Low-density Lipoprotein Receptor Activities, Lipids, Apolipoprotein, and Clinical Course of Patients with Steroid-resistant Nephrotic Syndrome Treated with Low-density Lipoprotein Apheresis: A Case Series.

We herein report three cases of steroid-resistant nephrotic syndrome successfully treated with low-density lipoprotein apheresis (LDL-A). All patients were treated with a combination of steroids, cyclosporine, and LDL-A. In all cases, the serum concentrations of LDL, total and high-density lipoprotein cholesterol, and triglycerides were significantly lowered following LDL-A administration. Furthermore, the estimated LDL receptor activity increased, while both serum LDL and total cholesterol levels decreased, suggesting that LDL-A increases LDL receptor activity by driving changes in serum cholesterol concentration. This case series suggests that LDL-A increases LDL receptor activity, which may improve the intracellular uptake of cyclosporine.

Efficacy and Safety of a Single-Pill Triple Combination of Olmesartan, Amlodipine, and Rosuvastatin in Hypertensive Patients with Low-to-Moderate Cardiovascular Risk: A Multicenter, Randomized, Open-Label, Active-Control, Phase IV Clinical Trial.

INTRODUCTION: This study evaluated the efficacy and safety of a single-pill triple-combination of olmesartan/amlodipine/rosuvastatin (Olme/Amlo/Rosu) in comparison with a single-pill dual-combination of olmesartan/amlodipine (Olme/Amlo) in hypertensive patients with low-to-moderate cardiovascular risk. METHODS: This multicenter, active-control, randomized study included 106 hypertensive patients at low-to-moderate cardiovascular risk who were randomly assigned to receive either Olme/Amlo/Rosu 20/5/5 mg (Treatment 1), Olme/Amlo/Rosu 20/5/10 mg (Treatment 2), or Amlo/Olme 20/5 mg (Control) once daily for 8 weeks. The primary endpoint was the difference of the percent change in low-density lipoprotein cholesterol (LDL-C) level at 8 weeks from baseline in the 3 groups. RESULTS: The difference in the least square mean percent change (standard deviation) of LDL-C in the Treatment 1 and 2 groups compared with the Control group at 8 weeks was -32.6 (3.7) % and -45.9 (3.3) %, respectively (P < .001). The achievement rates of LDL-C level <100 mg/dL at 8 weeks were significantly different between the 3 groups (65.8%, 86.7%, and 6.3% for Treatment 1, 2, and Control groups, respectively, P < .001). The results of total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A1 were superior in the Treatment 1 and 2 groups compared with the Control group. Serious adverse drug reaction did not occur in the 3 groups. Medication adherence rates were excellent in the 3 groups (98.0% for Treatment 1 group, 99.7% for Treatment 2 group, and 96.3% for the Control group, P > .05). CONCLUSION: Single-pill triple-combination of olmesartan/amlodipine/rosuvastatin was superior to the single-pill dual-combination of amlodipine/olmesartan in LDLC-lowering effects, with excellent safety profiles and adherence rates, in hypertensive patients at low-to-moderate cardiovascular risk.Trial Registration: CLinicalTrials.gov identifier NCT04120753.

Prospective randomized comparative study of the effect of pemafibrate add-on or double statin dose on small dense low-density lipoprotein-cholesterol in patients with type 2 diabetes and hypertriglyceridemia on statin therapy.

AIMS/INTRODUCTION: Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C levels, pemafibrate and statins can reduce sdLDL-C levels. However, it remains unclear whether adding pemafibrate or increasing statin doses would more effectively reduce sdLDL-C levels in patients receiving statin therapy. MATERIALS AND METHODS: A total of 97 patients with type 2 diabetes and hypertriglyceridemia who were treated with statins were randomly assigned to the pemafibrate 0.2 mg/day addition or statin dose doubled, and followed for 12 weeks. sdLDL-C was measured by our established homogenous assay. RESULTS: The percentage and absolute reductions of sdLDL-C levels were significantly greater in the pemafibrate add-on group than the statin doubling group (-32.8 vs -8.1%; -16 vs -3 mg/dL, respectively). Triglyceride levels were reduced only in the pemafibrate add-on group (-44%), and LDL-C levels were reduced only in the statin doubling group (-8%), whereas levels of non-high-density lipoprotein-C and apolipoprotein B were similarly decreased (7-9%) in both groups. The absolute reductions of sdLDL-C levels were closely associated with decreased triglyceride, LDL-C, non-high-density lipoprotein-C and apolipoprotein B. In the subgroup analysis, the effect of pemafibrate add-on on sdLDL-C reductions was observed irrespective of baseline lipid parameters or statin type. No serious adverse effects were observed in both groups. CONCLUSIONS: In patients with type 2 diabetes and hypertriglyceridemia, the addition of pemafibrate to a statin is superior to doubling a statin in reducing sdLDL-C without increasing adverse effects.

