Triple Combination Research Articles

‘Effectiveness of various sulbactam-based combination antibiotic therapy in the management of ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii in a tertiary care Health centre’

ObjectiveCarbapenem-resistant Acinetobacter baumannii (CRAB) is a common cause of ventilator-associated pneumonia (VAP). Some in vitro data favour various combination antibiotic therapy. However, there is a need for more in vivo studies for the management of VAP caused by CRAB. This retrospective study was done to evaluate the effectiveness of various combination antibiotic therapy including sulbactam on outcomes of VAP caused by CRAB. MethodsAdult patients (age ≥18 years) diagnosed with VAP caused by CRAB were included. Patients with polymicrobial infections were excluded from the study. Patients with CRAB associated VAP who were given sulbactam based antibiotic combinations were observed for outcomes. The primary outcome was 28-day mortality after diagnosis of VAP caused by CRAB. Reduction in serum HsCRP (High sensitivity C-reactive protein) during treatment and requirement of inotropes were the secondary outcomes. Outcomes were compared between various sulbactam based antibiotic combination therapies. ResultsA total of 103 patients were included. A total of 44 (42.7 %) patients received sulbactam and minocycline or sulbactam and polymyxin B dual antibiotic combination, and 59 (57.3 %) patients received sulbactam, polymyxin B and minocycline triple antibiotic combination. The percentage difference in 28 days mortality was 27.51 % (95 % CI 8.03 %–44.06 %; p = 0.005) in dual vs triple sulbactam based antibiotic combination therapy. The percentage difference in requirement of inotropes during therapy and HsCRP reduction after 7 days of therapy was 23.65 % (95 % CI 6.43 %–38.3 %; p = 0.007) and 25.1 % (95%CI 10.1 %–38.2 %; p < 0.001) respectively when compared between dual vs triple sulbactam based antibiotic combination therapy. ConclusionTreatment with sulbactam, polymyxin B and minocycline combination antibiotic therapy was associated with significantly lower 28-day mortality. Moreover, the lower requirement of inotropes during treatment and a significant reduction in HsCRP level favours this combination antibiotic therapy in VAP caused by CRAB.

Blood pressure lowering efficacy of antihypertensive drugs and their combinations: a systematic review and meta-analysis of 500 randomised, double-blind placebo-controlled trials

Abstract Background Each 1 mmHg reduction in systolic blood pressure (SBP) reduces the risk of major cardiovascular disease events by about 2%. However, there are currently no tools to provide randomised trial-derived estimates of blood pressure (BP)-lowering efficacy of different antihypertensive regimens despite the vast number of possible drug-dose permutations. There has also been no attempt to classify efficacy of treatment regimens into low, moderate, and high intensity. Purpose We aimed to quantify the BP-lowering efficacy of the five major classes of antihypertensive drugs and their combinations. Methods We conducted a systematic review and meta-analysis of randomised double-blind placebo-controlled trials. CENTRAL, MEDLINE and Epistimonikos were searched from inception until December 2022 to identify trials, that compared angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, and diuretics versus placebo, for 4-26 weeks. Primary outcomes were reduction in SBP and diastolic blood pressure (DBP). Doses were classified into standard dose based on the World Health Organisation Defined Daily Dose. BP-lowering efficacy was estimated for each drug and dose using fixed-effects meta-analyses and meta-regressions, standardised to baseline SBP 154 mmHg. Treatment regimens were categorised into low, moderate, and high intensity according to estimated SBP-lowering efficacy of &amp;lt;10, 10-19 and ≥20 mmHg, respectively. Results A total of 500 trials (106,358 participants, 44% female) were included, which included 66 single antihypertensive drugs (monotherapy) and 89 two drug (dual) combinations. The mean baseline BP was 154/100 mmHg and mean follow-up was 8.6 weeks. Monotherapy at one standard dose reduced SBP by 8.5 (95% CI, 8.2-8.9) mmHg, with an additional 1.2 (1.0-1.5) mmHg reduction for each 10 mmHg higher pre-treatment SBP, and an additional 1.5 (1.2-1.8) mmHg reduction with each doubling in dose. There was significant heterogeneity between monotherapies, and 72% were classified as low intensity efficacy. Dual combinations at one standard doses of both the drugs reduced SBP by 15.2 (13.4-17.1) mmHg, and an additional 2.6 (1.4-3.8) mmHg reduction with doubling the doses of both the drugs. There was considerable heterogeneity between dual combinations and 59% were classified as moderate, and 11% as high intensity efficacy. The BP lowering efficacy of adding additional drug classes was confirmed to be additive after accounting for pre-treatment SBP. Triple combinations were classified as high intensity efficacy based on meta-regression analyses. Conclusions There is significant variability in the efficacy of different BP-lowering regimens. The present analyses, available in an online tool, can estimate the BP lowering efficacy for any combination of drug(s) and dose(s), and can classify treatment regimens into low, moderate or high intensity.

