Combination Regimens Research Articles

CLINICAL MANAGEMENT OF CHRONIC ORANGUTAN RESPIRATORY DISEASE SYNDROME IN THREE ADULT MALE BORNEAN ORANGUTANS (PONGO PYGMAEUS).

Orangutan respiratory disease syndrome (ORDS) is a disease unique to orangutans (Pongo sp), characterized by chronic bacterial infection and inflammation of any region or combination of regions of the respiratory tract, including the sinuses, air sacs, cranial bones, airways, and lung parenchyma. Aggressive early intervention during a first episode may prevent progression to chronic disease. However, in the setting of an established chronic disease, intermittent acute exacerbations are associated with worsening symptoms and increased infection and inflammation. ORDS is ultimately fatal due to loss of respiratory function resulting from chronic structural damage. Utilizing potentially lifelong medications to slow the progression of chronic, destructive inflammation in the respiratory tract, chronic treatment is aimed at stabilizing the animals' respiratory function, decreasing the frequency of recurrent exacerbations, and improving their general well-being. Three adult male Bornean orangutans (Pongo pygmaeus) housed at an orangutan rehabilitation and reintroduction center in Indonesia have long histories of recurrent respiratory disease. Each underwent CT scans confirming ORDS with chronic airway disease prior to initiation of a long-term treatment protocol. Based on data-driven medical management of bronchiectasis in humans, the three orangutans have been treated with long-term combination regimens of oral azithromycin, nebulized salbutamol, and nebulized hypertonic saline. Follow-up CT scans in all three animals at least 1 yr following treatment initiation showed improvements throughout their respiratory tracts. The duration of each exacerbation period decreased, and the orangutans have longer symptom-free periods compared to before the start of treatment. At an average of 5 yr into the long-term treatment protocol, all three orangutans are thriving. Chronic medical management of ORDS modeled after human treatment of bronchiectasis has been efficacious in these three orangutans and encourages further study of this approach.

Effect of primary tumor volume on survival of concurrent chemoradiotherapy in stage IV non-small cell lung cancer.

To explore the survival effect of thoracic gross tumor volume (GTV) in three-dimensional (3D) radiotherapy for stage IV non-small cell lung cancer (NSCLC). The data cases were obtained from a single-center retrospective analysis. From May. From 2008 to August 2018, 377 treatment criteria were enrolled. GTV was defined as the volume of the primary lesion and the hilus as well as the mediastinal metastatic lymph node. Chemotherapy was a platinum-based combined regimen of two drugs. The number of median chemotherapy cycles was 4 (2-6), and the cut-off value of the planning target volume (PTV) dose of the primary tumor was 63 Gy (30-76.5 Gy). The cut-off value of GTV volume was 150 cm3 (5.83-3535.20 cm3). The survival rate of patients with GTV <150 cm3 is better than patients with GTV ≥150 cm3. Multivariate Cox regression analyses suggested that peripheral lung cancer, radiation dose ≥63 Gy, GTV <150 cm3, 4-6 cycles of chemotherapy, and CR + PR are good prognostic factors for patients with stage IV non-small cell lung cancer. The survival rate of patients with GTV <150 cm3 was longer than patients with ≥150 cm3 when they underwent 2 to 3 cycles of chemotherapy concurrent 3D radiotherapy (p < 0.05). When performing 4 to 6 cycles of chemotherapy concurrent 3D radiotherapy, there was no significant difference between <150 cm3 and ≥150 cm3. The volume of stage IV NSCLC primary tumor can affect the survival of patients. Appropriate treatment methods can be opted by considering the volume of tumors to extend patients' lifetime to the utmost.

Risk of dyslipidaemia in people living with HIV who are taking tenofovir alafenamide: a systematic review and meta-analysis.