Oridonin attenuates the progression of atherosclerosis by inhibiting NLRP3 and activating Nrf2 in apolipoprotein E-deficient mice.

Oridonin, a well-known traditional Chinese herbal medicinal product isolated from Isodon rubescens (Hemsl.) H.Hara, has many potential properties, including anti-inflammatory and antioxidant activities. However, there is no evidence whether oridonin have a protective effect on atherosclerosis. This study focused on the effects of oridonin on oxidative stress and inflammation generated from atherosclerosis. The therapeutic effect on atherosclerosis was evaluated by intraperitoneal injection of oridonin in a high-fat fed ApoE-/- mouse model. We isolated mouse peritoneal macrophages and detected the effect of oridonin on oxidized low-density lipoprotein-induced lipid deposition. Oil red O staining, Masson's staining, dihydroethidium fluorescence staining, immunohistochemical staining, western blotting analysis, immunofluorescence, enzyme-linked immunosorbent assay and quantitative real-time PCR were used to evaluate the effect on atherosclerosis and explore the mechanisms. Oridonin treatment significantly alleviated the progression of atherosclerosis, reduced macrophage infiltration and stabilized plaques. Oridonin could significantly inhibit inflammation associated with NLRP3 activation. Oridonin significantly reduced oxidative stress by blocking Nrf2 ubiquitination and degradation. We also found that oridonin could prevent the formation of foam cells by increasing lipid efflux protein and reducing lipid uptake protein in macrophages. Oridonin has a protective effect on atherosclerosis in ApoE-/- mice, which may be related to the inhibition of NLRP3 and the stabilization of Nrf2. Therefore, oridonin may be a potential therapeutic agent for atherosclerosis.

Rosuvastatin Attenuates Progression of Atherosclerosis and Reduces Serum IL6 and CCL2 Levels in Apolipoprotein-E-deficient Mice.

BACKGROUND/AIM: Apolipoprotein E-deficient (Apoe-/-) mice develop atherosclerotic lesions that closely resemble metabolic syndrome in humans. We sought to investigate how rosuvastatin mitigates the atherosclerotic profile of Apoe-/- mice over time and its effects on certain inflammatory chemokines. MATERIALS AND METHODS: Eighteen Apoe-/- mice were allocated into three groups of six mice each receiving: standard chow diet (SCD; control group); high-fat diet (HFD); and HFD and rosuvastatin at 5 mg/kg/d orally via gavage for 20 weeks. Analysis of aortic plaques and lipid deposition was conducted by means of en face Sudan IV staining and Oil Red O staining. Serum cholesterol, low-density lipoprotein, high-density lipoprotein, plasma glucose and triglyceride levels were determined at baseline and after 20 weeks of treatment. Serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor-α (TNFα) levels were measured by enzyme-linked immunosorbent assay at the time of euthanasia. RESULTS: The lipidemic profile of Apoe-/- mice on HFD deteriorated over time. Apoe-/- mice on HFD developed atherosclerotic lesions over time. Sudan IV and Oil Red O-stained sections of the aorta revealed increased plaque formation and plaque lipid deposition in HFD-fed mice compared with SCD-fed mice and reduced plaque development in HFD-fed mice treated with rosuvastatin compared with mice not receiving statin treatment. Serum analysis revealed reduced metabolic parameters in HFD-fed mice on rosuvastatin compared with non-statin, HFD-fed mice. At the time of euthanasia, HFD-fed mice treated with rosuvastatin had significantly lower IL6 as well as CCL2 levels when compared with HFD-fed mice not receiving rosuvastatin. TNFα levels were comparable among all groups of mice, irrespective of treatment. IL6 and CCL2 positively correlated with the extent of atherosclerotic lesions and lipid deposition in atherosclerotic plaques. CONCLUSION: Serum IL6 and CCL2 levels might potentially be used as clinical markers of progression of atherosclerosis during statin treatment for hypercholesterolemia.

