Effects of Combined Deferiprone and Deferoxamine Chelation Therapy on Iron Load Indices in β-Thalassemia

The benefits of combined deferoxamine (DFO) and deferiprone (L1) chelation therapy, focusing on reducing myocardial iron loading, have been widely reported. Herein, we present the efficacy of combined chelation and its effects on iron load indices. Five thalassemia major (TM) patients who were undergoing chelation monotherapy with DFO were enrolled. Inclusion criteria were magnetic resonance imaging (MRI) T2* values, indicating serious heart and/or liver transfusional hemosiderosis. Combined therapy was started with the same dose of DFO and the addition of L1. The MRI T2* studies were repeated 18 months later. An Echo-Doppler study was performed in order to further evaluate the left ventricular (LV) systolic function. Within the 18 months' follow-up period, there was a significant statical decrease in mean serum ferritin levels. All patients increased their MRI T2* liver values, while two patients with very low MRI T2* also increased their myocardial values. The MRI ejection fraction (EF) and Echo-Doppler study measurements confirmed the improvement of systolic function. No adverse effects were reported. Combined L1 and DFO therapy seems to be effective in reducing iron excess in organ iron overloaded thalassemic patients. Magnetic resonance imaging can accurately quantify iron load, while echocardiography remains a reliable monitoring technology.     

Is a Series of Blood Pressure Measurements by the General Practitioner or the Patient a Reliable Alternative to Ambulatory Blood Pressure Measurement?: A Study in General Practice With Reference to Short-term and Long-term Between-Visit Variability

We studied thereproducibility of a series of blood pressure measurements by general practitioner (GP) and patient in comparison with that of ambulatory blood pressure measurement (ABPM), with reference to short-term and long-term between-visit variability using a prospective, comparative diagnostic study. The study group was 88 potentially hypertensive primary care patients (initial systolic blood pressure [SBP] between 160 and 200 mm Hg or with diastolic blood pressure [DBP] between 95 and 115 mm Hg). ABPMs were measured on 2 separate days (at a 6 month interval). Two series of measurements by the doctor (at 1 to 6 month intervals), and the patient (at a 1 week interval) were measured. Mean differences and standard deviations of mean differences (SDD) between two successive series of measurements, and between two ABPMs were computed. The Wilcoxon signed-ranks test was used to compare these standard deviations. Mean initial office-blood pressures were 161 (SBP) and 102 (DBP) mm Hg. Long-term between-visit variability (measurements by GP) was larger than short-term between-visit variability: SDDs were 16 v 11 mm Hg (SBP), and 10 v 8 mm Hg (DBP). The differences in average SBP and DBP between successive ABPMs and between successive series of office measurements by GP and home measurements by patient were not statistically significant. Mean differences between two series of measurements by GP and patient, and between two ABPMs, were 0 ± 1 mm Hg. SDDs between successive ABPMs and series of measurements by GP and patient ranged from 8 to 11 mm Hg (SBP), and were 6 mm Hg (DBP). No statistically significant differences were found between the SDDs of the studied measurement procedures (SBP and DBP). In our study the reproducibility of ambulatory blood pressure measurement was not found to be better than that of a series of four duplicate measurements by GP or patient. Long-term (6 months interval) between-visit variability was larger than the short-term (1 week interval) between-visit variability.     

Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure,Glucose Metabolism and Endothelial Function: A Double-blind Randomized Crossover Clinical Trial

Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function.A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained.After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and −0.63 mm Hg in diastolic BP for CB; −0.71 mm Hg in systolic BP and −1.08 mm Hg in diastolic BP for LSB; and −0.75 mm Hg in systolic BP and −2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters.Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the effect of GABA on BP, preferably using a specific design for noninferiority trials and ambulatory BP monitoring as a measure of BP.This study was registered at Current Controlled Trials as ISRCTN31436822     

Are There Pleiotropic Effects of Antihypertensive Medications or Is It All About the Blood Pressure in the Patient With Diabetes and Hypertension?

Many small studies with varied surrogate end points and numerous preclinical data have suggested the likelihood of there being specific benefits that exceed simple blood pressure control with drug classes such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers, which may be particularly relevant to the patient with diabetes and hypertension. Large clinical trials, however, have provided only token support for this idea. Likewise, meta-analyses that have incorporated varied clinical trials, albeit with somewhat heterogeneous data, have not been particularly forthcoming in their support of this concept. In the patient with diabetes and hypertension, tight blood pressure control, more so than using a specific drug class, is the most important aspect of therapy.     