Clinical, echocardiographic and haemodynamic predictors of morbidity and mortality in pulmonary hypertension: a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we aimed to evaluate the clinical, echocardiographic,haemodynamic and neurohumoral predictors of morbidity and mortality. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). ESC/ERS 2022 risk scoring model was used for risk predictions at baseline assessment. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age was 51.27 + 21.37 years, and 72 % of patients were female. Incident cases were noted in 65.9 % of overall group. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of overall patients, respectively. Background mono and dual targeted combinations, and sequential dual or triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. Baseline low-, intermediate- and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time was 867 (412-1667) days. Overall rates of mortality and CEP were 26 % and 39%, respectively. Prevalent versus incident cases were associated signifinatly lower mortality and CEP rates (p=0.028 and p=0.024, respectively). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. CHD-PAH compared with other groups was associated with a higher Kaplan-Meier (K-M) survival and CEP-free survival (p&amp;lt; 0.0001 and p=0.00023, respectively). Survival was associated with prevalent versus incident status, baseline functional class (FC) and six-minute walk distance (6MWD) in all subgroups (p&amp;lt;0.0001 for all), NT-brain natriuretic peptide and right atrial area in IPAH,CHD-PAH and CTD-PAH, and mixed venous O2 saturation % in IPAH and CHD-PAH (p varying from &amp;lt;0.0001 to 0.027). But, TAPSE / systolic pulmonary artery pressure ratio, right atrial-pulmonary capillary wedge pressure difference, pulmonary vascular resistance and its ratio to systemic vascular resistance, cardiac index were not related with survival. Baseline high versus intermediate /low risk was associated with a lower overall survival and CEP-free survival ( p=0.03 and p=0.003, respectively). Male sex [hazard ratio(HR):1.73;1.2-2,51,p = 0.004], 6MWD (p&amp;lt;0.001), FC III/IV (HR: 2.52;1.47-4.32, p&amp;lt;0.001) and baseline low-risk (HR:0.37;0.21-0.65, p&amp;lt;0.001) were independent predictors of mortality. Conclusions Our nation-wide data revealed current insights regarding the clinical, echocardiographic,haemodynamic and neurohumoral predictors of morbidity and mortality in PAH and group IV PH.

Multiparametric risk predictions for morbidity and mortality in patients with pulmonary arterial hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we aimed to evaluate risk predictions for morbidity and mortality. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for baseline risk predictions, and COMPERA 2.0 model was used for risk evaluation at follow-up. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % of patients were female. Incident cases were noted in 65.9 % of overall study group. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of overall patients, respectively. Background mono and dual targeted combinations, and sequential dual or triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. According to the ESC/ERS 2022 baseline risk scoring, low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time was 867 (412-1667) days. Overall rates of mortality and CEP were 26 % and 39%, respectively. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. Baseline high versus intermediate /low risk status were associated with a lower survival estimates for mortality and CEP in patients with PAH ( p=0.03 and p=0.003, respectively). Baseline COMPERA 2.0 risk status revealed significant differences in overall survival and CEP-free survival among risk groups ( p&amp;lt;0.0001 for both), but 1st year COMPERA 2.0 score did not (p=0.39 and p=0.06, respectively) . As compared to baseline, 1st year COMPERA 2.0 score decreased in 31 %, and remained unchanged in 34 % of patients. Baseline REVEAL lite 2.0 score was associated with mortality (hazard ratio (HR): 1.14;1.08-1.2, p&amp;lt;0.0001) and CEP (HR:1.17;1.1-1.25, p&amp;lt;0.0001) risks. Male sex (HR: 1.73; 1.2-2.51, p = 0.004), six-minute walk distance (p&amp;lt;0.001), functional class III/IV (HR: 2.52;1.47-4.32, p&amp;lt;0.001) and baseline low-risk status (HR:0.37;0.21-0.65, p&amp;lt;0.001) were independent predictors of mortality. Conclusions Our nation-wide data revealed current insights concerning the multiparametric risk predictions for morbidity and mortality in PAH.