Among many antiretroviral drugs, tenofovir alafenamide is used extensively in combination regimens of tenofovir/emtricitabine or tenofovir/emtricitabine/bictegravir. However, concerns have arisen about the potential of tenofovir alafenamide to exacerbate hyperlipidaemia. This meta-analysis evaluates the relationship between tenofovir alafenamide use and lipid-profile alterations in people living with HIV. We searched PubMed, Ovid MEDLINE, EMBASE and the Cochrane Library to identify studies on changes in cholesterol levels (e.g. total cholesterol, low-density and high-density lipoprotein cholesterol, and triglycerides) in people living with HIV who received treatment with a regimen containing tenofovir alafenamide (data collected 31 March 2023, review completed 30 July 2023). Potential risk factors for worsening lipid profile during treatment with tenofovir alafenamide were also evaluated. Sixty-five studies involving 39,713 people living with HIV were selected. Significant increases in total cholesterol, low-density and high-density lipoprotein cholesterol, and triglycerides were observed after treatment with tenofovir alafenamide. Specifically, low-density lipoprotein cholesterol (+12.31 mg/dl) and total cholesterol (+18.86 mg/dl) increased markedly from the third month of tenofovir alafenamide use, with significant elevations observed across all time points up to 36 months. Comparatively, tenofovir alafenamide regimens resulted in higher lipid levels than tenofovir disoproxil fumarate regimens at 12 months of use. Notably, discontinuation of the tenofovir alafenamide regimen led to significant decreases in low-density lipoprotein cholesterol (-9.31 mg/dl) and total cholesterol (-8.91 mg/dl). Additionally, tenofovir alafenamide use was associated with increased bodyweight (+1.38 kg; 95% confidence interval: 0.92-1.84), which became more pronounced over time. Meta-regression analysis identified young age, male sex and low body mass index as risk factors for worsening cholesterol levels in individuals treated with tenofovir alafenamide. Tenofovir alafenamide use in people living with HIV is associated with significant alterations in lipid profile.

Effect of probiotics combined with Ulinastatin and Somatostatin in the treatment of severe acute pancreatitis.

To evaluate the clinical effect of probiotics combined with Ulinastatin and Somatostatin in the treatment of severe acute pancreatitis. A retrospective study was conducted on 160 patients with severe acute pancreatitis treated in the First Affiliated Hospital of Bengbu Medical College from July 2021 to June 2023. There were 78 patients received Ulinastatin and Somatostatin treatment (Control group), and 82 patients received probiotics in addition to Ulinastatin and Somatostatin treatment (Observation group). The treatment effect and the time required to alleviate clinical symptoms were compared between the two groups. Serum levels of inflammatory factors, intestinal mucosal indexes and the incidence of adverse reactions before and after treatment were analyzed. The total efficacy of the Observation group (95.12%) was higher than that of the Control group (85.90%) (P<0.05). Combined probiotic/Ulinastatin + Somatostatin treatment was associated with shorter time to remission of the clinical symptoms (P<0.05). After the treatment, serum levels of inflammatory factors in the two groups were decreased, and was significantly lower in the Observation group compared to the Control group (P<0.05). Similarly, post-treatment serum levels of intestinal mucosal indexes in the two groups were lower than before the treatment, and significantly lower in the Observation group (P<0.05). There was no significant difference in the incidence of adverse reactions between the groups (P>0.05). A combined regimen of probiotics, Ulinastatin and Somatostatin is safe and can more effectively relieve clinical symptoms in patients with severe acute pancreatitis, reduce levels of inflammatory factors, lower intestinal mucosal damage and improve the overall treatment effect compared to Ulinastatin and Somatostatin regimen alone.