Relationship of Blood Pressure With Mortality and Cardiovascular Events Among Hypertensive Patients aged ≥60 years in Rural Areas of China: A Strobe-Compliant Study

The Eighth Joint National Committee (JNC-8) panel recently recommended a systolic blood pressure (BP) threshold of ≥150 mmHg for the initiation of drug therapy and a therapeutic target of <150/90 mmHg in patients ≥60 years of age. However, results from some post-hoc analysis of randomized controlled trials and observational studies did not support these recommendations.In the prospective cohort study, 5006 eligible hypertensive patients aged ≥60 years from rural areas of China were enrolled for the present analysis.The association between the average follow-up BP and outcomes (all-cause and cardiovascular death, incident coronary heart disease [CHD], and stroke), followed by a median of 4.8 years, were evaluated using Cox proportional hazards models adjusting for other potential confounders. The relationship between BP (systolic or diastolic) showed an increased or J-shaped curve association with adverse outcomes. Compared with the reference group of BP <140/90 mmHg, the risk of all-cause death (hazard ratio [HR]: 2.698; 95% confidence interval [CI]: 1.989–3.659), cardiovascular death (HR: 2.702; 95% CI: 1.855–3.935), incident CHD (HR: 3.263; 95% CI: 2.063–5.161), and stroke (HR: 2.334; 95% CI: 1.559–3.945) was still significantly increased in the group with BP of 140–149/<90 mmHg.Older hypertensive patients with BP of 140–149/<90 mmHg were at higher risk of developing adverse outcomes, implying that lenient BP control of 140–149/<90 mmHg, based on the JNC-8 guidelines, may not be appropriate for hypertensive patients aged ≥60 years in rural areas of China.     

Relationship of Hypertension,Blood Pressure,and Blood Pressure Control With White Matter Abnormalities in the Women’s Health Initiative Memory Study (WHIMS)—MRI Trial

J Clin Hypertens (Greenwich). 2010;12:203–212. ^©2010 Wiley Periodicals, Inc. This paper evaluates the relationship of blood pressure (BP) levels at Women’s Health Initiative (WHI) baseline, treatment of hypertension, and white matter abnormalities among women in conjugated equine estrogen (CEE) and medroxyprogesterone acetate and CEE-alone arms. The WHI Memory Study—Magnetic Resonance Imaging (WHIMS-MRI) trial scanned 1424 participants. BP levels at baseline were significantly positively related to abnormal white matter lesion (WML) volumes. Participants treated for hypertension but who had BP ≥140/90 mm Hg had the greatest amount of WML volumes. Women with untreated BP ≥140/90 mm Hg had intermediate WML volumes. Abnormal WML volumes were related to hypertension in most areas of the brain and were greater in the frontal lobe than in the occipital, parietal, or temporal lobes. Level of BP at baseline was strongly related to amount of WML volumes. The results of the study reinforce the relationship of hypertension and BP control and white matter abnormalities in the brain. The evidence to date supports tight control of BP levels, especially beginning at younger and middle age as a possible and perhaps only way to prevent dementia.     

Comparable Benefit of β-Blocker Therapy in Heart Failure Across Regions of the World: Meta-analysis of Randomized Clinical Trials

Background

There is a concern about geographical region heterogeneity regarding clinical benefit of β-blocker (BB) therapy in heart failure with reduced ejection fraction (HFrEF). This study sought to compare benefits of BB use within randomized controlled trials (RCTs) that enrolled patients with HFrEF from North America (NA) compared with other regions of the world (ROW).

Methods

We conducted a meta-analysis using MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus (inceptions-December 2012) of BB RCTs stratified according to NA vs ROW. The primary end point was all-cause mortality and secondary end points were cardiovascular death, sudden death, death due to pump failure, and premature drug discontinuation. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for each outcome were calculated with interaction terms for region. Two-sided P values were calculated with P < 0.05 considered significant.

Results

The analysis included 16 RCTs with 14,452 patients; 7 trials were conducted in NA and 9 trials in ROW with follow-up durations of 3-58 months. All-cause mortality was consistently reduced in NA (OR, 0.82; 95% CI, 0.71-0.96; P = 0.01) and ROW (OR, 0.76; 95% CI, 0.69-0.84; P < 0.001; P-interaction = 0.40). Overall and according to region, all secondary end points including premature drug discontinuation were also less with BB therapy (P-interactions all ≥ 0.10).

Conclusions

For the regions represented in the included trials, there is no evidence to suggest that geographic region is a significant moderator of clinical outcomes with BB therapy in HFrEF patients.     

Anti-Hypertensive Effect of γ-Aminobutyric Acid (GABA)-Rich Chlorella on High-Normal Blood Pressure and Borderline Hypertension in Placebo-Controlled Double Blind Study

The anti-hypertensive effect of GABA-rich Chlorella was studied after oral administration for 12 weeks in the subjects with high-normal blood pressure and borderline hypertension in the placebo-controlled, double-blind manner in order to investigate if GABA-rich Chlorella, a dietary supplement, is useful in control of blood pressure. Eighty subjects with Systolic blood pressure (SBP) 130–159 mmHg or diastolic blood pressure (DBP) 85–99 mmHg (40 subjects/group) took the blinded substance of GABA-rich Chlorella (20 mg as γ-aminobutyric acid) or placebo twice daily for 12 weeks, and had follow-up observation for an additional 4 weeks. Systolic blood pressure in the subjects given GABA-rich Chlorella significantly decreased compared with placebo (p < 0.01). Diastolic blood pressure had the tendency to decrease after intake of GABA-rich Chlorella. Neither adverse events nor abnormal laboratory findings were reported throughout the study period. Reduction of SBP in the subjects with borderline hypertension was higher than those in the subjects with high-normal blood pressure. These results suggest that GABA-rich Chlorella significantly decreased high-normal blood pressure and borderline hypertension, and is a beneficial dietary supplement for prevention of the development of hypertension.     