Efficacy and tolerability of triple sequential combination therapies with selexipag in patients with pulmonary arterial hypertension: insights from a single-centre study

Abstract Background and aims In this single-centre study we aimed to evaluate the efficacy and tolerability of prostacyclin receptor agonist selexipag in patients with pulmonary arterial hypertension (PAH). Methods The study included 110 out of the 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES) and treated with selexipag added on background dual PAH therapies. The ESC/ERS 2022, SPAHR, French Registry, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Results Age (mean+SD) was 43.4+16.5 years and 84.5 % of patients were female. The PAH was idiopatic, and was associated with congenital heart disease (CHD), connective tissue disease (CTD) and drug in 47.2 %, 46.4 %, 5.5 % and 1 %, respectively. Background dual therapies, functional class (FC) was II, III and IV in 20 %, 65 %, and 15 % of patients. Six-minute walk distance (6MWD) was 314 + 134 m and serum N-terminal-pro-brain natriuretic peptide (NT-proBNP) level was 882+1732 ng/l. Tricuspid annular planary excursion (TAPSE) and tissue velocity (St), right atrial area and pulmonary arterial diameter were 2.02+0.48 cm,12.4+2.8 cm/sec,21.4+7.2 cm2 and 3.54+0.77 cm, respectively. Invasively evaluated pulmonary arterial mean pressure was 60.2±19.9 mm Hg, and pulmonary vascular resistance was 12.3±10.8 Wood units. COMPERA 2.0 1st, 2nd, 3rd and 4th risk strata were noted in 15.5 %, 31.8 %, 2.7 % and 10 %, and French Registry strata 0,1,2 and 3 were documented in 70 %, 14.5 %, 11 %, and 4.5 %, respectively. The SPAHR and REVEAL Lite 2 scores were 1.9+0.5 and 5.9+2.6, respectively. Background combinations were as follows; macitentan+tadalafil in 46.6 %, macitentan+sildenafil in13.6 %, macitentan+ riociguat in 6.8 %, bosentan +tadalafil in 8.7 %, bosentan+sildenafil in 16.5 %, bosentan+riociguat in 1 %, ambrisentan +tadalafil in 1.9 %, and ambrisentan+sildenafil in 2.9 % of patients. Maximally tolerable selexipag doses (ug)were 1600 bid in 21%, 1400 bid in 5 %, 1200 bid in 11%, 1000 bid in 17%, 800 bid in 12%, 600 bid in 9%, 400 bid in 14%, and 200 bid in 11%.Median follow-up period was 527( 278-831) days, and discontiuation rates of selexipag was 13.6 %. Headache, jaw-pain, diarrhoea, nausea, vomiting and flushing were main side effects. The changes in FC, 6MWD, Nt-pro-BNP and echocardiographic measures were not significant. French Registry score (p&amp;lt;0.001) and COMPERA 2.0 score (p&amp;lt;0.001) showed improvements, but SPAHR and REVEAL lite 2 did not. However, other PAH cohort compared with IPAH showed more pronounced improvements in REVEAL lite 2 and SPAHR scores. Clinical worsening and mortality rates were 23.6 % and 10.9 %, respectively. Survival for 1, 3 and 5 years were 95.8 %, 95.8 and 83.7 % in IPAH, and 92.6 %, 84.1 % and 78.8 % in other PAH patients. Conclusion Our results seem to be consistent with efficacy and tolerability of selexipag-included combinations in patients with PAH.