Assessing Disease Control in Mismatch Repair-Proficient Colorectal Cancer With Peritoneal Metastases Treated With Immune Checkpoint Blockade-Based Combination Therapies

PURPOSE Metastatic colorectal adenocarcinoma (mCRC) with proficient mismatch repair (pMMR) is associated with poor response to cytotoxic chemotherapy in the refractory setting. Immunotherapy regimens using a combination of immune checkpoint blockade (ICB)–based combination therapies have shown promise, although few studies include patients with peritoneal metastases (PMs). This study sought to examine the disease control rate (DCR) and overall survival (OS) of patients treated with PM who were treated with ICB-containing regimens. METHODS Patients with pMMR metastatic colorectal cancer treated with ICB-based combination regimens after progression on first- and second-line therapy at The University of Texas MD Anderson Cancer Center from 2015 to 2022 were identified. Disease response within each metastatic site was determined. OS and DCR were calculated. RESULTS A total of 30 patients with PM, with or without other metastases, had a median follow-up on an ICB containing regimen of 8.5 months and a median follow-up until death or censoring of 13.3 months. The median OS was 16.7 (10.0-Not reported) months, and 18-month survival was 47%. Among patients treated for ≥6 months, DCR at 6 months at each metastatic site was 20% (2/10) for liver, 68% for peritoneum (13/19, P = .02 v liver), 50% for lung (5/10, P = .35 v liver), and 0% for retroperitoneal adenopathy (0/2, P = 1.00 v liver). CONCLUSIONS Among patients with mCRC, ICB-based combination regimens can provide disease control in the peritoneum in the majority of patients, and median OS compares favorably to standard-of-care therapy in the refractory setting. Patients with peritoneal disease should be included in future ICB trials since treatment options are otherwise limited.

Combination therapy with IV fosfomycin for adult patients with serious Gram-negative infections: a review of the literature.

Treatment of patients with serious infections due to resistant Gram-negative bacteria remains highly problematic and has prompted clinicians to use existing antimicrobial agents in innovative ways. One approach gaining increased therapeutic use is combination therapy with IV fosfomycin. This article reviews the preclinical pharmacokinetic/pharmacodynamic (PK/PD) infection model and clinical data surrounding the use of combination therapy with IV fosfomycin for the treatment of serious infections caused by resistant Gram-negative bacteria. Data from dynamic in vitro and animal infection model studies of highly resistant Enterobacterales and non-lactose fermenters are positive and suggest IV fosfomycin in combination with a β-lactam, polymyxin or aminoglycoside produces a synergistic effect that rivals or surpasses that of other aminoglycoside- or polymyxin-containing regimens. Clinical studies performed to date primarily have involved patients with pneumonia and/or bacteraemia due to Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii. Overall, the observed success rates with fosfomycin combination regimens were consistent with those reported for other combination regimens commonly used to treat these patients. In studies in which direct treatment comparisons can be derived, the results suggest that patients who received fosfomycin combination therapy had similar or improved outcomes compared with other therapies and combinations, especially when it was used in combination with a β-lactam that (1) targets PBP-3 and (2) has exceptional stability in the presence of β-lactamases. Collectively, the data indicate that combination therapy with IV fosfomycin should be considered as a potential alternative to aminoglycoside or polymyxin combinations for patients with antibiotic-resistant Gram-negative infections when benefits outweigh risks.

Effectiveness of Ledipasvir-Sofosbuvir 12 Weeks After Hepatitis C Virus Genotype 1 Infection and the Factors Associated With Sustained Virologic Response: A Retrospective Study.