Development of sensitive magnetic nanoparticle assisted rapid sandwich assay(s-MARSA) to monitor Parkinson's disease and Schizophrenia pharmacotherapy.

Parkinson's disease and Schizophrenia fall under low dopamine neurodegenerative and high dopamine psychiatric disorders respectively. Pharmacological interventions to correct mid-brain dopamine concentrations sometimes overshoots the physiological dopamine levels leading to psychosis in Parkinson's disease patients and, extra-pyramidal symptoms in schizophrenia patients. Currently no validated method is available to monitor side effects in such patients, Apolipoprotein E is one of the CSF biomarkers identified in the recent past that shows an inverse relation to mid-brain dopamine concentration. In this study, we have developed s-MARSA for the detection of Apolipoprotein E from ultra-small volume (2 µL) of CSF. s-MARSA exhibits a broad detection range (5 fg mL-1 to 4 µg mL-1) with a better detection limit and could be performed within an hour utilizing only a small volume of CSF sample. The values measured by s-MARSA strongly correlates with the values measured by ELISA. Our method has advantages over ELISA in having a lower detection limit, a broader linear detection range, shorter analysis time, and requiring a low volume of CSF samples. The developed s-MARSA method holds promise for the detection of Apolipoprotein E with clinical utility for monitoring pharmacotherapy of Parkinson's and Schizophrenia patients.

Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the prognosis of the disease varied. This research aims to investigate the impact of serum lipid level on the outcome of DLBCL patients and their interaction with rituximab (RTX). Data of newly diagnosed DLBCL in the third affiliated hospital of Soochow University were retrospectively collected. Baseline serum lipid levels, clinical data, and survival information were simultaneously recorded. Data of healthy controls were collected with age matching. Serum lipid levels significantly differed for the patients. All were transformed into categorical variables for the analysis of survival. During a median follow-up of 58 months, 32.8% patients died. Univariate analysis revealed all serum lipid indicators were associated with overall survival (OS); all except for total cholesterol (TC) and apolipoprotein B (apoB) showed significant impact on progression-free survival (PFS). Multivariable analysis confirmed the adverse effect of triglyceride (TG) on PFS (P = 0.013) and favorable impact of high-density lipoprotein (HDL) on OS (P = 0.003). For cases treated without RTX, apolipoprotein A (apoA) had independent favorable effect on both PFS (P = 0.004) and OS (P = 0.001). Comparably, for patients who received RTX, HDL showed remarkably predictive value of PFS (P = 0.011) and OS (P = 0.019). In conclusion, the abnormal serum lipids occurred throughout the course of DLBCL, and the associations of serum lipids and the prognosis of the disease were interfered by RTX. Trial registration: 2022()CL033; June 26, 2022, retrospectively registered.

Apolipoprotein-mimetic Peptides: Current and Future Prospectives.

Apolipoprotein-mimetic peptides, mimicking the biological properties of apolipoproteins, have shown beneficial properties against various diseases (central and peripheral diseases) and have emerged as potential candidates for their treatments. Progress has been made from first-generation to second-generation apolipoprotein-mimetic peptides. Understanding these peptides from the first generation to the second generation is discussed in this review. First, we discussed the structural and therapeutic potentials of first-generation apolipoprotein-mimetic peptides. Further, we discussed the development of second-generation apolipoprotein-mimetic peptides, like dual-domain and bihelical peptides the emergence of second-generation apolipoprotein-mimetic peptides as potential candidates in different preclinical and clinical studies has also been emphasized.

Immunomodulatory potential of apolipoproteins and their mimetic peptides in asthma: Current perspective.