Real-world evidence on pulmonary arterial hypertension: interim analysis from the Italian observational study INSPECTIO

Abstract Background Pulmonary arterial hypertension (PAH) is a rare, progressive disease leading to right-sided heart failure. The interest in risk assessment based on non-invasive parameters is growing, and insights from clinical practice are needed in this regard. INSPECTIO is an Italian observational study aimed at filling this knowledge gap. The results of an interim analysis at month 12 are presented below. Purpose The primary objective was to assess the change from baseline to month 12 in the number of the non-invasive low-risk parameters among World Health Organization functional class, 6-minutes walking distance, Brain Natriuretic Peptide (BNP) or N-terminal proBNP. Secondary objectives are the evaluation of echocardiographic and haemodynamic parameters, and the proportion of patients in which the therapy was optimized according to the guidelines. Methods Prospective, multicentre study on PAH patients at low/intermediate mortality risk treated with macitentan and/or selexipag as part of the oral combination therapy. Results Among 177 patients who were enrolled in 29 centres, 148 patients [median age 63.0 years (Q1/Q3: 53.5/73.0), 76.4% females] completed the 12-month follow up and were considered for this analysis. The median time from PAH diagnosis was 22.6 months (4.9/60.1). Sixty-four (43.2%) patients had idiopathic PAH; 4 (2.7%) heritable; 80 (54.1%) associated with other diseases [58 (72.5%) connective tissue disease, 11 (13.8%) congenital heart disease corrected for at least one year, 5 (6.3%) portal hypertension, 5 (6.3%) human immunodeficiency virus infection, 1 (1.3%) drug and toxins]. At baseline, 45.9% patients and 28.4% were in double and triple oral combination therapy, respectively. Primary objective: at month 12, the number of noninvasive low-risk parameters increased in 43 (29.1%) patients and remained stable in 80 (54.1%) patients [mean change 0.16 (p=0.017)]. The values at baseline, at month 12 and the change from baseline for each noninvasive parameter are shown in Table 1. Mean right atrial (RA) area (end-systole) and tricuspid annular plane systolic excursion (TAPSE) remained unchanged while a reduction of systolic pulmonary artery pressure (sPAP) was observed. Regarding the haemodynamic parameters, the mean pulmonary arterial pressure decreased [median change -4.5, (p=0.0346)], while cardiac index, pulmonary vascular resistance, and RA pressure remained stable (Table 2). The number of patients on triple therapy increased from 42 to 51 (+21.4%). Conclusions This study confirms that a noninvasive low-risk profile can be achieved with current combination PAH therapy. The modest or absent changes in echocardiographic and hemodynamic parameters suggest that treatment of PAH in real world is yet to be improved; on the other hand, the optimization of therapy in a significant portion of patients can possibly account for the improvement or stabilization observed.Noninvasive parametersEcho and hemodynamic parameters

Changing patterns in clinical, echocardiographic and haemodynamic characteristics, and management strategies that may be translated to improved survival in pulmonary hypertension

Abstract Background and aims In this retrospective analysis of a single-center series on pulmonary hypertension (PH), we aimed to evaluate clinical, echocardiographic, and hemodynamic characteristics, management strategies, morbidity, and mortality in PH subgroups across three consecutive periods. Methods The study included 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES). In reference to enrollment time, patients were assessed in three periods ; before 2016, the era of primarily monotherapy or sequential combinations; between 2016 and 2019, post-approval and reimbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in pulmonary arterial hypertension (PAH). The ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Annual incidence curves for mortality and CEP were evaluated, but 2020 analysis was adjusted to account for the possible adverse effects of the COVID-19. Results During the 1st, 2nd and 3rd periods, 481, 352, and 238 patients with PH were diagnosed, respectively. Incident cases comprised 91% of them. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), group II, III, IV and V PH were documented in 24 %, 28 %, 4.6 %, 4.3 %, 11%, 27 % and 0.7 % of patients, respectively. Age and female dominance remained unchanged. Incidences of Group 1 PH and CHD-PAH decreased while IPAH, drug-associated PAH, and Group II and IV PH increased across three periods (p-values varying from &amp;lt;0.001 to 0.03). Although baseline functional class became worse (p=0.013), six-minute walk distance, N-terminal pro brain natriuretic peptide and risk scores showed no change (p=NS). Baseline echo and hemodynamic measures became better, and triple combinations increased after 2019 (p&amp;lt;0.001 for all). For overall PH, rates of all-cause mortality and CEPs at 1st, 2nd and 3rd periods were 52 % and 59 %, 30 % and 35 %, and 11 % and 13 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 36 %, 38 % and 26 % in IPAH, 60 %, 28 % and 13 % in CHD-PAH, 55 %, 22% and 22% in CTD-PAH, 38 %, 38% and 24 % in group IV PH, respectively (p&amp;lt; 0.001, for all). Mortality curves showed sudden increases in 2020, but excluding 2020, a steady improvement in the annual mortality was evident. Conclusions Our findings suggest a trend towards better clinical, echocardiographic, and hemodynamic presentations and improved survival in the PAH subgroups, and Group IV PH across the three periods that might be attributed to more proactive management strategies favouring earlier initiation of combinations.