The combination of ledipasvir and sofosbuvir (LDV/SOF) has been licensed to treat genotype 1 hepatitis C virus infection (HCV) with a 12-week regimen. However, there is scant data from Yemenregarding this combination regimen. Here, we investigate sustained virologic responses (SVR) 12 weeks after HCV treatment with LDV/SOF regimens and the factors that contribute to SVR failure. A retrospective cross-sectional study was conducted at Althora General Hospital in Ibb, Yemen, from June 1, 2019, to October 31, 2022, on 53 cases with HCV genotype 1 infection who received combined therapy of LDV/SOF and completed treatment for 12 weeks. The clinical characteristics and treatment follow-up were obtained from patient medical records. Factors associated with SVR failure were investigated in univariate analysis with odds ratio (OR) and 95% confidence interval (CI). The mean age was 50 ± 15.3 years, and most cases were female (n=36, 67.9%). Comorbidities were diabetes, hypertension, and fatty liver, which were represented in 12 (22.6%), nine (17.0%), and eight (15.1%) cases, respectively. A total of 13 (24.5%) patients had compensated liver cirrhosis, while the remaining 40 patients (75.5%) were non-cirrhotic healthy individuals. The baseline viral load (HCV RNA) was more than 800000 IU/mL in 21 patients (39.6%). Early virological response (ERV) was achieved in 51 patients (96.2%). After treatment, 46 of the patients (86.8%) achieved SVR at Week 12, while failure occurred in two patients (3.8%) and relapse occurred in five patients (9.4%). Blood liver enzymes, including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, returned to normal, with statistically significant improvements in non-cirrhotic healthy persons than compensated liver cirrhosis individuals (p= 0.006, 0.006, and 0.010; respectively). Factors associated with SVR failure were older age (OR:1.13; 95% CI: 1.03-1.30, p=0.009), presence of liver cirrhosis (OR: 5.48; 95% CI: 1.04-28.98, p=0.031), having diabetes (OR: 6.33; 95% CI: 1.19-37.93, p= 0.019), baseline higher viral load (OR: 2.27; 95% CI: 0.45-12.73, p<0.001), and not achieving EVR (OR:7.63; 95% CI: 3.77- 17.78, p= 0.009). In this study, we found that LDV/SOF regimens are effective against HCV genotype one infection, allowing for the expansion of 12-week treatment for suitable patients in clinical settings. Additionally, older age, liver cirrhosis, diabetes, higher pretreatment viral load, and non-completion of EVR were associated with SVR failure. However, due to the small number of HCV genotype 1 infected individuals in this study, more corporate data is required to get a clear conclusion.

Flow boiling in dimpled plate heat exchangers with different geometric parameters: Analysis of asymmetric channels

The evaporators of heat pumps extract heat from the environment. To improve the heat pump performance in cold environments, evaporators must operate with small temperature drops of the heat source, which requires large flow rates of the secondary fluid. This paper discusses dimpled plate heat exchangers (DPHEs) with flexible flow section areas. The flow boiling of R410A is measured in six channels. The flow section area ratios of neighboring channels are 0.86–2.83. To analyze outlet superheat, the two-phase and dryout zones are distinguished using infrared measurement. The dryout zone is a function of the superheat and mass flux, which is quantified. The heat transfer coefficients (HTCs) increase with increasing mass fluxes and heat fluxes. Compared with experimental results from a large scope, the present data fall into the combined regimes of convective boiling and nucleate boiling. Smaller hydraulic diameters slightly enhance the heat transfer. The experimental HTCs are accurately predicted by a correlation of chevron plate heat exchangers (CPHEs). The performances of the DPHEs and CPHE are compared for small temperature drops in cold environments. The DPHEs have superior performance by mitigating the unbalance of mass fluxes. The typical overall heat transfer coefficient is improved by 62%. The improvement depends on the flow section area ratios.

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study

ObjectiveThis study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).Design, setting and participantsThis is a phase 1–1b/2, open-label, multinational, multicentre study...

Effect of different single and combined antihypertensive drug regimens on the mortality of critical care patients.

