Effectiveness of upfront triple oral combination therapy with additional pirfenidone in a patient with severe pulmonary hypertension associated with lung diseases.

Diagnosis and treatment of pulmonary hypertension (PH) in patients with lung diseases (PH-LD) remain unestablished and pose significant challenges. In this report, we present a case of a 77-year-old patient with an indeterminate for usual interstitial pneumonia pattern along with chronic obstructive pulmonary disease, who developed groups 1 and 3 PH. Following diagnosis, upfront triple oral combination therapy (UTOCT) with macitentan, sildenafil, and selexipag was initiated. Stability in disease progression was achieved over 4 years with the addition of pirfenidone to address interstitial lung disease progression. To the best of our knowledge, this represents the first reported case of PH-LD, where disease control was maintained with the addition of pirfenidone to UTOCT. This case suggests that some patients with PH-LD, presenting with groups 1 and 3 PH, may benefit from combined UTOCT and antifibrotic agents, potentially improving symptoms and extending their prognosis.

Evaluating the efficacy and safety of oral triple sequential combination therapy for treating patients with pulmonary arterial hypertension: A multicenter retrospective study.

This study aimed to evaluate the effectiveness and safety of an oral sequential triple combination therapy with selexipag after dual combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5I)/riociguat in pulmonary arterial hypertension (PAH) patients. A total of 192 PAH patients from 10 centers had received oral sequential selexipag therapy after being on dual-combination therapy with ERA and PDE5i/riociguat for a minimum of 3 months. Clinical data were collected at baseline and after 6 months of treatment. The study analyzed the event-free survival at 6 months and all-cause death over 2 years. At baseline, the distribution of patients among the risk groups was as follows: 22 in the low-risk group, 35 in the intermediate-low-risk group, 91 in the intermediate-high-risk group, and 44 in the high-risk group. After 6 months of treatment, the oral sequential triple combination therapy resulted in reduced NT-proBNP levels (media from 1604 to 678 pg/mL), a decline in the percentage of WHO-FC III/IV (from 79.2% to 60.4%), an increased in the 6MWD (from 325 ± 147 to 378 ± 143 m) and a rise in the percentage of patients with three low-risk criteria (from 5.7% to 13.5%). Among the low-risk group, there was an improvement in the right heart remodeling, marked by a decrease in right atrium area and eccentricity index. The intermediate-low-risk group exhibited significant enhancements in WHO-FC and tricuspid annular plane systolic excursion. For those in the intermediate-high and high-risk groups, there were marked improvements in activity tolerance, as reflected by WHO-FC and 6MWD. The event-free survival rate at 6 months stood at 88%. Over the long-term follow-up, the survival rates at 1 and 2 years were 86.5% and 86.0%, respectively. In conclusion, the oral sequential triple combination therapy enhanced both exercise capacity and cardiac remodeling across PAH patients of different risk stratifications.

Impact of different sequential triple oral combination therapies based selexipag on outcomes in pulmonary arterial hypertension.

BACKGROUND: While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited. HYPOTHESIS: This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes. METHODS: A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment. RESULTS: Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minute walking distance (6MWD), pulmonary arterial systolic pressure, pulmonary arterial pressure, right ventricle, and eccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups. CONCLUSIONS: Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.

Long-term impact of add-on sequential triple combination therapy in pulmonary arterial hypertension: real world experience.

BACKGROUND: Sequential triple combination therapy is recommended for pulmonary arterial hypertension (PAH) patients who are not at therapeutic goal on dual therapy, but long-term data on efficacy and safety is scarce. OBJECTIVE: To assess the long-term impact of sequential triple combination therapy in patients with PAH who are not at goal on dual combination therapy. STUDY DESIGN AND METHODS: We performed a retrospective observational study in a racially/ethnically diverse cohort of consecutive PAH patients on a stable dual therapy regimen who remained in intermediate- or high-risk category and were subsequently initiated on sequential triple combination therapy. We studied interval change in functional, echocardiographic, and hemodynamic parameters, REVEAL 2.0 risk category and ERS/ESC 2022 simplified four-strata risk category. Multivariate logistic regression analysis was performed to identify independent predictors of successful risk reduction (achievement or maintenance of REVEAL 2.0 low-risk category). Kaplan-Meier survival curves were created to assess the effect of risk reduction on survival. RESULTS: Out of 414 PAH patients seen in our program, 55 patients received add-on sequential triple combination regimen and had follow-up hemodynamic data. The mean age was 57 years, with 85% women. The most common etiology of PAH was idiopathic/heritable (41.8%). Most patients were WHO functional class III (76.4%), and 34.5% of patients were in high-risk category (REVEAL 2.0). On a median follow-up of 68 weeks, there was a significant improvement in WHO Functional Class (p < 0.001), six-minute walk distance (35 m) with 61.8% of patients achieving low-risk status by REVEAL 2.0, and a 28% of patients' improvement in pulmonary vascular resistance. Female gender was identified as a strong predictor of successful risk reduction, whereas Hispanic ethnicity estimated right atrial pressure on echocardiogram and pericardial effusion predicted lower probability of risk reduction. Patients who achieved or maintained low-risk status had significantly improved survival. CONCLUSION: Add-on sequential triple combination therapy significantly increased functional, echocardiographic, and hemodynamic parameters with improvement in risk category and survival.

Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

A randomized, prospective pilot study for comparison of a triple combination of 2940 nm Er:YAG Laser and triamcinolone acetonide solution with either 308 nm excimer laser or 0.1% tacrolimus in treatment of stable segmental vitiligo.

This study aimed to assess and compare the clinical efficacy and safety of a triple combination treatment using 2940 nm Er:YAG laser, triamcinolone acetonide solution combined with either 308 nm excimer laser or 0.1% tacrolimus for the treatment of stable segmental vitiligo. Patients with stable segmental vitiligo were randomly divided into two groups and received a 5-month treatment with 2940 nm Er:YAG laser followed by triamcinolone acetonide and, either 308 nm excimer laser (Group A, N = 8) or 0.1% tacrolimus (Group B, N = 13). General information and imaging data were collected before and at 1 month after treatments. Marked repigmentation and overall repigmentation rates were analyzed and any adverse skin reactions were recorded. Both treatments significantly reduced the percent of skin lesions per total body surface area (p < 0.05) and no significant differences in repigmentation were observed between the two groups (p > 0.05). The marked repigmentation rate of Group A was 42.11% and overall repigmentation rate was 94.74%, while for Group B these rates were 51.16% and 100%, respectively. There were no significant differences in the number of fingertip units at each time point (p > 0.05). While there was a significant effect for time on the number of fingertip units without considering other factors (p < 0.05), the time x treatment interaction was not significant (p > 0.05). One Group A patient developed adverse reactions consisting of erythema, burning sensation and blisters and one Group B patient developed mild erythema and burning sensations. Both treatments demonstrated a high level of efficacy and safety in the treatment of stable segmental vitiligo.

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-ß/Smad Pathway.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1ß, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-ß1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-ß1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Supplementation of conventional anti-diabetic therapy with alpha-lipoic acid prevents early development and progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. METHOD: Fifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. RESULT: Induction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained ß-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1ß and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). CONCLUSION: ALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1ß secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers. Methods: Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1ß secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1ß secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1ß secretion. Conclusions: P2X7R expression is regulated by intracellular Cl- levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R-induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.

Triple-combination therapy assisted with ultrasound-active gold nanoparticles and ultrasound therapy against 3D cisplatin-resistant ovarian cancer model.

Cancer chemotherapy suffers from drug resistance and side effects of the drugs. Combination therapies have been attracted attention to overcome these limitations of traditional cancer treatments. Recently, increasing in intracellular chemotherapeutic concentration in the presence of ultrasonic waves (US) has been shown in the preclinical stage. In addition, some recent studies have shown that nanoparticles increase the effectiveness of ultrasound therapy. In this study, the US-active property of gold nanocones (AuNCs) was utilized for combinational US and cisplatin (Cis) to overcome drug resistance. The effect of the triple combination therapy US + AuNCs + Cis with low-dose Cis on 2/3D models of cisplatin-resistant ovarian cancer cell line (A2780cis) were investigated. In the 2D cell culture, 60% of the A2780cis cell population was suppressed with triple combination therapy; and the long-term therapeutic efficacy of the US + AuNCs + Cis with the low-dose drug was demonstrated by suppressing 83% of colony formation. According to the results in the 3D cell model, 60% of the spheroid formation was suppressed by the triple combination therapy with low-dose Cis. These results not only demonstrate the success of the US + AuNCs + Cis triple combination therapy for its long-term therapeutic effect on resistant cancer cells but also verified that it might enable effective cancer therapy in vivo and clinical stages based on the 3D tumor models. In addition, enhanced anti-cancer activity was demonstrated at the low-dose Cis on drug-resistant cancer cells indicating the triple-combination therapy successfully overcame drug resistance and this is a promising strategy to reduce the side effects of chemotherapy. This work exhibits a novel US and AuNCs-mediated combination cancer therapy, which demonstrates the role of ultrasound-active AuNCs to combat drug resistance with low-dose chemotherapy.