Fixed-Dose Combinations of Renin–Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension: A Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors

Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking.Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered.There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98–1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082–1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071–1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050–1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses.ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status.     

Combined Chelation Therapy with Deferoxamine and Deferiprone in β-Thalassemia Major: Compliance and Opinions of Young Thalassemic Patients

Treatment of β-thalassemia major (β-TM) includes regular blood transfusions and iron chelation with subcutaneous injection of deferoxamine (DFO). During the last decade, a new chelation agent, deferiprone (L1), was introduced. The purpose of our study was to determine the level of awareness/education regarding chelation therapy, the degree of compliance to this therapy and their views of L1 in patients with β-TM. A relevant questionnaire was administered to 36 patients (12–26 years old) who were on combination chelation therapy with both DFO and L1. The majority of patients was well aware/educated about chelation therapy (76.6%), was compliant with this therapy (74.4%) and had a positive view towards oral chelation (86.0%). In conclusion, most patients with β-TM who were on combination chelation therapy with DFO and L1 were satisfied with this treatment and this results in high compliance rates.     

Effect of Nitric Oxide Inhibition on Blood Pressure and Renal Sodium Handling: A Dose–Response Study in Healthy Man

Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretion. To further investigate the role of NO in renal sodium handling, we studied the effects of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in a crossover dose–response study. During NO inhibition mean arterial pressure increased dose-dependently and reached a plateau after 20 minutes of infusion. On the contrary, the fractional excretion of sodium was reduced equally in all three L-NMMA doses. This indicates that sodium excretion is highly sensitive to even small changes in renal NO bioavailability in healthy human.     

The Effect and Side Effect of Hydroxyurea Therapy on Patients With β-Thalassemia: A Systematic Review to December 2012

Hydroxyurea (HU) is being used for patients with transfusion-dependent β-thalassemia major (β-TM) as well as non transfusion-dependent β-TM. As controversy exists regarding efficacy and safety of HU, we searched the published literature on efficacy, effectiveness and toxicity of HU in patients with β-TM. The research sources we used were: Medline, SID, PubMed, Scopus, Request, Web of Knowledge, Springer, Ovid, Cochrane searched up to October 2012. Using search terms sensitive to studies of clinical trials combined with searches on terms related to thalassemia and HU. We selected studies on randomized trials, quasi experimental trials (before and after design), case reports (with 1–5 cases), side effect studies in patients with β-TM, studies related to the mechanism of action and toxicity when used in patients with other hemoglobinopathies. We researched studies in English and Persian. Eligible articles were reviewed by two independent reviewers. Patient’s characteristics, duration of trial, outcome and side effects were extracted. The main outcomes were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic, Tau² and I². Subgroup analyses were performed and the statistics data (STATA) software used. More than 500 articles were reviewed. No randomized clinical trial was found. Seventeen trials with before and after designs were found, 16 case reports (1–5 cases), 19 articles for mechanism of action and 16 studies for side effects were published from 1969 to October 2012. Hemoglobin levels after treatment showed modest but significant increase in non transfusion-dependent β-TM (p?p?相似文献   

Novel Metabolic Drugs and Blood Pressure: Implications for the Treatment of Obese Hypertensive Patients?

Hypertension and obesity often coexist, exposing patients to cardiovascular and metabolic risks, particularly type 2 diabetes mellitus. Moreover, obesity may render hypertensive patients treatment resistant. We review how drugs recently approved for obesity or type 2 diabetes mellitus treatment affect blood pressure. The weight-reducing drug lorcaserin induces modest reductions in body weight while slightly improving blood pressure. The fixed low-dose topiramate/phentermine combinations elicit larger reductions in body weight and blood pressure. Concomitant improvements in glucose metabolism, adiposity, and blood pressure differentiate the first clinically available SGLT2 inhibitor dapagliflozin from other oral antidiabetic drugs. Yet, the mechanisms through which metabolic drugs affect blood pressure and their interaction with antihypertensive drugs are poorly understood. Blood pressure-lowering effects of metabolic drugs could be exploited in the clinical management of obese hypertensive patients with and without type 2 diabetes mellitus, particularly in patients with difficult to control arterial hypertension.     

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells

Background/Aims

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARγ agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression.

Methods

Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis.

Results

Simvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF.

Conclusions

Simvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.