To investigate the effect of different single and combined pre-admission antihypertensive drug regimens on the prognosis of critically ill patients. We performed a retrospective cohort study using data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. All initial ICU admission records of patients with hypertension and previous antihypertensive exposure before ICU admission were included. Our primary outcome was 90-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance the distribution of baseline characteristics. Logistic regression analysis and subgroup analysis were performed to determine the independent effect of different single and combined antihypertensive drug regimens on 90-day mortality. A total of 13,142 patients were included in the final analysis. The 90-day mortality rate in the combined groups is lower than that in the single therapy group (10.94% vs 11.12%), but no statistical significance was found in the original cohort (p = 0.742). After adjustment for potential confounders, the significantly decreased 90-day mortality rate was found in the combined groups (10.78% vs 12.65%, p = 0.004 in PSM; 10.34% vs 11.90%, p = 0.007). Patients who were exposed to either ACEIs or ARBs had a better prognosis than those not exposed (7.19% vs 17.08%, p < 0.001 in single antihypertensive groups; 8.14% vs18.91%, p < 0.001 in combined antihypertensive groups). The results keep robustness in the PSM and IPTW cohorts. In the logistic regression model analysis, combined therapy was associated with a 12%-20% reduced risk of 90-day death after adjusting potential confounders (OR 0.80-0.88, all p < 0.05), while exposure to ACEIs or ARBs was associated with the decreased risk of 90-day death by 52%-62% (OR 0.38-0.48, all p < 0.001) and 40%-62% (OR 0.38-0.60, all p < 0.001) in the single and combined therapy groups, respectively. The results were still robust to subgroup analysis. Pre-admission combined antihypertensive therapy is associated with a significantly lower risk of death than exposure to single antihypertensives in critically ill patients. Meanwhile, either ACEIs or ARBs seem to be the optimal candidates for both single and combined therapy. Further high-quality trials are needed to confirm our findings.

Discovery of Novel, Potent and Orally Bioavailable SMARCA2 PROTACs with Synergistic Anti-tumor Activity in Combination with KRAS G12C Inhibitors.

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating SMARCA2 is a high value therapeutic target. Here, we disclose the discovery and characterization of potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs. Biochemically, YDR1 and YD54 are potent SMARCA2 degraders with an average DC 50 of 7.7nM and 3.5nM respectively in SMARCA4 mutant lung cancer cells. Phenotypically, both YDR1 and YD54 selectively inhibited growth of SMARCA4 mutant cancer cells. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth of SMARCA4 and KRAS G12C co-mutant lung cancer cells. These findings provide additional evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.

Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data

The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P < 0.05). These findings not only highlight the significance of multi-modal data analysis in enhancing treatment evaluation and personalized medicine for HER2-positive gastric cancer, but also the potential and clinical value of our model.

PD-1 inhibitor combined with SBRT, GM-CSF, and thymosin alpha-1 in metastatic breast cancer: A case report and literature review.

Triple-negative breast cancer is characterized by a worse prognosis compared with other breast cancer subtypes, especially in the case of pretreated metastatic triple-negative breast cancer (mTNBC). Because of the limited treatment options and suboptimal response rates, there is a pressing need to explore novel treatment protocols. A 48-year-old female patient diagnosed with mTNBC who had not responded to multiple lines of therapy (including surgery, chemotherapy, and radiotherapy) but demonstrated significant efficacy and abscopal effects after enrolling in our clinical trial. Triple-negative breast cancer with lung metastases. The clinical trial combined stereotactic body radiotherapy, immunotherapy, granulocyte-macrophage colony-stimulating factor, and thymosin alpha-1 to treat previously treated metastatic solid cancers. This combined treatment regimen implemented in this clinical trial yielded the patient's notable efficacy, accompanied by abscopal effects. The target lesion and the 3 observed lesions achieved a partial response according to the RECIST v1.1 criteria. reevaluation scans after 2 cycles of immunotherapy indicated a regression rate of -78.97% for the target lesion and -56.73% for the observed lesions. Hematological indexes were stable, and there was no apparent myelosuppression. Also, the tumor marker CA-199 exhibited a downward trend. During the course of treatment, the patient experienced a grade 2 skin reaction, which improved after receiving antiallergic treatment. No further adverse effects were observed. This treatment regimen may offer a promising treatment strategy for patients with mTNBC and other metastatic solid cancers.