Emerging topical therapies to treat pigmentary disorders: an evidence-based approach.

BACKGROUND: Hyperpigmentation disorders are commonly encountered in dermatology clinics. The use of prescription-grade and over-the-counter topical lightening agents has increased in popularity, leading to a substantial growth of research over the past decade. OBJECTIVE: We seek to review clinical studies evaluating the use of different Rx-grade and OTC ingredients in treating hyperpigmentation. METHODS AND MATERIALS: A comprehensive search on PubMed was conducted to identify patient-based evidence on the most common ingredients used as topical lightening agents: arbutin, ascorbic acid, cysteamine, hydroquinone, kojic acid, niacinamide, retinoids, and triple-combination therapy. The topicals were classified as either prescription-grade or over-the-counter. RESULTS: Varying levels of evidence support the use of topicals in treating hyperpigmentation. There were more clinical trials examining Rx-grade products than OTC products. Mild but tolerated side effects are noted in many of these agents. CONCLUSION: Careful monitoring and adjustment of doses will be needed to maximize skin lightening benefits and minimize side effects.

Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension.

BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26. RESULTS: Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.

Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III-IV Melanoma: A Systematic Review and Meta-Analysis.

Triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy is a promising antitumor strategy and is increasingly being used in clinical trials. To evaluate the safety and efficacy of triple combination of PD-1/PD-L1, BRAF, and MEK inhibition in patients diagnosed with stage III-IV melanoma, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). The PubMed, EMBASE, and Cochrane Library were searched for all studies published from inception to January 2021. The progression free survival (PFS), overall survival (OS), overall response rate (ORR), and risk of adverse events (AEs) were extracted by two independent investigators and pooled hazard ratio (HR) or risk ratio (RR) with 95% CI were determined using the random-effects model for data synthesis. Overall, five randomized controlled trials encompassing 1,266 patients with stage III-IV melanoma were selected. Triple combination therapy significantly improved PFS (HR = 0.71; 95% CI = 0.59 to 0.86; P = 0.0005) and 2-year OS (RR = 1.12; 95% CI = 1.03 to 1.23; P = 0.01), but had no impact on ORR (RR = 1.09; 95% CI = 0.91 to 1.30; P = 0.37) when compared with controlled treatment group. In addition, triple combination therapy was associated with increased risks of hypothyroidism, arthralgia, myalgia, ALT increased, AST increased, asthenia, and pyrexia compared with control group. Triple combination therapy of PD-1/PD-L1, BRAF, and MEK inhibition achieved better survival benefits but had higher incidence of some adverse events over two-drug combination or monotherapy. Further randomized controlled clinical trials are needed to verify our results. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2021 CRD42021235845 Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235845.

Novel diagnostic and therapeutic approaches to pulmonary hypertension due to the unilateral absence of a pulmonary artery.

We report the case of a 64-year-old female diagnosed with severe pulmonary hypertension due to the unilateral absence of a pulmonary artery. The four-dimensional computed tomography scan is a useful modality for revealing detailed anatomical findings for differential diagnoses and surgical decision-making. The patient had severe pulmonary hypertension with a mean pulmonary artery pressure (PAP) of 74 mmHg and was treated with triple upfront combination therapy, leading to significant improvement in pulmonary haemodynamics (to 27 mmHg in mean PAP) and functional capacity (WHO functional class, from III to II; 6-min walk distance, from 211 to 276 m).

Inhaled iloprost as third add-on therapy in idiopathic pulmonary arterial hypertension.

Triple combination therapy is suggested in current pulmonary arterial hypertension guidelines in case of unsatisfactory treatment with oral double combination therapy. However, there is a lack of evidence concerning some of the drug combinations currently employed. We demonstrate the clinical and hemodynamical benefits of inhaled iloprost as third add-on therapy in idiopathic pulmonary arterial hypertension.

NO-releasing polypeptide nanocomposites reverse cancer multidrug resistance via triple therapies.