Improving morbidity and mortality in patients with pulmonary hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we evaluated management strategies, morbidity and mortality across three consecutive time periods. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). Patients were divided into three enrollment periods: before 2016, the era of monotherapy or sequential combination therapies; between 2016 and 2019, post-approval and re-imbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in PAH. ESC/ERS 2022, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % were female. Incident cases were noted in 65.9 % of patients. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of patients, respectively. Background mono and dual targeted combinations, and sequential triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. Baseline low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time (day) was 867 (412-1667). Overall rates of mortality and CEP were 26 % and 39%, respectively. There were increases in the % of PAH and group IV PH, and decreases in the % of CHD-PAH across the three periods. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Outcomes for mortality and CEP were predicted by three risk models (p&amp;lt;0.0001 for all). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. In overall PH population, rates of mortality and CEP documented at 1st, 2nd and 3rd periods were 64 % and 67 %, 29 % and 31 %, and 3.5 % and 5.1 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 49 %, 39 % and 11 % in IPAH, 62 %, 33 % and 5.3 % in CHD-PAH, 47 %, 45 % and 7.7 in CTD-PAH, and 37 %, 52 % and 11 % in group IV, respectively (p&amp;lt; 0.001, for all). However, mortality curves showed sudden increases in 2020 that might be attributed to COVID-19. Conclusions Our nation-wide data revealed improving survival in the overall PH population, PAH and Group IV PH that might be associated with risk-based earlier targeted combination strategies. However, this trend seems to be counterbalanced with COVID-19 pandemic.

The triple combination DBDx alleviates cytokine storm and related lung injury

Cytokine storm is a life-threatening disorder, and therapeutic treatments are urgently needed. Here, we investigated the anti-cytokine storm efficacy of DBDx, a triple drug combination composed of dipyridamole, ubenimex and dexamethasone. Evaluated by lipopolysaccharide (LPS)-induced cytokine storm murine model, DBDx significantly improved survival rate and prolonged survival time of the model mice. Notably, the efficacy of DBDx was higher than that of dipyridamole, ubenimex and dexamethasone. Determined by ELISA, DBDx significantly reduced the LPS-stimulated serum levels of TNF-α, IL-6 and IL-1β in mice. Luminex assay showed that DBDx suppressed the serum levels of a wide variety of inflammatory cytokines and chemokines, which was more potent than dexamethasone alone. Otherwise, DBDx exerted similar inhibitory effects on cytokine profiles in bronchoalveolar lavage fluid. Histopathological observation showed that DBDx significantly reduced the LPS-induced thickening of alveolar septum, indicating its suppression of capillary congestion, edema and neutrophil infiltration in the lung. Ultra-structure analysis showed that DBDx suppressed the LPS-induced morphological changes of microvilli in type II pneumocytes. In vitro experiment showed that DBDx inhibited IL-6 and TNF-α secretion in THP-1 cells, and downregulated TLR4/NF-κB/HIF-1α signaling pathway. All of these results demonstrate that DBDx, a triple combination of clinical orally-administered drugs, can alleviate cytokine storm and related lung injury. DBDx is beneficial for treating cytokine storm disorders.

A New Ray of Hope in the Treatment of Seasonal Hyperacute Panuveitis: Could Intravitreal Triple Combination Therapy of an Antibiotic with Dual Steroids Play a Pivotal Role?