Use of dual intraventricular vasodilators for refractory cerebral vasospasm in a pediatric patient with traumatic subarachnoid hemorrhage: A case report.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Subarachnoid hemorrhage (SAH) is a rare but life-threatening clinical event for pediatric patients. Cerebral vasospasm is a common complication of SAH that often leads to poor outcomes. This case report describes the use of dual intraventricular (IVT) vasodilators in a pediatric patient. An 11-year-old male presented with traumatic diffuse SAH and cranial vasospasm. Despite treatment with IVT nicardipine, intravenous (IV) milrinone by continuous infusion, enteral nimodipine, and intraarterial verapamil and milrinone given during digital subtraction angiography, transcranial Doppler (TCD) mean velocities continued to rise. IVT milrinone was then added to IVT nicardipine and IV milrinone. The combination of IVT nicardipine, IV milrinone, and rescue therapy with IVT milrinone was continued for a total of 7 days. TCD mean velocities decreased into the mild to moderate range within 2 days of the patient receiving this combined regimen and remained globally low thereafter. This case illustrates the potential benefit of using dual IVT vasodilators to improve outcomes for pediatric patients with refractory cerebral vasospasm.

Investigating the timing and site of recurrence for ovarian clear cell carcinoma: Analysis of the JGOG/GCIG trial-JGOG 3017-A3

BackgroundThis study was conducted to determine the optimal monitoring after initial treatment of ovarian clear cell carcinoma (OCCC) using data from patients enrolled in the Japanese Gynecologic Oncology Group (JGOG) 3017 study. The JGOG study evaluated the efficacy of an irinotecan and cisplatin combination regimen compared with that of a paclitaxel and carboplatin regimen for OCCC patients who underwent primary surgery. MethodsYielding 619 total patients in this study, to analyze progression-free and overall survival, the hazards over time were estimated using kernel smoothing curves to identify the peak of event occurrence. The number of progression events was summed by progression site, and the cumulative incidence proportion was estimated for the major progression sites, considering competing risks. ResultsThe peak hazard for progression or death was observed at 12 months post-treatment, and most events were observed by 24 months. The hazard for death peaked at 18 months post-treatment, with most events being observed by 48 months. The hazard for lung, liver, and spleen metastases remained constant for 18 months post-treatment, with a decreasing trend thereafter; most events were observed by 18 months. The hazard for peritoneal dissemination was constant for 12 months, with a decreasing trend thereafter, with most exacerbations observed by 24 months. The risk of pelvic recurrence peaked at 6 months, with most exacerbations observed by 24 months. DiscussionThe incidence of progression events for OCCC peaked at 12 months and most progression events occurred within 24 months. Close follow-up for the initial 24 months post-treatment and fewer visits thereafter may be acceptable. However, closely monitoring symptoms and examining patients based on differences in progression rates at different sites may be important.

Serum metabolomics signatures after an acute bout of combined traditional or high-intensity tactical training in young males and females.

Exercise is a multipotent stimulus that results in large-scale dynamic changes to the systemic molecular profile. Alternative exercise prescriptions and doses would be expected to result in distinct signatures due to differences in duration and intensity. We tested two novel combined endurance and resistance exercise regimens to better understand how differing prescriptions alter the acute metabolomics response at multiple timepoints up to 24h post-exercise. Serum metabolomics for n=37 untrained individuals was analyzed for participants completing traditional combined exercise [TRAD; n = 20 (11M/9F)] or high-intensity tactical training [HITT; n= 17 (9M/8F)] before exercise (pre), and immediately (h0), 3 and 24 h post-exercise (h3 and h24, respectively). We found minimal metabolites had a group by time interaction (2 with FDR < 0.10; 31 with nominal p < 0.05;), but both stimuli resulted in large-scale within-group changes to the circulating metabolome. TRAD consistently had greater numbers of differentially abundant metabolites (FDR < 0.10) as compared to HITT at h0 (431 vs. 333), h3 (435 vs. 331) and h24 (168 vs. 76). The major metabolite classes altered were related to key energy substrates for both groups at h0 (e.g., glucose, pyruvate) and energy replenishment for h3 and h24 (e.g., 12,13 diHOME, palmitylcarnitine, free fatty acids). In summary, our data are the first to describe the acute changes in the circulating metabolome following combined endurance and resistance exercise. Additionally, we show the two distinct doses of combined exercise led to generally similar patterns of responses, with the longer duration TRAD dose resulting in a higher magnitude of change.