Asthma prevailed as a common inflammatory disease affecting mainly the lower respiratory tract, with notable inflammation in the upper airways leading to significant morbidity and mortality. An extensive search for a new therapeutic target is continuously being carried out. Still, the majority have failed in the trials, and eventually, the drugs, including ß2-adrenergic agonists, muscarinic antagonists, and certain corticosteroids, remain the backbone for asthma control. Numerous endogenous factors aid in maintaining the normal homeostasis of the lungs and prevents disease progression. One among them is the apolipoproteins which are different sets of lipoprotein moieties that not only aid in the transport and metabolism of lipids but also impart immunomodulatory roles in various pathologies. Modern research joins the links between the immunomodulatory nature of apolipoproteins in chronic respiratory diseases like asthma and COPD, which can assist in ameliorating the disease progression. Recent studies have elucidated the protective roles of apoA-I and apoE in asthma. This has enabled the utilization of certain apolipoprotein-mimetic peptides to treat these severe pulmonary diseases in the long run. In this review, we have described the prominent and probable mechanistic roles of apolipoproteins like apoA-I, apoB, apoE, apoJ, and apoM in the pathogenesis and treatment of asthma along with the development of apoA-I and apoE-mimetics as a cardinal treatment strategy for eosinophilic as well as corticosteroid resistant neutrophilic asthma.

Clinical, Pathologic, and Molecular Prognostic Factors in Patients with Early-Stage EGFR-Mutant NSCLC.

PURPOSE: In early-stage, EGFR mutation-positive (EGFR-M+) non-small cell lung cancer (NSCLC), surgery remains the primary treatment, without personalized adjuvant treatments. We aimed to identify risk factors for recurrence-free survival (RFS) to suggest personalized adjuvant strategies in resected early-stage EGFR-M+ NSCLC. EXPERIMENTAL DESIGN: From January 2008 to August 2020, a total of 2,340 patients with pathologic stage (pStage) IB-IIIA, non-squamous NSCLC underwent curative surgery. To identify clinicopathologic risk factors, 1,181 patients with pStage IB-IIIA, common EGFR-M+ NSCLC who underwent surgical resection were analyzed. To identify molecular risk factors, comprehensive genomic analysis was conducted in 56 patients with matched case-controls (pStage II and IIIA and type of EGFR mutation). RESULTS: Median follow-up duration was 38.8 months (0.5-156.2). Among 1,181 patients, pStage IB, II, and IIIA comprised 577 (48.9%), 331 (28.0%), and 273 (23.1%) subjects, respectively. Median RFS was 73.5 months [95% confidence interval (CI), 62.1-84.9], 48.7 months (95% CI, 41.2-56.3), and 22.7 months (95% CI, 19.4-26.0) for pStage IB, II, and IIIA, respectively (P < 0.001). In multivariate analysis of clinicopathologic risk factors, pStage, micropapillary subtype, vascular invasion, and pleural invasion, and pathologic classification by cell of origin (type II pneumocyte-like tumor cell vs. bronchial surface epithelial cell-like tumor cell) were associated with RFS. As molecular risk factors, the non-terminal respiratory unit (non-TRU) of the RNA subtype (HR, 3.49; 95% CI, 1.72-7.09; P < 0.01) and TP53 mutation (HR, 2.50; 95% CI, 1.24-5.04; P = 0.01) were associated with poor RFS independent of pStage II or IIIA. Among the patients with recurrence, progression-free survival of EGFR-tyrosine kinase inhibitor (TKI) in those with the Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) mutation signature was inferior compared with that of patients without this signature (8.6 vs. 28.8 months; HR, 4.16; 95% CI, 1.28-13.46; P = 0.02). CONCLUSIONS: The low-risk group with TRU subtype and TP53 wild-type without clinicopathologic risk factors might not need adjuvant EGFR-TKIs. In the high-risk group, with non-TRU subtype and/or TP 53 mutation, or clinicopathologic risk factors, a novel adjuvant strategy of EGFR-TKI with others, e.g., chemotherapy or antiangiogenic agents needs to be investigated. Given the poor outcome to EGFR-TKIs after recurrence in patients with the APOBEC mutation signature, an alternative adjuvant strategy might be needed.

Relation of Serum Lipoprotein(a) Levels to Lipoprotein and Apolipoprotein Profiles and Atherosclerotic Diseases in Japanese Patients with Heterozygous Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.