ABSTRACT Introduction Seasonal Hyperacute Panuveitis (SHAPU) is a blinding disease in Nepal with unknown aetiology. Henceforth, we proposed to study the treatment outcome of a triple intravitreal combination therapy of dual steroids triamcinolone (long-acting steroid) and dexamethasone (short-acting steroid) along with antibiotic moxifloxacin for patients with severe stage of SHAPU. Methods A prospective study was conducted among the SHAPU patients presenting in severe stages during the September to December 2023 outbreak. Intravitreal injection of 4-mg preservative-free triamcinolone acetonide (4 mg/0.1 ml) with intravitreal dexamethasone injection (0.4 mg/0.1 ml) and 0.5 mg/0.1 ml of moxifloxacin was given in the operating theatre. Best corrected visual acuity, intraocular pressure measurements, vitreous haze and fundus evaluation, were assessed to determine the treatment outcome on examination on day 7 and day 30 following intravitreal combination therapy. Result A total of 6 patients (2 female and 4 male) were enrolled. At presentation, the mean BCVA was 2.40 ± 0.30 logMAR, mean intraocular pressure was 12.8 mmHg and vitreous haze was 4+ haze in all cases. The evaluation on the 7th day and 30th after injection showed significant improvement in BCVA (p value = 0.039; p value = 0.040, respectively). The change in the IOP at day 7 (p value = 0.85) was insignificant. However, the IOP change was significant at day 30 (p value = 0.5). Similarly, there was a marked reduction in the vitreous haze with better fundus visibility after treatment. Conclusion This study depicted that steroids prevent the dreaded complication of hypotony due to ciliary shutdown by combating severe inflammation, thus adding new hope to the armamentarium of SHAPU management.

Update on the treatment of BRAFmut metastatic melanoma and future perspectives

Abstractv‐Raf murine sarcoma viral oncogene homolog B (BRAF) mutations were first identified in melanoma in 2002, leading to increased cell division and proliferation, and resultant tumour growth. The identification and characterisation of BRAF mutations (BRAFmut) led to the development of several highly specific, BRAF‐, then mitogen‐activated kinase enzyme (MEK)‐targeted therapies that have enabled rapid tumour responses and improved treatment outcomes in most patients with metastatic BRAFmut melanoma. The combination of these two drug classes (BRAF inhibitors and MEK inhibitors) has demonstrated improved response rates, progression‐free survival, and overall survival (OS), along with a more tolerable safety profile, compared with BRAF inhibition alone. In parallel, improved knowledge of the immune system has enabled the development of immune checkpoint inhibitors (ICIs), although immune‐related adverse events with ICIs may prove to be problematic in some patients and require careful management. While targeted therapy appears to provide rapid disease control in a relatively high proportion of patients, the development of secondary resistance may limit the overall duration of responses. Acquired resistance, along with primary resistance, has also been reported for ICIs, with a lower overall response rate to that with targeted therapy, although durable responses have been reported in some responding patients. A combination strategy of targeted therapy with ICIs has demonstrated modest increases in efficacy compared with targeted therapy combinations, although data significance varies across studies, there is increased risk of toxicity, and triple combination therapy has not yet received clinical approval in Europe. Thus, there is an ongoing need to establish optimal sequencing of these treatments in patients with advanced BRAFmut melanoma, and this has become the focus of current research. The aim of this narrative review was to provide an update on the treatment of BRAFmut metastatic melanoma, current guideline recommendations, and future clinical perspectives.

Use of long-acting triple therapy for chronic obstructive pulmonary disease (COPD) in practice: The ELETHON physicians' survey