Development of a proliposomal pretomanid dry powder inhaler as a novel alternative approach for combating pulmonary tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility. Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40–50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130–300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.

Efficacy of various combined treatment regimens in patients with stable effort angina, functional classes II-III

Introduction: Inflammation and metabolic disorders of cardiomyocytes are undoubtedly important pathogenetic links in the development of coronary heart disease and its complications. Our study assessed the effect of various combined treatment regimens on cycle ergometry performance and plasma concentrations of pro- and anti-inflammatory interleukins in patients with stable effort angina, functional classes II-III. Materials and Methods: The clinical study included 120 patients diagnosed with coronary heart disease: stable effort angina, functional classes II–III, and 40 healthy participants who met the inclusion criteria. Further, four groups were randomly formed: a group receiving the standard treatment; a group receiving Mexicor for 10 days in addition to the standard treatment; a group receiving Mexicor and Phosphogliv for 10 days in an addition to the standard treatment; and a group receiving Mexicor and Polyoxidonium for 10 days in addition to the standard treatment. After the treatment, cycle ergometry performance and plasma concentrations of pro- and anti-inflammatory cytokines were assessed in the patients. Mathematical statistical analysis was carried out using Statistica 10.0 software. The statistical significance of differences between the qualitative indicators was assessed using the χ2 test. The results of the statistical analysis were considered statistically significant at p&lt;0.05. Results: The combined treatment with using the above-mentioned pharmacological agents resulted in a statistically significant improvement in cycle ergometry indicators: Mexicor made it possible to increase the threshold load power by 43.0% and the total load power – by 70.3%. In the groups of patients with coronary heart disease who had received Mexicor and Phosphogliv or Mexicor and Polyoxidonium, there was an increase in the load duration by an average of 69.0% and in the rate-pressure product – by 25%, respectively. When analyzing the dynamics of plasma concentrations of pro-inflammatory cytokines, it was found that a statistically significant decrease in the concentrations of tumor necrosis factor-α, interleukin-1ß, interleukin-6 and interleukin-10 was registered only in the groups receiving Mexicor and Phosphogliv or Mexicorand Polyoxidonium in addition to the standard treatment. Conclusion: Applying the combined treatment regimens using Mexicor and Phosphogliv or Polyoxidonium results in the most effective improvement of the cycle ergometry performance and the dynamics of plasma concentrations of pro- and anti-inflammatory interleukins in patients with stable effort angina, functional classes II-III.

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: Unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

The effects of laser acupuncture on metabolic syndrome in obese postmenopausal women: a randomized controlled study

To study the laser acupuncture (LA) effects on postmenopausal obese women’s metabolic syndrome. Randomized controlled trial. Benha university hospital. Thirty postmenopausal women were randomized into two equal groups. Group A received a diet regimen and Group B received LA treatment for 30 min three times a week for two months beside the diet regimen. Included weight (W), body mass index (BMI), waist (WC), hip (HC), waist-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum level of total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), fasting blood glucose (FBG), fasting blood insulin (FBI), homeostatic model assessment-insulin resistance (HOMA-IR) before and after the end of treatment. The study’s findings showed that both groups experienced a highly statistically significant decrease in the post-testing mean value of W, BMI, WC, HC, WHR, SBP, DBP, TC, TG, LDL, FBG, FBI, and HOMA-IR, while both groups experienced a significant increase in the post-treatment mean value of HDL (p 0.0001). The posttreatment SBP, DBP, TC, TG, LDL, FBS, FBI and insulin resistance were significantly lower while HDL was significantly higher in women who received combined LA and diet regimen compared to those who received dietary regimen only. LA beside the nutritional intervention is a physical therapy technique that may be used safely, easily, and effectively to minimize metabolic syndrome features during menopause.