AIMS: Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a low-density lipoprotein (LDL)-like particle with apolipoprotein (Apo)(a), attached via a disulfide bond to Apo B100. Previous studies have shown that high Lp(a) levels are associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia (FH). To date, limited data are available as to distribution of Lp(a) in FH and associations of Lp(a) with other lipid profiles and cardiovascular disease. Our study aimed to investigate serum Lp(a) levels in relation to other lipid profiles and clinical conditions in the national largest-ever cohort of Japanese FH patients. METHODS: This study is a secondary analysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study that includes a Japanese nationwide cohort of FH patients. In 399 patients under treatment for heterozygous FH who had a baseline measurement of serum Lp(a), the present study examined the distribution of Lp(a) levels and associations of Lp(a) with other lipid profiles and clinical conditions including coronary artery disease (CAD). RESULTS: The distribution of Lp(a) was skewed to the right with a median of 20.8 mg/dL, showing a log-normal distribution. Serum Apo B and Apo E levels were positively associated with Lp(a) levels. Age-adjusted mean of Apo B was 8.77 mg/dL higher and that of Apo E was 0.39 mg/dL higher in the highest category (40+ mg/dL) of Lp(a) than in the lowest category (＜20 mg/dL). LDL-C levels did not show such an association with Lp(a) levels. A tendency towards a positive relationship between Lp(a) and prevalent CAD was observed in men. CONCLUSION: Our study demonstrated a distribution pattern of Lp(a) in Japanese FH patients and positive relationships of Lp(a) with Apo B and Apo E levels.

Apolipoprotein Mimetic Peptides: An Emerging Therapy against Diabetic Inflammation and Dyslipidemia.

Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol levels are inversely associated with coronary heart disease in humans. The beneficial effect of HDL is due, in part, to apolipoproteins A-I and E, which possess anti-inflammatory properties. The functional quality of HDL, however, may be reduced in the context of diabetes. Thus, raising levels of functional HDL is an important target for reducing inflammation and diabetic complications. Apo A-I possesses eight alpha-helical sequences, most of which form class A amphipathic helical structures. Peptides belonging to this class inhibit atherogenesis in several mouse models. Additional peptides based on structural components of apoE have been shown to mediate a rapid clearance of atherogenic lipoproteins in dyslipidemic mice. In this review, we discuss the efficacy of apolipoprotein mimetic peptides in improving lipoprotein function, reducing inflammation, and reversing insulin resistance and cardiometabolic disease processes in diabetic animals.

New kids on the block: the emerging role of apolipoproteins in the pathogenesis and treatment of asthma.

New treatments are needed for patients with severe asthma. We hypothesized that a clinically relevant experimental model of house dust mite (HDM)-induced murine asthma could be used to discover new pathways that regulate disease severity. In HDM-challenged mice, genome-wide expression profiling of the asthmatic lung transcriptome identified apolipoprotein E (apoE) as a steroid-unresponsive gene with persistently upregulated expression despite dexamethasone treatment. ApoE and low-density lipoprotein receptor (LDLR) knockout mice were used to demonstrate that apoE, which is produced by lung macrophages, functions in a paracrine fashion by binding to LDLRs expressed on ciliated airway epithelial cells, to negatively modulate airway hyperreactivity, mucin gene expression, and goblet cell hyperplasia. Furthermore, administration of an apoE mimetic peptide, which corresponded to the LDLR-binding domain of apoE, prevented the induction of airway inflammation, airway hyperreactivity, and goblet cell hyperplasia in HDM-challenged apoE knockout mice. This suggests that therapeutic strategies that activate the apoE-LDLR pathway, such as apoE mimetic peptides, may represent a novel treatment approach for patients with asthma. Similarly, we showed that administration of a 5A apolipoprotein A-I mimetic peptide attenuated the induction of HDM-mediated asthma in mice. These preclinical data suggest that apoE and apoA-I mimetic peptides might be developed into alternative treatments for patients with severe asthma. Future clinical trials will be required to determine whether inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides are effective for the treatment of severe asthma, including patients with phenotypes that lack effective therapeutic options.

Susceptibility of mice to Trypanosoma evansi treated with human plasma containing different concentrations of apolipoprotein L-1.