Gaps in optimal COPD management have been identified in clinical practice, with discrepancies between guideline recommendations and routine care. The reasons for such discrepancies are incompletely understood. The ELETHON survey aimed to identify physicians' attitudes towards general concepts of COPD management and, in particular, initiation of inhaled triple therapies. ELETHON was a nationwide cross-sectional survey with general practitioners (GP) and pulmonary specialists (PS) working in the ambulatory outpatient setting in Germany, using a structured 17-item questionnaire (single or multiple choice questions) addressing the topics of secondary prevention, exacerbation detection, strategies for therapy escalation, choice of inhaled triple therapies and evaluation of treatment benefits. Questionnaires filled by n=2028 GPs and n=371 PS were analyzed. In both groups, secondary prevention was deemed important in COPD care (GP/PS 76.4%/90.6%), with inhalation technique, vaccination status, and appropriate inhaled pharmacotherapy as key components. Activity/rehabilitation was rarely mentioned by GPs (48.3% vs. 84.5%). Exacerbations and symptomatic worsening were the main triggers for therapy escalation, but were not recorded in a structured way. "Hospitalization" and "≥2 ambulatory exacerbations" were mentioned most frequently as thresholds. Neither GPs nor PS measured eosinophils in the majority of patients. Fixed triple combinations were preferred, with availability of different treatment steps in the same device as important decision aid. Treatment success was evaluated by exacerbations, quality of life, symptoms, lung function and rescue medication use, while COPD Assessment Test (CAT) score was rarely used by GPs and PS. The ELETHON survey identified gaps in COPD management in Germany. While secondary prevention is deemed important, escalation of inhaled therapy is undertaken rather late, the reported importance of vaccinations does not match current quota in German COPD patients, and non-pharmacological measures are often unused. Exacerbation and symptom documentation is rather subjective, validated questionnaires and blood eosinophils are of minor relevance. These results provide evidence of barriers and hidden potentials towards optimization of routine ambulatory care for COPD patients in Germany.

Synergy between bio-control agents to trigger the defensive responses against Rhizoctonia root rot and enhance the growth, yield, and physiological and anatomical traits of pea plants

AbstractRhizoctonia solani (Rs) is the fungus that causes the primary and deadly disease that attacks pea plants throughout the cool growing season. It causes seed rot, damping off, and pea root rot diseases. The current study used arbuscular mycorrhizal fungi; Rhizoglomus clarum, Gigaspora margarita, Rhizophagus irregularis and Funneliformis mosseae (AMF), Pseudomonas fluorescens HE21 (Pf), and Trichoderma harzianum HL9 (TH) singly or in combination to suppress Rhizoctonia root rot of pea in a greenhouse. Using the in vitro dual culture assay, TH and Pf inhibited the radial growth of the Rs by 73.3 and 60.0%, respectively. The results of greenhouse experiments showed that all treatments significantly decreased the percentages of pre- and post-emergence damping while significantly increasing the number of surviving plants, particularly in the dual and triple combination treatments. Furthermore, all treatments improved yield and seed quality in addition to plant growth, total phenol content and antioxidant enzyme activity. There were also noted modifications to the treated plants’ anatomical, physiological, and distinctive features. The synergistic triple treatment consisting of M, TH, and Pf achieved the maximum reduction of disease severity (78.5%) compared to the untreated control treatment. As a result of the synergistic triple treatment due to their effectiveness and eco-safety, we recommend using the synergistic triple by M + Pf + TH to manage the root rot disease in peas caused by Rs and to enhance the crop’s growth, yield, and seed quality.

Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial

Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety. In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed. The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant. A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice. George Medicines.

Differences in sex and age response to single pill combination based antihypertensive therapy reflecting in blood pressure and arterial stiffness.

There are noticeable sex differences in the treatment response to antihypertensives, with limited data on the response to single pill combinations. The aim of the PRECIOUS trial was to assess the treatment response to perindopril/amlodipine and perindopril/amlodipine/indapamide dual and triple single-pill combination in men and women. Four hundred and forty adults with essential hypertension were assessed in the 16-week interventional, open-label, prospective, international, multicentre trial. Based on the previous antihypertensive therapy, patients were assigned to either perindopril/amlodipine 4/5 mg or perindopril/amlodipine/indapamide 4/5/1.25 mg, with the initial dose up-titrated in 4-week intervals in case of uncontrolled blood pressure. An additional analysis was performed for sex- and age-related differences on the blood pressure response and arterial stiffness in men and women aged 35-74 years. Women achieved better overall blood pressure control in all age groups, except for the 35-44 age group. Women presented higher average 24 h aortic augmentation indexes than men, but had more pronounced decreasing trends. The pulse wave velocity was only age-dependent, with reductions slightly greater in women. Both the aortic augmentation index and pulse wave velocity were significantly decreased in all groups compared to baseline. The results of the PRECIOUS trial contribute significant data to the expanding body of evidence on sex differences in hypertension, including the aspect of age-related changes during the life course of women. The differences between same-aged men and women tend to be smaller with advancing age, but with a greater treatment response in women in all age groups for all observed blood pressure parameters and arterial stiffness. ClinicalTrials.gov identifier NCT03738761.

Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial

BackgroundThe single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD.MethodsThis double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7–10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3.ResultsOf 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate.ConclusionsIn patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance.Trial registrationClinicalTrials.gov (NCT05097014), registered 27th October 2021.

Comparison of the Gut Microbiota of Patients Who Improve with Antibiotic Combination Therapy for Ulcerative Colitis and Those Who Do Not: Investigation by Fecal Metagenomic Analyses.

Background/Objectives: The cause of ulcerative colitis (UC) may be related to commensal bacteria in genetically susceptible patients. We previously demonstrated that triple antibiotic combination therapy induces remission in patients with active UC in randomized controlled trials (RCTs). Now, we investigate changes in the gut microbiota of patients who responded to the antibiotic combination therapy. Methods: Thirty-one patients with UC given ATM/AFM (amoxicillin, metronidazole, and tetracycline or fosfomycin) therapy for two weeks were enrolled in this study. The clinical conditions of these UC patients were evaluated by the partial Mayo score. The gut microbiota was compared via the metagenomic shot gun analysis of fecal samples. Results: Of the 31 patients, 16 and 8 experienced complete and partial remission, respectively, over three months in response to ATM/AFM therapy, whereas ATM/AFM showed no efficacy in 7 patients. The dysbiosis before treatment in the active stage could be associated with increased populations of Bacteroides, Parabacteroides, Rickenella, Clostridium, Flavonifractor, Pelagibacter, Bordetella, Massilia, and Piscrickettsia species. Metagenomic analysis revealed dramatic changes in the gut microbiota at an early stage, that is, just two weeks after starting ATM/AFM therapy. After treatment in the responder group, the populations of bifidobacterium and lactobacilli species were significantly increased, while the population of bacteroides decreased. Conclusions: These results suggest that metagenomic analysis demonstrated a marked change in the gut microbiota after antibiotic combination treatment. In the triple antibiotic combination therapy, remission was associated with an increase in bifidobacterium and lactobacilli species.

SMAC mimetic BV6 acts in synergy with mTOR inhibitor to increase cisplatin sensitivity in ovarian cancer.

The objective of this study is to observe the antitumor efficacy of the second mitochondria-derived activator of caspases (SMAC) mimetic bivalent smac mimetic (BV6) in combination with target of rapamycin (mTOR) inhibitor on DDP (cisplatin) sensitivity. Ovarian cancer cells were exposed to cisplatin, BV6, DDP + BV6, and DDP + BV6 + mTOR inhibitor Rapamycin. Using proteomics and bioinformatics, protein expression profiles in ovarian cancer were determined. Bagg Albino color nude mice were treated with DDP or BV6 alone or in combination, or BV6 + DDP + Rapamycin. The effects of different treatments on ovarian cancer cells and tumor growth were evaluated in vivo and in vitro. Proteomics and bioinformatics analysis revealed significant changes of protein kinase (AKT)/mTOR pathway. Consistently, western blot data indicated that AKT/mTOR axis was gradually activated in BV6-treated ovarian cancer cells and attenuated the cytotoxic effect of BV6. Functional assays showed that DDP or BV6 treatment alone significantly enhanced the sensitivity and inhibited the migration of ovarian cancer cells, but without any synergistic effects. In addition, combination with BV6 and mTOR inhibitor Rapamycin significantly decreased cell viability and inhibited migration of ovarian cancer cells exposed to DDP. Consistently, the xenograft model showed that co-treatment with Rapamycin with BV6 had significantly suppressed tumor growth and metastasis. Our study demonstrated that SMAC analogue BV6 exhibits a strong anticancer effect on ovarian cancer in vitro and in vivo. Combination with Rapamycin overcomes the activation of mTOR pathway by BV6 and increases the chemosensitivity to DDP. These data suggest a potential application of triple combination with DDP + BV6 + Rapamycin in clinical management of ovarian cancer.

Artemisinin-resistant malaria.

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).