)/mL. In conclusion, efficient Ka-ZnO-NPs nanoemulsion may be a promising solution for the fighting of ESKAPE pathogenic bacteria according to antibacterial activity and low toxicity.

Cost-effectiveness of single-pill and separate-pill administration of antihypertensive triple combination therapy: a population-based microsimulation study

BackgroundSingle-pill combination (SPC) of three antihypertensive drugs has been shown to improve adherence to therapy compared with free combinations, but little is known about its long-term costs and health consequences. This study aimed to evaluate the lifetime cost-effectiveness profile of a three-drug SPC of an angiotensin-converting enzyme inhibitor, a calcium-channel blocker, and a diuretic vs the corresponding two-pill administration (a two-drug SPC plus a third drug separately) from the Italian payer perspective.MethodsA cost-effectiveness analysis was conducted using multi-state semi-Markov modeling and microsimulation. Using the healthcare utilization database of the Lombardy Region (Italy), 30,172 and 65,817 patients aged ≥ 40 years who initiated SPC and two-pill combination, respectively, between 2015 and 2018 were identified. The observation period extended from the date of the first drug dispensation until death, emigration, or December 31, 2019. Disease and cost models were parametrized using the study cohort, and a lifetime microsimulation was applied to project costs and life expectancy for the compared strategies, assigning each of them to each cohort member. Costs and life-years gained were discounted by 3%. Probabilistic sensitivity analysis with 1,000 samples was performed to address parameter uncertainty.ResultsCompared with the two-pill combination, the SPC increased life expectancy by 0.86 years (95% confidence interval [CI] 0.61–1.14), with a mean cost differential of -€12 (95% CI -9,719–8,131), making it the dominant strategy (ICER = -14, 95% CI -€15,871–€7,113). The cost reduction associated with the SPC was primarily driven by savings in hospitalization costs, amounting to €1,850 (95% CI 17–7,813) and €2,027 (95% CI 19–8,603) for patients treated with the SPC and two-pill combination, respectively. Conversely, drug costs were higher for the SPC (€3,848, 95% CI 574–10,640 vs. €3,710, 95% CI 263–11,955). The cost-effectiveness profile did not significantly change according to age, sex, and clinical status.ConclusionsThe SPC was projected to be cost-effective compared with the two-pill combination at almost all reasonable willingness-to-pay thresholds. As it is currently prescribed to only a few patients, the widespread use of this strategy could result in benefits for both patients and the healthcare system.

Differential Adherence to Free and Single-Pill Combination of Rosuvastatin/Ezetimibe: Findings from a Real-World Analysis in Italy.

Adherence to cardiovascular drug treatment can significantly benefit from a reduced pill burden, but data on this matter derived from real-life settings are currently scanty. This analysis assessed the possible changes in adherence in patients treated with rosuvastatin and ezetimibe (ROS/EZE) as free multi-pill combination who switched to ROS/EZE as single-pill combination in the setting of real clinical practice in Italy. A retrospective analysis was conducted on the administrative databases for a catchment area of about sevenmillion health-assisted residents. Adults receiving ROS/EZE as a single-pill combination from January 2010 to June 2020 (followed up to 2021) were identified. The date of the first prescription of single-pill combination of ROS/EZE was considered as the index date. The analysis included the users of ROS/EZE as a free combination during the year before the index date. Baseline demographic and clinical characteristics were collected during the period of data availability prior to the index date. Adherence to therapy was evaluated as proportion of days covered (PDC), namely the percentage of days during which a patient had access to medication, in the 12-month interval preceding or following the index date (PDC < 25% non-adherence; PDC = 25-75% partial adherence; PDC > 75% adherence). A total of 1219 patients (61.1% male, aged 66.2 ± 10.4years) were included. Cardiovascular comorbidities were found in 83.3% of them, diabetes in 26.4%, and a combination of both in 16.2%. Single-pill combination of ROS/EZE was associated with a higher proportion of adherent patients compared to free-pill combination (75.2% vs 51.8%, p < 0.001). This real-world analysis suggested that switching from a regimen based on separate pills to one based on a single-pill combination resulted in improved adherence to ROS/EZE therapy.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD)=0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD=-2.06kg; 95% CI: -3.34 to -0.77), SBP (MD=-1.22mmHg; 95% CI: -2.41 to -0.04), and DBP (MD=-1.09mmHg; 95% CI: -1.94 to -0.24) between the two groups. In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.