The aim of this study was to test the susceptibility of mice to Trypanosoma evansi treated with human plasma containing different concentrations of apolipoprotein L-1 (APOL1). For this experiment, a strain of T. evansi and human plasma (plasmas 1, 2, and 3) from 3 adult males clinically healthy were used. In vivo test used 50 mice divided in 5 groups (A to E) with 10 animals in each group. Animals of groups B to E were infected, and then treated with 0.2 ml of human plasma in the following outline: negative control (A), positive control (B), treatment with plasma 1 (C), treatment with plasma 2 (D), and treatment with plasma 3 (E). Mice treated with human plasma showed an increase in longevity of 40.9 ± 0.3 (C), 20 ± 9.0 (D) and 35.6 ± 9.3 (E) days compared to the control group (B) which was 4.3 ± 0.5 days. The number of surviving mice and free of the parasite (blood smear and PCR negative) at the end of the experiment was 90%, 0%, and 60% for groups C, D, and E, respectively. The quantification of APOL1 was performed due to the large difference in the treatments that differed in the source plasma. In plasmas 1, 2, and 3 was detected the concentration of 194, 99, and 115 mg/dl of APOL1, respectively. However, we believe that this difference in the treatment efficiency is related to the level of APOL1 in plasmas.

Recent advances on the antiatherogenic effects of HDL-derived proteins and mimetic peptides.

The plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis and cardiovascular disease (CVD) in humans. One of the major mechanisms whereby HDL particles protect against atherosclerosis is that of reverse cholesterol transport from atherosclerotic lesion macrophages to the liver. HDL particles also exhibit various antiatherogenic and cardioprotective effects by modulating the function of various cells including the cells of the artery wall and by expressing antioxidant, anti-inflammatory, antithrombotic and antiapoptotic effects. Most these effects are mediated by various lipid and protein HDL components. A plethora of studies have been conducted in order to shed light on the mechanisms by which each HDL component contributes to the functionality of this lipoprotein. The complete elucidation of these mechanisms will significantly contribute to current efforts focused on the development of therapeutic strategies to promote the antiatherogenic potency of HDL. The present review discusses current knowledge on the biological activities of the major apolipoproteins and enzymes associated with HDL, which may significantly contribute to the overall antiatherogenic and cardioprotective effects of this lipoprotein.

The effect of apolipoprotein mimetic peptides in inflammatory disorders other than atherosclerosis.

Apolipoprotein mimetic peptides have been shown to dramatically reduce atherosclerosis in animal models. Atherosclerosis is an example of an inflammatory disorder. Published studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they may have efficacy in a wide range of inflammatory conditions.

Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I.

Humans have innate immunity against Trypanosoma brucei brucei that is known to involve apolipoprotein L-I (APOL1). Recently, a case of T. evansi infection in a human was identified in India. We investigated whether the APOL1 pathway was involved in this occurrence. The serum of the infected patient was found to have no trypanolytic activity, and the finding was linked to the lack of APOL1, which was due to frameshift mutations in both APOL1 alleles. Trypanolytic activity was restored by the addition of recombinant APOL1. The lack of APOL1 explained the patient's infection with T. evansi.

Treatment of stable angina with low dose diltiazem in combination with the metabolic agent trimetazidine.

BACKGROUND: The risk/benefit of moderate to high doses of calcium antagonists in stable angina is uncertain. This study investigates the efficacy and acceptability of low dose diltiazem in combination with trimetazidine for the treatment of stable angina. METHODS: In a 28-day, randomized, double blind study, treatment with 90 mg diltiazem in combination with 60 mg trimetazidine or placebo per day was compared in 50 patients with stable angina. The primary outcomes were time to 1-mm ST segment depression and the Duke treadmill score. RESULTS: Of the 25 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was, in time to 1-mm ST segment depression, 13 (52) versus 5 (20), P<0.05; in the Duke treadmill score, 18 (72) versus 8 (32), P<0.01; and in angina 17 (68) versus 3 (12), P<0.01. Compared to placebo there was an improvement with trimetazidine in mean exercise time to 1-mm ST segment depression of 128 s (95% confidence interval 45.0-208.5; P<0.01); in the mean Duke treadmill score of 57.4% (95% confidence interval 9.9-100; P<0.02); and in mean anginal attacks of 5.1 per week (95% confidence interval, 3.1-7.3, P<0.01). CONCLUSION: The combination of low dose diltiazem with trimetazidine is effective with few side-effects in the symptomatic control of patients with stable angina.