Multidrug resistance (MDR) induced by the overexpression of P-glycoprotein (P-gp) transporters mainly leads to chemotherapy (CT) failure. Herein, a NIR/pH dual-sensitive charge-reversal polypeptide nanocomposite (PDA-PLC) was developed for co-delivering a nitric oxide (NO) donor and doxorubicin (DOX). Under near-infrared (NIR) irradiation, the released high-concentration of NO gas inhibited the P-gp expression to sensitize the chemotherapeutic medicine DOX and assisted photothermal therapy (PTT) to eradicate cancer cells without skin scarring. Further, the distinctive charge-reversal capacity of PDA-PLC significantly facilitated cellular uptake in the tumor acidic microenvironment (pH 6.8) and enhanced its stability in the physiological environment (pH 7.4). This DOX-loading polypeptide nanocomposite (PDA-PLC/DOX) provides an effective strategy for the PTT-NO-CT triple-combination therapy to overcome MDR STATEMENT OF SIGNIFICANCE: Multidrug resistance (MDR) has been considered to be the paramount factor of chemotherapy (CT) failure in cancer. In this work, an NIR/pH dual-sensitive charge-reversal polypeptide nanomedicine (PDA-PLC/DOX) was developed to overcome MDR through the triple combination therapy of photothermal therapy (PTT), NO gas therapy, and CT. The distinctive charge-reversal capacity of PDA-PLC/DOX significantly facilitated cellular uptake in the tumor acidic microenvironment (pH 6.8) and enhanced its stability in the physiological environment (pH 7.4), while the NIR trigger-released NO gas greatly inhibited the expression of P-gp and synergistically enhanced PTT and CT efficacy. This polypeptide nanocomposite PDA-PLC/DOX provides an effective strategy of using the PTT-NO-CT triple combination therapy with charge-reversal property to completely eradicate the MCF-7/ADR tumor.

A polyoxyethylene sorbitan oleate modified hollow gold nanoparticle system to escape macrophage phagocytosis designed for triple combination lung cancer therapy via LDL-R mediated endocytosis.

Presently, a combination of chemotherapy, radiotherapy, thermotherapy, and other treatments has become a hot topic of research for the treatment of cancer, especially lung cancer. In this study, novel hollow gold nanoparticles (HGNPs) were used as drug carriers, and in order to improve the targeting ability of HGNPs to a lung tumor site, polyoxyethylene sorbitol oleate (PSO) was chosen here as a target ligand since it can be specifically recognized by the low-density lipoprotein (LDL) receptor which is usually over expressed on A549 lung cancer cells. In this way, a PSO-modified doxorubicin-loaded HGNP drug delivery system (PSO-HGNPs-DOX) was constructed and its physicochemical properties, photothermal conversion ability, and drug release of PSO-HGNPs-DOX was investigated. Further, the effects of triple combination therapy, the intracellular uptake, and the ability to escape macrophage phagocytosis of PSO-HGNPs-DOX were also studied using A549 cells in vitro. In addition, an in vivo mouse model was also used to study the targeting of PSO-HGNPs-DOX to lung cancer. PSO-HGNPs-DOX demonstrated a good triple therapeutic effect for lung cancer (A549 cell viability was only 10% at 500 µM) by LDL receptor mediated endocytosis and was able to escape macrophage phagocytosis to enhance its accumulation at the target site. Therefore, PSO-HGNPs-DOX is a novel, safe, promising, and targeted drug carrier designed for triple combination lung cancer therapy which should be further studied for such applications.

Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report.

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient's respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure.

New approach to blood pressure control: Triple combination pill.

Blood pressure (BP) control remains insufficient worldwide, mostly due to poor adherence to treatments, clinical inertia, adverse effects and underuse of drug-combination strategies. Monotherapy and its uptitration have been long considered the first-line strategy in the treatment of hypertension, often leading to ineffective, time consuming and frustrating results. On the other hand, several studies have demonstrated that starting and continuing antihypertensive therapy based on a drug combination is associated with a greater reduction of BP, an earlier achievement of therapeutic goals and a higher proportion of patients achieving targets with favorable implications on cardiovascular events. However, one-fourth to one-third of hypertensive patients fail to achieve BP control even with dual combination therapies, requiring three or more antihypertensive agents. The aim of this review is to discuss the effects of triple-drug associations in terms of BP lowering and prevention of major cardiovascular events, also in high-risk patients. We also discuss available data on side effects and tolerability of triple combination therapy, and the advantages to use a single-pill formulation to promote simplification and adherence to therapy. The findings reported have provided the background for most recent international guidelines on hypertension that support the use of dual and triple combination therapy for most patients.